0A4F4F9BD490A749D5437F821CF06DF1
Ordinance on Clinical Trials and Good Clinical Practice (2015)
https://narodne-novine.nn.hr/clanci/sluzbeni/2015_03_25_534.html
http://leaux.net/URLS/ConvertAPI Text Files/B7202FAFEA7A9238B73B921BAF61376A.en.txt
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This file was generated: 2020-07-14 08:15:04
| Indicators in focus are typically shown highlighted in yellow; |
Peer Indicators (that share the same Vulnerability association) are shown highlighted in pink; |
"Outside" Indicators (those that do NOT share the same Vulnerability association) are shown highlighted in green; |
Trigger Words/Phrases are shown highlighted in gray. |
Link to Orphaned Trigger Words (Appendix (Indicator List, Indicator Peers, Trigger Words, Type/Vulnerability/Indicator Overlay)
Applicable Type / Vulnerability / Indicator Overlay for this Input
Political / nomad
Searching for indicator nomads:
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p.000534: 1.60. An unexpected side effect
p.000534: A side effect whose nature or weight is inconsistent with valid product information (e.g., examiner instructions for disapproved test product or instructions
p.000534: on the product / summary of the product if it is an approved product) (see ICH Guidelines for the handling of clinical harm data: Definitions and
p.000534: standards for emergency reporting).
p.000534: 1.61. Particularly sensitive respondents
p.000534: Individuals whose willingness to participate in a clinical trial may be unduly influenced by the expectation, whether justified or not, that their participation
p.000534: to bring certain benefits, that is, otherwise they will be avenged by the elderly or superiors. Members can serve as an example
p.000534: hierarchical groups such as medical, pharmacy or dental students, hospital and laboratory staff, pharmaceutical employees
p.000534: industry, members of the military of that person in custody or prison. The mentioned respondents include patients with incurable diseases, residents
p.000534: housing, the unemployed and the poor, emergency patients, ethnic minorities, homeless people, nomads, refugees, minors and
p.000534: persons unable to consent.
p.000534: 1.62. Well-being (of respondents)
p.000534: Physical and spiritual integrity of the clinical trial participant.
p.000534: 2. ICH PRINCIPLES OF GOOD CLINICAL PRACTICE
p.000534: 2.1. Clinical trials must be conducted in accordance with the ethical principles of the Helsinki Declaration and in accordance with good practice.
p.000534: clinical practice and applicable law.
p.000534: 2.2. Before starting a clinical trial, the expected risks and disruptions to the expected benefits for the individual subject and
p.000534: society. Clinical trials should only be started and continued if the expected benefit justifies the risk.
p.000534: 2.3. The rights, safety and well-being of respondents who are ahead of the interests of science and society.
p.000534: 2.4. The available preclinical and clinical data on the product under test must sufficiently support the conduct of the clinical trial.
p.000534: 2.5. The scientific foundations of clinical trials must be sound and the Trial Plan must be clear and detailed.
p.000534: 2.6. Testing should be carried out in accordance with the Clinical Trials / Independent Review Panel approved / tested positive
p.000534: of the Ethics Committee.
p.000534: 2.7. Responsibility for the health care of the respondent and for decisions regarding his or her treatment must always rest with a qualified medical doctor,
p.000534: where appropriate, to a qualified dental doctor.
p.000534: 2.8. All persons conducting the examination must have the appropriate education, expertise and experience to be able to carry out their tasks.
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Political / vulnerable
Searching for indicator vulnerable:
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p.000534: influence the outcome of clinical trials.
p.000534: Many diseases are also affected by hormonal changes associated with puberty (eg, higher insulin resistance in diabetes mellitus, frequent occurrence
p.000534: epileptic seizures in the period around menarche, changes in the frequency and intensity of migraine and asthma attacks). Hormonal changes can also
p.000534: also influence the results of clinical trials.
p.000534: By entering this age group, adolescents take responsibility for their own health and treatment. Failure to follow the treatment regimen is here
p.000534: a specific problem, especially if drugs (eg steroids) affect appearance. It is very important to check that the subjects adhere to the treatment regimen in
p.000534: clinical trials.
p.000534: Particular attention should also be paid to the occasional use of non-prescribed medicines and to the consumption of alcohol and tobacco.
p.000534: The upper limit of this age group varies from country to country. Older adolescents may be involved in adult trials, though they may be
p.000534: difficulty adhering to the treatment regimen. Due to problems specific to adolescence, conducting tests may be appropriate
p.000534: (whether included in the adult test protocol or in a separate protocol) in healthcare settings with knowledge and experience in nursing
p.000534: of this patient population.
p.000534: 2.6. Ethical issues related to testing in children
p.000534: Children are a vulnerable group of respondents. It is therefore necessary to introduce specific measures to protect their rights in clinical trials and to prevent them
p.000534: exposure to unnecessary risk. The purpose of this section is to provide an ethical framework for conducting testing in children.
p.000534: For the clinical trial to be of benefit to its participants and other children, its plan must be such as to ensure the quality and clarity of the collected
p.000534: data. Respondents are also expected to benefit from the clinical trial, except in the special circumstances described in the ICH.
p.000534: document E6, section 4.8.14.
p.000534: 2.6.1. Clinical Trial Panel / Independent Ethics Committee (Committee)
p.000534: The role and authority of the Commission described in ICH document E6 is crucial in protecting the respondents. When considering protocols involving children,
p.000534: The committee among its membership must or must seek the professional opinion of persons with a good knowledge of ethical, clinical and psychosocial issues.
p.000534: related to children.
p.000534: 2.6.2. Involvement of respondents
p.000534: Respondents should be included in a way that completely excludes inappropriate prompting of respondents, or their parents / guardians, to participate in
p.000534: examination.
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p.000534: the consent should be determined by the Commission, or in accordance with local legal requirements).
p.000534: Participants who are mentally mature should personally sign and date either a specific consent form or a consent form. Anyway,
p.000534: Participants must be aware of their right to refuse participation or withdraw from the examination at any time. It should be addressed
p.000534: attention to the signs of excessive suffering in patients who are unable to clearly express their suffering. Although it must respect the respondent's decision to
p.000534: withdraw from testing, in therapeutic trials of serious and life-threatening diseases such circumstances are possible which, in the opinion of the examiner and
p.000534: parent / guardian, may jeopardize the welfare of the child in the event of his / her withdrawal. In these circumstances, further consent from the parent (guardian) is sufficient
p.000534: to continue the child's participation in the examination. Independent or elderly minors (as defined by local law) may be on their own
p.000534: able to give consent.
p.000534: Data that may be collected in a less vulnerable population that has consented to participate is not advisable to be collected in a more vulnerable population,
p.000534: that is, from patients who are unable to give informed consent. Examinations in handicapped or institutionalized children should be limited to those
p.000534: diseases and health conditions that are mainly or exclusively related to these populations, or to the circumstances in which their disease is expected
p.000534: or health change the behavior or pharmacodynamics of medical devices.
p.000534: 2.6.4. How to minimize risk
p.000534: Whatever the importance of testing in proving or denying the value of a treatment, it can lead to injury in the subjects even when
p.000534: polls benefit the entire community. Therefore, every effort should be made to anticipate and limit known hazards. Even before the beginning
p.000534: clinical trial, investigators must have complete insight into all preclinical and clinical data on drug toxicity. To take a risk in pediatric
p.000534: clinical trials minimized, the staff conducting them need to be well trained and experienced in testing with children, which
p.000534: it also involves identifying and treating possible side effects in children.
p.000534: When designing the test plan, every effort should be made to minimize the number of participants and procedures in the spirit of good test planning.
p.000534: Mechanisms need to be devised to quickly complete testing for unexpected hazards.
p.000534: 2.6.5. How to alleviate suffering as much as possible
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p.000534: Clinical trial phase (I, II, III, IV)
p.000534: List of countries in which clinical trials were approved and / or planned by the time the application was submitted to the ministry responsible for health
p.000534: implement
p.000534: Version and date of test plan
p.000534: Brochure for examiners
p.000534: Informed consent
p.000534: Insurance document
p.000534: Policy number, date of issue, period of insurance
p.000534: B. Information on examiners
p.000534: Chief Examiner in the Republic of Croatia
p.000534: Address:
p.000534: Phone / Fax
p.000534: e-mail
p.000534: Informed consent, version and date, signed by the Examiner
p.000534: Leaders of participating testing centers (examiners)
p.000534: C. Data on test substance
p.000534: Is the preparation approved in the Republic of Croatia
p.000534: Countries where the preparation is approved
p.000534: Generic name
p.000534: Trademark
p.000534: Manufacturer
p.000534: Dosage and administration of the drug in this study
p.000534: Results of non-clinical trials (or reasons why they were not performed)
p.000534: Primary test hypothesis (and secondary if significant)
p.000534: Ethical considerations of the trial (identify and list any possible problem, outline the potential gains of clinical knowledge
p.000534: examining and its importance, assessing the potential risk of injury or other hazards to participants, presenting an evaluation of the risk-benefit relationship
p.000534: If it is intended to provide reasons for the inclusion of persons from particularly vulnerable groups such as minors, non-conscious persons, persons who
p.000534: incapable of judgment, persons with disabilities
p.000534: Description of the recruitment procedures of the respondents (all materials to be used should be attached).
p.000534: Procedures for giving information and obtaining consent from potential respondents
p.000534: (parents or legal representatives - if included)
p.000534: Test procedures, state any required deviations from normal practice
p.000534: Risk assessment, foreseeable treatment risks and procedures to be used (including possible pain, discomfort, integrity violation and ways of avoidance
p.000534: and / or the management of unforeseen / adverse events)
p.000534: Previous experience in conducting similar procedures in the legal entity (s) where the clinical trial will be conducted:
p.000534: Predicted benefits for the respondent
p.000534: Describe the relationship between the respondent and the researcher (eg patient-doctor of medicine, student-teacher, etc.)
p.000534: Procedures to check whether a potential respondent is participating in another clinical trial at the same time or that sufficient time has elapsed
p.000534: having previously participated in a clinical trial (especially important when it comes to including healthy subjects in clinical trials):
p.000534: Procedures used to protect the privacy of recorded data, source documents, or samples:
p.000534: Treatment or care plan after completing clinical trial participation (who will be responsible and where to administer):
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Health / Cognitive Impairment
Searching for indicator cognitive:
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p.000534: 2.4.3. The harmlessness of the drug
p.000534: The guidelines in ICH documents E2 and E6 describing the recording of adverse reactions also apply to testing in children. It is necessary to record side effects
p.000534: rely on normal laboratory values and clinical measurements that are adjusted to the child's age. Accidental exposure to the drug (accidentally swallowed
p.000534: , etc.) provides an opportunity to obtain additional information on the safety and pharmacokinetics of the drug and to gain a better understanding of the relationship of side effects with the dose.
p.000534: Medications can affect physical and mental development, and children may differ in their experience of side effects. Because developing organisms
p.000534: they may respond differently to treatment from mature organisms, some side effects and interactions with other medicines observed in children may not occur and
p.000534: in adults. In addition, due to the dynamics of growth and development, some side effects may not occur acutely, but at a later stage of development and maturation. Do they want to
p.000534: identify potential effects on skeletal maturation and development, behavior, cognitive function, sexual organs and the immune system may be needed
p.000534: long-term testing of children on chronic treatment or their long-term follow-up after treatment.
p.000534: 2.4.4. Findings after placing the medicine on the market
p.000534: Usually, when obtaining a marketing authorization, the knowledge is limited. Therefore, it is especially important to monitor children after drug release
p.000534: into circulation. It is sometimes important to carry out long-term monitoring to determine the effects of certain drugs on the growth and development of children. Post-placement monitoring
p.000534: drug and / or long-term testing may provide insight into the harmlessness and / or efficacy of the drug to particular groups of children, or
p.000534: additional knowledge regarding the overall child population.
p.000534: 2.5. Division of children by age
p.000534: Any division of children by age is somewhat arbitrary, but can be a starting point for thinking about a test plan for children. For deciding how
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p.000534: substantiate with good reasons.
p.000534: If the routes of drug elimination and their maturation (ontogenesis) are known, the division into age ranges for pharmacokinetic evaluation may start from
p.000534: "Milestones" that bring about significant changes in elimination.
p.000534: It is sometimes more appropriate to collect data on children across a wider age range and to examine the impact of age as a constant covariate. Different parameters
p.000534: the efficacy of the drug may be varied for different age groups, and this division may not correspond to the one shown below. Dividing the population into many
p.000534: age groups may unnecessarily increase the number of children participating in the study. In the case of longer-term trials, children may switch from
p.000534: from one age group to another, and the test plan and statistical analysis must predict changes in the number of patients in a given age group.
p.000534: Below, one of the age groups is offered. However, there is significant overlap in development across all groups (e.g.,
p.000534: cognitive, psychosocial). Age is defined by days, months or years.
p.000534: • Newborns born before term (premature infants)
p.000534: • Newborns born within term (0 - 27 days, newborn born)
p.000534: • Children aged 28 days to 23 months (infants and young children)
p.000534: • Children aged 2 to 11 years
p.000534: • Adolescents (12 to 16-18 years, depending on country)
p.000534: 2.5.1. Newborns born before term (premature infants)
p.000534: The study of premature infants raises special questions, since both the pathology and the response to treatment are unique to this group. Complexity
p.000534: tests in preterm infants and related ethical issues indicate the need for careful protocol design in collaboration with neonatologists and neonatal
p.000534: pharmacologists. Only in rare cases will it be possible to apply the results of efficacy obtained in adults and even older children to premature babies.
p.000534: Newborns as an age group are not homogeneous. There is a big difference between having a baby weighing 500g born at week 25 and 1,500g
p.000534: premature infant born at 30 weeks gestation.
p.000534: It is also important to distinguish whether children with low birth weight are immature or with stunted growth.
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p.000534: 2.5.3. Children aged 28 days to 23 months (infants and young children)
p.000534: At this age, the CSF matures rapidly, the immune system develops and the entire body grows. Absorption after oral administration is now more reliable. It goes on and on
p.000534: rapid maturation of elimination mechanisms via the liver and kidney. Computing in mg / kg, many drugs are eliminated faster in children 1 - 2 years of age than
p.000534: in adults.
p.000534: The developmental maturation pathway depends on specific elimination pathways. Differences in maturation among children are often noticeable.
p.000534: 2.5.4. Children aged 2 to 11 years
p.000534: Most elimination pathways (via liver and kidney) are now mature, and elimination is often greater than in adults. Changes in drug elimination can
p.000534: depend on the maturation of specific metabolic pathways.
p.000534: Appropriate strategies should be set out in the protocol to identify any effects of the drug on the growth and development of the child. There are several at this age
p.000534: a milestone in the psychomotor development of a child that can be adversely affected by drugs acting on the CSW. School attendance and higher cognitive and
p.000534: motor skills may affect a child's ability to participate in some performance tests. Factors useful for measuring performance
p.000534: drugs in children include skeletal growth, weight gain, school attendance, and school success.
p.000534: Selection of respondents should ensure adequate representativeness for the whole age group, since it is important to raise enough young people
p.000534: respondents.
p.000534: It is seldom necessary in this age group to further divide children by age, but it may prove appropriate to divide them according to
p.000534: pharmacokinetic and / or efficacy parameters.
p.000534: Entry into puberty is very uneven among children and occurs earlier in girls, in which it is normal since the age of 9. Puberty can make an impact
p.000534: to the action of drug-degrading enzymes, so, counting in mg / kg, drastic reductions in the dosage of some drugs (eg teo lina) are sometimes necessary. U
p.000534: in some cases, it is better to specifically examine the impact of puberty on drug behavior by comparing children before they reach puberty
p.000534: puberty. In the second case, it is more appropriate to monitor the rates of pubertal development according to Tanner or to collect biological indicators of puberty and
p.000534: study the potential impact of changes in puberty.
p.000534: 2.5.5. Adolescents (12 to 16-18 years old, depending on country)
p.000534: This is the age of sexual maturation, and drugs can clash with the action of sex hormones and prevent development.
p.000534: In some studies, it is advisable to take a pregnancy test and monitor the sexual activity and contraceptive use of the subjects.
p.000534: This is also a period of accelerated physical growth and continued development of neurocognitive functions. Medicines and diseases that slow or accelerate entry into
p.000534: puberty can have a profound effect on pubertal growth and therefore the final height of the patient. Gradual changes in the cognitive and emotional realms can
p.000534: influence the outcome of clinical trials.
p.000534: Many diseases are also affected by hormonal changes associated with puberty (eg, higher insulin resistance in diabetes mellitus, frequent occurrence
p.000534: epileptic seizures in the period around menarche, changes in the frequency and intensity of migraine and asthma attacks). Hormonal changes can also
p.000534: also influence the results of clinical trials.
p.000534: By entering this age group, adolescents take responsibility for their own health and treatment. Failure to follow the treatment regimen is here
p.000534: a specific problem, especially if drugs (eg steroids) affect appearance. It is very important to check that the subjects adhere to the treatment regimen in
p.000534: clinical trials.
p.000534: Particular attention should also be paid to the occasional use of non-prescribed medicines and to the consumption of alcohol and tobacco.
p.000534: The upper limit of this age group varies from country to country. Older adolescents may be involved in adult trials, though they may be
p.000534: difficulty adhering to the treatment regimen. Due to problems specific to adolescence, conducting tests may be appropriate
p.000534: (whether included in the adult test protocol or in a separate protocol) in healthcare settings with knowledge and experience in nursing
p.000534: of this patient population.
p.000534: 2.6. Ethical issues related to testing in children
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Searching for indicator impaired:
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p.000534: its metabolites, as well as their relationship with pharmacological and toxicological findings in animal species.
p.000534: (c) Toxicology
p.000534: Where appropriate, a concise description of the observed toxic effects in different species of animals should follow this structure:
p.000534: - Single dose;
p.000534: - Repeated dose;
p.000534: - Carcinogenicity;
p.000534: - Specific research (eg irritation and sensitization);
p.000534: - Reproductive toxicity;
p.000534: - Genotoxicity (mutagenicity).
p.000534: 7.3.6. Effects on humans
p.000534: Introduction:
p.000534: The known effects of the test product on humans should be thoroughly discussed, including information on its pharmacokinetics, metabolism,
p.000534: pharmacodynamics, dose dependence, safety, efficacy (efficacy) and other pharmacological actions. Wherever possible
p.000534: is to provide a summary of all completed clinical trials. Also, information regarding the application of the product under test should be provided outside
p.000534: clinical trials, such as post-marketing experience.
p.000534: (a) Pharmacokinetics and metabolism of the test product in humans
p.000534: - the pharmacokinetics of the test product should be summarized, including the following available data:
p.000534: - pharmacokinetics (including metabolism and absorption, plasma protein binding, distribution and elimination);
p.000534: - bioavailability of the test product (absolute and relative where possible) using the reference preparation;
p.000534: - population subgroups (eg by sex, age and impaired organ function);
p.000534: - interactions (eg drug interactions and the impact of food);
p.000534: - other pharmacokinetic data (eg results of population-based studies conducted in clinical trials).
p.000534: (b) Safety and efficiency
p.000534: Summary information on the safety, pharmacodynamics, efficacy (efficacy) and dose dependency of the product under test (including
p.000534: its metabolites) from previous human studies (healthy volunteers and / or patients). The significance of this data needs to be discussed. Where it is
p.000534: completed multiple clinical trials, summary summaries of safety and efficacy results by subgroup indications may provide
p.000534: clear data presentation. It would be useful to summarize into the tables all the side effects of the drug (for all indications tested) observed in all clinical trials.
p.000534: Significant differences in side effects by indications and subgroups of subjects need to be discussed.
p.000534: Instructions for the examiner should describe the expected risks and side effects of the drug based on previous experience with the product tested and related drugs.
p.000534: Also, precautions and special monitoring should be indicated as an integral part of the application of the test product.
p.000534: (c) Experience after placing the test product on the market
p.000534: The instructions must indicate the countries in which the test product was approved or placed on the market. A summary of all important information should be provided
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Health / Drug Dependence
Searching for indicator dependence:
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p.000534: pharmaceutical properties.
p.000534: In order to be able to take appropriate precautionary measures during testing, formulations, including excipients, must be provided and explained
p.000534: their use where clinically relevant. Care and handling instructions should also be provided.
p.000534: Any structural similarity to other known compounds should be noted.
p.000534: 7.3.5. Preclinical research
p.000534: Introduction:
p.000534: The results of important preclinical studies of the pharmacology, toxicology, pharmacokinetics and metabolism of the test product should be summarized in
p.000534: form. The summary should contain the methodology, results and discussion of the importance of the results for the tested beneficial or potential adverse effects in the
p.000534: people.
p.000534: The data may include the following:
p.000534: • Species of experimental animals;
p.000534: • Number and sex of animals in each group;
p.000534: • Unit doses (eg milligrams / kilogram (mg / kg));
p.000534: • Dose spacing;
p.000534: • Application route;
p.000534: • Dosing duration;
p.000534: • System allocation information;
p.000534: • Duration of follow-up after cessation of exposure;
p.000534: • Results, including the following aspects:
p.000534: - The nature and frequency of pharmacological and toxic effects;
p.000534: - The severity and intensity of pharmacological and toxic effects;
p.000534: - The time of their beginning;
p.000534: - Reversibility of effects;
p.000534: - Duration of effects;
p.000534: - Dose-dependent effects.
p.000534: Wherever possible, tables should be used to make the data clearer.
p.000534: The following sections of the Package Leaflet should discuss the most important results of preclinical studies, including the observed dependence of dose effects,
p.000534: importance for human application and other aspects to be tested in humans. Where possible, the results of effective non-toxic doses should be compared
p.000534: used in the same animal species (eg therapeutic index should be discussed). The importance of this information for proper use in humans should be considered.
p.000534: Wherever possible, comparisons should be based on blood / tissue levels rather than mg / kg.
p.000534: (a) Preclinical pharmacology
p.000534: A summary of the pharmacological aspects of the test product and significant metabolites observed in experimental animals should be provided, where appropriate
p.000534: possible. Such a summary should include research evaluating the potential therapeutic action of a drug (e.g., efficacy models,
p.000534: receptor binding and specificity) and its safety (eg special studies of pharmacological activities other than therapeutic ones).
p.000534: (b) Pharmacokinetics and metabolism of the test product in animals
p.000534: A summary of the pharmacokinetics and biotransformation (metabolism) and elimination of the test product in all animals in which
p.000534: conducted preclinical research. In discussing the results, we should refer to the absorption and local and systemic bioavailability of the test product and
p.000534: its metabolites, as well as their relationship with pharmacological and toxicological findings in animal species.
p.000534: (c) Toxicology
p.000534: Where appropriate, a concise description of the observed toxic effects in different species of animals should follow this structure:
p.000534: - Single dose;
p.000534: - Repeated dose;
p.000534: - Carcinogenicity;
p.000534: - Specific research (eg irritation and sensitization);
p.000534: - Reproductive toxicity;
p.000534: - Genotoxicity (mutagenicity).
p.000534: 7.3.6. Effects on humans
p.000534: Introduction:
p.000534: The known effects of the test product on humans should be thoroughly discussed, including information on its pharmacokinetics, metabolism,
p.000534: pharmacodynamics, dose dependence, safety, efficacy (efficacy) and other pharmacological actions. Wherever possible
p.000534: is to provide a summary of all completed clinical trials. Also, information regarding the application of the product under test should be provided outside
p.000534: clinical trials, such as post-marketing experience.
p.000534: (a) Pharmacokinetics and metabolism of the test product in humans
p.000534: - the pharmacokinetics of the test product should be summarized, including the following available data:
p.000534: - pharmacokinetics (including metabolism and absorption, plasma protein binding, distribution and elimination);
p.000534: - bioavailability of the test product (absolute and relative where possible) using the reference preparation;
p.000534: - population subgroups (eg by sex, age and impaired organ function);
p.000534: - interactions (eg drug interactions and the impact of food);
p.000534: - other pharmacokinetic data (eg results of population-based studies conducted in clinical trials).
p.000534: (b) Safety and efficiency
p.000534: Summary information on the safety, pharmacodynamics, efficacy (efficacy) and dose dependency of the product under test (including
p.000534: its metabolites) from previous human studies (healthy volunteers and / or patients). The significance of this data needs to be discussed. Where it is
p.000534: completed multiple clinical trials, summary summaries of safety and efficacy results by subgroup indications may provide
...
Searching for indicator dependency:
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p.000534: - Repeated dose;
p.000534: - Carcinogenicity;
p.000534: - Specific research (eg irritation and sensitization);
p.000534: - Reproductive toxicity;
p.000534: - Genotoxicity (mutagenicity).
p.000534: 7.3.6. Effects on humans
p.000534: Introduction:
p.000534: The known effects of the test product on humans should be thoroughly discussed, including information on its pharmacokinetics, metabolism,
p.000534: pharmacodynamics, dose dependence, safety, efficacy (efficacy) and other pharmacological actions. Wherever possible
p.000534: is to provide a summary of all completed clinical trials. Also, information regarding the application of the product under test should be provided outside
p.000534: clinical trials, such as post-marketing experience.
p.000534: (a) Pharmacokinetics and metabolism of the test product in humans
p.000534: - the pharmacokinetics of the test product should be summarized, including the following available data:
p.000534: - pharmacokinetics (including metabolism and absorption, plasma protein binding, distribution and elimination);
p.000534: - bioavailability of the test product (absolute and relative where possible) using the reference preparation;
p.000534: - population subgroups (eg by sex, age and impaired organ function);
p.000534: - interactions (eg drug interactions and the impact of food);
p.000534: - other pharmacokinetic data (eg results of population-based studies conducted in clinical trials).
p.000534: (b) Safety and efficiency
p.000534: Summary information on the safety, pharmacodynamics, efficacy (efficacy) and dose dependency of the product under test (including
p.000534: its metabolites) from previous human studies (healthy volunteers and / or patients). The significance of this data needs to be discussed. Where it is
p.000534: completed multiple clinical trials, summary summaries of safety and efficacy results by subgroup indications may provide
p.000534: clear data presentation. It would be useful to summarize into the tables all the side effects of the drug (for all indications tested) observed in all clinical trials.
p.000534: Significant differences in side effects by indications and subgroups of subjects need to be discussed.
p.000534: Instructions for the examiner should describe the expected risks and side effects of the drug based on previous experience with the product tested and related drugs.
p.000534: Also, precautions and special monitoring should be indicated as an integral part of the application of the test product.
p.000534: (c) Experience after placing the test product on the market
p.000534: The instructions must indicate the countries in which the test product was approved or placed on the market. A summary of all important information should be provided
p.000534: resulting from its market application (eg, formulations, dosages, routes of administration, side effects). The Guidelines also indicate the countries where
p.000534: the tested product was not authorized or withdrawn from the market, or its registration was revoked.
p.000534: 7.3.7. Summary of results and guidelines for examiner
p.000534: This section should contain a comprehensive discussion of preclinical and clinical data and provide a summary of the various aspects of the product under test
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Health / Drug Usage
Searching for indicator drug:
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p.000534: Instructions for use E-mail
p.000534: Home
p.000534: Rulebook on clinical trials and good clinical practice
p.000534: Ordinance, OG 25 / 2015-534 More
p.000534: MINISTRY OF HEALTH
p.000534: 534
p.000534: Pursuant to Article 8 (3), Article 13 and Article 18 (1) of the Medicines Act (Official Gazette 76/2013 and 90/2014), the Minister of Health
p.000534: brings
p.000534: RULEBOOK
p.000534: ON CLINICAL TESTING OF MEDICINES AND GOOD CLINICAL PRACTICE
p.000534: Article 1
p.000534: (1) This Ordinance lays down the procedure and conditions for conducting clinical, unproven and non-interventional testing of a medicinal product as well as good clinical practice
p.000534: when conducting a clinical trial of a drug.
p.000534: (2) Compliance with the requirements of good clinical practice ensures the protection of the rights, safety and well-being of subjects and the credibility of the results of clinical
p.000534: testing.
p.000534: Article 2
p.000534: This Ordinance transposes into the legal order of the Republic of Croatia:
p.000534: - Directive 2001/20 / EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States
p.000534: relating to the application of good clinical practice in the conduct of clinical trials of medicinal products for human use (OJ L 121, 1.5.2001). [1]
p.000534: Article 3
p.000534: (1) Certain terms within the meaning of this Ordinance have the following meaning:
p.000534: Good clinical practice is a set of internationally recognized ethical and scientific requirements that are followed in the planning, implementation, recording and reporting
p.000534: on clinical trials.
p.000534: Investigational Medicinal Product Dossier (hereinafter: IMPD) is a document showing data relating to
p.000534: the quality of the test drug, the production and control of the test drug, and data from non-clinical and clinical trials as well as data on the administration of the test drug
p.000534: drug in humans.
p.000534: Informed consent is consent to participate in a clinical trial on a voluntary basis based on received and properly documented notices
p.000534: on the nature and importance, consequences and risks of the examination, in writing, signed by the interviewee and dated. If the person is incompetent
p.000534: to give such consent or is a minor, the consent is signed by a legal representative or guardian. If the respondent is illiterate or unable to write, he gives
p.000534: oral consent in the presence of at least one witness who is not a member of the examination team.
p.000534: Inspection supervision of clinical trials is the oversight of the competent authority over the conduct of the clinical trial, review of documentation, premises, records,
p.000534: quality assurance systems and other resources related to the conduct of clinical trials that may be conducted at the test site, at the premises
p.000534: of the clinical trial client and / or the contracting authority or in other legal entities where the competent authority deems it necessary to carry out supervision.
p.000534: The respondent is an individual who participates in a clinical trial and receives the study drug or is part of a control group.
p.000534: The examiner is a doctor of medicine or a person with appropriate professional qualifications for clinical trials due to his / her professional knowledge and necessary
p.000534: experience in treating patients. The examiner is responsible for conducting the clinical trial at the test site. If a clinical trial is conducted by a group
p.000534: individuals in one examiner site, the examiner is responsible and is called the lead examiner.
p.000534: The test site is the health facility where the clinical trial is conducted.
p.000534: Test drug is a pharmaceutical formulation with an active substance or a placebo that is being tested or used as a comparison in a clinical trial and includes
p.000534: medicinal products authorized on the market but used in a different way from the one approved or different in formulation or packaging, or
p.000534: are used in unauthorized indications or used to obtain additional information on a marketing authorization form.
p.000534: Clinical trial is any human trial designed to detect or confirm clinical, pharmacological and / or other pharmacodynamic effects
p.000534: one or more test drugs and / or detection of side effects of one or more test drugs, and / or studies on absorption, distribution, metabolism and
p.000534: excretion of one or more investigational drugs for the purpose of determining the safety of administration and / or efficacy. This includes clinical trials
p.000534: conducted in one or more testing sites, in one or more Member States of the European Union.
p.000534: An observer is a person who performs monitoring during a clinical trial and ensures that it is conducted, documented and recorded in accordance with the test plan,
p.000534: standard operating procedures, good clinical practice and specific regulations.
p.000534: Non-interventional drug testing is any trial in which the drug is prescribed in accordance with the marketing authorization. Involvement of patients in
p.000534: a particular therapeutic procedure is not predetermined by the test plan but is carried out in accordance with normal practice, and prescribing is
p.000534: regardless of the decision to enroll the patient in the trial. Additional diagnostic and patient follow-up procedures are not performed, but performed
p.000534: use epidemiological methods to analyze the data collected.
p.000534: A nonprofit clinical trial is a clinical trial conducted by an examiner without the involvement of the pharmaceutical industry.
p.000534: Clinical / non-intervention trial client is a legal or legal entity responsible for initiating a clinical / non-intervention trial,
p.000534: the management of the clinical / non-intervention trial and / or the cost of the clinical / non-intervention trial.
p.000534: A clinical trial plan is a document that describes the goals, design, methodology, statistical considerations, and organization of the clinical trial that
p.000534: includes the test plan itself, all subsequent versions of the test plan, and any amendments thereto.
p.000534: Pediatric Investigation Plan (PIP) means a test or development program that seeks to secure data collection
p.000534: necessary to determine the conditions under which the drug may be approved for the treatment of the pediatric population.
p.000534: The representative of the clinical / non-intervention trial client is a legal or registered person established in the European Union.
p.000534: a clinical / non-interventional trial based outside the European Union.
p.000534: The applicant for the clinical / non-profit trial (hereinafter referred to as the applicant) is a clinical trial client established in Europe.
p.000534: Union or its authorized representative established within the European Union if the contracting authority is outside the European Union.
p.000534: Applicant for non-intervention testing is the marketing authorization holder of the Republic of Croatia, the marketing authorization holder
p.000534: approved by a centralized procedure, ie representative of the marketing authorization holder.
p.000534: The Central Ethics Committee is an independent body made up of health professionals and other members of the non-medical profession whose task is to protect the rights, safety and
p.000534: the welfare of the subjects involved in the clinical trials, and to provide assurance as to that protection, inter alia by expressing their opinion on the test plan,
p.000534: the eligibility of the examiner, the legal entity being tested, the equipment and the methods and documents that will be used to inform the interviewee
p.000534: and obtaining their consent based on informed consent. The Central Ethics Committee shall be appointed by the Minister for Health (hereinafter referred to as "the Minister of Health")
p.000534: (Minister).
p.000534: The Test Guideline is a document that presents clinical and non-clinical data on a study drug that is relevant to a particular clinical trial.
p.000534: The request for a clinical / non-profit examination is a request made by the applicant to the Ministry of Health (hereinafter:
p.000534: The Ministry) with all the documentation required for the approval of the clinical trial.
p.000534: The request for non-interventional testing is a request made by the applicant to the Agency for Medicinal Products and Medical Devices (in
p.000534: hereinafter referred to as "the Agency") with all the documentation necessary for the approval of the non-intervention test.
p.000534: Significant changes to the clinical trial are those that can significantly affect:
p.000534: - the safety of the respondents, the physical or spiritual integrity of the respondents,
p.000534: - the scientific value (benefit) of the test.
p.000534: Article 4
p.000534: The clinical trial is conducted in a legal entity that meets the following conditions:
p.000534: - employ experts who, through their knowledge and experience, ensure that the trial will be conducted in accordance with the clinical trial plan,
p.000534: - has equipment that allows the clinical trial to be conducted according to the clinical trial plan, or has a system in place to use the equipment
p.000534: and / or the procedures provided for in the test plan,
p.000534: - has in place a system for storing documentation resulting from clinical trials under this Ordinance.
p.000534: Article 5
p.000534: The clinical trial is conducted by an examiner who:
p.000534: - has completed undergraduate and graduate university studies or an integrated undergraduate and graduate university degree in health care, and
p.000534: specific training if provided by the test plan,
p.000534: - has documented training on good clinical practice,
p.000534: - concurrently conducts a maximum of five clinical trials that are under active patient involvement.
p.000534: Article 6
...
p.000534: - the existence of the protection of the respondents 'privacy and the protection of the respondents' information,
p.000534: - eligibility of fees for examiners and respondents,
p.000534: - the eligibility of the financial examination plan,
p.000534: - the existence of insurance in the event of injury, death or treatment of the subjects in connection with the clinical trial,
p.000534: - the existence of liability insurance for the examiner or client,
p.000534: - the acceptability of significant changes to the clinical trial (if any).
p.000534: Article 12
p.000534: (1) The Central Ethics Committee is obliged to give a written opinion on the acceptability of the proposed clinical trial within 30 days from the date
p.000534: the receipt of a duly demanded one prescribed by this Ordinance.
p.000534: (2) An orderly request within the meaning of this Ordinance shall mean the submission of the complete documentation prescribed in Article 16 of this Ordinance.
p.000534: (3) The Central Ethics Committee shall, within 5 days from the receipt of the request, notify in writing (by electronic or fax)
p.000534: of the applicant if it finds that the documentation submitted is incomplete. Otherwise, the request submitted is considered to be orderly.
p.000534: (4) By way of derogation from paragraph 1 of this Article, the Central Ethics Committee is obliged to give a written opinion on the acceptability of the proposed clinical
p.000534: testing of a finished drug intended for gene therapy, treatment of somatic cells, including medicines containing genetically modified
p.000534: organisms within 90 days from the date of receipt of the duly required application prescribed by this Ordinance.
p.000534: (5) The time limit referred to in paragraph 1 of this Article may be extended by an additional 90 days in the case of consultation with experts or committees.
p.000534: (6) For xenogenic drugs, there is no time limit for giving opinions on the acceptability of conducting a clinical trial.
p.000534: (7) In the procedure for giving an opinion on the acceptability of a proposed clinical trial, the Central Ethics Committee may request only once
p.000534: supplementing the documentation, ie the submission of additional information supplementing the information already provided by the applicant. Deadlines set
p.000534: Paragraphs 1, 4 and 5 of this Article shall not run until the date of receipt of the requested documentation.
p.000534: Article 13
p.000534: The Central Ethics Committee shall be obliged to provide the applicant and the Ministry with the opinion referred to in Article 8 of this Ordinance in writing.
p.000534: Article 14
p.000534: (1) Authorization to conduct clinical trials, including non-profit clinical trials of medicinal products, is granted by the Ministry.
p.000534: (2) The applicant, after having received the positive opinion of the Central Ethics Committee, submits to the Ministry a request for conducting clinical
p.000534: testing in the Republic of Croatia.
p.000534: (3) The Ministry is obliged to approve or withhold approval for conducting a clinical trial within 30 days from the receipt of a duly requested request.
p.000534: (4) An orderly request within the meaning of this Ordinance shall mean the submission of the complete documentation prescribed in Article 16 of this Ordinance.
p.000534: (5) The Ministry shall, within 5 days of receipt of the request, notify the applicant in writing (electronically or by fax).
p.000534: requests if it finds that the documentation submitted is incomplete. Otherwise, the request submitted is considered to be orderly.
p.000534: (6) The applicant shall have the right to supplement the request, and the time limit referred to in paragraph 3 of this Article shall start to run from the date of receipt of the duly filed request.
p.000534: (7) In the period referred to in paragraph 3 of this Article, the applicant may, until the decision of the Ministry is issued, amend his request.
p.000534: (8) The time limit referred to in paragraph 3 of this Article may be extended by 30 days in the case of a clinical trial of a gene therapy medicinal product,
p.000534: treatment of somatic cells, including medicines containing genetically modified organisms and xenogenic drugs.
p.000534: (9) If, within the time limit referred to in paragraphs 3 and 8 of this Article, the Ministry does not or does not withhold the authorization, the authorization shall be deemed to have been granted, except when it was previously
p.000534: initiation of a clinical trial must obtain the written approval of the Ministry of Clinical Trials for Medicinal Products for Gene Therapy,
p.000534: somatic cell therapy, including medicines containing genetically modified organisms and xenogenic drug trials.
p.000534: (10) The Ministry will withhold authorization to conduct a clinical trial for gene therapy if there is a risk of genome alteration
p.000534: the reproductive cells of the subjects.
p.000534: (11) The Ministry shall inform the applicant of the deficiencies of the request referred to in paragraph 2 of this Article and request the supplementation of the documentation.
p.000534: An applicant may only amend the content of the application referred to in paragraph 2 of this Article once.
p.000534: (12) If the applicant does not submit the supplement of the documentation or a written justification stating the deadline within 5 days of receipt of the conclusion
p.000534: the Ministry will issue a decision refusing to submit the application (electronically or by fax).
p.000534: (13) The applicant is obliged to inform the Ministry of his intention to withdraw the submitted request for the approval of a clinical / non-clinical trial in
p.000534: as soon as possible after making that decision. Notification submitted electronically or by fax must be submitted as soon as possible
p.000534: Ministry and in writing, with a brief explanation of the reasons for the withdrawal of the request.
p.000534: (14) Where the applicant intends to resubmit for approval a request which he has previously withdrawn, he shall indicate
p.000534: request to the Ministry and EU EudraCT Clinical Trial Application Form, hereinafter CTA
p.000534: form) to be a repeated request, in accordance with Communication from the European Commission 2010 / C 82/01 - Communication from the Commission -
p.000534: Detailed guidance on the request to the competent authorities for the authorization of a clinical trial on a medicinal product for human use, the notification of a substantial
p.000534: amendments to the Trial End of Trial (CT-1).
p.000534: Article 15
...
p.000534: tests, name of test, test phase, name and address of the test client, name and address of the applicant and list of lead examiners and
p.000534: establishments where the clinical trial is planned to be conducted as well as a brief explanation of the application,
p.000534: 2. instructions for the examiner, for the investigational medicinal product not authorized for marketing, issued within one year,
p.000534: 3. summary description of the product characteristics, for investigational medicinal products with a valid marketing authorization,
p.000534: 4. the CV of the examiner showing that it meets the criteria referred to in Article 5 of this Ordinance,
p.000534: 5. the CV of the observer, which will show that it meets the criteria referred to in Article 6 of this Ordinance,
p.000534: 6. a list of countries where the same clinical trial is planned and at the time of application for authorization
p.000534: clinical trial the same trial approved or refused, including the reasons for the refusal,
p.000534: 7. examination plan and any amendments signed by the Examiner,
p.000534: 8. copy of the test list of respondents in electronic form,
p.000534: 9. informed consent form in the Croatian language and Latin script, and the original text,
p.000534: 10. a summary of the scientific opinion of the European Medicines Agency regarding the administration of the investigational medicinal product (if available),
p.000534: 11. copy of the decision of the European Medicines Agency on the pediatric trial plan and the opinion of the pediatric committee, if clinical trial
p.000534: implements according to the pediatric drug development plan (PIP),
p.000534: 12. an example of the labeling of the test drug,
p.000534: 13. financial test plan,
p.000534: 14. proof of insurance of the subjects from the possible adverse consequences of participation in the clinical trial,
p.000534: 15. written authorization to the legal person who submits the request to the Minister for approval of the clinical trial in case the request is not submitted by the client
p.000534: clinical trial,
p.000534: 16. proof of payment of costs in the process of granting approval for conducting a clinical trial.
p.000534: (2) In addition to the documentation referred to in paragraph 1 of this Article, the applicant shall submit to the Central Ethics Committee:
p.000534: - the completed form in Annex IV. and Annex V which are annexed to this Ordinance and form an integral part thereof.
p.000534: (3) In addition to the documentation referred to in paragraph 1 of this Article, the applicant shall submit to the Ministry:
p.000534: - the completed form in Annex III. which is annexed to this Ordinance and forms an integral part thereof,
p.000534: - IMPD
p.000534: - CTA form in English,
p.000534: - proof of payment of the administrative fee.
p.000534: Article 17
p.000534: (1) In the process of approving a clinical trial intended for children or treating psychiatric patients, the Central Ethics Committee may request
p.000534: expert assistance and consult with the Ministry of Pediatrics and Psychiatry Commissions in accordance with point 3.2.6. Of Annex I to this Ordinance.
p.000534: (2) The Central Ethics Commission shall hold the consultations referred to in paragraph 1 of this Article within the time limits provided for in Article 12, paragraph 1 of this Article.
p.000534: Of the Rules.
p.000534: Article 18
...
p.000534: do not require.
p.000534: (2) The Agency is obliged to keep records of development safety update reports (DSURs), of suspected
p.000534: Suspected Unexpected Serious Adverse Reactions (SUSAR) that have occurred in clinical trials in
p.000534: Inform the Central Ethics Committee and the Ministry thereof.
p.000534: Article 27
p.000534: If the clinical trial is completed before it is specified in the clinical trial plan or is suspended, the applicant is
p.000534: obliged, with a detailed explanation of the cause, to inform the Central Ethics Committee, which gave a positive opinion, within 15 days
p.000534: and the Ministry.
p.000534: Article 28
p.000534: (1) The applicant shall submit to the Central Ethics Committee and the Ministry a notification of the completion of the clinical trial within 90
p.000534: days from the end of the clinical trial.
p.000534: (2) Completion of the clinical trial referred to in paragraph 1 of this Article shall be considered as the day of the last examination / examination of the last included respondent in the clinical trial.
p.000534: examination.
p.000534: Article 29
p.000534: Upon completion of the clinical trial, the applicant is required to submit to the Central Ethics Committee and the Ministry a summary of the final
p.000534: reports, within one year of the end of the clinical trial.
p.000534: Article 30
p.000534: (1) The clinical trial client may allow subjects to participate in the program upon completion of their participation in the clinical trial
p.000534: prolonged treatment with investigational drug, eng. "Expanded access programs", (hereinafter referred to as "the program").
p.000534: (2) In the case referred to in paragraph 1 of this Article, the applicant shall inform the Central Ethics Committee of the planned program and request
p.000534: consent of the Ministry.
p.000534: (3) The applicant is obliged to state the reasons for launching and the duration of the program, the number of examining places and respondents in each examiner
p.000534: the site that will participate in the program and the dose and route of administration. With the request, the applicant is required to attach the statements of the Chief Examiners to whom
p.000534: confirm their participation in the program and agree to continue monitoring the safety of drug administration and that the risk-benefit ratio justifies the administration of the drug
p.000534: in doses and in the manner prescribed by the proposed program.
p.000534: (4) At least once a year, the applicant shall notify the Central Ethics Committee and the Ministry of the implementation of the program, with emphasis
p.000534: to the safety of drug administration.
p.000534: (5) The applicant shall notify the Central Ethics Committee and the Ministry of the completion of the program within 90 days from the end of the program.
p.000534: program.
p.000534: Article 31
p.000534: (1) In the process of submitting a request to the Agency for approval of conducting non-intervention testing and obtaining the opinion of the Central Ethics
p.000534: Commissions, the applicant is required to provide the following documentation:
p.000534: - request in the Croatian language, with the signature of the applicant's responsible person; the request should include the name and address of the contracting authority, the name and
p.000534: the applicant's address and a list of the principal examiners and institutions where the non-interventional test will be conducted,
p.000534: - a test plan indicating the designation of the test plan, the version and the date of the test plan version,
p.000534: - test list of respondents,
p.000534: - the marketing authorization decision, if applicable,
p.000534: - approved summary of product characteristics and package leaflet in Croatian,
p.000534: - informed consent for the patient in the Croatian language, indicating the informed consent version and the date of the version,
p.000534: - the original informed consent for the patient in English, if applicable,
p.000534: - financial examination plan,
...
p.000534: Class: 011-02 / 14-02 / 84
p.000534: Reg. No: 534-02-1-1 / 2-15-01
p.000534: Zagreb, 20 February 2015
p.000534: Minister
p.000534: cf. Siniša Varga, Ph.D. med. dent., v. r.
p.000534: ANNEX I
p.000534: GOOD CLINICAL PRACTICE
p.000534: GUIDELINES FOR GOOD CLINICAL PRACTICE
p.000534: INTRODUCTION
p.000534: Good clinical practice (GCP) includes international ethical and scientific standards for the quality of planning, implementation,
p.000534: human monitoring and reporting. Adherence to these standards provides public guarantees for the protection of the rights, safety and well-being of respondents in the
p.000534: in accordance with the principles of the Helsinki Declaration, and that the clinical trial data are credible.
p.000534: The aim of these ICH Good Clinical Practice Guidelines is to provide a single standard for the European Union (EU), Japan and the United States of America.
p.000534: to facilitate the mutual acceptance of clinical data by the competent authorities of those countries.
p.000534: The guidelines have been developed keeping in mind good clinical practice in the practice of the European Union, Japan and the United States, as well as Australia, Canada,
p.000534: the Nordic countries and the World Health Organization (WHO).
p.000534: These guidelines should be followed when preparing clinical trial data that are made available to the competent authorities.
p.000534: The principles set out in these Guidelines may also be applied in other clinical trials that may affect the safety and well-being of subjects.
p.000534: 1. GLOSSARY
p.000534: 1.1. Side effects
p.000534: Clinical experience with a new drug / medicinal product or its new application that is prior to approval, especially if not
p.000534: established therapeutic doses: all adverse and adverse reactions to the drug / medicinal product regardless of the dose received are considered side effects. Expression
p.000534: "Reaction to a drug / medical device" means that the causal link between the medicinal product / medical device and a side effect has at least been identified as an option, ie.
p.000534: that it cannot be ruled out.
p.000534: In terms of market-approved medicines / medical products: harmful and adverse reactions of humans at doses commonly administered in prophylaxis,
p.000534: diagnosis, treatment of disease, or modification of a biological function (see ICH Guidelines for the Management of Clinical Safety Information:
p.000534: Definitions and standards for emergency reporting).
p.000534: 1.2. Harmful event
p.000534: Any undesirable medical event in a clinical trial in a patient or respondent who has received a pharmaceutical product that is not necessary
p.000534: causally related to its application. Therefore, any adverse and unwanted sign (including
p.000534: deviation in laboratory findings), a symptom or disease that is temporally associated with the administration of the medicinal (tested) drug / product, without
p.000534: whether it is the cause or not (see ICH Guidelines for the Management of Clinical Safety Data: Emergency Deviations and Standards
p.000534: reporting).
p.000534: 1.3. Modifications and Additions (Clinical Trial Plan)
p.000534: See Changes and additions to the Clinical Trial Plan.
p.000534: 1.4. Legislation in force (s)
p.000534: Law (s) and regulation (s) related to the conduct of a clinical study of drug / medical product testing.
p.000534: 1.5. Approval (Refers to Clinical Trials Council)
p.000534: Positive decision of the Clinical Trial Council on clinical trial to be carried out within the institution within the limits set by the
p.000534: clinical trials, facilities, good clinical practices, and applicable law.
p.000534: 1.6. Supervision
p.000534: Systematic and independent review of clinical trial activities and related documentation to determine if activities in which
p.000534: performs surveillance conducted, data entered and analyzed and reported in accordance with the Clinical Trial Plan, standard operational
p.000534: test client procedures, good clinical practice, and applicable legal requirements.
p.000534: 1.7. Certificate of inspection
p.000534: A statement confirming that surveillance has been carried out.
p.000534: 1.8. Surveillance report
p.000534: A written statement informing the testing authority of the results of the surveillance.
p.000534: 1.9. Documenting surveillance
p.000534: Documentation to track the sequence of events.
p.000534: 1.10. Clinical trial blindness / masking
p.000534: A process in which one or more parties participating in a clinical trial do not know how treatment is assigned. Single blind trial
p.000534: usually refers to a patient who does not know the division of treatment, and double-blind to a respondent, examiner, observer, and in some cases,
p.000534: data analysts.
p.000534: 1.11. Test list
p.000534: Printed, optical or electronic document intended to record all data required by the Clinical Trial Plan used by the trial client
p.000534: reports on each respondent.
p.000534: 1.12. Clinical trial / clinical study
p.000534: Any human study intended to detect or confirm the clinical, pharmacological and / or other pharmacodynamic effects of the subject
...
p.000534: 3.3.2. Defines the schedule of meetings, their conduct and the notification of members.
p.000534: 3.3.3. It defines the conduct of the first test evaluation and its continuous monitoring.
p.000534: 3.3.4. Defines the frequency of grading as needed.
p.000534: 3.3.5. In accordance with applicable legal regulations, conduct accelerated assessment and give approval / positive opinion on minor changes
p.000534: ongoing trials that have already received prior approval / positive opinion from the Commission.
p.000534: 3.3.6. It defines that no examinee may be included in the examination before it is approved by the Commission.
p.000534: 3.3.7. Deals that no deviation from the Examination Plan or its modification without prior written approval / positive is allowed
p.000534: the opinions of the Commission, except where it is necessary to immediately remove the immediate danger to the respondents, or where the changes relate exclusively to the
p.000534: logistical or administrative aspects of testing (eg change of telephone number of observers) (see 4.5.2.).
p.000534: 3.3.8. Defines that the examiner is obliged to immediately inform the Commission of:
p.000534: (a) deviations from the Examination Plan or amendments thereto to eliminate imminent danger to respondents (see 3.3.7, 4.5.2, 4.5.4);
p.000534: (b) changes that increase the risk to the respondent and / or significantly affect the conduct of the examination (see 4.10.2);
p.000534: (c) any serious and unexpected side effects of the drug;
p.000534: (d) new knowledge that may adversely affect the safety of the subjects or the conduct of the examination.
p.000534: 3.3.9. Ensures that the Examination Committee / Institution immediately informs of:
p.000534: (a) their decisions / opinions regarding the examination;
p.000534: (b) the reasons for the decision / opinion;
p.000534: (c) decision / opinion appeal procedures.
p.000534: 3.4. Documentation
p.000534: The committee should keep all relevant documentation (eg procedure description, list of members, list of professions and parent institutions of members, received
p.000534: documents, meeting minutes and correspondence) for at least three years after the end of the examination and make them available to the competent authorities for their
p.000534: request.
p.000534: The examiners, contracting authorities or competent authorities may request the Commission to provide a description of the procedures and a list of members.
p.000534: 4. EXAMINER
p.000534: 4.1. Qualifications of examiner and preconditions for his / her actions
p.000534: 4.1.1. In order to be able to undertake the proper conduct of the examination, the examiner must be qualified in terms of education, professional development and
p.000534: experience, qualifications should meet current legal requirements and provide evidence of their qualifications through an updated CV and / or other
p.000534: relevant documentation requested by the contracting authority, the Commission and / or the competent authority.
...
p.000534: 4.9.6. The financial aspects of the test should be documented by agreement between the test client and the examiner / institution.
p.000534: 4.9.7. The examiner / institution shall be obliged to allow the observer, the person supervising, the Commission or the competent authority, upon their request, a direct
p.000534: access to examination documents.
p.000534: 4.10. Test progress reports
p.000534: 4.10.1. The examiner is obliged to submit a written summary of the progress of the examination to the Committee once a year, and more frequently at the special request of the Committee.
p.000534: 4.10.2. The examiner is obliged to immediately submit a written report on the ordering authority, the Committee (see 3.3.8) and, where appropriate, the health institution.
p.000534: changes that significantly affect the conduct of the test and / or increase the risk to respondents.
p.000534: 4.11. Product Safety Reporting
p.000534: 4.11.1. Any serious adverse event should be reported promptly to the testing contractor, except for those events for which it is in the Test Plan or otherwise.
p.000534: document (eg in the Examiner's Instructions) stated that they should not be reported immediately. A detailed report should be written immediately after the application
p.000534: event. In this report, their associated unique identifier should be used in place of the name, identification number (e.g., MBG) and / or address of the respondent
p.000534: tag. The examiner should also comply with the applicable legal requirements of the reporting requirements of the competent authorities and the
p.000534: unexpected serious side effects of the drug.
p.000534: 4.11.2. Reports of adverse events and / or abnormal laboratory findings identified by the Test Plan as critical to the assessment
p.000534: security should be delivered to the test client in accordance with the reporting rules and at intervals specified by the test client at
p.000534: Test plan.
p.000534: 4.11.3. When reporting a death, the examiner should provide additional information to the investigator and to the Commission upon request (eg autopsy findings and
p.000534: medical report of the cause of death).
p.000534: 4.12. Premature termination or termination of examination
p.000534: If, for any reason, the examination is terminated or terminated prematurely, the examiner / institution should inform the subjects immediately, ensure
p.000534: their proper treatment and monitoring and inform the competent authorities in accordance with the relevant legal provisions. In addition:
p.000534: 4.12.1. If the examiner completes or terminates the examination without the consent of the examining authority, he shall inform the institution thereof, and
p.000534: the examiner / institution should immediately inform the test client and the Committee and provide them with a detailed explanation of such procedure.
p.000534: 4.12.2. If the contracting authority completes or terminates the examination (see 5.21), the examiner is obliged to inform the institution immediately, and the examiner / institution
p.000534: the Commission should be informed immediately and a detailed explanation of such procedure should be provided.
p.000534: 4.12.3. If the Committee withdraws its approval / positive opinion on the examination (see 3.1.2 and 3.3.9), the examiner shall inform the institution accordingly,
...
p.000534: 5.3. Expert medical opinion
p.000534: Nursing staff with appropriate qualifications should be identified who will always be able to give their expert opinion on issues and issues related to
p.000534: with examination. If necessary, the contracting authority may also appoint external consultants for this purpose.
p.000534: 5.4. Test plan
p.000534: 5.4.1. The client of the trial should hire qualified persons (eg biostatistics, clinical pharmacologists and medical doctors in accordance with the needs).
p.000534: all stages of testing, from the design of the Test Plan and Test List, through the planning of the analysis, to the analysis and preparation of interim and final clinical trials
p.000534: test reports.
p.000534: 5.4.2. For further guidance, see 6. Clinical Trial Plan and its Amendments and Appendices, ICH Guidelines for Compilation and Content of Clinical Trial Report
p.000534: Examination and other ICH Guidelines related to test planning, development of the Test Plan and conduct of the test.
p.000534: 5.5. Test management, data handling and record keeping
p.000534: 5.5.1. The contracting authority should hire qualified persons to supervise the overall conduct of the examination, to manage the data obtained,
p.000534: verify their accuracy, perform statistical analyzes and prepare reports.
p.000534: 5.5.2. The trial contracting authority may appoint an independent data monitoring committee to periodically evaluate the progress of the clinical trial,
p.000534: including safety data and key drug efficacy parameters, and to recommend whether the trial client should continue the trial, amend
p.000534: or stop it. The Independent Data Monitoring Commission should, in writing, derogate from operating procedures (operating procedures) and maintain
p.000534: notes from all their meetings.
p.000534: 5.5.3. When handling electronic data directly or through a remote control system, the contracting authority shall:
p.000534: (a) ensure and record the compliance of the electronic data processing system with the requirements of the test client's completeness, accuracy, reliability and
p.000534: consistency of processing (i.e. validation);
p.000534: (b) have standard operating procedures for the use of these systems;
p.000534: (c) ensure that the systems are designed to allow data to be modified in such a way that each change is recorded and that there is no possibility
p.000534: deletion of data entered (ie to keep a trace of surveillance, a data trace and a trace of their editing);
p.000534: (d) take care of the security of the system preventing unauthorized access to the data;
p.000534: (e) keep a list of persons authorized to modify the data (see 4.1.5 and 4.9.3);
p.000534: (f) keep a copy of the information in order to protect against its loss;
p.000534: (g) if the test is blind, protect its blindness (eg when entering and processing data).
p.000534: 5.5.4. If there is a change in the data during their processing, it should always be possible to compare the original data and comments with the processed
p.000534: data.
...
p.000534: the consent of that other written notice intended for the respondents, depending on their recruitment procedures, as well as documentation relating to
p.000534: fees to respondents and other documents requested by the Commission.
p.000534: 5.11.2. If the Committee gives its approval / positive opinion changes to any aspect of the examination such as changes to the Plan
p.000534: Examination, Consent Statement Form, Other Written Notices Intended for Respondents and / or Other Procedures
p.000534: the examiner / institution must receive a copy of the modification document and the date of approval / positive opinion of the Commission.
p.000534: 5.11.3. The contracting authority shall obtain from the examiner / institution the documentation and dates of re-approvals / supervision of the Commission, as well as
p.000534: withdrawal / revocation of approval / positive opinion.
p.000534: 5.12. Data on the product tested
p.000534: 5.12.1. When planning a test, the test client should make sure that sufficient safety and performance information is available
p.000534: from preclinical and / or clinical trials related to route of administration, dose, duration and appropriate population of subjects.
p.000534: 5.12.2. As soon as it becomes aware of the new data, the test client is obliged to update the Testing Instructions.
p.000534: 5.13. Production, packaging and labeling and coding of the product under test
p.000534: 5.13.1. The test client shall ensure that the test product (including, if applicable, comparative active drug and placebo) is labeled in accordance with
p.000534: the stage of its development, that it has been manufactured in accordance with all applicable good manufacturing practices, that it has been coded and labeled in such a way that
p.000534: if necessary, it protects the blind process. In addition, labeling should be in accordance with applicable legal regulations.
p.000534: 5.13.2. The contracting authority shall state the appropriate storage conditions for the medicinal product such as temperature, light protection, storage time,
p.000534: then, if necessary, fluid reconstitution procedures and accessories used for infusion of the test product. The contracting authority should inquire about this
p.000534: inform all interested parties (ie observers, examiners, pharmacists, warehouse managers).
p.000534: 5.13.3. The packaging of the test product should be such as to prevent its contamination and unacceptable changes in transport and storage.
p.000534: 5.13.4. In blind studies, the labeling system of the product under test should also include a mechanism that allows for rapid identification of the drug in the
p.000534: emergency but which does not allow identity disclosure to go unnoticed.
p.000534: 5.13.5. If there are any significant changes in the formulation of the test product or comparator at the clinical stage of development,
p.000534: testing new formulations to obtain the results of additional testing (eg stability, dissolution rate, bioavailability) required for evaluation
p.000534: can these changes significantly alter the pharmacokinetics of the drug.
p.000534: 5.14. Supply and handling of tested product
p.000534: 5.14.1. The test client is responsible for supplying the tester / institution with the product being tested.
p.000534: 5.14.2. The test contractor may not supply the examiner / institution with the product under test until he has obtained all the necessary documentation (e.g.
p.000534: approval / favorable opinion of the Commission and the competent authorities).
p.000534: 5.14.3. The test client shall ensure that the description of the procedures also includes the instructions for handling and storage of the test product and its associated
p.000534: documentation to be followed by the examiner / institution. These instructions should cover proper and secure receipt, handling, storage and issuance
p.000534: test product, collection of unused test product from the respondent and return it to the test client (or otherwise)
p.000534: disposal of unused product in accordance with applicable legal regulations).
p.000534: 5.14.4. The contracting authority shall:
p.000534: (a) ensure timely delivery of the test product to the examiner;
p.000534: (b) keep records of the dispatch, receipt, removal, return and destruction of the investigated product (see 8. Basic clinical implementation documents
p.000534: examinations);
p.000534: (c) maintain a system of return for the test product and record its return (eg for withdrawal of defective product, return on completion
p.000534: tests, returns of expired products);
p.000534: (d) maintain a system for removing unused test products and recording their disposal.
p.000534: 5.14.5. The contracting authority shall:
p.000534: (a) take the necessary measures to ensure the stability of the test product during application;
...
p.000534: any applicable law, whichever is later.
p.000534: 5.15. Access to documentation
p.000534: 5.15.1. The examining authority should ensure that the Examination Plan or other written agreement clearly states that the examiner / institution must
p.000534: provide direct access to original data / documents for monitoring, monitoring, evaluation of the Commission and inspection by the competent authorities.
p.000534: 5.15.2. The trial contracting authority should check that each respondent has given his or her written consent that his or her original health information may be obtained
p.000534: access directly for monitoring, monitoring, evaluation of the Commission and inspection by the competent authorities.
p.000534: 5.16. Product Safety Information
p.000534: 5.16.1. The test client is responsible for assessing the safety of the product being tested.
p.000534: 5.16.2. The contracting authority shall promptly inform all examiners / institutions and competent authorities of information which may adversely affect
p.000534: the safety of the respondents, influence the conduct of the examination, or withdraw the approval / positive opinion of the Commission.
p.000534: 5.17. Reporting of side effects of the drug
p.000534: 5.17.1. The contracting authority shall promptly inform all examiners / institutions, the Committees (where appropriate) and the competent authorities of all serious and
p.000534: unexpected side effects of the drug.
p.000534: 5.17.2. These emergency reports should comply with applicable laws and ICH's Clinical Safety Information Management Guidelines:
p.000534: Definitions and standards for emergency reporting.
p.000534: 5.17.3. The contracting authority shall provide the competent authorities with all new safety data and periodic reports in accordance with the applicable legal requirements
p.000534: regulations.
p.000534: 5.18. Observation
p.000534: 5.18.1. Purpose
p.000534: The purpose of observing a test is to verify that:
p.000534: (a) the rights and welfare of the respondents are protected;
p.000534: (b) that the information in the reports is accurate, complete and can be verified / verified using the original documents;
p.000534: (c) the test is conducted in accordance with the current approved Test Plan and any amendments thereto, with good clinical
p.000534: practice and with applicable legal regulations.
p.000534: 5.18.2. Selection and qualifications of observers
p.000534: (a) Observers shall be appointed by the contracting authority.
p.000534: (b) Observers must have appropriate education and scientific and / or clinical knowledge necessary to properly monitor the examination. It should
p.000534: keep track of the observer's qualifications.
p.000534: (c) The observer should be fully familiar with the product tested, the Test Plan, the Consent Declaration Form, other written notices
p.000534: intended for interviewees, the client's standard operating procedures and applicable legal requirements.
...
p.000534: related to the examination (if it is a person other than the examiner).
p.000534: 6.1.7. Name and address of the clinical laboratory and other participating health / technical departments and / or institutions.
p.000534: 6.2. Basic information
p.000534: 6.2.1. Name and description of the product under test.
p.000534: 6.2.2. Summary of clinically relevant findings from preclinical studies and relevant clinical trials.
p.000534: 6.2.3. Summary of known potential risks and benefits to respondents.
p.000534: 6.2.4. Description and rationale for the particular route of administration, its dosage regimen and duration of treatment.
p.000534: 6.2.5. A statement that the trial will be conducted in accordance with the Clinical Trial Plan, Good Clinical Practice and applicable legal requirements.
p.000534: 6.2.6. Description of the respondent population.
p.000534: 6.2.7. Literature references and dates relevant to the examination that provide basic information about the examination.
p.000534: 6.3. Purpose (s) and purpose of the test
p.000534: A detailed description of the objectives and purpose of the test.
p.000534: 6.4. Test plan
p.000534: The scientific value of the test and the reliability of the test data depend significantly on the Test Plan. Description of the Test Plan should
p.000534: contain:
p.000534: 6.4.1. Specific definition of primary and secondary test parameters.
p.000534: 6.4.2. Description of test type / layout (eg, double-blind, comparator, placebo control group) and diagram of the Test Plan, Procedures and Phases.
p.000534: 6.4.3. Description of measures taken to maximize objectivity, including:
p.000534: (a) random selection;
p.000534: (b) blind technique.
p.000534: 6.4.4. Description of treatment in study with study drug doses and dose regimens. This includes a description of the form, packaging and labeling of the investigational medicinal product.
p.000534: 6.4.5. Expected duration of participation of respondents in the examination and description of the sequence and duration of all parts of the examination, including monitoring (where it is
p.000534: needed).
p.000534: 6.4.6. Description of criteria for termination or termination of part / entire examination, or for exclusion of individual respondents from the examination.
p.000534: 6.4.7. Procedures for recording the inputs and outputs of the test product, placebo and comparator drugs.
p.000534: 6.4.8. Description of storing random selection codes and procedures for decrypting them.
p.000534: 6.4.9. A description of all the data that should be entered directly into the test list of respondents (ie, those not previously recorded in an electronic or written document) and
p.000534: information considered original.
p.000534: 6.5. Selection of respondents and their withdrawal from examination
p.000534: 6.5.1. Criteria for inclusion of respondents in the examination.
p.000534: 6.5.2. Exclusion criteria for respondents.
p.000534: 6.5.3. Criteria for withdrawal of test subjects (ie discontinuation of treatment with test product) and procedures specifying the following:
p.000534: (a) when and how subjects may withdraw from testing / treatment with the product tested;
p.000534: (b) the type of data and the timetable for collecting it from the withdrawing respondents;
p.000534: (c) whether these respondents replace each other and how;
p.000534: (d) monitoring of subjects who withdraw from testing / treatment with the product under examination.
p.000534: 6.6. Treatment of subjects
p.000534: 6.6.1. Planned treatment, including the names of all products, their doses and dosage schedules, route / route of administration and periods of administration, including
p.000534: the follow-up period of respondents from each group who received the product under test.
p.000534: 6.6.2. Description of medicines / treatments that are (including emergency medicines), that is, not allowed before and / or during the test.
p.000534: 6.6.3. Observation procedures designed to determine whether a respondent adheres to the prescribed treatment.
p.000534: 6.7. Performance evaluation
p.000534: 6.7.1. List of drug efficacy parameters.
p.000534: 6.7.2. Methods and schedule for evaluating, recording and analyzing performance parameters.
p.000534: 6.8. Security rating
p.000534: 6.8.1. List of drug safety parameters.
p.000534: 6.8.2. Methods and schedule for assessing, recording and analyzing security parameters.
p.000534: 6.8.3. Procedures for recording and reporting adverse events and emerging diseases.
p.000534: 6.8.4. Form and duration of follow-up of the respondent after the adverse event.
p.000534: 6.9. Statistical processing
p.000534: 6.9.1. Description of the statistical methods, including a schedule of any interim analyzes for the duration of the test.
p.000534: 6.9.2. Number of planned respondents. In multicenter trials, the intended number of subjects for each test site should be indicated. The reason
p.000534: for the selection of a particular sample (number of subjects), including considerations (calculations) of the significance of the trial and its clinical justification.
p.000534: 6.9.3. Significance level to be used in statistical processing.
p.000534: 6.9.4. Criteria for completing the examination.
p.000534: 6.9.5. Procedures for recording missing, unused, and false data.
p.000534: 6.9.6. Procedures for reporting deviations from the original statistical plan (all deviations from the original statistical plan should also be described
p.000534: justify in the Test Plan and / or Final Report).
p.000534: 6.9.7. Selection of subjects for analysis (eg all subjects selected by random selection, all subjects who received the drug, all respondents who
p.000534: meet the criteria for participation in the study, respondents who report a measurable response to treatment).
p.000534: 6.10. Direct access to original data / documents
p.000534: The test client shall ensure that the Test Plan or other written agreement clearly states that the examiner / institution will allow observation and monitoring.
p.000534: examinations, evaluation by the Commission and inspections by the competent authorities, by providing access to original data / documents.
p.000534: 6.11. Quality assurance and quality control procedures
p.000534: 6.12. Ethical issues
p.000534: Description of ethical considerations related to the examination.
p.000534: 6.13. Data handling and record keeping
p.000534: 6.14. Financing and insurance
p.000534: Financing and insurance, unless regulated by a separate agreement.
p.000534: 6.15. Publication policy
p.000534: Policy on the publication of test results, unless regulated by a separate agreement.
p.000534: 6.16. Appendices to the Clinical Trial Plan
p.000534: (Note: Because the Study Plan and Clinical Trial / Study Report are very close, additional information on this can be found in the ICHs
p.000534: Guidelines for the design and content of clinical trial reports.)
p.000534: 7. INSTRUCTIONS TO THE TESTOR
p.000534: 7.1. Introduction
p.000534: The examiner's instructions are the sum of the clinical and preclinical information on the product under test that is important for its testing in humans. The purpose of these Instructions is
p.000534: to provide examiners and other persons participating in the examination with information that facilitates understanding and facilitates adherence to many important
p.000534: clinical trial plan items such as dosage, frequency and route of administration, and procedures for monitoring drug safety. The instructions also provide insight into
p.000534: clinical procedures with the subject for the duration of the clinical trial. While avoiding product promotion, information should be presented in a concise, simple,
p.000534: an objective and balanced manner that enables the clinician or examiner to fully understand and independently make an objective risk assessment and
p.000534: the benefits of the proposed test. Therefore, it is, in principle, necessary for the qualified health staff to be involved in drawing up the Guidelines for Examiners, but
p.000534: only the profession that provided the information in the Instructions may approve.
p.000534: These Guidelines state only the minimum information that should be contained in the Guidelines for Examiners and suggest the layout of the Guidelines. The species is also expected to
p.000534: the range of information available depends on the stage of product development. If the test product is already on the market and its pharmacological properties
p.000534: widely known in medical practice, the examiner's instructions probably do not need to be comprehensive. Where permitted by the competent authorities, appropriate replacement for
p.000534: The instructions can be basic product information, instructions in the packaging, or labels on the packaging, provided they include extensive and detailed
p.000534: information on all aspects of the test product that may be relevant to the examiner. If a marketed product is tested for a new application (eg a new product)
p.000534: indication), Instructions specifically addressing this new application should be prepared. The instructions should be reconsidered at least once a year and by
p.000534: need to be modified in accordance with the client's written procedures. More frequent changes may also be needed depending on the stage of development and new important ones
...
p.000534: people.
p.000534: The data may include the following:
p.000534: • Species of experimental animals;
p.000534: • Number and sex of animals in each group;
p.000534: • Unit doses (eg milligrams / kilogram (mg / kg));
p.000534: • Dose spacing;
p.000534: • Application route;
p.000534: • Dosing duration;
p.000534: • System allocation information;
p.000534: • Duration of follow-up after cessation of exposure;
p.000534: • Results, including the following aspects:
p.000534: - The nature and frequency of pharmacological and toxic effects;
p.000534: - The severity and intensity of pharmacological and toxic effects;
p.000534: - The time of their beginning;
p.000534: - Reversibility of effects;
p.000534: - Duration of effects;
p.000534: - Dose-dependent effects.
p.000534: Wherever possible, tables should be used to make the data clearer.
p.000534: The following sections of the Package Leaflet should discuss the most important results of preclinical studies, including the observed dependence of dose effects,
p.000534: importance for human application and other aspects to be tested in humans. Where possible, the results of effective non-toxic doses should be compared
p.000534: used in the same animal species (eg therapeutic index should be discussed). The importance of this information for proper use in humans should be considered.
p.000534: Wherever possible, comparisons should be based on blood / tissue levels rather than mg / kg.
p.000534: (a) Preclinical pharmacology
p.000534: A summary of the pharmacological aspects of the test product and significant metabolites observed in experimental animals should be provided, where appropriate
p.000534: possible. Such a summary should include research evaluating the potential therapeutic action of a drug (e.g., efficacy models,
p.000534: receptor binding and specificity) and its safety (eg special studies of pharmacological activities other than therapeutic ones).
p.000534: (b) Pharmacokinetics and metabolism of the test product in animals
p.000534: A summary of the pharmacokinetics and biotransformation (metabolism) and elimination of the test product in all animals in which
p.000534: conducted preclinical research. In discussing the results, we should refer to the absorption and local and systemic bioavailability of the test product and
p.000534: its metabolites, as well as their relationship with pharmacological and toxicological findings in animal species.
p.000534: (c) Toxicology
p.000534: Where appropriate, a concise description of the observed toxic effects in different species of animals should follow this structure:
p.000534: - Single dose;
p.000534: - Repeated dose;
p.000534: - Carcinogenicity;
p.000534: - Specific research (eg irritation and sensitization);
p.000534: - Reproductive toxicity;
p.000534: - Genotoxicity (mutagenicity).
p.000534: 7.3.6. Effects on humans
p.000534: Introduction:
p.000534: The known effects of the test product on humans should be thoroughly discussed, including information on its pharmacokinetics, metabolism,
p.000534: pharmacodynamics, dose dependence, safety, efficacy (efficacy) and other pharmacological actions. Wherever possible
p.000534: is to provide a summary of all completed clinical trials. Also, information regarding the application of the product under test should be provided outside
p.000534: clinical trials, such as post-marketing experience.
p.000534: (a) Pharmacokinetics and metabolism of the test product in humans
p.000534: - the pharmacokinetics of the test product should be summarized, including the following available data:
p.000534: - pharmacokinetics (including metabolism and absorption, plasma protein binding, distribution and elimination);
p.000534: - bioavailability of the test product (absolute and relative where possible) using the reference preparation;
p.000534: - population subgroups (eg by sex, age and impaired organ function);
p.000534: - interactions (eg drug interactions and the impact of food);
p.000534: - other pharmacokinetic data (eg results of population-based studies conducted in clinical trials).
p.000534: (b) Safety and efficiency
p.000534: Summary information on the safety, pharmacodynamics, efficacy (efficacy) and dose dependency of the product under test (including
p.000534: its metabolites) from previous human studies (healthy volunteers and / or patients). The significance of this data needs to be discussed. Where it is
p.000534: completed multiple clinical trials, summary summaries of safety and efficacy results by subgroup indications may provide
p.000534: clear data presentation. It would be useful to summarize into the tables all the side effects of the drug (for all indications tested) observed in all clinical trials.
p.000534: Significant differences in side effects by indications and subgroups of subjects need to be discussed.
p.000534: Instructions for the examiner should describe the expected risks and side effects of the drug based on previous experience with the product tested and related drugs.
p.000534: Also, precautions and special monitoring should be indicated as an integral part of the application of the test product.
p.000534: (c) Experience after placing the test product on the market
p.000534: The instructions must indicate the countries in which the test product was approved or placed on the market. A summary of all important information should be provided
p.000534: resulting from its market application (eg, formulations, dosages, routes of administration, side effects). The Guidelines also indicate the countries where
p.000534: the tested product was not authorized or withdrawn from the market, or its registration was revoked.
p.000534: 7.3.7. Summary of results and guidelines for examiner
p.000534: This section should contain a comprehensive discussion of preclinical and clinical data and provide a summary of the various aspects of the product under test
p.000534: based on data from different sources. This gives the examiner an extensive interpretation of the data available and an assessment of their significance for future clinical
p.000534: testing.
p.000534: Where appropriate, published reports of related products should be discussed. This may help the examiner to anticipate the side effects of the drug or others
p.000534: clinical trial difficulties.
p.000534: The ultimate goal of this section of the Instruction is to provide the examiner with clear insight into the potential risks and side effects, specific tests, observations and precautions that may be taken
p.000534: be required in the conduct of the clinical trial. The insight should be based on available chemical, pharmaceutical, pharmacological,
p.000534: toxicological and clinical data on the product tested. The examiner should also be given guidelines for identifying and treating overdose and
p.000534: side effects based on previous experience with humans and the pharmacological profile of the product under study.
p.000534: The ultimate goal of this section of the Instruction is to provide the examiner with clear insight into the potential risks and side effects, specific tests, observations and precautions that may be taken
p.000534: be required in the conduct of the clinical trial. The insight should be based on available chemical, pharmaceutical, pharmacological,
p.000534: toxicological and clinical data on the product tested. The examiner should also be given guidelines for identifying and treating overdose and
p.000534: side effects based on previous experience with humans and the pharmacological profile of the product under study.
p.000534: ____________________________ 7.4. APPENDIX 1:
p.000534: HOME (Example)
p.000534: TITLE OF THE TEST ORDER
p.000534: Product:
p.000534: Number of Surveys:
p.000534: Product name (s): Chemical name, (approved) generic name, protected name (if authorized by the contracting authority and permitted by law):
p.000534: INSTRUCTIONS TO THE TESTOR
p.000534: Issue Number:
p.000534: Release Date:
p.000534: Previous issue number:
p.000534: Previous issue date:
...
p.000534: PROVIDED FOR TESTING PLAN
p.000534: X
p.000534: Document the suitability of the department / laboratory for implementation
p.000534: 8.2.12. MEDICAL / LABORATORY / TECHNICAL PROCEDURES / TESTS X
p.000534: predicted tests and confirm the reliability of the findings.
p.000534: (where necessary)
p.000534: - confirmation or
p.000534: - authorization or
p.000534: - established quality control and / or external quality assessment
p.000534: - other forms of validation (where appropriate)
p.000534: Document compliance with applicable labeling regulations and
p.000534: 8.2.13. SAMPLE MARK ON TANK OF TESTED PRODUCT X
p.000534: the appropriateness of the instructions for the respondents.
p.000534: 8.2.14. INSTRUCTIONS FOR THE MANAGEMENT OF THE TESTED PRODUCT I Document the instructions necessary for proper storage, packaging,
p.000534: TEST MATERIALS (if not included in Test Plan or Distribution and Removal of Tested Product and Material for X X
p.000534: Instructions for the examiner) examination.
p.000534: Document the date of dispatch, batch number and shipping method of the subject
p.000534: 8.2.15. RECORD OF DELIVERY OF THE TESTED PRODUCT I
p.000534: products and test materials. Lets track the X X series
p.000534: TEST MATERIAL
p.000534: products, checking shipping conditions, and logging inputs and outputs
p.000534: 8.2.16. CERTIFICATES ON ANALYSIS OF SHIPPED TESTED
p.000534: Document the identity, purity and strength of the product being tested. X
p.000534: PRODUCTS
p.000534: X (po
p.000534: Document the way in which the product under test is identified in an emergency
p.000534: 2/8/17 DECISION PROCEDURES IN BLIND TESTS X
p.000534: case, without disclosing to the respondent the further administration of the drug. the third
p.000534: page)
p.000534: X (po
p.000534: need
p.000534: 8.2.18. RANDOM SELECTION LIST Document the method of random selection of respondents.
p.000534: the third
p.000534: page)
p.000534: Document that the test site is appropriate for his
p.000534: 8.2.19. MONITORING REPORT BEFORE BEGINNING X
p.000534: implementation (may be consolidated with 8.2.20).
p.000534: Document that the procedures used in the examination have been considered
p.000534: 8.2.20. MONITORING REPORT AT THE BEGINNING OF THE TEST X X
p.000534: with the examiner and his staff (may be combined with 8.2.19).
p.000534: 8.3. During the clinical phase of the trial
p.000534: In addition to storing the above documents, they should be accompanied by the following evidence that all new information is documented as soon as it is available.
p.000534: Stored with the Client
p.000534: Document name Purpose
p.000534: Examiner / testing institution
p.000534: Document that the examiner is informed in a timely manner of the most recent information
p.000534: 8.3.1. SUPPLEMENTARY INSTRUCTIONS TO TESTOR X X
p.000534: as soon as they are available.
p.000534: Document changes to the said documents that take effect for
p.000534: 8.3.2. ALL CHANGES: X X
p.000534: test time.
p.000534: - Modifications and additions to the Test Plan and Test Sheet
p.000534: - consent form
p.000534: - other written notices intended for the respondents
p.000534: - Respondent engagement ads (if scheduled)
p.000534: 8.3.3. DATED AND DOCUMENTED
p.000534: Document that changes and additions and / or changes are made available to the Commission and
p.000534: CLINICAL COUNCIL APPROVAL / POSITIVE OPINION
p.000534: that it approved them / gave their positive opinion. Identify version number and X X
...
p.000534: CONCLUSION BY CLOSURE X
p.000534: stored in appropriate scriptures.
p.000534: TESTING
p.000534: 8.4.6. ALLOCATION DOCUMENTATION
p.000534: Returns to the test client to document any decryption procedures. X
p.000534: THERAPY AND DECRIPTION
p.000534: 8.4.7. FINAL REPORT WHICH
p.000534: EXPERT EXCHANGE
p.000534: Document completion of testing. X
p.000534: CONFIDENTIAL AND / OR COMPETENT
p.000534: BODIES
p.000534: X
p.000534: 8.4.8. CLINICAL REPORT
p.000534: Document test results and their interpretation. X
p.000534: TESTING / STUDY
p.000534: (where necessary)
p.000534: ANNEX II.
p.000534: European Medicines Agency
p.000534: Evaluation of medicines for human use
p.000534: London, 27 July 2000.
p.000534: CPMP / ICH / 2711/99
p.000534: ICH theme E 11
p.000534: CLINICAL TESTING OF MEDICINES IN CHILDREN
p.000534: Step 4 of the ICH Procedure
p.000534: GUIDELINES FOR CLINICAL TESTING OF MEDICINES IN CHILDREN (CPMP / ICH / 2711/99)
p.000534: Entry into force: January 2001.
p.000534: CLINICAL TESTING OF MEDICINES IN CHILDREN
p.000534: 1. INTRODUCTION
p.000534: 1.1. Objectives of the guideline
p.000534: The choice of medicines registered for use in children is currently limited. The aim of this guideline is to encourage and facilitate the timely development of medicines for children
p.000534: internationally. This guideline gives a brief overview of key issues related to the development of medicines for children and the different approaches to achieving them
p.000534: safe, successful and ethically sound drug trials in children.
p.000534: 1.2. Starting point
p.000534: ICH documents relevant to child testing include:
p.000534: E2: Manage innocuous data
p.000534: E3: Compilation and content of clinical trial reports
p.000534: E4: Dose efficacy data on drug registration
p.000534: E5: Ethnic factors affecting the acceptance of clinical data from other countries
p.000534: E6: Good clinical practice: integrated guidelines
p.000534: E8: General considerations related to clinical trials
p.000534: E9: Statistical principles applicable in clinical trials
p.000534: E10: Selection of control group for clinical trial
p.000534: M3: Preclinical safety testing of pharmaceutical products for clinical trials in humans
p.000534: Q1: Stability testing
p.000534: Q2: Validation of analytical procedures
p.000534: Q3: Impurity testing
p.000534: 1.3. Scope of the Guidelines
p.000534: This guideline covers the following issues related to clinical trials in children: (1) considerations regarding the introduction of a drug testing program in children
p.000534: children; (2) planning the start of testing in children with respect to the developmental phase of the drug; (3) types of testing (pharmacokinetics,
p.000534: pharmacokinetics / pharmacodynamics, efficacy, safety); (4) age groups and (5) ethical justification for clinical trials in children. The intention
p.000534: these guidelines do not provide a detailed overview of all issues; these are further elaborated in other ICH guidance and regulatory documents
p.000534: bodies and pediatric associations of individual countries.
p.000534: 1.4. General principles
p.000534: Children should only receive medicines that have been properly tested and evaluated for use in children. For safe and effective treatment
p.000534: children need timely knowledge of the proper use of medicines in children of different ages, and often the development of formulations that are appropriate
p.000534: for use in children. Advances in formulation chemistry and the development of a test plan for children will facilitate the development of medicines for use in children. In general
p.000534: when it comes to medicines for the illnesses or problems of adults that are expected to be applied to children, their development programs should
p.000534: include the child population. One important goal is to learn about the effects of medicines on sick children. However, this goal should not be reached
p.000534: questioning the well-being of the child participating in the clinical trial. Responsibility for this is shared by pharmaceutical companies, regulatory bodies, healthcare
p.000534: workers and society at large.
p.000534: 2. GUIDELINES
p.000534: 2.1. Issues to consider when starting to develop a drug for use in children
p.000534: Information on the appropriate use of the medicine in children should be collected, except in the case of medicines whose use is inappropriate in children. In Section 2.3.
p.000534: planning the start of a clinical trial in relation to a trial in adult patients is discussed and may be influenced by the needs of the public
p.000534: country health and health care. From the very beginning of drug development, it is clear from time to time with regulatory authorities
p.000534: de nition when the start and approach of the clinical trial program are justified. The drug development program for children should not delay completion
p.000534: trials of the drug for use in adults and thus its availability to adult patients.
p.000534: The decision to implement a drug development program for use in children and the nature of the program depend on many factors, including these:
p.000534: • the prevalence of the illness to be treated in children,
p.000534: • the severity of the illness to be treated in children,
p.000534: • the existence / availability and appropriateness of other forms of treatment, including their efficacy and side effects (including all specific
p.000534: pediatric safety considerations),
p.000534: • whether the drug is new or belongs to a group of compounds whose properties are known,
p.000534: • if there are specific pediatric indications for the use of the drug,
p.000534: • the need to define specific pediatric parameters,
p.000534: • the age range of children in which the drug is most likely to be used,
p.000534: • specific pediatric (developmental) questions about the safety of the drug, including any pre-clinical issues,
p.000534: • the possible need to develop a new formulation for children.
p.000534: The most important among these factors is the presence of a serious, or life-threatening, illness in which administration of the test drug may signify an important
p.000534: advances in treatment. In these cases, it is necessary to initiate a relatively rapid investigation of the drug in children.
p.000534: Considerations of data from preclinical safety studies of medicinal products relevant to clinical trials in children are described in ICH document M3,
p.000534: Section 11. It should be noted that the most relevant safety data for children are obtained from adult exposure studies.
p.000534: In general, repeated dose toxicity tests and reproductive and genotoxicity studies should be performed. Consideration should also be given to
p.000534: the need for individual developmental toxicology studies in young animals on a case by case basis.
p.000534: 2.2. Formulations for children
p.000534: Formulations for children are needed because they allow accurate dosing and contribute to adherence to the treatment regimen in children. In oral administration, certain
p.000534: the type of formulations, flavors, and colors may prove more acceptable in a country or region than another. For children of different ages may be desirable
p.000534: or need different formulations such as liquids, suspensions and chewable tablets. Different concentrations of the drug in
p.000534: these formulations. Other forms of drug administration should also be considered.
p.000534: Injections with appropriate drug concentrations should be de-injected to allow accurate and safe dose administration. When it comes to medicines in
p.000534: disposable vials, the appropriate packing of these single doses should be considered.
p.000534: There may be a difference in the toxicity of some of the excipients between children of different ages and between children and adults; e.g. benzyl alcohol is toxic to
p.000534: preterm infants.
p.000534: Depending on the active ingredient and excipients, appropriate administration of the drug to infants may necessitate a new formulation, or
p.000534: appropriate dilution information of the existing formulation. Harmonization of acceptable excipients in the formulation and their processes
p.000534: validation at the international level will make the availability of appropriate pediatric formulations everywhere in the world.
p.000534: 2.3. Timing of testing
p.000534: In the clinical phase of drug development, the planning of its use in children will depend on the drug itself, the disease it is intended for, its harmlessness, and
p.000534: efficacy and harmlessness of other possible treatments. Because developing formulations for children can be demanding and time-consuming, this is important
p.000534: formulation development to plan at an early stage of drug development.
p.000534: 2.3.1. Medicines for diseases most or exclusively affected by children
p.000534: In such cases, the entire development program will be implemented on children, except when it comes to testing the harmlessness and tolerability of a drug that
p.000534: is usually performed on adults. With some drugs, even in these early stages, it may make sense to carry out the test only on children, e.g. where
p.000534: tests on adults would not provide any new knowledge or put them at unnecessary risk. One example is respiratory surfactant
p.000534: distress syndrome in premature infants and medicines for metabolic or congenital diseases unique to the pediatric population.
p.000534: 2.3.2. Medicines for serious and life-threatening illnesses that occur in both adults and children, for which they have no other treatment options or are limited
p.000534: The presence of a serious or life-threatening illness in which administration of the test drug may signify a significant improvement in treatment
p.000534: immediate start of the trial of the drug in children. In this case, the development of the drug in children should be started early, immediately after the initial insight into
p.000534: harmlessness of the drug and indicators of its potential beneficial action. The results of drug testing in children should be included in the application for
p.000534: placing the drug on the market. Where this is not possible, the absence of this information should be explained in detail.
p.000534: 2.3.3. Medicines for the treatment of other diseases and medical conditions
p.000534: Although the drug will also be administered to children, in this case the trial may start at later stages of clinical development, and there may be some
p.000534: Concerns about the harmfulness of the drug, even after sufficient experience with the market has been gained in adult use. Pharmaceutical companies must have
p.000534: a clear schedule and justified timetable for drug testing in children. The study of these drugs in children should not be started before tests 2 or 3.
p.000534: phase. At the time of applying for marketing, limited information related to children is available, and more knowledge is expected.
p.000534: after release of the drug.
p.000534: Namely, after testing Phases 1 and 2, testing of a considerable number of new chemical compounds in adults is terminated due to their ineffectiveness or
p.000534: unacceptable side effects. Therefore, early participation in testing may unnecessarily expose children to the action of a compound that will prove useless. There
p.000534: where the drug represents an important advance in the treatment of children, even if it is not a serious illness, trials should be started at an early stage of drug development, and
p.000534: the request for marketing should also include information on its use in children.
p.000534: The possible absence of this information should be explained in detail. Therefore, it is important to carefully weigh the possible before starting a drug test in children
p.000534: the benefit, risk of treatment and the need for its introduction.
p.000534: 2.4. Types of testing
p.000534: The principles outlined in ICH documents E4, E5, E6 and E10 also apply to testing in children. There are several issues that are specific to children.
p.000534: When examining a medicine in children in a country or region, internal (eg pharmacogenetic) and external factors should be taken into account 1 [1] [1]
p.000534: (e.g., nutrition) that may affect the application of results in another country or region.
p.000534: The efficacy data for the indications tested and approved in adults may be applicable to children for the same indications if
p.000534: the development of the disease and the likelihood of treatment outcome are similar in the two populations. In this case, pharmacokinetics testing in all age groups of children
p.000534: receiving the drug and these harmless studies may provide sufficient data for administration through pediatric doses that will lead to drug levels in
p.000534: blood similar to those seen in the adult population. If the test is approached in this way, it is necessary to have data in order to plan tests in children
p.000534: on the pharmacokinetics of the drug in adults.
p.000534: Elderly drug efficacy data may prove applicable to younger children for the same indications if disease development and likelihood are
p.000534: treatment outcomes similar in the two age groups. In this case, pharmacokinetics testing in appropriate age groups of children receiving the drug
p.000534: these safety tests may provide sufficient data for the administration of the drug to children.
p.000534: A pharmacokinetic-based approach is unlikely to be sufficient for drugs known or expected to be inappropriate for blood levels
p.000534: their efficacy, ie the dose-response relationship is assumed to be different between adults and children.
p.000534: In this case, a clinical and pharmacological effect study is expected to be conducted. Where a similar course or outcome of the disease is to be expected
p.000534: between children and adults, but where appropriate levels of the drug are unknown in the blood, to confirm its efficacy and to determine dose and concentration
p.000534: it is possible to measure the pharmacodynamics of the drug with respect to its clinical efficacy. These tests reinforce the confidence that certain
p.000534: drug exposure may lead to the desired outcome in children. So by examining pharmacokinetics and pharmacodynamics, harmlessness and other important
p.000534: factors may be avoided by clinical trials of the efficacy of the drug in children.
p.000534: Where pharmacokinetics cannot be applied, as with topical medicinal products, the administration of results from one group of patients to another may
p.000534: be based on studies incorporating pharmacodynamic parameters and / or other appropriate studies. The need for
p.000534: by examining drug delivery at the application site. To evaluate the harmlessness of a drug, it may also be important to determine its level in the blood and systemic
p.000534: effects.
p.000534: Whether these are new indications for the use of the drug in children, or whether different course of illness and outcome of treatment between adults and children are expected,
p.000534: clinical trials on the efficacy of the drug in children should be performed.
p.000534: 2.4.1. Pharmacokinetics
p.000534: Pharmacokinetic studies are mainly performed to verify the newly developed formulation and to determine pharmacokinetic parameters for various
p.000534: age groups supporting the recommended doses.
p.000534: Comparisons of relative bioavailability between formulations for children and oral formulations for adults should be performed on adults. It's on the kids
p.000534: final pharmacokinetic studies should be conducted to determine the appropriate dose for each age group of children
p.000534: drug intended.
p.000534: In general, pharmacokinetic studies are performed on ill children. This may mean greater heterogeneity among subjects than in healthy subjects
p.000534: volunteers, but the data obtained better reflects clinical application.
p.000534: In the case of medicinal products exhibiting linear pharmacokinetics in adults, single use in pharmacokinetic studies in children
p.000534: may provide sufficient knowledge for dose selection.
p.000534: If necessary, this choice can be confirmed by occasional sampling in repeated dose clinical trials. Any
p.000534: nonlinearity in the absorption, distribution and elimination of the drug and any difference in the time of action between single and multiple dose in adults
p.000534: points to the need to test a drug in children when its dynamic balance is reached. Performing all of these procedures makes it easy to see
p.000534: pharmacokinetic parameters in adults. Knowledge of drug elimination pathways can often prove useful in planning trials in children
p.000534: (via the kidney and metabolism) and age-dependent changes in these processes.
p.000534: For most medicines, the recommended doses for children are based on milligrams per kilogram body weight (mg / kg) and range up to the highest adult dose.
p.000534: Although the first choice may be a dosage based on mg / m2 of body surface area, clinical experience indicates that frequent errors in height measurement or
p.000534: length (especially young children and infants), as well as in calculating the body surface area from these measurements. It is important to administer some medications on a physical basis
p.000534: surfaces (eg drugs with a narrow therapeutic index such as oncology), but extra caution should be exercised to calculate the amount
p.000534: correct.
p.000534: Practical considerations facilitating the conduct of pharmacokinetic studies
p.000534: The blood volume taken from children should be as small as possible. It must be justified within the protocol. Clinical Trials Board / Independent Ethics
p.000534: Committees (Committees) consider and may determine the highest amount of blood (usually in milliliters per kilogram (mL / kg), or as a percentage of
p.000534: total blood volume) that can be taken for testing. There are several ways to minimize blood sampling and vein injection
p.000534: a possible measure.
p.000534: • Using sensitive assays for the drug and its metabolites that require lower blood volume in the sample.
p.000534: • Involvement of laboratories with experience in the processing of low blood volume samples for pharmacokinetic and safety analysis (blood tests, clinical
p.000534: chemistry).
p.000534: • Collecting regular blood samples for both clinical and pharmacokinetic analysis whenever possible.
p.000534: • Using a permanent catheter, etc. to minimize discomfort as discussed in Section 2.6.5.
p.000534: • Applying population pharmacokinetics and sparse sampling based on optimal sampling settings to sample number
p.000534: taken from each patient to a minimum. Sampling techniques include:
p.000534: • Rare sampling in which each patient participates with 2 to 4 tests in a predetermined time in the total population covered
p.000534: "The area under the curve."
p.000534: • Analyzing population pharmacokinetics and planning the most optimal sampling schedule according to the adult model.
p.000534: 2.4.2 Effectiveness
p.000534: Principles of test planning, statistical processing and selection of control groups described in ICH documents ICH E6, E9 and E10, largely
p.000534: also valid for drug efficacy studies in children. However, some details are unique to pediatric trials. In Section 2.4. is discussed about
p.000534: the applicability of the results of efficacy tests in adults to children or trials in older children to young people. Where Performance Tests Are
p.000534: Necessary, it is necessary to develop, validate and apply different parameters for different age and development groups. For subjective symptoms such as pain
p.000534: different measuring instruments are needed, appropriate for each age group of patients. In children with chronic illness, the answer to the drug may be
p.000534: uneven, not only because of the duration of the disease and its chronic effects, but also because of the stage of development in which the patient is present. There are many diseases
p.000534: preterm infants and newborns are unique to these groups or their manifestations are unique, making it impossible to apply the results
p.000534: the effectiveness of the drug on older children and requires new methods of evaluating treatment outcomes.
p.000534: 2.4.3. The harmlessness of the drug
p.000534: The guidelines in ICH documents E2 and E6 describing the recording of adverse reactions also apply to testing in children. It is necessary to record side effects
p.000534: rely on normal laboratory values and clinical measurements that are adjusted to the child's age. Accidental exposure to the drug (accidentally swallowed
p.000534: , etc.) provides an opportunity to obtain additional information on the safety and pharmacokinetics of the drug and to gain a better understanding of the relationship of side effects with the dose.
p.000534: Medications can affect physical and mental development, and children may differ in their experience of side effects. Because developing organisms
p.000534: they may respond differently to treatment from mature organisms, some side effects and interactions with other medicines observed in children may not occur and
p.000534: in adults. In addition, due to the dynamics of growth and development, some side effects may not occur acutely, but at a later stage of development and maturation. Do they want to
p.000534: identify potential effects on skeletal maturation and development, behavior, cognitive function, sexual organs and the immune system may be needed
p.000534: long-term testing of children on chronic treatment or their long-term follow-up after treatment.
p.000534: 2.4.4. Findings after placing the medicine on the market
p.000534: Usually, when obtaining a marketing authorization, the knowledge is limited. Therefore, it is especially important to monitor children after drug release
p.000534: into circulation. It is sometimes important to carry out long-term monitoring to determine the effects of certain drugs on the growth and development of children. Post-placement monitoring
p.000534: drug and / or long-term testing may provide insight into the harmlessness and / or efficacy of the drug to particular groups of children, or
p.000534: additional knowledge regarding the overall child population.
p.000534: 2.5. Division of children by age
p.000534: Any division of children by age is somewhat arbitrary, but can be a starting point for thinking about a test plan for children. For deciding how
p.000534: to distribute tests and data according to the age of the child, developmental biology and pharmacology should be kept in mind. Therefore, a flexible approach is needed which
p.000534: will ensure the presence of the latest findings in pediatric pharmacology in studies. The choice of age to test should depend on the particular drug and is valid
p.000534: substantiate with good reasons.
p.000534: If the routes of drug elimination and their maturation (ontogenesis) are known, the division into age ranges for pharmacokinetic evaluation may start from
p.000534: "Milestones" that bring about significant changes in elimination.
p.000534: It is sometimes more appropriate to collect data on children across a wider age range and to examine the impact of age as a constant covariate. Different parameters
p.000534: the efficacy of the drug may be varied for different age groups, and this division may not correspond to the one shown below. Dividing the population into many
p.000534: age groups may unnecessarily increase the number of children participating in the study. In the case of longer-term trials, children may switch from
p.000534: from one age group to another, and the test plan and statistical analysis must predict changes in the number of patients in a given age group.
p.000534: Below, one of the age groups is offered. However, there is significant overlap in development across all groups (e.g.,
p.000534: cognitive, psychosocial). Age is defined by days, months or years.
p.000534: • Newborns born before term (premature infants)
p.000534: • Newborns born within term (0 - 27 days, newborn born)
p.000534: • Children aged 28 days to 23 months (infants and young children)
p.000534: • Children aged 2 to 11 years
p.000534: • Adolescents (12 to 16-18 years, depending on country)
p.000534: 2.5.1. Newborns born before term (premature infants)
p.000534: The study of premature infants raises special questions, since both the pathology and the response to treatment are unique to this group. Complexity
p.000534: tests in preterm infants and related ethical issues indicate the need for careful protocol design in collaboration with neonatologists and neonatal
p.000534: pharmacologists. Only in rare cases will it be possible to apply the results of efficacy obtained in adults and even older children to premature babies.
p.000534: Newborns as an age group are not homogeneous. There is a big difference between having a baby weighing 500g born at week 25 and 1,500g
p.000534: premature infant born at 30 weeks gestation.
p.000534: It is also important to distinguish whether children with low birth weight are immature or with stunted growth.
p.000534: It is important for these patients to consider the following features: (1) gestational and postnatal age (adjusted age); (2) immaturity of elimination mechanisms
p.000534: via the kidney and liver; (3) problems with protein binding and displacement (especially bilirubin); (4) penetration of the drug into the central nervous system (CNS); (5)
p.000534: health conditions unique to the newborn (eg respiratory stress syndrome, patent ductusarteriosus, primary pulmonary hypertension);
p.000534: (6) preferences inherent in preterm infants (eg, propensity for necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of preterm infants); (7) quickly
p.000534: and unequal maturation of all the biological and pharmacological processes, which necessitates a change in dosage regimen upon long-term drug exposure; and (8)
p.000534: absorption of the drug and other chemical compounds through the skin.
p.000534: Issues to consider in exam planning include: (1) division by body weight and age (gestational and postnatal); (2) small volume
p.000534: blood (prematurely weighing 500 g has only 40 mL of blood); (3) the small number of such patients in a particular healthcare facility and the differences in their treatment among
p.000534: and (4) difficulties in evaluating treatment outcomes.
p.000534: 2.5.2. Newborn born within term (0 - 27 days, newborn born)
p.000534: Although newborns are born within the term mature in development from preterm infants, many of the more described zoological and pharmacological values apply to them
p.000534: settings. In these, the volume of drug distribution may differ from that of older children because of the different ratio of body fluid and fat and because
p.000534: high ratio of skin surface area to body weight. The blood-brain barrier is not yet fully mature, so drugs and endogenous substances (eg bilirubin) may
p.000534: penetrate the CSF and act toxic. Absorption of the drug after oral administration is less predictable than in older children. Elimination mechanisms
p.000534: through the liver and kidney are not yet mature and undergoing rapid changes; therefore, the dosage of the drug should be adjusted in the first weeks of the infant's life.
p.000534: There are many examples of newborn susceptibility to drug toxicity resulting from limited elimination (eg, aplastic anemia caused by
p.000534: chloramphenicol, eng. chloramphenicolgreybabysyndrome). On the other hand, a term-born infant is less sensitive to some side effects
p.000534: (e.g., nephrotoxicity ofaminoglycoside) from elderly patients.
p.000534: 2.5.3. Children aged 28 days to 23 months (infants and young children)
p.000534: At this age, the CSF matures rapidly, the immune system develops and the entire body grows. Absorption after oral administration is now more reliable. It goes on and on
p.000534: rapid maturation of elimination mechanisms via the liver and kidney. Computing in mg / kg, many drugs are eliminated faster in children 1 - 2 years of age than
p.000534: in adults.
p.000534: The developmental maturation pathway depends on specific elimination pathways. Differences in maturation among children are often noticeable.
p.000534: 2.5.4. Children aged 2 to 11 years
p.000534: Most elimination pathways (via liver and kidney) are now mature, and elimination is often greater than in adults. Changes in drug elimination can
p.000534: depend on the maturation of specific metabolic pathways.
p.000534: Appropriate strategies should be set out in the protocol to identify any effects of the drug on the growth and development of the child. There are several at this age
p.000534: a milestone in the psychomotor development of a child that can be adversely affected by drugs acting on the CSW. School attendance and higher cognitive and
p.000534: motor skills may affect a child's ability to participate in some performance tests. Factors useful for measuring performance
p.000534: drugs in children include skeletal growth, weight gain, school attendance, and school success.
p.000534: Selection of respondents should ensure adequate representativeness for the whole age group, since it is important to raise enough young people
p.000534: respondents.
p.000534: It is seldom necessary in this age group to further divide children by age, but it may prove appropriate to divide them according to
p.000534: pharmacokinetic and / or efficacy parameters.
p.000534: Entry into puberty is very uneven among children and occurs earlier in girls, in which it is normal since the age of 9. Puberty can make an impact
p.000534: to the action of drug-degrading enzymes, so, counting in mg / kg, drastic reductions in the dosage of some drugs (eg teo lina) are sometimes necessary. U
p.000534: in some cases, it is better to specifically examine the impact of puberty on drug behavior by comparing children before they reach puberty
p.000534: puberty. In the second case, it is more appropriate to monitor the rates of pubertal development according to Tanner or to collect biological indicators of puberty and
p.000534: study the potential impact of changes in puberty.
p.000534: 2.5.5. Adolescents (12 to 16-18 years old, depending on country)
p.000534: This is the age of sexual maturation, and drugs can clash with the action of sex hormones and prevent development.
p.000534: In some studies, it is advisable to take a pregnancy test and monitor the sexual activity and contraceptive use of the subjects.
p.000534: This is also a period of accelerated physical growth and continued development of neurocognitive functions. Medicines and diseases that slow or accelerate entry into
p.000534: puberty can have a profound effect on pubertal growth and therefore the final height of the patient. Gradual changes in the cognitive and emotional realms can
p.000534: influence the outcome of clinical trials.
p.000534: Many diseases are also affected by hormonal changes associated with puberty (eg, higher insulin resistance in diabetes mellitus, frequent occurrence
p.000534: epileptic seizures in the period around menarche, changes in the frequency and intensity of migraine and asthma attacks). Hormonal changes can also
p.000534: also influence the results of clinical trials.
...
p.000534: to continue the child's participation in the examination. Independent or elderly minors (as defined by local law) may be on their own
p.000534: able to give consent.
p.000534: Data that may be collected in a less vulnerable population that has consented to participate is not advisable to be collected in a more vulnerable population,
p.000534: that is, from patients who are unable to give informed consent. Examinations in handicapped or institutionalized children should be limited to those
p.000534: diseases and health conditions that are mainly or exclusively related to these populations, or to the circumstances in which their disease is expected
p.000534: or health change the behavior or pharmacodynamics of medical devices.
p.000534: 2.6.4. How to minimize risk
p.000534: Whatever the importance of testing in proving or denying the value of a treatment, it can lead to injury in the subjects even when
p.000534: polls benefit the entire community. Therefore, every effort should be made to anticipate and limit known hazards. Even before the beginning
p.000534: clinical trial, investigators must have complete insight into all preclinical and clinical data on drug toxicity. To take a risk in pediatric
p.000534: clinical trials minimized, the staff conducting them need to be well trained and experienced in testing with children, which
p.000534: it also involves identifying and treating possible side effects in children.
p.000534: When designing the test plan, every effort should be made to minimize the number of participants and procedures in the spirit of good test planning.
p.000534: Mechanisms need to be devised to quickly complete testing for unexpected hazards.
p.000534: 2.6.5. How to alleviate suffering as much as possible
p.000534: Frequent invasive procedures can hurt and scare a child.
p.000534: Uncomfortable feelings can be minimized if examinations are planned and conducted by examiners experienced in treating children.
p.000534: Testing protocols and procedures must be specifically designed for the pediatric population (not just adapted from adult protocols) and should be approved
p.000534: The Commission, as described in Section 2.6.1.
p.000534: Listed below are some practical assumptions that can contribute to a positive clinical trial experience and minimize feelings
p.000534: discomfort and suffering:
p.000534: • Staff with knowledge and experience in working with children and adjusting to their age, including experience in pediatric procedures.
p.000534: • Physical space with furniture, toys, daily activities and food adapted to the age of the children.
...
p.000534: ANNEX III.
p.000534: APPLICATION FORM FOR THE APPROVAL OF THE MINISTER OF HEALTH CARE FOR CARRYING OUT THE CLINICAL TESTING OF MEDICINES IN THE REPUBLIC
p.000534: HRVATSKOJ
p.000534: - completed by the contracting authority or the applicant responsible for the accuracy of the information provided
p.000534: Clinical trial client:
p.000534: Applicant for clinical trial:
p.000534: * Date of receipt of the item:
p.000534: * Date of receipt of complete documentation:
p.000534: A. General information
p.000534: Test Name:
p.000534: Test Plan Designation
p.000534: EUDRACT number:
p.000534: Clinical trial phase (I, II, III, IV)
p.000534: List of countries in which clinical trials were approved and / or planned by the time the application was submitted to the ministry responsible for health
p.000534: implement
p.000534: Version and date of test plan
p.000534: Brochure for examiners
p.000534: Informed consent
p.000534: Insurance document
p.000534: Policy number, date of issue, period of insurance
p.000534: B. Information on examiners
p.000534: Chief Examiner in the Republic of Croatia
p.000534: Address:
p.000534: Phone / Fax
p.000534: e-mail
p.000534: Informed consent, version and date, signed by the Examiner
p.000534: Leaders of participating testing centers (examiners)
p.000534: C. Data on test substance
p.000534: Is the preparation approved in the Republic of Croatia
p.000534: Countries where the preparation is approved
p.000534: Generic name
p.000534: Trademark
p.000534: Manufacturer
p.000534: Dosage and administration of the drug in this study
p.000534: Results of non-clinical trials (or reasons why they were not performed)
p.000534: Primary test hypothesis (and secondary if significant)
p.000534: Ethical considerations of the trial (identify and list any possible problem, outline the potential gains of clinical knowledge
p.000534: examining and its importance, assessing the potential risk of injury or other hazards to participants, presenting an evaluation of the risk-benefit relationship
p.000534: If it is intended to provide reasons for the inclusion of persons from particularly vulnerable groups such as minors, non-conscious persons, persons who
p.000534: incapable of judgment, persons with disabilities
p.000534: Description of the recruitment procedures of the respondents (all materials to be used should be attached).
p.000534: Procedures for giving information and obtaining consent from potential respondents
p.000534: (parents or legal representatives - if included)
p.000534: Test procedures, state any required deviations from normal practice
p.000534: Risk assessment, foreseeable treatment risks and procedures to be used (including possible pain, discomfort, integrity violation and ways of avoidance
p.000534: and / or the management of unforeseen / adverse events)
p.000534: Previous experience in conducting similar procedures in the legal entity (s) where the clinical trial will be conducted:
p.000534: Predicted benefits for the respondent
...
p.000534: - completed by the clinical trial client or the applicant responsible for the accuracy of the information provided
p.000534: - The Chief Examiner only signs the informed consent by signing his signature
p.000534: Clinical trial client:
p.000534: Applicant for clinical trial:
p.000534: SEP - Registration number
p.000534: EUDRACT number
p.000534: Date of receipt of complete documentation
p.000534: A. General information
p.000534: Test name, label
p.000534: Clinical trial phase (I, II, III, IV.)
p.000534: version and date of test plan
p.000534: Examiner brochure (version and date)
p.000534: Informed Consent ((Version and Date)
p.000534: Insurance document Policy number, date of issue, duration of insurance
p.000534: Certificate of payment of the fee
p.000534: Test Summary (Version and Date) According to the SEP Special Form
p.000534: B. Information on examiners
p.000534: Chief Examiner in the Republic of Croatia
p.000534: Address *
p.000534: Phone and fax
p.000534: e-mail
p.000534: Chief Examiner
p.000534: reviewed the translation of informed consent
p.000534: specify version and date -
p.000534: which is confirmed by the signature of this section
p.000534: Leaders of participating testing centers (examiners),
p.000534: (addresses, tel, fax, e-mail)
p.000534: C. Data on test substance
p.000534: Is the preparation approved in the Republic of Croatia
p.000534: Countries where the preparation is approved
p.000534: Generic name
p.000534: Trademark
p.000534: Manufacturer
p.000534: Dosage and administration of the drug in this study
p.000534: Summary of non-clinical trials (Phase I and Phase II trials only)
p.000534: Known side effects
p.000534: Known contraindications
p.000534: Known interactions
p.000534: D. Use of placebo Yes No
p.000534: If yes: information on existing accepted effective treatment options for this condition or disease.
p.000534: Danger of untreated or placebo use in this disease or condition
p.000534: E. Drug Supply
p.000534: Will the patient and / or institution receive the drug for free for clinical trial purposes
p.000534: Is the continuation of the open-label study scheduled, whether participants will receive the drug at no charge, and for how long
p.000534: * The address of the lead examiner, which is also the address for all communications between the SEP and the researcher in the project
p.000534: ANNEX V.
p.000534: Clinical trial summary
p.000534: (filled in by the client or applicant responsible for accuracy of information)
p.000534: Clinical trial sponsor (sponsor):
p.000534: Applicant for clinical trial:
p.000534: Name of test
p.000534: Institution (s) at which the test (s) will be conducted
p.000534: Total number of centers
p.000534: Test Plan Mark (Protocol), EUDRACT
p.000534: Clinical trial phase I. II. III. IV.
p.000534: Indication
p.000534: Primary:
p.000534: Objectives of the research
p.000534: (comparing drugs)
p.000534: Secondary objective:
p.000534: Patient population diagnosis and main criterion for inclusion
p.000534: Duration of the experiment
p.000534: Beginning and end of the experiment (in Croatia, worldwide)
p.000534: Criteria for measuring the effect of treatment
p.000534: Methodology
p.000534: open, double-blind, placebo
p.000534: controlled
p.000534: (type of test) (tick)
p.000534: Number of visits, controls
p.000534: Side effects
p.000534: Method of administration and dosage
p.000534: Special notes
p.000534: The principal investigator reviewed the translation of the informed consent (specify version and date) and a summary of the test plan, which is confirmed by the signature
p.000534: of this SEP form
p.000534: Applicant / clinical trial applicant signature and date
p.000534: ANNEX VI.
p.000534: CENTRAL ETHICAL COMMITTEE
p.000534: APPLICATION FORM AND EVALUATION OF NON-INTERVENTIONAL TEST
p.000534: Non-interventional background information (to be completed by the applicant)
p.000534: Name of non-intervention drug test in Croatian:
p.000534: Name of non-intervention drug test in English:
p.000534: Test plan designation:
p.000534: Name and address of the contracting authority:
p.000534: Applicant's name and address:
p.000534: Principal examiners and establishments where non-interventional drug testing will be conducted (number of establishments and examiners): The list is attached to this form and is an integral part of it
p.000534: Objectives of the test:
p.000534: Inclusion criteria:
p.000534: Anticipated number of patients to be monitored:
p.000534: Estimated duration of testing in the Republic of Croatia:
p.000534: Documents provided (filled in by applicant)
p.000534: Test plan (mark, version and date):
p.000534: Approved Summary of Product Characteristics in the Republic of Croatia (approval date):
p.000534: Package leaflet for the medicinal product in the Republic of Croatia (date of approval):
p.000534: Decision on marketing authorization (date):
p.000534: Informed consent for the patient in Croatian language (version and date):
p.000534: Original informed consent in English (version and date):
p.000534: Test financial plan:
p.000534: Other documentation (list, with version and date of documents):
p.000534: Certificate of payment of the costs of giving the opinion of the SPS:
p.000534: Applicant's signature and date:
p.000534: _________________________________________
p.000534: Documentation evaluation (to be completed by the rapporteur)
p.000534: Test plan YES NO
p.000534: The medicine is prescribed according to the marketing authorization: ∑ ☐ Comment:
p.000534: Involvement of patients in a particular therapeutic procedure is not determined in advance by the test plan but is carried out in accordance with normal practice: ∑ ☐ Comment:
p.000534: Prescribing a drug is independent of the decision to include patients in the trial: ∑ ☐ Comment:
p.000534: Additional diagnostic and patient monitoring procedures are not performed (except those that form part of normal practice): ∑ ☐ Comment:
p.000534: Epidemiological methods are used to analyze the data collected: ∑ ☐ Comment:
p.000534: Testing does not promote prescribing of monitored drug: ∑ ☐ Comment:
p.000534: Informed consent in Croatian: YES NO
p.000534: The text clearly describes the conduct of the test, listing all the information needed to make the decision: ∑ ☐ Comment:
p.000534: The text of informed consent is understandable for patients: ∑ ☐ Comment:
p.000534: The informed consent text is linguistic, spelling and typographical correct: ∑ ☐ Comment:
p.000534: Other documentation provided: YES NO
p.000534: Fits test plan: ∑ ☐ Comment:
p.000534: Test Financial Plan: YES NO
p.000534: The test's financial plan is clear: ∑ ☐ Comment:
p.000534: Examiner fees match the estimated scope of work: ∑ ☐ Comment:
p.000534: Rapporteur's recommendation for the adoption of the SPS opinion at the meeting (specify date):
p.000534: (delete unnecessarily; in case b, c or d, reasons must be provided)
p.000534: a. positive thinking
p.000534: b. conditional positive thinking
p.000534: c. it is delayed
p.000534: d. negative thinking
p.000534: Reasons:
p.000534: Report date Reporter's signature:
p.000534: [1] 1 [1] In ICH's E5 Guidelines on Ethnic Factors Affecting Clinical Acceptance from Other Countries, Factors
p.000534: which may influence different drug response in different populations are divided into internal and external ethnic factors. Here you are
p.000534: categories are called internal or external factors only.
p.000534: ANNEX VII.
p.000534: AGENCY FOR MEDICINAL PRODUCTS AND MEDICAL PRODUCTS
p.000534: APPLICATION FORM FOR APPLICATION AND ASSESSMENT OF NON-INTERVENTION TEST
p.000534: Non-interventional background information (to be completed by the applicant)
p.000534: Name of non-intervention test in Croatian:
p.000534: Name of the non-intervention test in English:
p.000534: Name of the active substance (INN):
p.000534: Name of drug:
p.000534: Test plan designation:
p.000534: Authorization holder name and address:
p.000534: Name and address of the contracting authority:
p.000534: Applicant's name and address:
p.000534: Name and surname of the local pharmacovigilance officer
p.000534: Principal examiners and institutions where non-intervention testing will be conducted (names of institutions and examiners' names):
p.000534: Objectives of the test:
p.000534: Inclusion criteria:
p.000534: Exclusion criteria:
p.000534: Anticipated number of patients to be monitored:
p.000534: Estimated duration of testing in the Republic of Croatia:
p.000534: Countries where the non-intervention testing in question is already underway
p.000534: Countries where a request has been made to conduct the non-intervention test in question
p.000534: EU PAS registry number *
p.000534: Shared PASS **
p.000534: * indicate whether PASS is registered in the EU PAS registry
p.000534: ** in the case where multiple marketing authorization holders participate in the planning and implementation of the PASS
p.000534: Documents provided (filled in by applicant)
p.000534: Test plan (mark, version and date):
p.000534: Test list (version and date):
p.000534: Approved Summary of Product Characteristics in the Croatian language (approval date):
p.000534: Approved package leaflet in the Croatian language (authorization date):
p.000534: Decision on marketing authorization (date):
p.000534: Informed consent for the patient in Croatian language (version and date):
p.000534: Original informed consent in English (version and date), if applicable:
...
Searching for indicator influence:
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p.000534: notice for respondent.
p.000534: 1.27. Independent Ethics Committee
p.000534: An independent body (jury or committee, be it an institution, province, state or international body) composed of
p.000534: medical professionals and members of the non-medical profession who are required to ensure the protection of the rights, safety and well-being of clinical participants
p.000534: trials and publicly guarantee such protection, inter alia, by verifying and approving / giving favorable opinion on the Clinical Trial Plan,
p.000534: the eligibility of the examiner, the conditions, methods and materials that will be used to obtain and document the informed consent of the subjects in the clinical
p.000534: examination.
p.000534: The legal status, composition, operation and regulations of independent ethics committees may vary from country to country, but they must
p.000534: enable the independent ethics committee to act in accordance with good clinical practice described in these guidelines.
p.000534: 1.28. Informed consent
p.000534: Procedure whereby the subject voluntarily affirms his or her willingness to participate in a particular clinical trial after being familiar with all
p.000534: aspects of the clinical trial that may influence the decision to participate. The informed consent of the informed respondent shall be documented in writing
p.000534: the form on which the signature and date are entered.
p.000534: 1.29. Inspection
p.000534: Procedure by the competent authority to review documents, assets, equipment and premises, records and all other matters that the body considers related to
p.000534: clinical trial and can be found at the site of the clinical trial, at the trial sponsor and / or contracting research organization, or
p.000534: to other institutions that the competent authority deems appropriate.
p.000534: 1.30. Institution (medical)
p.000534: Any public or private entity, institute or medical or dental institution where clinical trials are conducted.
p.000534: 1.31. Clinical Trials Board
p.000534: An independent body composed of medical professionals and non-medical members whose responsibility is to ensure the protection of rights,
p.000534: the safety and well-being of the people participating in the clinical trial, including by reviewing, approving and ensuring ongoing review of the Plan
p.000534: clinical trial and its appendices are used to obtain and document the informed consent of the clinical trial investigator.
p.000534: 1.32. Clinical trial / study interim report
p.000534: Report on intermediate results and their evaluation based on analysis performed during the clinical trial.
p.000534: 1.33. Tested product
...
p.000534: 4.8. Consent of respondents
p.000534: 4.8.1. In the process of obtaining and recording the subject's consent to participate in the examination, the examiner must comply with the applicable legal requirements.
p.000534: regulations, good clinical practice and ethical principles that are the origin of the Declaration of Helsinki. In order to begin the examination, the examiner must have
p.000534: written approval / positive opinion of the Commission on the form of the statement of consent and other written notifications intended for the respondents.
p.000534: 4.8.2. After any new findings that might affect the Respondent's consent, the Consent Statement form and other written notice intended
p.000534: respondents should be amended accordingly. Prior to use, amended consent statement form and other written notices
p.000534: intended for the respondents should receive the approval / positive opinion of the Commission. Respondent, that is, his legal representative is valid
p.000534: inform in a timely manner new findings that may affect the respondent's willingness to continue to participate in the examination. This kind of notification
p.000534: should be documented.
p.000534: 4.8.3. Neither the examiner nor the examining staff shall coerce or unduly influence the respondent to participate in, or continue to participate in
p.000534: examination.
p.000534: 4.8.4. Oral and written testimony notices, including the statement of consent form, must not contain language formulations that would allow the respondent,
p.000534: that is, his legal representative stated that he at least ostensibly waives his legal rights, that is, which examiner, institution, contracting authority
p.000534: interrogation or their representative, at least apparently, absolves them of their negligence liability.
p.000534: 4.8.5. The examiner, ie the person appointed by him, needs the respondent or his legal representative, if the respondent is not competent to give
p.000534: consent, fully acquainted with all aspects of the examination, including written notice and approval / positive opinion of the Commission.
p.000534: 4.8.6. The choice of words and style of oral and written test reports, including the statement of consent form, should avoid technical terms as much as possible and
p.000534: be understandable to the respondent, that is, his / her legal representative and impartial witness.
p.000534: 4.8.7. Prior to obtaining the consent, the examiner or the person appointed by him / her must provide the respondent or his / her legal representative
p.000534: enough time and opportunity to find out the details of the examination that interest him to decide whether or not he wants to participate. Answer all the questions
p.000534: the test should satisfy the respondent or his / her legal representative.
...
p.000534: (b) have sufficient quantities of the test product available to confirm its specifications, that is, to keep records of batch analyzes; and
p.000534: product properties. To the extent that the stability of the medicinal product permits, samples should be kept either until the analysis of the test results has been completed or until the prescribed deadline.
p.000534: any applicable law, whichever is later.
p.000534: 5.15. Access to documentation
p.000534: 5.15.1. The examining authority should ensure that the Examination Plan or other written agreement clearly states that the examiner / institution must
p.000534: provide direct access to original data / documents for monitoring, monitoring, evaluation of the Commission and inspection by the competent authorities.
p.000534: 5.15.2. The trial contracting authority should check that each respondent has given his or her written consent that his or her original health information may be obtained
p.000534: access directly for monitoring, monitoring, evaluation of the Commission and inspection by the competent authorities.
p.000534: 5.16. Product Safety Information
p.000534: 5.16.1. The test client is responsible for assessing the safety of the product being tested.
p.000534: 5.16.2. The contracting authority shall promptly inform all examiners / institutions and competent authorities of information which may adversely affect
p.000534: the safety of the respondents, influence the conduct of the examination, or withdraw the approval / positive opinion of the Commission.
p.000534: 5.17. Reporting of side effects of the drug
p.000534: 5.17.1. The contracting authority shall promptly inform all examiners / institutions, the Committees (where appropriate) and the competent authorities of all serious and
p.000534: unexpected side effects of the drug.
p.000534: 5.17.2. These emergency reports should comply with applicable laws and ICH's Clinical Safety Information Management Guidelines:
p.000534: Definitions and standards for emergency reporting.
p.000534: 5.17.3. The contracting authority shall provide the competent authorities with all new safety data and periodic reports in accordance with the applicable legal requirements
p.000534: regulations.
p.000534: 5.18. Observation
p.000534: 5.18.1. Purpose
p.000534: The purpose of observing a test is to verify that:
p.000534: (a) the rights and welfare of the respondents are protected;
p.000534: (b) that the information in the reports is accurate, complete and can be verified / verified using the original documents;
p.000534: (c) the test is conducted in accordance with the current approved Test Plan and any amendments thereto, with good clinical
p.000534: practice and with applicable legal regulations.
p.000534: 5.18.2. Selection and qualifications of observers
...
p.000534: to the action of drug-degrading enzymes, so, counting in mg / kg, drastic reductions in the dosage of some drugs (eg teo lina) are sometimes necessary. U
p.000534: in some cases, it is better to specifically examine the impact of puberty on drug behavior by comparing children before they reach puberty
p.000534: puberty. In the second case, it is more appropriate to monitor the rates of pubertal development according to Tanner or to collect biological indicators of puberty and
p.000534: study the potential impact of changes in puberty.
p.000534: 2.5.5. Adolescents (12 to 16-18 years old, depending on country)
p.000534: This is the age of sexual maturation, and drugs can clash with the action of sex hormones and prevent development.
p.000534: In some studies, it is advisable to take a pregnancy test and monitor the sexual activity and contraceptive use of the subjects.
p.000534: This is also a period of accelerated physical growth and continued development of neurocognitive functions. Medicines and diseases that slow or accelerate entry into
p.000534: puberty can have a profound effect on pubertal growth and therefore the final height of the patient. Gradual changes in the cognitive and emotional realms can
p.000534: influence the outcome of clinical trials.
p.000534: Many diseases are also affected by hormonal changes associated with puberty (eg, higher insulin resistance in diabetes mellitus, frequent occurrence
p.000534: epileptic seizures in the period around menarche, changes in the frequency and intensity of migraine and asthma attacks). Hormonal changes can also
p.000534: also influence the results of clinical trials.
p.000534: By entering this age group, adolescents take responsibility for their own health and treatment. Failure to follow the treatment regimen is here
p.000534: a specific problem, especially if drugs (eg steroids) affect appearance. It is very important to check that the subjects adhere to the treatment regimen in
p.000534: clinical trials.
p.000534: Particular attention should also be paid to the occasional use of non-prescribed medicines and to the consumption of alcohol and tobacco.
p.000534: The upper limit of this age group varies from country to country. Older adolescents may be involved in adult trials, though they may be
p.000534: difficulty adhering to the treatment regimen. Due to problems specific to adolescence, conducting tests may be appropriate
p.000534: (whether included in the adult test protocol or in a separate protocol) in healthcare settings with knowledge and experience in nursing
p.000534: of this patient population.
p.000534: 2.6. Ethical issues related to testing in children
p.000534: Children are a vulnerable group of respondents. It is therefore necessary to introduce specific measures to protect their rights in clinical trials and to prevent them
p.000534: exposure to unnecessary risk. The purpose of this section is to provide an ethical framework for conducting testing in children.
...
p.000534: Epidemiological methods are used to analyze the data collected: ∑ ☐ Comment:
p.000534: Testing does not promote prescribing of monitored drug: ∑ ☐ Comment:
p.000534: Informed consent in Croatian: YES NO
p.000534: The text clearly describes the conduct of the test, listing all the information needed to make the decision: ∑ ☐ Comment:
p.000534: The text of informed consent is understandable for patients: ∑ ☐ Comment:
p.000534: The informed consent text is linguistic, spelling and typographical correct: ∑ ☐ Comment:
p.000534: Other documentation provided: YES NO
p.000534: Fits test plan: ∑ ☐ Comment:
p.000534: Test Financial Plan: YES NO
p.000534: The test's financial plan is clear: ∑ ☐ Comment:
p.000534: Examiner fees match the estimated scope of work: ∑ ☐ Comment:
p.000534: Rapporteur's recommendation for the adoption of the SPS opinion at the meeting (specify date):
p.000534: (delete unnecessarily; in case b, c or d, reasons must be provided)
p.000534: a. positive thinking
p.000534: b. conditional positive thinking
p.000534: c. it is delayed
p.000534: d. negative thinking
p.000534: Reasons:
p.000534: Report date Reporter's signature:
p.000534: [1] 1 [1] In ICH's E5 Guidelines on Ethnic Factors Affecting Clinical Acceptance from Other Countries, Factors
p.000534: which may influence different drug response in different populations are divided into internal and external ethnic factors. Here you are
p.000534: categories are called internal or external factors only.
p.000534: ANNEX VII.
p.000534: AGENCY FOR MEDICINAL PRODUCTS AND MEDICAL PRODUCTS
p.000534: APPLICATION FORM FOR APPLICATION AND ASSESSMENT OF NON-INTERVENTION TEST
p.000534: Non-interventional background information (to be completed by the applicant)
p.000534: Name of non-intervention test in Croatian:
p.000534: Name of the non-intervention test in English:
p.000534: Name of the active substance (INN):
p.000534: Name of drug:
p.000534: Test plan designation:
p.000534: Authorization holder name and address:
p.000534: Name and address of the contracting authority:
p.000534: Applicant's name and address:
p.000534: Name and surname of the local pharmacovigilance officer
p.000534: Principal examiners and institutions where non-intervention testing will be conducted (names of institutions and examiners' names):
p.000534: Objectives of the test:
p.000534: Inclusion criteria:
p.000534: Exclusion criteria:
p.000534: Anticipated number of patients to be monitored:
p.000534: Estimated duration of testing in the Republic of Croatia:
p.000534: Countries where the non-intervention testing in question is already underway
p.000534: Countries where a request has been made to conduct the non-intervention test in question
p.000534: EU PAS registry number *
p.000534: Shared PASS **
...
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p.000534: oral consent in the presence of at least one witness who is not a member of the examination team.
p.000534: Inspection supervision of clinical trials is the oversight of the competent authority over the conduct of the clinical trial, review of documentation, premises, records,
p.000534: quality assurance systems and other resources related to the conduct of clinical trials that may be conducted at the test site, at the premises
p.000534: of the clinical trial client and / or the contracting authority or in other legal entities where the competent authority deems it necessary to carry out supervision.
p.000534: The respondent is an individual who participates in a clinical trial and receives the study drug or is part of a control group.
p.000534: The examiner is a doctor of medicine or a person with appropriate professional qualifications for clinical trials due to his / her professional knowledge and necessary
p.000534: experience in treating patients. The examiner is responsible for conducting the clinical trial at the test site. If a clinical trial is conducted by a group
p.000534: individuals in one examiner site, the examiner is responsible and is called the lead examiner.
p.000534: The test site is the health facility where the clinical trial is conducted.
p.000534: Test drug is a pharmaceutical formulation with an active substance or a placebo that is being tested or used as a comparison in a clinical trial and includes
p.000534: medicinal products authorized on the market but used in a different way from the one approved or different in formulation or packaging, or
p.000534: are used in unauthorized indications or used to obtain additional information on a marketing authorization form.
p.000534: Clinical trial is any human trial designed to detect or confirm clinical, pharmacological and / or other pharmacodynamic effects
p.000534: one or more test drugs and / or detection of side effects of one or more test drugs, and / or studies on absorption, distribution, metabolism and
p.000534: excretion of one or more investigational drugs for the purpose of determining the safety of administration and / or efficacy. This includes clinical trials
p.000534: conducted in one or more testing sites, in one or more Member States of the European Union.
p.000534: An observer is a person who performs monitoring during a clinical trial and ensures that it is conducted, documented and recorded in accordance with the test plan,
p.000534: standard operating procedures, good clinical practice and specific regulations.
p.000534: Non-interventional drug testing is any trial in which the drug is prescribed in accordance with the marketing authorization. Involvement of patients in
p.000534: a particular therapeutic procedure is not predetermined by the test plan but is carried out in accordance with normal practice, and prescribing is
...
p.000534: the form on which the signature and date are entered.
p.000534: 1.29. Inspection
p.000534: Procedure by the competent authority to review documents, assets, equipment and premises, records and all other matters that the body considers related to
p.000534: clinical trial and can be found at the site of the clinical trial, at the trial sponsor and / or contracting research organization, or
p.000534: to other institutions that the competent authority deems appropriate.
p.000534: 1.30. Institution (medical)
p.000534: Any public or private entity, institute or medical or dental institution where clinical trials are conducted.
p.000534: 1.31. Clinical Trials Board
p.000534: An independent body composed of medical professionals and non-medical members whose responsibility is to ensure the protection of rights,
p.000534: the safety and well-being of the people participating in the clinical trial, including by reviewing, approving and ensuring ongoing review of the Plan
p.000534: clinical trial and its appendices are used to obtain and document the informed consent of the clinical trial investigator.
p.000534: 1.32. Clinical trial / study interim report
p.000534: Report on intermediate results and their evaluation based on analysis performed during the clinical trial.
p.000534: 1.33. Tested product
p.000534: Pharmaceutical form of the active substance or placebo to be tested in a clinical trial for comparison, including a product approved on the market if
p.000534: its use or method (formulation or packaging) differ from the approved one, or, if used for an indication that is not approved, or used for
p.000534: collecting further information on approved application.
p.000534: 1.34. Examiner
p.000534: The person responsible for conducting the clinical trial at the place where it is conducted. If a group of individuals conducts a site survey,
p.000534: the examiner is the person responsible for leading the group and is also referred to as the lead examiner. See also Assistant Examiner.
p.000534: 1.35. Examiner / Institution
p.000534: A term that designates "examiner and / or institution in accordance with applicable law."
p.000534: 1.36. Instructions for the examiner
p.000534: A set of clinical and preclinical data on an investigational product that is relevant to its human test (see 7. Test Guideline).
p.000534: 1.37. Legal representative
p.000534: An individual or legal entity or other body authorized by applicable law to consent to participate in a clinical trial on behalf of the respondent.
p.000534: 1.38. Observation
p.000534: The act of monitoring the progress of the clinical trial and ensuring that its implementation, documentation and reporting are consistent with the Clinical Trial Plan,
p.000534: standard operating procedures, good clinical practice and applicable legal requirements.
p.000534: 1.39. Observation report
p.000534: A written report submitted by the observer to the contracting authority after each visit to the examination site and / or upon new knowledge relating to
p.000534: testing in accordance with standard operating procedures of the test client.
...
p.000534: understanding of procedures in the event that a permanent catheter becomes unusable over time. Respondent's right to refuse further participation must be respected
p.000534: in the test procedures, except in the case described in section 2.6.3.
p.000534: ANNEX III.
p.000534: APPLICATION FORM FOR THE APPROVAL OF THE MINISTER OF HEALTH CARE FOR CARRYING OUT THE CLINICAL TESTING OF MEDICINES IN THE REPUBLIC
p.000534: HRVATSKOJ
p.000534: - completed by the contracting authority or the applicant responsible for the accuracy of the information provided
p.000534: Clinical trial client:
p.000534: Applicant for clinical trial:
p.000534: * Date of receipt of the item:
p.000534: * Date of receipt of complete documentation:
p.000534: A. General information
p.000534: Test Name:
p.000534: Test Plan Designation
p.000534: EUDRACT number:
p.000534: Clinical trial phase (I, II, III, IV)
p.000534: List of countries in which clinical trials were approved and / or planned by the time the application was submitted to the ministry responsible for health
p.000534: implement
p.000534: Version and date of test plan
p.000534: Brochure for examiners
p.000534: Informed consent
p.000534: Insurance document
p.000534: Policy number, date of issue, period of insurance
p.000534: B. Information on examiners
p.000534: Chief Examiner in the Republic of Croatia
p.000534: Address:
p.000534: Phone / Fax
p.000534: e-mail
p.000534: Informed consent, version and date, signed by the Examiner
p.000534: Leaders of participating testing centers (examiners)
p.000534: C. Data on test substance
p.000534: Is the preparation approved in the Republic of Croatia
p.000534: Countries where the preparation is approved
p.000534: Generic name
p.000534: Trademark
p.000534: Manufacturer
p.000534: Dosage and administration of the drug in this study
p.000534: Results of non-clinical trials (or reasons why they were not performed)
p.000534: Primary test hypothesis (and secondary if significant)
p.000534: Ethical considerations of the trial (identify and list any possible problem, outline the potential gains of clinical knowledge
p.000534: examining and its importance, assessing the potential risk of injury or other hazards to participants, presenting an evaluation of the risk-benefit relationship
p.000534: If it is intended to provide reasons for the inclusion of persons from particularly vulnerable groups such as minors, non-conscious persons, persons who
p.000534: incapable of judgment, persons with disabilities
p.000534: Description of the recruitment procedures of the respondents (all materials to be used should be attached).
p.000534: Procedures for giving information and obtaining consent from potential respondents
p.000534: (parents or legal representatives - if included)
p.000534: Test procedures, state any required deviations from normal practice
p.000534: Risk assessment, foreseeable treatment risks and procedures to be used (including possible pain, discomfort, integrity violation and ways of avoidance
...
p.000534: Date:
p.000534: Signature:
p.000534: * meets MIZ
p.000534: ANNEX IV.
p.000534: Application form for submission to the Central Ethics Committee of the opinion on the admissibility of a clinical trial of a medicinal product
p.000534: - completed by the clinical trial client or the applicant responsible for the accuracy of the information provided
p.000534: - The Chief Examiner only signs the informed consent by signing his signature
p.000534: Clinical trial client:
p.000534: Applicant for clinical trial:
p.000534: SEP - Registration number
p.000534: EUDRACT number
p.000534: Date of receipt of complete documentation
p.000534: A. General information
p.000534: Test name, label
p.000534: Clinical trial phase (I, II, III, IV.)
p.000534: version and date of test plan
p.000534: Examiner brochure (version and date)
p.000534: Informed Consent ((Version and Date)
p.000534: Insurance document Policy number, date of issue, duration of insurance
p.000534: Certificate of payment of the fee
p.000534: Test Summary (Version and Date) According to the SEP Special Form
p.000534: B. Information on examiners
p.000534: Chief Examiner in the Republic of Croatia
p.000534: Address *
p.000534: Phone and fax
p.000534: e-mail
p.000534: Chief Examiner
p.000534: reviewed the translation of informed consent
p.000534: specify version and date -
p.000534: which is confirmed by the signature of this section
p.000534: Leaders of participating testing centers (examiners),
p.000534: (addresses, tel, fax, e-mail)
p.000534: C. Data on test substance
p.000534: Is the preparation approved in the Republic of Croatia
p.000534: Countries where the preparation is approved
p.000534: Generic name
p.000534: Trademark
p.000534: Manufacturer
p.000534: Dosage and administration of the drug in this study
p.000534: Summary of non-clinical trials (Phase I and Phase II trials only)
p.000534: Known side effects
p.000534: Known contraindications
p.000534: Known interactions
p.000534: D. Use of placebo Yes No
p.000534: If yes: information on existing accepted effective treatment options for this condition or disease.
p.000534: Danger of untreated or placebo use in this disease or condition
p.000534: E. Drug Supply
p.000534: Will the patient and / or institution receive the drug for free for clinical trial purposes
p.000534: Is the continuation of the open-label study scheduled, whether participants will receive the drug at no charge, and for how long
p.000534: * The address of the lead examiner, which is also the address for all communications between the SEP and the researcher in the project
p.000534: ANNEX V.
p.000534: Clinical trial summary
p.000534: (filled in by the client or applicant responsible for accuracy of information)
p.000534: Clinical trial sponsor (sponsor):
p.000534: Applicant for clinical trial:
p.000534: Name of test
p.000534: Institution (s) at which the test (s) will be conducted
p.000534: Total number of centers
...
p.000534: Other documentation provided: YES NO
p.000534: Fits test plan: ∑ ☐ Comment:
p.000534: Test Financial Plan: YES NO
p.000534: The test's financial plan is clear: ∑ ☐ Comment:
p.000534: Examiner fees match the estimated scope of work: ∑ ☐ Comment:
p.000534: Rapporteur's recommendation for the adoption of the SPS opinion at the meeting (specify date):
p.000534: (delete unnecessarily; in case b, c or d, reasons must be provided)
p.000534: a. positive thinking
p.000534: b. conditional positive thinking
p.000534: c. it is delayed
p.000534: d. negative thinking
p.000534: Reasons:
p.000534: Report date Reporter's signature:
p.000534: [1] 1 [1] In ICH's E5 Guidelines on Ethnic Factors Affecting Clinical Acceptance from Other Countries, Factors
p.000534: which may influence different drug response in different populations are divided into internal and external ethnic factors. Here you are
p.000534: categories are called internal or external factors only.
p.000534: ANNEX VII.
p.000534: AGENCY FOR MEDICINAL PRODUCTS AND MEDICAL PRODUCTS
p.000534: APPLICATION FORM FOR APPLICATION AND ASSESSMENT OF NON-INTERVENTION TEST
p.000534: Non-interventional background information (to be completed by the applicant)
p.000534: Name of non-intervention test in Croatian:
p.000534: Name of the non-intervention test in English:
p.000534: Name of the active substance (INN):
p.000534: Name of drug:
p.000534: Test plan designation:
p.000534: Authorization holder name and address:
p.000534: Name and address of the contracting authority:
p.000534: Applicant's name and address:
p.000534: Name and surname of the local pharmacovigilance officer
p.000534: Principal examiners and institutions where non-intervention testing will be conducted (names of institutions and examiners' names):
p.000534: Objectives of the test:
p.000534: Inclusion criteria:
p.000534: Exclusion criteria:
p.000534: Anticipated number of patients to be monitored:
p.000534: Estimated duration of testing in the Republic of Croatia:
p.000534: Countries where the non-intervention testing in question is already underway
p.000534: Countries where a request has been made to conduct the non-intervention test in question
p.000534: EU PAS registry number *
p.000534: Shared PASS **
p.000534: * indicate whether PASS is registered in the EU PAS registry
p.000534: ** in the case where multiple marketing authorization holders participate in the planning and implementation of the PASS
p.000534: Documents provided (filled in by applicant)
p.000534: Test plan (mark, version and date):
p.000534: Test list (version and date):
p.000534: Approved Summary of Product Characteristics in the Croatian language (approval date):
p.000534: Approved package leaflet in the Croatian language (authorization date):
p.000534: Decision on marketing authorization (date):
p.000534: Informed consent for the patient in Croatian language (version and date):
...
Health / Healthy People
Searching for indicator healthy volunteers:
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p.000534: - Reproductive toxicity;
p.000534: - Genotoxicity (mutagenicity).
p.000534: 7.3.6. Effects on humans
p.000534: Introduction:
p.000534: The known effects of the test product on humans should be thoroughly discussed, including information on its pharmacokinetics, metabolism,
p.000534: pharmacodynamics, dose dependence, safety, efficacy (efficacy) and other pharmacological actions. Wherever possible
p.000534: is to provide a summary of all completed clinical trials. Also, information regarding the application of the product under test should be provided outside
p.000534: clinical trials, such as post-marketing experience.
p.000534: (a) Pharmacokinetics and metabolism of the test product in humans
p.000534: - the pharmacokinetics of the test product should be summarized, including the following available data:
p.000534: - pharmacokinetics (including metabolism and absorption, plasma protein binding, distribution and elimination);
p.000534: - bioavailability of the test product (absolute and relative where possible) using the reference preparation;
p.000534: - population subgroups (eg by sex, age and impaired organ function);
p.000534: - interactions (eg drug interactions and the impact of food);
p.000534: - other pharmacokinetic data (eg results of population-based studies conducted in clinical trials).
p.000534: (b) Safety and efficiency
p.000534: Summary information on the safety, pharmacodynamics, efficacy (efficacy) and dose dependency of the product under test (including
p.000534: its metabolites) from previous human studies (healthy volunteers and / or patients). The significance of this data needs to be discussed. Where it is
p.000534: completed multiple clinical trials, summary summaries of safety and efficacy results by subgroup indications may provide
p.000534: clear data presentation. It would be useful to summarize into the tables all the side effects of the drug (for all indications tested) observed in all clinical trials.
p.000534: Significant differences in side effects by indications and subgroups of subjects need to be discussed.
p.000534: Instructions for the examiner should describe the expected risks and side effects of the drug based on previous experience with the product tested and related drugs.
p.000534: Also, precautions and special monitoring should be indicated as an integral part of the application of the test product.
p.000534: (c) Experience after placing the test product on the market
p.000534: The instructions must indicate the countries in which the test product was approved or placed on the market. A summary of all important information should be provided
p.000534: resulting from its market application (eg, formulations, dosages, routes of administration, side effects). The Guidelines also indicate the countries where
p.000534: the tested product was not authorized or withdrawn from the market, or its registration was revoked.
p.000534: 7.3.7. Summary of results and guidelines for examiner
p.000534: This section should contain a comprehensive discussion of preclinical and clinical data and provide a summary of the various aspects of the product under test
p.000534: based on data from different sources. This gives the examiner an extensive interpretation of the data available and an assessment of their significance for future clinical
p.000534: testing.
...
Health / Mentally Disabled
Searching for indicator mentally:
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p.000534: 2.6.2. Involvement of respondents
p.000534: Respondents should be included in a way that completely excludes inappropriate prompting of respondents, or their parents / guardians, to participate in
p.000534: examination.
p.000534: Fees and living expenses may be included in the cost of the pediatric clinical trial. Fees should be approved by
p.000534: Committees.
p.000534: When conducting child testing, it is a good idea to include individuals who represent the demographic country / region and the disease being tested, except where
p.000534: there are valid reasons for limited participation in the examination.
p.000534: 2.6.3. Consent and consent
p.000534: As a rule, children are legally incapable of giving their consent to participate in the examination. Therefore, their participation depends on their decision
p.000534: parents or guardians to take responsibility for their participation in the clinical trial. Fully familiarize the caregiver with the examination and
p.000534: obtaining his consent should be in accordance with local laws and regulations. All participants need to be better acquainted with the testing using
p.000534: the consent should be determined by the Commission, or in accordance with local legal requirements).
p.000534: Participants who are mentally mature should personally sign and date either a specific consent form or a consent form. Anyway,
p.000534: Participants must be aware of their right to refuse participation or withdraw from the examination at any time. It should be addressed
p.000534: attention to the signs of excessive suffering in patients who are unable to clearly express their suffering. Although it must respect the respondent's decision to
p.000534: withdraw from testing, in therapeutic trials of serious and life-threatening diseases such circumstances are possible which, in the opinion of the examiner and
p.000534: parent / guardian, may jeopardize the welfare of the child in the event of his / her withdrawal. In these circumstances, further consent from the parent (guardian) is sufficient
p.000534: to continue the child's participation in the examination. Independent or elderly minors (as defined by local law) may be on their own
p.000534: able to give consent.
p.000534: Data that may be collected in a less vulnerable population that has consented to participate is not advisable to be collected in a more vulnerable population,
...
Searching for indicator disability:
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p.000534: A document outlining the objectives, plan, methodology, statistics and organization of the test. In addition, it is usually explained in the Clinical Trial Plan
p.000534: background and meaning of the trial, but this can also be found in other documents referenced in the Clinical Trial Plan. In these ICH Guidelines
p.000534: the term "Clinical Trial Plan" refers to the Clinical Trial Plan itself and its amendments and additions.
p.000534: 1.45. Modifications and additions to the Clinical Trial Plan
p.000534: Amendments to the Clinical Trial Plan in writing or its formal clarification.
p.000534: 1.46. Quality assurance
p.000534: All planned and systematic activities aimed at ensuring compliance of the clinical trial, documenting (recording) results and reporting with
p.000534: good clinical practice and applicable legislation.
p.000534: 1.47. Quality control
p.000534: Implementation techniques and activities in the field of quality assurance aimed at verifying that all the quality requirements related to testing are fulfilled.
p.000534: 1.48. Random selection
p.000534: The process of randomly selecting subjects into treatment groups or control groups, thereby reducing bias.
p.000534: 1.49. Competent authorities
p.000534: Bodies competent for the adoption of legislation. For the purposes of these Guidelines, the term competent authorities includes bodies that consider the clinical data obtained
p.000534: and those conducting the inspection (see 1.29). These bodies are sometimes referred to as competent authorities.
p.000534: 1.50. Serious adverse event or serious side effect
p.000534: Any undesirable medical occurrence involving any of the following:
p.000534: - death of a person,
p.000534: - life-threatening condition,
p.000534: - the need for hospital treatment or extension of pre-existing hospital treatment,
p.000534: - permanent or severe disability or incapacity,
p.000534: - congenital anomaly / birth defect.
p.000534: (see ICH Clinical Safety Information Guidelines: Definitions and Standards for Emergency Reporting).
p.000534: 1.51. Original data
p.000534: All data in original documents and certified copies of original records of clinical findings of observations or other procedures in clinical trials
p.000534: required to monitor the course and evaluate the clinical trial.
p.000534: The original information is contained in the original documentation (original records or certified copies).
p.000534: 1.52. Original documentation
p.000534: Original files, data, and records (e.g., hospital records, hospital and medical records, laboratory notes, memos, test subjects' diaries, or
p.000534: checklists, medication lists, recorded data from automated devices, copies and transcripts certified as authentic copies, micro-shi,
p.000534: negatives, micro lms and magnetic media, x-rays, test files and records from pharmacies, laboratories and health departments
p.000534: involved in the clinical trial.
p.000534: 1.53. Investigator
p.000534: An individual, company, institution or organization responsible for initiating, conducting and / or financing a clinical trial.
p.000534: 1.54. Investigator - examiner
p.000534: An individual who initiates and conducts, alone or with others, a clinical trial and under whose immediate management the test product is prescribed, dispensed, or
p.000534: the respondent applies it. This term is restricted to natural persons (ie does not include legal persons such as corporations or agencies).
p.000534: Obligations of the client-examiner include both the obligations of the clinical trial client and those of the clinical trial examiner.
...
Health / Mentally Incapacitated
Searching for indicator incapable:
(return to top)
p.000534: document E6, section 4.8.14.
p.000534: 2.6.1. Clinical Trial Panel / Independent Ethics Committee (Committee)
p.000534: The role and authority of the Commission described in ICH document E6 is crucial in protecting the respondents. When considering protocols involving children,
p.000534: The committee among its membership must or must seek the professional opinion of persons with a good knowledge of ethical, clinical and psychosocial issues.
p.000534: related to children.
p.000534: 2.6.2. Involvement of respondents
p.000534: Respondents should be included in a way that completely excludes inappropriate prompting of respondents, or their parents / guardians, to participate in
p.000534: examination.
p.000534: Fees and living expenses may be included in the cost of the pediatric clinical trial. Fees should be approved by
p.000534: Committees.
p.000534: When conducting child testing, it is a good idea to include individuals who represent the demographic country / region and the disease being tested, except where
p.000534: there are valid reasons for limited participation in the examination.
p.000534: 2.6.3. Consent and consent
p.000534: As a rule, children are legally incapable of giving their consent to participate in the examination. Therefore, their participation depends on their decision
p.000534: parents or guardians to take responsibility for their participation in the clinical trial. Fully familiarize the caregiver with the examination and
p.000534: obtaining his consent should be in accordance with local laws and regulations. All participants need to be better acquainted with the testing using
p.000534: the consent should be determined by the Commission, or in accordance with local legal requirements).
p.000534: Participants who are mentally mature should personally sign and date either a specific consent form or a consent form. Anyway,
p.000534: Participants must be aware of their right to refuse participation or withdraw from the examination at any time. It should be addressed
p.000534: attention to the signs of excessive suffering in patients who are unable to clearly express their suffering. Although it must respect the respondent's decision to
p.000534: withdraw from testing, in therapeutic trials of serious and life-threatening diseases such circumstances are possible which, in the opinion of the examiner and
...
p.000534: implement
p.000534: Version and date of test plan
p.000534: Brochure for examiners
p.000534: Informed consent
p.000534: Insurance document
p.000534: Policy number, date of issue, period of insurance
p.000534: B. Information on examiners
p.000534: Chief Examiner in the Republic of Croatia
p.000534: Address:
p.000534: Phone / Fax
p.000534: e-mail
p.000534: Informed consent, version and date, signed by the Examiner
p.000534: Leaders of participating testing centers (examiners)
p.000534: C. Data on test substance
p.000534: Is the preparation approved in the Republic of Croatia
p.000534: Countries where the preparation is approved
p.000534: Generic name
p.000534: Trademark
p.000534: Manufacturer
p.000534: Dosage and administration of the drug in this study
p.000534: Results of non-clinical trials (or reasons why they were not performed)
p.000534: Primary test hypothesis (and secondary if significant)
p.000534: Ethical considerations of the trial (identify and list any possible problem, outline the potential gains of clinical knowledge
p.000534: examining and its importance, assessing the potential risk of injury or other hazards to participants, presenting an evaluation of the risk-benefit relationship
p.000534: If it is intended to provide reasons for the inclusion of persons from particularly vulnerable groups such as minors, non-conscious persons, persons who
p.000534: incapable of judgment, persons with disabilities
p.000534: Description of the recruitment procedures of the respondents (all materials to be used should be attached).
p.000534: Procedures for giving information and obtaining consent from potential respondents
p.000534: (parents or legal representatives - if included)
p.000534: Test procedures, state any required deviations from normal practice
p.000534: Risk assessment, foreseeable treatment risks and procedures to be used (including possible pain, discomfort, integrity violation and ways of avoidance
p.000534: and / or the management of unforeseen / adverse events)
p.000534: Previous experience in conducting similar procedures in the legal entity (s) where the clinical trial will be conducted:
p.000534: Predicted benefits for the respondent
p.000534: Describe the relationship between the respondent and the researcher (eg patient-doctor of medicine, student-teacher, etc.)
p.000534: Procedures to check whether a potential respondent is participating in another clinical trial at the same time or that sufficient time has elapsed
p.000534: having previously participated in a clinical trial (especially important when it comes to including healthy subjects in clinical trials):
p.000534: Procedures used to protect the privacy of recorded data, source documents, or samples:
p.000534: Treatment or care plan after completing clinical trial participation (who will be responsible and where to administer):
p.000534: Statistical considerations and reasons for including a specified number of subjects in a clinical trial
...
Health / Motherhood/Family
Searching for indicator family:
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p.000534: 4.1.4. The examiner / institution should allow the investigator to monitor and monitor and inspect the relevant competent authorities.
p.000534: 4.1.5. The examiner should draw up a list of qualified persons to whom he or she has delegated the important tasks associated with the examination.
p.000534: 4.2. Appropriate opportunities / resources
p.000534: 4.2.1. The examiner should prove (eg based on previous indicators) that he / she is able to gather the required number of appropriate respondents in the agreed
p.000534: period.
p.000534: 4.2.2. The examiner should have sufficient time to properly conduct and complete the examination within the agreed period.
p.000534: 4.2.3. In order for the test to be conducted properly and safely, the examiner should have a sufficient number of qualified staff and adequate facilities and equipment for
p.000534: the estimated duration of the test.
p.000534: 4.2.4. The examiner must make sure that all his associates are adequately informed about the Test Plan, the product tested and their obligations and
p.000534: test-related tasks.
p.000534: 4.3. Health care for respondents
p.000534: 4.3.1. Qualified medical doctor - examiner (if necessary, dental doctor) or doctor of medicine conducting the examination should be
p.000534: responsible for all health decisions related to testing.
p.000534: 4.3.2. During and after the respondent's participation in the examination, the examiner / institution should provide adequate health care to the respondents with
p.000534: test-related adverse reactions, including clinically relevant laboratory findings. Does the examiner / institution establish that the respondent is in the meantime
p.000534: suffering from a disease, should be informed of the need for its treatment.
p.000534: 4.3.3. It is recommended that the examiner inform the respondent family physician / general practitioner of his / her participation in the examination, if the respondent has
p.000534: your family doctor / general practitioner and if he / she agrees.
p.000534: 4.3.4. Although the respondent is not required to explain the reasons for his / her early withdrawal from the examination, the examiner should make reasonable efforts to:
p.000534: determine the reasons, respecting all the respondent's rights.
p.000534: 4.4. Communication with the Commission
p.000534: 4.4.1. In order to begin the examination at all, the examiner / institution should have the written and dated approval / positive opinion of the Committee on the Examination Plan,
p.000534: Written Respondent's Statement of Consent and Amendments, Description of Respondent's Recruitment (e.g., by Ad) and Other Written Notices Intended
p.000534: to the respondents.
p.000534: 4.4.2. An up-to-date version of the Examiner's Guide is an integral part of the written request submitted by the examiner / institution to the Commission. If changes occur and
p.000534: Amendments to the Instructions for Examiners During the examination, the examiner / institution is obliged to submit updated Instructions to the Commission.
p.000534: 4.4.3. During the examination, the examiner / institution is obliged to submit to the Commission all documentation necessary for consideration.
p.000534: 4.5. Adherence to the Examination Plan
p.000534: 4.5.1. The examiner / institution should carry out the test in accordance with the Test Plan agreed with the test client and, if necessary, with
p.000534: competent authority, which has received approval / positive opinion from the Commission. In confirmation of the agreement, the examiner / institution and the contracting authority
...
Health / Physically Disabled
Searching for indicator illness:
(return to top)
p.000534: questioning the well-being of the child participating in the clinical trial. Responsibility for this is shared by pharmaceutical companies, regulatory bodies, healthcare
p.000534: workers and society at large.
p.000534: 2. GUIDELINES
p.000534: 2.1. Issues to consider when starting to develop a drug for use in children
p.000534: Information on the appropriate use of the medicine in children should be collected, except in the case of medicines whose use is inappropriate in children. In Section 2.3.
p.000534: planning the start of a clinical trial in relation to a trial in adult patients is discussed and may be influenced by the needs of the public
p.000534: country health and health care. From the very beginning of drug development, it is clear from time to time with regulatory authorities
p.000534: de nition when the start and approach of the clinical trial program are justified. The drug development program for children should not delay completion
p.000534: trials of the drug for use in adults and thus its availability to adult patients.
p.000534: The decision to implement a drug development program for use in children and the nature of the program depend on many factors, including these:
p.000534: • the prevalence of the illness to be treated in children,
p.000534: • the severity of the illness to be treated in children,
p.000534: • the existence / availability and appropriateness of other forms of treatment, including their efficacy and side effects (including all specific
p.000534: pediatric safety considerations),
p.000534: • whether the drug is new or belongs to a group of compounds whose properties are known,
p.000534: • if there are specific pediatric indications for the use of the drug,
p.000534: • the need to define specific pediatric parameters,
p.000534: • the age range of children in which the drug is most likely to be used,
p.000534: • specific pediatric (developmental) questions about the safety of the drug, including any pre-clinical issues,
p.000534: • the possible need to develop a new formulation for children.
p.000534: The most important among these factors is the presence of a serious, or life-threatening, illness in which administration of the test drug may signify an important
p.000534: advances in treatment. In these cases, it is necessary to initiate a relatively rapid investigation of the drug in children.
p.000534: Considerations of data from preclinical safety studies of medicinal products relevant to clinical trials in children are described in ICH document M3,
p.000534: Section 11. It should be noted that the most relevant safety data for children are obtained from adult exposure studies.
p.000534: In general, repeated dose toxicity tests and reproductive and genotoxicity studies should be performed. Consideration should also be given to
p.000534: the need for individual developmental toxicology studies in young animals on a case by case basis.
p.000534: 2.2. Formulations for children
p.000534: Formulations for children are needed because they allow accurate dosing and contribute to adherence to the treatment regimen in children. In oral administration, certain
p.000534: the type of formulations, flavors, and colors may prove more acceptable in a country or region than another. For children of different ages may be desirable
p.000534: or need different formulations such as liquids, suspensions and chewable tablets. Different concentrations of the drug in
...
p.000534: efficacy and harmlessness of other possible treatments. Because developing formulations for children can be demanding and time-consuming, this is important
p.000534: formulation development to plan at an early stage of drug development.
p.000534: 2.3.1. Medicines for diseases most or exclusively affected by children
p.000534: In such cases, the entire development program will be implemented on children, except when it comes to testing the harmlessness and tolerability of a drug that
p.000534: is usually performed on adults. With some drugs, even in these early stages, it may make sense to carry out the test only on children, e.g. where
p.000534: tests on adults would not provide any new knowledge or put them at unnecessary risk. One example is respiratory surfactant
p.000534: distress syndrome in premature infants and medicines for metabolic or congenital diseases unique to the pediatric population.
p.000534: 2.3.2. Medicines for serious and life-threatening illnesses that occur in both adults and children, for which they have no other treatment options or are limited
p.000534: The presence of a serious or life-threatening illness in which administration of the test drug may signify a significant improvement in treatment
p.000534: immediate start of the trial of the drug in children. In this case, the development of the drug in children should be started early, immediately after the initial insight into
p.000534: harmlessness of the drug and indicators of its potential beneficial action. The results of drug testing in children should be included in the application for
p.000534: placing the drug on the market. Where this is not possible, the absence of this information should be explained in detail.
p.000534: 2.3.3. Medicines for the treatment of other diseases and medical conditions
p.000534: Although the drug will also be administered to children, in this case the trial may start at later stages of clinical development, and there may be some
p.000534: Concerns about the harmfulness of the drug, even after sufficient experience with the market has been gained in adult use. Pharmaceutical companies must have
p.000534: a clear schedule and justified timetable for drug testing in children. The study of these drugs in children should not be started before tests 2 or 3.
p.000534: phase. At the time of applying for marketing, limited information related to children is available, and more knowledge is expected.
p.000534: after release of the drug.
p.000534: Namely, after testing Phases 1 and 2, testing of a considerable number of new chemical compounds in adults is terminated due to their ineffectiveness or
p.000534: unacceptable side effects. Therefore, early participation in testing may unnecessarily expose children to the action of a compound that will prove useless. There
p.000534: where the drug represents an important advance in the treatment of children, even if it is not a serious illness, trials should be started at an early stage of drug development, and
p.000534: the request for marketing should also include information on its use in children.
p.000534: The possible absence of this information should be explained in detail. Therefore, it is important to carefully weigh the possible before starting a drug test in children
p.000534: the benefit, risk of treatment and the need for its introduction.
p.000534: 2.4. Types of testing
p.000534: The principles outlined in ICH documents E4, E5, E6 and E10 also apply to testing in children. There are several issues that are specific to children.
p.000534: When examining a medicine in children in a country or region, internal (eg pharmacogenetic) and external factors should be taken into account 1 [1] [1]
p.000534: (e.g., nutrition) that may affect the application of results in another country or region.
p.000534: The efficacy data for the indications tested and approved in adults may be applicable to children for the same indications if
p.000534: the development of the disease and the likelihood of treatment outcome are similar in the two populations. In this case, pharmacokinetics testing in all age groups of children
...
p.000534: between children and adults, but where appropriate levels of the drug are unknown in the blood, to confirm its efficacy and to determine dose and concentration
p.000534: it is possible to measure the pharmacodynamics of the drug with respect to its clinical efficacy. These tests reinforce the confidence that certain
p.000534: drug exposure may lead to the desired outcome in children. So by examining pharmacokinetics and pharmacodynamics, harmlessness and other important
p.000534: factors may be avoided by clinical trials of the efficacy of the drug in children.
p.000534: Where pharmacokinetics cannot be applied, as with topical medicinal products, the administration of results from one group of patients to another may
p.000534: be based on studies incorporating pharmacodynamic parameters and / or other appropriate studies. The need for
p.000534: by examining drug delivery at the application site. To evaluate the harmlessness of a drug, it may also be important to determine its level in the blood and systemic
p.000534: effects.
p.000534: Whether these are new indications for the use of the drug in children, or whether different course of illness and outcome of treatment between adults and children are expected,
p.000534: clinical trials on the efficacy of the drug in children should be performed.
p.000534: 2.4.1. Pharmacokinetics
p.000534: Pharmacokinetic studies are mainly performed to verify the newly developed formulation and to determine pharmacokinetic parameters for various
p.000534: age groups supporting the recommended doses.
p.000534: Comparisons of relative bioavailability between formulations for children and oral formulations for adults should be performed on adults. It's on the kids
p.000534: final pharmacokinetic studies should be conducted to determine the appropriate dose for each age group of children
p.000534: drug intended.
p.000534: In general, pharmacokinetic studies are performed on ill children. This may mean greater heterogeneity among subjects than in healthy subjects
p.000534: volunteers, but the data obtained better reflects clinical application.
p.000534: In the case of medicinal products exhibiting linear pharmacokinetics in adults, single use in pharmacokinetic studies in children
p.000534: may provide sufficient knowledge for dose selection.
p.000534: If necessary, this choice can be confirmed by occasional sampling in repeated dose clinical trials. Any
...
p.000534: • Collecting regular blood samples for both clinical and pharmacokinetic analysis whenever possible.
p.000534: • Using a permanent catheter, etc. to minimize discomfort as discussed in Section 2.6.5.
p.000534: • Applying population pharmacokinetics and sparse sampling based on optimal sampling settings to sample number
p.000534: taken from each patient to a minimum. Sampling techniques include:
p.000534: • Rare sampling in which each patient participates with 2 to 4 tests in a predetermined time in the total population covered
p.000534: "The area under the curve."
p.000534: • Analyzing population pharmacokinetics and planning the most optimal sampling schedule according to the adult model.
p.000534: 2.4.2 Effectiveness
p.000534: Principles of test planning, statistical processing and selection of control groups described in ICH documents ICH E6, E9 and E10, largely
p.000534: also valid for drug efficacy studies in children. However, some details are unique to pediatric trials. In Section 2.4. is discussed about
p.000534: the applicability of the results of efficacy tests in adults to children or trials in older children to young people. Where Performance Tests Are
p.000534: Necessary, it is necessary to develop, validate and apply different parameters for different age and development groups. For subjective symptoms such as pain
p.000534: different measuring instruments are needed, appropriate for each age group of patients. In children with chronic illness, the answer to the drug may be
p.000534: uneven, not only because of the duration of the disease and its chronic effects, but also because of the stage of development in which the patient is present. There are many diseases
p.000534: preterm infants and newborns are unique to these groups or their manifestations are unique, making it impossible to apply the results
p.000534: the effectiveness of the drug on older children and requires new methods of evaluating treatment outcomes.
p.000534: 2.4.3. The harmlessness of the drug
p.000534: The guidelines in ICH documents E2 and E6 describing the recording of adverse reactions also apply to testing in children. It is necessary to record side effects
p.000534: rely on normal laboratory values and clinical measurements that are adjusted to the child's age. Accidental exposure to the drug (accidentally swallowed
p.000534: , etc.) provides an opportunity to obtain additional information on the safety and pharmacokinetics of the drug and to gain a better understanding of the relationship of side effects with the dose.
p.000534: Medications can affect physical and mental development, and children may differ in their experience of side effects. Because developing organisms
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p.000534: pharmacokinetics / pharmacodynamics, efficacy, safety); (4) age groups and (5) ethical justification for clinical trials in children. The intention
p.000534: these guidelines do not provide a detailed overview of all issues; these are further elaborated in other ICH guidance and regulatory documents
p.000534: bodies and pediatric associations of individual countries.
p.000534: 1.4. General principles
p.000534: Children should only receive medicines that have been properly tested and evaluated for use in children. For safe and effective treatment
p.000534: children need timely knowledge of the proper use of medicines in children of different ages, and often the development of formulations that are appropriate
p.000534: for use in children. Advances in formulation chemistry and the development of a test plan for children will facilitate the development of medicines for use in children. In general
p.000534: when it comes to medicines for the illnesses or problems of adults that are expected to be applied to children, their development programs should
p.000534: include the child population. One important goal is to learn about the effects of medicines on sick children. However, this goal should not be reached
p.000534: questioning the well-being of the child participating in the clinical trial. Responsibility for this is shared by pharmaceutical companies, regulatory bodies, healthcare
p.000534: workers and society at large.
p.000534: 2. GUIDELINES
p.000534: 2.1. Issues to consider when starting to develop a drug for use in children
p.000534: Information on the appropriate use of the medicine in children should be collected, except in the case of medicines whose use is inappropriate in children. In Section 2.3.
p.000534: planning the start of a clinical trial in relation to a trial in adult patients is discussed and may be influenced by the needs of the public
p.000534: country health and health care. From the very beginning of drug development, it is clear from time to time with regulatory authorities
p.000534: de nition when the start and approach of the clinical trial program are justified. The drug development program for children should not delay completion
p.000534: trials of the drug for use in adults and thus its availability to adult patients.
p.000534: The decision to implement a drug development program for use in children and the nature of the program depend on many factors, including these:
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p.000534: by examining drug delivery at the application site. To evaluate the harmlessness of a drug, it may also be important to determine its level in the blood and systemic
p.000534: effects.
p.000534: Whether these are new indications for the use of the drug in children, or whether different course of illness and outcome of treatment between adults and children are expected,
p.000534: clinical trials on the efficacy of the drug in children should be performed.
p.000534: 2.4.1. Pharmacokinetics
p.000534: Pharmacokinetic studies are mainly performed to verify the newly developed formulation and to determine pharmacokinetic parameters for various
p.000534: age groups supporting the recommended doses.
p.000534: Comparisons of relative bioavailability between formulations for children and oral formulations for adults should be performed on adults. It's on the kids
p.000534: final pharmacokinetic studies should be conducted to determine the appropriate dose for each age group of children
p.000534: drug intended.
p.000534: In general, pharmacokinetic studies are performed on ill children. This may mean greater heterogeneity among subjects than in healthy subjects
p.000534: volunteers, but the data obtained better reflects clinical application.
p.000534: In the case of medicinal products exhibiting linear pharmacokinetics in adults, single use in pharmacokinetic studies in children
p.000534: may provide sufficient knowledge for dose selection.
p.000534: If necessary, this choice can be confirmed by occasional sampling in repeated dose clinical trials. Any
p.000534: nonlinearity in the absorption, distribution and elimination of the drug and any difference in the time of action between single and multiple dose in adults
p.000534: points to the need to test a drug in children when its dynamic balance is reached. Performing all of these procedures makes it easy to see
p.000534: pharmacokinetic parameters in adults. Knowledge of drug elimination pathways can often prove useful in planning trials in children
p.000534: (via the kidney and metabolism) and age-dependent changes in these processes.
p.000534: For most medicines, the recommended doses for children are based on milligrams per kilogram body weight (mg / kg) and range up to the highest adult dose.
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Social / Access to Social Goods
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p.000534: Suspected Unexpected Serious Adverse Reactions (SUSAR) that have occurred in clinical trials in
p.000534: Inform the Central Ethics Committee and the Ministry thereof.
p.000534: Article 27
p.000534: If the clinical trial is completed before it is specified in the clinical trial plan or is suspended, the applicant is
p.000534: obliged, with a detailed explanation of the cause, to inform the Central Ethics Committee, which gave a positive opinion, within 15 days
p.000534: and the Ministry.
p.000534: Article 28
p.000534: (1) The applicant shall submit to the Central Ethics Committee and the Ministry a notification of the completion of the clinical trial within 90
p.000534: days from the end of the clinical trial.
p.000534: (2) Completion of the clinical trial referred to in paragraph 1 of this Article shall be considered as the day of the last examination / examination of the last included respondent in the clinical trial.
p.000534: examination.
p.000534: Article 29
p.000534: Upon completion of the clinical trial, the applicant is required to submit to the Central Ethics Committee and the Ministry a summary of the final
p.000534: reports, within one year of the end of the clinical trial.
p.000534: Article 30
p.000534: (1) The clinical trial client may allow subjects to participate in the program upon completion of their participation in the clinical trial
p.000534: prolonged treatment with investigational drug, eng. "Expanded access programs", (hereinafter referred to as "the program").
p.000534: (2) In the case referred to in paragraph 1 of this Article, the applicant shall inform the Central Ethics Committee of the planned program and request
p.000534: consent of the Ministry.
p.000534: (3) The applicant is obliged to state the reasons for launching and the duration of the program, the number of examining places and respondents in each examiner
p.000534: the site that will participate in the program and the dose and route of administration. With the request, the applicant is required to attach the statements of the Chief Examiners to whom
p.000534: confirm their participation in the program and agree to continue monitoring the safety of drug administration and that the risk-benefit ratio justifies the administration of the drug
p.000534: in doses and in the manner prescribed by the proposed program.
p.000534: (4) At least once a year, the applicant shall notify the Central Ethics Committee and the Ministry of the implementation of the program, with emphasis
p.000534: to the safety of drug administration.
p.000534: (5) The applicant shall notify the Central Ethics Committee and the Ministry of the completion of the program within 90 days from the end of the program.
p.000534: program.
p.000534: Article 31
...
p.000534: clinical and statistical description, presentation and analysis form a single report (see ICH Guidelines for the Structure and Content of the Clinical Report
p.000534: examination).
p.000534: 1.14. Product of comparison
p.000534: Tested or marketed product (ie active control), or placebo, used in the clinical trial as a comparison product.
p.000534: 1.15. Compliance (applies to clinical trial procedures)
p.000534: Compliance with all clinical trial requirements, good clinical practices and applicable legal requirements.
p.000534: 1.16. Confidentiality
p.000534: Preventing the disclosure, except to authorized persons, of the protected data of the test client, or the identity of the respondents.
p.000534: 1.17. The contract
p.000534: A written, dated and signed agreement between two or more parties specifying the delegation and distribution of tasks and obligations, and nancial matters there
p.000534: where necessary. The contract may be based on a Clinical Trial Plan.
p.000534: 1.18. Commission for Coordination
p.000534: A committee that may be set up by a trial client to coordinate the implementation of a multicenter clinical trial.
p.000534: 1.19. Examiner Coordinator
p.000534: Examiner responsible for coordinating examiners at different centers participating in multicenter testing.
p.000534: 1.20. Contracting research organization
p.000534: Person or organization (commercial, academic or otherwise) with whom the contracting authority has contracted to perform one or more duties and activities
p.000534: related to the clinical trial.
p.000534: 1.21. Direct access
p.000534: Approval to review, analyze, verify and transmit all data and reports relevant to the evaluation of the clinical trial. Any side that has a direct
p.000534: access to documentation (eg domestic or foreign competent authorities, observers, and supervisors of the contracting authority) is obliged to take all reasonable steps
p.000534: precautionary measures within the framework of the applicable legal regulations in order to preserve the confidentiality of the respondents' identities and data owned by the contracting authority.
p.000534: 1.22. Documentation
p.000534: All information in any form (including, but not limited to, written, electronic, magnetic and optical records and recordings, x-rays and
p.000534: electrocardiograms) that describe or record methods, and the conduct and / or results of the clinical trial, the factors affecting it, and the actions taken.
p.000534: 1.23. Basic documents
p.000534: Documents that, individually or together, enable the evaluation of the conduct of the clinical trial and the quality of the data obtained (see 8. Basic
p.000534: clinical trial documents).
p.000534: 1.24. Good clinical practice
p.000534: Clinical trial standard including planning, implementation, monitoring, monitoring, recording, analysis and human research reports
p.000534: ensuring that the data and results are credible and accurate and that the rights, integrity and confidentiality of the respondent's data are protected.
p.000534: 1.25. Independent Data Monitoring Commission
p.000534: (Committee for the Monitoring of Medicines Safety Data, Monitoring Committee, Monitoring Committee)
p.000534: Independent Monitoring Committee on the information that the trial client may establish to periodically evaluate the progress of the clinical trial,
p.000534: data on harmlessness (side effects) and critical efficacy points and to recommend to the contracting authority whether to proceed, adjust
...
p.000534: (a) That the examination is of an investigative nature;
p.000534: (b) Purpose of the test;
p.000534: (c) Test procedures and the likelihood that the subject will be randomly assigned to a particular treatment group;
p.000534: (d) Procedures provided for in the test, including invasive procedures;
p.000534: (e) Respondents' obligations;
p.000534: (f) Experimental aspects of testing;
p.000534: (g) Predictable risks and discomforts for the respondent, namely the embryo, fetus or infant;
p.000534: (h) Benefits to be expected. Where no clinical benefit is expected for the respondent, it should be made known to the respondent;
p.000534: (i) Alternative procedures, ie treatment options available to the respondent, and the risks and benefits they may bring to the respondent;
p.000534: (j) Compensation and / or treatment provided to the respondent in the event of an injury resulting from his participation in the examination;
p.000534: (k) Expected timetable for payment of installments of any compensation to respondents for participation in the examination;
p.000534: (l) Any expected costs for the respondent for participating in the examination;
p.000534: (m) that the respondent's participation in the examination is voluntary and that the respondent may refuse to participate in the examination or withdraw from it at any time,
p.000534: without being punished or losing the rights he otherwise exercises;
p.000534: (n) That the observer (s), the persons supervising (s), the Commission and the competent authorities will have direct access to the respondent's original health information for the sake of
p.000534: validation of clinical trial procedures and data obtained, with full protection of the confidentiality of the respondents' identities within the limits of applicable laws and regulations, as well as
p.000534: that the respondent or his / her legal representative expresses his / her consent to such access to information by signing the statement of consent;
p.000534: (o) That the personal data of the respondents will be kept confidential and, within the limits of applicable laws and / or regulations, will not be made available to the public. If results are published
p.000534: questioning, the identity of the respondents will remain secret;
p.000534: (p) That the respondent or his / her legal representative will be informed in a timely manner of new findings that may affect the respondent
p.000534: willingness to continue to participate in the examination;
p.000534: (q) Name of contact person for information related to the examination and rights of respondents, as well as name of contact person for possible injury arising from participation in
p.000534: examination;
p.000534: (r) the foreseeable circumstances and / or reasons why the respondent may terminate his / her participation in the examination;
p.000534: (s) The expected duration of the respondent's participation in the examination;
p.000534: (t) Indicative number of respondents envisaged for examination.
p.000534: 4.8.11. Before entering the examination, the respondent or his / her legal representative should receive a copy of the signed and dated statement of consent, as well as
...
p.000534: The examiner is obliged to give the examiner and / or the appointed person instructions for making these corrections. The client of the examination shall be in writing
p.000534: initiate a process to ensure that changes or corrections to the test list made by the appointed person are necessary, recorded and paired
p.000534: by the examiner. The examiner should keep a record of all changes and corrections.
p.000534: 4.9.4. The examiner / institution should keep the examination documentation in accordance with the Instructions given in the section Basic Implementation Documents
p.000534: clinical trial (see 8.), as well as with applicable legal regulations. The examiner / institution should take measures to prevent accidental or
p.000534: premature destruction of these documents.
p.000534: 4.9.5. Basic documents should be kept for at least two years after the last marketing authorization was granted
p.000534: countries at least two years after the official cessation of the clinical development of the product under test. If they seek such a legal requirement
p.000534: regulations or agreement with the contracting authority, these documents should be kept for longer than stated above. The contracting authority is obliged to inform
p.000534: examiner / institution when it is no longer necessary to keep this documentation (see 5.5.12).
p.000534: 4.9.6. The financial aspects of the test should be documented by agreement between the test client and the examiner / institution.
p.000534: 4.9.7. The examiner / institution shall be obliged to allow the observer, the person supervising, the Commission or the competent authority, upon their request, a direct
p.000534: access to examination documents.
p.000534: 4.10. Test progress reports
p.000534: 4.10.1. The examiner is obliged to submit a written summary of the progress of the examination to the Committee once a year, and more frequently at the special request of the Committee.
p.000534: 4.10.2. The examiner is obliged to immediately submit a written report on the ordering authority, the Committee (see 3.3.8) and, where appropriate, the health institution.
p.000534: changes that significantly affect the conduct of the test and / or increase the risk to respondents.
p.000534: 4.11. Product Safety Reporting
p.000534: 4.11.1. Any serious adverse event should be reported promptly to the testing contractor, except for those events for which it is in the Test Plan or otherwise.
p.000534: document (eg in the Examiner's Instructions) stated that they should not be reported immediately. A detailed report should be written immediately after the application
p.000534: event. In this report, their associated unique identifier should be used in place of the name, identification number (e.g., MBG) and / or address of the respondent
p.000534: tag. The examiner should also comply with the applicable legal requirements of the reporting requirements of the competent authorities and the
p.000534: unexpected serious side effects of the drug.
p.000534: 4.11.2. Reports of adverse events and / or abnormal laboratory findings identified by the Test Plan as critical to the assessment
p.000534: security should be delivered to the test client in accordance with the reporting rules and at intervals specified by the test client at
p.000534: Test plan.
...
p.000534: the examiner / institution should immediately inform the test client and the Committee and provide them with a detailed explanation of such procedure.
p.000534: 4.12.2. If the contracting authority completes or terminates the examination (see 5.21), the examiner is obliged to inform the institution immediately, and the examiner / institution
p.000534: the Commission should be informed immediately and a detailed explanation of such procedure should be provided.
p.000534: 4.12.3. If the Committee withdraws its approval / positive opinion on the examination (see 3.1.2 and 3.3.9), the examiner shall inform the institution accordingly,
p.000534: and the examiner / institution should immediately inform the contracting authority and provide him with a detailed explanation of such procedure.
p.000534: 4.13. Final report of examiner (s)
p.000534: Upon completion of the examination, the examiner should inform the institution. The examiner / institution should provide the committee with a summary of the test results, a
p.000534: all necessary reports to the competent authorities.
p.000534: 5. TEST ORDER
p.000534: 5.1. Quality assurance and control
p.000534: 5.1.1. The testing contractor is responsible for establishing and maintaining a quality assurance and quality control system through standard operating systems
p.000534: procedures to ensure that the clinical trial is conducted, documented (recorded) and reported to the Trial Plan,
p.000534: good clinical practice and applicable legislation.
p.000534: 5.1.2. The test client is responsible for reaching an agreement between the parties on direct access (see 1.21) to all test sites, original
p.000534: data / documents and reports so that it can monitor and supervise the test, or in order for the domestic or foreign competent authority
p.000534: could carry out an inspection.
p.000534: 5.1.3. Quality should be monitored at every stage of data handling to ensure its reliability and proper processing.
p.000534: 5.1.4. Agreements between the client and the examiner / institution and other parties involved in the clinical trial should be in writing
p.000534: as an integral part of the Examination Plan or as a separate agreement.
p.000534: 5.2. Contracting Research Organization (ITA)
p.000534: 5.2.1. The contracting authority may delegate all its obligations or tasks or part thereof to the contracting research organization, with ultimate responsibility
p.000534: the quality and completeness of the test results shall continue to be borne by the contracting authority. The ITA's job is to implement quality assurance and quality control procedures.
p.000534: 5.2.2. Each obligation and task related to the examination, which is transferred to the ITA, must be individually stated in writing.
p.000534: 5.2.3. The contracting authority retains those obligations and tasks that are not explicitly delegated to the ITA.
p.000534: 5.2.4. Anything in this Guideline that applies to the contracting authority shall also apply to the ITA to the extent that the ITA has assumed the obligations and tasks of
p.000534: of the contracting authority.
...
p.000534: 5.5. Test management, data handling and record keeping
p.000534: 5.5.1. The contracting authority should hire qualified persons to supervise the overall conduct of the examination, to manage the data obtained,
p.000534: verify their accuracy, perform statistical analyzes and prepare reports.
p.000534: 5.5.2. The trial contracting authority may appoint an independent data monitoring committee to periodically evaluate the progress of the clinical trial,
p.000534: including safety data and key drug efficacy parameters, and to recommend whether the trial client should continue the trial, amend
p.000534: or stop it. The Independent Data Monitoring Commission should, in writing, derogate from operating procedures (operating procedures) and maintain
p.000534: notes from all their meetings.
p.000534: 5.5.3. When handling electronic data directly or through a remote control system, the contracting authority shall:
p.000534: (a) ensure and record the compliance of the electronic data processing system with the requirements of the test client's completeness, accuracy, reliability and
p.000534: consistency of processing (i.e. validation);
p.000534: (b) have standard operating procedures for the use of these systems;
p.000534: (c) ensure that the systems are designed to allow data to be modified in such a way that each change is recorded and that there is no possibility
p.000534: deletion of data entered (ie to keep a trace of surveillance, a data trace and a trace of their editing);
p.000534: (d) take care of the security of the system preventing unauthorized access to the data;
p.000534: (e) keep a list of persons authorized to modify the data (see 4.1.5 and 4.9.3);
p.000534: (f) keep a copy of the information in order to protect against its loss;
p.000534: (g) if the test is blind, protect its blindness (eg when entering and processing data).
p.000534: 5.5.4. If there is a change in the data during their processing, it should always be possible to compare the original data and comments with the processed
p.000534: data.
p.000534: 5.5.5. The contracting authority should use the unambiguous identification marks of the respondents (see 1.58.) That allow the connection of all recorded
p.000534: data with each individual respondent.
p.000534: 5.5.6. The test client, or the data owner, should keep all his or her basic documents pertaining to the test (see 8. Basic
p.000534: clinical trial documents).
p.000534: 5.5.7. These documents should be retained by the contracting authority in accordance with the laws in force in the countries where the product is authorized and / or
p.000534: the countries where it intends to apply for its approval.
p.000534: 5.5.8. If the trial client interrupts the clinical development of the test product (due to some or all indications, routes of administration or dosage form)
p.000534: is obliged to keep all its basic documents for at least two years from the official cessation of the clinical development of the tested product, ie
p.000534: for as long as required by applicable law.
p.000534: 5.5.9. If the trial contractor interrupts the clinical development of the test product, it should inform all examiners / institutions and all competent authorities.
...
p.000534: 5.14.3. The test client shall ensure that the description of the procedures also includes the instructions for handling and storage of the test product and its associated
p.000534: documentation to be followed by the examiner / institution. These instructions should cover proper and secure receipt, handling, storage and issuance
p.000534: test product, collection of unused test product from the respondent and return it to the test client (or otherwise)
p.000534: disposal of unused product in accordance with applicable legal regulations).
p.000534: 5.14.4. The contracting authority shall:
p.000534: (a) ensure timely delivery of the test product to the examiner;
p.000534: (b) keep records of the dispatch, receipt, removal, return and destruction of the investigated product (see 8. Basic clinical implementation documents
p.000534: examinations);
p.000534: (c) maintain a system of return for the test product and record its return (eg for withdrawal of defective product, return on completion
p.000534: tests, returns of expired products);
p.000534: (d) maintain a system for removing unused test products and recording their disposal.
p.000534: 5.14.5. The contracting authority shall:
p.000534: (a) take the necessary measures to ensure the stability of the test product during application;
p.000534: (b) have sufficient quantities of the test product available to confirm its specifications, that is, to keep records of batch analyzes; and
p.000534: product properties. To the extent that the stability of the medicinal product permits, samples should be kept either until the analysis of the test results has been completed or until the prescribed deadline.
p.000534: any applicable law, whichever is later.
p.000534: 5.15. Access to documentation
p.000534: 5.15.1. The examining authority should ensure that the Examination Plan or other written agreement clearly states that the examiner / institution must
p.000534: provide direct access to original data / documents for monitoring, monitoring, evaluation of the Commission and inspection by the competent authorities.
p.000534: 5.15.2. The trial contracting authority should check that each respondent has given his or her written consent that his or her original health information may be obtained
p.000534: access directly for monitoring, monitoring, evaluation of the Commission and inspection by the competent authorities.
p.000534: 5.16. Product Safety Information
p.000534: 5.16.1. The test client is responsible for assessing the safety of the product being tested.
p.000534: 5.16.2. The contracting authority shall promptly inform all examiners / institutions and competent authorities of information which may adversely affect
p.000534: the safety of the respondents, influence the conduct of the examination, or withdraw the approval / positive opinion of the Commission.
p.000534: 5.17. Reporting of side effects of the drug
p.000534: 5.17.1. The contracting authority shall promptly inform all examiners / institutions, the Committees (where appropriate) and the competent authorities of all serious and
p.000534: unexpected side effects of the drug.
p.000534: 5.17.2. These emergency reports should comply with applicable laws and ICH's Clinical Safety Information Management Guidelines:
p.000534: Definitions and standards for emergency reporting.
p.000534: 5.17.3. The contracting authority shall provide the competent authorities with all new safety data and periodic reports in accordance with the applicable legal requirements
p.000534: regulations.
p.000534: 5.18. Observation
p.000534: 5.18.1. Purpose
p.000534: The purpose of observing a test is to verify that:
...
p.000534: (a) For the purpose of carrying out supervision, the contracting authority shall appoint persons who are not dependent on the clinical trial.
p.000534: (b) The contracting authority shall ensure that persons are properly qualified by their education and experience to carry out the supervision properly. It should exist
p.000534: records of the qualifications of the supervisor.
p.000534: 5.19.3. Control procedure
p.000534: (a) The contracting authority should ensure that clinical trial supervision is conducted in accordance with the contracting authority's written provisions as to what should be monitored;
p.000534: how to conduct surveillance, how often, and what form and content of surveillance reports should be.
p.000534: (b) The contracting authority's plan and procedures for examining the test should take into account the importance of testing to resolve the request submitted to the competent authorities, no.
p.000534: test subjects, the type and complexity of the test, the level of risk for the respondents, and any problems identified.
p.000534: (c) The observations and findings of the person supervising should be documented.
p.000534: (d) In order to preserve the independence and value of the controls, inspection by the competent authorities of the surveillance report need not be part of the ordinary procedure. Competent authorities
p.000534: may request access to a case-by-case monitoring report when there is evidence of a serious departure from good clinical practice,
p.000534: that is, during court proceedings.
p.000534: (e) Where required by applicable law or regulation, the contracting authority shall provide a certificate of inspection.
p.000534: 5.20. Non-compliance
p.000534: 5.20.1. In case of non-compliance with the Examination Plan, standard operating procedures, good clinical practice and / or applicable legislation by
p.000534: the examiner / institution or the contracting authority's staff, the contracting authority must respond promptly to ensure compliance.
p.000534: 5.20.2. If serious and / or regular non-compliance by the examiner / institution is identified in the monitoring and / or monitoring process, the contracting authority should terminate
p.000534: his participation in the examination. If the examiner / institution ceases to participate due to non-compliance, the contracting authority must immediately do so
p.000534: inform the competent authorities.
p.000534: 5.21. Premature termination or termination of examination
p.000534: If an early termination or termination of testing occurs, the contracting authority should immediately inform the examiner / institution and the competent authorities and
p.000534: state the reasons for its termination or termination. It is also necessary to notify the Commission immediately and state the reasons for termination, respectively
p.000534: termination of examination by the client or examiner / institution, in accordance with the applicable legal regulations.
...
p.000534: 6.7.2. Methods and schedule for evaluating, recording and analyzing performance parameters.
p.000534: 6.8. Security rating
p.000534: 6.8.1. List of drug safety parameters.
p.000534: 6.8.2. Methods and schedule for assessing, recording and analyzing security parameters.
p.000534: 6.8.3. Procedures for recording and reporting adverse events and emerging diseases.
p.000534: 6.8.4. Form and duration of follow-up of the respondent after the adverse event.
p.000534: 6.9. Statistical processing
p.000534: 6.9.1. Description of the statistical methods, including a schedule of any interim analyzes for the duration of the test.
p.000534: 6.9.2. Number of planned respondents. In multicenter trials, the intended number of subjects for each test site should be indicated. The reason
p.000534: for the selection of a particular sample (number of subjects), including considerations (calculations) of the significance of the trial and its clinical justification.
p.000534: 6.9.3. Significance level to be used in statistical processing.
p.000534: 6.9.4. Criteria for completing the examination.
p.000534: 6.9.5. Procedures for recording missing, unused, and false data.
p.000534: 6.9.6. Procedures for reporting deviations from the original statistical plan (all deviations from the original statistical plan should also be described
p.000534: justify in the Test Plan and / or Final Report).
p.000534: 6.9.7. Selection of subjects for analysis (eg all subjects selected by random selection, all subjects who received the drug, all respondents who
p.000534: meet the criteria for participation in the study, respondents who report a measurable response to treatment).
p.000534: 6.10. Direct access to original data / documents
p.000534: The test client shall ensure that the Test Plan or other written agreement clearly states that the examiner / institution will allow observation and monitoring.
p.000534: examinations, evaluation by the Commission and inspections by the competent authorities, by providing access to original data / documents.
p.000534: 6.11. Quality assurance and quality control procedures
p.000534: 6.12. Ethical issues
p.000534: Description of ethical considerations related to the examination.
p.000534: 6.13. Data handling and record keeping
p.000534: 6.14. Financing and insurance
p.000534: Financing and insurance, unless regulated by a separate agreement.
p.000534: 6.15. Publication policy
p.000534: Policy on the publication of test results, unless regulated by a separate agreement.
p.000534: 6.16. Appendices to the Clinical Trial Plan
p.000534: (Note: Because the Study Plan and Clinical Trial / Study Report are very close, additional information on this can be found in the ICHs
p.000534: Guidelines for the design and content of clinical trial reports.)
p.000534: 7. INSTRUCTIONS TO THE TESTOR
p.000534: 7.1. Introduction
p.000534: The examiner's instructions are the sum of the clinical and preclinical information on the product under test that is important for its testing in humans. The purpose of these Instructions is
p.000534: to provide examiners and other persons participating in the examination with information that facilitates understanding and facilitates adherence to many important
p.000534: clinical trial plan items such as dosage, frequency and route of administration, and procedures for monitoring drug safety. The instructions also provide insight into
p.000534: clinical procedures with the subject for the duration of the clinical trial. While avoiding product promotion, information should be presented in a concise, simple,
p.000534: an objective and balanced manner that enables the clinician or examiner to fully understand and independently make an objective risk assessment and
...
p.000534: (see 8.2.10.) X X
p.000534: CONDUCTING TESTING
p.000534: 8.3.6. NORMAL VALUES / RANGE SUPPLEMENTS
p.000534: DOCTORAL / LABORATORY / TECHNICAL VALUES Document the revised normal values and their ranges over time
p.000534: X X
p.000534: PROCEDURES AND / OR TESTS PROVIDED FOR INVESTMENT PLAN (see 8.2.11).
p.000534: TESTING
p.000534: X
p.000534: 8.3.7. PHYSICAL / LABORATORY / TECHNICAL ADDITIONS
p.000534: Document the suitability of tests for the duration of the test (see 8.2.12.). X
p.000534: PROCEDURES / TESTS
p.000534: (where necessary)
p.000534: - confirmation or
p.000534: - authorization or
p.000534: - established quality control and / or external quality assessment or
p.000534: - other form of validation (where necessary)
p.000534: 8.3.8. DOCUMENTATION OF SHIPMENT OF THE TESTED PRODUCT
p.000534: (see 8.2.15.) X X
p.000534: AND TEST MATERIAL
p.000534: 8.3.9. CERTIFICATES OF ANALYSIS OF NEW SERIES TESTED
p.000534: (see 8.2.16.) X
p.000534: PRODUCTS
p.000534: 8.3.10. MONITORING REPORTS AFTER VISIT TO DOCUMENT Documentation of observation findings during site visit
p.000534: X
p.000534: CONDUCTING TESTING TESTING.
p.000534: Document agreements and important discussions regarding administration, breach
p.000534: 8.3.11. COMMUNICATION OUTSIDE THE VISIT OF THE PLACE
p.000534: provision of Test Plan, Test Execution, Reporting of Harmful X X
p.000534: TESTING
p.000534: events.
p.000534: - letters / letters
p.000534: - meeting notes
p.000534: - telephone conversation notes
p.000534: Document that the respondent gave his or her consent in accordance with Good Clinical
p.000534: 3/8/12 SIGNATURE DECLARATIONS CONCERNED with the practice and the Examination Plan prior to its participation in the examination. With that X
p.000534: document permission for direct access to data (see 8.2.3).
p.000534: Document the existence of respondents and prove the integrity of the collected
p.000534: 3/8/13 ORIGINAL DOCUMENTS of test data. Include original documents related to testing, X
p.000534: treatment and medical history of the subjects.
p.000534: Document that the examiner or the examiner's authorized staff confirmed X
p.000534: 3/8/14 FILLED, SIGNED AND DATED TEST SHEET X (copy)
p.000534: recorded observations. (original)
p.000534: Document any changes / corrections or corrections to the test sheet after entering X
p.000534: 3/8/15 TEST SHEET X DOCUMENTATION (copy)
p.000534: initial data. (original)
p.000534: 3/8/16 NOTICE OF DANGEROUS EVENTS
p.000534: ASSOCIATED REPORTS SUBMITTED BY AN EXAMINER TO NOTIFY NOTIFICATIONS OF SERIOUS ADVERSE EVENTS AND ASSOCIATED REPORTS
p.000534: X X
p.000534: shall submit to the contracting authority the examination in accordance with Section 4. 11. of the Guidelines.
p.000534: TO THE ORDERING TEST
p.000534: 3/8/17 NOTICE OF Unexpected DANGER Notices of unexpected serious side effects, or other information on
p.000534: ADVERSE REVIEWS AND OTHER INFORMATION ON THE SAFETY OF THE MEDICINAL PRODUCT The safety of the medicinal product submitted to the competent X (where
p.000534: X
p.000534: WHICH THE TEST ORDER AND / OR TESTER PROVIDES TO THE AUTHORITIES AND THE COMMISSION IN ACCORDANCE WITH SECTION 5.17. and paragraph 4.11.1, as applicable)
p.000534: TO THE COMPETENT AUTHORITIES paragraphs 5.16.2. and 4.11.2. Guideline.
p.000534: 3/8/18 SAFETY NOTES SUBMITTED BY THE CONTRACTING AUTHORITY The safety notices provided by the contracting authority to the examiner in accordance with
p.000534: X X
p.000534: TESTS THE TESTS TO THE TESTOR paragraph 5.16.2. Guideline.
...
p.000534: Test procedures, state any required deviations from normal practice
p.000534: Risk assessment, foreseeable treatment risks and procedures to be used (including possible pain, discomfort, integrity violation and ways of avoidance
p.000534: and / or the management of unforeseen / adverse events)
p.000534: Previous experience in conducting similar procedures in the legal entity (s) where the clinical trial will be conducted:
p.000534: Predicted benefits for the respondent
p.000534: Describe the relationship between the respondent and the researcher (eg patient-doctor of medicine, student-teacher, etc.)
p.000534: Procedures to check whether a potential respondent is participating in another clinical trial at the same time or that sufficient time has elapsed
p.000534: having previously participated in a clinical trial (especially important when it comes to including healthy subjects in clinical trials):
p.000534: Procedures used to protect the privacy of recorded data, source documents, or samples:
p.000534: Treatment or care plan after completing clinical trial participation (who will be responsible and where to administer):
p.000534: Statistical considerations and reasons for including a specified number of subjects in a clinical trial
p.000534: Amount and procedure for reimbursement to respondents (amount and description of expenses paid during examinations, eg travel expenses, lost earnings,
p.000534: compensation for pain and discomfort, etc.):
p.000534: Rules for termination (or early termination) of a clinical trial in a legal entity (or persons) where the clinical trial will be conducted:
p.000534: Contract on access to data by examiners, principles of publication of results, etc. (unless specified in clinical trial plan):
p.000534: Funding sources (if not provided in the clinical trial plan) and information about the examiner's financial or other interests.
p.000534: Clinical trial observer:
p.000534: Responsible for the clinical trial by the applicant / client for the clinical trial
p.000534: Date:
p.000534: Signature:
p.000534: * meets MIZ
p.000534: ANNEX IV.
p.000534: Application form for submission to the Central Ethics Committee of the opinion on the admissibility of a clinical trial of a medicinal product
p.000534: - completed by the clinical trial client or the applicant responsible for the accuracy of the information provided
p.000534: - The Chief Examiner only signs the informed consent by signing his signature
p.000534: Clinical trial client:
p.000534: Applicant for clinical trial:
p.000534: SEP - Registration number
p.000534: EUDRACT number
p.000534: Date of receipt of complete documentation
p.000534: A. General information
p.000534: Test name, label
p.000534: Clinical trial phase (I, II, III, IV.)
p.000534: version and date of test plan
p.000534: Examiner brochure (version and date)
p.000534: Informed Consent ((Version and Date)
p.000534: Insurance document Policy number, date of issue, duration of insurance
p.000534: Certificate of payment of the fee
p.000534: Test Summary (Version and Date) According to the SEP Special Form
p.000534: B. Information on examiners
p.000534: Chief Examiner in the Republic of Croatia
p.000534: Address *
p.000534: Phone and fax
p.000534: e-mail
p.000534: Chief Examiner
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p.000534: (g) Predictable risks and discomforts for the respondent, namely the embryo, fetus or infant;
p.000534: (h) Benefits to be expected. Where no clinical benefit is expected for the respondent, it should be made known to the respondent;
p.000534: (i) Alternative procedures, ie treatment options available to the respondent, and the risks and benefits they may bring to the respondent;
p.000534: (j) Compensation and / or treatment provided to the respondent in the event of an injury resulting from his participation in the examination;
p.000534: (k) Expected timetable for payment of installments of any compensation to respondents for participation in the examination;
p.000534: (l) Any expected costs for the respondent for participating in the examination;
p.000534: (m) that the respondent's participation in the examination is voluntary and that the respondent may refuse to participate in the examination or withdraw from it at any time,
p.000534: without being punished or losing the rights he otherwise exercises;
p.000534: (n) That the observer (s), the persons supervising (s), the Commission and the competent authorities will have direct access to the respondent's original health information for the sake of
p.000534: validation of clinical trial procedures and data obtained, with full protection of the confidentiality of the respondents' identities within the limits of applicable laws and regulations, as well as
p.000534: that the respondent or his / her legal representative expresses his / her consent to such access to information by signing the statement of consent;
p.000534: (o) That the personal data of the respondents will be kept confidential and, within the limits of applicable laws and / or regulations, will not be made available to the public. If results are published
p.000534: questioning, the identity of the respondents will remain secret;
p.000534: (p) That the respondent or his / her legal representative will be informed in a timely manner of new findings that may affect the respondent
p.000534: willingness to continue to participate in the examination;
p.000534: (q) Name of contact person for information related to the examination and rights of respondents, as well as name of contact person for possible injury arising from participation in
p.000534: examination;
p.000534: (r) the foreseeable circumstances and / or reasons why the respondent may terminate his / her participation in the examination;
p.000534: (s) The expected duration of the respondent's participation in the examination;
p.000534: (t) Indicative number of respondents envisaged for examination.
p.000534: 4.8.11. Before entering the examination, the respondent or his / her legal representative should receive a copy of the signed and dated statement of consent, as well as
p.000534: other written notices intended for the respondents. During the examination, the respondent or his / her legal representative is required
p.000534: receive signed and dated copies of updated statements of consent, as well as copies of amendments to notices intended for respondents.
p.000534: 4.8.12. When a clinical trial (whether therapeutic action is expected or not) involves subjects whose consent is required
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Social / Age
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p.000534: conducted preclinical research. In discussing the results, we should refer to the absorption and local and systemic bioavailability of the test product and
p.000534: its metabolites, as well as their relationship with pharmacological and toxicological findings in animal species.
p.000534: (c) Toxicology
p.000534: Where appropriate, a concise description of the observed toxic effects in different species of animals should follow this structure:
p.000534: - Single dose;
p.000534: - Repeated dose;
p.000534: - Carcinogenicity;
p.000534: - Specific research (eg irritation and sensitization);
p.000534: - Reproductive toxicity;
p.000534: - Genotoxicity (mutagenicity).
p.000534: 7.3.6. Effects on humans
p.000534: Introduction:
p.000534: The known effects of the test product on humans should be thoroughly discussed, including information on its pharmacokinetics, metabolism,
p.000534: pharmacodynamics, dose dependence, safety, efficacy (efficacy) and other pharmacological actions. Wherever possible
p.000534: is to provide a summary of all completed clinical trials. Also, information regarding the application of the product under test should be provided outside
p.000534: clinical trials, such as post-marketing experience.
p.000534: (a) Pharmacokinetics and metabolism of the test product in humans
p.000534: - the pharmacokinetics of the test product should be summarized, including the following available data:
p.000534: - pharmacokinetics (including metabolism and absorption, plasma protein binding, distribution and elimination);
p.000534: - bioavailability of the test product (absolute and relative where possible) using the reference preparation;
p.000534: - population subgroups (eg by sex, age and impaired organ function);
p.000534: - interactions (eg drug interactions and the impact of food);
p.000534: - other pharmacokinetic data (eg results of population-based studies conducted in clinical trials).
p.000534: (b) Safety and efficiency
p.000534: Summary information on the safety, pharmacodynamics, efficacy (efficacy) and dose dependency of the product under test (including
p.000534: its metabolites) from previous human studies (healthy volunteers and / or patients). The significance of this data needs to be discussed. Where it is
p.000534: completed multiple clinical trials, summary summaries of safety and efficacy results by subgroup indications may provide
p.000534: clear data presentation. It would be useful to summarize into the tables all the side effects of the drug (for all indications tested) observed in all clinical trials.
p.000534: Significant differences in side effects by indications and subgroups of subjects need to be discussed.
p.000534: Instructions for the examiner should describe the expected risks and side effects of the drug based on previous experience with the product tested and related drugs.
p.000534: Also, precautions and special monitoring should be indicated as an integral part of the application of the test product.
p.000534: (c) Experience after placing the test product on the market
p.000534: The instructions must indicate the countries in which the test product was approved or placed on the market. A summary of all important information should be provided
...
p.000534: 1.2. Starting point
p.000534: ICH documents relevant to child testing include:
p.000534: E2: Manage innocuous data
p.000534: E3: Compilation and content of clinical trial reports
p.000534: E4: Dose efficacy data on drug registration
p.000534: E5: Ethnic factors affecting the acceptance of clinical data from other countries
p.000534: E6: Good clinical practice: integrated guidelines
p.000534: E8: General considerations related to clinical trials
p.000534: E9: Statistical principles applicable in clinical trials
p.000534: E10: Selection of control group for clinical trial
p.000534: M3: Preclinical safety testing of pharmaceutical products for clinical trials in humans
p.000534: Q1: Stability testing
p.000534: Q2: Validation of analytical procedures
p.000534: Q3: Impurity testing
p.000534: 1.3. Scope of the Guidelines
p.000534: This guideline covers the following issues related to clinical trials in children: (1) considerations regarding the introduction of a drug testing program in children
p.000534: children; (2) planning the start of testing in children with respect to the developmental phase of the drug; (3) types of testing (pharmacokinetics,
p.000534: pharmacokinetics / pharmacodynamics, efficacy, safety); (4) age groups and (5) ethical justification for clinical trials in children. The intention
p.000534: these guidelines do not provide a detailed overview of all issues; these are further elaborated in other ICH guidance and regulatory documents
p.000534: bodies and pediatric associations of individual countries.
p.000534: 1.4. General principles
p.000534: Children should only receive medicines that have been properly tested and evaluated for use in children. For safe and effective treatment
p.000534: children need timely knowledge of the proper use of medicines in children of different ages, and often the development of formulations that are appropriate
p.000534: for use in children. Advances in formulation chemistry and the development of a test plan for children will facilitate the development of medicines for use in children. In general
p.000534: when it comes to medicines for the illnesses or problems of adults that are expected to be applied to children, their development programs should
p.000534: include the child population. One important goal is to learn about the effects of medicines on sick children. However, this goal should not be reached
...
p.000534: country health and health care. From the very beginning of drug development, it is clear from time to time with regulatory authorities
p.000534: de nition when the start and approach of the clinical trial program are justified. The drug development program for children should not delay completion
p.000534: trials of the drug for use in adults and thus its availability to adult patients.
p.000534: The decision to implement a drug development program for use in children and the nature of the program depend on many factors, including these:
p.000534: • the prevalence of the illness to be treated in children,
p.000534: • the severity of the illness to be treated in children,
p.000534: • the existence / availability and appropriateness of other forms of treatment, including their efficacy and side effects (including all specific
p.000534: pediatric safety considerations),
p.000534: • whether the drug is new or belongs to a group of compounds whose properties are known,
p.000534: • if there are specific pediatric indications for the use of the drug,
p.000534: • the need to define specific pediatric parameters,
p.000534: • the age range of children in which the drug is most likely to be used,
p.000534: • specific pediatric (developmental) questions about the safety of the drug, including any pre-clinical issues,
p.000534: • the possible need to develop a new formulation for children.
p.000534: The most important among these factors is the presence of a serious, or life-threatening, illness in which administration of the test drug may signify an important
p.000534: advances in treatment. In these cases, it is necessary to initiate a relatively rapid investigation of the drug in children.
p.000534: Considerations of data from preclinical safety studies of medicinal products relevant to clinical trials in children are described in ICH document M3,
p.000534: Section 11. It should be noted that the most relevant safety data for children are obtained from adult exposure studies.
p.000534: In general, repeated dose toxicity tests and reproductive and genotoxicity studies should be performed. Consideration should also be given to
p.000534: the need for individual developmental toxicology studies in young animals on a case by case basis.
p.000534: 2.2. Formulations for children
...
p.000534: the request for marketing should also include information on its use in children.
p.000534: The possible absence of this information should be explained in detail. Therefore, it is important to carefully weigh the possible before starting a drug test in children
p.000534: the benefit, risk of treatment and the need for its introduction.
p.000534: 2.4. Types of testing
p.000534: The principles outlined in ICH documents E4, E5, E6 and E10 also apply to testing in children. There are several issues that are specific to children.
p.000534: When examining a medicine in children in a country or region, internal (eg pharmacogenetic) and external factors should be taken into account 1 [1] [1]
p.000534: (e.g., nutrition) that may affect the application of results in another country or region.
p.000534: The efficacy data for the indications tested and approved in adults may be applicable to children for the same indications if
p.000534: the development of the disease and the likelihood of treatment outcome are similar in the two populations. In this case, pharmacokinetics testing in all age groups of children
p.000534: receiving the drug and these harmless studies may provide sufficient data for administration through pediatric doses that will lead to drug levels in
p.000534: blood similar to those seen in the adult population. If the test is approached in this way, it is necessary to have data in order to plan tests in children
p.000534: on the pharmacokinetics of the drug in adults.
p.000534: Elderly drug efficacy data may prove applicable to younger children for the same indications if disease development and likelihood are
p.000534: treatment outcomes similar in the two age groups. In this case, pharmacokinetics testing in appropriate age groups of children receiving the drug
p.000534: these safety tests may provide sufficient data for the administration of the drug to children.
p.000534: A pharmacokinetic-based approach is unlikely to be sufficient for drugs known or expected to be inappropriate for blood levels
p.000534: their efficacy, ie the dose-response relationship is assumed to be different between adults and children.
p.000534: In this case, a clinical and pharmacological effect study is expected to be conducted. Where a similar course or outcome of the disease is to be expected
p.000534: between children and adults, but where appropriate levels of the drug are unknown in the blood, to confirm its efficacy and to determine dose and concentration
p.000534: it is possible to measure the pharmacodynamics of the drug with respect to its clinical efficacy. These tests reinforce the confidence that certain
p.000534: drug exposure may lead to the desired outcome in children. So by examining pharmacokinetics and pharmacodynamics, harmlessness and other important
p.000534: factors may be avoided by clinical trials of the efficacy of the drug in children.
p.000534: Where pharmacokinetics cannot be applied, as with topical medicinal products, the administration of results from one group of patients to another may
p.000534: be based on studies incorporating pharmacodynamic parameters and / or other appropriate studies. The need for
p.000534: by examining drug delivery at the application site. To evaluate the harmlessness of a drug, it may also be important to determine its level in the blood and systemic
p.000534: effects.
p.000534: Whether these are new indications for the use of the drug in children, or whether different course of illness and outcome of treatment between adults and children are expected,
p.000534: clinical trials on the efficacy of the drug in children should be performed.
p.000534: 2.4.1. Pharmacokinetics
p.000534: Pharmacokinetic studies are mainly performed to verify the newly developed formulation and to determine pharmacokinetic parameters for various
p.000534: age groups supporting the recommended doses.
p.000534: Comparisons of relative bioavailability between formulations for children and oral formulations for adults should be performed on adults. It's on the kids
p.000534: final pharmacokinetic studies should be conducted to determine the appropriate dose for each age group of children
p.000534: drug intended.
p.000534: In general, pharmacokinetic studies are performed on ill children. This may mean greater heterogeneity among subjects than in healthy subjects
p.000534: volunteers, but the data obtained better reflects clinical application.
p.000534: In the case of medicinal products exhibiting linear pharmacokinetics in adults, single use in pharmacokinetic studies in children
p.000534: may provide sufficient knowledge for dose selection.
p.000534: If necessary, this choice can be confirmed by occasional sampling in repeated dose clinical trials. Any
p.000534: nonlinearity in the absorption, distribution and elimination of the drug and any difference in the time of action between single and multiple dose in adults
p.000534: points to the need to test a drug in children when its dynamic balance is reached. Performing all of these procedures makes it easy to see
p.000534: pharmacokinetic parameters in adults. Knowledge of drug elimination pathways can often prove useful in planning trials in children
p.000534: (via the kidney and metabolism) and age-dependent changes in these processes.
p.000534: For most medicines, the recommended doses for children are based on milligrams per kilogram body weight (mg / kg) and range up to the highest adult dose.
p.000534: Although the first choice may be a dosage based on mg / m2 of body surface area, clinical experience indicates that frequent errors in height measurement or
p.000534: length (especially young children and infants), as well as in calculating the body surface area from these measurements. It is important to administer some medications on a physical basis
p.000534: surfaces (eg drugs with a narrow therapeutic index such as oncology), but extra caution should be exercised to calculate the amount
p.000534: correct.
p.000534: Practical considerations facilitating the conduct of pharmacokinetic studies
p.000534: The blood volume taken from children should be as small as possible. It must be justified within the protocol. Clinical Trials Board / Independent Ethics
p.000534: Committees (Committees) consider and may determine the highest amount of blood (usually in milliliters per kilogram (mL / kg), or as a percentage of
p.000534: total blood volume) that can be taken for testing. There are several ways to minimize blood sampling and vein injection
p.000534: a possible measure.
p.000534: • Using sensitive assays for the drug and its metabolites that require lower blood volume in the sample.
p.000534: • Involvement of laboratories with experience in the processing of low blood volume samples for pharmacokinetic and safety analysis (blood tests, clinical
p.000534: chemistry).
p.000534: • Collecting regular blood samples for both clinical and pharmacokinetic analysis whenever possible.
p.000534: • Using a permanent catheter, etc. to minimize discomfort as discussed in Section 2.6.5.
p.000534: • Applying population pharmacokinetics and sparse sampling based on optimal sampling settings to sample number
p.000534: taken from each patient to a minimum. Sampling techniques include:
p.000534: • Rare sampling in which each patient participates with 2 to 4 tests in a predetermined time in the total population covered
p.000534: "The area under the curve."
p.000534: • Analyzing population pharmacokinetics and planning the most optimal sampling schedule according to the adult model.
p.000534: 2.4.2 Effectiveness
p.000534: Principles of test planning, statistical processing and selection of control groups described in ICH documents ICH E6, E9 and E10, largely
p.000534: also valid for drug efficacy studies in children. However, some details are unique to pediatric trials. In Section 2.4. is discussed about
p.000534: the applicability of the results of efficacy tests in adults to children or trials in older children to young people. Where Performance Tests Are
p.000534: Necessary, it is necessary to develop, validate and apply different parameters for different age and development groups. For subjective symptoms such as pain
p.000534: different measuring instruments are needed, appropriate for each age group of patients. In children with chronic illness, the answer to the drug may be
p.000534: uneven, not only because of the duration of the disease and its chronic effects, but also because of the stage of development in which the patient is present. There are many diseases
p.000534: preterm infants and newborns are unique to these groups or their manifestations are unique, making it impossible to apply the results
p.000534: the effectiveness of the drug on older children and requires new methods of evaluating treatment outcomes.
p.000534: 2.4.3. The harmlessness of the drug
p.000534: The guidelines in ICH documents E2 and E6 describing the recording of adverse reactions also apply to testing in children. It is necessary to record side effects
p.000534: rely on normal laboratory values and clinical measurements that are adjusted to the child's age. Accidental exposure to the drug (accidentally swallowed
p.000534: , etc.) provides an opportunity to obtain additional information on the safety and pharmacokinetics of the drug and to gain a better understanding of the relationship of side effects with the dose.
p.000534: Medications can affect physical and mental development, and children may differ in their experience of side effects. Because developing organisms
p.000534: they may respond differently to treatment from mature organisms, some side effects and interactions with other medicines observed in children may not occur and
p.000534: in adults. In addition, due to the dynamics of growth and development, some side effects may not occur acutely, but at a later stage of development and maturation. Do they want to
p.000534: identify potential effects on skeletal maturation and development, behavior, cognitive function, sexual organs and the immune system may be needed
p.000534: long-term testing of children on chronic treatment or their long-term follow-up after treatment.
p.000534: 2.4.4. Findings after placing the medicine on the market
p.000534: Usually, when obtaining a marketing authorization, the knowledge is limited. Therefore, it is especially important to monitor children after drug release
p.000534: into circulation. It is sometimes important to carry out long-term monitoring to determine the effects of certain drugs on the growth and development of children. Post-placement monitoring
p.000534: drug and / or long-term testing may provide insight into the harmlessness and / or efficacy of the drug to particular groups of children, or
p.000534: additional knowledge regarding the overall child population.
p.000534: 2.5. Division of children by age
p.000534: Any division of children by age is somewhat arbitrary, but can be a starting point for thinking about a test plan for children. For deciding how
p.000534: to distribute tests and data according to the age of the child, developmental biology and pharmacology should be kept in mind. Therefore, a flexible approach is needed which
p.000534: will ensure the presence of the latest findings in pediatric pharmacology in studies. The choice of age to test should depend on the particular drug and is valid
p.000534: substantiate with good reasons.
p.000534: If the routes of drug elimination and their maturation (ontogenesis) are known, the division into age ranges for pharmacokinetic evaluation may start from
p.000534: "Milestones" that bring about significant changes in elimination.
p.000534: It is sometimes more appropriate to collect data on children across a wider age range and to examine the impact of age as a constant covariate. Different parameters
p.000534: the efficacy of the drug may be varied for different age groups, and this division may not correspond to the one shown below. Dividing the population into many
p.000534: age groups may unnecessarily increase the number of children participating in the study. In the case of longer-term trials, children may switch from
p.000534: from one age group to another, and the test plan and statistical analysis must predict changes in the number of patients in a given age group.
p.000534: Below, one of the age groups is offered. However, there is significant overlap in development across all groups (e.g.,
p.000534: cognitive, psychosocial). Age is defined by days, months or years.
p.000534: • Newborns born before term (premature infants)
p.000534: • Newborns born within term (0 - 27 days, newborn born)
p.000534: • Children aged 28 days to 23 months (infants and young children)
p.000534: • Children aged 2 to 11 years
p.000534: • Adolescents (12 to 16-18 years, depending on country)
p.000534: 2.5.1. Newborns born before term (premature infants)
p.000534: The study of premature infants raises special questions, since both the pathology and the response to treatment are unique to this group. Complexity
p.000534: tests in preterm infants and related ethical issues indicate the need for careful protocol design in collaboration with neonatologists and neonatal
p.000534: pharmacologists. Only in rare cases will it be possible to apply the results of efficacy obtained in adults and even older children to premature babies.
p.000534: Newborns as an age group are not homogeneous. There is a big difference between having a baby weighing 500g born at week 25 and 1,500g
p.000534: premature infant born at 30 weeks gestation.
p.000534: It is also important to distinguish whether children with low birth weight are immature or with stunted growth.
p.000534: It is important for these patients to consider the following features: (1) gestational and postnatal age (adjusted age); (2) immaturity of elimination mechanisms
p.000534: via the kidney and liver; (3) problems with protein binding and displacement (especially bilirubin); (4) penetration of the drug into the central nervous system (CNS); (5)
p.000534: health conditions unique to the newborn (eg respiratory stress syndrome, patent ductusarteriosus, primary pulmonary hypertension);
p.000534: (6) preferences inherent in preterm infants (eg, propensity for necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of preterm infants); (7) quickly
p.000534: and unequal maturation of all the biological and pharmacological processes, which necessitates a change in dosage regimen upon long-term drug exposure; and (8)
p.000534: absorption of the drug and other chemical compounds through the skin.
p.000534: Issues to consider in exam planning include: (1) division by body weight and age (gestational and postnatal); (2) small volume
p.000534: blood (prematurely weighing 500 g has only 40 mL of blood); (3) the small number of such patients in a particular healthcare facility and the differences in their treatment among
p.000534: and (4) difficulties in evaluating treatment outcomes.
p.000534: 2.5.2. Newborn born within term (0 - 27 days, newborn born)
p.000534: Although newborns are born within the term mature in development from preterm infants, many of the more described zoological and pharmacological values apply to them
p.000534: settings. In these, the volume of drug distribution may differ from that of older children because of the different ratio of body fluid and fat and because
p.000534: high ratio of skin surface area to body weight. The blood-brain barrier is not yet fully mature, so drugs and endogenous substances (eg bilirubin) may
p.000534: penetrate the CSF and act toxic. Absorption of the drug after oral administration is less predictable than in older children. Elimination mechanisms
p.000534: through the liver and kidney are not yet mature and undergoing rapid changes; therefore, the dosage of the drug should be adjusted in the first weeks of the infant's life.
p.000534: There are many examples of newborn susceptibility to drug toxicity resulting from limited elimination (eg, aplastic anemia caused by
p.000534: chloramphenicol, eng. chloramphenicolgreybabysyndrome). On the other hand, a term-born infant is less sensitive to some side effects
p.000534: (e.g., nephrotoxicity ofaminoglycoside) from elderly patients.
p.000534: 2.5.3. Children aged 28 days to 23 months (infants and young children)
p.000534: At this age, the CSF matures rapidly, the immune system develops and the entire body grows. Absorption after oral administration is now more reliable. It goes on and on
p.000534: rapid maturation of elimination mechanisms via the liver and kidney. Computing in mg / kg, many drugs are eliminated faster in children 1 - 2 years of age than
p.000534: in adults.
p.000534: The developmental maturation pathway depends on specific elimination pathways. Differences in maturation among children are often noticeable.
p.000534: 2.5.4. Children aged 2 to 11 years
p.000534: Most elimination pathways (via liver and kidney) are now mature, and elimination is often greater than in adults. Changes in drug elimination can
p.000534: depend on the maturation of specific metabolic pathways.
p.000534: Appropriate strategies should be set out in the protocol to identify any effects of the drug on the growth and development of the child. There are several at this age
p.000534: a milestone in the psychomotor development of a child that can be adversely affected by drugs acting on the CSW. School attendance and higher cognitive and
p.000534: motor skills may affect a child's ability to participate in some performance tests. Factors useful for measuring performance
p.000534: drugs in children include skeletal growth, weight gain, school attendance, and school success.
p.000534: Selection of respondents should ensure adequate representativeness for the whole age group, since it is important to raise enough young people
p.000534: respondents.
p.000534: It is seldom necessary in this age group to further divide children by age, but it may prove appropriate to divide them according to
p.000534: pharmacokinetic and / or efficacy parameters.
p.000534: Entry into puberty is very uneven among children and occurs earlier in girls, in which it is normal since the age of 9. Puberty can make an impact
p.000534: to the action of drug-degrading enzymes, so, counting in mg / kg, drastic reductions in the dosage of some drugs (eg teo lina) are sometimes necessary. U
p.000534: in some cases, it is better to specifically examine the impact of puberty on drug behavior by comparing children before they reach puberty
p.000534: puberty. In the second case, it is more appropriate to monitor the rates of pubertal development according to Tanner or to collect biological indicators of puberty and
p.000534: study the potential impact of changes in puberty.
p.000534: 2.5.5. Adolescents (12 to 16-18 years old, depending on country)
p.000534: This is the age of sexual maturation, and drugs can clash with the action of sex hormones and prevent development.
p.000534: In some studies, it is advisable to take a pregnancy test and monitor the sexual activity and contraceptive use of the subjects.
p.000534: This is also a period of accelerated physical growth and continued development of neurocognitive functions. Medicines and diseases that slow or accelerate entry into
p.000534: puberty can have a profound effect on pubertal growth and therefore the final height of the patient. Gradual changes in the cognitive and emotional realms can
p.000534: influence the outcome of clinical trials.
p.000534: Many diseases are also affected by hormonal changes associated with puberty (eg, higher insulin resistance in diabetes mellitus, frequent occurrence
p.000534: epileptic seizures in the period around menarche, changes in the frequency and intensity of migraine and asthma attacks). Hormonal changes can also
p.000534: also influence the results of clinical trials.
p.000534: By entering this age group, adolescents take responsibility for their own health and treatment. Failure to follow the treatment regimen is here
p.000534: a specific problem, especially if drugs (eg steroids) affect appearance. It is very important to check that the subjects adhere to the treatment regimen in
p.000534: clinical trials.
p.000534: Particular attention should also be paid to the occasional use of non-prescribed medicines and to the consumption of alcohol and tobacco.
p.000534: The upper limit of this age group varies from country to country. Older adolescents may be involved in adult trials, though they may be
p.000534: difficulty adhering to the treatment regimen. Due to problems specific to adolescence, conducting tests may be appropriate
p.000534: (whether included in the adult test protocol or in a separate protocol) in healthcare settings with knowledge and experience in nursing
p.000534: of this patient population.
p.000534: 2.6. Ethical issues related to testing in children
p.000534: Children are a vulnerable group of respondents. It is therefore necessary to introduce specific measures to protect their rights in clinical trials and to prevent them
p.000534: exposure to unnecessary risk. The purpose of this section is to provide an ethical framework for conducting testing in children.
p.000534: For the clinical trial to be of benefit to its participants and other children, its plan must be such as to ensure the quality and clarity of the collected
p.000534: data. Respondents are also expected to benefit from the clinical trial, except in the special circumstances described in the ICH.
p.000534: document E6, section 4.8.14.
p.000534: 2.6.1. Clinical Trial Panel / Independent Ethics Committee (Committee)
...
p.000534: clinical trial, investigators must have complete insight into all preclinical and clinical data on drug toxicity. To take a risk in pediatric
p.000534: clinical trials minimized, the staff conducting them need to be well trained and experienced in testing with children, which
p.000534: it also involves identifying and treating possible side effects in children.
p.000534: When designing the test plan, every effort should be made to minimize the number of participants and procedures in the spirit of good test planning.
p.000534: Mechanisms need to be devised to quickly complete testing for unexpected hazards.
p.000534: 2.6.5. How to alleviate suffering as much as possible
p.000534: Frequent invasive procedures can hurt and scare a child.
p.000534: Uncomfortable feelings can be minimized if examinations are planned and conducted by examiners experienced in treating children.
p.000534: Testing protocols and procedures must be specifically designed for the pediatric population (not just adapted from adult protocols) and should be approved
p.000534: The Commission, as described in Section 2.6.1.
p.000534: Listed below are some practical assumptions that can contribute to a positive clinical trial experience and minimize feelings
p.000534: discomfort and suffering:
p.000534: • Staff with knowledge and experience in working with children and adjusting to their age, including experience in pediatric procedures.
p.000534: • Physical space with furniture, toys, daily activities and food adapted to the age of the children.
p.000534: • Conducting tests in a well-known environment such as a hospital or clinic where the subjects are otherwise receiving medical care.
p.000534: • Ways to reduce the discomfort associated with performing procedures such as:
p.000534: • local anesthesia before the introduction of an intravenous catheter,
p.000534: • use of permanent catheters instead of frequent veins in the blood to collect blood samples,
p.000534: • simultaneous collection of blood samples for protocol-defined purposes when routine clinical sampling is performed.
p.000534: The committee should consider how many veins in the vein are acceptable to obtain the blood samples prescribed by the protocol and make sure that
p.000534: understanding of procedures in the event that a permanent catheter becomes unusable over time. Respondent's right to refuse further participation must be respected
p.000534: in the test procedures, except in the case described in section 2.6.3.
p.000534: ANNEX III.
p.000534: APPLICATION FORM FOR THE APPROVAL OF THE MINISTER OF HEALTH CARE FOR CARRYING OUT THE CLINICAL TESTING OF MEDICINES IN THE REPUBLIC
p.000534: HRVATSKOJ
p.000534: - completed by the contracting authority or the applicant responsible for the accuracy of the information provided
p.000534: Clinical trial client:
p.000534: Applicant for clinical trial:
p.000534: * Date of receipt of the item:
p.000534: * Date of receipt of complete documentation:
p.000534: A. General information
p.000534: Test Name:
p.000534: Test Plan Designation
p.000534: EUDRACT number:
p.000534: Clinical trial phase (I, II, III, IV)
p.000534: List of countries in which clinical trials were approved and / or planned by the time the application was submitted to the ministry responsible for health
p.000534: implement
...
Social / Child
Searching for indicator child:
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p.000534: (where necessary)
p.000534: ANNEX II.
p.000534: European Medicines Agency
p.000534: Evaluation of medicines for human use
p.000534: London, 27 July 2000.
p.000534: CPMP / ICH / 2711/99
p.000534: ICH theme E 11
p.000534: CLINICAL TESTING OF MEDICINES IN CHILDREN
p.000534: Step 4 of the ICH Procedure
p.000534: GUIDELINES FOR CLINICAL TESTING OF MEDICINES IN CHILDREN (CPMP / ICH / 2711/99)
p.000534: Entry into force: January 2001.
p.000534: CLINICAL TESTING OF MEDICINES IN CHILDREN
p.000534: 1. INTRODUCTION
p.000534: 1.1. Objectives of the guideline
p.000534: The choice of medicines registered for use in children is currently limited. The aim of this guideline is to encourage and facilitate the timely development of medicines for children
p.000534: internationally. This guideline gives a brief overview of key issues related to the development of medicines for children and the different approaches to achieving them
p.000534: safe, successful and ethically sound drug trials in children.
p.000534: 1.2. Starting point
p.000534: ICH documents relevant to child testing include:
p.000534: E2: Manage innocuous data
p.000534: E3: Compilation and content of clinical trial reports
p.000534: E4: Dose efficacy data on drug registration
p.000534: E5: Ethnic factors affecting the acceptance of clinical data from other countries
p.000534: E6: Good clinical practice: integrated guidelines
p.000534: E8: General considerations related to clinical trials
p.000534: E9: Statistical principles applicable in clinical trials
p.000534: E10: Selection of control group for clinical trial
p.000534: M3: Preclinical safety testing of pharmaceutical products for clinical trials in humans
p.000534: Q1: Stability testing
p.000534: Q2: Validation of analytical procedures
p.000534: Q3: Impurity testing
p.000534: 1.3. Scope of the Guidelines
p.000534: This guideline covers the following issues related to clinical trials in children: (1) considerations regarding the introduction of a drug testing program in children
p.000534: children; (2) planning the start of testing in children with respect to the developmental phase of the drug; (3) types of testing (pharmacokinetics,
...
p.000534: these guidelines do not provide a detailed overview of all issues; these are further elaborated in other ICH guidance and regulatory documents
p.000534: bodies and pediatric associations of individual countries.
p.000534: 1.4. General principles
p.000534: Children should only receive medicines that have been properly tested and evaluated for use in children. For safe and effective treatment
p.000534: children need timely knowledge of the proper use of medicines in children of different ages, and often the development of formulations that are appropriate
p.000534: for use in children. Advances in formulation chemistry and the development of a test plan for children will facilitate the development of medicines for use in children. In general
p.000534: when it comes to medicines for the illnesses or problems of adults that are expected to be applied to children, their development programs should
p.000534: include the child population. One important goal is to learn about the effects of medicines on sick children. However, this goal should not be reached
p.000534: questioning the well-being of the child participating in the clinical trial. Responsibility for this is shared by pharmaceutical companies, regulatory bodies, healthcare
p.000534: workers and society at large.
p.000534: 2. GUIDELINES
p.000534: 2.1. Issues to consider when starting to develop a drug for use in children
p.000534: Information on the appropriate use of the medicine in children should be collected, except in the case of medicines whose use is inappropriate in children. In Section 2.3.
p.000534: planning the start of a clinical trial in relation to a trial in adult patients is discussed and may be influenced by the needs of the public
p.000534: country health and health care. From the very beginning of drug development, it is clear from time to time with regulatory authorities
p.000534: de nition when the start and approach of the clinical trial program are justified. The drug development program for children should not delay completion
p.000534: trials of the drug for use in adults and thus its availability to adult patients.
...
p.000534: Necessary, it is necessary to develop, validate and apply different parameters for different age and development groups. For subjective symptoms such as pain
p.000534: different measuring instruments are needed, appropriate for each age group of patients. In children with chronic illness, the answer to the drug may be
p.000534: uneven, not only because of the duration of the disease and its chronic effects, but also because of the stage of development in which the patient is present. There are many diseases
p.000534: preterm infants and newborns are unique to these groups or their manifestations are unique, making it impossible to apply the results
p.000534: the effectiveness of the drug on older children and requires new methods of evaluating treatment outcomes.
p.000534: 2.4.3. The harmlessness of the drug
p.000534: The guidelines in ICH documents E2 and E6 describing the recording of adverse reactions also apply to testing in children. It is necessary to record side effects
p.000534: rely on normal laboratory values and clinical measurements that are adjusted to the child's age. Accidental exposure to the drug (accidentally swallowed
p.000534: , etc.) provides an opportunity to obtain additional information on the safety and pharmacokinetics of the drug and to gain a better understanding of the relationship of side effects with the dose.
p.000534: Medications can affect physical and mental development, and children may differ in their experience of side effects. Because developing organisms
p.000534: they may respond differently to treatment from mature organisms, some side effects and interactions with other medicines observed in children may not occur and
p.000534: in adults. In addition, due to the dynamics of growth and development, some side effects may not occur acutely, but at a later stage of development and maturation. Do they want to
p.000534: identify potential effects on skeletal maturation and development, behavior, cognitive function, sexual organs and the immune system may be needed
p.000534: long-term testing of children on chronic treatment or their long-term follow-up after treatment.
p.000534: 2.4.4. Findings after placing the medicine on the market
p.000534: Usually, when obtaining a marketing authorization, the knowledge is limited. Therefore, it is especially important to monitor children after drug release
p.000534: into circulation. It is sometimes important to carry out long-term monitoring to determine the effects of certain drugs on the growth and development of children. Post-placement monitoring
p.000534: drug and / or long-term testing may provide insight into the harmlessness and / or efficacy of the drug to particular groups of children, or
p.000534: additional knowledge regarding the overall child population.
p.000534: 2.5. Division of children by age
p.000534: Any division of children by age is somewhat arbitrary, but can be a starting point for thinking about a test plan for children. For deciding how
p.000534: to distribute tests and data according to the age of the child, developmental biology and pharmacology should be kept in mind. Therefore, a flexible approach is needed which
p.000534: will ensure the presence of the latest findings in pediatric pharmacology in studies. The choice of age to test should depend on the particular drug and is valid
p.000534: substantiate with good reasons.
p.000534: If the routes of drug elimination and their maturation (ontogenesis) are known, the division into age ranges for pharmacokinetic evaluation may start from
p.000534: "Milestones" that bring about significant changes in elimination.
p.000534: It is sometimes more appropriate to collect data on children across a wider age range and to examine the impact of age as a constant covariate. Different parameters
p.000534: the efficacy of the drug may be varied for different age groups, and this division may not correspond to the one shown below. Dividing the population into many
p.000534: age groups may unnecessarily increase the number of children participating in the study. In the case of longer-term trials, children may switch from
...
p.000534: 2.5.3. Children aged 28 days to 23 months (infants and young children)
p.000534: At this age, the CSF matures rapidly, the immune system develops and the entire body grows. Absorption after oral administration is now more reliable. It goes on and on
p.000534: rapid maturation of elimination mechanisms via the liver and kidney. Computing in mg / kg, many drugs are eliminated faster in children 1 - 2 years of age than
p.000534: in adults.
p.000534: The developmental maturation pathway depends on specific elimination pathways. Differences in maturation among children are often noticeable.
p.000534: 2.5.4. Children aged 2 to 11 years
p.000534: Most elimination pathways (via liver and kidney) are now mature, and elimination is often greater than in adults. Changes in drug elimination can
p.000534: depend on the maturation of specific metabolic pathways.
p.000534: Appropriate strategies should be set out in the protocol to identify any effects of the drug on the growth and development of the child. There are several at this age
p.000534: a milestone in the psychomotor development of a child that can be adversely affected by drugs acting on the CSW. School attendance and higher cognitive and
p.000534: motor skills may affect a child's ability to participate in some performance tests. Factors useful for measuring performance
p.000534: drugs in children include skeletal growth, weight gain, school attendance, and school success.
p.000534: Selection of respondents should ensure adequate representativeness for the whole age group, since it is important to raise enough young people
p.000534: respondents.
p.000534: It is seldom necessary in this age group to further divide children by age, but it may prove appropriate to divide them according to
p.000534: pharmacokinetic and / or efficacy parameters.
p.000534: Entry into puberty is very uneven among children and occurs earlier in girls, in which it is normal since the age of 9. Puberty can make an impact
p.000534: to the action of drug-degrading enzymes, so, counting in mg / kg, drastic reductions in the dosage of some drugs (eg teo lina) are sometimes necessary. U
p.000534: in some cases, it is better to specifically examine the impact of puberty on drug behavior by comparing children before they reach puberty
...
p.000534: For the clinical trial to be of benefit to its participants and other children, its plan must be such as to ensure the quality and clarity of the collected
p.000534: data. Respondents are also expected to benefit from the clinical trial, except in the special circumstances described in the ICH.
p.000534: document E6, section 4.8.14.
p.000534: 2.6.1. Clinical Trial Panel / Independent Ethics Committee (Committee)
p.000534: The role and authority of the Commission described in ICH document E6 is crucial in protecting the respondents. When considering protocols involving children,
p.000534: The committee among its membership must or must seek the professional opinion of persons with a good knowledge of ethical, clinical and psychosocial issues.
p.000534: related to children.
p.000534: 2.6.2. Involvement of respondents
p.000534: Respondents should be included in a way that completely excludes inappropriate prompting of respondents, or their parents / guardians, to participate in
p.000534: examination.
p.000534: Fees and living expenses may be included in the cost of the pediatric clinical trial. Fees should be approved by
p.000534: Committees.
p.000534: When conducting child testing, it is a good idea to include individuals who represent the demographic country / region and the disease being tested, except where
p.000534: there are valid reasons for limited participation in the examination.
p.000534: 2.6.3. Consent and consent
p.000534: As a rule, children are legally incapable of giving their consent to participate in the examination. Therefore, their participation depends on their decision
p.000534: parents or guardians to take responsibility for their participation in the clinical trial. Fully familiarize the caregiver with the examination and
p.000534: obtaining his consent should be in accordance with local laws and regulations. All participants need to be better acquainted with the testing using
p.000534: the consent should be determined by the Commission, or in accordance with local legal requirements).
p.000534: Participants who are mentally mature should personally sign and date either a specific consent form or a consent form. Anyway,
p.000534: Participants must be aware of their right to refuse participation or withdraw from the examination at any time. It should be addressed
p.000534: attention to the signs of excessive suffering in patients who are unable to clearly express their suffering. Although it must respect the respondent's decision to
p.000534: withdraw from testing, in therapeutic trials of serious and life-threatening diseases such circumstances are possible which, in the opinion of the examiner and
p.000534: parent / guardian, may jeopardize the welfare of the child in the event of his / her withdrawal. In these circumstances, further consent from the parent (guardian) is sufficient
p.000534: to continue the child's participation in the examination. Independent or elderly minors (as defined by local law) may be on their own
p.000534: able to give consent.
p.000534: Data that may be collected in a less vulnerable population that has consented to participate is not advisable to be collected in a more vulnerable population,
p.000534: that is, from patients who are unable to give informed consent. Examinations in handicapped or institutionalized children should be limited to those
p.000534: diseases and health conditions that are mainly or exclusively related to these populations, or to the circumstances in which their disease is expected
p.000534: or health change the behavior or pharmacodynamics of medical devices.
p.000534: 2.6.4. How to minimize risk
p.000534: Whatever the importance of testing in proving or denying the value of a treatment, it can lead to injury in the subjects even when
p.000534: polls benefit the entire community. Therefore, every effort should be made to anticipate and limit known hazards. Even before the beginning
p.000534: clinical trial, investigators must have complete insight into all preclinical and clinical data on drug toxicity. To take a risk in pediatric
p.000534: clinical trials minimized, the staff conducting them need to be well trained and experienced in testing with children, which
p.000534: it also involves identifying and treating possible side effects in children.
p.000534: When designing the test plan, every effort should be made to minimize the number of participants and procedures in the spirit of good test planning.
p.000534: Mechanisms need to be devised to quickly complete testing for unexpected hazards.
p.000534: 2.6.5. How to alleviate suffering as much as possible
p.000534: Frequent invasive procedures can hurt and scare a child.
p.000534: Uncomfortable feelings can be minimized if examinations are planned and conducted by examiners experienced in treating children.
p.000534: Testing protocols and procedures must be specifically designed for the pediatric population (not just adapted from adult protocols) and should be approved
p.000534: The Commission, as described in Section 2.6.1.
p.000534: Listed below are some practical assumptions that can contribute to a positive clinical trial experience and minimize feelings
p.000534: discomfort and suffering:
p.000534: • Staff with knowledge and experience in working with children and adjusting to their age, including experience in pediatric procedures.
p.000534: • Physical space with furniture, toys, daily activities and food adapted to the age of the children.
p.000534: • Conducting tests in a well-known environment such as a hospital or clinic where the subjects are otherwise receiving medical care.
p.000534: • Ways to reduce the discomfort associated with performing procedures such as:
p.000534: • local anesthesia before the introduction of an intravenous catheter,
p.000534: • use of permanent catheters instead of frequent veins in the blood to collect blood samples,
p.000534: • simultaneous collection of blood samples for protocol-defined purposes when routine clinical sampling is performed.
p.000534: The committee should consider how many veins in the vein are acceptable to obtain the blood samples prescribed by the protocol and make sure that
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p.000534: 11. copy of the decision of the European Medicines Agency on the pediatric trial plan and the opinion of the pediatric committee, if clinical trial
p.000534: implements according to the pediatric drug development plan (PIP),
p.000534: 12. an example of the labeling of the test drug,
p.000534: 13. financial test plan,
p.000534: 14. proof of insurance of the subjects from the possible adverse consequences of participation in the clinical trial,
p.000534: 15. written authorization to the legal person who submits the request to the Minister for approval of the clinical trial in case the request is not submitted by the client
p.000534: clinical trial,
p.000534: 16. proof of payment of costs in the process of granting approval for conducting a clinical trial.
p.000534: (2) In addition to the documentation referred to in paragraph 1 of this Article, the applicant shall submit to the Central Ethics Committee:
p.000534: - the completed form in Annex IV. and Annex V which are annexed to this Ordinance and form an integral part thereof.
p.000534: (3) In addition to the documentation referred to in paragraph 1 of this Article, the applicant shall submit to the Ministry:
p.000534: - the completed form in Annex III. which is annexed to this Ordinance and forms an integral part thereof,
p.000534: - IMPD
p.000534: - CTA form in English,
p.000534: - proof of payment of the administrative fee.
p.000534: Article 17
p.000534: (1) In the process of approving a clinical trial intended for children or treating psychiatric patients, the Central Ethics Committee may request
p.000534: expert assistance and consult with the Ministry of Pediatrics and Psychiatry Commissions in accordance with point 3.2.6. Of Annex I to this Ordinance.
p.000534: (2) The Central Ethics Commission shall hold the consultations referred to in paragraph 1 of this Article within the time limits provided for in Article 12, paragraph 1 of this Article.
p.000534: Of the Rules.
p.000534: Article 18
p.000534: (1) The CTA form referred to in Article 16, paragraph 3, subparagraph 3 of this Ordinance shall be submitted to the Ministry in .xml and .pdf format on CD-ROM and in .pdf.
p.000534: in written form with the date indicated and signed by the applicant's responsible person.
p.000534: (2) The CTA form must be submitted to the Ministry when submitting a request for conducting a clinical trial as well as when submitting
p.000534: requests for significant changes to the clinical trial.
p.000534: (3) Upon completion of the completion of the CTA form, it is necessary to carry out a validation of the completed data and submit it to the Ministry on CD-ROM
p.000534: Validation Report document in .pdf format, which confirms the validity of the completed form.
p.000534: (4) Each CD-ROM submitted must be marked with the EudraCT number, date of submission of the form, name of the contracting authority and applicant
p.000534: requests and a brief description of the content.
p.000534: (5) In addition to the CTA form, the applicant is obliged to submit to the Ministry the completed forms in writing, which shall be notified to the Ministry.
p.000534: on the significant amendment of the clinical trial and on the completion of the trial.
...
p.000534: X
p.000534: LOCATION OF TESTING divided by respondents, how much returned from the respondents, how much returned to the client of the examination.
p.000534: X (if destroyed)
p.000534: 8.4.2. DOCUMENTATION
p.000534: Document the destruction of unused test products at the test site or at the site organization
p.000534: DESTRUCTION OF TESTED X
p.000534: of the contracting authority. conducting
p.000534: PRODUCTS
p.000534: testing)
p.000534: 8.4.3. COMPLETE LIST
p.000534: Provide identification of all respondents who participated in the examination for monitoring purposes. List
p.000534: IDENTIFICATION MARKS X
p.000534: should be kept confidential for the agreed duration.
p.000534: EXAMINER
p.000534: 8.4.4. CERTIFICATE OF CONTROL (where
p.000534: Document that supervision has been carried out. X
p.000534: available)
p.000534: 8.4.5. FINAL REPORT ON
p.000534: Document that all closing activities are completed and copies of basic documents
p.000534: CONCLUSION BY CLOSURE X
p.000534: stored in appropriate scriptures.
p.000534: TESTING
p.000534: 8.4.6. ALLOCATION DOCUMENTATION
p.000534: Returns to the test client to document any decryption procedures. X
p.000534: THERAPY AND DECRIPTION
p.000534: 8.4.7. FINAL REPORT WHICH
p.000534: EXPERT EXCHANGE
p.000534: Document completion of testing. X
p.000534: CONFIDENTIAL AND / OR COMPETENT
p.000534: BODIES
p.000534: X
p.000534: 8.4.8. CLINICAL REPORT
p.000534: Document test results and their interpretation. X
p.000534: TESTING / STUDY
p.000534: (where necessary)
p.000534: ANNEX II.
p.000534: European Medicines Agency
p.000534: Evaluation of medicines for human use
p.000534: London, 27 July 2000.
p.000534: CPMP / ICH / 2711/99
p.000534: ICH theme E 11
p.000534: CLINICAL TESTING OF MEDICINES IN CHILDREN
p.000534: Step 4 of the ICH Procedure
p.000534: GUIDELINES FOR CLINICAL TESTING OF MEDICINES IN CHILDREN (CPMP / ICH / 2711/99)
p.000534: Entry into force: January 2001.
p.000534: CLINICAL TESTING OF MEDICINES IN CHILDREN
p.000534: 1. INTRODUCTION
p.000534: 1.1. Objectives of the guideline
p.000534: The choice of medicines registered for use in children is currently limited. The aim of this guideline is to encourage and facilitate the timely development of medicines for children
p.000534: internationally. This guideline gives a brief overview of key issues related to the development of medicines for children and the different approaches to achieving them
p.000534: safe, successful and ethically sound drug trials in children.
p.000534: 1.2. Starting point
p.000534: ICH documents relevant to child testing include:
p.000534: E2: Manage innocuous data
p.000534: E3: Compilation and content of clinical trial reports
p.000534: E4: Dose efficacy data on drug registration
p.000534: E5: Ethnic factors affecting the acceptance of clinical data from other countries
p.000534: E6: Good clinical practice: integrated guidelines
p.000534: E8: General considerations related to clinical trials
p.000534: E9: Statistical principles applicable in clinical trials
p.000534: E10: Selection of control group for clinical trial
p.000534: M3: Preclinical safety testing of pharmaceutical products for clinical trials in humans
p.000534: Q1: Stability testing
p.000534: Q2: Validation of analytical procedures
p.000534: Q3: Impurity testing
p.000534: 1.3. Scope of the Guidelines
p.000534: This guideline covers the following issues related to clinical trials in children: (1) considerations regarding the introduction of a drug testing program in children
p.000534: children; (2) planning the start of testing in children with respect to the developmental phase of the drug; (3) types of testing (pharmacokinetics,
p.000534: pharmacokinetics / pharmacodynamics, efficacy, safety); (4) age groups and (5) ethical justification for clinical trials in children. The intention
p.000534: these guidelines do not provide a detailed overview of all issues; these are further elaborated in other ICH guidance and regulatory documents
p.000534: bodies and pediatric associations of individual countries.
p.000534: 1.4. General principles
p.000534: Children should only receive medicines that have been properly tested and evaluated for use in children. For safe and effective treatment
p.000534: children need timely knowledge of the proper use of medicines in children of different ages, and often the development of formulations that are appropriate
p.000534: for use in children. Advances in formulation chemistry and the development of a test plan for children will facilitate the development of medicines for use in children. In general
p.000534: when it comes to medicines for the illnesses or problems of adults that are expected to be applied to children, their development programs should
p.000534: include the child population. One important goal is to learn about the effects of medicines on sick children. However, this goal should not be reached
p.000534: questioning the well-being of the child participating in the clinical trial. Responsibility for this is shared by pharmaceutical companies, regulatory bodies, healthcare
p.000534: workers and society at large.
p.000534: 2. GUIDELINES
p.000534: 2.1. Issues to consider when starting to develop a drug for use in children
p.000534: Information on the appropriate use of the medicine in children should be collected, except in the case of medicines whose use is inappropriate in children. In Section 2.3.
p.000534: planning the start of a clinical trial in relation to a trial in adult patients is discussed and may be influenced by the needs of the public
p.000534: country health and health care. From the very beginning of drug development, it is clear from time to time with regulatory authorities
p.000534: de nition when the start and approach of the clinical trial program are justified. The drug development program for children should not delay completion
p.000534: trials of the drug for use in adults and thus its availability to adult patients.
p.000534: The decision to implement a drug development program for use in children and the nature of the program depend on many factors, including these:
p.000534: • the prevalence of the illness to be treated in children,
p.000534: • the severity of the illness to be treated in children,
p.000534: • the existence / availability and appropriateness of other forms of treatment, including their efficacy and side effects (including all specific
p.000534: pediatric safety considerations),
p.000534: • whether the drug is new or belongs to a group of compounds whose properties are known,
p.000534: • if there are specific pediatric indications for the use of the drug,
p.000534: • the need to define specific pediatric parameters,
p.000534: • the age range of children in which the drug is most likely to be used,
p.000534: • specific pediatric (developmental) questions about the safety of the drug, including any pre-clinical issues,
p.000534: • the possible need to develop a new formulation for children.
p.000534: The most important among these factors is the presence of a serious, or life-threatening, illness in which administration of the test drug may signify an important
p.000534: advances in treatment. In these cases, it is necessary to initiate a relatively rapid investigation of the drug in children.
p.000534: Considerations of data from preclinical safety studies of medicinal products relevant to clinical trials in children are described in ICH document M3,
p.000534: Section 11. It should be noted that the most relevant safety data for children are obtained from adult exposure studies.
p.000534: In general, repeated dose toxicity tests and reproductive and genotoxicity studies should be performed. Consideration should also be given to
p.000534: the need for individual developmental toxicology studies in young animals on a case by case basis.
p.000534: 2.2. Formulations for children
p.000534: Formulations for children are needed because they allow accurate dosing and contribute to adherence to the treatment regimen in children. In oral administration, certain
p.000534: the type of formulations, flavors, and colors may prove more acceptable in a country or region than another. For children of different ages may be desirable
p.000534: or need different formulations such as liquids, suspensions and chewable tablets. Different concentrations of the drug in
p.000534: these formulations. Other forms of drug administration should also be considered.
p.000534: Injections with appropriate drug concentrations should be de-injected to allow accurate and safe dose administration. When it comes to medicines in
p.000534: disposable vials, the appropriate packing of these single doses should be considered.
p.000534: There may be a difference in the toxicity of some of the excipients between children of different ages and between children and adults; e.g. benzyl alcohol is toxic to
p.000534: preterm infants.
p.000534: Depending on the active ingredient and excipients, appropriate administration of the drug to infants may necessitate a new formulation, or
p.000534: appropriate dilution information of the existing formulation. Harmonization of acceptable excipients in the formulation and their processes
p.000534: validation at the international level will make the availability of appropriate pediatric formulations everywhere in the world.
p.000534: 2.3. Timing of testing
p.000534: In the clinical phase of drug development, the planning of its use in children will depend on the drug itself, the disease it is intended for, its harmlessness, and
p.000534: efficacy and harmlessness of other possible treatments. Because developing formulations for children can be demanding and time-consuming, this is important
p.000534: formulation development to plan at an early stage of drug development.
p.000534: 2.3.1. Medicines for diseases most or exclusively affected by children
p.000534: In such cases, the entire development program will be implemented on children, except when it comes to testing the harmlessness and tolerability of a drug that
p.000534: is usually performed on adults. With some drugs, even in these early stages, it may make sense to carry out the test only on children, e.g. where
p.000534: tests on adults would not provide any new knowledge or put them at unnecessary risk. One example is respiratory surfactant
p.000534: distress syndrome in premature infants and medicines for metabolic or congenital diseases unique to the pediatric population.
p.000534: 2.3.2. Medicines for serious and life-threatening illnesses that occur in both adults and children, for which they have no other treatment options or are limited
p.000534: The presence of a serious or life-threatening illness in which administration of the test drug may signify a significant improvement in treatment
p.000534: immediate start of the trial of the drug in children. In this case, the development of the drug in children should be started early, immediately after the initial insight into
p.000534: harmlessness of the drug and indicators of its potential beneficial action. The results of drug testing in children should be included in the application for
p.000534: placing the drug on the market. Where this is not possible, the absence of this information should be explained in detail.
p.000534: 2.3.3. Medicines for the treatment of other diseases and medical conditions
p.000534: Although the drug will also be administered to children, in this case the trial may start at later stages of clinical development, and there may be some
p.000534: Concerns about the harmfulness of the drug, even after sufficient experience with the market has been gained in adult use. Pharmaceutical companies must have
p.000534: a clear schedule and justified timetable for drug testing in children. The study of these drugs in children should not be started before tests 2 or 3.
p.000534: phase. At the time of applying for marketing, limited information related to children is available, and more knowledge is expected.
p.000534: after release of the drug.
p.000534: Namely, after testing Phases 1 and 2, testing of a considerable number of new chemical compounds in adults is terminated due to their ineffectiveness or
p.000534: unacceptable side effects. Therefore, early participation in testing may unnecessarily expose children to the action of a compound that will prove useless. There
p.000534: where the drug represents an important advance in the treatment of children, even if it is not a serious illness, trials should be started at an early stage of drug development, and
p.000534: the request for marketing should also include information on its use in children.
p.000534: The possible absence of this information should be explained in detail. Therefore, it is important to carefully weigh the possible before starting a drug test in children
p.000534: the benefit, risk of treatment and the need for its introduction.
p.000534: 2.4. Types of testing
p.000534: The principles outlined in ICH documents E4, E5, E6 and E10 also apply to testing in children. There are several issues that are specific to children.
p.000534: When examining a medicine in children in a country or region, internal (eg pharmacogenetic) and external factors should be taken into account 1 [1] [1]
p.000534: (e.g., nutrition) that may affect the application of results in another country or region.
p.000534: The efficacy data for the indications tested and approved in adults may be applicable to children for the same indications if
p.000534: the development of the disease and the likelihood of treatment outcome are similar in the two populations. In this case, pharmacokinetics testing in all age groups of children
p.000534: receiving the drug and these harmless studies may provide sufficient data for administration through pediatric doses that will lead to drug levels in
p.000534: blood similar to those seen in the adult population. If the test is approached in this way, it is necessary to have data in order to plan tests in children
p.000534: on the pharmacokinetics of the drug in adults.
p.000534: Elderly drug efficacy data may prove applicable to younger children for the same indications if disease development and likelihood are
p.000534: treatment outcomes similar in the two age groups. In this case, pharmacokinetics testing in appropriate age groups of children receiving the drug
p.000534: these safety tests may provide sufficient data for the administration of the drug to children.
p.000534: A pharmacokinetic-based approach is unlikely to be sufficient for drugs known or expected to be inappropriate for blood levels
p.000534: their efficacy, ie the dose-response relationship is assumed to be different between adults and children.
p.000534: In this case, a clinical and pharmacological effect study is expected to be conducted. Where a similar course or outcome of the disease is to be expected
p.000534: between children and adults, but where appropriate levels of the drug are unknown in the blood, to confirm its efficacy and to determine dose and concentration
p.000534: it is possible to measure the pharmacodynamics of the drug with respect to its clinical efficacy. These tests reinforce the confidence that certain
p.000534: drug exposure may lead to the desired outcome in children. So by examining pharmacokinetics and pharmacodynamics, harmlessness and other important
p.000534: factors may be avoided by clinical trials of the efficacy of the drug in children.
p.000534: Where pharmacokinetics cannot be applied, as with topical medicinal products, the administration of results from one group of patients to another may
p.000534: be based on studies incorporating pharmacodynamic parameters and / or other appropriate studies. The need for
p.000534: by examining drug delivery at the application site. To evaluate the harmlessness of a drug, it may also be important to determine its level in the blood and systemic
p.000534: effects.
p.000534: Whether these are new indications for the use of the drug in children, or whether different course of illness and outcome of treatment between adults and children are expected,
p.000534: clinical trials on the efficacy of the drug in children should be performed.
p.000534: 2.4.1. Pharmacokinetics
p.000534: Pharmacokinetic studies are mainly performed to verify the newly developed formulation and to determine pharmacokinetic parameters for various
p.000534: age groups supporting the recommended doses.
p.000534: Comparisons of relative bioavailability between formulations for children and oral formulations for adults should be performed on adults. It's on the kids
p.000534: final pharmacokinetic studies should be conducted to determine the appropriate dose for each age group of children
p.000534: drug intended.
p.000534: In general, pharmacokinetic studies are performed on ill children. This may mean greater heterogeneity among subjects than in healthy subjects
p.000534: volunteers, but the data obtained better reflects clinical application.
p.000534: In the case of medicinal products exhibiting linear pharmacokinetics in adults, single use in pharmacokinetic studies in children
p.000534: may provide sufficient knowledge for dose selection.
p.000534: If necessary, this choice can be confirmed by occasional sampling in repeated dose clinical trials. Any
p.000534: nonlinearity in the absorption, distribution and elimination of the drug and any difference in the time of action between single and multiple dose in adults
p.000534: points to the need to test a drug in children when its dynamic balance is reached. Performing all of these procedures makes it easy to see
p.000534: pharmacokinetic parameters in adults. Knowledge of drug elimination pathways can often prove useful in planning trials in children
p.000534: (via the kidney and metabolism) and age-dependent changes in these processes.
p.000534: For most medicines, the recommended doses for children are based on milligrams per kilogram body weight (mg / kg) and range up to the highest adult dose.
p.000534: Although the first choice may be a dosage based on mg / m2 of body surface area, clinical experience indicates that frequent errors in height measurement or
p.000534: length (especially young children and infants), as well as in calculating the body surface area from these measurements. It is important to administer some medications on a physical basis
p.000534: surfaces (eg drugs with a narrow therapeutic index such as oncology), but extra caution should be exercised to calculate the amount
p.000534: correct.
p.000534: Practical considerations facilitating the conduct of pharmacokinetic studies
p.000534: The blood volume taken from children should be as small as possible. It must be justified within the protocol. Clinical Trials Board / Independent Ethics
p.000534: Committees (Committees) consider and may determine the highest amount of blood (usually in milliliters per kilogram (mL / kg), or as a percentage of
p.000534: total blood volume) that can be taken for testing. There are several ways to minimize blood sampling and vein injection
p.000534: a possible measure.
p.000534: • Using sensitive assays for the drug and its metabolites that require lower blood volume in the sample.
p.000534: • Involvement of laboratories with experience in the processing of low blood volume samples for pharmacokinetic and safety analysis (blood tests, clinical
p.000534: chemistry).
p.000534: • Collecting regular blood samples for both clinical and pharmacokinetic analysis whenever possible.
p.000534: • Using a permanent catheter, etc. to minimize discomfort as discussed in Section 2.6.5.
p.000534: • Applying population pharmacokinetics and sparse sampling based on optimal sampling settings to sample number
p.000534: taken from each patient to a minimum. Sampling techniques include:
p.000534: • Rare sampling in which each patient participates with 2 to 4 tests in a predetermined time in the total population covered
p.000534: "The area under the curve."
p.000534: • Analyzing population pharmacokinetics and planning the most optimal sampling schedule according to the adult model.
p.000534: 2.4.2 Effectiveness
p.000534: Principles of test planning, statistical processing and selection of control groups described in ICH documents ICH E6, E9 and E10, largely
p.000534: also valid for drug efficacy studies in children. However, some details are unique to pediatric trials. In Section 2.4. is discussed about
p.000534: the applicability of the results of efficacy tests in adults to children or trials in older children to young people. Where Performance Tests Are
p.000534: Necessary, it is necessary to develop, validate and apply different parameters for different age and development groups. For subjective symptoms such as pain
p.000534: different measuring instruments are needed, appropriate for each age group of patients. In children with chronic illness, the answer to the drug may be
p.000534: uneven, not only because of the duration of the disease and its chronic effects, but also because of the stage of development in which the patient is present. There are many diseases
p.000534: preterm infants and newborns are unique to these groups or their manifestations are unique, making it impossible to apply the results
p.000534: the effectiveness of the drug on older children and requires new methods of evaluating treatment outcomes.
p.000534: 2.4.3. The harmlessness of the drug
p.000534: The guidelines in ICH documents E2 and E6 describing the recording of adverse reactions also apply to testing in children. It is necessary to record side effects
p.000534: rely on normal laboratory values and clinical measurements that are adjusted to the child's age. Accidental exposure to the drug (accidentally swallowed
p.000534: , etc.) provides an opportunity to obtain additional information on the safety and pharmacokinetics of the drug and to gain a better understanding of the relationship of side effects with the dose.
p.000534: Medications can affect physical and mental development, and children may differ in their experience of side effects. Because developing organisms
p.000534: they may respond differently to treatment from mature organisms, some side effects and interactions with other medicines observed in children may not occur and
p.000534: in adults. In addition, due to the dynamics of growth and development, some side effects may not occur acutely, but at a later stage of development and maturation. Do they want to
p.000534: identify potential effects on skeletal maturation and development, behavior, cognitive function, sexual organs and the immune system may be needed
p.000534: long-term testing of children on chronic treatment or their long-term follow-up after treatment.
p.000534: 2.4.4. Findings after placing the medicine on the market
p.000534: Usually, when obtaining a marketing authorization, the knowledge is limited. Therefore, it is especially important to monitor children after drug release
p.000534: into circulation. It is sometimes important to carry out long-term monitoring to determine the effects of certain drugs on the growth and development of children. Post-placement monitoring
p.000534: drug and / or long-term testing may provide insight into the harmlessness and / or efficacy of the drug to particular groups of children, or
p.000534: additional knowledge regarding the overall child population.
p.000534: 2.5. Division of children by age
p.000534: Any division of children by age is somewhat arbitrary, but can be a starting point for thinking about a test plan for children. For deciding how
p.000534: to distribute tests and data according to the age of the child, developmental biology and pharmacology should be kept in mind. Therefore, a flexible approach is needed which
p.000534: will ensure the presence of the latest findings in pediatric pharmacology in studies. The choice of age to test should depend on the particular drug and is valid
p.000534: substantiate with good reasons.
p.000534: If the routes of drug elimination and their maturation (ontogenesis) are known, the division into age ranges for pharmacokinetic evaluation may start from
p.000534: "Milestones" that bring about significant changes in elimination.
p.000534: It is sometimes more appropriate to collect data on children across a wider age range and to examine the impact of age as a constant covariate. Different parameters
p.000534: the efficacy of the drug may be varied for different age groups, and this division may not correspond to the one shown below. Dividing the population into many
p.000534: age groups may unnecessarily increase the number of children participating in the study. In the case of longer-term trials, children may switch from
p.000534: from one age group to another, and the test plan and statistical analysis must predict changes in the number of patients in a given age group.
p.000534: Below, one of the age groups is offered. However, there is significant overlap in development across all groups (e.g.,
p.000534: cognitive, psychosocial). Age is defined by days, months or years.
p.000534: • Newborns born before term (premature infants)
p.000534: • Newborns born within term (0 - 27 days, newborn born)
p.000534: • Children aged 28 days to 23 months (infants and young children)
p.000534: • Children aged 2 to 11 years
p.000534: • Adolescents (12 to 16-18 years, depending on country)
p.000534: 2.5.1. Newborns born before term (premature infants)
p.000534: The study of premature infants raises special questions, since both the pathology and the response to treatment are unique to this group. Complexity
p.000534: tests in preterm infants and related ethical issues indicate the need for careful protocol design in collaboration with neonatologists and neonatal
p.000534: pharmacologists. Only in rare cases will it be possible to apply the results of efficacy obtained in adults and even older children to premature babies.
p.000534: Newborns as an age group are not homogeneous. There is a big difference between having a baby weighing 500g born at week 25 and 1,500g
p.000534: premature infant born at 30 weeks gestation.
p.000534: It is also important to distinguish whether children with low birth weight are immature or with stunted growth.
p.000534: It is important for these patients to consider the following features: (1) gestational and postnatal age (adjusted age); (2) immaturity of elimination mechanisms
p.000534: via the kidney and liver; (3) problems with protein binding and displacement (especially bilirubin); (4) penetration of the drug into the central nervous system (CNS); (5)
p.000534: health conditions unique to the newborn (eg respiratory stress syndrome, patent ductusarteriosus, primary pulmonary hypertension);
p.000534: (6) preferences inherent in preterm infants (eg, propensity for necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of preterm infants); (7) quickly
p.000534: and unequal maturation of all the biological and pharmacological processes, which necessitates a change in dosage regimen upon long-term drug exposure; and (8)
p.000534: absorption of the drug and other chemical compounds through the skin.
p.000534: Issues to consider in exam planning include: (1) division by body weight and age (gestational and postnatal); (2) small volume
p.000534: blood (prematurely weighing 500 g has only 40 mL of blood); (3) the small number of such patients in a particular healthcare facility and the differences in their treatment among
p.000534: and (4) difficulties in evaluating treatment outcomes.
p.000534: 2.5.2. Newborn born within term (0 - 27 days, newborn born)
p.000534: Although newborns are born within the term mature in development from preterm infants, many of the more described zoological and pharmacological values apply to them
p.000534: settings. In these, the volume of drug distribution may differ from that of older children because of the different ratio of body fluid and fat and because
p.000534: high ratio of skin surface area to body weight. The blood-brain barrier is not yet fully mature, so drugs and endogenous substances (eg bilirubin) may
p.000534: penetrate the CSF and act toxic. Absorption of the drug after oral administration is less predictable than in older children. Elimination mechanisms
p.000534: through the liver and kidney are not yet mature and undergoing rapid changes; therefore, the dosage of the drug should be adjusted in the first weeks of the infant's life.
p.000534: There are many examples of newborn susceptibility to drug toxicity resulting from limited elimination (eg, aplastic anemia caused by
p.000534: chloramphenicol, eng. chloramphenicolgreybabysyndrome). On the other hand, a term-born infant is less sensitive to some side effects
p.000534: (e.g., nephrotoxicity ofaminoglycoside) from elderly patients.
p.000534: 2.5.3. Children aged 28 days to 23 months (infants and young children)
p.000534: At this age, the CSF matures rapidly, the immune system develops and the entire body grows. Absorption after oral administration is now more reliable. It goes on and on
p.000534: rapid maturation of elimination mechanisms via the liver and kidney. Computing in mg / kg, many drugs are eliminated faster in children 1 - 2 years of age than
p.000534: in adults.
p.000534: The developmental maturation pathway depends on specific elimination pathways. Differences in maturation among children are often noticeable.
p.000534: 2.5.4. Children aged 2 to 11 years
p.000534: Most elimination pathways (via liver and kidney) are now mature, and elimination is often greater than in adults. Changes in drug elimination can
p.000534: depend on the maturation of specific metabolic pathways.
p.000534: Appropriate strategies should be set out in the protocol to identify any effects of the drug on the growth and development of the child. There are several at this age
p.000534: a milestone in the psychomotor development of a child that can be adversely affected by drugs acting on the CSW. School attendance and higher cognitive and
p.000534: motor skills may affect a child's ability to participate in some performance tests. Factors useful for measuring performance
p.000534: drugs in children include skeletal growth, weight gain, school attendance, and school success.
p.000534: Selection of respondents should ensure adequate representativeness for the whole age group, since it is important to raise enough young people
p.000534: respondents.
p.000534: It is seldom necessary in this age group to further divide children by age, but it may prove appropriate to divide them according to
p.000534: pharmacokinetic and / or efficacy parameters.
p.000534: Entry into puberty is very uneven among children and occurs earlier in girls, in which it is normal since the age of 9. Puberty can make an impact
p.000534: to the action of drug-degrading enzymes, so, counting in mg / kg, drastic reductions in the dosage of some drugs (eg teo lina) are sometimes necessary. U
p.000534: in some cases, it is better to specifically examine the impact of puberty on drug behavior by comparing children before they reach puberty
p.000534: puberty. In the second case, it is more appropriate to monitor the rates of pubertal development according to Tanner or to collect biological indicators of puberty and
p.000534: study the potential impact of changes in puberty.
p.000534: 2.5.5. Adolescents (12 to 16-18 years old, depending on country)
p.000534: This is the age of sexual maturation, and drugs can clash with the action of sex hormones and prevent development.
p.000534: In some studies, it is advisable to take a pregnancy test and monitor the sexual activity and contraceptive use of the subjects.
p.000534: This is also a period of accelerated physical growth and continued development of neurocognitive functions. Medicines and diseases that slow or accelerate entry into
p.000534: puberty can have a profound effect on pubertal growth and therefore the final height of the patient. Gradual changes in the cognitive and emotional realms can
p.000534: influence the outcome of clinical trials.
p.000534: Many diseases are also affected by hormonal changes associated with puberty (eg, higher insulin resistance in diabetes mellitus, frequent occurrence
p.000534: epileptic seizures in the period around menarche, changes in the frequency and intensity of migraine and asthma attacks). Hormonal changes can also
p.000534: also influence the results of clinical trials.
p.000534: By entering this age group, adolescents take responsibility for their own health and treatment. Failure to follow the treatment regimen is here
p.000534: a specific problem, especially if drugs (eg steroids) affect appearance. It is very important to check that the subjects adhere to the treatment regimen in
p.000534: clinical trials.
p.000534: Particular attention should also be paid to the occasional use of non-prescribed medicines and to the consumption of alcohol and tobacco.
p.000534: The upper limit of this age group varies from country to country. Older adolescents may be involved in adult trials, though they may be
p.000534: difficulty adhering to the treatment regimen. Due to problems specific to adolescence, conducting tests may be appropriate
p.000534: (whether included in the adult test protocol or in a separate protocol) in healthcare settings with knowledge and experience in nursing
p.000534: of this patient population.
p.000534: 2.6. Ethical issues related to testing in children
p.000534: Children are a vulnerable group of respondents. It is therefore necessary to introduce specific measures to protect their rights in clinical trials and to prevent them
p.000534: exposure to unnecessary risk. The purpose of this section is to provide an ethical framework for conducting testing in children.
p.000534: For the clinical trial to be of benefit to its participants and other children, its plan must be such as to ensure the quality and clarity of the collected
p.000534: data. Respondents are also expected to benefit from the clinical trial, except in the special circumstances described in the ICH.
p.000534: document E6, section 4.8.14.
p.000534: 2.6.1. Clinical Trial Panel / Independent Ethics Committee (Committee)
p.000534: The role and authority of the Commission described in ICH document E6 is crucial in protecting the respondents. When considering protocols involving children,
p.000534: The committee among its membership must or must seek the professional opinion of persons with a good knowledge of ethical, clinical and psychosocial issues.
p.000534: related to children.
p.000534: 2.6.2. Involvement of respondents
p.000534: Respondents should be included in a way that completely excludes inappropriate prompting of respondents, or their parents / guardians, to participate in
p.000534: examination.
p.000534: Fees and living expenses may be included in the cost of the pediatric clinical trial. Fees should be approved by
p.000534: Committees.
p.000534: When conducting child testing, it is a good idea to include individuals who represent the demographic country / region and the disease being tested, except where
p.000534: there are valid reasons for limited participation in the examination.
p.000534: 2.6.3. Consent and consent
p.000534: As a rule, children are legally incapable of giving their consent to participate in the examination. Therefore, their participation depends on their decision
p.000534: parents or guardians to take responsibility for their participation in the clinical trial. Fully familiarize the caregiver with the examination and
p.000534: obtaining his consent should be in accordance with local laws and regulations. All participants need to be better acquainted with the testing using
p.000534: the consent should be determined by the Commission, or in accordance with local legal requirements).
p.000534: Participants who are mentally mature should personally sign and date either a specific consent form or a consent form. Anyway,
p.000534: Participants must be aware of their right to refuse participation or withdraw from the examination at any time. It should be addressed
p.000534: attention to the signs of excessive suffering in patients who are unable to clearly express their suffering. Although it must respect the respondent's decision to
p.000534: withdraw from testing, in therapeutic trials of serious and life-threatening diseases such circumstances are possible which, in the opinion of the examiner and
p.000534: parent / guardian, may jeopardize the welfare of the child in the event of his / her withdrawal. In these circumstances, further consent from the parent (guardian) is sufficient
p.000534: to continue the child's participation in the examination. Independent or elderly minors (as defined by local law) may be on their own
p.000534: able to give consent.
p.000534: Data that may be collected in a less vulnerable population that has consented to participate is not advisable to be collected in a more vulnerable population,
p.000534: that is, from patients who are unable to give informed consent. Examinations in handicapped or institutionalized children should be limited to those
p.000534: diseases and health conditions that are mainly or exclusively related to these populations, or to the circumstances in which their disease is expected
p.000534: or health change the behavior or pharmacodynamics of medical devices.
p.000534: 2.6.4. How to minimize risk
p.000534: Whatever the importance of testing in proving or denying the value of a treatment, it can lead to injury in the subjects even when
p.000534: polls benefit the entire community. Therefore, every effort should be made to anticipate and limit known hazards. Even before the beginning
p.000534: clinical trial, investigators must have complete insight into all preclinical and clinical data on drug toxicity. To take a risk in pediatric
p.000534: clinical trials minimized, the staff conducting them need to be well trained and experienced in testing with children, which
p.000534: it also involves identifying and treating possible side effects in children.
p.000534: When designing the test plan, every effort should be made to minimize the number of participants and procedures in the spirit of good test planning.
p.000534: Mechanisms need to be devised to quickly complete testing for unexpected hazards.
p.000534: 2.6.5. How to alleviate suffering as much as possible
p.000534: Frequent invasive procedures can hurt and scare a child.
p.000534: Uncomfortable feelings can be minimized if examinations are planned and conducted by examiners experienced in treating children.
p.000534: Testing protocols and procedures must be specifically designed for the pediatric population (not just adapted from adult protocols) and should be approved
p.000534: The Commission, as described in Section 2.6.1.
p.000534: Listed below are some practical assumptions that can contribute to a positive clinical trial experience and minimize feelings
p.000534: discomfort and suffering:
p.000534: • Staff with knowledge and experience in working with children and adjusting to their age, including experience in pediatric procedures.
p.000534: • Physical space with furniture, toys, daily activities and food adapted to the age of the children.
p.000534: • Conducting tests in a well-known environment such as a hospital or clinic where the subjects are otherwise receiving medical care.
p.000534: • Ways to reduce the discomfort associated with performing procedures such as:
p.000534: • local anesthesia before the introduction of an intravenous catheter,
p.000534: • use of permanent catheters instead of frequent veins in the blood to collect blood samples,
p.000534: • simultaneous collection of blood samples for protocol-defined purposes when routine clinical sampling is performed.
p.000534: The committee should consider how many veins in the vein are acceptable to obtain the blood samples prescribed by the protocol and make sure that
p.000534: understanding of procedures in the event that a permanent catheter becomes unusable over time. Respondent's right to refuse further participation must be respected
p.000534: in the test procedures, except in the case described in section 2.6.3.
p.000534: ANNEX III.
p.000534: APPLICATION FORM FOR THE APPROVAL OF THE MINISTER OF HEALTH CARE FOR CARRYING OUT THE CLINICAL TESTING OF MEDICINES IN THE REPUBLIC
p.000534: HRVATSKOJ
p.000534: - completed by the contracting authority or the applicant responsible for the accuracy of the information provided
p.000534: Clinical trial client:
p.000534: Applicant for clinical trial:
p.000534: * Date of receipt of the item:
p.000534: * Date of receipt of complete documentation:
p.000534: A. General information
p.000534: Test Name:
p.000534: Test Plan Designation
p.000534: EUDRACT number:
p.000534: Clinical trial phase (I, II, III, IV)
p.000534: List of countries in which clinical trials were approved and / or planned by the time the application was submitted to the ministry responsible for health
p.000534: implement
p.000534: Version and date of test plan
p.000534: Brochure for examiners
...
Social / Elderly
Searching for indicator elderly:
(return to top)
p.000534: 1.56. Assistant Examiner
p.000534: Each individual member of the clinical trial team assigned or supervised by the examiner at the clinical trial establishment
p.000534: performing clinical trial procedures and / or making clinical trial decisions (eg associates, specialists, scientific
p.000534: associates). See also Examiner.
p.000534: 1.57. Respondent / clinical trial participant
p.000534: The person participating in the clinical trial, whether receiving the test product or serving as a control.
p.000534: 1.58. Respondent's identification mark
p.000534: Unique identifier assigned by the examiner to each respondent to protect the respondent's identity, which is used instead of the name
p.000534: the respondent when the examiner reports adverse event and / or other information related to the examination.
p.000534: 1.59. Location of clinical trial
p.000534: Site where clinical trial activities are conducted.
p.000534: 1.60. An unexpected side effect
p.000534: A side effect whose nature or weight is inconsistent with valid product information (e.g., examiner instructions for disapproved test product or instructions
p.000534: on the product / summary of the product if it is an approved product) (see ICH Guidelines for the handling of clinical harm data: Definitions and
p.000534: standards for emergency reporting).
p.000534: 1.61. Particularly sensitive respondents
p.000534: Individuals whose willingness to participate in a clinical trial may be unduly influenced by the expectation, whether justified or not, that their participation
p.000534: to bring certain benefits, that is, otherwise they will be avenged by the elderly or superiors. Members can serve as an example
p.000534: hierarchical groups such as medical, pharmacy or dental students, hospital and laboratory staff, pharmaceutical employees
p.000534: industry, members of the military of that person in custody or prison. The mentioned respondents include patients with incurable diseases, residents
p.000534: housing, the unemployed and the poor, emergency patients, ethnic minorities, homeless people, nomads, refugees, minors and
p.000534: persons unable to consent.
p.000534: 1.62. Well-being (of respondents)
p.000534: Physical and spiritual integrity of the clinical trial participant.
p.000534: 2. ICH PRINCIPLES OF GOOD CLINICAL PRACTICE
p.000534: 2.1. Clinical trials must be conducted in accordance with the ethical principles of the Helsinki Declaration and in accordance with good practice.
p.000534: clinical practice and applicable law.
p.000534: 2.2. Before starting a clinical trial, the expected risks and disruptions to the expected benefits for the individual subject and
p.000534: society. Clinical trials should only be started and continued if the expected benefit justifies the risk.
p.000534: 2.3. The rights, safety and well-being of respondents who are ahead of the interests of science and society.
...
p.000534: 2.4. Types of testing
p.000534: The principles outlined in ICH documents E4, E5, E6 and E10 also apply to testing in children. There are several issues that are specific to children.
p.000534: When examining a medicine in children in a country or region, internal (eg pharmacogenetic) and external factors should be taken into account 1 [1] [1]
p.000534: (e.g., nutrition) that may affect the application of results in another country or region.
p.000534: The efficacy data for the indications tested and approved in adults may be applicable to children for the same indications if
p.000534: the development of the disease and the likelihood of treatment outcome are similar in the two populations. In this case, pharmacokinetics testing in all age groups of children
p.000534: receiving the drug and these harmless studies may provide sufficient data for administration through pediatric doses that will lead to drug levels in
p.000534: blood similar to those seen in the adult population. If the test is approached in this way, it is necessary to have data in order to plan tests in children
p.000534: on the pharmacokinetics of the drug in adults.
p.000534: Elderly drug efficacy data may prove applicable to younger children for the same indications if disease development and likelihood are
p.000534: treatment outcomes similar in the two age groups. In this case, pharmacokinetics testing in appropriate age groups of children receiving the drug
p.000534: these safety tests may provide sufficient data for the administration of the drug to children.
p.000534: A pharmacokinetic-based approach is unlikely to be sufficient for drugs known or expected to be inappropriate for blood levels
p.000534: their efficacy, ie the dose-response relationship is assumed to be different between adults and children.
p.000534: In this case, a clinical and pharmacological effect study is expected to be conducted. Where a similar course or outcome of the disease is to be expected
p.000534: between children and adults, but where appropriate levels of the drug are unknown in the blood, to confirm its efficacy and to determine dose and concentration
p.000534: it is possible to measure the pharmacodynamics of the drug with respect to its clinical efficacy. These tests reinforce the confidence that certain
...
p.000534: and (4) difficulties in evaluating treatment outcomes.
p.000534: 2.5.2. Newborn born within term (0 - 27 days, newborn born)
p.000534: Although newborns are born within the term mature in development from preterm infants, many of the more described zoological and pharmacological values apply to them
p.000534: settings. In these, the volume of drug distribution may differ from that of older children because of the different ratio of body fluid and fat and because
p.000534: high ratio of skin surface area to body weight. The blood-brain barrier is not yet fully mature, so drugs and endogenous substances (eg bilirubin) may
p.000534: penetrate the CSF and act toxic. Absorption of the drug after oral administration is less predictable than in older children. Elimination mechanisms
p.000534: through the liver and kidney are not yet mature and undergoing rapid changes; therefore, the dosage of the drug should be adjusted in the first weeks of the infant's life.
p.000534: There are many examples of newborn susceptibility to drug toxicity resulting from limited elimination (eg, aplastic anemia caused by
p.000534: chloramphenicol, eng. chloramphenicolgreybabysyndrome). On the other hand, a term-born infant is less sensitive to some side effects
p.000534: (e.g., nephrotoxicity ofaminoglycoside) from elderly patients.
p.000534: 2.5.3. Children aged 28 days to 23 months (infants and young children)
p.000534: At this age, the CSF matures rapidly, the immune system develops and the entire body grows. Absorption after oral administration is now more reliable. It goes on and on
p.000534: rapid maturation of elimination mechanisms via the liver and kidney. Computing in mg / kg, many drugs are eliminated faster in children 1 - 2 years of age than
p.000534: in adults.
p.000534: The developmental maturation pathway depends on specific elimination pathways. Differences in maturation among children are often noticeable.
p.000534: 2.5.4. Children aged 2 to 11 years
p.000534: Most elimination pathways (via liver and kidney) are now mature, and elimination is often greater than in adults. Changes in drug elimination can
p.000534: depend on the maturation of specific metabolic pathways.
p.000534: Appropriate strategies should be set out in the protocol to identify any effects of the drug on the growth and development of the child. There are several at this age
...
p.000534: obtaining his consent should be in accordance with local laws and regulations. All participants need to be better acquainted with the testing using
p.000534: the consent should be determined by the Commission, or in accordance with local legal requirements).
p.000534: Participants who are mentally mature should personally sign and date either a specific consent form or a consent form. Anyway,
p.000534: Participants must be aware of their right to refuse participation or withdraw from the examination at any time. It should be addressed
p.000534: attention to the signs of excessive suffering in patients who are unable to clearly express their suffering. Although it must respect the respondent's decision to
p.000534: withdraw from testing, in therapeutic trials of serious and life-threatening diseases such circumstances are possible which, in the opinion of the examiner and
p.000534: parent / guardian, may jeopardize the welfare of the child in the event of his / her withdrawal. In these circumstances, further consent from the parent (guardian) is sufficient
p.000534: to continue the child's participation in the examination. Independent or elderly minors (as defined by local law) may be on their own
p.000534: able to give consent.
p.000534: Data that may be collected in a less vulnerable population that has consented to participate is not advisable to be collected in a more vulnerable population,
p.000534: that is, from patients who are unable to give informed consent. Examinations in handicapped or institutionalized children should be limited to those
p.000534: diseases and health conditions that are mainly or exclusively related to these populations, or to the circumstances in which their disease is expected
p.000534: or health change the behavior or pharmacodynamics of medical devices.
p.000534: 2.6.4. How to minimize risk
p.000534: Whatever the importance of testing in proving or denying the value of a treatment, it can lead to injury in the subjects even when
p.000534: polls benefit the entire community. Therefore, every effort should be made to anticipate and limit known hazards. Even before the beginning
p.000534: clinical trial, investigators must have complete insight into all preclinical and clinical data on drug toxicity. To take a risk in pediatric
p.000534: clinical trials minimized, the staff conducting them need to be well trained and experienced in testing with children, which
...
Social / Ethnicity
Searching for indicator ethnic:
(return to top)
p.000534: 1.59. Location of clinical trial
p.000534: Site where clinical trial activities are conducted.
p.000534: 1.60. An unexpected side effect
p.000534: A side effect whose nature or weight is inconsistent with valid product information (e.g., examiner instructions for disapproved test product or instructions
p.000534: on the product / summary of the product if it is an approved product) (see ICH Guidelines for the handling of clinical harm data: Definitions and
p.000534: standards for emergency reporting).
p.000534: 1.61. Particularly sensitive respondents
p.000534: Individuals whose willingness to participate in a clinical trial may be unduly influenced by the expectation, whether justified or not, that their participation
p.000534: to bring certain benefits, that is, otherwise they will be avenged by the elderly or superiors. Members can serve as an example
p.000534: hierarchical groups such as medical, pharmacy or dental students, hospital and laboratory staff, pharmaceutical employees
p.000534: industry, members of the military of that person in custody or prison. The mentioned respondents include patients with incurable diseases, residents
p.000534: housing, the unemployed and the poor, emergency patients, ethnic minorities, homeless people, nomads, refugees, minors and
p.000534: persons unable to consent.
p.000534: 1.62. Well-being (of respondents)
p.000534: Physical and spiritual integrity of the clinical trial participant.
p.000534: 2. ICH PRINCIPLES OF GOOD CLINICAL PRACTICE
p.000534: 2.1. Clinical trials must be conducted in accordance with the ethical principles of the Helsinki Declaration and in accordance with good practice.
p.000534: clinical practice and applicable law.
p.000534: 2.2. Before starting a clinical trial, the expected risks and disruptions to the expected benefits for the individual subject and
p.000534: society. Clinical trials should only be started and continued if the expected benefit justifies the risk.
p.000534: 2.3. The rights, safety and well-being of respondents who are ahead of the interests of science and society.
p.000534: 2.4. The available preclinical and clinical data on the product under test must sufficiently support the conduct of the clinical trial.
p.000534: 2.5. The scientific foundations of clinical trials must be sound and the Trial Plan must be clear and detailed.
p.000534: 2.6. Testing should be carried out in accordance with the Clinical Trials / Independent Review Panel approved / tested positive
p.000534: of the Ethics Committee.
p.000534: 2.7. Responsibility for the health care of the respondent and for decisions regarding his or her treatment must always rest with a qualified medical doctor,
p.000534: where appropriate, to a qualified dental doctor.
...
p.000534: TESTING / STUDY
p.000534: (where necessary)
p.000534: ANNEX II.
p.000534: European Medicines Agency
p.000534: Evaluation of medicines for human use
p.000534: London, 27 July 2000.
p.000534: CPMP / ICH / 2711/99
p.000534: ICH theme E 11
p.000534: CLINICAL TESTING OF MEDICINES IN CHILDREN
p.000534: Step 4 of the ICH Procedure
p.000534: GUIDELINES FOR CLINICAL TESTING OF MEDICINES IN CHILDREN (CPMP / ICH / 2711/99)
p.000534: Entry into force: January 2001.
p.000534: CLINICAL TESTING OF MEDICINES IN CHILDREN
p.000534: 1. INTRODUCTION
p.000534: 1.1. Objectives of the guideline
p.000534: The choice of medicines registered for use in children is currently limited. The aim of this guideline is to encourage and facilitate the timely development of medicines for children
p.000534: internationally. This guideline gives a brief overview of key issues related to the development of medicines for children and the different approaches to achieving them
p.000534: safe, successful and ethically sound drug trials in children.
p.000534: 1.2. Starting point
p.000534: ICH documents relevant to child testing include:
p.000534: E2: Manage innocuous data
p.000534: E3: Compilation and content of clinical trial reports
p.000534: E4: Dose efficacy data on drug registration
p.000534: E5: Ethnic factors affecting the acceptance of clinical data from other countries
p.000534: E6: Good clinical practice: integrated guidelines
p.000534: E8: General considerations related to clinical trials
p.000534: E9: Statistical principles applicable in clinical trials
p.000534: E10: Selection of control group for clinical trial
p.000534: M3: Preclinical safety testing of pharmaceutical products for clinical trials in humans
p.000534: Q1: Stability testing
p.000534: Q2: Validation of analytical procedures
p.000534: Q3: Impurity testing
p.000534: 1.3. Scope of the Guidelines
p.000534: This guideline covers the following issues related to clinical trials in children: (1) considerations regarding the introduction of a drug testing program in children
p.000534: children; (2) planning the start of testing in children with respect to the developmental phase of the drug; (3) types of testing (pharmacokinetics,
p.000534: pharmacokinetics / pharmacodynamics, efficacy, safety); (4) age groups and (5) ethical justification for clinical trials in children. The intention
p.000534: these guidelines do not provide a detailed overview of all issues; these are further elaborated in other ICH guidance and regulatory documents
p.000534: bodies and pediatric associations of individual countries.
p.000534: 1.4. General principles
...
p.000534: Prescribing a drug is independent of the decision to include patients in the trial: ∑ ☐ Comment:
p.000534: Additional diagnostic and patient monitoring procedures are not performed (except those that form part of normal practice): ∑ ☐ Comment:
p.000534: Epidemiological methods are used to analyze the data collected: ∑ ☐ Comment:
p.000534: Testing does not promote prescribing of monitored drug: ∑ ☐ Comment:
p.000534: Informed consent in Croatian: YES NO
p.000534: The text clearly describes the conduct of the test, listing all the information needed to make the decision: ∑ ☐ Comment:
p.000534: The text of informed consent is understandable for patients: ∑ ☐ Comment:
p.000534: The informed consent text is linguistic, spelling and typographical correct: ∑ ☐ Comment:
p.000534: Other documentation provided: YES NO
p.000534: Fits test plan: ∑ ☐ Comment:
p.000534: Test Financial Plan: YES NO
p.000534: The test's financial plan is clear: ∑ ☐ Comment:
p.000534: Examiner fees match the estimated scope of work: ∑ ☐ Comment:
p.000534: Rapporteur's recommendation for the adoption of the SPS opinion at the meeting (specify date):
p.000534: (delete unnecessarily; in case b, c or d, reasons must be provided)
p.000534: a. positive thinking
p.000534: b. conditional positive thinking
p.000534: c. it is delayed
p.000534: d. negative thinking
p.000534: Reasons:
p.000534: Report date Reporter's signature:
p.000534: [1] 1 [1] In ICH's E5 Guidelines on Ethnic Factors Affecting Clinical Acceptance from Other Countries, Factors
p.000534: which may influence different drug response in different populations are divided into internal and external ethnic factors. Here you are
p.000534: categories are called internal or external factors only.
p.000534: ANNEX VII.
p.000534: AGENCY FOR MEDICINAL PRODUCTS AND MEDICAL PRODUCTS
p.000534: APPLICATION FORM FOR APPLICATION AND ASSESSMENT OF NON-INTERVENTION TEST
p.000534: Non-interventional background information (to be completed by the applicant)
p.000534: Name of non-intervention test in Croatian:
p.000534: Name of the non-intervention test in English:
p.000534: Name of the active substance (INN):
p.000534: Name of drug:
p.000534: Test plan designation:
p.000534: Authorization holder name and address:
p.000534: Name and address of the contracting authority:
p.000534: Applicant's name and address:
p.000534: Name and surname of the local pharmacovigilance officer
p.000534: Principal examiners and institutions where non-intervention testing will be conducted (names of institutions and examiners' names):
p.000534: Objectives of the test:
p.000534: Inclusion criteria:
p.000534: Exclusion criteria:
p.000534: Anticipated number of patients to be monitored:
p.000534: Estimated duration of testing in the Republic of Croatia:
p.000534: Countries where the non-intervention testing in question is already underway
p.000534: Countries where a request has been made to conduct the non-intervention test in question
p.000534: EU PAS registry number *
p.000534: Shared PASS **
p.000534: * indicate whether PASS is registered in the EU PAS registry
p.000534: ** in the case where multiple marketing authorization holders participate in the planning and implementation of the PASS
p.000534: Documents provided (filled in by applicant)
p.000534: Test plan (mark, version and date):
p.000534: Test list (version and date):
...
Social / Fetus/Neonate
Searching for indicator fetus:
(return to top)
p.000534: 4.8.9. If the respondent or his legal representative cannot read, an impartial witness must be present for the entire duration of the interview. After
p.000534: that the respondent and / or his / her legal representative be read the consent form and other written information intended
p.000534: and after the respondent, or his / her legal representative, orally agrees to the respondent's participation in the examination and, if able,
p.000534: sign and date the statement form, the form should also be signed and dated by an impartial witness. By signing the statement, witness
p.000534: confirms that the information in the form and other information is accurately explained and is, in his estimation, the respondent or his legal representative
p.000534: well understood and willingly gave his consent.
p.000534: 4.8.10. The interview to obtain consent, the consent form, and other written notice intended for the respondents must state and explain the following:
p.000534: (a) That the examination is of an investigative nature;
p.000534: (b) Purpose of the test;
p.000534: (c) Test procedures and the likelihood that the subject will be randomly assigned to a particular treatment group;
p.000534: (d) Procedures provided for in the test, including invasive procedures;
p.000534: (e) Respondents' obligations;
p.000534: (f) Experimental aspects of testing;
p.000534: (g) Predictable risks and discomforts for the respondent, namely the embryo, fetus or infant;
p.000534: (h) Benefits to be expected. Where no clinical benefit is expected for the respondent, it should be made known to the respondent;
p.000534: (i) Alternative procedures, ie treatment options available to the respondent, and the risks and benefits they may bring to the respondent;
p.000534: (j) Compensation and / or treatment provided to the respondent in the event of an injury resulting from his participation in the examination;
p.000534: (k) Expected timetable for payment of installments of any compensation to respondents for participation in the examination;
p.000534: (l) Any expected costs for the respondent for participating in the examination;
p.000534: (m) that the respondent's participation in the examination is voluntary and that the respondent may refuse to participate in the examination or withdraw from it at any time,
p.000534: without being punished or losing the rights he otherwise exercises;
p.000534: (n) That the observer (s), the persons supervising (s), the Commission and the competent authorities will have direct access to the respondent's original health information for the sake of
p.000534: validation of clinical trial procedures and data obtained, with full protection of the confidentiality of the respondents' identities within the limits of applicable laws and regulations, as well as
p.000534: that the respondent or his / her legal representative expresses his / her consent to such access to information by signing the statement of consent;
...
Social / Homeless Persons
Searching for indicator homeless:
(return to top)
p.000534: 1.59. Location of clinical trial
p.000534: Site where clinical trial activities are conducted.
p.000534: 1.60. An unexpected side effect
p.000534: A side effect whose nature or weight is inconsistent with valid product information (e.g., examiner instructions for disapproved test product or instructions
p.000534: on the product / summary of the product if it is an approved product) (see ICH Guidelines for the handling of clinical harm data: Definitions and
p.000534: standards for emergency reporting).
p.000534: 1.61. Particularly sensitive respondents
p.000534: Individuals whose willingness to participate in a clinical trial may be unduly influenced by the expectation, whether justified or not, that their participation
p.000534: to bring certain benefits, that is, otherwise they will be avenged by the elderly or superiors. Members can serve as an example
p.000534: hierarchical groups such as medical, pharmacy or dental students, hospital and laboratory staff, pharmaceutical employees
p.000534: industry, members of the military of that person in custody or prison. The mentioned respondents include patients with incurable diseases, residents
p.000534: housing, the unemployed and the poor, emergency patients, ethnic minorities, homeless people, nomads, refugees, minors and
p.000534: persons unable to consent.
p.000534: 1.62. Well-being (of respondents)
p.000534: Physical and spiritual integrity of the clinical trial participant.
p.000534: 2. ICH PRINCIPLES OF GOOD CLINICAL PRACTICE
p.000534: 2.1. Clinical trials must be conducted in accordance with the ethical principles of the Helsinki Declaration and in accordance with good practice.
p.000534: clinical practice and applicable law.
p.000534: 2.2. Before starting a clinical trial, the expected risks and disruptions to the expected benefits for the individual subject and
p.000534: society. Clinical trials should only be started and continued if the expected benefit justifies the risk.
p.000534: 2.3. The rights, safety and well-being of respondents who are ahead of the interests of science and society.
p.000534: 2.4. The available preclinical and clinical data on the product under test must sufficiently support the conduct of the clinical trial.
p.000534: 2.5. The scientific foundations of clinical trials must be sound and the Trial Plan must be clear and detailed.
p.000534: 2.6. Testing should be carried out in accordance with the Clinical Trials / Independent Review Panel approved / tested positive
p.000534: of the Ethics Committee.
p.000534: 2.7. Responsibility for the health care of the respondent and for decisions regarding his or her treatment must always rest with a qualified medical doctor,
p.000534: where appropriate, to a qualified dental doctor.
p.000534: 2.8. All persons conducting the examination must have the appropriate education, expertise and experience to be able to carry out their tasks.
...
Social / Incarcerated
Searching for indicator prison:
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p.000534: 1.58. Respondent's identification mark
p.000534: Unique identifier assigned by the examiner to each respondent to protect the respondent's identity, which is used instead of the name
p.000534: the respondent when the examiner reports adverse event and / or other information related to the examination.
p.000534: 1.59. Location of clinical trial
p.000534: Site where clinical trial activities are conducted.
p.000534: 1.60. An unexpected side effect
p.000534: A side effect whose nature or weight is inconsistent with valid product information (e.g., examiner instructions for disapproved test product or instructions
p.000534: on the product / summary of the product if it is an approved product) (see ICH Guidelines for the handling of clinical harm data: Definitions and
p.000534: standards for emergency reporting).
p.000534: 1.61. Particularly sensitive respondents
p.000534: Individuals whose willingness to participate in a clinical trial may be unduly influenced by the expectation, whether justified or not, that their participation
p.000534: to bring certain benefits, that is, otherwise they will be avenged by the elderly or superiors. Members can serve as an example
p.000534: hierarchical groups such as medical, pharmacy or dental students, hospital and laboratory staff, pharmaceutical employees
p.000534: industry, members of the military of that person in custody or prison. The mentioned respondents include patients with incurable diseases, residents
p.000534: housing, the unemployed and the poor, emergency patients, ethnic minorities, homeless people, nomads, refugees, minors and
p.000534: persons unable to consent.
p.000534: 1.62. Well-being (of respondents)
p.000534: Physical and spiritual integrity of the clinical trial participant.
p.000534: 2. ICH PRINCIPLES OF GOOD CLINICAL PRACTICE
p.000534: 2.1. Clinical trials must be conducted in accordance with the ethical principles of the Helsinki Declaration and in accordance with good practice.
p.000534: clinical practice and applicable law.
p.000534: 2.2. Before starting a clinical trial, the expected risks and disruptions to the expected benefits for the individual subject and
p.000534: society. Clinical trials should only be started and continued if the expected benefit justifies the risk.
p.000534: 2.3. The rights, safety and well-being of respondents who are ahead of the interests of science and society.
p.000534: 2.4. The available preclinical and clinical data on the product under test must sufficiently support the conduct of the clinical trial.
p.000534: 2.5. The scientific foundations of clinical trials must be sound and the Trial Plan must be clear and detailed.
p.000534: 2.6. Testing should be carried out in accordance with the Clinical Trials / Independent Review Panel approved / tested positive
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Searching for indicator restricted:
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p.000534: - death of a person,
p.000534: - life-threatening condition,
p.000534: - the need for hospital treatment or extension of pre-existing hospital treatment,
p.000534: - permanent or severe disability or incapacity,
p.000534: - congenital anomaly / birth defect.
p.000534: (see ICH Clinical Safety Information Guidelines: Definitions and Standards for Emergency Reporting).
p.000534: 1.51. Original data
p.000534: All data in original documents and certified copies of original records of clinical findings of observations or other procedures in clinical trials
p.000534: required to monitor the course and evaluate the clinical trial.
p.000534: The original information is contained in the original documentation (original records or certified copies).
p.000534: 1.52. Original documentation
p.000534: Original files, data, and records (e.g., hospital records, hospital and medical records, laboratory notes, memos, test subjects' diaries, or
p.000534: checklists, medication lists, recorded data from automated devices, copies and transcripts certified as authentic copies, micro-shi,
p.000534: negatives, micro lms and magnetic media, x-rays, test files and records from pharmacies, laboratories and health departments
p.000534: involved in the clinical trial.
p.000534: 1.53. Investigator
p.000534: An individual, company, institution or organization responsible for initiating, conducting and / or financing a clinical trial.
p.000534: 1.54. Investigator - examiner
p.000534: An individual who initiates and conducts, alone or with others, a clinical trial and under whose immediate management the test product is prescribed, dispensed, or
p.000534: the respondent applies it. This term is restricted to natural persons (ie does not include legal persons such as corporations or agencies).
p.000534: Obligations of the client-examiner include both the obligations of the clinical trial client and those of the clinical trial examiner.
p.000534: 1.55. Standard Operating Procedures (SOPs)
p.000534: Detailed written Instructions to ensure uniformity in the conduct of certain tasks.
p.000534: 1.56. Assistant Examiner
p.000534: Each individual member of the clinical trial team assigned or supervised by the examiner at the clinical trial establishment
p.000534: performing clinical trial procedures and / or making clinical trial decisions (eg associates, specialists, scientific
p.000534: associates). See also Examiner.
p.000534: 1.57. Respondent / clinical trial participant
p.000534: The person participating in the clinical trial, whether receiving the test product or serving as a control.
p.000534: 1.58. Respondent's identification mark
p.000534: Unique identifier assigned by the examiner to each respondent to protect the respondent's identity, which is used instead of the name
p.000534: the respondent when the examiner reports adverse event and / or other information related to the examination.
p.000534: 1.59. Location of clinical trial
p.000534: Site where clinical trial activities are conducted.
p.000534: 1.60. An unexpected side effect
p.000534: A side effect whose nature or weight is inconsistent with valid product information (e.g., examiner instructions for disapproved test product or instructions
p.000534: on the product / summary of the product if it is an approved product) (see ICH Guidelines for the handling of clinical harm data: Definitions and
p.000534: standards for emergency reporting).
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Social / Infant
Searching for indicator infant:
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p.000534: 4.8.9. If the respondent or his legal representative cannot read, an impartial witness must be present for the entire duration of the interview. After
p.000534: that the respondent and / or his / her legal representative be read the consent form and other written information intended
p.000534: and after the respondent, or his / her legal representative, orally agrees to the respondent's participation in the examination and, if able,
p.000534: sign and date the statement form, the form should also be signed and dated by an impartial witness. By signing the statement, witness
p.000534: confirms that the information in the form and other information is accurately explained and is, in his estimation, the respondent or his legal representative
p.000534: well understood and willingly gave his consent.
p.000534: 4.8.10. The interview to obtain consent, the consent form, and other written notice intended for the respondents must state and explain the following:
p.000534: (a) That the examination is of an investigative nature;
p.000534: (b) Purpose of the test;
p.000534: (c) Test procedures and the likelihood that the subject will be randomly assigned to a particular treatment group;
p.000534: (d) Procedures provided for in the test, including invasive procedures;
p.000534: (e) Respondents' obligations;
p.000534: (f) Experimental aspects of testing;
p.000534: (g) Predictable risks and discomforts for the respondent, namely the embryo, fetus or infant;
p.000534: (h) Benefits to be expected. Where no clinical benefit is expected for the respondent, it should be made known to the respondent;
p.000534: (i) Alternative procedures, ie treatment options available to the respondent, and the risks and benefits they may bring to the respondent;
p.000534: (j) Compensation and / or treatment provided to the respondent in the event of an injury resulting from his participation in the examination;
p.000534: (k) Expected timetable for payment of installments of any compensation to respondents for participation in the examination;
p.000534: (l) Any expected costs for the respondent for participating in the examination;
p.000534: (m) that the respondent's participation in the examination is voluntary and that the respondent may refuse to participate in the examination or withdraw from it at any time,
p.000534: without being punished or losing the rights he otherwise exercises;
p.000534: (n) That the observer (s), the persons supervising (s), the Commission and the competent authorities will have direct access to the respondent's original health information for the sake of
p.000534: validation of clinical trial procedures and data obtained, with full protection of the confidentiality of the respondents' identities within the limits of applicable laws and regulations, as well as
p.000534: that the respondent or his / her legal representative expresses his / her consent to such access to information by signing the statement of consent;
...
p.000534: Below, one of the age groups is offered. However, there is significant overlap in development across all groups (e.g.,
p.000534: cognitive, psychosocial). Age is defined by days, months or years.
p.000534: • Newborns born before term (premature infants)
p.000534: • Newborns born within term (0 - 27 days, newborn born)
p.000534: • Children aged 28 days to 23 months (infants and young children)
p.000534: • Children aged 2 to 11 years
p.000534: • Adolescents (12 to 16-18 years, depending on country)
p.000534: 2.5.1. Newborns born before term (premature infants)
p.000534: The study of premature infants raises special questions, since both the pathology and the response to treatment are unique to this group. Complexity
p.000534: tests in preterm infants and related ethical issues indicate the need for careful protocol design in collaboration with neonatologists and neonatal
p.000534: pharmacologists. Only in rare cases will it be possible to apply the results of efficacy obtained in adults and even older children to premature babies.
p.000534: Newborns as an age group are not homogeneous. There is a big difference between having a baby weighing 500g born at week 25 and 1,500g
p.000534: premature infant born at 30 weeks gestation.
p.000534: It is also important to distinguish whether children with low birth weight are immature or with stunted growth.
p.000534: It is important for these patients to consider the following features: (1) gestational and postnatal age (adjusted age); (2) immaturity of elimination mechanisms
p.000534: via the kidney and liver; (3) problems with protein binding and displacement (especially bilirubin); (4) penetration of the drug into the central nervous system (CNS); (5)
p.000534: health conditions unique to the newborn (eg respiratory stress syndrome, patent ductusarteriosus, primary pulmonary hypertension);
p.000534: (6) preferences inherent in preterm infants (eg, propensity for necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of preterm infants); (7) quickly
p.000534: and unequal maturation of all the biological and pharmacological processes, which necessitates a change in dosage regimen upon long-term drug exposure; and (8)
p.000534: absorption of the drug and other chemical compounds through the skin.
p.000534: Issues to consider in exam planning include: (1) division by body weight and age (gestational and postnatal); (2) small volume
p.000534: blood (prematurely weighing 500 g has only 40 mL of blood); (3) the small number of such patients in a particular healthcare facility and the differences in their treatment among
p.000534: and (4) difficulties in evaluating treatment outcomes.
p.000534: 2.5.2. Newborn born within term (0 - 27 days, newborn born)
p.000534: Although newborns are born within the term mature in development from preterm infants, many of the more described zoological and pharmacological values apply to them
p.000534: settings. In these, the volume of drug distribution may differ from that of older children because of the different ratio of body fluid and fat and because
p.000534: high ratio of skin surface area to body weight. The blood-brain barrier is not yet fully mature, so drugs and endogenous substances (eg bilirubin) may
p.000534: penetrate the CSF and act toxic. Absorption of the drug after oral administration is less predictable than in older children. Elimination mechanisms
p.000534: through the liver and kidney are not yet mature and undergoing rapid changes; therefore, the dosage of the drug should be adjusted in the first weeks of the infant's life.
p.000534: There are many examples of newborn susceptibility to drug toxicity resulting from limited elimination (eg, aplastic anemia caused by
p.000534: chloramphenicol, eng. chloramphenicolgreybabysyndrome). On the other hand, a term-born infant is less sensitive to some side effects
p.000534: (e.g., nephrotoxicity ofaminoglycoside) from elderly patients.
p.000534: 2.5.3. Children aged 28 days to 23 months (infants and young children)
p.000534: At this age, the CSF matures rapidly, the immune system develops and the entire body grows. Absorption after oral administration is now more reliable. It goes on and on
p.000534: rapid maturation of elimination mechanisms via the liver and kidney. Computing in mg / kg, many drugs are eliminated faster in children 1 - 2 years of age than
p.000534: in adults.
p.000534: The developmental maturation pathway depends on specific elimination pathways. Differences in maturation among children are often noticeable.
p.000534: 2.5.4. Children aged 2 to 11 years
p.000534: Most elimination pathways (via liver and kidney) are now mature, and elimination is often greater than in adults. Changes in drug elimination can
p.000534: depend on the maturation of specific metabolic pathways.
p.000534: Appropriate strategies should be set out in the protocol to identify any effects of the drug on the growth and development of the child. There are several at this age
...
Social / Institutionalized
Searching for indicator institutionalized:
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p.000534: Participants must be aware of their right to refuse participation or withdraw from the examination at any time. It should be addressed
p.000534: attention to the signs of excessive suffering in patients who are unable to clearly express their suffering. Although it must respect the respondent's decision to
p.000534: withdraw from testing, in therapeutic trials of serious and life-threatening diseases such circumstances are possible which, in the opinion of the examiner and
p.000534: parent / guardian, may jeopardize the welfare of the child in the event of his / her withdrawal. In these circumstances, further consent from the parent (guardian) is sufficient
p.000534: to continue the child's participation in the examination. Independent or elderly minors (as defined by local law) may be on their own
p.000534: able to give consent.
p.000534: Data that may be collected in a less vulnerable population that has consented to participate is not advisable to be collected in a more vulnerable population,
p.000534: that is, from patients who are unable to give informed consent. Examinations in handicapped or institutionalized children should be limited to those
p.000534: diseases and health conditions that are mainly or exclusively related to these populations, or to the circumstances in which their disease is expected
p.000534: or health change the behavior or pharmacodynamics of medical devices.
p.000534: 2.6.4. How to minimize risk
p.000534: Whatever the importance of testing in proving or denying the value of a treatment, it can lead to injury in the subjects even when
p.000534: polls benefit the entire community. Therefore, every effort should be made to anticipate and limit known hazards. Even before the beginning
p.000534: clinical trial, investigators must have complete insight into all preclinical and clinical data on drug toxicity. To take a risk in pediatric
p.000534: clinical trials minimized, the staff conducting them need to be well trained and experienced in testing with children, which
p.000534: it also involves identifying and treating possible side effects in children.
p.000534: When designing the test plan, every effort should be made to minimize the number of participants and procedures in the spirit of good test planning.
p.000534: Mechanisms need to be devised to quickly complete testing for unexpected hazards.
p.000534: 2.6.5. How to alleviate suffering as much as possible
p.000534: Frequent invasive procedures can hurt and scare a child.
p.000534: Uncomfortable feelings can be minimized if examinations are planned and conducted by examiners experienced in treating children.
...
Social / Laboratory Staff
Searching for indicator laboratory staff:
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p.000534: associates). See also Examiner.
p.000534: 1.57. Respondent / clinical trial participant
p.000534: The person participating in the clinical trial, whether receiving the test product or serving as a control.
p.000534: 1.58. Respondent's identification mark
p.000534: Unique identifier assigned by the examiner to each respondent to protect the respondent's identity, which is used instead of the name
p.000534: the respondent when the examiner reports adverse event and / or other information related to the examination.
p.000534: 1.59. Location of clinical trial
p.000534: Site where clinical trial activities are conducted.
p.000534: 1.60. An unexpected side effect
p.000534: A side effect whose nature or weight is inconsistent with valid product information (e.g., examiner instructions for disapproved test product or instructions
p.000534: on the product / summary of the product if it is an approved product) (see ICH Guidelines for the handling of clinical harm data: Definitions and
p.000534: standards for emergency reporting).
p.000534: 1.61. Particularly sensitive respondents
p.000534: Individuals whose willingness to participate in a clinical trial may be unduly influenced by the expectation, whether justified or not, that their participation
p.000534: to bring certain benefits, that is, otherwise they will be avenged by the elderly or superiors. Members can serve as an example
p.000534: hierarchical groups such as medical, pharmacy or dental students, hospital and laboratory staff, pharmaceutical employees
p.000534: industry, members of the military of that person in custody or prison. The mentioned respondents include patients with incurable diseases, residents
p.000534: housing, the unemployed and the poor, emergency patients, ethnic minorities, homeless people, nomads, refugees, minors and
p.000534: persons unable to consent.
p.000534: 1.62. Well-being (of respondents)
p.000534: Physical and spiritual integrity of the clinical trial participant.
p.000534: 2. ICH PRINCIPLES OF GOOD CLINICAL PRACTICE
p.000534: 2.1. Clinical trials must be conducted in accordance with the ethical principles of the Helsinki Declaration and in accordance with good practice.
p.000534: clinical practice and applicable law.
p.000534: 2.2. Before starting a clinical trial, the expected risks and disruptions to the expected benefits for the individual subject and
p.000534: society. Clinical trials should only be started and continued if the expected benefit justifies the risk.
p.000534: 2.3. The rights, safety and well-being of respondents who are ahead of the interests of science and society.
p.000534: 2.4. The available preclinical and clinical data on the product under test must sufficiently support the conduct of the clinical trial.
p.000534: 2.5. The scientific foundations of clinical trials must be sound and the Trial Plan must be clear and detailed.
...
Social / Linguistic Proficiency
Searching for indicator language:
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p.000534: - the safety of the respondents, the physical or spiritual integrity of the respondents,
p.000534: - the scientific value (benefit) of the test.
p.000534: Article 4
p.000534: The clinical trial is conducted in a legal entity that meets the following conditions:
p.000534: - employ experts who, through their knowledge and experience, ensure that the trial will be conducted in accordance with the clinical trial plan,
p.000534: - has equipment that allows the clinical trial to be conducted according to the clinical trial plan, or has a system in place to use the equipment
p.000534: and / or the procedures provided for in the test plan,
p.000534: - has in place a system for storing documentation resulting from clinical trials under this Ordinance.
p.000534: Article 5
p.000534: The clinical trial is conducted by an examiner who:
p.000534: - has completed undergraduate and graduate university studies or an integrated undergraduate and graduate university degree in health care, and
p.000534: specific training if provided by the test plan,
p.000534: - has documented training on good clinical practice,
p.000534: - concurrently conducts a maximum of five clinical trials that are under active patient involvement.
p.000534: Article 6
p.000534: (1) A clinical trial observer is a person appointed by an applicant who:
p.000534: - has a professional or undergraduate degree or undergraduate or graduate university degree or an integrated undergraduate or graduate degree
p.000534: university study,
p.000534: - has documented training on good clinical practice,
p.000534: - is a citizen of the Republic of Croatia or an alien with a permit or consent to work in accordance with special regulations on aliens and with evidence of
p.000534: knowledge of the Croatian language.
p.000534: (2) The acceptability of the observers shall be assessed by the Ministry.
p.000534: (3) The observer's register shall be kept by the Ministry.
p.000534: Article 7
p.000534: (1) A clinical trial of a medicinal product, including an incorrect clinical trial, cannot be initiated in the Republic of Croatia without a favorable opinion.
p.000534: Of the Central Ethics Committee and the approval of the Ministry, except as provided for in Article 14, paragraph 9 of this Ordinance.
p.000534: (2) Applicant, who has been approved by the Ministry to conduct a clinical trial based on the positive opinion of the Central
p.000534: The Ethics Committee, while seeking approval for conducting clinical trials in additional legal entities, is obliged to obtain the consent of the Central
p.000534: an ethics committee for each subsequent legal entity to be included in the clinical trial, as well as seek the approval of the Ministry.
p.000534: Article 8
p.000534: The Central Ethics Committee is responsible for giving opinions in the approval process as well as in the opinion process on significant changes and
p.000534: additions to clinical, non-intervention and non-profit trials in the Republic of Croatia.
p.000534: Article 9
p.000534: (1) The Central Ethics Committee is an independent body composed of health professionals and other members of the non-medical profession, set up in accordance with
...
p.000534: as soon as possible after making that decision. Notification submitted electronically or by fax must be submitted as soon as possible
p.000534: Ministry and in writing, with a brief explanation of the reasons for the withdrawal of the request.
p.000534: (14) Where the applicant intends to resubmit for approval a request which he has previously withdrawn, he shall indicate
p.000534: request to the Ministry and EU EudraCT Clinical Trial Application Form, hereinafter CTA
p.000534: form) to be a repeated request, in accordance with Communication from the European Commission 2010 / C 82/01 - Communication from the Commission -
p.000534: Detailed guidance on the request to the competent authorities for the authorization of a clinical trial on a medicinal product for human use, the notification of a substantial
p.000534: amendments to the Trial End of Trial (CT-1).
p.000534: Article 15
p.000534: (1) The Ministry shall grant, or deny, a decision to conduct a clinical trial, including an incorrect clinical trial, by a decision against
p.000534: which may not be appealed but an administrative dispute may be brought against the decision.
p.000534: (2) The Ministry shall submit the approval for conducting a clinical trial to the applicant, the Central Ethics Committee, the Agency, the Croatian
p.000534: Department of Health Insurance and Pharmaceutical Inspection of the Ministry.
p.000534: Article 16
p.000534: (1) In the process of applying to the Ministry for approval to carry out a clinical trial of a medicinal product, including an incorrect test, and to obtain
p.000534: the opinions of the Central Ethics Committee, the following documentation must be submitted:
p.000534: 1. Request in the Croatian language, with the signature of the applicant's responsible person. The application must include: the test plan code, the EudraCT number
p.000534: tests, name of test, test phase, name and address of the test client, name and address of the applicant and list of lead examiners and
p.000534: establishments where the clinical trial is planned to be conducted as well as a brief explanation of the application,
p.000534: 2. instructions for the examiner, for the investigational medicinal product not authorized for marketing, issued within one year,
p.000534: 3. summary description of the product characteristics, for investigational medicinal products with a valid marketing authorization,
p.000534: 4. the CV of the examiner showing that it meets the criteria referred to in Article 5 of this Ordinance,
p.000534: 5. the CV of the observer, which will show that it meets the criteria referred to in Article 6 of this Ordinance,
p.000534: 6. a list of countries where the same clinical trial is planned and at the time of application for authorization
p.000534: clinical trial the same trial approved or refused, including the reasons for the refusal,
p.000534: 7. examination plan and any amendments signed by the Examiner,
p.000534: 8. copy of the test list of respondents in electronic form,
p.000534: 9. informed consent form in the Croatian language and Latin script, and the original text,
p.000534: 10. a summary of the scientific opinion of the European Medicines Agency regarding the administration of the investigational medicinal product (if available),
p.000534: 11. copy of the decision of the European Medicines Agency on the pediatric trial plan and the opinion of the pediatric committee, if clinical trial
p.000534: implements according to the pediatric drug development plan (PIP),
p.000534: 12. an example of the labeling of the test drug,
p.000534: 13. financial test plan,
p.000534: 14. proof of insurance of the subjects from the possible adverse consequences of participation in the clinical trial,
p.000534: 15. written authorization to the legal person who submits the request to the Minister for approval of the clinical trial in case the request is not submitted by the client
p.000534: clinical trial,
p.000534: 16. proof of payment of costs in the process of granting approval for conducting a clinical trial.
p.000534: (2) In addition to the documentation referred to in paragraph 1 of this Article, the applicant shall submit to the Central Ethics Committee:
p.000534: - the completed form in Annex IV. and Annex V which are annexed to this Ordinance and form an integral part thereof.
p.000534: (3) In addition to the documentation referred to in paragraph 1 of this Article, the applicant shall submit to the Ministry:
p.000534: - the completed form in Annex III. which is annexed to this Ordinance and forms an integral part thereof,
p.000534: - IMPD
p.000534: - CTA form in English,
p.000534: - proof of payment of the administrative fee.
p.000534: Article 17
...
p.000534: examination sites, the total number of subjects screened and the total number of subjects included in the examination.
p.000534: (2) The applicant shall inform the Central Ethics Committee and the Ministry of any changes to the clinical trial.
p.000534: (3) Significant amendments shall be subject to the procedure of obtaining the opinion of the Central Ethics Committee and the approval of the Ministry.
p.000534: (4) Minor administrative amendments shall not be subject to the procedure of obtaining the opinion of the Central Ethics Committee and the approval of the Ministry,
p.000534: the Central Ethics Commission and the Ministry are already informed.
p.000534: (5) The applicant for the approval of significant changes and additions to the clinical trial shall also be required to submit a certificate of payment of costs
p.000534: procedure in accordance with the decision of the competent authority.
p.000534: Article 21
p.000534: Clinical trials in the Republic of Croatia are conducted in accordance with the standard set out in the Guideline of the European Medicines Agency and its body
p.000534: Committee for Proprietary Medicinal Products: "Note for Guidance on GoodClinicalPractice" (CPMP / ICH / 135/95). The text of the Guidelines is translated into
p.000534: the Croatian language is set out in Annex I to this Ordinance and forms an integral part thereof.
p.000534: Article 22
p.000534: In addition to the Guideline referred to in Article 21 of this Ordinance, clinical trials of minors shall be conducted in accordance with the standard specified in
p.000534: Guideline of the European Medicines Agency and its body Committee for Proprietary Medicinal Products: »ClinicalInvestigation of Medicinal Products
p.000534: in the Pediatric Population ”(CPMP / ICH / 2711/99). The text of the Guidelines translated into Croatian is reproduced in Annex II. of this Ordinance does
p.000534: its integral part.
p.000534: Article 23
p.000534: (1) In conducting the clinical trial, the personal integrity and well-being of the subjects should be ensured in accordance with the Declaration of Helsinki.
p.000534: (2) All approved clinical trials in the Republic of Croatia shall be published on the Ministry's website as well as on the European Agency's website
p.000534: for medicinal products in the Clinical Trials Register (www.clinicaltrialsregister.eu).
p.000534: (3) The Ministry shall keep a register of all approved clinical trials in the Republic of Croatia.
p.000534: Article 24
p.000534: (1) Inspection supervision of clinical trials shall be conducted by a pharmaceutical inspection of the Ministry.
p.000534: (2) The pharmaceutical inspector of the Ministry shall conduct the inspection of clinical trials at the testing site, at the premises of the clinical trial client.
p.000534: and / or contracting authorities or in other legal entities where the competent authority deems it necessary to carry out supervision.
p.000534: (3) The pharmaceutical inspection shall carry out regular and extraordinary supervision over the clinical trial of medicinal products:
p.000534: - regular inspections are carried out in accordance with the annual control plan,
...
p.000534: consent of the Ministry.
p.000534: (3) The applicant is obliged to state the reasons for launching and the duration of the program, the number of examining places and respondents in each examiner
p.000534: the site that will participate in the program and the dose and route of administration. With the request, the applicant is required to attach the statements of the Chief Examiners to whom
p.000534: confirm their participation in the program and agree to continue monitoring the safety of drug administration and that the risk-benefit ratio justifies the administration of the drug
p.000534: in doses and in the manner prescribed by the proposed program.
p.000534: (4) At least once a year, the applicant shall notify the Central Ethics Committee and the Ministry of the implementation of the program, with emphasis
p.000534: to the safety of drug administration.
p.000534: (5) The applicant shall notify the Central Ethics Committee and the Ministry of the completion of the program within 90 days from the end of the program.
p.000534: program.
p.000534: Article 31
p.000534: (1) In the process of submitting a request to the Agency for approval of conducting non-intervention testing and obtaining the opinion of the Central Ethics
p.000534: Commissions, the applicant is required to provide the following documentation:
p.000534: - request in the Croatian language, with the signature of the applicant's responsible person; the request should include the name and address of the contracting authority, the name and
p.000534: the applicant's address and a list of the principal examiners and institutions where the non-interventional test will be conducted,
p.000534: - a test plan indicating the designation of the test plan, the version and the date of the test plan version,
p.000534: - test list of respondents,
p.000534: - the marketing authorization decision, if applicable,
p.000534: - approved summary of product characteristics and package leaflet in Croatian,
p.000534: - informed consent for the patient in the Croatian language, indicating the informed consent version and the date of the version,
p.000534: - the original informed consent for the patient in English, if applicable,
p.000534: - financial examination plan,
p.000534: - proof of payment of costs in the process of giving opinion to the Central Ethics Committee and authorizing the implementation of non-intervention
p.000534: testing.
p.000534: (2) In addition to the documentation referred to in paragraph 1 of this Article, the applicant shall submit to the Central Ethics Committee:
p.000534: - the completed form in Annex VI. which is annexed to this Ordinance and forms an integral part thereof.
p.000534: (3) In addition to the documentation referred to in paragraph 1 of this Article, the applicant shall submit to the Agency:
p.000534: - the completed form in Annex VII. which is annexed to this Ordinance and forms an integral part thereof,
p.000534: - opinion of the Central Ethics Committee on non-intervention testing,
p.000534: - proof of payment of the administrative fee.
p.000534: (4) The Central Ethics Committee is obliged to give a written opinion on the admissibility or inadmissibility of the proposed non-intervention test in
p.000534: within 30 days from the date of receipt of the duly filed request.
p.000534: (5) An orderly request within the meaning of this Ordinance shall mean the submission of the complete documentation prescribed in paragraph 1 of this Article.
...
p.000534: (12) The Agency is obliged to submit the decision on conducting the non-intervention examination to the applicant, the Ministry and the Croatian Institute for
p.000534: health insurance.
p.000534: (13) In the case referred to in paragraph 11 of this Article, the applicant shall submit to the Ministry and the Croatian Health Insurance Institute a notification.
p.000534: on the expiry of the deadline referred to in paragraph 8 of this Article and, instead of the Agency's approval, submit a positive opinion of the Central Ethics Committee and proof of proper
p.000534: the request received at the Agency.
p.000534: (14) The Agency shall keep records of all approved non-interventional testing.
p.000534: (15) All approved non-intervention testing in the Republic of Croatia is published on the Agency's website.
p.000534: Article 32
p.000534: (1) In the case of non-interventional safety testing of the medicinal product after obtaining marketing authorization for which the Agency does not
p.000534: authorizing the implementation, the applicant is obliged to submit to the Agency for inspection the following:
p.000534: - the written consent of the Pharmacovigilance Risk Assessment Committee (hereinafter: PRAC) to conduct a non-intervention test,
p.000534: - a non-intervention test plan approved by the PRAC,
p.000534: - test list of respondents,
p.000534: - informed consent for the patient in the Croatian language,
p.000534: - the original informed consent for the patient in English, if applicable,
p.000534: - a list of the main examiners and institutions where non-intervention testing will be carried out,
p.000534: - planned start and end of non-intervention testing,
p.000534: (2) The examination referred to in paragraph 1 of this Article may be initiated in the Republic of Croatia on the basis of the written consent of the PRAC, and after the holder of the authorization
p.000534: submit the approved test plan to the Agency.
p.000534: Article 33
p.000534: All clinical trials approved before the entry into force of this Ordinance will continue in accordance with the regulations under which they were initiated.
p.000534: Article 34
p.000534: On the day of the entry into force of this Ordinance, the Ordinance on Clinical Trials and Good Clinical Practice (Official Gazette, No.
p.000534: 14/2010 and 127/2010).
p.000534: Article 35
p.000534: This Ordinance shall enter into force on the eighth day after its publication in the Official Gazette.
p.000534: Class: 011-02 / 14-02 / 84
p.000534: Reg. No: 534-02-1-1 / 2-15-01
p.000534: Zagreb, 20 February 2015
p.000534: Minister
p.000534: cf. Siniša Varga, Ph.D. med. dent., v. r.
p.000534: ANNEX I
p.000534: GOOD CLINICAL PRACTICE
p.000534: GUIDELINES FOR GOOD CLINICAL PRACTICE
p.000534: INTRODUCTION
p.000534: Good clinical practice (GCP) includes international ethical and scientific standards for the quality of planning, implementation,
p.000534: human monitoring and reporting. Adherence to these standards provides public guarantees for the protection of the rights, safety and well-being of respondents in the
...
p.000534: regulations, good clinical practice and ethical principles that are the origin of the Declaration of Helsinki. In order to begin the examination, the examiner must have
p.000534: written approval / positive opinion of the Commission on the form of the statement of consent and other written notifications intended for the respondents.
p.000534: 4.8.2. After any new findings that might affect the Respondent's consent, the Consent Statement form and other written notice intended
p.000534: respondents should be amended accordingly. Prior to use, amended consent statement form and other written notices
p.000534: intended for the respondents should receive the approval / positive opinion of the Commission. Respondent, that is, his legal representative is valid
p.000534: inform in a timely manner new findings that may affect the respondent's willingness to continue to participate in the examination. This kind of notification
p.000534: should be documented.
p.000534: 4.8.3. Neither the examiner nor the examining staff shall coerce or unduly influence the respondent to participate in, or continue to participate in
p.000534: examination.
p.000534: 4.8.4. Oral and written testimony notices, including the statement of consent form, must not contain language formulations that would allow the respondent,
p.000534: that is, his legal representative stated that he at least ostensibly waives his legal rights, that is, which examiner, institution, contracting authority
p.000534: interrogation or their representative, at least apparently, absolves them of their negligence liability.
p.000534: 4.8.5. The examiner, ie the person appointed by him, needs the respondent or his legal representative, if the respondent is not competent to give
p.000534: consent, fully acquainted with all aspects of the examination, including written notice and approval / positive opinion of the Commission.
p.000534: 4.8.6. The choice of words and style of oral and written test reports, including the statement of consent form, should avoid technical terms as much as possible and
p.000534: be understandable to the respondent, that is, his / her legal representative and impartial witness.
p.000534: 4.8.7. Prior to obtaining the consent, the examiner or the person appointed by him / her must provide the respondent or his / her legal representative
p.000534: enough time and opportunity to find out the details of the examination that interest him to decide whether or not he wants to participate. Answer all the questions
p.000534: the test should satisfy the respondent or his / her legal representative.
p.000534: 4.8.8. Prior to the inclusion of the respondents in the examination, the respondent or his / her legal representative must be signed and personally dated
p.000534: statement of consent, also signed by the person interviewing the respondent / legal representative.
...
p.000534: The principal investigator reviewed the translation of the informed consent (specify version and date) and a summary of the test plan, which is confirmed by the signature
p.000534: of this SEP form
p.000534: Applicant / clinical trial applicant signature and date
p.000534: ANNEX VI.
p.000534: CENTRAL ETHICAL COMMITTEE
p.000534: APPLICATION FORM AND EVALUATION OF NON-INTERVENTIONAL TEST
p.000534: Non-interventional background information (to be completed by the applicant)
p.000534: Name of non-intervention drug test in Croatian:
p.000534: Name of non-intervention drug test in English:
p.000534: Test plan designation:
p.000534: Name and address of the contracting authority:
p.000534: Applicant's name and address:
p.000534: Principal examiners and establishments where non-interventional drug testing will be conducted (number of establishments and examiners): The list is attached to this form and is an integral part of it
p.000534: Objectives of the test:
p.000534: Inclusion criteria:
p.000534: Anticipated number of patients to be monitored:
p.000534: Estimated duration of testing in the Republic of Croatia:
p.000534: Documents provided (filled in by applicant)
p.000534: Test plan (mark, version and date):
p.000534: Approved Summary of Product Characteristics in the Republic of Croatia (approval date):
p.000534: Package leaflet for the medicinal product in the Republic of Croatia (date of approval):
p.000534: Decision on marketing authorization (date):
p.000534: Informed consent for the patient in Croatian language (version and date):
p.000534: Original informed consent in English (version and date):
p.000534: Test financial plan:
p.000534: Other documentation (list, with version and date of documents):
p.000534: Certificate of payment of the costs of giving the opinion of the SPS:
p.000534: Applicant's signature and date:
p.000534: _________________________________________
p.000534: Documentation evaluation (to be completed by the rapporteur)
p.000534: Test plan YES NO
p.000534: The medicine is prescribed according to the marketing authorization: ∑ ☐ Comment:
p.000534: Involvement of patients in a particular therapeutic procedure is not determined in advance by the test plan but is carried out in accordance with normal practice: ∑ ☐ Comment:
p.000534: Prescribing a drug is independent of the decision to include patients in the trial: ∑ ☐ Comment:
p.000534: Additional diagnostic and patient monitoring procedures are not performed (except those that form part of normal practice): ∑ ☐ Comment:
p.000534: Epidemiological methods are used to analyze the data collected: ∑ ☐ Comment:
p.000534: Testing does not promote prescribing of monitored drug: ∑ ☐ Comment:
p.000534: Informed consent in Croatian: YES NO
p.000534: The text clearly describes the conduct of the test, listing all the information needed to make the decision: ∑ ☐ Comment:
p.000534: The text of informed consent is understandable for patients: ∑ ☐ Comment:
...
p.000534: ANNEX VII.
p.000534: AGENCY FOR MEDICINAL PRODUCTS AND MEDICAL PRODUCTS
p.000534: APPLICATION FORM FOR APPLICATION AND ASSESSMENT OF NON-INTERVENTION TEST
p.000534: Non-interventional background information (to be completed by the applicant)
p.000534: Name of non-intervention test in Croatian:
p.000534: Name of the non-intervention test in English:
p.000534: Name of the active substance (INN):
p.000534: Name of drug:
p.000534: Test plan designation:
p.000534: Authorization holder name and address:
p.000534: Name and address of the contracting authority:
p.000534: Applicant's name and address:
p.000534: Name and surname of the local pharmacovigilance officer
p.000534: Principal examiners and institutions where non-intervention testing will be conducted (names of institutions and examiners' names):
p.000534: Objectives of the test:
p.000534: Inclusion criteria:
p.000534: Exclusion criteria:
p.000534: Anticipated number of patients to be monitored:
p.000534: Estimated duration of testing in the Republic of Croatia:
p.000534: Countries where the non-intervention testing in question is already underway
p.000534: Countries where a request has been made to conduct the non-intervention test in question
p.000534: EU PAS registry number *
p.000534: Shared PASS **
p.000534: * indicate whether PASS is registered in the EU PAS registry
p.000534: ** in the case where multiple marketing authorization holders participate in the planning and implementation of the PASS
p.000534: Documents provided (filled in by applicant)
p.000534: Test plan (mark, version and date):
p.000534: Test list (version and date):
p.000534: Approved Summary of Product Characteristics in the Croatian language (approval date):
p.000534: Approved package leaflet in the Croatian language (authorization date):
p.000534: Decision on marketing authorization (date):
p.000534: Informed consent for the patient in Croatian language (version and date):
p.000534: Original informed consent in English (version and date), if applicable:
p.000534: Test financial plan:
p.000534: Proposal of Notice to the Directorate of the Institution on Conducting Non-Intervention Testing
p.000534: Other documentation (list, with version and date of documents):
p.000534: SEP Opinion
p.000534: Signature of the applicant's responsible person
p.000534: requests and date
p.000534: __________________________
p.000534: [1] This Directive does not regulate the non-intervention testing of a medicinal product.
...
Searching for indicator linguistic:
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p.000534: Original informed consent in English (version and date):
p.000534: Test financial plan:
p.000534: Other documentation (list, with version and date of documents):
p.000534: Certificate of payment of the costs of giving the opinion of the SPS:
p.000534: Applicant's signature and date:
p.000534: _________________________________________
p.000534: Documentation evaluation (to be completed by the rapporteur)
p.000534: Test plan YES NO
p.000534: The medicine is prescribed according to the marketing authorization: ∑ ☐ Comment:
p.000534: Involvement of patients in a particular therapeutic procedure is not determined in advance by the test plan but is carried out in accordance with normal practice: ∑ ☐ Comment:
p.000534: Prescribing a drug is independent of the decision to include patients in the trial: ∑ ☐ Comment:
p.000534: Additional diagnostic and patient monitoring procedures are not performed (except those that form part of normal practice): ∑ ☐ Comment:
p.000534: Epidemiological methods are used to analyze the data collected: ∑ ☐ Comment:
p.000534: Testing does not promote prescribing of monitored drug: ∑ ☐ Comment:
p.000534: Informed consent in Croatian: YES NO
p.000534: The text clearly describes the conduct of the test, listing all the information needed to make the decision: ∑ ☐ Comment:
p.000534: The text of informed consent is understandable for patients: ∑ ☐ Comment:
p.000534: The informed consent text is linguistic, spelling and typographical correct: ∑ ☐ Comment:
p.000534: Other documentation provided: YES NO
p.000534: Fits test plan: ∑ ☐ Comment:
p.000534: Test Financial Plan: YES NO
p.000534: The test's financial plan is clear: ∑ ☐ Comment:
p.000534: Examiner fees match the estimated scope of work: ∑ ☐ Comment:
p.000534: Rapporteur's recommendation for the adoption of the SPS opinion at the meeting (specify date):
p.000534: (delete unnecessarily; in case b, c or d, reasons must be provided)
p.000534: a. positive thinking
p.000534: b. conditional positive thinking
p.000534: c. it is delayed
p.000534: d. negative thinking
p.000534: Reasons:
p.000534: Report date Reporter's signature:
p.000534: [1] 1 [1] In ICH's E5 Guidelines on Ethnic Factors Affecting Clinical Acceptance from Other Countries, Factors
p.000534: which may influence different drug response in different populations are divided into internal and external ethnic factors. Here you are
p.000534: categories are called internal or external factors only.
p.000534: ANNEX VII.
p.000534: AGENCY FOR MEDICINAL PRODUCTS AND MEDICAL PRODUCTS
p.000534: APPLICATION FORM FOR APPLICATION AND ASSESSMENT OF NON-INTERVENTION TEST
p.000534: Non-interventional background information (to be completed by the applicant)
p.000534: Name of non-intervention test in Croatian:
p.000534: Name of the non-intervention test in English:
p.000534: Name of the active substance (INN):
p.000534: Name of drug:
p.000534: Test plan designation:
p.000534: Authorization holder name and address:
...
Social / Literacy
Searching for indicator illiterate:
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p.000534: relating to the application of good clinical practice in the conduct of clinical trials of medicinal products for human use (OJ L 121, 1.5.2001). [1]
p.000534: Article 3
p.000534: (1) Certain terms within the meaning of this Ordinance have the following meaning:
p.000534: Good clinical practice is a set of internationally recognized ethical and scientific requirements that are followed in the planning, implementation, recording and reporting
p.000534: on clinical trials.
p.000534: Investigational Medicinal Product Dossier (hereinafter: IMPD) is a document showing data relating to
p.000534: the quality of the test drug, the production and control of the test drug, and data from non-clinical and clinical trials as well as data on the administration of the test drug
p.000534: drug in humans.
p.000534: Informed consent is consent to participate in a clinical trial on a voluntary basis based on received and properly documented notices
p.000534: on the nature and importance, consequences and risks of the examination, in writing, signed by the interviewee and dated. If the person is incompetent
p.000534: to give such consent or is a minor, the consent is signed by a legal representative or guardian. If the respondent is illiterate or unable to write, he gives
p.000534: oral consent in the presence of at least one witness who is not a member of the examination team.
p.000534: Inspection supervision of clinical trials is the oversight of the competent authority over the conduct of the clinical trial, review of documentation, premises, records,
p.000534: quality assurance systems and other resources related to the conduct of clinical trials that may be conducted at the test site, at the premises
p.000534: of the clinical trial client and / or the contracting authority or in other legal entities where the competent authority deems it necessary to carry out supervision.
p.000534: The respondent is an individual who participates in a clinical trial and receives the study drug or is part of a control group.
p.000534: The examiner is a doctor of medicine or a person with appropriate professional qualifications for clinical trials due to his / her professional knowledge and necessary
p.000534: experience in treating patients. The examiner is responsible for conducting the clinical trial at the test site. If a clinical trial is conducted by a group
p.000534: individuals in one examiner site, the examiner is responsible and is called the lead examiner.
p.000534: The test site is the health facility where the clinical trial is conducted.
...
Social / Marital Status
Searching for indicator single:
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p.000534: - planned start and end of non-intervention testing,
p.000534: (2) The examination referred to in paragraph 1 of this Article may be initiated in the Republic of Croatia on the basis of the written consent of the PRAC, and after the holder of the authorization
p.000534: submit the approved test plan to the Agency.
p.000534: Article 33
p.000534: All clinical trials approved before the entry into force of this Ordinance will continue in accordance with the regulations under which they were initiated.
p.000534: Article 34
p.000534: On the day of the entry into force of this Ordinance, the Ordinance on Clinical Trials and Good Clinical Practice (Official Gazette, No.
p.000534: 14/2010 and 127/2010).
p.000534: Article 35
p.000534: This Ordinance shall enter into force on the eighth day after its publication in the Official Gazette.
p.000534: Class: 011-02 / 14-02 / 84
p.000534: Reg. No: 534-02-1-1 / 2-15-01
p.000534: Zagreb, 20 February 2015
p.000534: Minister
p.000534: cf. Siniša Varga, Ph.D. med. dent., v. r.
p.000534: ANNEX I
p.000534: GOOD CLINICAL PRACTICE
p.000534: GUIDELINES FOR GOOD CLINICAL PRACTICE
p.000534: INTRODUCTION
p.000534: Good clinical practice (GCP) includes international ethical and scientific standards for the quality of planning, implementation,
p.000534: human monitoring and reporting. Adherence to these standards provides public guarantees for the protection of the rights, safety and well-being of respondents in the
p.000534: in accordance with the principles of the Helsinki Declaration, and that the clinical trial data are credible.
p.000534: The aim of these ICH Good Clinical Practice Guidelines is to provide a single standard for the European Union (EU), Japan and the United States of America.
p.000534: to facilitate the mutual acceptance of clinical data by the competent authorities of those countries.
p.000534: The guidelines have been developed keeping in mind good clinical practice in the practice of the European Union, Japan and the United States, as well as Australia, Canada,
p.000534: the Nordic countries and the World Health Organization (WHO).
p.000534: These guidelines should be followed when preparing clinical trial data that are made available to the competent authorities.
p.000534: The principles set out in these Guidelines may also be applied in other clinical trials that may affect the safety and well-being of subjects.
p.000534: 1. GLOSSARY
p.000534: 1.1. Side effects
p.000534: Clinical experience with a new drug / medicinal product or its new application that is prior to approval, especially if not
p.000534: established therapeutic doses: all adverse and adverse reactions to the drug / medicinal product regardless of the dose received are considered side effects. Expression
p.000534: "Reaction to a drug / medical device" means that the causal link between the medicinal product / medical device and a side effect has at least been identified as an option, ie.
p.000534: that it cannot be ruled out.
p.000534: In terms of market-approved medicines / medical products: harmful and adverse reactions of humans at doses commonly administered in prophylaxis,
p.000534: diagnosis, treatment of disease, or modification of a biological function (see ICH Guidelines for the Management of Clinical Safety Information:
...
p.000534: whether it is the cause or not (see ICH Guidelines for the Management of Clinical Safety Data: Emergency Deviations and Standards
p.000534: reporting).
p.000534: 1.3. Modifications and Additions (Clinical Trial Plan)
p.000534: See Changes and additions to the Clinical Trial Plan.
p.000534: 1.4. Legislation in force (s)
p.000534: Law (s) and regulation (s) related to the conduct of a clinical study of drug / medical product testing.
p.000534: 1.5. Approval (Refers to Clinical Trials Council)
p.000534: Positive decision of the Clinical Trial Council on clinical trial to be carried out within the institution within the limits set by the
p.000534: clinical trials, facilities, good clinical practices, and applicable law.
p.000534: 1.6. Supervision
p.000534: Systematic and independent review of clinical trial activities and related documentation to determine if activities in which
p.000534: performs surveillance conducted, data entered and analyzed and reported in accordance with the Clinical Trial Plan, standard operational
p.000534: test client procedures, good clinical practice, and applicable legal requirements.
p.000534: 1.7. Certificate of inspection
p.000534: A statement confirming that surveillance has been carried out.
p.000534: 1.8. Surveillance report
p.000534: A written statement informing the testing authority of the results of the surveillance.
p.000534: 1.9. Documenting surveillance
p.000534: Documentation to track the sequence of events.
p.000534: 1.10. Clinical trial blindness / masking
p.000534: A process in which one or more parties participating in a clinical trial do not know how treatment is assigned. Single blind trial
p.000534: usually refers to a patient who does not know the division of treatment, and double-blind to a respondent, examiner, observer, and in some cases,
p.000534: data analysts.
p.000534: 1.11. Test list
p.000534: Printed, optical or electronic document intended to record all data required by the Clinical Trial Plan used by the trial client
p.000534: reports on each respondent.
p.000534: 1.12. Clinical trial / clinical study
p.000534: Any human study intended to detect or confirm the clinical, pharmacological and / or other pharmacodynamic effects of the subject
p.000534: product, and / or the determination of side effects and / or the study of absorption, distribution, metabolism and excretion, with a view to determining the safety and / or
p.000534: the effectiveness of the test product. The terms clinical trial and clinical study are ambiguous.
p.000534: 1.13. Clinical Trial / Clinical Study Report
p.000534: Description of the clinical trial / study in writing of any therapeutic, pro-lactic or diagnostic agent administered in humans, and
p.000534: clinical and statistical description, presentation and analysis form a single report (see ICH Guidelines for the Structure and Content of the Clinical Report
p.000534: examination).
p.000534: 1.14. Product of comparison
p.000534: Tested or marketed product (ie active control), or placebo, used in the clinical trial as a comparison product.
p.000534: 1.15. Compliance (applies to clinical trial procedures)
p.000534: Compliance with all clinical trial requirements, good clinical practices and applicable legal requirements.
p.000534: 1.16. Confidentiality
p.000534: Preventing the disclosure, except to authorized persons, of the protected data of the test client, or the identity of the respondents.
p.000534: 1.17. The contract
p.000534: A written, dated and signed agreement between two or more parties specifying the delegation and distribution of tasks and obligations, and nancial matters there
p.000534: where necessary. The contract may be based on a Clinical Trial Plan.
p.000534: 1.18. Commission for Coordination
p.000534: A committee that may be set up by a trial client to coordinate the implementation of a multicenter clinical trial.
p.000534: 1.19. Examiner Coordinator
p.000534: Examiner responsible for coordinating examiners at different centers participating in multicenter testing.
p.000534: 1.20. Contracting research organization
p.000534: Person or organization (commercial, academic or otherwise) with whom the contracting authority has contracted to perform one or more duties and activities
p.000534: related to the clinical trial.
p.000534: 1.21. Direct access
p.000534: Approval to review, analyze, verify and transmit all data and reports relevant to the evaluation of the clinical trial. Any side that has a direct
...
p.000534: its use or method (formulation or packaging) differ from the approved one, or, if used for an indication that is not approved, or used for
p.000534: collecting further information on approved application.
p.000534: 1.34. Examiner
p.000534: The person responsible for conducting the clinical trial at the place where it is conducted. If a group of individuals conducts a site survey,
p.000534: the examiner is the person responsible for leading the group and is also referred to as the lead examiner. See also Assistant Examiner.
p.000534: 1.35. Examiner / Institution
p.000534: A term that designates "examiner and / or institution in accordance with applicable law."
p.000534: 1.36. Instructions for the examiner
p.000534: A set of clinical and preclinical data on an investigational product that is relevant to its human test (see 7. Test Guideline).
p.000534: 1.37. Legal representative
p.000534: An individual or legal entity or other body authorized by applicable law to consent to participate in a clinical trial on behalf of the respondent.
p.000534: 1.38. Observation
p.000534: The act of monitoring the progress of the clinical trial and ensuring that its implementation, documentation and reporting are consistent with the Clinical Trial Plan,
p.000534: standard operating procedures, good clinical practice and applicable legal requirements.
p.000534: 1.39. Observation report
p.000534: A written report submitted by the observer to the contracting authority after each visit to the examination site and / or upon new knowledge relating to
p.000534: testing in accordance with standard operating procedures of the test client.
p.000534: 1.40. Multicenter testing
p.000534: A clinical trial conducted in accordance with a single Clinical Trial Plan in more than one site and therefore conducted by more than one
p.000534: of the examiner.
p.000534: 1.41. Preclinical research
p.000534: Non-human biomedical research.
p.000534: 1.42. Opinion (applies to the Independent Ethics Committee)
p.000534: Assessment and / or recommendation issued by an independent ethics committee.
p.000534: 1.43. Original health information
p.000534: See Original Documents.
p.000534: 1.44. Clinical trial plan
p.000534: A document outlining the objectives, plan, methodology, statistics and organization of the test. In addition, it is usually explained in the Clinical Trial Plan
p.000534: background and meaning of the trial, but this can also be found in other documents referenced in the Clinical Trial Plan. In these ICH Guidelines
p.000534: the term "Clinical Trial Plan" refers to the Clinical Trial Plan itself and its amendments and additions.
p.000534: 1.45. Modifications and additions to the Clinical Trial Plan
p.000534: Amendments to the Clinical Trial Plan in writing or its formal clarification.
p.000534: 1.46. Quality assurance
p.000534: All planned and systematic activities aimed at ensuring compliance of the clinical trial, documenting (recording) results and reporting with
p.000534: good clinical practice and applicable legislation.
p.000534: 1.47. Quality control
p.000534: Implementation techniques and activities in the field of quality assurance aimed at verifying that all the quality requirements related to testing are fulfilled.
p.000534: 1.48. Random selection
p.000534: The process of randomly selecting subjects into treatment groups or control groups, thereby reducing bias.
p.000534: 1.49. Competent authorities
...
p.000534: The following sections of the Package Leaflet should discuss the most important results of preclinical studies, including the observed dependence of dose effects,
p.000534: importance for human application and other aspects to be tested in humans. Where possible, the results of effective non-toxic doses should be compared
p.000534: used in the same animal species (eg therapeutic index should be discussed). The importance of this information for proper use in humans should be considered.
p.000534: Wherever possible, comparisons should be based on blood / tissue levels rather than mg / kg.
p.000534: (a) Preclinical pharmacology
p.000534: A summary of the pharmacological aspects of the test product and significant metabolites observed in experimental animals should be provided, where appropriate
p.000534: possible. Such a summary should include research evaluating the potential therapeutic action of a drug (e.g., efficacy models,
p.000534: receptor binding and specificity) and its safety (eg special studies of pharmacological activities other than therapeutic ones).
p.000534: (b) Pharmacokinetics and metabolism of the test product in animals
p.000534: A summary of the pharmacokinetics and biotransformation (metabolism) and elimination of the test product in all animals in which
p.000534: conducted preclinical research. In discussing the results, we should refer to the absorption and local and systemic bioavailability of the test product and
p.000534: its metabolites, as well as their relationship with pharmacological and toxicological findings in animal species.
p.000534: (c) Toxicology
p.000534: Where appropriate, a concise description of the observed toxic effects in different species of animals should follow this structure:
p.000534: - Single dose;
p.000534: - Repeated dose;
p.000534: - Carcinogenicity;
p.000534: - Specific research (eg irritation and sensitization);
p.000534: - Reproductive toxicity;
p.000534: - Genotoxicity (mutagenicity).
p.000534: 7.3.6. Effects on humans
p.000534: Introduction:
p.000534: The known effects of the test product on humans should be thoroughly discussed, including information on its pharmacokinetics, metabolism,
p.000534: pharmacodynamics, dose dependence, safety, efficacy (efficacy) and other pharmacological actions. Wherever possible
p.000534: is to provide a summary of all completed clinical trials. Also, information regarding the application of the product under test should be provided outside
p.000534: clinical trials, such as post-marketing experience.
p.000534: (a) Pharmacokinetics and metabolism of the test product in humans
p.000534: - the pharmacokinetics of the test product should be summarized, including the following available data:
p.000534: - pharmacokinetics (including metabolism and absorption, plasma protein binding, distribution and elimination);
p.000534: - bioavailability of the test product (absolute and relative where possible) using the reference preparation;
p.000534: - population subgroups (eg by sex, age and impaired organ function);
p.000534: - interactions (eg drug interactions and the impact of food);
p.000534: - other pharmacokinetic data (eg results of population-based studies conducted in clinical trials).
p.000534: (b) Safety and efficiency
p.000534: Summary information on the safety, pharmacodynamics, efficacy (efficacy) and dose dependency of the product under test (including
...
p.000534: Considerations of data from preclinical safety studies of medicinal products relevant to clinical trials in children are described in ICH document M3,
p.000534: Section 11. It should be noted that the most relevant safety data for children are obtained from adult exposure studies.
p.000534: In general, repeated dose toxicity tests and reproductive and genotoxicity studies should be performed. Consideration should also be given to
p.000534: the need for individual developmental toxicology studies in young animals on a case by case basis.
p.000534: 2.2. Formulations for children
p.000534: Formulations for children are needed because they allow accurate dosing and contribute to adherence to the treatment regimen in children. In oral administration, certain
p.000534: the type of formulations, flavors, and colors may prove more acceptable in a country or region than another. For children of different ages may be desirable
p.000534: or need different formulations such as liquids, suspensions and chewable tablets. Different concentrations of the drug in
p.000534: these formulations. Other forms of drug administration should also be considered.
p.000534: Injections with appropriate drug concentrations should be de-injected to allow accurate and safe dose administration. When it comes to medicines in
p.000534: disposable vials, the appropriate packing of these single doses should be considered.
p.000534: There may be a difference in the toxicity of some of the excipients between children of different ages and between children and adults; e.g. benzyl alcohol is toxic to
p.000534: preterm infants.
p.000534: Depending on the active ingredient and excipients, appropriate administration of the drug to infants may necessitate a new formulation, or
p.000534: appropriate dilution information of the existing formulation. Harmonization of acceptable excipients in the formulation and their processes
p.000534: validation at the international level will make the availability of appropriate pediatric formulations everywhere in the world.
p.000534: 2.3. Timing of testing
p.000534: In the clinical phase of drug development, the planning of its use in children will depend on the drug itself, the disease it is intended for, its harmlessness, and
p.000534: efficacy and harmlessness of other possible treatments. Because developing formulations for children can be demanding and time-consuming, this is important
p.000534: formulation development to plan at an early stage of drug development.
p.000534: 2.3.1. Medicines for diseases most or exclusively affected by children
...
p.000534: Whether these are new indications for the use of the drug in children, or whether different course of illness and outcome of treatment between adults and children are expected,
p.000534: clinical trials on the efficacy of the drug in children should be performed.
p.000534: 2.4.1. Pharmacokinetics
p.000534: Pharmacokinetic studies are mainly performed to verify the newly developed formulation and to determine pharmacokinetic parameters for various
p.000534: age groups supporting the recommended doses.
p.000534: Comparisons of relative bioavailability between formulations for children and oral formulations for adults should be performed on adults. It's on the kids
p.000534: final pharmacokinetic studies should be conducted to determine the appropriate dose for each age group of children
p.000534: drug intended.
p.000534: In general, pharmacokinetic studies are performed on ill children. This may mean greater heterogeneity among subjects than in healthy subjects
p.000534: volunteers, but the data obtained better reflects clinical application.
p.000534: In the case of medicinal products exhibiting linear pharmacokinetics in adults, single use in pharmacokinetic studies in children
p.000534: may provide sufficient knowledge for dose selection.
p.000534: If necessary, this choice can be confirmed by occasional sampling in repeated dose clinical trials. Any
p.000534: nonlinearity in the absorption, distribution and elimination of the drug and any difference in the time of action between single and multiple dose in adults
p.000534: points to the need to test a drug in children when its dynamic balance is reached. Performing all of these procedures makes it easy to see
p.000534: pharmacokinetic parameters in adults. Knowledge of drug elimination pathways can often prove useful in planning trials in children
p.000534: (via the kidney and metabolism) and age-dependent changes in these processes.
p.000534: For most medicines, the recommended doses for children are based on milligrams per kilogram body weight (mg / kg) and range up to the highest adult dose.
p.000534: Although the first choice may be a dosage based on mg / m2 of body surface area, clinical experience indicates that frequent errors in height measurement or
p.000534: length (especially young children and infants), as well as in calculating the body surface area from these measurements. It is important to administer some medications on a physical basis
p.000534: surfaces (eg drugs with a narrow therapeutic index such as oncology), but extra caution should be exercised to calculate the amount
p.000534: correct.
p.000534: Practical considerations facilitating the conduct of pharmacokinetic studies
p.000534: The blood volume taken from children should be as small as possible. It must be justified within the protocol. Clinical Trials Board / Independent Ethics
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p.000534: all necessary reports to the competent authorities.
p.000534: 5. TEST ORDER
p.000534: 5.1. Quality assurance and control
p.000534: 5.1.1. The testing contractor is responsible for establishing and maintaining a quality assurance and quality control system through standard operating systems
p.000534: procedures to ensure that the clinical trial is conducted, documented (recorded) and reported to the Trial Plan,
p.000534: good clinical practice and applicable legislation.
p.000534: 5.1.2. The test client is responsible for reaching an agreement between the parties on direct access (see 1.21) to all test sites, original
p.000534: data / documents and reports so that it can monitor and supervise the test, or in order for the domestic or foreign competent authority
p.000534: could carry out an inspection.
p.000534: 5.1.3. Quality should be monitored at every stage of data handling to ensure its reliability and proper processing.
p.000534: 5.1.4. Agreements between the client and the examiner / institution and other parties involved in the clinical trial should be in writing
p.000534: as an integral part of the Examination Plan or as a separate agreement.
p.000534: 5.2. Contracting Research Organization (ITA)
p.000534: 5.2.1. The contracting authority may delegate all its obligations or tasks or part thereof to the contracting research organization, with ultimate responsibility
p.000534: the quality and completeness of the test results shall continue to be borne by the contracting authority. The ITA's job is to implement quality assurance and quality control procedures.
p.000534: 5.2.2. Each obligation and task related to the examination, which is transferred to the ITA, must be individually stated in writing.
p.000534: 5.2.3. The contracting authority retains those obligations and tasks that are not explicitly delegated to the ITA.
p.000534: 5.2.4. Anything in this Guideline that applies to the contracting authority shall also apply to the ITA to the extent that the ITA has assumed the obligations and tasks of
p.000534: of the contracting authority.
p.000534: 5.3. Expert medical opinion
p.000534: Nursing staff with appropriate qualifications should be identified who will always be able to give their expert opinion on issues and issues related to
p.000534: with examination. If necessary, the contracting authority may also appoint external consultants for this purpose.
p.000534: 5.4. Test plan
p.000534: 5.4.1. The client of the trial should hire qualified persons (eg biostatistics, clinical pharmacologists and medical doctors in accordance with the needs).
p.000534: all stages of testing, from the design of the Test Plan and Test List, through the planning of the analysis, to the analysis and preparation of interim and final clinical trials
p.000534: test reports.
p.000534: 5.4.2. For further guidance, see 6. Clinical Trial Plan and its Amendments and Appendices, ICH Guidelines for Compilation and Content of Clinical Trial Report
p.000534: Examination and other ICH Guidelines related to test planning, development of the Test Plan and conduct of the test.
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Social / Presence of Coercion
Searching for indicator coerce:
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p.000534: disclosure of a code linking the respondent and the product under investigation (eg by accident or due to a serious adverse reaction).
p.000534: 4.8. Consent of respondents
p.000534: 4.8.1. In the process of obtaining and recording the subject's consent to participate in the examination, the examiner must comply with the applicable legal requirements.
p.000534: regulations, good clinical practice and ethical principles that are the origin of the Declaration of Helsinki. In order to begin the examination, the examiner must have
p.000534: written approval / positive opinion of the Commission on the form of the statement of consent and other written notifications intended for the respondents.
p.000534: 4.8.2. After any new findings that might affect the Respondent's consent, the Consent Statement form and other written notice intended
p.000534: respondents should be amended accordingly. Prior to use, amended consent statement form and other written notices
p.000534: intended for the respondents should receive the approval / positive opinion of the Commission. Respondent, that is, his legal representative is valid
p.000534: inform in a timely manner new findings that may affect the respondent's willingness to continue to participate in the examination. This kind of notification
p.000534: should be documented.
p.000534: 4.8.3. Neither the examiner nor the examining staff shall coerce or unduly influence the respondent to participate in, or continue to participate in
p.000534: examination.
p.000534: 4.8.4. Oral and written testimony notices, including the statement of consent form, must not contain language formulations that would allow the respondent,
p.000534: that is, his legal representative stated that he at least ostensibly waives his legal rights, that is, which examiner, institution, contracting authority
p.000534: interrogation or their representative, at least apparently, absolves them of their negligence liability.
p.000534: 4.8.5. The examiner, ie the person appointed by him, needs the respondent or his legal representative, if the respondent is not competent to give
p.000534: consent, fully acquainted with all aspects of the examination, including written notice and approval / positive opinion of the Commission.
p.000534: 4.8.6. The choice of words and style of oral and written test reports, including the statement of consent form, should avoid technical terms as much as possible and
p.000534: be understandable to the respondent, that is, his / her legal representative and impartial witness.
p.000534: 4.8.7. Prior to obtaining the consent, the examiner or the person appointed by him / her must provide the respondent or his / her legal representative
p.000534: enough time and opportunity to find out the details of the examination that interest him to decide whether or not he wants to participate. Answer all the questions
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Social / Property Ownership
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p.000534: Instructions for use E-mail
p.000534: Home
p.000534: Rulebook on clinical trials and good clinical practice
p.000534: Ordinance, OG 25 / 2015-534 More
p.000534: MINISTRY OF HEALTH
p.000534: 534
p.000534: Pursuant to Article 8 (3), Article 13 and Article 18 (1) of the Medicines Act (Official Gazette 76/2013 and 90/2014), the Minister of Health
p.000534: brings
p.000534: RULEBOOK
p.000534: ON CLINICAL TESTING OF MEDICINES AND GOOD CLINICAL PRACTICE
p.000534: Article 1
p.000534: (1) This Ordinance lays down the procedure and conditions for conducting clinical, unproven and non-interventional testing of a medicinal product as well as good clinical practice
p.000534: when conducting a clinical trial of a drug.
p.000534: (2) Compliance with the requirements of good clinical practice ensures the protection of the rights, safety and well-being of subjects and the credibility of the results of clinical
p.000534: testing.
p.000534: Article 2
p.000534: This Ordinance transposes into the legal order of the Republic of Croatia:
p.000534: - Directive 2001/20 / EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States
p.000534: relating to the application of good clinical practice in the conduct of clinical trials of medicinal products for human use (OJ L 121, 1.5.2001). [1]
p.000534: Article 3
p.000534: (1) Certain terms within the meaning of this Ordinance have the following meaning:
p.000534: Good clinical practice is a set of internationally recognized ethical and scientific requirements that are followed in the planning, implementation, recording and reporting
p.000534: on clinical trials.
p.000534: Investigational Medicinal Product Dossier (hereinafter: IMPD) is a document showing data relating to
...
p.000534: based on data from different sources. This gives the examiner an extensive interpretation of the data available and an assessment of their significance for future clinical
p.000534: testing.
p.000534: Where appropriate, published reports of related products should be discussed. This may help the examiner to anticipate the side effects of the drug or others
p.000534: clinical trial difficulties.
p.000534: The ultimate goal of this section of the Instruction is to provide the examiner with clear insight into the potential risks and side effects, specific tests, observations and precautions that may be taken
p.000534: be required in the conduct of the clinical trial. The insight should be based on available chemical, pharmaceutical, pharmacological,
p.000534: toxicological and clinical data on the product tested. The examiner should also be given guidelines for identifying and treating overdose and
p.000534: side effects based on previous experience with humans and the pharmacological profile of the product under study.
p.000534: The ultimate goal of this section of the Instruction is to provide the examiner with clear insight into the potential risks and side effects, specific tests, observations and precautions that may be taken
p.000534: be required in the conduct of the clinical trial. The insight should be based on available chemical, pharmaceutical, pharmacological,
p.000534: toxicological and clinical data on the product tested. The examiner should also be given guidelines for identifying and treating overdose and
p.000534: side effects based on previous experience with humans and the pharmacological profile of the product under study.
p.000534: ____________________________ 7.4. APPENDIX 1:
p.000534: HOME (Example)
p.000534: TITLE OF THE TEST ORDER
p.000534: Product:
p.000534: Number of Surveys:
p.000534: Product name (s): Chemical name, (approved) generic name, protected name (if authorized by the contracting authority and permitted by law):
p.000534: INSTRUCTIONS TO THE TESTOR
p.000534: Issue Number:
p.000534: Release Date:
p.000534: Previous issue number:
p.000534: Previous issue date:
p.000534: ____________________________ 7.5. APPENDIX 2:
p.000534: TABLE OF CONTENTS OF EXAMINER INSTRUCTIONS (Example)
p.000534: 8. BASIC DOCUMENTS FOR CONDUCTING A CLINICAL TEST
p.000534: 8.1. Introduction
p.000534: Basic documents are those documents which, individually or together, enable the assessment of the performance of the tests and the quality of the data obtained. These documents
p.000534: serve as evidence that the examiner, client and observer have complied with the Good Clinical Practice standards and all applicable legal requirements.
p.000534: In addition, basic documents have a broad and important purpose. Timely storage of basic documents with examiners / institutions and contracting authorities may
p.000534: significantly contribute to the successful conduct of the examination by examiners, contracting authorities and observers.
p.000534: In addition, these documents are the most common subject to control and inspection as part of the validation process of testing and completeness
p.000534: of the data collected.
p.000534: The following is a list of the most essential basic documents. The different documents are divided into three groups according to the test phase in which they are usually created. 1) before
p.000534: the beginning of the clinical phase of the trial, 2) during the clinical phase of the trial, and 3) after the conclusion or termination of the study. It is listed
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p.000534: 1.57. Respondent / clinical trial participant
p.000534: The person participating in the clinical trial, whether receiving the test product or serving as a control.
p.000534: 1.58. Respondent's identification mark
p.000534: Unique identifier assigned by the examiner to each respondent to protect the respondent's identity, which is used instead of the name
p.000534: the respondent when the examiner reports adverse event and / or other information related to the examination.
p.000534: 1.59. Location of clinical trial
p.000534: Site where clinical trial activities are conducted.
p.000534: 1.60. An unexpected side effect
p.000534: A side effect whose nature or weight is inconsistent with valid product information (e.g., examiner instructions for disapproved test product or instructions
p.000534: on the product / summary of the product if it is an approved product) (see ICH Guidelines for the handling of clinical harm data: Definitions and
p.000534: standards for emergency reporting).
p.000534: 1.61. Particularly sensitive respondents
p.000534: Individuals whose willingness to participate in a clinical trial may be unduly influenced by the expectation, whether justified or not, that their participation
p.000534: to bring certain benefits, that is, otherwise they will be avenged by the elderly or superiors. Members can serve as an example
p.000534: hierarchical groups such as medical, pharmacy or dental students, hospital and laboratory staff, pharmaceutical employees
p.000534: industry, members of the military of that person in custody or prison. The mentioned respondents include patients with incurable diseases, residents
p.000534: housing, the unemployed and the poor, emergency patients, ethnic minorities, homeless people, nomads, refugees, minors and
p.000534: persons unable to consent.
p.000534: 1.62. Well-being (of respondents)
p.000534: Physical and spiritual integrity of the clinical trial participant.
p.000534: 2. ICH PRINCIPLES OF GOOD CLINICAL PRACTICE
p.000534: 2.1. Clinical trials must be conducted in accordance with the ethical principles of the Helsinki Declaration and in accordance with good practice.
p.000534: clinical practice and applicable law.
p.000534: 2.2. Before starting a clinical trial, the expected risks and disruptions to the expected benefits for the individual subject and
p.000534: society. Clinical trials should only be started and continued if the expected benefit justifies the risk.
p.000534: 2.3. The rights, safety and well-being of respondents who are ahead of the interests of science and society.
p.000534: 2.4. The available preclinical and clinical data on the product under test must sufficiently support the conduct of the clinical trial.
p.000534: 2.5. The scientific foundations of clinical trials must be sound and the Trial Plan must be clear and detailed.
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Social / Student
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p.000534: Primary test hypothesis (and secondary if significant)
p.000534: Ethical considerations of the trial (identify and list any possible problem, outline the potential gains of clinical knowledge
p.000534: examining and its importance, assessing the potential risk of injury or other hazards to participants, presenting an evaluation of the risk-benefit relationship
p.000534: If it is intended to provide reasons for the inclusion of persons from particularly vulnerable groups such as minors, non-conscious persons, persons who
p.000534: incapable of judgment, persons with disabilities
p.000534: Description of the recruitment procedures of the respondents (all materials to be used should be attached).
p.000534: Procedures for giving information and obtaining consent from potential respondents
p.000534: (parents or legal representatives - if included)
p.000534: Test procedures, state any required deviations from normal practice
p.000534: Risk assessment, foreseeable treatment risks and procedures to be used (including possible pain, discomfort, integrity violation and ways of avoidance
p.000534: and / or the management of unforeseen / adverse events)
p.000534: Previous experience in conducting similar procedures in the legal entity (s) where the clinical trial will be conducted:
p.000534: Predicted benefits for the respondent
p.000534: Describe the relationship between the respondent and the researcher (eg patient-doctor of medicine, student-teacher, etc.)
p.000534: Procedures to check whether a potential respondent is participating in another clinical trial at the same time or that sufficient time has elapsed
p.000534: having previously participated in a clinical trial (especially important when it comes to including healthy subjects in clinical trials):
p.000534: Procedures used to protect the privacy of recorded data, source documents, or samples:
p.000534: Treatment or care plan after completing clinical trial participation (who will be responsible and where to administer):
p.000534: Statistical considerations and reasons for including a specified number of subjects in a clinical trial
p.000534: Amount and procedure for reimbursement to respondents (amount and description of expenses paid during examinations, eg travel expenses, lost earnings,
p.000534: compensation for pain and discomfort, etc.):
p.000534: Rules for termination (or early termination) of a clinical trial in a legal entity (or persons) where the clinical trial will be conducted:
p.000534: Contract on access to data by examiners, principles of publication of results, etc. (unless specified in clinical trial plan):
p.000534: Funding sources (if not provided in the clinical trial plan) and information about the examiner's financial or other interests.
p.000534: Clinical trial observer:
p.000534: Responsible for the clinical trial by the applicant / client for the clinical trial
p.000534: Date:
p.000534: Signature:
p.000534: * meets MIZ
p.000534: ANNEX IV.
p.000534: Application form for submission to the Central Ethics Committee of the opinion on the admissibility of a clinical trial of a medicinal product
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p.000534: The examiner is a doctor of medicine or a person with appropriate professional qualifications for clinical trials due to his / her professional knowledge and necessary
p.000534: experience in treating patients. The examiner is responsible for conducting the clinical trial at the test site. If a clinical trial is conducted by a group
p.000534: individuals in one examiner site, the examiner is responsible and is called the lead examiner.
p.000534: The test site is the health facility where the clinical trial is conducted.
p.000534: Test drug is a pharmaceutical formulation with an active substance or a placebo that is being tested or used as a comparison in a clinical trial and includes
p.000534: medicinal products authorized on the market but used in a different way from the one approved or different in formulation or packaging, or
p.000534: are used in unauthorized indications or used to obtain additional information on a marketing authorization form.
p.000534: Clinical trial is any human trial designed to detect or confirm clinical, pharmacological and / or other pharmacodynamic effects
p.000534: one or more test drugs and / or detection of side effects of one or more test drugs, and / or studies on absorption, distribution, metabolism and
p.000534: excretion of one or more investigational drugs for the purpose of determining the safety of administration and / or efficacy. This includes clinical trials
p.000534: conducted in one or more testing sites, in one or more Member States of the European Union.
p.000534: An observer is a person who performs monitoring during a clinical trial and ensures that it is conducted, documented and recorded in accordance with the test plan,
p.000534: standard operating procedures, good clinical practice and specific regulations.
p.000534: Non-interventional drug testing is any trial in which the drug is prescribed in accordance with the marketing authorization. Involvement of patients in
p.000534: a particular therapeutic procedure is not predetermined by the test plan but is carried out in accordance with normal practice, and prescribing is
p.000534: regardless of the decision to enroll the patient in the trial. Additional diagnostic and patient follow-up procedures are not performed, but performed
p.000534: use epidemiological methods to analyze the data collected.
p.000534: A nonprofit clinical trial is a clinical trial conducted by an examiner without the involvement of the pharmaceutical industry.
p.000534: Clinical / non-intervention trial client is a legal or legal entity responsible for initiating a clinical / non-intervention trial,
p.000534: the management of the clinical / non-intervention trial and / or the cost of the clinical / non-intervention trial.
p.000534: A clinical trial plan is a document that describes the goals, design, methodology, statistical considerations, and organization of the clinical trial that
p.000534: includes the test plan itself, all subsequent versions of the test plan, and any amendments thereto.
p.000534: Pediatric Investigation Plan (PIP) means a test or development program that seeks to secure data collection
p.000534: necessary to determine the conditions under which the drug may be approved for the treatment of the pediatric population.
p.000534: The representative of the clinical / non-intervention trial client is a legal or registered person established in the European Union.
p.000534: a clinical / non-interventional trial based outside the European Union.
p.000534: The applicant for the clinical / non-profit trial (hereinafter referred to as the applicant) is a clinical trial client established in Europe.
p.000534: Union or its authorized representative established within the European Union if the contracting authority is outside the European Union.
p.000534: Applicant for non-intervention testing is the marketing authorization holder of the Republic of Croatia, the marketing authorization holder
p.000534: approved by a centralized procedure, ie representative of the marketing authorization holder.
p.000534: The Central Ethics Committee is an independent body made up of health professionals and other members of the non-medical profession whose task is to protect the rights, safety and
p.000534: the welfare of the subjects involved in the clinical trials, and to provide assurance as to that protection, inter alia by expressing their opinion on the test plan,
p.000534: the eligibility of the examiner, the legal entity being tested, the equipment and the methods and documents that will be used to inform the interviewee
p.000534: and obtaining their consent based on informed consent. The Central Ethics Committee shall be appointed by the Minister for Health (hereinafter referred to as "the Minister of Health")
p.000534: (Minister).
p.000534: The Test Guideline is a document that presents clinical and non-clinical data on a study drug that is relevant to a particular clinical trial.
p.000534: The request for a clinical / non-profit examination is a request made by the applicant to the Ministry of Health (hereinafter:
p.000534: The Ministry) with all the documentation required for the approval of the clinical trial.
...
p.000534: (2) All approved clinical trials in the Republic of Croatia shall be published on the Ministry's website as well as on the European Agency's website
p.000534: for medicinal products in the Clinical Trials Register (www.clinicaltrialsregister.eu).
p.000534: (3) The Ministry shall keep a register of all approved clinical trials in the Republic of Croatia.
p.000534: Article 24
p.000534: (1) Inspection supervision of clinical trials shall be conducted by a pharmaceutical inspection of the Ministry.
p.000534: (2) The pharmaceutical inspector of the Ministry shall conduct the inspection of clinical trials at the testing site, at the premises of the clinical trial client.
p.000534: and / or contracting authorities or in other legal entities where the competent authority deems it necessary to carry out supervision.
p.000534: (3) The pharmaceutical inspection shall carry out regular and extraordinary supervision over the clinical trial of medicinal products:
p.000534: - regular inspections are carried out in accordance with the annual control plan,
p.000534: - Extraordinary supervision of the clinical trial of medicines is carried out in the event of incidental conditions.
p.000534: (4) The inspection of clinical trials of medicinal products may be requested and coordinated by the European Medicines Agency.
p.000534: (5) Inspection of clinical trials of medicinal products may be carried out:
p.000534: - before, during or after conducting the clinical trial,
p.000534: - as part of the marketing authorization procedure,
p.000534: - as a repeated inspection after obtaining marketing authorization.
p.000534: (6) Inspection of clinical trials is carried out in accordance with guidelines and guidelines published on the European Union's website
p.000534: EudraLex Commissions - Volume 10 Clinical trials guidelines.
p.000534: Article 25
p.000534: In the event of an event affecting the safety of the subjects, the examiner and the client of the clinical trial are obliged to take immediate protection measures
p.000534: subjects, and upon taking these measures, are obliged to report promptly on the measures taken and changes to the clinical trial plan
p.000534: Ethics Committee, Agency and Ministry.
p.000534: Article 26
p.000534: (1) The examiner, as well as the healthcare professional participating in the clinical trial, shall learn about the adverse event that occurred during the clinical trial.
p.000534: are obliged to notify the applicant, in accordance with special regulations, except those for whom the test plan and the examiner's instructions
p.000534: do not require.
p.000534: (2) The Agency is obliged to keep records of development safety update reports (DSURs), of suspected
p.000534: Suspected Unexpected Serious Adverse Reactions (SUSAR) that have occurred in clinical trials in
p.000534: Inform the Central Ethics Committee and the Ministry thereof.
p.000534: Article 27
p.000534: If the clinical trial is completed before it is specified in the clinical trial plan or is suspended, the applicant is
p.000534: obliged, with a detailed explanation of the cause, to inform the Central Ethics Committee, which gave a positive opinion, within 15 days
p.000534: and the Ministry.
p.000534: Article 28
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p.000534: - planned start and end of non-intervention testing,
p.000534: (2) The examination referred to in paragraph 1 of this Article may be initiated in the Republic of Croatia on the basis of the written consent of the PRAC, and after the holder of the authorization
p.000534: submit the approved test plan to the Agency.
p.000534: Article 33
p.000534: All clinical trials approved before the entry into force of this Ordinance will continue in accordance with the regulations under which they were initiated.
p.000534: Article 34
p.000534: On the day of the entry into force of this Ordinance, the Ordinance on Clinical Trials and Good Clinical Practice (Official Gazette, No.
p.000534: 14/2010 and 127/2010).
p.000534: Article 35
p.000534: This Ordinance shall enter into force on the eighth day after its publication in the Official Gazette.
p.000534: Class: 011-02 / 14-02 / 84
p.000534: Reg. No: 534-02-1-1 / 2-15-01
p.000534: Zagreb, 20 February 2015
p.000534: Minister
p.000534: cf. Siniša Varga, Ph.D. med. dent., v. r.
p.000534: ANNEX I
p.000534: GOOD CLINICAL PRACTICE
p.000534: GUIDELINES FOR GOOD CLINICAL PRACTICE
p.000534: INTRODUCTION
p.000534: Good clinical practice (GCP) includes international ethical and scientific standards for the quality of planning, implementation,
p.000534: human monitoring and reporting. Adherence to these standards provides public guarantees for the protection of the rights, safety and well-being of respondents in the
p.000534: in accordance with the principles of the Helsinki Declaration, and that the clinical trial data are credible.
p.000534: The aim of these ICH Good Clinical Practice Guidelines is to provide a single standard for the European Union (EU), Japan and the United States of America.
p.000534: to facilitate the mutual acceptance of clinical data by the competent authorities of those countries.
p.000534: The guidelines have been developed keeping in mind good clinical practice in the practice of the European Union, Japan and the United States, as well as Australia, Canada,
p.000534: the Nordic countries and the World Health Organization (WHO).
p.000534: These guidelines should be followed when preparing clinical trial data that are made available to the competent authorities.
p.000534: The principles set out in these Guidelines may also be applied in other clinical trials that may affect the safety and well-being of subjects.
p.000534: 1. GLOSSARY
p.000534: 1.1. Side effects
p.000534: Clinical experience with a new drug / medicinal product or its new application that is prior to approval, especially if not
p.000534: established therapeutic doses: all adverse and adverse reactions to the drug / medicinal product regardless of the dose received are considered side effects. Expression
p.000534: "Reaction to a drug / medical device" means that the causal link between the medicinal product / medical device and a side effect has at least been identified as an option, ie.
p.000534: that it cannot be ruled out.
p.000534: In terms of market-approved medicines / medical products: harmful and adverse reactions of humans at doses commonly administered in prophylaxis,
p.000534: diagnosis, treatment of disease, or modification of a biological function (see ICH Guidelines for the Management of Clinical Safety Information:
p.000534: Definitions and standards for emergency reporting).
p.000534: 1.2. Harmful event
p.000534: Any undesirable medical event in a clinical trial in a patient or respondent who has received a pharmaceutical product that is not necessary
p.000534: causally related to its application. Therefore, any adverse and unwanted sign (including
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Social / Unemployment
Searching for indicator unemployed:
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p.000534: the respondent when the examiner reports adverse event and / or other information related to the examination.
p.000534: 1.59. Location of clinical trial
p.000534: Site where clinical trial activities are conducted.
p.000534: 1.60. An unexpected side effect
p.000534: A side effect whose nature or weight is inconsistent with valid product information (e.g., examiner instructions for disapproved test product or instructions
p.000534: on the product / summary of the product if it is an approved product) (see ICH Guidelines for the handling of clinical harm data: Definitions and
p.000534: standards for emergency reporting).
p.000534: 1.61. Particularly sensitive respondents
p.000534: Individuals whose willingness to participate in a clinical trial may be unduly influenced by the expectation, whether justified or not, that their participation
p.000534: to bring certain benefits, that is, otherwise they will be avenged by the elderly or superiors. Members can serve as an example
p.000534: hierarchical groups such as medical, pharmacy or dental students, hospital and laboratory staff, pharmaceutical employees
p.000534: industry, members of the military of that person in custody or prison. The mentioned respondents include patients with incurable diseases, residents
p.000534: housing, the unemployed and the poor, emergency patients, ethnic minorities, homeless people, nomads, refugees, minors and
p.000534: persons unable to consent.
p.000534: 1.62. Well-being (of respondents)
p.000534: Physical and spiritual integrity of the clinical trial participant.
p.000534: 2. ICH PRINCIPLES OF GOOD CLINICAL PRACTICE
p.000534: 2.1. Clinical trials must be conducted in accordance with the ethical principles of the Helsinki Declaration and in accordance with good practice.
p.000534: clinical practice and applicable law.
p.000534: 2.2. Before starting a clinical trial, the expected risks and disruptions to the expected benefits for the individual subject and
p.000534: society. Clinical trials should only be started and continued if the expected benefit justifies the risk.
p.000534: 2.3. The rights, safety and well-being of respondents who are ahead of the interests of science and society.
p.000534: 2.4. The available preclinical and clinical data on the product under test must sufficiently support the conduct of the clinical trial.
p.000534: 2.5. The scientific foundations of clinical trials must be sound and the Trial Plan must be clear and detailed.
p.000534: 2.6. Testing should be carried out in accordance with the Clinical Trials / Independent Review Panel approved / tested positive
p.000534: of the Ethics Committee.
p.000534: 2.7. Responsibility for the health care of the respondent and for decisions regarding his or her treatment must always rest with a qualified medical doctor,
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Social / Youth/Minors
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p.000534: testing.
p.000534: Article 2
p.000534: This Ordinance transposes into the legal order of the Republic of Croatia:
p.000534: - Directive 2001/20 / EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States
p.000534: relating to the application of good clinical practice in the conduct of clinical trials of medicinal products for human use (OJ L 121, 1.5.2001). [1]
p.000534: Article 3
p.000534: (1) Certain terms within the meaning of this Ordinance have the following meaning:
p.000534: Good clinical practice is a set of internationally recognized ethical and scientific requirements that are followed in the planning, implementation, recording and reporting
p.000534: on clinical trials.
p.000534: Investigational Medicinal Product Dossier (hereinafter: IMPD) is a document showing data relating to
p.000534: the quality of the test drug, the production and control of the test drug, and data from non-clinical and clinical trials as well as data on the administration of the test drug
p.000534: drug in humans.
p.000534: Informed consent is consent to participate in a clinical trial on a voluntary basis based on received and properly documented notices
p.000534: on the nature and importance, consequences and risks of the examination, in writing, signed by the interviewee and dated. If the person is incompetent
p.000534: to give such consent or is a minor, the consent is signed by a legal representative or guardian. If the respondent is illiterate or unable to write, he gives
p.000534: oral consent in the presence of at least one witness who is not a member of the examination team.
p.000534: Inspection supervision of clinical trials is the oversight of the competent authority over the conduct of the clinical trial, review of documentation, premises, records,
p.000534: quality assurance systems and other resources related to the conduct of clinical trials that may be conducted at the test site, at the premises
p.000534: of the clinical trial client and / or the contracting authority or in other legal entities where the competent authority deems it necessary to carry out supervision.
p.000534: The respondent is an individual who participates in a clinical trial and receives the study drug or is part of a control group.
p.000534: The examiner is a doctor of medicine or a person with appropriate professional qualifications for clinical trials due to his / her professional knowledge and necessary
p.000534: experience in treating patients. The examiner is responsible for conducting the clinical trial at the test site. If a clinical trial is conducted by a group
p.000534: individuals in one examiner site, the examiner is responsible and is called the lead examiner.
p.000534: The test site is the health facility where the clinical trial is conducted.
...
p.000534: plan and / or amended contract in accordance with the Ministry's instruction.
p.000534: (6) Significant changes to the approved nancial plan, within the meaning of this Ordinance, are all those changes which may affect the safety of the respondents or
p.000534: to the final outcome of the clinical trial.
p.000534: (7) After the expiry of the period prescribed in Article 14, paragraph 3 of this Ordinance, the applicant shall have the right to submit to the Ministry the remaining
p.000534: signed Agreements, which were not originally submitted. According to the signed Agreements, the Ministry will issue decisions on clinical implementation
p.000534: interrogations with these legal entities.
p.000534: Article 20
p.000534: (1) An applicant who has been approved by the Ministry for conducting a clinical trial is obliged to annually by 31 January for
p.000534: the previous year, submit a report to the Ministry and the Central Ethics Committee on the course of conducting the clinical trial in approved
p.000534: examination sites, the total number of subjects screened and the total number of subjects included in the examination.
p.000534: (2) The applicant shall inform the Central Ethics Committee and the Ministry of any changes to the clinical trial.
p.000534: (3) Significant amendments shall be subject to the procedure of obtaining the opinion of the Central Ethics Committee and the approval of the Ministry.
p.000534: (4) Minor administrative amendments shall not be subject to the procedure of obtaining the opinion of the Central Ethics Committee and the approval of the Ministry,
p.000534: the Central Ethics Commission and the Ministry are already informed.
p.000534: (5) The applicant for the approval of significant changes and additions to the clinical trial shall also be required to submit a certificate of payment of costs
p.000534: procedure in accordance with the decision of the competent authority.
p.000534: Article 21
p.000534: Clinical trials in the Republic of Croatia are conducted in accordance with the standard set out in the Guideline of the European Medicines Agency and its body
p.000534: Committee for Proprietary Medicinal Products: "Note for Guidance on GoodClinicalPractice" (CPMP / ICH / 135/95). The text of the Guidelines is translated into
p.000534: the Croatian language is set out in Annex I to this Ordinance and forms an integral part thereof.
p.000534: Article 22
p.000534: In addition to the Guideline referred to in Article 21 of this Ordinance, clinical trials of minors shall be conducted in accordance with the standard specified in
p.000534: Guideline of the European Medicines Agency and its body Committee for Proprietary Medicinal Products: »ClinicalInvestigation of Medicinal Products
p.000534: in the Pediatric Population ”(CPMP / ICH / 2711/99). The text of the Guidelines translated into Croatian is reproduced in Annex II. of this Ordinance does
p.000534: its integral part.
p.000534: Article 23
...
p.000534: 3.2.2. The committee should carry out its tasks in accordance with written operational procedures, document its work and draw up minutes of its
p.000534: meetings, and should adhere to good clinical practice and applicable law.
p.000534: 3.2.3. The committee should announce at which meeting the decisions will be taken and there must be a quorum for their adoption in accordance with the written
p.000534: by operating procedures.
p.000534: 3.2.4. Only those members of the Committee who participated in the deliberations and deliberations should have the right to vote or to express opinions and / or recommendations.
p.000534: about the examination.
p.000534: 3.2.5. The examiner may be required to provide the Committee with information on any aspect of the examination, but he may not participate in the committee's deliberations
p.000534: that is, his vote / opinion.
p.000534: 3.2.6. The Commission may seek the assistance of experts in specific fields other than its members.
p.000534: 3.3. Procedures
p.000534: The Commission shall define in writing the procedures of its action and adhere to them, and by these procedures:
p.000534: 3.3.1. It defines the composition of the Commission (the names and qualifications of the members) and the body to which the Commission is responsible.
p.000534: 3.3.2. Defines the schedule of meetings, their conduct and the notification of members.
p.000534: 3.3.3. It defines the conduct of the first test evaluation and its continuous monitoring.
p.000534: 3.3.4. Defines the frequency of grading as needed.
p.000534: 3.3.5. In accordance with applicable legal regulations, conduct accelerated assessment and give approval / positive opinion on minor changes
p.000534: ongoing trials that have already received prior approval / positive opinion from the Commission.
p.000534: 3.3.6. It defines that no examinee may be included in the examination before it is approved by the Commission.
p.000534: 3.3.7. Deals that no deviation from the Examination Plan or its modification without prior written approval / positive is allowed
p.000534: the opinions of the Commission, except where it is necessary to immediately remove the immediate danger to the respondents, or where the changes relate exclusively to the
p.000534: logistical or administrative aspects of testing (eg change of telephone number of observers) (see 4.5.2.).
p.000534: 3.3.8. Defines that the examiner is obliged to immediately inform the Commission of:
p.000534: (a) deviations from the Examination Plan or amendments thereto to eliminate imminent danger to respondents (see 3.3.7, 4.5.2, 4.5.4);
p.000534: (b) changes that increase the risk to the respondent and / or significantly affect the conduct of the examination (see 4.10.2);
p.000534: (c) any serious and unexpected side effects of the drug;
p.000534: (d) new knowledge that may adversely affect the safety of the subjects or the conduct of the examination.
p.000534: 3.3.9. Ensures that the Examination Committee / Institution immediately informs of:
p.000534: (a) their decisions / opinions regarding the examination;
p.000534: (b) the reasons for the decision / opinion;
p.000534: (c) decision / opinion appeal procedures.
p.000534: 3.4. Documentation
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Social / education
Searching for indicator education:
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p.000534: persons unable to consent.
p.000534: 1.62. Well-being (of respondents)
p.000534: Physical and spiritual integrity of the clinical trial participant.
p.000534: 2. ICH PRINCIPLES OF GOOD CLINICAL PRACTICE
p.000534: 2.1. Clinical trials must be conducted in accordance with the ethical principles of the Helsinki Declaration and in accordance with good practice.
p.000534: clinical practice and applicable law.
p.000534: 2.2. Before starting a clinical trial, the expected risks and disruptions to the expected benefits for the individual subject and
p.000534: society. Clinical trials should only be started and continued if the expected benefit justifies the risk.
p.000534: 2.3. The rights, safety and well-being of respondents who are ahead of the interests of science and society.
p.000534: 2.4. The available preclinical and clinical data on the product under test must sufficiently support the conduct of the clinical trial.
p.000534: 2.5. The scientific foundations of clinical trials must be sound and the Trial Plan must be clear and detailed.
p.000534: 2.6. Testing should be carried out in accordance with the Clinical Trials / Independent Review Panel approved / tested positive
p.000534: of the Ethics Committee.
p.000534: 2.7. Responsibility for the health care of the respondent and for decisions regarding his or her treatment must always rest with a qualified medical doctor,
p.000534: where appropriate, to a qualified dental doctor.
p.000534: 2.8. All persons conducting the examination must have the appropriate education, expertise and experience to be able to carry out their tasks.
p.000534: 2.9. Prior to the inclusion of any subject in the clinical trial, he or she should be acquainted with him and obtain his / her consent to participate in the clinical trial.
p.000534: examination.
p.000534: 2.10. All clinical trial data should be documented and the records handled and stored in such a way as to be accurate
p.000534: reporting, interpretation and certification.
p.000534: 2.11. The confidentiality of documents by which respondents can be identified must be protected, while respecting the principles of privacy and confidentiality in accordance with
p.000534: applicable legal requirements.
p.000534: 2.12. The production, handling and storage / storage of tested products must be in accordance with good manufacturing practice. In theirs
p.000534: the approved Test Plan must be followed.
p.000534: 2.13. Those systems of procedures that ensure the quality of all aspects of the test should be applied.
p.000534: 3. CLINICAL TESTING COUNCIL / INDEPENDENT ETHICAL COMMITTEE (irb / iec)
p.000534: 3.1. Competencies
p.000534: 3.1.1. The Clinical Trials / Independent Ethics Committee (hereinafter: the Committee) must protect the rights, safety and well-being of all
p.000534: respondents. Particular attention should be given to surveys involving particularly sensitive respondents.
p.000534: 3.1.2. The committee shall receive for inspection the following documents: Clinical trial plan and amendments thereto, forms of consent statements and
...
p.000534: (a) deviations from the Examination Plan or amendments thereto to eliminate imminent danger to respondents (see 3.3.7, 4.5.2, 4.5.4);
p.000534: (b) changes that increase the risk to the respondent and / or significantly affect the conduct of the examination (see 4.10.2);
p.000534: (c) any serious and unexpected side effects of the drug;
p.000534: (d) new knowledge that may adversely affect the safety of the subjects or the conduct of the examination.
p.000534: 3.3.9. Ensures that the Examination Committee / Institution immediately informs of:
p.000534: (a) their decisions / opinions regarding the examination;
p.000534: (b) the reasons for the decision / opinion;
p.000534: (c) decision / opinion appeal procedures.
p.000534: 3.4. Documentation
p.000534: The committee should keep all relevant documentation (eg procedure description, list of members, list of professions and parent institutions of members, received
p.000534: documents, meeting minutes and correspondence) for at least three years after the end of the examination and make them available to the competent authorities for their
p.000534: request.
p.000534: The examiners, contracting authorities or competent authorities may request the Commission to provide a description of the procedures and a list of members.
p.000534: 4. EXAMINER
p.000534: 4.1. Qualifications of examiner and preconditions for his / her actions
p.000534: 4.1.1. In order to be able to undertake the proper conduct of the examination, the examiner must be qualified in terms of education, professional development and
p.000534: experience, qualifications should meet current legal requirements and provide evidence of their qualifications through an updated CV and / or other
p.000534: relevant documentation requested by the contracting authority, the Commission and / or the competent authority.
p.000534: 4.1.2. The examiner must be fully aware of the proper application of the test product, as described in the Test Plan, the applicable Guidelines for
p.000534: examiners, product data and other sources of information obtained from the contracting authority.
p.000534: 4.1.3. The examiner must be familiar with, and adhere to, good clinical practice and applicable legal requirements.
p.000534: 4.1.4. The examiner / institution should allow the investigator to monitor and monitor and inspect the relevant competent authorities.
p.000534: 4.1.5. The examiner should draw up a list of qualified persons to whom he or she has delegated the important tasks associated with the examination.
p.000534: 4.2. Appropriate opportunities / resources
p.000534: 4.2.1. The examiner should prove (eg based on previous indicators) that he / she is able to gather the required number of appropriate respondents in the agreed
p.000534: period.
p.000534: 4.2.2. The examiner should have sufficient time to properly conduct and complete the examination within the agreed period.
p.000534: 4.2.3. In order for the test to be conducted properly and safely, the examiner should have a sufficient number of qualified staff and adequate facilities and equipment for
p.000534: the estimated duration of the test.
p.000534: 4.2.4. The examiner must make sure that all his associates are adequately informed about the Test Plan, the product tested and their obligations and
...
p.000534: is obliged to keep all its basic documents for at least two years from the official cessation of the clinical development of the tested product, ie
p.000534: for as long as required by applicable law.
p.000534: 5.5.9. If the trial contractor interrupts the clinical development of the test product, it should inform all examiners / institutions and all competent authorities.
p.000534: 5.5.10. The relevant authorities should also be informed of any transfer of ownership of the data, in accordance with applicable legal requirements.
p.000534: 5.5.11. The basic documents shall be retained by the contracting authority for at least two years after the last approval of the request for submission has been obtained
p.000534: of the medicinal product in the ICH countries, that is, as long as the application for marketing in those countries is at least two years
p.000534: after the official cessation of the clinical development of the test product. Depending on the applicable legislation or the needs of the contracting authority,
p.000534: these documents should be kept longer.
p.000534: 5.5.12. The contracting authority shall inform the examiner / institution in writing of the need for further safeguarding of test data as well as of
p.000534: ceasing the need to store them.
p.000534: 5.6. Choice of examiner
p.000534: 5.6.1. The contracting authority is responsible for selecting the examiner / institution. For the proper conduct of the examination for which he was selected, each examiner should be
p.000534: qualified by their education and experience and should have adequate opportunities / resources (see 4.1, 4.2). The test client is
p.000534: responsible for setting up a coordinating committee and / or selecting coordinators required to organize multicenter trials.
p.000534: 5.6.2. Before concluding an agreement to conduct the test with the examiner / institution, the contracting authority shall submit a plan to the examiner / institution.
p.000534: examinations and updated Instructions for the Examiner and must allow him / her sufficient time to study the Examination Plan and the documentation obtained.
p.000534: 5.6.3. The examiner / institution should oblige the test client to:
p.000534: (a) Carry out the examination in accordance with good clinical practice, applicable legislation (see 4.1.3) and the Test Plan approved by them.
p.000534: the contracting authority and the Commission (see 4.5.1.);
p.000534: (b) adhere to data recording and reporting procedures;
p.000534: (c) enable monitoring, monitoring and inspection of tests (see 4.1.4); and
p.000534: (d) keep all basic documents pertaining to the test until it receives notice from the contracting authority that there is no longer a need for them
p.000534: keeping (see 4.9.4. and 5.5.12.).
p.000534: In order to confirm the agreement, the examiner / institution and the contracting authority shall sign the Test Plan or another contract.
p.000534: 5.7. Division of competencies
p.000534: Prior to the commencement of the test, the test client shall define, determine and share all the duties and tasks associated with the test.
p.000534: 5.8. Respondents 'and examiners' fees
...
p.000534: 5.17. Reporting of side effects of the drug
p.000534: 5.17.1. The contracting authority shall promptly inform all examiners / institutions, the Committees (where appropriate) and the competent authorities of all serious and
p.000534: unexpected side effects of the drug.
p.000534: 5.17.2. These emergency reports should comply with applicable laws and ICH's Clinical Safety Information Management Guidelines:
p.000534: Definitions and standards for emergency reporting.
p.000534: 5.17.3. The contracting authority shall provide the competent authorities with all new safety data and periodic reports in accordance with the applicable legal requirements
p.000534: regulations.
p.000534: 5.18. Observation
p.000534: 5.18.1. Purpose
p.000534: The purpose of observing a test is to verify that:
p.000534: (a) the rights and welfare of the respondents are protected;
p.000534: (b) that the information in the reports is accurate, complete and can be verified / verified using the original documents;
p.000534: (c) the test is conducted in accordance with the current approved Test Plan and any amendments thereto, with good clinical
p.000534: practice and with applicable legal regulations.
p.000534: 5.18.2. Selection and qualifications of observers
p.000534: (a) Observers shall be appointed by the contracting authority.
p.000534: (b) Observers must have appropriate education and scientific and / or clinical knowledge necessary to properly monitor the examination. It should
p.000534: keep track of the observer's qualifications.
p.000534: (c) The observer should be fully familiar with the product tested, the Test Plan, the Consent Declaration Form, other written notices
p.000534: intended for interviewees, the client's standard operating procedures and applicable legal requirements.
p.000534: 5.18.3. I also cover the nature of the observation
p.000534: The contracting authority shall ensure proper monitoring of the examination. The contracting authority shall determine the appropriate volume and nature
p.000534: observations. Determination of the scope and nature of the observations should be based on such frameworks as the objective, purpose, plan, complexity, blindness, size and parameters.
p.000534: testing. On-site monitoring is generally required before, during and after testing. However, in exceptional circumstances the client may
p.000534: determine that centralized monitoring of procedures such as examiner professional training and professional meetings and detailed written guidance may
p.000534: Ensure proper testing is conducted in accordance with good clinical practice. Statistically controlled sampling can be demonstrated
p.000534: by an acceptable method of selecting data for verification.
p.000534: 5.18.4. Observer's powers
p.000534: In accordance with the requirements of the contracting authority, observers should ensure that the examination is properly conducted and recorded, carrying out the following activities:
p.000534: related to the test or location of the test:
...
p.000534: submit a report.
p.000534: (b) The reports should include the date, place, name of the observer and the name of the examiner, or other person with whom the observer communicated.
p.000534: (c) The reports should include a concise account of the observation and the observer's statement of important findings / findings, discrepancies and shortcomings, conclusions and
p.000534: measures taken or to be taken and / or recommended measures to comply with the request.
p.000534: (d) The representative of the contracting authority shall record the client's assessment of the monitoring reports and of the follow-up activities resulting from the report.
p.000534: 5.19. Supervision
p.000534: When conducting quality control oversight, the contracting authority should consider the following:
p.000534: 5.19.1. The purpose of surveillance
p.000534: The purpose of the contracting authority's monitoring procedure, which is independent of and separate from routine monitoring or quality control, is to evaluate the conduct of testing and
p.000534: its adherence to the Examination Plan, standard operating procedures, good clinical practice and applicable legal requirements.
p.000534: 5.19.2. Selection and qualifications of supervisors
p.000534: (a) For the purpose of carrying out supervision, the contracting authority shall appoint persons who are not dependent on the clinical trial.
p.000534: (b) The contracting authority shall ensure that persons are properly qualified by their education and experience to carry out the supervision properly. It should exist
p.000534: records of the qualifications of the supervisor.
p.000534: 5.19.3. Control procedure
p.000534: (a) The contracting authority should ensure that clinical trial supervision is conducted in accordance with the contracting authority's written provisions as to what should be monitored;
p.000534: how to conduct surveillance, how often, and what form and content of surveillance reports should be.
p.000534: (b) The contracting authority's plan and procedures for examining the test should take into account the importance of testing to resolve the request submitted to the competent authorities, no.
p.000534: test subjects, the type and complexity of the test, the level of risk for the respondents, and any problems identified.
p.000534: (c) The observations and findings of the person supervising should be documented.
p.000534: (d) In order to preserve the independence and value of the controls, inspection by the competent authorities of the surveillance report need not be part of the ordinary procedure. Competent authorities
p.000534: may request access to a case-by-case monitoring report when there is evidence of a serious departure from good clinical practice,
p.000534: that is, during court proceedings.
p.000534: (e) Where required by applicable law or regulation, the contracting authority shall provide a certificate of inspection.
p.000534: 5.20. Non-compliance
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Social / embryo
Searching for indicator embryo:
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p.000534: statement of consent, also signed by the person interviewing the respondent / legal representative.
p.000534: 4.8.9. If the respondent or his legal representative cannot read, an impartial witness must be present for the entire duration of the interview. After
p.000534: that the respondent and / or his / her legal representative be read the consent form and other written information intended
p.000534: and after the respondent, or his / her legal representative, orally agrees to the respondent's participation in the examination and, if able,
p.000534: sign and date the statement form, the form should also be signed and dated by an impartial witness. By signing the statement, witness
p.000534: confirms that the information in the form and other information is accurately explained and is, in his estimation, the respondent or his legal representative
p.000534: well understood and willingly gave his consent.
p.000534: 4.8.10. The interview to obtain consent, the consent form, and other written notice intended for the respondents must state and explain the following:
p.000534: (a) That the examination is of an investigative nature;
p.000534: (b) Purpose of the test;
p.000534: (c) Test procedures and the likelihood that the subject will be randomly assigned to a particular treatment group;
p.000534: (d) Procedures provided for in the test, including invasive procedures;
p.000534: (e) Respondents' obligations;
p.000534: (f) Experimental aspects of testing;
p.000534: (g) Predictable risks and discomforts for the respondent, namely the embryo, fetus or infant;
p.000534: (h) Benefits to be expected. Where no clinical benefit is expected for the respondent, it should be made known to the respondent;
p.000534: (i) Alternative procedures, ie treatment options available to the respondent, and the risks and benefits they may bring to the respondent;
p.000534: (j) Compensation and / or treatment provided to the respondent in the event of an injury resulting from his participation in the examination;
p.000534: (k) Expected timetable for payment of installments of any compensation to respondents for participation in the examination;
p.000534: (l) Any expected costs for the respondent for participating in the examination;
p.000534: (m) that the respondent's participation in the examination is voluntary and that the respondent may refuse to participate in the examination or withdraw from it at any time,
p.000534: without being punished or losing the rights he otherwise exercises;
p.000534: (n) That the observer (s), the persons supervising (s), the Commission and the competent authorities will have direct access to the respondent's original health information for the sake of
p.000534: validation of clinical trial procedures and data obtained, with full protection of the confidentiality of the respondents' identities within the limits of applicable laws and regulations, as well as
p.000534: that the respondent or his / her legal representative expresses his / her consent to such access to information by signing the statement of consent;
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Social / parents
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p.000534: 3.3.6. It defines that no examinee may be included in the examination before it is approved by the Commission.
p.000534: 3.3.7. Deals that no deviation from the Examination Plan or its modification without prior written approval / positive is allowed
p.000534: the opinions of the Commission, except where it is necessary to immediately remove the immediate danger to the respondents, or where the changes relate exclusively to the
p.000534: logistical or administrative aspects of testing (eg change of telephone number of observers) (see 4.5.2.).
p.000534: 3.3.8. Defines that the examiner is obliged to immediately inform the Commission of:
p.000534: (a) deviations from the Examination Plan or amendments thereto to eliminate imminent danger to respondents (see 3.3.7, 4.5.2, 4.5.4);
p.000534: (b) changes that increase the risk to the respondent and / or significantly affect the conduct of the examination (see 4.10.2);
p.000534: (c) any serious and unexpected side effects of the drug;
p.000534: (d) new knowledge that may adversely affect the safety of the subjects or the conduct of the examination.
p.000534: 3.3.9. Ensures that the Examination Committee / Institution immediately informs of:
p.000534: (a) their decisions / opinions regarding the examination;
p.000534: (b) the reasons for the decision / opinion;
p.000534: (c) decision / opinion appeal procedures.
p.000534: 3.4. Documentation
p.000534: The committee should keep all relevant documentation (eg procedure description, list of members, list of professions and parent institutions of members, received
p.000534: documents, meeting minutes and correspondence) for at least three years after the end of the examination and make them available to the competent authorities for their
p.000534: request.
p.000534: The examiners, contracting authorities or competent authorities may request the Commission to provide a description of the procedures and a list of members.
p.000534: 4. EXAMINER
p.000534: 4.1. Qualifications of examiner and preconditions for his / her actions
p.000534: 4.1.1. In order to be able to undertake the proper conduct of the examination, the examiner must be qualified in terms of education, professional development and
p.000534: experience, qualifications should meet current legal requirements and provide evidence of their qualifications through an updated CV and / or other
p.000534: relevant documentation requested by the contracting authority, the Commission and / or the competent authority.
p.000534: 4.1.2. The examiner must be fully aware of the proper application of the test product, as described in the Test Plan, the applicable Guidelines for
p.000534: examiners, product data and other sources of information obtained from the contracting authority.
p.000534: 4.1.3. The examiner must be familiar with, and adhere to, good clinical practice and applicable legal requirements.
p.000534: 4.1.4. The examiner / institution should allow the investigator to monitor and monitor and inspect the relevant competent authorities.
p.000534: 4.1.5. The examiner should draw up a list of qualified persons to whom he or she has delegated the important tasks associated with the examination.
p.000534: 4.2. Appropriate opportunities / resources
...
p.000534: As a rule, children are legally incapable of giving their consent to participate in the examination. Therefore, their participation depends on their decision
p.000534: parents or guardians to take responsibility for their participation in the clinical trial. Fully familiarize the caregiver with the examination and
p.000534: obtaining his consent should be in accordance with local laws and regulations. All participants need to be better acquainted with the testing using
p.000534: the consent should be determined by the Commission, or in accordance with local legal requirements).
p.000534: Participants who are mentally mature should personally sign and date either a specific consent form or a consent form. Anyway,
p.000534: Participants must be aware of their right to refuse participation or withdraw from the examination at any time. It should be addressed
p.000534: attention to the signs of excessive suffering in patients who are unable to clearly express their suffering. Although it must respect the respondent's decision to
p.000534: withdraw from testing, in therapeutic trials of serious and life-threatening diseases such circumstances are possible which, in the opinion of the examiner and
p.000534: parent / guardian, may jeopardize the welfare of the child in the event of his / her withdrawal. In these circumstances, further consent from the parent (guardian) is sufficient
p.000534: to continue the child's participation in the examination. Independent or elderly minors (as defined by local law) may be on their own
p.000534: able to give consent.
p.000534: Data that may be collected in a less vulnerable population that has consented to participate is not advisable to be collected in a more vulnerable population,
p.000534: that is, from patients who are unable to give informed consent. Examinations in handicapped or institutionalized children should be limited to those
p.000534: diseases and health conditions that are mainly or exclusively related to these populations, or to the circumstances in which their disease is expected
p.000534: or health change the behavior or pharmacodynamics of medical devices.
p.000534: 2.6.4. How to minimize risk
p.000534: Whatever the importance of testing in proving or denying the value of a treatment, it can lead to injury in the subjects even when
p.000534: polls benefit the entire community. Therefore, every effort should be made to anticipate and limit known hazards. Even before the beginning
p.000534: clinical trial, investigators must have complete insight into all preclinical and clinical data on drug toxicity. To take a risk in pediatric
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p.000534: exposure to unnecessary risk. The purpose of this section is to provide an ethical framework for conducting testing in children.
p.000534: For the clinical trial to be of benefit to its participants and other children, its plan must be such as to ensure the quality and clarity of the collected
p.000534: data. Respondents are also expected to benefit from the clinical trial, except in the special circumstances described in the ICH.
p.000534: document E6, section 4.8.14.
p.000534: 2.6.1. Clinical Trial Panel / Independent Ethics Committee (Committee)
p.000534: The role and authority of the Commission described in ICH document E6 is crucial in protecting the respondents. When considering protocols involving children,
p.000534: The committee among its membership must or must seek the professional opinion of persons with a good knowledge of ethical, clinical and psychosocial issues.
p.000534: related to children.
p.000534: 2.6.2. Involvement of respondents
p.000534: Respondents should be included in a way that completely excludes inappropriate prompting of respondents, or their parents / guardians, to participate in
p.000534: examination.
p.000534: Fees and living expenses may be included in the cost of the pediatric clinical trial. Fees should be approved by
p.000534: Committees.
p.000534: When conducting child testing, it is a good idea to include individuals who represent the demographic country / region and the disease being tested, except where
p.000534: there are valid reasons for limited participation in the examination.
p.000534: 2.6.3. Consent and consent
p.000534: As a rule, children are legally incapable of giving their consent to participate in the examination. Therefore, their participation depends on their decision
p.000534: parents or guardians to take responsibility for their participation in the clinical trial. Fully familiarize the caregiver with the examination and
p.000534: obtaining his consent should be in accordance with local laws and regulations. All participants need to be better acquainted with the testing using
p.000534: the consent should be determined by the Commission, or in accordance with local legal requirements).
p.000534: Participants who are mentally mature should personally sign and date either a specific consent form or a consent form. Anyway,
p.000534: Participants must be aware of their right to refuse participation or withdraw from the examination at any time. It should be addressed
p.000534: attention to the signs of excessive suffering in patients who are unable to clearly express their suffering. Although it must respect the respondent's decision to
p.000534: withdraw from testing, in therapeutic trials of serious and life-threatening diseases such circumstances are possible which, in the opinion of the examiner and
p.000534: parent / guardian, may jeopardize the welfare of the child in the event of his / her withdrawal. In these circumstances, further consent from the parent (guardian) is sufficient
...
p.000534: Chief Examiner in the Republic of Croatia
p.000534: Address:
p.000534: Phone / Fax
p.000534: e-mail
p.000534: Informed consent, version and date, signed by the Examiner
p.000534: Leaders of participating testing centers (examiners)
p.000534: C. Data on test substance
p.000534: Is the preparation approved in the Republic of Croatia
p.000534: Countries where the preparation is approved
p.000534: Generic name
p.000534: Trademark
p.000534: Manufacturer
p.000534: Dosage and administration of the drug in this study
p.000534: Results of non-clinical trials (or reasons why they were not performed)
p.000534: Primary test hypothesis (and secondary if significant)
p.000534: Ethical considerations of the trial (identify and list any possible problem, outline the potential gains of clinical knowledge
p.000534: examining and its importance, assessing the potential risk of injury or other hazards to participants, presenting an evaluation of the risk-benefit relationship
p.000534: If it is intended to provide reasons for the inclusion of persons from particularly vulnerable groups such as minors, non-conscious persons, persons who
p.000534: incapable of judgment, persons with disabilities
p.000534: Description of the recruitment procedures of the respondents (all materials to be used should be attached).
p.000534: Procedures for giving information and obtaining consent from potential respondents
p.000534: (parents or legal representatives - if included)
p.000534: Test procedures, state any required deviations from normal practice
p.000534: Risk assessment, foreseeable treatment risks and procedures to be used (including possible pain, discomfort, integrity violation and ways of avoidance
p.000534: and / or the management of unforeseen / adverse events)
p.000534: Previous experience in conducting similar procedures in the legal entity (s) where the clinical trial will be conducted:
p.000534: Predicted benefits for the respondent
p.000534: Describe the relationship between the respondent and the researcher (eg patient-doctor of medicine, student-teacher, etc.)
p.000534: Procedures to check whether a potential respondent is participating in another clinical trial at the same time or that sufficient time has elapsed
p.000534: having previously participated in a clinical trial (especially important when it comes to including healthy subjects in clinical trials):
p.000534: Procedures used to protect the privacy of recorded data, source documents, or samples:
p.000534: Treatment or care plan after completing clinical trial participation (who will be responsible and where to administer):
p.000534: Statistical considerations and reasons for including a specified number of subjects in a clinical trial
p.000534: Amount and procedure for reimbursement to respondents (amount and description of expenses paid during examinations, eg travel expenses, lost earnings,
p.000534: compensation for pain and discomfort, etc.):
p.000534: Rules for termination (or early termination) of a clinical trial in a legal entity (or persons) where the clinical trial will be conducted:
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Social / philosophical differences/differences of opinion
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p.000534: necessary to determine the conditions under which the drug may be approved for the treatment of the pediatric population.
p.000534: The representative of the clinical / non-intervention trial client is a legal or registered person established in the European Union.
p.000534: a clinical / non-interventional trial based outside the European Union.
p.000534: The applicant for the clinical / non-profit trial (hereinafter referred to as the applicant) is a clinical trial client established in Europe.
p.000534: Union or its authorized representative established within the European Union if the contracting authority is outside the European Union.
p.000534: Applicant for non-intervention testing is the marketing authorization holder of the Republic of Croatia, the marketing authorization holder
p.000534: approved by a centralized procedure, ie representative of the marketing authorization holder.
p.000534: The Central Ethics Committee is an independent body made up of health professionals and other members of the non-medical profession whose task is to protect the rights, safety and
p.000534: the welfare of the subjects involved in the clinical trials, and to provide assurance as to that protection, inter alia by expressing their opinion on the test plan,
p.000534: the eligibility of the examiner, the legal entity being tested, the equipment and the methods and documents that will be used to inform the interviewee
p.000534: and obtaining their consent based on informed consent. The Central Ethics Committee shall be appointed by the Minister for Health (hereinafter referred to as "the Minister of Health")
p.000534: (Minister).
p.000534: The Test Guideline is a document that presents clinical and non-clinical data on a study drug that is relevant to a particular clinical trial.
p.000534: The request for a clinical / non-profit examination is a request made by the applicant to the Ministry of Health (hereinafter:
p.000534: The Ministry) with all the documentation required for the approval of the clinical trial.
p.000534: The request for non-interventional testing is a request made by the applicant to the Agency for Medicinal Products and Medical Devices (in
p.000534: hereinafter referred to as "the Agency") with all the documentation necessary for the approval of the non-intervention test.
p.000534: Significant changes to the clinical trial are those that can significantly affect:
p.000534: - the safety of the respondents, the physical or spiritual integrity of the respondents,
p.000534: - the scientific value (benefit) of the test.
p.000534: Article 4
p.000534: The clinical trial is conducted in a legal entity that meets the following conditions:
p.000534: - employ experts who, through their knowledge and experience, ensure that the trial will be conducted in accordance with the clinical trial plan,
p.000534: - has equipment that allows the clinical trial to be conducted according to the clinical trial plan, or has a system in place to use the equipment
p.000534: and / or the procedures provided for in the test plan,
p.000534: - has in place a system for storing documentation resulting from clinical trials under this Ordinance.
p.000534: Article 5
p.000534: The clinical trial is conducted by an examiner who:
p.000534: - has completed undergraduate and graduate university studies or an integrated undergraduate and graduate university degree in health care, and
p.000534: specific training if provided by the test plan,
p.000534: - has documented training on good clinical practice,
p.000534: - concurrently conducts a maximum of five clinical trials that are under active patient involvement.
p.000534: Article 6
p.000534: (1) A clinical trial observer is a person appointed by an applicant who:
p.000534: - has a professional or undergraduate degree or undergraduate or graduate university degree or an integrated undergraduate or graduate degree
p.000534: university study,
p.000534: - has documented training on good clinical practice,
p.000534: - is a citizen of the Republic of Croatia or an alien with a permit or consent to work in accordance with special regulations on aliens and with evidence of
p.000534: knowledge of the Croatian language.
p.000534: (2) The acceptability of the observers shall be assessed by the Ministry.
p.000534: (3) The observer's register shall be kept by the Ministry.
p.000534: Article 7
p.000534: (1) A clinical trial of a medicinal product, including an incorrect clinical trial, cannot be initiated in the Republic of Croatia without a favorable opinion.
p.000534: Of the Central Ethics Committee and the approval of the Ministry, except as provided for in Article 14, paragraph 9 of this Ordinance.
p.000534: (2) Applicant, who has been approved by the Ministry to conduct a clinical trial based on the positive opinion of the Central
p.000534: The Ethics Committee, while seeking approval for conducting clinical trials in additional legal entities, is obliged to obtain the consent of the Central
p.000534: an ethics committee for each subsequent legal entity to be included in the clinical trial, as well as seek the approval of the Ministry.
p.000534: Article 8
p.000534: The Central Ethics Committee is responsible for giving opinions in the approval process as well as in the opinion process on significant changes and
p.000534: additions to clinical, non-intervention and non-profit trials in the Republic of Croatia.
p.000534: Article 9
p.000534: (1) The Central Ethics Committee is an independent body composed of health professionals and other members of the non-medical profession, set up in accordance with
p.000534: requirements of Good Clinical Practice and has nineteen members.
p.000534: (2) The President, the Deputy President and the members of the Central Ethics Committee shall be appointed by the Minister.
p.000534: (3) Administrative tasks for the needs of the work of the Central Ethics Committee shall be performed by the Agency.
p.000534: Article 10
p.000534: The rules of procedure of the Central Ethics Committee shall be governed by the Rules of Procedure.
p.000534: Article 11
p.000534: In adopting an opinion on the eligibility of conducting a clinical trial, the Central Ethics Committee shall specifically consider:
p.000534: - the suitability of the clinical trial plan,
p.000534: - justification of foreseeable hazards and risks in relation to the assumed benefit for the respondents,
p.000534: - eligibility of examiners and study sites proposed for clinical trial,
p.000534: - acceptability of the method of selection and inclusion of the subjects in the clinical trial,
p.000534: - the admissibility of the information given in the test guide,
p.000534: - completeness, appropriateness and understandability of all information provided to the respondents, as well as the procedures used to obtain it
p.000534: informed consent and the justification for questioning individuals who are unable to give their consent on their own,
p.000534: - the existence of the protection of the respondents 'privacy and the protection of the respondents' information,
p.000534: - eligibility of fees for examiners and respondents,
p.000534: - the eligibility of the financial examination plan,
p.000534: - the existence of insurance in the event of injury, death or treatment of the subjects in connection with the clinical trial,
p.000534: - the existence of liability insurance for the examiner or client,
p.000534: - the acceptability of significant changes to the clinical trial (if any).
p.000534: Article 12
p.000534: (1) The Central Ethics Committee is obliged to give a written opinion on the acceptability of the proposed clinical trial within 30 days from the date
p.000534: the receipt of a duly demanded one prescribed by this Ordinance.
p.000534: (2) An orderly request within the meaning of this Ordinance shall mean the submission of the complete documentation prescribed in Article 16 of this Ordinance.
p.000534: (3) The Central Ethics Committee shall, within 5 days from the receipt of the request, notify in writing (by electronic or fax)
p.000534: of the applicant if it finds that the documentation submitted is incomplete. Otherwise, the request submitted is considered to be orderly.
p.000534: (4) By way of derogation from paragraph 1 of this Article, the Central Ethics Committee is obliged to give a written opinion on the acceptability of the proposed clinical
p.000534: testing of a finished drug intended for gene therapy, treatment of somatic cells, including medicines containing genetically modified
p.000534: organisms within 90 days from the date of receipt of the duly required application prescribed by this Ordinance.
p.000534: (5) The time limit referred to in paragraph 1 of this Article may be extended by an additional 90 days in the case of consultation with experts or committees.
p.000534: (6) For xenogenic drugs, there is no time limit for giving opinions on the acceptability of conducting a clinical trial.
p.000534: (7) In the procedure for giving an opinion on the acceptability of a proposed clinical trial, the Central Ethics Committee may request only once
p.000534: supplementing the documentation, ie the submission of additional information supplementing the information already provided by the applicant. Deadlines set
p.000534: Paragraphs 1, 4 and 5 of this Article shall not run until the date of receipt of the requested documentation.
p.000534: Article 13
p.000534: The Central Ethics Committee shall be obliged to provide the applicant and the Ministry with the opinion referred to in Article 8 of this Ordinance in writing.
p.000534: Article 14
p.000534: (1) Authorization to conduct clinical trials, including non-profit clinical trials of medicinal products, is granted by the Ministry.
p.000534: (2) The applicant, after having received the positive opinion of the Central Ethics Committee, submits to the Ministry a request for conducting clinical
p.000534: testing in the Republic of Croatia.
p.000534: (3) The Ministry is obliged to approve or withhold approval for conducting a clinical trial within 30 days from the receipt of a duly requested request.
p.000534: (4) An orderly request within the meaning of this Ordinance shall mean the submission of the complete documentation prescribed in Article 16 of this Ordinance.
p.000534: (5) The Ministry shall, within 5 days of receipt of the request, notify the applicant in writing (electronically or by fax).
p.000534: requests if it finds that the documentation submitted is incomplete. Otherwise, the request submitted is considered to be orderly.
p.000534: (6) The applicant shall have the right to supplement the request, and the time limit referred to in paragraph 3 of this Article shall start to run from the date of receipt of the duly filed request.
p.000534: (7) In the period referred to in paragraph 3 of this Article, the applicant may, until the decision of the Ministry is issued, amend his request.
p.000534: (8) The time limit referred to in paragraph 3 of this Article may be extended by 30 days in the case of a clinical trial of a gene therapy medicinal product,
p.000534: treatment of somatic cells, including medicines containing genetically modified organisms and xenogenic drugs.
p.000534: (9) If, within the time limit referred to in paragraphs 3 and 8 of this Article, the Ministry does not or does not withhold the authorization, the authorization shall be deemed to have been granted, except when it was previously
p.000534: initiation of a clinical trial must obtain the written approval of the Ministry of Clinical Trials for Medicinal Products for Gene Therapy,
...
p.000534: the opinions of the Central Ethics Committee, the following documentation must be submitted:
p.000534: 1. Request in the Croatian language, with the signature of the applicant's responsible person. The application must include: the test plan code, the EudraCT number
p.000534: tests, name of test, test phase, name and address of the test client, name and address of the applicant and list of lead examiners and
p.000534: establishments where the clinical trial is planned to be conducted as well as a brief explanation of the application,
p.000534: 2. instructions for the examiner, for the investigational medicinal product not authorized for marketing, issued within one year,
p.000534: 3. summary description of the product characteristics, for investigational medicinal products with a valid marketing authorization,
p.000534: 4. the CV of the examiner showing that it meets the criteria referred to in Article 5 of this Ordinance,
p.000534: 5. the CV of the observer, which will show that it meets the criteria referred to in Article 6 of this Ordinance,
p.000534: 6. a list of countries where the same clinical trial is planned and at the time of application for authorization
p.000534: clinical trial the same trial approved or refused, including the reasons for the refusal,
p.000534: 7. examination plan and any amendments signed by the Examiner,
p.000534: 8. copy of the test list of respondents in electronic form,
p.000534: 9. informed consent form in the Croatian language and Latin script, and the original text,
p.000534: 10. a summary of the scientific opinion of the European Medicines Agency regarding the administration of the investigational medicinal product (if available),
p.000534: 11. copy of the decision of the European Medicines Agency on the pediatric trial plan and the opinion of the pediatric committee, if clinical trial
p.000534: implements according to the pediatric drug development plan (PIP),
p.000534: 12. an example of the labeling of the test drug,
p.000534: 13. financial test plan,
p.000534: 14. proof of insurance of the subjects from the possible adverse consequences of participation in the clinical trial,
p.000534: 15. written authorization to the legal person who submits the request to the Minister for approval of the clinical trial in case the request is not submitted by the client
p.000534: clinical trial,
p.000534: 16. proof of payment of costs in the process of granting approval for conducting a clinical trial.
p.000534: (2) In addition to the documentation referred to in paragraph 1 of this Article, the applicant shall submit to the Central Ethics Committee:
p.000534: - the completed form in Annex IV. and Annex V which are annexed to this Ordinance and form an integral part thereof.
p.000534: (3) In addition to the documentation referred to in paragraph 1 of this Article, the applicant shall submit to the Ministry:
p.000534: - the completed form in Annex III. which is annexed to this Ordinance and forms an integral part thereof,
p.000534: - IMPD
p.000534: - CTA form in English,
p.000534: - proof of payment of the administrative fee.
p.000534: Article 17
p.000534: (1) In the process of approving a clinical trial intended for children or treating psychiatric patients, the Central Ethics Committee may request
p.000534: expert assistance and consult with the Ministry of Pediatrics and Psychiatry Commissions in accordance with point 3.2.6. Of Annex I to this Ordinance.
...
p.000534: requests for significant changes to the clinical trial.
p.000534: (3) Upon completion of the completion of the CTA form, it is necessary to carry out a validation of the completed data and submit it to the Ministry on CD-ROM
p.000534: Validation Report document in .pdf format, which confirms the validity of the completed form.
p.000534: (4) Each CD-ROM submitted must be marked with the EudraCT number, date of submission of the form, name of the contracting authority and applicant
p.000534: requests and a brief description of the content.
p.000534: (5) In addition to the CTA form, the applicant is obliged to submit to the Ministry the completed forms in writing, which shall be notified to the Ministry.
p.000534: on the significant amendment of the clinical trial and on the completion of the trial.
p.000534: (6) The forms referred to in paragraphs 1 and 5 of this Article are available and published on the European Commission's website (EudraLex - Volume 10 Clinical trials
p.000534: guidelines).
p.000534: Article 19
p.000534: (1) The contract between the applicant and the legal entity (hereinafter referred to as the "Contract") in which the examination is to be conducted shall specify:
p.000534: - the total cost of conducting the clinical trial,
p.000534: - the costs borne by the applicant, including the costs of medical and other services provided by the legal entity conducting the clinical trial,
p.000534: - the amount of compensation for legal entities, examiners and respondents,
p.000534: - the obligation of the applicant to bear the costs of all diagnostic procedures and examinations provided for in the test plan.
p.000534: (2) In the process of obtaining the opinion of the Central Ethics Committee, the applicant shall submit to the Central Ethics Committee for each
p.000534: the legal entity where the clinical trial is planned to be conducted, the nancial plan of the trial, which must describe the nancial aspects of the clinical trial
p.000534: tests including the elements referred to in paragraph 1 of this Article, subparagraphs 1 to 4.
p.000534: (3) In the process of approving a clinical trial, the applicant shall submit to the Ministry a nancial examination plan for each legal
p.000534: a person who is scheduled to conduct a clinical trial approved by the Central Ethics Committee (hereinafter: approved
p.000534: plan), and by the expiry of the deadline prescribed in Article 14, paragraph 3 of this Ordinance, at least one signed Contract, otherwise the Ministry shall by decision
p.000534: deny the request.
p.000534: (4) If, upon reviewing the approved nancial plan and the signed contract, the Ministry determines that significant changes in the nancial aspects have occurred
p.000534: clinical trial and / or minimum contract requirements prescribed by the Minister may, within 5 days, be made in writing (electronically or
p.000534: fax) request the applicant to submit an amended contract in accordance with the Ministry's instruction and / or to the Central Ethics Committee
p.000534: obtains an additional opinion on the eligibility of the financial plan. Otherwise, the approved financial plan and the signed contract are considered to be in order.
p.000534: (5) The time limit referred to in paragraph 4 of this Article shall also apply in the case of the submission of an additional opinion of the Central Ethics Committee on the eligibility of
p.000534: plan and / or amended contract in accordance with the Ministry's instruction.
p.000534: (6) Significant changes to the approved nancial plan, within the meaning of this Ordinance, are all those changes which may affect the safety of the respondents or
p.000534: to the final outcome of the clinical trial.
p.000534: (7) After the expiry of the period prescribed in Article 14, paragraph 3 of this Ordinance, the applicant shall have the right to submit to the Ministry the remaining
p.000534: signed Agreements, which were not originally submitted. According to the signed Agreements, the Ministry will issue decisions on clinical implementation
p.000534: interrogations with these legal entities.
p.000534: Article 20
p.000534: (1) An applicant who has been approved by the Ministry for conducting a clinical trial is obliged to annually by 31 January for
p.000534: the previous year, submit a report to the Ministry and the Central Ethics Committee on the course of conducting the clinical trial in approved
p.000534: examination sites, the total number of subjects screened and the total number of subjects included in the examination.
p.000534: (2) The applicant shall inform the Central Ethics Committee and the Ministry of any changes to the clinical trial.
p.000534: (3) Significant amendments shall be subject to the procedure of obtaining the opinion of the Central Ethics Committee and the approval of the Ministry.
p.000534: (4) Minor administrative amendments shall not be subject to the procedure of obtaining the opinion of the Central Ethics Committee and the approval of the Ministry,
p.000534: the Central Ethics Commission and the Ministry are already informed.
p.000534: (5) The applicant for the approval of significant changes and additions to the clinical trial shall also be required to submit a certificate of payment of costs
p.000534: procedure in accordance with the decision of the competent authority.
p.000534: Article 21
p.000534: Clinical trials in the Republic of Croatia are conducted in accordance with the standard set out in the Guideline of the European Medicines Agency and its body
p.000534: Committee for Proprietary Medicinal Products: "Note for Guidance on GoodClinicalPractice" (CPMP / ICH / 135/95). The text of the Guidelines is translated into
p.000534: the Croatian language is set out in Annex I to this Ordinance and forms an integral part thereof.
p.000534: Article 22
p.000534: In addition to the Guideline referred to in Article 21 of this Ordinance, clinical trials of minors shall be conducted in accordance with the standard specified in
p.000534: Guideline of the European Medicines Agency and its body Committee for Proprietary Medicinal Products: »ClinicalInvestigation of Medicinal Products
p.000534: in the Pediatric Population ”(CPMP / ICH / 2711/99). The text of the Guidelines translated into Croatian is reproduced in Annex II. of this Ordinance does
p.000534: its integral part.
p.000534: Article 23
p.000534: (1) In conducting the clinical trial, the personal integrity and well-being of the subjects should be ensured in accordance with the Declaration of Helsinki.
...
p.000534: (6) Inspection of clinical trials is carried out in accordance with guidelines and guidelines published on the European Union's website
p.000534: EudraLex Commissions - Volume 10 Clinical trials guidelines.
p.000534: Article 25
p.000534: In the event of an event affecting the safety of the subjects, the examiner and the client of the clinical trial are obliged to take immediate protection measures
p.000534: subjects, and upon taking these measures, are obliged to report promptly on the measures taken and changes to the clinical trial plan
p.000534: Ethics Committee, Agency and Ministry.
p.000534: Article 26
p.000534: (1) The examiner, as well as the healthcare professional participating in the clinical trial, shall learn about the adverse event that occurred during the clinical trial.
p.000534: are obliged to notify the applicant, in accordance with special regulations, except those for whom the test plan and the examiner's instructions
p.000534: do not require.
p.000534: (2) The Agency is obliged to keep records of development safety update reports (DSURs), of suspected
p.000534: Suspected Unexpected Serious Adverse Reactions (SUSAR) that have occurred in clinical trials in
p.000534: Inform the Central Ethics Committee and the Ministry thereof.
p.000534: Article 27
p.000534: If the clinical trial is completed before it is specified in the clinical trial plan or is suspended, the applicant is
p.000534: obliged, with a detailed explanation of the cause, to inform the Central Ethics Committee, which gave a positive opinion, within 15 days
p.000534: and the Ministry.
p.000534: Article 28
p.000534: (1) The applicant shall submit to the Central Ethics Committee and the Ministry a notification of the completion of the clinical trial within 90
p.000534: days from the end of the clinical trial.
p.000534: (2) Completion of the clinical trial referred to in paragraph 1 of this Article shall be considered as the day of the last examination / examination of the last included respondent in the clinical trial.
p.000534: examination.
p.000534: Article 29
p.000534: Upon completion of the clinical trial, the applicant is required to submit to the Central Ethics Committee and the Ministry a summary of the final
p.000534: reports, within one year of the end of the clinical trial.
p.000534: Article 30
p.000534: (1) The clinical trial client may allow subjects to participate in the program upon completion of their participation in the clinical trial
p.000534: prolonged treatment with investigational drug, eng. "Expanded access programs", (hereinafter referred to as "the program").
p.000534: (2) In the case referred to in paragraph 1 of this Article, the applicant shall inform the Central Ethics Committee of the planned program and request
p.000534: consent of the Ministry.
p.000534: (3) The applicant is obliged to state the reasons for launching and the duration of the program, the number of examining places and respondents in each examiner
p.000534: the site that will participate in the program and the dose and route of administration. With the request, the applicant is required to attach the statements of the Chief Examiners to whom
p.000534: confirm their participation in the program and agree to continue monitoring the safety of drug administration and that the risk-benefit ratio justifies the administration of the drug
p.000534: in doses and in the manner prescribed by the proposed program.
p.000534: (4) At least once a year, the applicant shall notify the Central Ethics Committee and the Ministry of the implementation of the program, with emphasis
p.000534: to the safety of drug administration.
p.000534: (5) The applicant shall notify the Central Ethics Committee and the Ministry of the completion of the program within 90 days from the end of the program.
p.000534: program.
p.000534: Article 31
p.000534: (1) In the process of submitting a request to the Agency for approval of conducting non-intervention testing and obtaining the opinion of the Central Ethics
p.000534: Commissions, the applicant is required to provide the following documentation:
p.000534: - request in the Croatian language, with the signature of the applicant's responsible person; the request should include the name and address of the contracting authority, the name and
p.000534: the applicant's address and a list of the principal examiners and institutions where the non-interventional test will be conducted,
p.000534: - a test plan indicating the designation of the test plan, the version and the date of the test plan version,
p.000534: - test list of respondents,
p.000534: - the marketing authorization decision, if applicable,
p.000534: - approved summary of product characteristics and package leaflet in Croatian,
p.000534: - informed consent for the patient in the Croatian language, indicating the informed consent version and the date of the version,
p.000534: - the original informed consent for the patient in English, if applicable,
p.000534: - financial examination plan,
p.000534: - proof of payment of costs in the process of giving opinion to the Central Ethics Committee and authorizing the implementation of non-intervention
p.000534: testing.
p.000534: (2) In addition to the documentation referred to in paragraph 1 of this Article, the applicant shall submit to the Central Ethics Committee:
p.000534: - the completed form in Annex VI. which is annexed to this Ordinance and forms an integral part thereof.
p.000534: (3) In addition to the documentation referred to in paragraph 1 of this Article, the applicant shall submit to the Agency:
p.000534: - the completed form in Annex VII. which is annexed to this Ordinance and forms an integral part thereof,
p.000534: - opinion of the Central Ethics Committee on non-intervention testing,
p.000534: - proof of payment of the administrative fee.
p.000534: (4) The Central Ethics Committee is obliged to give a written opinion on the admissibility or inadmissibility of the proposed non-intervention test in
p.000534: within 30 days from the date of receipt of the duly filed request.
p.000534: (5) An orderly request within the meaning of this Ordinance shall mean the submission of the complete documentation prescribed in paragraph 1 of this Article.
p.000534: (6) The Central Ethics Committee shall, within 5 days from the receipt of the request, notify in writing (by electronic or fax)
p.000534: of the applicant that the documentation submitted was incomplete. Otherwise, the request submitted is considered to be orderly.
p.000534: (7) The Central Ethics Committee shall notify the Agency and the Ministry in writing of the opinion on admissibility given
p.000534: conducting non-interventional testing.
p.000534: (8) Upon receipt of a duly requested request, the Agency shall, within 30 days, approve or withhold authorization to conduct a non-intervention
p.000534: testing.
p.000534: (9) An orderly request within the meaning of this Ordinance shall mean the submission of the complete documentation prescribed in paragraph 1 of this Article.
p.000534: (10) The Agency shall, within 5 days from the receipt of the request, notify the applicant in writing (electronically or by fax)
p.000534: if it determines that the submitted documentation is incomplete. Otherwise, the request submitted is considered to be orderly.
p.000534: (11) If, within the time limit referred to in paragraph 8 of this Article, the Agency does not give or refuse approval, it shall be deemed to have been given and the examination may commence.
p.000534: (12) The Agency is obliged to submit the decision on conducting the non-intervention examination to the applicant, the Ministry and the Croatian Institute for
p.000534: health insurance.
p.000534: (13) In the case referred to in paragraph 11 of this Article, the applicant shall submit to the Ministry and the Croatian Health Insurance Institute a notification.
p.000534: on the expiry of the deadline referred to in paragraph 8 of this Article and, instead of the Agency's approval, submit a positive opinion of the Central Ethics Committee and proof of proper
p.000534: the request received at the Agency.
p.000534: (14) The Agency shall keep records of all approved non-interventional testing.
p.000534: (15) All approved non-intervention testing in the Republic of Croatia is published on the Agency's website.
p.000534: Article 32
p.000534: (1) In the case of non-interventional safety testing of the medicinal product after obtaining marketing authorization for which the Agency does not
p.000534: authorizing the implementation, the applicant is obliged to submit to the Agency for inspection the following:
p.000534: - the written consent of the Pharmacovigilance Risk Assessment Committee (hereinafter: PRAC) to conduct a non-intervention test,
p.000534: - a non-intervention test plan approved by the PRAC,
p.000534: - test list of respondents,
p.000534: - informed consent for the patient in the Croatian language,
p.000534: - the original informed consent for the patient in English, if applicable,
p.000534: - a list of the main examiners and institutions where non-intervention testing will be carried out,
p.000534: - planned start and end of non-intervention testing,
p.000534: (2) The examination referred to in paragraph 1 of this Article may be initiated in the Republic of Croatia on the basis of the written consent of the PRAC, and after the holder of the authorization
p.000534: submit the approved test plan to the Agency.
p.000534: Article 33
...
p.000534: ensuring that the data and results are credible and accurate and that the rights, integrity and confidentiality of the respondent's data are protected.
p.000534: 1.25. Independent Data Monitoring Commission
p.000534: (Committee for the Monitoring of Medicines Safety Data, Monitoring Committee, Monitoring Committee)
p.000534: Independent Monitoring Committee on the information that the trial client may establish to periodically evaluate the progress of the clinical trial,
p.000534: data on harmlessness (side effects) and critical efficacy points and to recommend to the contracting authority whether to proceed, adjust
p.000534: or interrupt the clinical trial.
p.000534: 1.26. An impartial witness
p.000534: Person independent of the clinical trial who cannot be biased by the people involved in the clinical trial present in the administration process
p.000534: informed consent if the respondent or his legal representative cannot read, and who reads the respondent's consent form and any other written
p.000534: notice for respondent.
p.000534: 1.27. Independent Ethics Committee
p.000534: An independent body (jury or committee, be it an institution, province, state or international body) composed of
p.000534: medical professionals and members of the non-medical profession who are required to ensure the protection of the rights, safety and well-being of clinical participants
p.000534: trials and publicly guarantee such protection, inter alia, by verifying and approving / giving favorable opinion on the Clinical Trial Plan,
p.000534: the eligibility of the examiner, the conditions, methods and materials that will be used to obtain and document the informed consent of the subjects in the clinical
p.000534: examination.
p.000534: The legal status, composition, operation and regulations of independent ethics committees may vary from country to country, but they must
p.000534: enable the independent ethics committee to act in accordance with good clinical practice described in these guidelines.
p.000534: 1.28. Informed consent
p.000534: Procedure whereby the subject voluntarily affirms his or her willingness to participate in a particular clinical trial after being familiar with all
p.000534: aspects of the clinical trial that may influence the decision to participate. The informed consent of the informed respondent shall be documented in writing
p.000534: the form on which the signature and date are entered.
p.000534: 1.29. Inspection
p.000534: Procedure by the competent authority to review documents, assets, equipment and premises, records and all other matters that the body considers related to
p.000534: clinical trial and can be found at the site of the clinical trial, at the trial sponsor and / or contracting research organization, or
p.000534: to other institutions that the competent authority deems appropriate.
p.000534: 1.30. Institution (medical)
p.000534: Any public or private entity, institute or medical or dental institution where clinical trials are conducted.
...
p.000534: The person responsible for conducting the clinical trial at the place where it is conducted. If a group of individuals conducts a site survey,
p.000534: the examiner is the person responsible for leading the group and is also referred to as the lead examiner. See also Assistant Examiner.
p.000534: 1.35. Examiner / Institution
p.000534: A term that designates "examiner and / or institution in accordance with applicable law."
p.000534: 1.36. Instructions for the examiner
p.000534: A set of clinical and preclinical data on an investigational product that is relevant to its human test (see 7. Test Guideline).
p.000534: 1.37. Legal representative
p.000534: An individual or legal entity or other body authorized by applicable law to consent to participate in a clinical trial on behalf of the respondent.
p.000534: 1.38. Observation
p.000534: The act of monitoring the progress of the clinical trial and ensuring that its implementation, documentation and reporting are consistent with the Clinical Trial Plan,
p.000534: standard operating procedures, good clinical practice and applicable legal requirements.
p.000534: 1.39. Observation report
p.000534: A written report submitted by the observer to the contracting authority after each visit to the examination site and / or upon new knowledge relating to
p.000534: testing in accordance with standard operating procedures of the test client.
p.000534: 1.40. Multicenter testing
p.000534: A clinical trial conducted in accordance with a single Clinical Trial Plan in more than one site and therefore conducted by more than one
p.000534: of the examiner.
p.000534: 1.41. Preclinical research
p.000534: Non-human biomedical research.
p.000534: 1.42. Opinion (applies to the Independent Ethics Committee)
p.000534: Assessment and / or recommendation issued by an independent ethics committee.
p.000534: 1.43. Original health information
p.000534: See Original Documents.
p.000534: 1.44. Clinical trial plan
p.000534: A document outlining the objectives, plan, methodology, statistics and organization of the test. In addition, it is usually explained in the Clinical Trial Plan
p.000534: background and meaning of the trial, but this can also be found in other documents referenced in the Clinical Trial Plan. In these ICH Guidelines
p.000534: the term "Clinical Trial Plan" refers to the Clinical Trial Plan itself and its amendments and additions.
p.000534: 1.45. Modifications and additions to the Clinical Trial Plan
p.000534: Amendments to the Clinical Trial Plan in writing or its formal clarification.
p.000534: 1.46. Quality assurance
p.000534: All planned and systematic activities aimed at ensuring compliance of the clinical trial, documenting (recording) results and reporting with
p.000534: good clinical practice and applicable legislation.
p.000534: 1.47. Quality control
p.000534: Implementation techniques and activities in the field of quality assurance aimed at verifying that all the quality requirements related to testing are fulfilled.
p.000534: 1.48. Random selection
p.000534: The process of randomly selecting subjects into treatment groups or control groups, thereby reducing bias.
p.000534: 1.49. Competent authorities
p.000534: Bodies competent for the adoption of legislation. For the purposes of these Guidelines, the term competent authorities includes bodies that consider the clinical data obtained
p.000534: and those conducting the inspection (see 1.29). These bodies are sometimes referred to as competent authorities.
...
p.000534: applicable legal requirements.
p.000534: 2.12. The production, handling and storage / storage of tested products must be in accordance with good manufacturing practice. In theirs
p.000534: the approved Test Plan must be followed.
p.000534: 2.13. Those systems of procedures that ensure the quality of all aspects of the test should be applied.
p.000534: 3. CLINICAL TESTING COUNCIL / INDEPENDENT ETHICAL COMMITTEE (irb / iec)
p.000534: 3.1. Competencies
p.000534: 3.1.1. The Clinical Trials / Independent Ethics Committee (hereinafter: the Committee) must protect the rights, safety and well-being of all
p.000534: respondents. Particular attention should be given to surveys involving particularly sensitive respondents.
p.000534: 3.1.2. The committee shall receive for inspection the following documents: Clinical trial plan and amendments thereto, forms of consent statements and
p.000534: their amendments which the examiner intends to use in the examination, a description of the recruitment of the respondents (eg by advertisement), written notifications intended
p.000534: the examiner, the examiner's instructions, the security information available, the interviewee's compensation information, the examiner's CV and / or other documents that
p.000534: testify to its qualifications and other documentation that these committees may consider necessary to fulfill their obligations. On
p.000534: It is for the committee to review and evaluate the proposed clinical trial within a reasonable timeframe and provide its opinion in writing, clearly stating
p.000534: the date of the opinion, the examination in question and the documents reviewed for the following:
p.000534: - approval / positive opinion;
p.000534: - necessary changes before approval / positive opinion;
p.000534: - rejection / negative opinion; te
p.000534: - termination / revocation of a previously granted approval / positive opinion.
p.000534: 3.1.3. The committee should also consider the examiner's qualifications for the proposed examination as recorded in his CV and / or
p.000534: other relevant documents requested by the Commission.
p.000534: 3.1.4. The committee should periodically review any ongoing research at intervals appropriate to the risk for the respondents, and at least
p.000534: once a year.
p.000534: 3.1.5. The Commission has the right to request that the respondent be provided with more information than the one mentioned in paragraph 4.8.10. when according to his
p.000534: in the opinion, such supplementary information may be useful in protecting the rights, safety and / or well-being of the respondents.
p.000534: 3.1.6. When it is intended to conduct a non-therapeutic trial requiring the consent of the respondent's legal representative (see 4.8.12, 4.8.14),
p.000534: The committee should determine whether the proposed Test Plan and / or other documentation has sufficiently taken into account ethical issues and meets the applicable
p.000534: legal regulations for such tests.
p.000534: 3.1.7. Where the Examination Plan indicates that it is not possible to obtain the prior consent of the respondent or his / her legal representative (ie in an emergency
p.000534: cases, see 4.8.15), the Committee should determine whether the proposed Test Plan and / or other documentation has sufficiently taken into account ethical issues and
p.000534: whether it meets the applicable legal requirements for such tests.
p.000534: 3.1.8. The Commission should consider the amount and manner of payment of the respondents' remuneration in order to eliminate any possibility of coercion and undue influence.
p.000534: to the respondents. The payment of compensation should be distributed in installments, not that it depends entirely on the respondent's participation by the end of the examination.
p.000534: 3.1.9. The Commission should ensure that notices of compensation for respondents, including the manner, amount and timing of payments, are included in the written
p.000534: the consent statement form as well as any other written notice for the respondents. The amount and schedule of payment of the installment of the compensation should be stated.
p.000534: 3.2. Composition, tasks and work
p.000534: 3.2.1. The committee should consist of a reasonable number of members, who combine the expertise and experience needed to consider and evaluate
p.000534: the scientific, health and ethical aspects of the proposed test. It is recommended that the Commission:
p.000534: (a) has at least five members;
p.000534: (b) that at least one member by his / her vocation is not from the scientific field;
p.000534: (c) at least one member is independent of the institution conducting the examination or of the place of examination.
p.000534: Only members of the Commission who are independent of the examiner and the contracting authority should have the right to vote or to express an opinion on the examination.
p.000534: testing. The list of Committee members and their qualifications should be regularly updated.
p.000534: 3.2.2. The committee should carry out its tasks in accordance with written operational procedures, document its work and draw up minutes of its
p.000534: meetings, and should adhere to good clinical practice and applicable law.
p.000534: 3.2.3. The committee should announce at which meeting the decisions will be taken and there must be a quorum for their adoption in accordance with the written
p.000534: by operating procedures.
p.000534: 3.2.4. Only those members of the Committee who participated in the deliberations and deliberations should have the right to vote or to express opinions and / or recommendations.
p.000534: about the examination.
p.000534: 3.2.5. The examiner may be required to provide the Committee with information on any aspect of the examination, but he may not participate in the committee's deliberations
p.000534: that is, his vote / opinion.
p.000534: 3.2.6. The Commission may seek the assistance of experts in specific fields other than its members.
p.000534: 3.3. Procedures
p.000534: The Commission shall define in writing the procedures of its action and adhere to them, and by these procedures:
p.000534: 3.3.1. It defines the composition of the Commission (the names and qualifications of the members) and the body to which the Commission is responsible.
p.000534: 3.3.2. Defines the schedule of meetings, their conduct and the notification of members.
p.000534: 3.3.3. It defines the conduct of the first test evaluation and its continuous monitoring.
p.000534: 3.3.4. Defines the frequency of grading as needed.
p.000534: 3.3.5. In accordance with applicable legal regulations, conduct accelerated assessment and give approval / positive opinion on minor changes
p.000534: ongoing trials that have already received prior approval / positive opinion from the Commission.
p.000534: 3.3.6. It defines that no examinee may be included in the examination before it is approved by the Commission.
p.000534: 3.3.7. Deals that no deviation from the Examination Plan or its modification without prior written approval / positive is allowed
p.000534: the opinions of the Commission, except where it is necessary to immediately remove the immediate danger to the respondents, or where the changes relate exclusively to the
p.000534: logistical or administrative aspects of testing (eg change of telephone number of observers) (see 4.5.2.).
p.000534: 3.3.8. Defines that the examiner is obliged to immediately inform the Commission of:
p.000534: (a) deviations from the Examination Plan or amendments thereto to eliminate imminent danger to respondents (see 3.3.7, 4.5.2, 4.5.4);
p.000534: (b) changes that increase the risk to the respondent and / or significantly affect the conduct of the examination (see 4.10.2);
p.000534: (c) any serious and unexpected side effects of the drug;
p.000534: (d) new knowledge that may adversely affect the safety of the subjects or the conduct of the examination.
p.000534: 3.3.9. Ensures that the Examination Committee / Institution immediately informs of:
p.000534: (a) their decisions / opinions regarding the examination;
p.000534: (b) the reasons for the decision / opinion;
p.000534: (c) decision / opinion appeal procedures.
p.000534: 3.4. Documentation
p.000534: The committee should keep all relevant documentation (eg procedure description, list of members, list of professions and parent institutions of members, received
p.000534: documents, meeting minutes and correspondence) for at least three years after the end of the examination and make them available to the competent authorities for their
p.000534: request.
p.000534: The examiners, contracting authorities or competent authorities may request the Commission to provide a description of the procedures and a list of members.
p.000534: 4. EXAMINER
p.000534: 4.1. Qualifications of examiner and preconditions for his / her actions
p.000534: 4.1.1. In order to be able to undertake the proper conduct of the examination, the examiner must be qualified in terms of education, professional development and
p.000534: experience, qualifications should meet current legal requirements and provide evidence of their qualifications through an updated CV and / or other
p.000534: relevant documentation requested by the contracting authority, the Commission and / or the competent authority.
p.000534: 4.1.2. The examiner must be fully aware of the proper application of the test product, as described in the Test Plan, the applicable Guidelines for
p.000534: examiners, product data and other sources of information obtained from the contracting authority.
p.000534: 4.1.3. The examiner must be familiar with, and adhere to, good clinical practice and applicable legal requirements.
...
p.000534: the estimated duration of the test.
p.000534: 4.2.4. The examiner must make sure that all his associates are adequately informed about the Test Plan, the product tested and their obligations and
p.000534: test-related tasks.
p.000534: 4.3. Health care for respondents
p.000534: 4.3.1. Qualified medical doctor - examiner (if necessary, dental doctor) or doctor of medicine conducting the examination should be
p.000534: responsible for all health decisions related to testing.
p.000534: 4.3.2. During and after the respondent's participation in the examination, the examiner / institution should provide adequate health care to the respondents with
p.000534: test-related adverse reactions, including clinically relevant laboratory findings. Does the examiner / institution establish that the respondent is in the meantime
p.000534: suffering from a disease, should be informed of the need for its treatment.
p.000534: 4.3.3. It is recommended that the examiner inform the respondent family physician / general practitioner of his / her participation in the examination, if the respondent has
p.000534: your family doctor / general practitioner and if he / she agrees.
p.000534: 4.3.4. Although the respondent is not required to explain the reasons for his / her early withdrawal from the examination, the examiner should make reasonable efforts to:
p.000534: determine the reasons, respecting all the respondent's rights.
p.000534: 4.4. Communication with the Commission
p.000534: 4.4.1. In order to begin the examination at all, the examiner / institution should have the written and dated approval / positive opinion of the Committee on the Examination Plan,
p.000534: Written Respondent's Statement of Consent and Amendments, Description of Respondent's Recruitment (e.g., by Ad) and Other Written Notices Intended
p.000534: to the respondents.
p.000534: 4.4.2. An up-to-date version of the Examiner's Guide is an integral part of the written request submitted by the examiner / institution to the Commission. If changes occur and
p.000534: Amendments to the Instructions for Examiners During the examination, the examiner / institution is obliged to submit updated Instructions to the Commission.
p.000534: 4.4.3. During the examination, the examiner / institution is obliged to submit to the Commission all documentation necessary for consideration.
p.000534: 4.5. Adherence to the Examination Plan
p.000534: 4.5.1. The examiner / institution should carry out the test in accordance with the Test Plan agreed with the test client and, if necessary, with
p.000534: competent authority, which has received approval / positive opinion from the Commission. In confirmation of the agreement, the examiner / institution and the contracting authority
p.000534: sign the Testing Plan or another contract.
p.000534: 4.5.2. The examiner must not deviate from the Test Plan, or amend it without agreeing with the test client and without first
p.000534: written approval / positive opinion of the Commission, except where it is necessary to immediately remove the immediate danger to the respondent, or where
p.000534: the changes relate exclusively to the logistical or administrative aspects of the examination (eg change of telephone number of observers).
p.000534: 4.5.3. The examiner, ie the person appointed by him, should document and explain any deviation from the approved Test Plan.
p.000534: 4.5.4. The examiner may deviate from the Examination Plan, or change it without the prior approval / positive opinion of the Committee exclusively
p.000534: to eliminate imminent danger to respondents. Deviations from the Examination Plan, or changes thereto, reasons for their introduction and where it is
p.000534: changes and additions required to the Test Plan should be submitted as soon as possible:
p.000534: (a) Evaluation Committee and approval / favorable opinion;
p.000534: (b) the contracting authority for acceptance,
p.000534: (c) to the competent authorities, as appropriate.
p.000534: 4.6. Tested Product (s)
p.000534: 4.6.1. The examiner / institution is responsible for recording the inputs and outputs of the test product at the test site.
p.000534: 4.6.2. Where permitted / required, the examiner / institution may / should all or part of the obligation to record the inputs and outputs of the test product at
p.000534: transfer the test site to the pharmacist or other appropriate person under the supervision of the examiner / institution.
p.000534: 4.6.3. The examiner / institution and / or pharmacist, or other appropriate person appointed by the examiner / institution, should properly record the delivery
p.000534: the product and its condition at the test site, its application per respondent, and return to the test client or other disposal method
p.000534: unused product. Data should include dates, quantities, serial numbers, expiry dates (where appropriate), and unique
p.000534: a tag linking the product being tested and the respondent. The examiner should properly record whether the subjects have received the doses indicated in the Test Plan and
p.000534: compare all quantities of test product obtained from the test client.
p.000534: 4.6.4. The test product should be stored in accordance with the instructions of the test client (see 5.13.2 and 5.14.3) and the applicable legal regulations.
p.000534: 4.6.5. The examiner should ensure that the application of the test product follows an approved test plan only.
p.000534: 4.6.6. The examiner, ie the person appointed by the examiner / institution, is obliged to explain to each respondent the proper use of the test product and
p.000534: periodically, at appropriate intervals, to check that each respondent complies with the instructions given.
p.000534: 4.7. Random selection and decryption procedures
p.000534: The examiner should follow random selection procedures (if intended for testing) and ensure that decryption is carried out exclusively in accordance with
p.000534: with the Test Plan. If the test is blind, the examiner must immediately provide the examiner with the documentation and the reasons for each premature test
p.000534: disclosure of a code linking the respondent and the product under investigation (eg by accident or due to a serious adverse reaction).
p.000534: 4.8. Consent of respondents
p.000534: 4.8.1. In the process of obtaining and recording the subject's consent to participate in the examination, the examiner must comply with the applicable legal requirements.
p.000534: regulations, good clinical practice and ethical principles that are the origin of the Declaration of Helsinki. In order to begin the examination, the examiner must have
p.000534: written approval / positive opinion of the Commission on the form of the statement of consent and other written notifications intended for the respondents.
p.000534: 4.8.2. After any new findings that might affect the Respondent's consent, the Consent Statement form and other written notice intended
p.000534: respondents should be amended accordingly. Prior to use, amended consent statement form and other written notices
p.000534: intended for the respondents should receive the approval / positive opinion of the Commission. Respondent, that is, his legal representative is valid
p.000534: inform in a timely manner new findings that may affect the respondent's willingness to continue to participate in the examination. This kind of notification
p.000534: should be documented.
p.000534: 4.8.3. Neither the examiner nor the examining staff shall coerce or unduly influence the respondent to participate in, or continue to participate in
p.000534: examination.
p.000534: 4.8.4. Oral and written testimony notices, including the statement of consent form, must not contain language formulations that would allow the respondent,
p.000534: that is, his legal representative stated that he at least ostensibly waives his legal rights, that is, which examiner, institution, contracting authority
p.000534: interrogation or their representative, at least apparently, absolves them of their negligence liability.
p.000534: 4.8.5. The examiner, ie the person appointed by him, needs the respondent or his legal representative, if the respondent is not competent to give
p.000534: consent, fully acquainted with all aspects of the examination, including written notice and approval / positive opinion of the Commission.
p.000534: 4.8.6. The choice of words and style of oral and written test reports, including the statement of consent form, should avoid technical terms as much as possible and
p.000534: be understandable to the respondent, that is, his / her legal representative and impartial witness.
p.000534: 4.8.7. Prior to obtaining the consent, the examiner or the person appointed by him / her must provide the respondent or his / her legal representative
p.000534: enough time and opportunity to find out the details of the examination that interest him to decide whether or not he wants to participate. Answer all the questions
p.000534: the test should satisfy the respondent or his / her legal representative.
p.000534: 4.8.8. Prior to the inclusion of the respondents in the examination, the respondent or his / her legal representative must be signed and personally dated
p.000534: statement of consent, also signed by the person interviewing the respondent / legal representative.
p.000534: 4.8.9. If the respondent or his legal representative cannot read, an impartial witness must be present for the entire duration of the interview. After
p.000534: that the respondent and / or his / her legal representative be read the consent form and other written information intended
p.000534: and after the respondent, or his / her legal representative, orally agrees to the respondent's participation in the examination and, if able,
p.000534: sign and date the statement form, the form should also be signed and dated by an impartial witness. By signing the statement, witness
...
p.000534: receive signed and dated copies of updated statements of consent, as well as copies of amendments to notices intended for respondents.
p.000534: 4.8.12. When a clinical trial (whether therapeutic action is expected or not) involves subjects whose consent is required
p.000534: legal representative (eg minors, or patients with marked dementia), such respondents should be familiarized with the examination according to
p.000534: their ability to understand and those who are able to obtain a signed and personally dated written statement of consent.
p.000534: 4.8.13. With the exception described in paragraph 4.8.14, a non-therapeutic trial (ie, a trial in which no direct clinical benefit is expected for the respondent) should
p.000534: be conducted only on the respondent who can express his / her personal consent and sign and date the statement of consent.
p.000534: 4.8.14. Non-therapeutic testing may also be conducted on the respondent who requires the consent of their legal representatives, if they are satisfied
p.000534: the following assumptions:
p.000534: (a) It is not possible to achieve the objectives of the examination if it is conducted on a respondent who can give his or her personal consent;
p.000534: (b) The foreseeable risks per respondent are small;
p.000534: (c) The negative impact on respondents' well-being is low and minimized;
p.000534: (d) Examination is not prohibited by law;
p.000534: (e) The explicit approval / positive opinion of the Commission on the involvement of these respondents has been sought and obtained.
p.000534: With justified exceptions, these tests should be performed on the patient whose condition or condition the product under study is intended for.
p.000534: Respondents should be closely monitored and withdrawn from the examination if they appear overly disturbed.
p.000534: 8/4/15 In urgent cases where it is not possible to obtain the prior consent of the respondents, it must be requested from the respondent's legal representative.
p.000534: Where it is not possible to obtain the prior consent of the respondents and his / her legal representative is not available, the inclusion of the respondents should be followed by measures
p.000534: described in the Examination Plan and / or elsewhere, approved by the Commission, to protect the rights, safety and welfare of the respondents and to ensure
p.000534: compliance with applicable legislation. The respondent or his / her legal representative should be informed as soon as possible about the examination and
p.000534: to seek their consent in order to proceed with the examination or to seek other appropriate consent (see 4.8.10.)
p.000534: 4.9. Record keeping and reporting
p.000534: 4.9.1. The examiner should make sure that the test client is provided with test specimens and other necessary reports in a timely manner with accurate, complete and
p.000534: comprehensible data.
p.000534: 4.9.2. The data in the test lists of the respondents taken from the original documents should be the same as the data in the original documents, and possibly
...
p.000534: 4.11.2. Reports of adverse events and / or abnormal laboratory findings identified by the Test Plan as critical to the assessment
p.000534: security should be delivered to the test client in accordance with the reporting rules and at intervals specified by the test client at
p.000534: Test plan.
p.000534: 4.11.3. When reporting a death, the examiner should provide additional information to the investigator and to the Commission upon request (eg autopsy findings and
p.000534: medical report of the cause of death).
p.000534: 4.12. Premature termination or termination of examination
p.000534: If, for any reason, the examination is terminated or terminated prematurely, the examiner / institution should inform the subjects immediately, ensure
p.000534: their proper treatment and monitoring and inform the competent authorities in accordance with the relevant legal provisions. In addition:
p.000534: 4.12.1. If the examiner completes or terminates the examination without the consent of the examining authority, he shall inform the institution thereof, and
p.000534: the examiner / institution should immediately inform the test client and the Committee and provide them with a detailed explanation of such procedure.
p.000534: 4.12.2. If the contracting authority completes or terminates the examination (see 5.21), the examiner is obliged to inform the institution immediately, and the examiner / institution
p.000534: the Commission should be informed immediately and a detailed explanation of such procedure should be provided.
p.000534: 4.12.3. If the Committee withdraws its approval / positive opinion on the examination (see 3.1.2 and 3.3.9), the examiner shall inform the institution accordingly,
p.000534: and the examiner / institution should immediately inform the contracting authority and provide him with a detailed explanation of such procedure.
p.000534: 4.13. Final report of examiner (s)
p.000534: Upon completion of the examination, the examiner should inform the institution. The examiner / institution should provide the committee with a summary of the test results, a
p.000534: all necessary reports to the competent authorities.
p.000534: 5. TEST ORDER
p.000534: 5.1. Quality assurance and control
p.000534: 5.1.1. The testing contractor is responsible for establishing and maintaining a quality assurance and quality control system through standard operating systems
p.000534: procedures to ensure that the clinical trial is conducted, documented (recorded) and reported to the Trial Plan,
p.000534: good clinical practice and applicable legislation.
p.000534: 5.1.2. The test client is responsible for reaching an agreement between the parties on direct access (see 1.21) to all test sites, original
p.000534: data / documents and reports so that it can monitor and supervise the test, or in order for the domestic or foreign competent authority
p.000534: could carry out an inspection.
p.000534: 5.1.3. Quality should be monitored at every stage of data handling to ensure its reliability and proper processing.
p.000534: 5.1.4. Agreements between the client and the examiner / institution and other parties involved in the clinical trial should be in writing
p.000534: as an integral part of the Examination Plan or as a separate agreement.
p.000534: 5.2. Contracting Research Organization (ITA)
p.000534: 5.2.1. The contracting authority may delegate all its obligations or tasks or part thereof to the contracting research organization, with ultimate responsibility
p.000534: the quality and completeness of the test results shall continue to be borne by the contracting authority. The ITA's job is to implement quality assurance and quality control procedures.
p.000534: 5.2.2. Each obligation and task related to the examination, which is transferred to the ITA, must be individually stated in writing.
p.000534: 5.2.3. The contracting authority retains those obligations and tasks that are not explicitly delegated to the ITA.
p.000534: 5.2.4. Anything in this Guideline that applies to the contracting authority shall also apply to the ITA to the extent that the ITA has assumed the obligations and tasks of
p.000534: of the contracting authority.
p.000534: 5.3. Expert medical opinion
p.000534: Nursing staff with appropriate qualifications should be identified who will always be able to give their expert opinion on issues and issues related to
p.000534: with examination. If necessary, the contracting authority may also appoint external consultants for this purpose.
p.000534: 5.4. Test plan
p.000534: 5.4.1. The client of the trial should hire qualified persons (eg biostatistics, clinical pharmacologists and medical doctors in accordance with the needs).
p.000534: all stages of testing, from the design of the Test Plan and Test List, through the planning of the analysis, to the analysis and preparation of interim and final clinical trials
p.000534: test reports.
p.000534: 5.4.2. For further guidance, see 6. Clinical Trial Plan and its Amendments and Appendices, ICH Guidelines for Compilation and Content of Clinical Trial Report
p.000534: Examination and other ICH Guidelines related to test planning, development of the Test Plan and conduct of the test.
p.000534: 5.5. Test management, data handling and record keeping
p.000534: 5.5.1. The contracting authority should hire qualified persons to supervise the overall conduct of the examination, to manage the data obtained,
p.000534: verify their accuracy, perform statistical analyzes and prepare reports.
p.000534: 5.5.2. The trial contracting authority may appoint an independent data monitoring committee to periodically evaluate the progress of the clinical trial,
p.000534: including safety data and key drug efficacy parameters, and to recommend whether the trial client should continue the trial, amend
p.000534: or stop it. The Independent Data Monitoring Commission should, in writing, derogate from operating procedures (operating procedures) and maintain
p.000534: notes from all their meetings.
...
p.000534: from interrogation, ie to provide redress, except in the case of a malpractice lawsuit and / or negligence.
p.000534: 5.8.2. The contracting authority shall determine in its provisions and procedures the amount of the costs of treating the respondent in the event of an injury resulting from his
p.000534: participation in the examination in accordance with applicable legal regulations.
p.000534: 5.8.3. The procedure and manner of providing compensation to the respondent should be in accordance with the applicable legal regulations.
p.000534: 5.9. Financing
p.000534: The financial aspects of the test should be documented by agreement between the test client and the examiner / institution.
p.000534: 5.10. Notification / submission of requests to competent authorities
p.000534: Prior to the commencement of the clinical trial, the trial sponsor (or trial sponsor and examiner, if required by applicable law)
p.000534: regulations) should be submitted to the appropriate authorities for assessment, acceptance and / or approval (in accordance with applicable legal regulations) of the required requirements
p.000534: to begin testing. Each notification / request should be dated and contain sufficient information to identify the Test Plan.
p.000534: 5.11. Commission Appraisal Certificate
p.000534: 5.11.1. The contracting authority shall obtain from the examiner / institution:
p.000534: (a) the name and address of the Examiner's Health Care Committee;
p.000534: (b) a statement by the Commission that its composition and operation are in accordance with good clinical practice and applicable laws and regulations;
p.000534: (c) a document with the approval / affirmative opinion of the Commission and, at the client's request, a current copy of the Examination Plan, a statement form on
p.000534: the consent of that other written notice intended for the respondents, depending on their recruitment procedures, as well as documentation relating to
p.000534: fees to respondents and other documents requested by the Commission.
p.000534: 5.11.2. If the Committee gives its approval / positive opinion changes to any aspect of the examination such as changes to the Plan
p.000534: Examination, Consent Statement Form, Other Written Notices Intended for Respondents and / or Other Procedures
p.000534: the examiner / institution must receive a copy of the modification document and the date of approval / positive opinion of the Commission.
p.000534: 5.11.3. The contracting authority shall obtain from the examiner / institution the documentation and dates of re-approvals / supervision of the Commission, as well as
p.000534: withdrawal / revocation of approval / positive opinion.
p.000534: 5.12. Data on the product tested
p.000534: 5.12.1. When planning a test, the test client should make sure that sufficient safety and performance information is available
p.000534: from preclinical and / or clinical trials related to route of administration, dose, duration and appropriate population of subjects.
p.000534: 5.12.2. As soon as it becomes aware of the new data, the test client is obliged to update the Testing Instructions.
p.000534: 5.13. Production, packaging and labeling and coding of the product under test
p.000534: 5.13.1. The test client shall ensure that the test product (including, if applicable, comparative active drug and placebo) is labeled in accordance with
p.000534: the stage of its development, that it has been manufactured in accordance with all applicable good manufacturing practices, that it has been coded and labeled in such a way that
p.000534: if necessary, it protects the blind process. In addition, labeling should be in accordance with applicable legal regulations.
p.000534: 5.13.2. The contracting authority shall state the appropriate storage conditions for the medicinal product such as temperature, light protection, storage time,
p.000534: then, if necessary, fluid reconstitution procedures and accessories used for infusion of the test product. The contracting authority should inquire about this
p.000534: inform all interested parties (ie observers, examiners, pharmacists, warehouse managers).
p.000534: 5.13.3. The packaging of the test product should be such as to prevent its contamination and unacceptable changes in transport and storage.
p.000534: 5.13.4. In blind studies, the labeling system of the product under test should also include a mechanism that allows for rapid identification of the drug in the
p.000534: emergency but which does not allow identity disclosure to go unnoticed.
p.000534: 5.13.5. If there are any significant changes in the formulation of the test product or comparator at the clinical stage of development,
p.000534: testing new formulations to obtain the results of additional testing (eg stability, dissolution rate, bioavailability) required for evaluation
p.000534: can these changes significantly alter the pharmacokinetics of the drug.
p.000534: 5.14. Supply and handling of tested product
p.000534: 5.14.1. The test client is responsible for supplying the tester / institution with the product being tested.
p.000534: 5.14.2. The test contractor may not supply the examiner / institution with the product under test until he has obtained all the necessary documentation (e.g.
p.000534: approval / favorable opinion of the Commission and the competent authorities).
p.000534: 5.14.3. The test client shall ensure that the description of the procedures also includes the instructions for handling and storage of the test product and its associated
p.000534: documentation to be followed by the examiner / institution. These instructions should cover proper and secure receipt, handling, storage and issuance
p.000534: test product, collection of unused test product from the respondent and return it to the test client (or otherwise)
p.000534: disposal of unused product in accordance with applicable legal regulations).
p.000534: 5.14.4. The contracting authority shall:
p.000534: (a) ensure timely delivery of the test product to the examiner;
p.000534: (b) keep records of the dispatch, receipt, removal, return and destruction of the investigated product (see 8. Basic clinical implementation documents
p.000534: examinations);
p.000534: (c) maintain a system of return for the test product and record its return (eg for withdrawal of defective product, return on completion
p.000534: tests, returns of expired products);
p.000534: (d) maintain a system for removing unused test products and recording their disposal.
p.000534: 5.14.5. The contracting authority shall:
p.000534: (a) take the necessary measures to ensure the stability of the test product during application;
p.000534: (b) have sufficient quantities of the test product available to confirm its specifications, that is, to keep records of batch analyzes; and
p.000534: product properties. To the extent that the stability of the medicinal product permits, samples should be kept either until the analysis of the test results has been completed or until the prescribed deadline.
p.000534: any applicable law, whichever is later.
p.000534: 5.15. Access to documentation
p.000534: 5.15.1. The examining authority should ensure that the Examination Plan or other written agreement clearly states that the examiner / institution must
p.000534: provide direct access to original data / documents for monitoring, monitoring, evaluation of the Commission and inspection by the competent authorities.
p.000534: 5.15.2. The trial contracting authority should check that each respondent has given his or her written consent that his or her original health information may be obtained
p.000534: access directly for monitoring, monitoring, evaluation of the Commission and inspection by the competent authorities.
p.000534: 5.16. Product Safety Information
p.000534: 5.16.1. The test client is responsible for assessing the safety of the product being tested.
p.000534: 5.16.2. The contracting authority shall promptly inform all examiners / institutions and competent authorities of information which may adversely affect
p.000534: the safety of the respondents, influence the conduct of the examination, or withdraw the approval / positive opinion of the Commission.
p.000534: 5.17. Reporting of side effects of the drug
p.000534: 5.17.1. The contracting authority shall promptly inform all examiners / institutions, the Committees (where appropriate) and the competent authorities of all serious and
p.000534: unexpected side effects of the drug.
p.000534: 5.17.2. These emergency reports should comply with applicable laws and ICH's Clinical Safety Information Management Guidelines:
p.000534: Definitions and standards for emergency reporting.
p.000534: 5.17.3. The contracting authority shall provide the competent authorities with all new safety data and periodic reports in accordance with the applicable legal requirements
p.000534: regulations.
p.000534: 5.18. Observation
p.000534: 5.18.1. Purpose
p.000534: The purpose of observing a test is to verify that:
p.000534: (a) the rights and welfare of the respondents are protected;
p.000534: (b) that the information in the reports is accurate, complete and can be verified / verified using the original documents;
p.000534: (c) the test is conducted in accordance with the current approved Test Plan and any amendments thereto, with good clinical
p.000534: practice and with applicable legal regulations.
p.000534: 5.18.2. Selection and qualifications of observers
p.000534: (a) Observers shall be appointed by the contracting authority.
...
p.000534: as well as Test Lists
p.000534: 8.2.3. NOTICE TO THE RESPONDENTS
p.000534: - CONSENT STATEMENT FORM (including all relevant translations) Document interviewee consent X X
p.000534: Document that respondent will receive appropriate written notice
p.000534: - OTHER WRITTEN NOTES on the basis of which he or she may choose to participate in X X
p.000534: examination
p.000534: - ADVERTISING TO INCLUDE THE RESPONDENTS (if advertising is planned) Document that the inclusion of the respondents is appropriate and without coercion X
p.000534: Document the financial agreement on conducting the test between
p.000534: 8.2.4. FINANCIAL ASPECTS OF TESTING X X
p.000534: the examiner / institution and the contracting authority
p.000534: Document that the respondent will be compensated for any damages
p.000534: 8.2.5. INSURANCE STATEMENT (where applicable) X X
p.000534: injuries resulting from his participation in the examination.
p.000534: 8.2.6. SIGNED AGREEMENTS BETWEEN TEST PARTICIPANTS, eg: Document the said agreements
p.000534: - examiner / institution and contracting authority X X
p.000534: X
p.000534: - the examiner / institution and the contracting research organization X
p.000534: (where necessary)
p.000534: - the contracting authority and the contracting research organization X
p.000534: - examiner / institution and competent authorities (where applicable) X X
p.000534: 8.2.7. DATED AND DOCUMENTED APPROVAL / POSITIVE Document that examination was considered by the Committee and provided its
p.000534: OPINION OF THE HEALTHCARE MEDICINE COMMITTEE / approval / positive opinion. Identify version number and date X X
p.000534: INDEPENDENT ETHICAL COMMITTEE ON THE FOLLOWING: document (s).
p.000534: - Test plan and amendments thereto
p.000534: - Test sheets
p.000534: - Consent form
p.000534: - other written notices intended for the respondents
p.000534: - Respondent recruitment ad (if scheduled)
p.000534: - Respondent's fees (if any):
p.000534: - other approved documents
p.000534: 8.2.8. COMPOSITION OF THE CLINICAL TRIAL / INDEPENDENT COUNCIL Document that the composition of the committee is consistent with good clinical X (where
p.000534: X
p.000534: ETHICAL TRUSTEE practice. needed)
p.000534: Document that an authorization / approval / notification has been obtained from X
p.000534: 8.2.9. AUTHORIZATION / APPROVAL / NOTICE OF TEST PLAN X (where is
p.000534: of the competent authority before the commencement of the examination and in accordance with the applicable one
p.000534: COMPETENT AUTHORITY (where applicable) required)
p.000534: legal regulations. (where necessary)
p.000534: 8.2.10. BIOGRAPHY AND / OR OTHER EVIDENCE DOCUMENTS Document the qualifications and suitability for conducting the tests and / or
p.000534: X X
p.000534: QUALIFICATIONS OF THE TESTIGATORS AND PERSONS WHO CONDUCT THE TESTING OF THE HEALTH MONITORING OF THE RESPONDENTS.
p.000534: 8.2.11. NORMAL VALUES / VALUES FOR
p.000534: MEDICAL / LABORATORY / TECHNICAL PROCEDURES AND / OR TESTS Document normal values and / or ranges of test values. X X
p.000534: PROVIDED FOR TESTING PLAN
p.000534: X
p.000534: Document the suitability of the department / laboratory for implementation
p.000534: 8.2.12. MEDICAL / LABORATORY / TECHNICAL PROCEDURES / TESTS X
p.000534: predicted tests and confirm the reliability of the findings.
p.000534: (where necessary)
...
p.000534: case, without disclosing to the respondent the further administration of the drug. the third
p.000534: page)
p.000534: X (po
p.000534: need
p.000534: 8.2.18. RANDOM SELECTION LIST Document the method of random selection of respondents.
p.000534: the third
p.000534: page)
p.000534: Document that the test site is appropriate for his
p.000534: 8.2.19. MONITORING REPORT BEFORE BEGINNING X
p.000534: implementation (may be consolidated with 8.2.20).
p.000534: Document that the procedures used in the examination have been considered
p.000534: 8.2.20. MONITORING REPORT AT THE BEGINNING OF THE TEST X X
p.000534: with the examiner and his staff (may be combined with 8.2.19).
p.000534: 8.3. During the clinical phase of the trial
p.000534: In addition to storing the above documents, they should be accompanied by the following evidence that all new information is documented as soon as it is available.
p.000534: Stored with the Client
p.000534: Document name Purpose
p.000534: Examiner / testing institution
p.000534: Document that the examiner is informed in a timely manner of the most recent information
p.000534: 8.3.1. SUPPLEMENTARY INSTRUCTIONS TO TESTOR X X
p.000534: as soon as they are available.
p.000534: Document changes to the said documents that take effect for
p.000534: 8.3.2. ALL CHANGES: X X
p.000534: test time.
p.000534: - Modifications and additions to the Test Plan and Test Sheet
p.000534: - consent form
p.000534: - other written notices intended for the respondents
p.000534: - Respondent engagement ads (if scheduled)
p.000534: 8.3.3. DATED AND DOCUMENTED
p.000534: Document that changes and additions and / or changes are made available to the Commission and
p.000534: CLINICAL COUNCIL APPROVAL / POSITIVE OPINION
p.000534: that it approved them / gave their positive opinion. Identify version number and X X
p.000534: TESTS / INDEPENDENT ETHICAL COMMITTEE ON
p.000534: date document (s) that.
p.000534: FOLLOWING:
p.000534: - modifications and additions to the Test Plan
p.000534: - changes:
p.000534: - consent form
p.000534: - other written notices intended for the respondents
p.000534: - Respondent engagement ads (if scheduled)
p.000534: - other approved documents
p.000534: - continuous monitoring of testing (where necessary)
p.000534: X
p.000534: 8.3.4. AUTHORIZATION / APPROVAL / NOTICE OF COMPETENT
p.000534: Document compliance with applicable legal regulations. X
p.000534: BODIES, WHERE REQUIRED, TO:
p.000534: (where necessary)
p.000534: - modifications and additions to the Examination Plan and other documents
p.000534: 8.3.5. CVS OF NEW TESTERS AND / OR PERSONS WHO
p.000534: (see 8.2.10.) X X
p.000534: CONDUCTING TESTING
p.000534: 8.3.6. NORMAL VALUES / RANGE SUPPLEMENTS
p.000534: DOCTORAL / LABORATORY / TECHNICAL VALUES Document the revised normal values and their ranges over time
p.000534: X X
p.000534: PROCEDURES AND / OR TESTS PROVIDED FOR INVESTMENT PLAN (see 8.2.11).
p.000534: TESTING
p.000534: X
p.000534: 8.3.7. PHYSICAL / LABORATORY / TECHNICAL ADDITIONS
p.000534: Document the suitability of tests for the duration of the test (see 8.2.12.). X
p.000534: PROCEDURES / TESTS
p.000534: (where necessary)
p.000534: - confirmation or
p.000534: - authorization or
p.000534: - established quality control and / or external quality assessment or
p.000534: - other form of validation (where necessary)
p.000534: 8.3.8. DOCUMENTATION OF SHIPMENT OF THE TESTED PRODUCT
p.000534: (see 8.2.15.) X X
p.000534: AND TEST MATERIAL
p.000534: 8.3.9. CERTIFICATES OF ANALYSIS OF NEW SERIES TESTED
p.000534: (see 8.2.16.) X
p.000534: PRODUCTS
...
p.000534: (whether included in the adult test protocol or in a separate protocol) in healthcare settings with knowledge and experience in nursing
p.000534: of this patient population.
p.000534: 2.6. Ethical issues related to testing in children
p.000534: Children are a vulnerable group of respondents. It is therefore necessary to introduce specific measures to protect their rights in clinical trials and to prevent them
p.000534: exposure to unnecessary risk. The purpose of this section is to provide an ethical framework for conducting testing in children.
p.000534: For the clinical trial to be of benefit to its participants and other children, its plan must be such as to ensure the quality and clarity of the collected
p.000534: data. Respondents are also expected to benefit from the clinical trial, except in the special circumstances described in the ICH.
p.000534: document E6, section 4.8.14.
p.000534: 2.6.1. Clinical Trial Panel / Independent Ethics Committee (Committee)
p.000534: The role and authority of the Commission described in ICH document E6 is crucial in protecting the respondents. When considering protocols involving children,
p.000534: The committee among its membership must or must seek the professional opinion of persons with a good knowledge of ethical, clinical and psychosocial issues.
p.000534: related to children.
p.000534: 2.6.2. Involvement of respondents
p.000534: Respondents should be included in a way that completely excludes inappropriate prompting of respondents, or their parents / guardians, to participate in
p.000534: examination.
p.000534: Fees and living expenses may be included in the cost of the pediatric clinical trial. Fees should be approved by
p.000534: Committees.
p.000534: When conducting child testing, it is a good idea to include individuals who represent the demographic country / region and the disease being tested, except where
p.000534: there are valid reasons for limited participation in the examination.
p.000534: 2.6.3. Consent and consent
p.000534: As a rule, children are legally incapable of giving their consent to participate in the examination. Therefore, their participation depends on their decision
p.000534: parents or guardians to take responsibility for their participation in the clinical trial. Fully familiarize the caregiver with the examination and
p.000534: obtaining his consent should be in accordance with local laws and regulations. All participants need to be better acquainted with the testing using
p.000534: the consent should be determined by the Commission, or in accordance with local legal requirements).
p.000534: Participants who are mentally mature should personally sign and date either a specific consent form or a consent form. Anyway,
p.000534: Participants must be aware of their right to refuse participation or withdraw from the examination at any time. It should be addressed
p.000534: attention to the signs of excessive suffering in patients who are unable to clearly express their suffering. Although it must respect the respondent's decision to
p.000534: withdraw from testing, in therapeutic trials of serious and life-threatening diseases such circumstances are possible which, in the opinion of the examiner and
p.000534: parent / guardian, may jeopardize the welfare of the child in the event of his / her withdrawal. In these circumstances, further consent from the parent (guardian) is sufficient
p.000534: to continue the child's participation in the examination. Independent or elderly minors (as defined by local law) may be on their own
p.000534: able to give consent.
p.000534: Data that may be collected in a less vulnerable population that has consented to participate is not advisable to be collected in a more vulnerable population,
p.000534: that is, from patients who are unable to give informed consent. Examinations in handicapped or institutionalized children should be limited to those
p.000534: diseases and health conditions that are mainly or exclusively related to these populations, or to the circumstances in which their disease is expected
p.000534: or health change the behavior or pharmacodynamics of medical devices.
p.000534: 2.6.4. How to minimize risk
p.000534: Whatever the importance of testing in proving or denying the value of a treatment, it can lead to injury in the subjects even when
...
p.000534: Procedures to check whether a potential respondent is participating in another clinical trial at the same time or that sufficient time has elapsed
p.000534: having previously participated in a clinical trial (especially important when it comes to including healthy subjects in clinical trials):
p.000534: Procedures used to protect the privacy of recorded data, source documents, or samples:
p.000534: Treatment or care plan after completing clinical trial participation (who will be responsible and where to administer):
p.000534: Statistical considerations and reasons for including a specified number of subjects in a clinical trial
p.000534: Amount and procedure for reimbursement to respondents (amount and description of expenses paid during examinations, eg travel expenses, lost earnings,
p.000534: compensation for pain and discomfort, etc.):
p.000534: Rules for termination (or early termination) of a clinical trial in a legal entity (or persons) where the clinical trial will be conducted:
p.000534: Contract on access to data by examiners, principles of publication of results, etc. (unless specified in clinical trial plan):
p.000534: Funding sources (if not provided in the clinical trial plan) and information about the examiner's financial or other interests.
p.000534: Clinical trial observer:
p.000534: Responsible for the clinical trial by the applicant / client for the clinical trial
p.000534: Date:
p.000534: Signature:
p.000534: * meets MIZ
p.000534: ANNEX IV.
p.000534: Application form for submission to the Central Ethics Committee of the opinion on the admissibility of a clinical trial of a medicinal product
p.000534: - completed by the clinical trial client or the applicant responsible for the accuracy of the information provided
p.000534: - The Chief Examiner only signs the informed consent by signing his signature
p.000534: Clinical trial client:
p.000534: Applicant for clinical trial:
p.000534: SEP - Registration number
p.000534: EUDRACT number
p.000534: Date of receipt of complete documentation
p.000534: A. General information
p.000534: Test name, label
p.000534: Clinical trial phase (I, II, III, IV.)
p.000534: version and date of test plan
p.000534: Examiner brochure (version and date)
p.000534: Informed Consent ((Version and Date)
p.000534: Insurance document Policy number, date of issue, duration of insurance
p.000534: Certificate of payment of the fee
p.000534: Test Summary (Version and Date) According to the SEP Special Form
p.000534: B. Information on examiners
p.000534: Chief Examiner in the Republic of Croatia
p.000534: Address *
p.000534: Phone and fax
p.000534: e-mail
p.000534: Chief Examiner
p.000534: reviewed the translation of informed consent
p.000534: specify version and date -
p.000534: which is confirmed by the signature of this section
p.000534: Leaders of participating testing centers (examiners),
p.000534: (addresses, tel, fax, e-mail)
p.000534: C. Data on test substance
p.000534: Is the preparation approved in the Republic of Croatia
p.000534: Countries where the preparation is approved
p.000534: Generic name
p.000534: Trademark
p.000534: Manufacturer
p.000534: Dosage and administration of the drug in this study
...
p.000534: APPLICATION FORM AND EVALUATION OF NON-INTERVENTIONAL TEST
p.000534: Non-interventional background information (to be completed by the applicant)
p.000534: Name of non-intervention drug test in Croatian:
p.000534: Name of non-intervention drug test in English:
p.000534: Test plan designation:
p.000534: Name and address of the contracting authority:
p.000534: Applicant's name and address:
p.000534: Principal examiners and establishments where non-interventional drug testing will be conducted (number of establishments and examiners): The list is attached to this form and is an integral part of it
p.000534: Objectives of the test:
p.000534: Inclusion criteria:
p.000534: Anticipated number of patients to be monitored:
p.000534: Estimated duration of testing in the Republic of Croatia:
p.000534: Documents provided (filled in by applicant)
p.000534: Test plan (mark, version and date):
p.000534: Approved Summary of Product Characteristics in the Republic of Croatia (approval date):
p.000534: Package leaflet for the medicinal product in the Republic of Croatia (date of approval):
p.000534: Decision on marketing authorization (date):
p.000534: Informed consent for the patient in Croatian language (version and date):
p.000534: Original informed consent in English (version and date):
p.000534: Test financial plan:
p.000534: Other documentation (list, with version and date of documents):
p.000534: Certificate of payment of the costs of giving the opinion of the SPS:
p.000534: Applicant's signature and date:
p.000534: _________________________________________
p.000534: Documentation evaluation (to be completed by the rapporteur)
p.000534: Test plan YES NO
p.000534: The medicine is prescribed according to the marketing authorization: ∑ ☐ Comment:
p.000534: Involvement of patients in a particular therapeutic procedure is not determined in advance by the test plan but is carried out in accordance with normal practice: ∑ ☐ Comment:
p.000534: Prescribing a drug is independent of the decision to include patients in the trial: ∑ ☐ Comment:
p.000534: Additional diagnostic and patient monitoring procedures are not performed (except those that form part of normal practice): ∑ ☐ Comment:
p.000534: Epidemiological methods are used to analyze the data collected: ∑ ☐ Comment:
p.000534: Testing does not promote prescribing of monitored drug: ∑ ☐ Comment:
p.000534: Informed consent in Croatian: YES NO
p.000534: The text clearly describes the conduct of the test, listing all the information needed to make the decision: ∑ ☐ Comment:
p.000534: The text of informed consent is understandable for patients: ∑ ☐ Comment:
p.000534: The informed consent text is linguistic, spelling and typographical correct: ∑ ☐ Comment:
p.000534: Other documentation provided: YES NO
p.000534: Fits test plan: ∑ ☐ Comment:
p.000534: Test Financial Plan: YES NO
p.000534: The test's financial plan is clear: ∑ ☐ Comment:
p.000534: Examiner fees match the estimated scope of work: ∑ ☐ Comment:
p.000534: Rapporteur's recommendation for the adoption of the SPS opinion at the meeting (specify date):
p.000534: (delete unnecessarily; in case b, c or d, reasons must be provided)
p.000534: a. positive thinking
p.000534: b. conditional positive thinking
p.000534: c. it is delayed
p.000534: d. negative thinking
p.000534: Reasons:
p.000534: Report date Reporter's signature:
p.000534: [1] 1 [1] In ICH's E5 Guidelines on Ethnic Factors Affecting Clinical Acceptance from Other Countries, Factors
p.000534: which may influence different drug response in different populations are divided into internal and external ethnic factors. Here you are
p.000534: categories are called internal or external factors only.
p.000534: ANNEX VII.
p.000534: AGENCY FOR MEDICINAL PRODUCTS AND MEDICAL PRODUCTS
p.000534: APPLICATION FORM FOR APPLICATION AND ASSESSMENT OF NON-INTERVENTION TEST
p.000534: Non-interventional background information (to be completed by the applicant)
p.000534: Name of non-intervention test in Croatian:
p.000534: Name of the non-intervention test in English:
p.000534: Name of the active substance (INN):
p.000534: Name of drug:
p.000534: Test plan designation:
p.000534: Authorization holder name and address:
p.000534: Name and address of the contracting authority:
p.000534: Applicant's name and address:
p.000534: Name and surname of the local pharmacovigilance officer
p.000534: Principal examiners and institutions where non-intervention testing will be conducted (names of institutions and examiners' names):
p.000534: Objectives of the test:
p.000534: Inclusion criteria:
p.000534: Exclusion criteria:
p.000534: Anticipated number of patients to be monitored:
p.000534: Estimated duration of testing in the Republic of Croatia:
p.000534: Countries where the non-intervention testing in question is already underway
p.000534: Countries where a request has been made to conduct the non-intervention test in question
p.000534: EU PAS registry number *
p.000534: Shared PASS **
p.000534: * indicate whether PASS is registered in the EU PAS registry
p.000534: ** in the case where multiple marketing authorization holders participate in the planning and implementation of the PASS
p.000534: Documents provided (filled in by applicant)
p.000534: Test plan (mark, version and date):
p.000534: Test list (version and date):
p.000534: Approved Summary of Product Characteristics in the Croatian language (approval date):
p.000534: Approved package leaflet in the Croatian language (authorization date):
p.000534: Decision on marketing authorization (date):
p.000534: Informed consent for the patient in Croatian language (version and date):
p.000534: Original informed consent in English (version and date), if applicable:
p.000534: Test financial plan:
p.000534: Proposal of Notice to the Directorate of the Institution on Conducting Non-Intervention Testing
p.000534: Other documentation (list, with version and date of documents):
p.000534: SEP Opinion
p.000534: Signature of the applicant's responsible person
p.000534: requests and date
p.000534: __________________________
p.000534: [1] This Directive does not regulate the non-intervention testing of a medicinal product.
...
Economic / Economic/Poverty
Searching for indicator poor:
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p.000534: the respondent when the examiner reports adverse event and / or other information related to the examination.
p.000534: 1.59. Location of clinical trial
p.000534: Site where clinical trial activities are conducted.
p.000534: 1.60. An unexpected side effect
p.000534: A side effect whose nature or weight is inconsistent with valid product information (e.g., examiner instructions for disapproved test product or instructions
p.000534: on the product / summary of the product if it is an approved product) (see ICH Guidelines for the handling of clinical harm data: Definitions and
p.000534: standards for emergency reporting).
p.000534: 1.61. Particularly sensitive respondents
p.000534: Individuals whose willingness to participate in a clinical trial may be unduly influenced by the expectation, whether justified or not, that their participation
p.000534: to bring certain benefits, that is, otherwise they will be avenged by the elderly or superiors. Members can serve as an example
p.000534: hierarchical groups such as medical, pharmacy or dental students, hospital and laboratory staff, pharmaceutical employees
p.000534: industry, members of the military of that person in custody or prison. The mentioned respondents include patients with incurable diseases, residents
p.000534: housing, the unemployed and the poor, emergency patients, ethnic minorities, homeless people, nomads, refugees, minors and
p.000534: persons unable to consent.
p.000534: 1.62. Well-being (of respondents)
p.000534: Physical and spiritual integrity of the clinical trial participant.
p.000534: 2. ICH PRINCIPLES OF GOOD CLINICAL PRACTICE
p.000534: 2.1. Clinical trials must be conducted in accordance with the ethical principles of the Helsinki Declaration and in accordance with good practice.
p.000534: clinical practice and applicable law.
p.000534: 2.2. Before starting a clinical trial, the expected risks and disruptions to the expected benefits for the individual subject and
p.000534: society. Clinical trials should only be started and continued if the expected benefit justifies the risk.
p.000534: 2.3. The rights, safety and well-being of respondents who are ahead of the interests of science and society.
p.000534: 2.4. The available preclinical and clinical data on the product under test must sufficiently support the conduct of the clinical trial.
p.000534: 2.5. The scientific foundations of clinical trials must be sound and the Trial Plan must be clear and detailed.
p.000534: 2.6. Testing should be carried out in accordance with the Clinical Trials / Independent Review Panel approved / tested positive
p.000534: of the Ethics Committee.
p.000534: 2.7. Responsibility for the health care of the respondent and for decisions regarding his or her treatment must always rest with a qualified medical doctor,
p.000534: where appropriate, to a qualified dental doctor.
...
General/Other / Dependent
Searching for indicator dependent:
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p.000534: testing.
p.000534: 5.18.6. Observation report
p.000534: (a) The observer shall, after each visit to the site of the test, or after each receipt of the test notification,
p.000534: submit a report.
p.000534: (b) The reports should include the date, place, name of the observer and the name of the examiner, or other person with whom the observer communicated.
p.000534: (c) The reports should include a concise account of the observation and the observer's statement of important findings / findings, discrepancies and shortcomings, conclusions and
p.000534: measures taken or to be taken and / or recommended measures to comply with the request.
p.000534: (d) The representative of the contracting authority shall record the client's assessment of the monitoring reports and of the follow-up activities resulting from the report.
p.000534: 5.19. Supervision
p.000534: When conducting quality control oversight, the contracting authority should consider the following:
p.000534: 5.19.1. The purpose of surveillance
p.000534: The purpose of the contracting authority's monitoring procedure, which is independent of and separate from routine monitoring or quality control, is to evaluate the conduct of testing and
p.000534: its adherence to the Examination Plan, standard operating procedures, good clinical practice and applicable legal requirements.
p.000534: 5.19.2. Selection and qualifications of supervisors
p.000534: (a) For the purpose of carrying out supervision, the contracting authority shall appoint persons who are not dependent on the clinical trial.
p.000534: (b) The contracting authority shall ensure that persons are properly qualified by their education and experience to carry out the supervision properly. It should exist
p.000534: records of the qualifications of the supervisor.
p.000534: 5.19.3. Control procedure
p.000534: (a) The contracting authority should ensure that clinical trial supervision is conducted in accordance with the contracting authority's written provisions as to what should be monitored;
p.000534: how to conduct surveillance, how often, and what form and content of surveillance reports should be.
p.000534: (b) The contracting authority's plan and procedures for examining the test should take into account the importance of testing to resolve the request submitted to the competent authorities, no.
p.000534: test subjects, the type and complexity of the test, the level of risk for the respondents, and any problems identified.
p.000534: (c) The observations and findings of the person supervising should be documented.
p.000534: (d) In order to preserve the independence and value of the controls, inspection by the competent authorities of the surveillance report need not be part of the ordinary procedure. Competent authorities
p.000534: may request access to a case-by-case monitoring report when there is evidence of a serious departure from good clinical practice,
p.000534: that is, during court proceedings.
...
p.000534: product.
p.000534: 7.3.4. Physical, chemical and pharmaceutical properties and product formulation
p.000534: The substances that make up the test product (including chemical and / or structural formulas) should be described and a brief overview of the main chemical, chemical and / or chemical formulas.
p.000534: pharmaceutical properties.
p.000534: In order to be able to take appropriate precautionary measures during testing, formulations, including excipients, must be provided and explained
p.000534: their use where clinically relevant. Care and handling instructions should also be provided.
p.000534: Any structural similarity to other known compounds should be noted.
p.000534: 7.3.5. Preclinical research
p.000534: Introduction:
p.000534: The results of important preclinical studies of the pharmacology, toxicology, pharmacokinetics and metabolism of the test product should be summarized in
p.000534: form. The summary should contain the methodology, results and discussion of the importance of the results for the tested beneficial or potential adverse effects in the
p.000534: people.
p.000534: The data may include the following:
p.000534: • Species of experimental animals;
p.000534: • Number and sex of animals in each group;
p.000534: • Unit doses (eg milligrams / kilogram (mg / kg));
p.000534: • Dose spacing;
p.000534: • Application route;
p.000534: • Dosing duration;
p.000534: • System allocation information;
p.000534: • Duration of follow-up after cessation of exposure;
p.000534: • Results, including the following aspects:
p.000534: - The nature and frequency of pharmacological and toxic effects;
p.000534: - The severity and intensity of pharmacological and toxic effects;
p.000534: - The time of their beginning;
p.000534: - Reversibility of effects;
p.000534: - Duration of effects;
p.000534: - Dose-dependent effects.
p.000534: Wherever possible, tables should be used to make the data clearer.
p.000534: The following sections of the Package Leaflet should discuss the most important results of preclinical studies, including the observed dependence of dose effects,
p.000534: importance for human application and other aspects to be tested in humans. Where possible, the results of effective non-toxic doses should be compared
p.000534: used in the same animal species (eg therapeutic index should be discussed). The importance of this information for proper use in humans should be considered.
p.000534: Wherever possible, comparisons should be based on blood / tissue levels rather than mg / kg.
p.000534: (a) Preclinical pharmacology
p.000534: A summary of the pharmacological aspects of the test product and significant metabolites observed in experimental animals should be provided, where appropriate
p.000534: possible. Such a summary should include research evaluating the potential therapeutic action of a drug (e.g., efficacy models,
p.000534: receptor binding and specificity) and its safety (eg special studies of pharmacological activities other than therapeutic ones).
p.000534: (b) Pharmacokinetics and metabolism of the test product in animals
p.000534: A summary of the pharmacokinetics and biotransformation (metabolism) and elimination of the test product in all animals in which
p.000534: conducted preclinical research. In discussing the results, we should refer to the absorption and local and systemic bioavailability of the test product and
p.000534: its metabolites, as well as their relationship with pharmacological and toxicological findings in animal species.
p.000534: (c) Toxicology
...
p.000534: drug intended.
p.000534: In general, pharmacokinetic studies are performed on ill children. This may mean greater heterogeneity among subjects than in healthy subjects
p.000534: volunteers, but the data obtained better reflects clinical application.
p.000534: In the case of medicinal products exhibiting linear pharmacokinetics in adults, single use in pharmacokinetic studies in children
p.000534: may provide sufficient knowledge for dose selection.
p.000534: If necessary, this choice can be confirmed by occasional sampling in repeated dose clinical trials. Any
p.000534: nonlinearity in the absorption, distribution and elimination of the drug and any difference in the time of action between single and multiple dose in adults
p.000534: points to the need to test a drug in children when its dynamic balance is reached. Performing all of these procedures makes it easy to see
p.000534: pharmacokinetic parameters in adults. Knowledge of drug elimination pathways can often prove useful in planning trials in children
p.000534: (via the kidney and metabolism) and age-dependent changes in these processes.
p.000534: For most medicines, the recommended doses for children are based on milligrams per kilogram body weight (mg / kg) and range up to the highest adult dose.
p.000534: Although the first choice may be a dosage based on mg / m2 of body surface area, clinical experience indicates that frequent errors in height measurement or
p.000534: length (especially young children and infants), as well as in calculating the body surface area from these measurements. It is important to administer some medications on a physical basis
p.000534: surfaces (eg drugs with a narrow therapeutic index such as oncology), but extra caution should be exercised to calculate the amount
p.000534: correct.
p.000534: Practical considerations facilitating the conduct of pharmacokinetic studies
p.000534: The blood volume taken from children should be as small as possible. It must be justified within the protocol. Clinical Trials Board / Independent Ethics
p.000534: Committees (Committees) consider and may determine the highest amount of blood (usually in milliliters per kilogram (mL / kg), or as a percentage of
p.000534: total blood volume) that can be taken for testing. There are several ways to minimize blood sampling and vein injection
p.000534: a possible measure.
p.000534: • Using sensitive assays for the drug and its metabolites that require lower blood volume in the sample.
p.000534: • Involvement of laboratories with experience in the processing of low blood volume samples for pharmacokinetic and safety analysis (blood tests, clinical
p.000534: chemistry).
...
General/Other / Incapacitated
Searching for indicator incapacity:
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p.000534: background and meaning of the trial, but this can also be found in other documents referenced in the Clinical Trial Plan. In these ICH Guidelines
p.000534: the term "Clinical Trial Plan" refers to the Clinical Trial Plan itself and its amendments and additions.
p.000534: 1.45. Modifications and additions to the Clinical Trial Plan
p.000534: Amendments to the Clinical Trial Plan in writing or its formal clarification.
p.000534: 1.46. Quality assurance
p.000534: All planned and systematic activities aimed at ensuring compliance of the clinical trial, documenting (recording) results and reporting with
p.000534: good clinical practice and applicable legislation.
p.000534: 1.47. Quality control
p.000534: Implementation techniques and activities in the field of quality assurance aimed at verifying that all the quality requirements related to testing are fulfilled.
p.000534: 1.48. Random selection
p.000534: The process of randomly selecting subjects into treatment groups or control groups, thereby reducing bias.
p.000534: 1.49. Competent authorities
p.000534: Bodies competent for the adoption of legislation. For the purposes of these Guidelines, the term competent authorities includes bodies that consider the clinical data obtained
p.000534: and those conducting the inspection (see 1.29). These bodies are sometimes referred to as competent authorities.
p.000534: 1.50. Serious adverse event or serious side effect
p.000534: Any undesirable medical occurrence involving any of the following:
p.000534: - death of a person,
p.000534: - life-threatening condition,
p.000534: - the need for hospital treatment or extension of pre-existing hospital treatment,
p.000534: - permanent or severe disability or incapacity,
p.000534: - congenital anomaly / birth defect.
p.000534: (see ICH Clinical Safety Information Guidelines: Definitions and Standards for Emergency Reporting).
p.000534: 1.51. Original data
p.000534: All data in original documents and certified copies of original records of clinical findings of observations or other procedures in clinical trials
p.000534: required to monitor the course and evaluate the clinical trial.
p.000534: The original information is contained in the original documentation (original records or certified copies).
p.000534: 1.52. Original documentation
p.000534: Original files, data, and records (e.g., hospital records, hospital and medical records, laboratory notes, memos, test subjects' diaries, or
p.000534: checklists, medication lists, recorded data from automated devices, copies and transcripts certified as authentic copies, micro-shi,
p.000534: negatives, micro lms and magnetic media, x-rays, test files and records from pharmacies, laboratories and health departments
p.000534: involved in the clinical trial.
p.000534: 1.53. Investigator
p.000534: An individual, company, institution or organization responsible for initiating, conducting and / or financing a clinical trial.
p.000534: 1.54. Investigator - examiner
p.000534: An individual who initiates and conducts, alone or with others, a clinical trial and under whose immediate management the test product is prescribed, dispensed, or
p.000534: the respondent applies it. This term is restricted to natural persons (ie does not include legal persons such as corporations or agencies).
p.000534: Obligations of the client-examiner include both the obligations of the clinical trial client and those of the clinical trial examiner.
p.000534: 1.55. Standard Operating Procedures (SOPs)
...
General/Other / Other Country
Searching for indicator another country:
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p.000534: unacceptable side effects. Therefore, early participation in testing may unnecessarily expose children to the action of a compound that will prove useless. There
p.000534: where the drug represents an important advance in the treatment of children, even if it is not a serious illness, trials should be started at an early stage of drug development, and
p.000534: the request for marketing should also include information on its use in children.
p.000534: The possible absence of this information should be explained in detail. Therefore, it is important to carefully weigh the possible before starting a drug test in children
p.000534: the benefit, risk of treatment and the need for its introduction.
p.000534: 2.4. Types of testing
p.000534: The principles outlined in ICH documents E4, E5, E6 and E10 also apply to testing in children. There are several issues that are specific to children.
p.000534: When examining a medicine in children in a country or region, internal (eg pharmacogenetic) and external factors should be taken into account 1 [1] [1]
p.000534: (e.g., nutrition) that may affect the application of results in another country or region.
p.000534: The efficacy data for the indications tested and approved in adults may be applicable to children for the same indications if
p.000534: the development of the disease and the likelihood of treatment outcome are similar in the two populations. In this case, pharmacokinetics testing in all age groups of children
p.000534: receiving the drug and these harmless studies may provide sufficient data for administration through pediatric doses that will lead to drug levels in
p.000534: blood similar to those seen in the adult population. If the test is approached in this way, it is necessary to have data in order to plan tests in children
p.000534: on the pharmacokinetics of the drug in adults.
p.000534: Elderly drug efficacy data may prove applicable to younger children for the same indications if disease development and likelihood are
p.000534: treatment outcomes similar in the two age groups. In this case, pharmacokinetics testing in appropriate age groups of children receiving the drug
...
General/Other / Public Emergency
Searching for indicator emergency:
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p.000534: to facilitate the mutual acceptance of clinical data by the competent authorities of those countries.
p.000534: The guidelines have been developed keeping in mind good clinical practice in the practice of the European Union, Japan and the United States, as well as Australia, Canada,
p.000534: the Nordic countries and the World Health Organization (WHO).
p.000534: These guidelines should be followed when preparing clinical trial data that are made available to the competent authorities.
p.000534: The principles set out in these Guidelines may also be applied in other clinical trials that may affect the safety and well-being of subjects.
p.000534: 1. GLOSSARY
p.000534: 1.1. Side effects
p.000534: Clinical experience with a new drug / medicinal product or its new application that is prior to approval, especially if not
p.000534: established therapeutic doses: all adverse and adverse reactions to the drug / medicinal product regardless of the dose received are considered side effects. Expression
p.000534: "Reaction to a drug / medical device" means that the causal link between the medicinal product / medical device and a side effect has at least been identified as an option, ie.
p.000534: that it cannot be ruled out.
p.000534: In terms of market-approved medicines / medical products: harmful and adverse reactions of humans at doses commonly administered in prophylaxis,
p.000534: diagnosis, treatment of disease, or modification of a biological function (see ICH Guidelines for the Management of Clinical Safety Information:
p.000534: Definitions and standards for emergency reporting).
p.000534: 1.2. Harmful event
p.000534: Any undesirable medical event in a clinical trial in a patient or respondent who has received a pharmaceutical product that is not necessary
p.000534: causally related to its application. Therefore, any adverse and unwanted sign (including
p.000534: deviation in laboratory findings), a symptom or disease that is temporally associated with the administration of the medicinal (tested) drug / product, without
p.000534: whether it is the cause or not (see ICH Guidelines for the Management of Clinical Safety Data: Emergency Deviations and Standards
p.000534: reporting).
p.000534: 1.3. Modifications and Additions (Clinical Trial Plan)
p.000534: See Changes and additions to the Clinical Trial Plan.
p.000534: 1.4. Legislation in force (s)
p.000534: Law (s) and regulation (s) related to the conduct of a clinical study of drug / medical product testing.
p.000534: 1.5. Approval (Refers to Clinical Trials Council)
p.000534: Positive decision of the Clinical Trial Council on clinical trial to be carried out within the institution within the limits set by the
p.000534: clinical trials, facilities, good clinical practices, and applicable law.
p.000534: 1.6. Supervision
p.000534: Systematic and independent review of clinical trial activities and related documentation to determine if activities in which
p.000534: performs surveillance conducted, data entered and analyzed and reported in accordance with the Clinical Trial Plan, standard operational
p.000534: test client procedures, good clinical practice, and applicable legal requirements.
p.000534: 1.7. Certificate of inspection
p.000534: A statement confirming that surveillance has been carried out.
p.000534: 1.8. Surveillance report
p.000534: A written statement informing the testing authority of the results of the surveillance.
p.000534: 1.9. Documenting surveillance
p.000534: Documentation to track the sequence of events.
p.000534: 1.10. Clinical trial blindness / masking
p.000534: A process in which one or more parties participating in a clinical trial do not know how treatment is assigned. Single blind trial
p.000534: usually refers to a patient who does not know the division of treatment, and double-blind to a respondent, examiner, observer, and in some cases,
p.000534: data analysts.
p.000534: 1.11. Test list
...
p.000534: the term "Clinical Trial Plan" refers to the Clinical Trial Plan itself and its amendments and additions.
p.000534: 1.45. Modifications and additions to the Clinical Trial Plan
p.000534: Amendments to the Clinical Trial Plan in writing or its formal clarification.
p.000534: 1.46. Quality assurance
p.000534: All planned and systematic activities aimed at ensuring compliance of the clinical trial, documenting (recording) results and reporting with
p.000534: good clinical practice and applicable legislation.
p.000534: 1.47. Quality control
p.000534: Implementation techniques and activities in the field of quality assurance aimed at verifying that all the quality requirements related to testing are fulfilled.
p.000534: 1.48. Random selection
p.000534: The process of randomly selecting subjects into treatment groups or control groups, thereby reducing bias.
p.000534: 1.49. Competent authorities
p.000534: Bodies competent for the adoption of legislation. For the purposes of these Guidelines, the term competent authorities includes bodies that consider the clinical data obtained
p.000534: and those conducting the inspection (see 1.29). These bodies are sometimes referred to as competent authorities.
p.000534: 1.50. Serious adverse event or serious side effect
p.000534: Any undesirable medical occurrence involving any of the following:
p.000534: - death of a person,
p.000534: - life-threatening condition,
p.000534: - the need for hospital treatment or extension of pre-existing hospital treatment,
p.000534: - permanent or severe disability or incapacity,
p.000534: - congenital anomaly / birth defect.
p.000534: (see ICH Clinical Safety Information Guidelines: Definitions and Standards for Emergency Reporting).
p.000534: 1.51. Original data
p.000534: All data in original documents and certified copies of original records of clinical findings of observations or other procedures in clinical trials
p.000534: required to monitor the course and evaluate the clinical trial.
p.000534: The original information is contained in the original documentation (original records or certified copies).
p.000534: 1.52. Original documentation
p.000534: Original files, data, and records (e.g., hospital records, hospital and medical records, laboratory notes, memos, test subjects' diaries, or
p.000534: checklists, medication lists, recorded data from automated devices, copies and transcripts certified as authentic copies, micro-shi,
p.000534: negatives, micro lms and magnetic media, x-rays, test files and records from pharmacies, laboratories and health departments
p.000534: involved in the clinical trial.
p.000534: 1.53. Investigator
p.000534: An individual, company, institution or organization responsible for initiating, conducting and / or financing a clinical trial.
p.000534: 1.54. Investigator - examiner
p.000534: An individual who initiates and conducts, alone or with others, a clinical trial and under whose immediate management the test product is prescribed, dispensed, or
p.000534: the respondent applies it. This term is restricted to natural persons (ie does not include legal persons such as corporations or agencies).
p.000534: Obligations of the client-examiner include both the obligations of the clinical trial client and those of the clinical trial examiner.
p.000534: 1.55. Standard Operating Procedures (SOPs)
p.000534: Detailed written Instructions to ensure uniformity in the conduct of certain tasks.
p.000534: 1.56. Assistant Examiner
p.000534: Each individual member of the clinical trial team assigned or supervised by the examiner at the clinical trial establishment
p.000534: performing clinical trial procedures and / or making clinical trial decisions (eg associates, specialists, scientific
p.000534: associates). See also Examiner.
p.000534: 1.57. Respondent / clinical trial participant
p.000534: The person participating in the clinical trial, whether receiving the test product or serving as a control.
p.000534: 1.58. Respondent's identification mark
p.000534: Unique identifier assigned by the examiner to each respondent to protect the respondent's identity, which is used instead of the name
p.000534: the respondent when the examiner reports adverse event and / or other information related to the examination.
p.000534: 1.59. Location of clinical trial
p.000534: Site where clinical trial activities are conducted.
p.000534: 1.60. An unexpected side effect
p.000534: A side effect whose nature or weight is inconsistent with valid product information (e.g., examiner instructions for disapproved test product or instructions
p.000534: on the product / summary of the product if it is an approved product) (see ICH Guidelines for the handling of clinical harm data: Definitions and
p.000534: standards for emergency reporting).
p.000534: 1.61. Particularly sensitive respondents
p.000534: Individuals whose willingness to participate in a clinical trial may be unduly influenced by the expectation, whether justified or not, that their participation
p.000534: to bring certain benefits, that is, otherwise they will be avenged by the elderly or superiors. Members can serve as an example
p.000534: hierarchical groups such as medical, pharmacy or dental students, hospital and laboratory staff, pharmaceutical employees
p.000534: industry, members of the military of that person in custody or prison. The mentioned respondents include patients with incurable diseases, residents
p.000534: housing, the unemployed and the poor, emergency patients, ethnic minorities, homeless people, nomads, refugees, minors and
p.000534: persons unable to consent.
p.000534: 1.62. Well-being (of respondents)
p.000534: Physical and spiritual integrity of the clinical trial participant.
p.000534: 2. ICH PRINCIPLES OF GOOD CLINICAL PRACTICE
p.000534: 2.1. Clinical trials must be conducted in accordance with the ethical principles of the Helsinki Declaration and in accordance with good practice.
p.000534: clinical practice and applicable law.
p.000534: 2.2. Before starting a clinical trial, the expected risks and disruptions to the expected benefits for the individual subject and
p.000534: society. Clinical trials should only be started and continued if the expected benefit justifies the risk.
p.000534: 2.3. The rights, safety and well-being of respondents who are ahead of the interests of science and society.
p.000534: 2.4. The available preclinical and clinical data on the product under test must sufficiently support the conduct of the clinical trial.
p.000534: 2.5. The scientific foundations of clinical trials must be sound and the Trial Plan must be clear and detailed.
p.000534: 2.6. Testing should be carried out in accordance with the Clinical Trials / Independent Review Panel approved / tested positive
p.000534: of the Ethics Committee.
p.000534: 2.7. Responsibility for the health care of the respondent and for decisions regarding his or her treatment must always rest with a qualified medical doctor,
p.000534: where appropriate, to a qualified dental doctor.
...
p.000534: - necessary changes before approval / positive opinion;
p.000534: - rejection / negative opinion; te
p.000534: - termination / revocation of a previously granted approval / positive opinion.
p.000534: 3.1.3. The committee should also consider the examiner's qualifications for the proposed examination as recorded in his CV and / or
p.000534: other relevant documents requested by the Commission.
p.000534: 3.1.4. The committee should periodically review any ongoing research at intervals appropriate to the risk for the respondents, and at least
p.000534: once a year.
p.000534: 3.1.5. The Commission has the right to request that the respondent be provided with more information than the one mentioned in paragraph 4.8.10. when according to his
p.000534: in the opinion, such supplementary information may be useful in protecting the rights, safety and / or well-being of the respondents.
p.000534: 3.1.6. When it is intended to conduct a non-therapeutic trial requiring the consent of the respondent's legal representative (see 4.8.12, 4.8.14),
p.000534: The committee should determine whether the proposed Test Plan and / or other documentation has sufficiently taken into account ethical issues and meets the applicable
p.000534: legal regulations for such tests.
p.000534: 3.1.7. Where the Examination Plan indicates that it is not possible to obtain the prior consent of the respondent or his / her legal representative (ie in an emergency
p.000534: cases, see 4.8.15), the Committee should determine whether the proposed Test Plan and / or other documentation has sufficiently taken into account ethical issues and
p.000534: whether it meets the applicable legal requirements for such tests.
p.000534: 3.1.8. The Commission should consider the amount and manner of payment of the respondents' remuneration in order to eliminate any possibility of coercion and undue influence.
p.000534: to the respondents. The payment of compensation should be distributed in installments, not that it depends entirely on the respondent's participation by the end of the examination.
p.000534: 3.1.9. The Commission should ensure that notices of compensation for respondents, including the manner, amount and timing of payments, are included in the written
p.000534: the consent statement form as well as any other written notice for the respondents. The amount and schedule of payment of the installment of the compensation should be stated.
p.000534: 3.2. Composition, tasks and work
p.000534: 3.2.1. The committee should consist of a reasonable number of members, who combine the expertise and experience needed to consider and evaluate
p.000534: the scientific, health and ethical aspects of the proposed test. It is recommended that the Commission:
p.000534: (a) has at least five members;
p.000534: (b) that at least one member by his / her vocation is not from the scientific field;
p.000534: (c) at least one member is independent of the institution conducting the examination or of the place of examination.
...
p.000534: 5.12.2. As soon as it becomes aware of the new data, the test client is obliged to update the Testing Instructions.
p.000534: 5.13. Production, packaging and labeling and coding of the product under test
p.000534: 5.13.1. The test client shall ensure that the test product (including, if applicable, comparative active drug and placebo) is labeled in accordance with
p.000534: the stage of its development, that it has been manufactured in accordance with all applicable good manufacturing practices, that it has been coded and labeled in such a way that
p.000534: if necessary, it protects the blind process. In addition, labeling should be in accordance with applicable legal regulations.
p.000534: 5.13.2. The contracting authority shall state the appropriate storage conditions for the medicinal product such as temperature, light protection, storage time,
p.000534: then, if necessary, fluid reconstitution procedures and accessories used for infusion of the test product. The contracting authority should inquire about this
p.000534: inform all interested parties (ie observers, examiners, pharmacists, warehouse managers).
p.000534: 5.13.3. The packaging of the test product should be such as to prevent its contamination and unacceptable changes in transport and storage.
p.000534: 5.13.4. In blind studies, the labeling system of the product under test should also include a mechanism that allows for rapid identification of the drug in the
p.000534: emergency but which does not allow identity disclosure to go unnoticed.
p.000534: 5.13.5. If there are any significant changes in the formulation of the test product or comparator at the clinical stage of development,
p.000534: testing new formulations to obtain the results of additional testing (eg stability, dissolution rate, bioavailability) required for evaluation
p.000534: can these changes significantly alter the pharmacokinetics of the drug.
p.000534: 5.14. Supply and handling of tested product
p.000534: 5.14.1. The test client is responsible for supplying the tester / institution with the product being tested.
p.000534: 5.14.2. The test contractor may not supply the examiner / institution with the product under test until he has obtained all the necessary documentation (e.g.
p.000534: approval / favorable opinion of the Commission and the competent authorities).
p.000534: 5.14.3. The test client shall ensure that the description of the procedures also includes the instructions for handling and storage of the test product and its associated
p.000534: documentation to be followed by the examiner / institution. These instructions should cover proper and secure receipt, handling, storage and issuance
p.000534: test product, collection of unused test product from the respondent and return it to the test client (or otherwise)
p.000534: disposal of unused product in accordance with applicable legal regulations).
p.000534: 5.14.4. The contracting authority shall:
p.000534: (a) ensure timely delivery of the test product to the examiner;
p.000534: (b) keep records of the dispatch, receipt, removal, return and destruction of the investigated product (see 8. Basic clinical implementation documents
p.000534: examinations);
...
p.000534: provide direct access to original data / documents for monitoring, monitoring, evaluation of the Commission and inspection by the competent authorities.
p.000534: 5.15.2. The trial contracting authority should check that each respondent has given his or her written consent that his or her original health information may be obtained
p.000534: access directly for monitoring, monitoring, evaluation of the Commission and inspection by the competent authorities.
p.000534: 5.16. Product Safety Information
p.000534: 5.16.1. The test client is responsible for assessing the safety of the product being tested.
p.000534: 5.16.2. The contracting authority shall promptly inform all examiners / institutions and competent authorities of information which may adversely affect
p.000534: the safety of the respondents, influence the conduct of the examination, or withdraw the approval / positive opinion of the Commission.
p.000534: 5.17. Reporting of side effects of the drug
p.000534: 5.17.1. The contracting authority shall promptly inform all examiners / institutions, the Committees (where appropriate) and the competent authorities of all serious and
p.000534: unexpected side effects of the drug.
p.000534: 5.17.2. These emergency reports should comply with applicable laws and ICH's Clinical Safety Information Management Guidelines:
p.000534: Definitions and standards for emergency reporting.
p.000534: 5.17.3. The contracting authority shall provide the competent authorities with all new safety data and periodic reports in accordance with the applicable legal requirements
p.000534: regulations.
p.000534: 5.18. Observation
p.000534: 5.18.1. Purpose
p.000534: The purpose of observing a test is to verify that:
p.000534: (a) the rights and welfare of the respondents are protected;
p.000534: (b) that the information in the reports is accurate, complete and can be verified / verified using the original documents;
p.000534: (c) the test is conducted in accordance with the current approved Test Plan and any amendments thereto, with good clinical
p.000534: practice and with applicable legal regulations.
p.000534: 5.18.2. Selection and qualifications of observers
p.000534: (a) Observers shall be appointed by the contracting authority.
p.000534: (b) Observers must have appropriate education and scientific and / or clinical knowledge necessary to properly monitor the examination. It should
p.000534: keep track of the observer's qualifications.
p.000534: (c) The observer should be fully familiar with the product tested, the Test Plan, the Consent Declaration Form, other written notices
p.000534: intended for interviewees, the client's standard operating procedures and applicable legal requirements.
p.000534: 5.18.3. I also cover the nature of the observation
p.000534: The contracting authority shall ensure proper monitoring of the examination. The contracting authority shall determine the appropriate volume and nature
...
p.000534: needed).
p.000534: 6.4.6. Description of criteria for termination or termination of part / entire examination, or for exclusion of individual respondents from the examination.
p.000534: 6.4.7. Procedures for recording the inputs and outputs of the test product, placebo and comparator drugs.
p.000534: 6.4.8. Description of storing random selection codes and procedures for decrypting them.
p.000534: 6.4.9. A description of all the data that should be entered directly into the test list of respondents (ie, those not previously recorded in an electronic or written document) and
p.000534: information considered original.
p.000534: 6.5. Selection of respondents and their withdrawal from examination
p.000534: 6.5.1. Criteria for inclusion of respondents in the examination.
p.000534: 6.5.2. Exclusion criteria for respondents.
p.000534: 6.5.3. Criteria for withdrawal of test subjects (ie discontinuation of treatment with test product) and procedures specifying the following:
p.000534: (a) when and how subjects may withdraw from testing / treatment with the product tested;
p.000534: (b) the type of data and the timetable for collecting it from the withdrawing respondents;
p.000534: (c) whether these respondents replace each other and how;
p.000534: (d) monitoring of subjects who withdraw from testing / treatment with the product under examination.
p.000534: 6.6. Treatment of subjects
p.000534: 6.6.1. Planned treatment, including the names of all products, their doses and dosage schedules, route / route of administration and periods of administration, including
p.000534: the follow-up period of respondents from each group who received the product under test.
p.000534: 6.6.2. Description of medicines / treatments that are (including emergency medicines), that is, not allowed before and / or during the test.
p.000534: 6.6.3. Observation procedures designed to determine whether a respondent adheres to the prescribed treatment.
p.000534: 6.7. Performance evaluation
p.000534: 6.7.1. List of drug efficacy parameters.
p.000534: 6.7.2. Methods and schedule for evaluating, recording and analyzing performance parameters.
p.000534: 6.8. Security rating
p.000534: 6.8.1. List of drug safety parameters.
p.000534: 6.8.2. Methods and schedule for assessing, recording and analyzing security parameters.
p.000534: 6.8.3. Procedures for recording and reporting adverse events and emerging diseases.
p.000534: 6.8.4. Form and duration of follow-up of the respondent after the adverse event.
p.000534: 6.9. Statistical processing
p.000534: 6.9.1. Description of the statistical methods, including a schedule of any interim analyzes for the duration of the test.
p.000534: 6.9.2. Number of planned respondents. In multicenter trials, the intended number of subjects for each test site should be indicated. The reason
p.000534: for the selection of a particular sample (number of subjects), including considerations (calculations) of the significance of the trial and its clinical justification.
p.000534: 6.9.3. Significance level to be used in statistical processing.
p.000534: 6.9.4. Criteria for completing the examination.
p.000534: 6.9.5. Procedures for recording missing, unused, and false data.
p.000534: 6.9.6. Procedures for reporting deviations from the original statistical plan (all deviations from the original statistical plan should also be described
p.000534: justify in the Test Plan and / or Final Report).
...
p.000534: 8.2.11. NORMAL VALUES / VALUES FOR
p.000534: MEDICAL / LABORATORY / TECHNICAL PROCEDURES AND / OR TESTS Document normal values and / or ranges of test values. X X
p.000534: PROVIDED FOR TESTING PLAN
p.000534: X
p.000534: Document the suitability of the department / laboratory for implementation
p.000534: 8.2.12. MEDICAL / LABORATORY / TECHNICAL PROCEDURES / TESTS X
p.000534: predicted tests and confirm the reliability of the findings.
p.000534: (where necessary)
p.000534: - confirmation or
p.000534: - authorization or
p.000534: - established quality control and / or external quality assessment
p.000534: - other forms of validation (where appropriate)
p.000534: Document compliance with applicable labeling regulations and
p.000534: 8.2.13. SAMPLE MARK ON TANK OF TESTED PRODUCT X
p.000534: the appropriateness of the instructions for the respondents.
p.000534: 8.2.14. INSTRUCTIONS FOR THE MANAGEMENT OF THE TESTED PRODUCT I Document the instructions necessary for proper storage, packaging,
p.000534: TEST MATERIALS (if not included in Test Plan or Distribution and Removal of Tested Product and Material for X X
p.000534: Instructions for the examiner) examination.
p.000534: Document the date of dispatch, batch number and shipping method of the subject
p.000534: 8.2.15. RECORD OF DELIVERY OF THE TESTED PRODUCT I
p.000534: products and test materials. Lets track the X X series
p.000534: TEST MATERIAL
p.000534: products, checking shipping conditions, and logging inputs and outputs
p.000534: 8.2.16. CERTIFICATES ON ANALYSIS OF SHIPPED TESTED
p.000534: Document the identity, purity and strength of the product being tested. X
p.000534: PRODUCTS
p.000534: X (po
p.000534: Document the way in which the product under test is identified in an emergency
p.000534: 2/8/17 DECISION PROCEDURES IN BLIND TESTS X
p.000534: case, without disclosing to the respondent the further administration of the drug. the third
p.000534: page)
p.000534: X (po
p.000534: need
p.000534: 8.2.18. RANDOM SELECTION LIST Document the method of random selection of respondents.
p.000534: the third
p.000534: page)
p.000534: Document that the test site is appropriate for his
p.000534: 8.2.19. MONITORING REPORT BEFORE BEGINNING X
p.000534: implementation (may be consolidated with 8.2.20).
p.000534: Document that the procedures used in the examination have been considered
p.000534: 8.2.20. MONITORING REPORT AT THE BEGINNING OF THE TEST X X
p.000534: with the examiner and his staff (may be combined with 8.2.19).
p.000534: 8.3. During the clinical phase of the trial
p.000534: In addition to storing the above documents, they should be accompanied by the following evidence that all new information is documented as soon as it is available.
p.000534: Stored with the Client
p.000534: Document name Purpose
p.000534: Examiner / testing institution
p.000534: Document that the examiner is informed in a timely manner of the most recent information
p.000534: 8.3.1. SUPPLEMENTARY INSTRUCTIONS TO TESTOR X X
p.000534: as soon as they are available.
p.000534: Document changes to the said documents that take effect for
p.000534: 8.3.2. ALL CHANGES: X X
p.000534: test time.
p.000534: - Modifications and additions to the Test Plan and Test Sheet
p.000534: - consent form
p.000534: - other written notices intended for the respondents
p.000534: - Respondent engagement ads (if scheduled)
p.000534: 8.3.3. DATED AND DOCUMENTED
p.000534: Document that changes and additions and / or changes are made available to the Commission and
...
General/Other / Relationship to Authority
Searching for indicator authority:
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p.000534: Good clinical practice is a set of internationally recognized ethical and scientific requirements that are followed in the planning, implementation, recording and reporting
p.000534: on clinical trials.
p.000534: Investigational Medicinal Product Dossier (hereinafter: IMPD) is a document showing data relating to
p.000534: the quality of the test drug, the production and control of the test drug, and data from non-clinical and clinical trials as well as data on the administration of the test drug
p.000534: drug in humans.
p.000534: Informed consent is consent to participate in a clinical trial on a voluntary basis based on received and properly documented notices
p.000534: on the nature and importance, consequences and risks of the examination, in writing, signed by the interviewee and dated. If the person is incompetent
p.000534: to give such consent or is a minor, the consent is signed by a legal representative or guardian. If the respondent is illiterate or unable to write, he gives
p.000534: oral consent in the presence of at least one witness who is not a member of the examination team.
p.000534: Inspection supervision of clinical trials is the oversight of the competent authority over the conduct of the clinical trial, review of documentation, premises, records,
p.000534: quality assurance systems and other resources related to the conduct of clinical trials that may be conducted at the test site, at the premises
p.000534: of the clinical trial client and / or the contracting authority or in other legal entities where the competent authority deems it necessary to carry out supervision.
p.000534: The respondent is an individual who participates in a clinical trial and receives the study drug or is part of a control group.
p.000534: The examiner is a doctor of medicine or a person with appropriate professional qualifications for clinical trials due to his / her professional knowledge and necessary
p.000534: experience in treating patients. The examiner is responsible for conducting the clinical trial at the test site. If a clinical trial is conducted by a group
p.000534: individuals in one examiner site, the examiner is responsible and is called the lead examiner.
p.000534: The test site is the health facility where the clinical trial is conducted.
p.000534: Test drug is a pharmaceutical formulation with an active substance or a placebo that is being tested or used as a comparison in a clinical trial and includes
p.000534: medicinal products authorized on the market but used in a different way from the one approved or different in formulation or packaging, or
p.000534: are used in unauthorized indications or used to obtain additional information on a marketing authorization form.
p.000534: Clinical trial is any human trial designed to detect or confirm clinical, pharmacological and / or other pharmacodynamic effects
p.000534: one or more test drugs and / or detection of side effects of one or more test drugs, and / or studies on absorption, distribution, metabolism and
p.000534: excretion of one or more investigational drugs for the purpose of determining the safety of administration and / or efficacy. This includes clinical trials
...
p.000534: use epidemiological methods to analyze the data collected.
p.000534: A nonprofit clinical trial is a clinical trial conducted by an examiner without the involvement of the pharmaceutical industry.
p.000534: Clinical / non-intervention trial client is a legal or legal entity responsible for initiating a clinical / non-intervention trial,
p.000534: the management of the clinical / non-intervention trial and / or the cost of the clinical / non-intervention trial.
p.000534: A clinical trial plan is a document that describes the goals, design, methodology, statistical considerations, and organization of the clinical trial that
p.000534: includes the test plan itself, all subsequent versions of the test plan, and any amendments thereto.
p.000534: Pediatric Investigation Plan (PIP) means a test or development program that seeks to secure data collection
p.000534: necessary to determine the conditions under which the drug may be approved for the treatment of the pediatric population.
p.000534: The representative of the clinical / non-intervention trial client is a legal or registered person established in the European Union.
p.000534: a clinical / non-interventional trial based outside the European Union.
p.000534: The applicant for the clinical / non-profit trial (hereinafter referred to as the applicant) is a clinical trial client established in Europe.
p.000534: Union or its authorized representative established within the European Union if the contracting authority is outside the European Union.
p.000534: Applicant for non-intervention testing is the marketing authorization holder of the Republic of Croatia, the marketing authorization holder
p.000534: approved by a centralized procedure, ie representative of the marketing authorization holder.
p.000534: The Central Ethics Committee is an independent body made up of health professionals and other members of the non-medical profession whose task is to protect the rights, safety and
p.000534: the welfare of the subjects involved in the clinical trials, and to provide assurance as to that protection, inter alia by expressing their opinion on the test plan,
p.000534: the eligibility of the examiner, the legal entity being tested, the equipment and the methods and documents that will be used to inform the interviewee
p.000534: and obtaining their consent based on informed consent. The Central Ethics Committee shall be appointed by the Minister for Health (hereinafter referred to as "the Minister of Health")
p.000534: (Minister).
p.000534: The Test Guideline is a document that presents clinical and non-clinical data on a study drug that is relevant to a particular clinical trial.
p.000534: The request for a clinical / non-profit examination is a request made by the applicant to the Ministry of Health (hereinafter:
...
p.000534: - the completed form in Annex III. which is annexed to this Ordinance and forms an integral part thereof,
p.000534: - IMPD
p.000534: - CTA form in English,
p.000534: - proof of payment of the administrative fee.
p.000534: Article 17
p.000534: (1) In the process of approving a clinical trial intended for children or treating psychiatric patients, the Central Ethics Committee may request
p.000534: expert assistance and consult with the Ministry of Pediatrics and Psychiatry Commissions in accordance with point 3.2.6. Of Annex I to this Ordinance.
p.000534: (2) The Central Ethics Commission shall hold the consultations referred to in paragraph 1 of this Article within the time limits provided for in Article 12, paragraph 1 of this Article.
p.000534: Of the Rules.
p.000534: Article 18
p.000534: (1) The CTA form referred to in Article 16, paragraph 3, subparagraph 3 of this Ordinance shall be submitted to the Ministry in .xml and .pdf format on CD-ROM and in .pdf.
p.000534: in written form with the date indicated and signed by the applicant's responsible person.
p.000534: (2) The CTA form must be submitted to the Ministry when submitting a request for conducting a clinical trial as well as when submitting
p.000534: requests for significant changes to the clinical trial.
p.000534: (3) Upon completion of the completion of the CTA form, it is necessary to carry out a validation of the completed data and submit it to the Ministry on CD-ROM
p.000534: Validation Report document in .pdf format, which confirms the validity of the completed form.
p.000534: (4) Each CD-ROM submitted must be marked with the EudraCT number, date of submission of the form, name of the contracting authority and applicant
p.000534: requests and a brief description of the content.
p.000534: (5) In addition to the CTA form, the applicant is obliged to submit to the Ministry the completed forms in writing, which shall be notified to the Ministry.
p.000534: on the significant amendment of the clinical trial and on the completion of the trial.
p.000534: (6) The forms referred to in paragraphs 1 and 5 of this Article are available and published on the European Commission's website (EudraLex - Volume 10 Clinical trials
p.000534: guidelines).
p.000534: Article 19
p.000534: (1) The contract between the applicant and the legal entity (hereinafter referred to as the "Contract") in which the examination is to be conducted shall specify:
p.000534: - the total cost of conducting the clinical trial,
p.000534: - the costs borne by the applicant, including the costs of medical and other services provided by the legal entity conducting the clinical trial,
p.000534: - the amount of compensation for legal entities, examiners and respondents,
p.000534: - the obligation of the applicant to bear the costs of all diagnostic procedures and examinations provided for in the test plan.
p.000534: (2) In the process of obtaining the opinion of the Central Ethics Committee, the applicant shall submit to the Central Ethics Committee for each
p.000534: the legal entity where the clinical trial is planned to be conducted, the nancial plan of the trial, which must describe the nancial aspects of the clinical trial
p.000534: tests including the elements referred to in paragraph 1 of this Article, subparagraphs 1 to 4.
p.000534: (3) In the process of approving a clinical trial, the applicant shall submit to the Ministry a nancial examination plan for each legal
...
p.000534: signed Agreements, which were not originally submitted. According to the signed Agreements, the Ministry will issue decisions on clinical implementation
p.000534: interrogations with these legal entities.
p.000534: Article 20
p.000534: (1) An applicant who has been approved by the Ministry for conducting a clinical trial is obliged to annually by 31 January for
p.000534: the previous year, submit a report to the Ministry and the Central Ethics Committee on the course of conducting the clinical trial in approved
p.000534: examination sites, the total number of subjects screened and the total number of subjects included in the examination.
p.000534: (2) The applicant shall inform the Central Ethics Committee and the Ministry of any changes to the clinical trial.
p.000534: (3) Significant amendments shall be subject to the procedure of obtaining the opinion of the Central Ethics Committee and the approval of the Ministry.
p.000534: (4) Minor administrative amendments shall not be subject to the procedure of obtaining the opinion of the Central Ethics Committee and the approval of the Ministry,
p.000534: the Central Ethics Commission and the Ministry are already informed.
p.000534: (5) The applicant for the approval of significant changes and additions to the clinical trial shall also be required to submit a certificate of payment of costs
p.000534: procedure in accordance with the decision of the competent authority.
p.000534: Article 21
p.000534: Clinical trials in the Republic of Croatia are conducted in accordance with the standard set out in the Guideline of the European Medicines Agency and its body
p.000534: Committee for Proprietary Medicinal Products: "Note for Guidance on GoodClinicalPractice" (CPMP / ICH / 135/95). The text of the Guidelines is translated into
p.000534: the Croatian language is set out in Annex I to this Ordinance and forms an integral part thereof.
p.000534: Article 22
p.000534: In addition to the Guideline referred to in Article 21 of this Ordinance, clinical trials of minors shall be conducted in accordance with the standard specified in
p.000534: Guideline of the European Medicines Agency and its body Committee for Proprietary Medicinal Products: »ClinicalInvestigation of Medicinal Products
p.000534: in the Pediatric Population ”(CPMP / ICH / 2711/99). The text of the Guidelines translated into Croatian is reproduced in Annex II. of this Ordinance does
p.000534: its integral part.
p.000534: Article 23
p.000534: (1) In conducting the clinical trial, the personal integrity and well-being of the subjects should be ensured in accordance with the Declaration of Helsinki.
p.000534: (2) All approved clinical trials in the Republic of Croatia shall be published on the Ministry's website as well as on the European Agency's website
p.000534: for medicinal products in the Clinical Trials Register (www.clinicaltrialsregister.eu).
p.000534: (3) The Ministry shall keep a register of all approved clinical trials in the Republic of Croatia.
p.000534: Article 24
p.000534: (1) Inspection supervision of clinical trials shall be conducted by a pharmaceutical inspection of the Ministry.
p.000534: (2) The pharmaceutical inspector of the Ministry shall conduct the inspection of clinical trials at the testing site, at the premises of the clinical trial client.
p.000534: and / or contracting authorities or in other legal entities where the competent authority deems it necessary to carry out supervision.
p.000534: (3) The pharmaceutical inspection shall carry out regular and extraordinary supervision over the clinical trial of medicinal products:
p.000534: - regular inspections are carried out in accordance with the annual control plan,
p.000534: - Extraordinary supervision of the clinical trial of medicines is carried out in the event of incidental conditions.
p.000534: (4) The inspection of clinical trials of medicinal products may be requested and coordinated by the European Medicines Agency.
p.000534: (5) Inspection of clinical trials of medicinal products may be carried out:
p.000534: - before, during or after conducting the clinical trial,
p.000534: - as part of the marketing authorization procedure,
p.000534: - as a repeated inspection after obtaining marketing authorization.
p.000534: (6) Inspection of clinical trials is carried out in accordance with guidelines and guidelines published on the European Union's website
p.000534: EudraLex Commissions - Volume 10 Clinical trials guidelines.
p.000534: Article 25
p.000534: In the event of an event affecting the safety of the subjects, the examiner and the client of the clinical trial are obliged to take immediate protection measures
p.000534: subjects, and upon taking these measures, are obliged to report promptly on the measures taken and changes to the clinical trial plan
p.000534: Ethics Committee, Agency and Ministry.
p.000534: Article 26
p.000534: (1) The examiner, as well as the healthcare professional participating in the clinical trial, shall learn about the adverse event that occurred during the clinical trial.
...
p.000534: the site that will participate in the program and the dose and route of administration. With the request, the applicant is required to attach the statements of the Chief Examiners to whom
p.000534: confirm their participation in the program and agree to continue monitoring the safety of drug administration and that the risk-benefit ratio justifies the administration of the drug
p.000534: in doses and in the manner prescribed by the proposed program.
p.000534: (4) At least once a year, the applicant shall notify the Central Ethics Committee and the Ministry of the implementation of the program, with emphasis
p.000534: to the safety of drug administration.
p.000534: (5) The applicant shall notify the Central Ethics Committee and the Ministry of the completion of the program within 90 days from the end of the program.
p.000534: program.
p.000534: Article 31
p.000534: (1) In the process of submitting a request to the Agency for approval of conducting non-intervention testing and obtaining the opinion of the Central Ethics
p.000534: Commissions, the applicant is required to provide the following documentation:
p.000534: - request in the Croatian language, with the signature of the applicant's responsible person; the request should include the name and address of the contracting authority, the name and
p.000534: the applicant's address and a list of the principal examiners and institutions where the non-interventional test will be conducted,
p.000534: - a test plan indicating the designation of the test plan, the version and the date of the test plan version,
p.000534: - test list of respondents,
p.000534: - the marketing authorization decision, if applicable,
p.000534: - approved summary of product characteristics and package leaflet in Croatian,
p.000534: - informed consent for the patient in the Croatian language, indicating the informed consent version and the date of the version,
p.000534: - the original informed consent for the patient in English, if applicable,
p.000534: - financial examination plan,
p.000534: - proof of payment of costs in the process of giving opinion to the Central Ethics Committee and authorizing the implementation of non-intervention
p.000534: testing.
p.000534: (2) In addition to the documentation referred to in paragraph 1 of this Article, the applicant shall submit to the Central Ethics Committee:
p.000534: - the completed form in Annex VI. which is annexed to this Ordinance and forms an integral part thereof.
p.000534: (3) In addition to the documentation referred to in paragraph 1 of this Article, the applicant shall submit to the Agency:
p.000534: - the completed form in Annex VII. which is annexed to this Ordinance and forms an integral part thereof,
...
p.000534: causally related to its application. Therefore, any adverse and unwanted sign (including
p.000534: deviation in laboratory findings), a symptom or disease that is temporally associated with the administration of the medicinal (tested) drug / product, without
p.000534: whether it is the cause or not (see ICH Guidelines for the Management of Clinical Safety Data: Emergency Deviations and Standards
p.000534: reporting).
p.000534: 1.3. Modifications and Additions (Clinical Trial Plan)
p.000534: See Changes and additions to the Clinical Trial Plan.
p.000534: 1.4. Legislation in force (s)
p.000534: Law (s) and regulation (s) related to the conduct of a clinical study of drug / medical product testing.
p.000534: 1.5. Approval (Refers to Clinical Trials Council)
p.000534: Positive decision of the Clinical Trial Council on clinical trial to be carried out within the institution within the limits set by the
p.000534: clinical trials, facilities, good clinical practices, and applicable law.
p.000534: 1.6. Supervision
p.000534: Systematic and independent review of clinical trial activities and related documentation to determine if activities in which
p.000534: performs surveillance conducted, data entered and analyzed and reported in accordance with the Clinical Trial Plan, standard operational
p.000534: test client procedures, good clinical practice, and applicable legal requirements.
p.000534: 1.7. Certificate of inspection
p.000534: A statement confirming that surveillance has been carried out.
p.000534: 1.8. Surveillance report
p.000534: A written statement informing the testing authority of the results of the surveillance.
p.000534: 1.9. Documenting surveillance
p.000534: Documentation to track the sequence of events.
p.000534: 1.10. Clinical trial blindness / masking
p.000534: A process in which one or more parties participating in a clinical trial do not know how treatment is assigned. Single blind trial
p.000534: usually refers to a patient who does not know the division of treatment, and double-blind to a respondent, examiner, observer, and in some cases,
p.000534: data analysts.
p.000534: 1.11. Test list
p.000534: Printed, optical or electronic document intended to record all data required by the Clinical Trial Plan used by the trial client
p.000534: reports on each respondent.
p.000534: 1.12. Clinical trial / clinical study
p.000534: Any human study intended to detect or confirm the clinical, pharmacological and / or other pharmacodynamic effects of the subject
p.000534: product, and / or the determination of side effects and / or the study of absorption, distribution, metabolism and excretion, with a view to determining the safety and / or
p.000534: the effectiveness of the test product. The terms clinical trial and clinical study are ambiguous.
p.000534: 1.13. Clinical Trial / Clinical Study Report
p.000534: Description of the clinical trial / study in writing of any therapeutic, pro-lactic or diagnostic agent administered in humans, and
p.000534: clinical and statistical description, presentation and analysis form a single report (see ICH Guidelines for the Structure and Content of the Clinical Report
p.000534: examination).
p.000534: 1.14. Product of comparison
p.000534: Tested or marketed product (ie active control), or placebo, used in the clinical trial as a comparison product.
p.000534: 1.15. Compliance (applies to clinical trial procedures)
p.000534: Compliance with all clinical trial requirements, good clinical practices and applicable legal requirements.
p.000534: 1.16. Confidentiality
p.000534: Preventing the disclosure, except to authorized persons, of the protected data of the test client, or the identity of the respondents.
p.000534: 1.17. The contract
p.000534: A written, dated and signed agreement between two or more parties specifying the delegation and distribution of tasks and obligations, and nancial matters there
p.000534: where necessary. The contract may be based on a Clinical Trial Plan.
p.000534: 1.18. Commission for Coordination
p.000534: A committee that may be set up by a trial client to coordinate the implementation of a multicenter clinical trial.
p.000534: 1.19. Examiner Coordinator
p.000534: Examiner responsible for coordinating examiners at different centers participating in multicenter testing.
p.000534: 1.20. Contracting research organization
p.000534: Person or organization (commercial, academic or otherwise) with whom the contracting authority has contracted to perform one or more duties and activities
p.000534: related to the clinical trial.
p.000534: 1.21. Direct access
p.000534: Approval to review, analyze, verify and transmit all data and reports relevant to the evaluation of the clinical trial. Any side that has a direct
p.000534: access to documentation (eg domestic or foreign competent authorities, observers, and supervisors of the contracting authority) is obliged to take all reasonable steps
p.000534: precautionary measures within the framework of the applicable legal regulations in order to preserve the confidentiality of the respondents' identities and data owned by the contracting authority.
p.000534: 1.22. Documentation
p.000534: All information in any form (including, but not limited to, written, electronic, magnetic and optical records and recordings, x-rays and
p.000534: electrocardiograms) that describe or record methods, and the conduct and / or results of the clinical trial, the factors affecting it, and the actions taken.
p.000534: 1.23. Basic documents
p.000534: Documents that, individually or together, enable the evaluation of the conduct of the clinical trial and the quality of the data obtained (see 8. Basic
p.000534: clinical trial documents).
p.000534: 1.24. Good clinical practice
p.000534: Clinical trial standard including planning, implementation, monitoring, monitoring, recording, analysis and human research reports
p.000534: ensuring that the data and results are credible and accurate and that the rights, integrity and confidentiality of the respondent's data are protected.
p.000534: 1.25. Independent Data Monitoring Commission
p.000534: (Committee for the Monitoring of Medicines Safety Data, Monitoring Committee, Monitoring Committee)
p.000534: Independent Monitoring Committee on the information that the trial client may establish to periodically evaluate the progress of the clinical trial,
p.000534: data on harmlessness (side effects) and critical efficacy points and to recommend to the contracting authority whether to proceed, adjust
p.000534: or interrupt the clinical trial.
p.000534: 1.26. An impartial witness
p.000534: Person independent of the clinical trial who cannot be biased by the people involved in the clinical trial present in the administration process
p.000534: informed consent if the respondent or his legal representative cannot read, and who reads the respondent's consent form and any other written
p.000534: notice for respondent.
p.000534: 1.27. Independent Ethics Committee
p.000534: An independent body (jury or committee, be it an institution, province, state or international body) composed of
p.000534: medical professionals and members of the non-medical profession who are required to ensure the protection of the rights, safety and well-being of clinical participants
p.000534: trials and publicly guarantee such protection, inter alia, by verifying and approving / giving favorable opinion on the Clinical Trial Plan,
p.000534: the eligibility of the examiner, the conditions, methods and materials that will be used to obtain and document the informed consent of the subjects in the clinical
p.000534: examination.
p.000534: The legal status, composition, operation and regulations of independent ethics committees may vary from country to country, but they must
p.000534: enable the independent ethics committee to act in accordance with good clinical practice described in these guidelines.
p.000534: 1.28. Informed consent
p.000534: Procedure whereby the subject voluntarily affirms his or her willingness to participate in a particular clinical trial after being familiar with all
p.000534: aspects of the clinical trial that may influence the decision to participate. The informed consent of the informed respondent shall be documented in writing
p.000534: the form on which the signature and date are entered.
p.000534: 1.29. Inspection
p.000534: Procedure by the competent authority to review documents, assets, equipment and premises, records and all other matters that the body considers related to
p.000534: clinical trial and can be found at the site of the clinical trial, at the trial sponsor and / or contracting research organization, or
p.000534: to other institutions that the competent authority deems appropriate.
p.000534: 1.30. Institution (medical)
p.000534: Any public or private entity, institute or medical or dental institution where clinical trials are conducted.
p.000534: 1.31. Clinical Trials Board
p.000534: An independent body composed of medical professionals and non-medical members whose responsibility is to ensure the protection of rights,
p.000534: the safety and well-being of the people participating in the clinical trial, including by reviewing, approving and ensuring ongoing review of the Plan
p.000534: clinical trial and its appendices are used to obtain and document the informed consent of the clinical trial investigator.
p.000534: 1.32. Clinical trial / study interim report
p.000534: Report on intermediate results and their evaluation based on analysis performed during the clinical trial.
p.000534: 1.33. Tested product
p.000534: Pharmaceutical form of the active substance or placebo to be tested in a clinical trial for comparison, including a product approved on the market if
p.000534: its use or method (formulation or packaging) differ from the approved one, or, if used for an indication that is not approved, or used for
p.000534: collecting further information on approved application.
p.000534: 1.34. Examiner
p.000534: The person responsible for conducting the clinical trial at the place where it is conducted. If a group of individuals conducts a site survey,
p.000534: the examiner is the person responsible for leading the group and is also referred to as the lead examiner. See also Assistant Examiner.
p.000534: 1.35. Examiner / Institution
p.000534: A term that designates "examiner and / or institution in accordance with applicable law."
p.000534: 1.36. Instructions for the examiner
p.000534: A set of clinical and preclinical data on an investigational product that is relevant to its human test (see 7. Test Guideline).
p.000534: 1.37. Legal representative
p.000534: An individual or legal entity or other body authorized by applicable law to consent to participate in a clinical trial on behalf of the respondent.
p.000534: 1.38. Observation
p.000534: The act of monitoring the progress of the clinical trial and ensuring that its implementation, documentation and reporting are consistent with the Clinical Trial Plan,
p.000534: standard operating procedures, good clinical practice and applicable legal requirements.
p.000534: 1.39. Observation report
p.000534: A written report submitted by the observer to the contracting authority after each visit to the examination site and / or upon new knowledge relating to
p.000534: testing in accordance with standard operating procedures of the test client.
p.000534: 1.40. Multicenter testing
p.000534: A clinical trial conducted in accordance with a single Clinical Trial Plan in more than one site and therefore conducted by more than one
p.000534: of the examiner.
p.000534: 1.41. Preclinical research
p.000534: Non-human biomedical research.
p.000534: 1.42. Opinion (applies to the Independent Ethics Committee)
p.000534: Assessment and / or recommendation issued by an independent ethics committee.
p.000534: 1.43. Original health information
p.000534: See Original Documents.
p.000534: 1.44. Clinical trial plan
p.000534: A document outlining the objectives, plan, methodology, statistics and organization of the test. In addition, it is usually explained in the Clinical Trial Plan
p.000534: background and meaning of the trial, but this can also be found in other documents referenced in the Clinical Trial Plan. In these ICH Guidelines
p.000534: the term "Clinical Trial Plan" refers to the Clinical Trial Plan itself and its amendments and additions.
p.000534: 1.45. Modifications and additions to the Clinical Trial Plan
p.000534: Amendments to the Clinical Trial Plan in writing or its formal clarification.
p.000534: 1.46. Quality assurance
p.000534: All planned and systematic activities aimed at ensuring compliance of the clinical trial, documenting (recording) results and reporting with
p.000534: good clinical practice and applicable legislation.
p.000534: 1.47. Quality control
...
p.000534: cases, see 4.8.15), the Committee should determine whether the proposed Test Plan and / or other documentation has sufficiently taken into account ethical issues and
p.000534: whether it meets the applicable legal requirements for such tests.
p.000534: 3.1.8. The Commission should consider the amount and manner of payment of the respondents' remuneration in order to eliminate any possibility of coercion and undue influence.
p.000534: to the respondents. The payment of compensation should be distributed in installments, not that it depends entirely on the respondent's participation by the end of the examination.
p.000534: 3.1.9. The Commission should ensure that notices of compensation for respondents, including the manner, amount and timing of payments, are included in the written
p.000534: the consent statement form as well as any other written notice for the respondents. The amount and schedule of payment of the installment of the compensation should be stated.
p.000534: 3.2. Composition, tasks and work
p.000534: 3.2.1. The committee should consist of a reasonable number of members, who combine the expertise and experience needed to consider and evaluate
p.000534: the scientific, health and ethical aspects of the proposed test. It is recommended that the Commission:
p.000534: (a) has at least five members;
p.000534: (b) that at least one member by his / her vocation is not from the scientific field;
p.000534: (c) at least one member is independent of the institution conducting the examination or of the place of examination.
p.000534: Only members of the Commission who are independent of the examiner and the contracting authority should have the right to vote or to express an opinion on the examination.
p.000534: testing. The list of Committee members and their qualifications should be regularly updated.
p.000534: 3.2.2. The committee should carry out its tasks in accordance with written operational procedures, document its work and draw up minutes of its
p.000534: meetings, and should adhere to good clinical practice and applicable law.
p.000534: 3.2.3. The committee should announce at which meeting the decisions will be taken and there must be a quorum for their adoption in accordance with the written
p.000534: by operating procedures.
p.000534: 3.2.4. Only those members of the Committee who participated in the deliberations and deliberations should have the right to vote or to express opinions and / or recommendations.
p.000534: about the examination.
p.000534: 3.2.5. The examiner may be required to provide the Committee with information on any aspect of the examination, but he may not participate in the committee's deliberations
p.000534: that is, his vote / opinion.
p.000534: 3.2.6. The Commission may seek the assistance of experts in specific fields other than its members.
p.000534: 3.3. Procedures
p.000534: The Commission shall define in writing the procedures of its action and adhere to them, and by these procedures:
p.000534: 3.3.1. It defines the composition of the Commission (the names and qualifications of the members) and the body to which the Commission is responsible.
p.000534: 3.3.2. Defines the schedule of meetings, their conduct and the notification of members.
p.000534: 3.3.3. It defines the conduct of the first test evaluation and its continuous monitoring.
p.000534: 3.3.4. Defines the frequency of grading as needed.
...
p.000534: (c) any serious and unexpected side effects of the drug;
p.000534: (d) new knowledge that may adversely affect the safety of the subjects or the conduct of the examination.
p.000534: 3.3.9. Ensures that the Examination Committee / Institution immediately informs of:
p.000534: (a) their decisions / opinions regarding the examination;
p.000534: (b) the reasons for the decision / opinion;
p.000534: (c) decision / opinion appeal procedures.
p.000534: 3.4. Documentation
p.000534: The committee should keep all relevant documentation (eg procedure description, list of members, list of professions and parent institutions of members, received
p.000534: documents, meeting minutes and correspondence) for at least three years after the end of the examination and make them available to the competent authorities for their
p.000534: request.
p.000534: The examiners, contracting authorities or competent authorities may request the Commission to provide a description of the procedures and a list of members.
p.000534: 4. EXAMINER
p.000534: 4.1. Qualifications of examiner and preconditions for his / her actions
p.000534: 4.1.1. In order to be able to undertake the proper conduct of the examination, the examiner must be qualified in terms of education, professional development and
p.000534: experience, qualifications should meet current legal requirements and provide evidence of their qualifications through an updated CV and / or other
p.000534: relevant documentation requested by the contracting authority, the Commission and / or the competent authority.
p.000534: 4.1.2. The examiner must be fully aware of the proper application of the test product, as described in the Test Plan, the applicable Guidelines for
p.000534: examiners, product data and other sources of information obtained from the contracting authority.
p.000534: 4.1.3. The examiner must be familiar with, and adhere to, good clinical practice and applicable legal requirements.
p.000534: 4.1.4. The examiner / institution should allow the investigator to monitor and monitor and inspect the relevant competent authorities.
p.000534: 4.1.5. The examiner should draw up a list of qualified persons to whom he or she has delegated the important tasks associated with the examination.
p.000534: 4.2. Appropriate opportunities / resources
p.000534: 4.2.1. The examiner should prove (eg based on previous indicators) that he / she is able to gather the required number of appropriate respondents in the agreed
p.000534: period.
p.000534: 4.2.2. The examiner should have sufficient time to properly conduct and complete the examination within the agreed period.
p.000534: 4.2.3. In order for the test to be conducted properly and safely, the examiner should have a sufficient number of qualified staff and adequate facilities and equipment for
p.000534: the estimated duration of the test.
p.000534: 4.2.4. The examiner must make sure that all his associates are adequately informed about the Test Plan, the product tested and their obligations and
p.000534: test-related tasks.
p.000534: 4.3. Health care for respondents
p.000534: 4.3.1. Qualified medical doctor - examiner (if necessary, dental doctor) or doctor of medicine conducting the examination should be
p.000534: responsible for all health decisions related to testing.
p.000534: 4.3.2. During and after the respondent's participation in the examination, the examiner / institution should provide adequate health care to the respondents with
p.000534: test-related adverse reactions, including clinically relevant laboratory findings. Does the examiner / institution establish that the respondent is in the meantime
p.000534: suffering from a disease, should be informed of the need for its treatment.
p.000534: 4.3.3. It is recommended that the examiner inform the respondent family physician / general practitioner of his / her participation in the examination, if the respondent has
p.000534: your family doctor / general practitioner and if he / she agrees.
p.000534: 4.3.4. Although the respondent is not required to explain the reasons for his / her early withdrawal from the examination, the examiner should make reasonable efforts to:
p.000534: determine the reasons, respecting all the respondent's rights.
p.000534: 4.4. Communication with the Commission
p.000534: 4.4.1. In order to begin the examination at all, the examiner / institution should have the written and dated approval / positive opinion of the Committee on the Examination Plan,
p.000534: Written Respondent's Statement of Consent and Amendments, Description of Respondent's Recruitment (e.g., by Ad) and Other Written Notices Intended
p.000534: to the respondents.
p.000534: 4.4.2. An up-to-date version of the Examiner's Guide is an integral part of the written request submitted by the examiner / institution to the Commission. If changes occur and
p.000534: Amendments to the Instructions for Examiners During the examination, the examiner / institution is obliged to submit updated Instructions to the Commission.
p.000534: 4.4.3. During the examination, the examiner / institution is obliged to submit to the Commission all documentation necessary for consideration.
p.000534: 4.5. Adherence to the Examination Plan
p.000534: 4.5.1. The examiner / institution should carry out the test in accordance with the Test Plan agreed with the test client and, if necessary, with
p.000534: competent authority, which has received approval / positive opinion from the Commission. In confirmation of the agreement, the examiner / institution and the contracting authority
p.000534: sign the Testing Plan or another contract.
p.000534: 4.5.2. The examiner must not deviate from the Test Plan, or amend it without agreeing with the test client and without first
p.000534: written approval / positive opinion of the Commission, except where it is necessary to immediately remove the immediate danger to the respondent, or where
p.000534: the changes relate exclusively to the logistical or administrative aspects of the examination (eg change of telephone number of observers).
p.000534: 4.5.3. The examiner, ie the person appointed by him, should document and explain any deviation from the approved Test Plan.
p.000534: 4.5.4. The examiner may deviate from the Examination Plan, or change it without the prior approval / positive opinion of the Committee exclusively
p.000534: to eliminate imminent danger to respondents. Deviations from the Examination Plan, or changes thereto, reasons for their introduction and where it is
p.000534: changes and additions required to the Test Plan should be submitted as soon as possible:
p.000534: (a) Evaluation Committee and approval / favorable opinion;
p.000534: (b) the contracting authority for acceptance,
p.000534: (c) to the competent authorities, as appropriate.
p.000534: 4.6. Tested Product (s)
p.000534: 4.6.1. The examiner / institution is responsible for recording the inputs and outputs of the test product at the test site.
p.000534: 4.6.2. Where permitted / required, the examiner / institution may / should all or part of the obligation to record the inputs and outputs of the test product at
p.000534: transfer the test site to the pharmacist or other appropriate person under the supervision of the examiner / institution.
p.000534: 4.6.3. The examiner / institution and / or pharmacist, or other appropriate person appointed by the examiner / institution, should properly record the delivery
p.000534: the product and its condition at the test site, its application per respondent, and return to the test client or other disposal method
p.000534: unused product. Data should include dates, quantities, serial numbers, expiry dates (where appropriate), and unique
p.000534: a tag linking the product being tested and the respondent. The examiner should properly record whether the subjects have received the doses indicated in the Test Plan and
p.000534: compare all quantities of test product obtained from the test client.
p.000534: 4.6.4. The test product should be stored in accordance with the instructions of the test client (see 5.13.2 and 5.14.3) and the applicable legal regulations.
p.000534: 4.6.5. The examiner should ensure that the application of the test product follows an approved test plan only.
p.000534: 4.6.6. The examiner, ie the person appointed by the examiner / institution, is obliged to explain to each respondent the proper use of the test product and
p.000534: periodically, at appropriate intervals, to check that each respondent complies with the instructions given.
p.000534: 4.7. Random selection and decryption procedures
...
p.000534: written approval / positive opinion of the Commission on the form of the statement of consent and other written notifications intended for the respondents.
p.000534: 4.8.2. After any new findings that might affect the Respondent's consent, the Consent Statement form and other written notice intended
p.000534: respondents should be amended accordingly. Prior to use, amended consent statement form and other written notices
p.000534: intended for the respondents should receive the approval / positive opinion of the Commission. Respondent, that is, his legal representative is valid
p.000534: inform in a timely manner new findings that may affect the respondent's willingness to continue to participate in the examination. This kind of notification
p.000534: should be documented.
p.000534: 4.8.3. Neither the examiner nor the examining staff shall coerce or unduly influence the respondent to participate in, or continue to participate in
p.000534: examination.
p.000534: 4.8.4. Oral and written testimony notices, including the statement of consent form, must not contain language formulations that would allow the respondent,
p.000534: that is, his legal representative stated that he at least ostensibly waives his legal rights, that is, which examiner, institution, contracting authority
p.000534: interrogation or their representative, at least apparently, absolves them of their negligence liability.
p.000534: 4.8.5. The examiner, ie the person appointed by him, needs the respondent or his legal representative, if the respondent is not competent to give
p.000534: consent, fully acquainted with all aspects of the examination, including written notice and approval / positive opinion of the Commission.
p.000534: 4.8.6. The choice of words and style of oral and written test reports, including the statement of consent form, should avoid technical terms as much as possible and
p.000534: be understandable to the respondent, that is, his / her legal representative and impartial witness.
p.000534: 4.8.7. Prior to obtaining the consent, the examiner or the person appointed by him / her must provide the respondent or his / her legal representative
p.000534: enough time and opportunity to find out the details of the examination that interest him to decide whether or not he wants to participate. Answer all the questions
p.000534: the test should satisfy the respondent or his / her legal representative.
p.000534: 4.8.8. Prior to the inclusion of the respondents in the examination, the respondent or his / her legal representative must be signed and personally dated
p.000534: statement of consent, also signed by the person interviewing the respondent / legal representative.
p.000534: 4.8.9. If the respondent or his legal representative cannot read, an impartial witness must be present for the entire duration of the interview. After
...
p.000534: comprehensible data.
p.000534: 4.9.2. The data in the test lists of the respondents taken from the original documents should be the same as the data in the original documents, and possibly
p.000534: the differences should be explained.
p.000534: 4.9.3. Any changes or corrections to the test list should be dated, paired and (where necessary) explained and the original record should not be deleted or overlaid.
p.000534: (i.e. a trace of surveillance should be maintained); this applies equally to changes and corrections in written and electronic documents (see 5.18.4 (n)). Client
p.000534: The examiner is obliged to give the examiner and / or the appointed person instructions for making these corrections. The client of the examination shall be in writing
p.000534: initiate a process to ensure that changes or corrections to the test list made by the appointed person are necessary, recorded and paired
p.000534: by the examiner. The examiner should keep a record of all changes and corrections.
p.000534: 4.9.4. The examiner / institution should keep the examination documentation in accordance with the Instructions given in the section Basic Implementation Documents
p.000534: clinical trial (see 8.), as well as with applicable legal regulations. The examiner / institution should take measures to prevent accidental or
p.000534: premature destruction of these documents.
p.000534: 4.9.5. Basic documents should be kept for at least two years after the last marketing authorization was granted
p.000534: countries at least two years after the official cessation of the clinical development of the product under test. If they seek such a legal requirement
p.000534: regulations or agreement with the contracting authority, these documents should be kept for longer than stated above. The contracting authority is obliged to inform
p.000534: examiner / institution when it is no longer necessary to keep this documentation (see 5.5.12).
p.000534: 4.9.6. The financial aspects of the test should be documented by agreement between the test client and the examiner / institution.
p.000534: 4.9.7. The examiner / institution shall be obliged to allow the observer, the person supervising, the Commission or the competent authority, upon their request, a direct
p.000534: access to examination documents.
p.000534: 4.10. Test progress reports
p.000534: 4.10.1. The examiner is obliged to submit a written summary of the progress of the examination to the Committee once a year, and more frequently at the special request of the Committee.
p.000534: 4.10.2. The examiner is obliged to immediately submit a written report on the ordering authority, the Committee (see 3.3.8) and, where appropriate, the health institution.
p.000534: changes that significantly affect the conduct of the test and / or increase the risk to respondents.
p.000534: 4.11. Product Safety Reporting
p.000534: 4.11.1. Any serious adverse event should be reported promptly to the testing contractor, except for those events for which it is in the Test Plan or otherwise.
p.000534: document (eg in the Examiner's Instructions) stated that they should not be reported immediately. A detailed report should be written immediately after the application
p.000534: event. In this report, their associated unique identifier should be used in place of the name, identification number (e.g., MBG) and / or address of the respondent
p.000534: tag. The examiner should also comply with the applicable legal requirements of the reporting requirements of the competent authorities and the
p.000534: unexpected serious side effects of the drug.
p.000534: 4.11.2. Reports of adverse events and / or abnormal laboratory findings identified by the Test Plan as critical to the assessment
p.000534: security should be delivered to the test client in accordance with the reporting rules and at intervals specified by the test client at
p.000534: Test plan.
p.000534: 4.11.3. When reporting a death, the examiner should provide additional information to the investigator and to the Commission upon request (eg autopsy findings and
p.000534: medical report of the cause of death).
p.000534: 4.12. Premature termination or termination of examination
p.000534: If, for any reason, the examination is terminated or terminated prematurely, the examiner / institution should inform the subjects immediately, ensure
p.000534: their proper treatment and monitoring and inform the competent authorities in accordance with the relevant legal provisions. In addition:
p.000534: 4.12.1. If the examiner completes or terminates the examination without the consent of the examining authority, he shall inform the institution thereof, and
p.000534: the examiner / institution should immediately inform the test client and the Committee and provide them with a detailed explanation of such procedure.
p.000534: 4.12.2. If the contracting authority completes or terminates the examination (see 5.21), the examiner is obliged to inform the institution immediately, and the examiner / institution
p.000534: the Commission should be informed immediately and a detailed explanation of such procedure should be provided.
p.000534: 4.12.3. If the Committee withdraws its approval / positive opinion on the examination (see 3.1.2 and 3.3.9), the examiner shall inform the institution accordingly,
p.000534: and the examiner / institution should immediately inform the contracting authority and provide him with a detailed explanation of such procedure.
p.000534: 4.13. Final report of examiner (s)
p.000534: Upon completion of the examination, the examiner should inform the institution. The examiner / institution should provide the committee with a summary of the test results, a
p.000534: all necessary reports to the competent authorities.
p.000534: 5. TEST ORDER
p.000534: 5.1. Quality assurance and control
p.000534: 5.1.1. The testing contractor is responsible for establishing and maintaining a quality assurance and quality control system through standard operating systems
p.000534: procedures to ensure that the clinical trial is conducted, documented (recorded) and reported to the Trial Plan,
p.000534: good clinical practice and applicable legislation.
p.000534: 5.1.2. The test client is responsible for reaching an agreement between the parties on direct access (see 1.21) to all test sites, original
p.000534: data / documents and reports so that it can monitor and supervise the test, or in order for the domestic or foreign competent authority
p.000534: could carry out an inspection.
p.000534: 5.1.3. Quality should be monitored at every stage of data handling to ensure its reliability and proper processing.
p.000534: 5.1.4. Agreements between the client and the examiner / institution and other parties involved in the clinical trial should be in writing
p.000534: as an integral part of the Examination Plan or as a separate agreement.
p.000534: 5.2. Contracting Research Organization (ITA)
p.000534: 5.2.1. The contracting authority may delegate all its obligations or tasks or part thereof to the contracting research organization, with ultimate responsibility
p.000534: the quality and completeness of the test results shall continue to be borne by the contracting authority. The ITA's job is to implement quality assurance and quality control procedures.
p.000534: 5.2.2. Each obligation and task related to the examination, which is transferred to the ITA, must be individually stated in writing.
p.000534: 5.2.3. The contracting authority retains those obligations and tasks that are not explicitly delegated to the ITA.
p.000534: 5.2.4. Anything in this Guideline that applies to the contracting authority shall also apply to the ITA to the extent that the ITA has assumed the obligations and tasks of
p.000534: of the contracting authority.
p.000534: 5.3. Expert medical opinion
p.000534: Nursing staff with appropriate qualifications should be identified who will always be able to give their expert opinion on issues and issues related to
p.000534: with examination. If necessary, the contracting authority may also appoint external consultants for this purpose.
p.000534: 5.4. Test plan
p.000534: 5.4.1. The client of the trial should hire qualified persons (eg biostatistics, clinical pharmacologists and medical doctors in accordance with the needs).
p.000534: all stages of testing, from the design of the Test Plan and Test List, through the planning of the analysis, to the analysis and preparation of interim and final clinical trials
p.000534: test reports.
p.000534: 5.4.2. For further guidance, see 6. Clinical Trial Plan and its Amendments and Appendices, ICH Guidelines for Compilation and Content of Clinical Trial Report
p.000534: Examination and other ICH Guidelines related to test planning, development of the Test Plan and conduct of the test.
p.000534: 5.5. Test management, data handling and record keeping
p.000534: 5.5.1. The contracting authority should hire qualified persons to supervise the overall conduct of the examination, to manage the data obtained,
p.000534: verify their accuracy, perform statistical analyzes and prepare reports.
p.000534: 5.5.2. The trial contracting authority may appoint an independent data monitoring committee to periodically evaluate the progress of the clinical trial,
p.000534: including safety data and key drug efficacy parameters, and to recommend whether the trial client should continue the trial, amend
p.000534: or stop it. The Independent Data Monitoring Commission should, in writing, derogate from operating procedures (operating procedures) and maintain
p.000534: notes from all their meetings.
p.000534: 5.5.3. When handling electronic data directly or through a remote control system, the contracting authority shall:
p.000534: (a) ensure and record the compliance of the electronic data processing system with the requirements of the test client's completeness, accuracy, reliability and
p.000534: consistency of processing (i.e. validation);
p.000534: (b) have standard operating procedures for the use of these systems;
p.000534: (c) ensure that the systems are designed to allow data to be modified in such a way that each change is recorded and that there is no possibility
p.000534: deletion of data entered (ie to keep a trace of surveillance, a data trace and a trace of their editing);
p.000534: (d) take care of the security of the system preventing unauthorized access to the data;
p.000534: (e) keep a list of persons authorized to modify the data (see 4.1.5 and 4.9.3);
p.000534: (f) keep a copy of the information in order to protect against its loss;
p.000534: (g) if the test is blind, protect its blindness (eg when entering and processing data).
p.000534: 5.5.4. If there is a change in the data during their processing, it should always be possible to compare the original data and comments with the processed
p.000534: data.
p.000534: 5.5.5. The contracting authority should use the unambiguous identification marks of the respondents (see 1.58.) That allow the connection of all recorded
p.000534: data with each individual respondent.
p.000534: 5.5.6. The test client, or the data owner, should keep all his or her basic documents pertaining to the test (see 8. Basic
p.000534: clinical trial documents).
p.000534: 5.5.7. These documents should be retained by the contracting authority in accordance with the laws in force in the countries where the product is authorized and / or
p.000534: the countries where it intends to apply for its approval.
p.000534: 5.5.8. If the trial client interrupts the clinical development of the test product (due to some or all indications, routes of administration or dosage form)
p.000534: is obliged to keep all its basic documents for at least two years from the official cessation of the clinical development of the tested product, ie
p.000534: for as long as required by applicable law.
p.000534: 5.5.9. If the trial contractor interrupts the clinical development of the test product, it should inform all examiners / institutions and all competent authorities.
p.000534: 5.5.10. The relevant authorities should also be informed of any transfer of ownership of the data, in accordance with applicable legal requirements.
p.000534: 5.5.11. The basic documents shall be retained by the contracting authority for at least two years after the last approval of the request for submission has been obtained
p.000534: of the medicinal product in the ICH countries, that is, as long as the application for marketing in those countries is at least two years
p.000534: after the official cessation of the clinical development of the test product. Depending on the applicable legislation or the needs of the contracting authority,
p.000534: these documents should be kept longer.
p.000534: 5.5.12. The contracting authority shall inform the examiner / institution in writing of the need for further safeguarding of test data as well as of
p.000534: ceasing the need to store them.
p.000534: 5.6. Choice of examiner
p.000534: 5.6.1. The contracting authority is responsible for selecting the examiner / institution. For the proper conduct of the examination for which he was selected, each examiner should be
p.000534: qualified by their education and experience and should have adequate opportunities / resources (see 4.1, 4.2). The test client is
p.000534: responsible for setting up a coordinating committee and / or selecting coordinators required to organize multicenter trials.
p.000534: 5.6.2. Before concluding an agreement to conduct the test with the examiner / institution, the contracting authority shall submit a plan to the examiner / institution.
p.000534: examinations and updated Instructions for the Examiner and must allow him / her sufficient time to study the Examination Plan and the documentation obtained.
p.000534: 5.6.3. The examiner / institution should oblige the test client to:
p.000534: (a) Carry out the examination in accordance with good clinical practice, applicable legislation (see 4.1.3) and the Test Plan approved by them.
p.000534: the contracting authority and the Commission (see 4.5.1.);
p.000534: (b) adhere to data recording and reporting procedures;
p.000534: (c) enable monitoring, monitoring and inspection of tests (see 4.1.4); and
p.000534: (d) keep all basic documents pertaining to the test until it receives notice from the contracting authority that there is no longer a need for them
p.000534: keeping (see 4.9.4. and 5.5.12.).
p.000534: In order to confirm the agreement, the examiner / institution and the contracting authority shall sign the Test Plan or another contract.
p.000534: 5.7. Division of competencies
p.000534: Prior to the commencement of the test, the test client shall define, determine and share all the duties and tasks associated with the test.
p.000534: 5.8. Respondents 'and examiners' fees
p.000534: 5.8.1. If so required by applicable law, the contracting authority should ensure that the examiner / institution (legal and material) is safeguarded against claims arising
p.000534: from interrogation, ie to provide redress, except in the case of a malpractice lawsuit and / or negligence.
p.000534: 5.8.2. The contracting authority shall determine in its provisions and procedures the amount of the costs of treating the respondent in the event of an injury resulting from his
p.000534: participation in the examination in accordance with applicable legal regulations.
p.000534: 5.8.3. The procedure and manner of providing compensation to the respondent should be in accordance with the applicable legal regulations.
p.000534: 5.9. Financing
p.000534: The financial aspects of the test should be documented by agreement between the test client and the examiner / institution.
p.000534: 5.10. Notification / submission of requests to competent authorities
p.000534: Prior to the commencement of the clinical trial, the trial sponsor (or trial sponsor and examiner, if required by applicable law)
p.000534: regulations) should be submitted to the appropriate authorities for assessment, acceptance and / or approval (in accordance with applicable legal regulations) of the required requirements
p.000534: to begin testing. Each notification / request should be dated and contain sufficient information to identify the Test Plan.
p.000534: 5.11. Commission Appraisal Certificate
p.000534: 5.11.1. The contracting authority shall obtain from the examiner / institution:
p.000534: (a) the name and address of the Examiner's Health Care Committee;
p.000534: (b) a statement by the Commission that its composition and operation are in accordance with good clinical practice and applicable laws and regulations;
p.000534: (c) a document with the approval / affirmative opinion of the Commission and, at the client's request, a current copy of the Examination Plan, a statement form on
p.000534: the consent of that other written notice intended for the respondents, depending on their recruitment procedures, as well as documentation relating to
p.000534: fees to respondents and other documents requested by the Commission.
p.000534: 5.11.2. If the Committee gives its approval / positive opinion changes to any aspect of the examination such as changes to the Plan
p.000534: Examination, Consent Statement Form, Other Written Notices Intended for Respondents and / or Other Procedures
p.000534: the examiner / institution must receive a copy of the modification document and the date of approval / positive opinion of the Commission.
p.000534: 5.11.3. The contracting authority shall obtain from the examiner / institution the documentation and dates of re-approvals / supervision of the Commission, as well as
p.000534: withdrawal / revocation of approval / positive opinion.
p.000534: 5.12. Data on the product tested
p.000534: 5.12.1. When planning a test, the test client should make sure that sufficient safety and performance information is available
p.000534: from preclinical and / or clinical trials related to route of administration, dose, duration and appropriate population of subjects.
p.000534: 5.12.2. As soon as it becomes aware of the new data, the test client is obliged to update the Testing Instructions.
p.000534: 5.13. Production, packaging and labeling and coding of the product under test
p.000534: 5.13.1. The test client shall ensure that the test product (including, if applicable, comparative active drug and placebo) is labeled in accordance with
p.000534: the stage of its development, that it has been manufactured in accordance with all applicable good manufacturing practices, that it has been coded and labeled in such a way that
p.000534: if necessary, it protects the blind process. In addition, labeling should be in accordance with applicable legal regulations.
p.000534: 5.13.2. The contracting authority shall state the appropriate storage conditions for the medicinal product such as temperature, light protection, storage time,
p.000534: then, if necessary, fluid reconstitution procedures and accessories used for infusion of the test product. The contracting authority should inquire about this
p.000534: inform all interested parties (ie observers, examiners, pharmacists, warehouse managers).
p.000534: 5.13.3. The packaging of the test product should be such as to prevent its contamination and unacceptable changes in transport and storage.
p.000534: 5.13.4. In blind studies, the labeling system of the product under test should also include a mechanism that allows for rapid identification of the drug in the
p.000534: emergency but which does not allow identity disclosure to go unnoticed.
p.000534: 5.13.5. If there are any significant changes in the formulation of the test product or comparator at the clinical stage of development,
p.000534: testing new formulations to obtain the results of additional testing (eg stability, dissolution rate, bioavailability) required for evaluation
p.000534: can these changes significantly alter the pharmacokinetics of the drug.
p.000534: 5.14. Supply and handling of tested product
p.000534: 5.14.1. The test client is responsible for supplying the tester / institution with the product being tested.
p.000534: 5.14.2. The test contractor may not supply the examiner / institution with the product under test until he has obtained all the necessary documentation (e.g.
p.000534: approval / favorable opinion of the Commission and the competent authorities).
p.000534: 5.14.3. The test client shall ensure that the description of the procedures also includes the instructions for handling and storage of the test product and its associated
p.000534: documentation to be followed by the examiner / institution. These instructions should cover proper and secure receipt, handling, storage and issuance
p.000534: test product, collection of unused test product from the respondent and return it to the test client (or otherwise)
p.000534: disposal of unused product in accordance with applicable legal regulations).
p.000534: 5.14.4. The contracting authority shall:
p.000534: (a) ensure timely delivery of the test product to the examiner;
p.000534: (b) keep records of the dispatch, receipt, removal, return and destruction of the investigated product (see 8. Basic clinical implementation documents
p.000534: examinations);
p.000534: (c) maintain a system of return for the test product and record its return (eg for withdrawal of defective product, return on completion
p.000534: tests, returns of expired products);
p.000534: (d) maintain a system for removing unused test products and recording their disposal.
p.000534: 5.14.5. The contracting authority shall:
p.000534: (a) take the necessary measures to ensure the stability of the test product during application;
p.000534: (b) have sufficient quantities of the test product available to confirm its specifications, that is, to keep records of batch analyzes; and
p.000534: product properties. To the extent that the stability of the medicinal product permits, samples should be kept either until the analysis of the test results has been completed or until the prescribed deadline.
p.000534: any applicable law, whichever is later.
p.000534: 5.15. Access to documentation
p.000534: 5.15.1. The examining authority should ensure that the Examination Plan or other written agreement clearly states that the examiner / institution must
p.000534: provide direct access to original data / documents for monitoring, monitoring, evaluation of the Commission and inspection by the competent authorities.
p.000534: 5.15.2. The trial contracting authority should check that each respondent has given his or her written consent that his or her original health information may be obtained
p.000534: access directly for monitoring, monitoring, evaluation of the Commission and inspection by the competent authorities.
p.000534: 5.16. Product Safety Information
p.000534: 5.16.1. The test client is responsible for assessing the safety of the product being tested.
p.000534: 5.16.2. The contracting authority shall promptly inform all examiners / institutions and competent authorities of information which may adversely affect
p.000534: the safety of the respondents, influence the conduct of the examination, or withdraw the approval / positive opinion of the Commission.
p.000534: 5.17. Reporting of side effects of the drug
p.000534: 5.17.1. The contracting authority shall promptly inform all examiners / institutions, the Committees (where appropriate) and the competent authorities of all serious and
p.000534: unexpected side effects of the drug.
p.000534: 5.17.2. These emergency reports should comply with applicable laws and ICH's Clinical Safety Information Management Guidelines:
p.000534: Definitions and standards for emergency reporting.
p.000534: 5.17.3. The contracting authority shall provide the competent authorities with all new safety data and periodic reports in accordance with the applicable legal requirements
p.000534: regulations.
p.000534: 5.18. Observation
p.000534: 5.18.1. Purpose
p.000534: The purpose of observing a test is to verify that:
p.000534: (a) the rights and welfare of the respondents are protected;
p.000534: (b) that the information in the reports is accurate, complete and can be verified / verified using the original documents;
p.000534: (c) the test is conducted in accordance with the current approved Test Plan and any amendments thereto, with good clinical
p.000534: practice and with applicable legal regulations.
p.000534: 5.18.2. Selection and qualifications of observers
p.000534: (a) Observers shall be appointed by the contracting authority.
p.000534: (b) Observers must have appropriate education and scientific and / or clinical knowledge necessary to properly monitor the examination. It should
p.000534: keep track of the observer's qualifications.
p.000534: (c) The observer should be fully familiar with the product tested, the Test Plan, the Consent Declaration Form, other written notices
p.000534: intended for interviewees, the client's standard operating procedures and applicable legal requirements.
p.000534: 5.18.3. I also cover the nature of the observation
p.000534: The contracting authority shall ensure proper monitoring of the examination. The contracting authority shall determine the appropriate volume and nature
p.000534: observations. Determination of the scope and nature of the observations should be based on such frameworks as the objective, purpose, plan, complexity, blindness, size and parameters.
p.000534: testing. On-site monitoring is generally required before, during and after testing. However, in exceptional circumstances the client may
p.000534: determine that centralized monitoring of procedures such as examiner professional training and professional meetings and detailed written guidance may
p.000534: Ensure proper testing is conducted in accordance with good clinical practice. Statistically controlled sampling can be demonstrated
p.000534: by an acceptable method of selecting data for verification.
p.000534: 5.18.4. Observer's powers
p.000534: In accordance with the requirements of the contracting authority, observers should ensure that the examination is properly conducted and recorded, carrying out the following activities:
p.000534: related to the test or location of the test:
p.000534: (a) serving as the main communication channel between the contracting authority and the examiner;
p.000534: (b) verifying that the examiner has the appropriate qualifications and capabilities / means (see 4.1., 4.2., 5.6.) for the entire duration of the test, and whether
p.000534: premises, laboratories, equipment and staff with requirements for the safe and proper conduct of testing throughout the duration of the test;
p.000534: (c) checking the following in relation to the product tested:
p.000534: (i) that the storage time and conditions are acceptable and that the supplies are sufficient for the duration of the test;
p.000534: (ii) that the test product is given exclusively to subjects who may receive it at the doses specified in the Test Plan;
p.000534: (iii) Respondents have received appropriate instructions for the proper use, handling, storage and return of the test product;
p.000534: (iv) that there is adequate monitoring and records of the receipt, use and return of the test product at the test site;
p.000534: (v) that the disposal of unused tested products at the test site is in accordance with applicable legal requirements and requirements
p.000534: the contracting authority;
p.000534: (d) verifying that the examiner complies with the approved Test Plan and any approved amendments;
p.000534: (e) individually verifying that the statement of consent was obtained before the respondent was included in the examination;
p.000534: (f) ensuring that the Examiner receives current Instructions for the Examiner, all documentation, and is properly supplied to properly conduct the examination and
p.000534: complied with applicable legal regulations;
p.000534: (g) ensuring that the examiner and his staff are well informed of the examination;
p.000534: (h) verifying that the examiner and his or her staff complete the assigned examination tasks in accordance with the Test Plan and other written
p.000534: by agreement between the contracting authority and the examiner / institution and that he has not delegated his tasks to unauthorized persons;
p.000534: (i) verifying that the examiner included only those subjects who met the eligibility criteria in the examination;
p.000534: (j) reporting on the number of respondents covered;
p.000534: (k) verifying that the original documents and other test documentation are accurate, complete, and up-to-date;
p.000534: (l) verifying that the examiner submits all necessary reports, notices and requests and that they are accurate, complete and comprehensible; are delivered on time
p.000534: and whether they indicate the date and name / number of the Clinical Trial Plan;
p.000534: (m) verifying the accuracy and completeness of the test sheets, comparing them with the original documents and other test documentation. An observer in particular
p.000534: must check:
p.000534: (i) the information in the test sheets required by the Test Plan is accurate and fully consistent with the information in the original documents;
p.000534: (ii) whether all changes in dosage / treatment are sufficiently documented for each individual subject;
p.000534: (iii) whether adverse events, concomitant administration of medications and newly emerged diseases are recorded in the test lists in accordance with the Test Plan;
p.000534: (iv) whether absentee visits, non-completed searches and examinations are properly recorded in the test lists;
p.000534: (v) whether the withdrawal or withdrawal of the examiners and the reasons therefor are recorded in the test sheets;
p.000534: (n) informing the examiner of any errors, omissions or illegibility of the data in the test sheets;
p.000534: The observer should ensure that corrections and additions are made, that is, the deletion of data and the verification of these changes by their dating, with explanation
p.000534: the reasons for the change (where necessary) and the initials of the examiner or his / her staff authorized to arrange for changes in the test lists on the examiner's behalf.
p.000534: This authorization should be recorded in the documentation;
p.000534: (o) determining that all adverse event reporting was in order and in accordance with the requirements of good clinical practice, the Test Plan,
p.000534: Committees, contracting authorities and applicable legislation;
p.000534: (p) determining whether the examiner keeps the basic documentation (see 8. Basic documents for conducting the clinical trial);
p.000534: (q) informing the examiner of deviations from the Examination Plan, standard operating procedures, good clinical practice and applicable legal requirements
p.000534: regulations and taking appropriate measures not to repeat the observed deviations.
p.000534: 5.18.5. Observation procedures
p.000534: Observation procedures must follow established standard operating procedures and those procedures established by the contracting authority to monitor specific
p.000534: testing.
p.000534: 5.18.6. Observation report
p.000534: (a) The observer shall, after each visit to the site of the test, or after each receipt of the test notification,
p.000534: submit a report.
p.000534: (b) The reports should include the date, place, name of the observer and the name of the examiner, or other person with whom the observer communicated.
p.000534: (c) The reports should include a concise account of the observation and the observer's statement of important findings / findings, discrepancies and shortcomings, conclusions and
p.000534: measures taken or to be taken and / or recommended measures to comply with the request.
p.000534: (d) The representative of the contracting authority shall record the client's assessment of the monitoring reports and of the follow-up activities resulting from the report.
p.000534: 5.19. Supervision
p.000534: When conducting quality control oversight, the contracting authority should consider the following:
p.000534: 5.19.1. The purpose of surveillance
p.000534: The purpose of the contracting authority's monitoring procedure, which is independent of and separate from routine monitoring or quality control, is to evaluate the conduct of testing and
p.000534: its adherence to the Examination Plan, standard operating procedures, good clinical practice and applicable legal requirements.
p.000534: 5.19.2. Selection and qualifications of supervisors
p.000534: (a) For the purpose of carrying out supervision, the contracting authority shall appoint persons who are not dependent on the clinical trial.
p.000534: (b) The contracting authority shall ensure that persons are properly qualified by their education and experience to carry out the supervision properly. It should exist
p.000534: records of the qualifications of the supervisor.
p.000534: 5.19.3. Control procedure
p.000534: (a) The contracting authority should ensure that clinical trial supervision is conducted in accordance with the contracting authority's written provisions as to what should be monitored;
p.000534: how to conduct surveillance, how often, and what form and content of surveillance reports should be.
p.000534: (b) The contracting authority's plan and procedures for examining the test should take into account the importance of testing to resolve the request submitted to the competent authorities, no.
p.000534: test subjects, the type and complexity of the test, the level of risk for the respondents, and any problems identified.
p.000534: (c) The observations and findings of the person supervising should be documented.
p.000534: (d) In order to preserve the independence and value of the controls, inspection by the competent authorities of the surveillance report need not be part of the ordinary procedure. Competent authorities
p.000534: may request access to a case-by-case monitoring report when there is evidence of a serious departure from good clinical practice,
p.000534: that is, during court proceedings.
p.000534: (e) Where required by applicable law or regulation, the contracting authority shall provide a certificate of inspection.
p.000534: 5.20. Non-compliance
p.000534: 5.20.1. In case of non-compliance with the Examination Plan, standard operating procedures, good clinical practice and / or applicable legislation by
p.000534: the examiner / institution or the contracting authority's staff, the contracting authority must respond promptly to ensure compliance.
p.000534: 5.20.2. If serious and / or regular non-compliance by the examiner / institution is identified in the monitoring and / or monitoring process, the contracting authority should terminate
p.000534: his participation in the examination. If the examiner / institution ceases to participate due to non-compliance, the contracting authority must immediately do so
p.000534: inform the competent authorities.
p.000534: 5.21. Premature termination or termination of examination
p.000534: If an early termination or termination of testing occurs, the contracting authority should immediately inform the examiner / institution and the competent authorities and
p.000534: state the reasons for its termination or termination. It is also necessary to notify the Commission immediately and state the reasons for termination, respectively
p.000534: termination of examination by the client or examiner / institution, in accordance with the applicable legal regulations.
p.000534: 5.22. Clinical trial / study reporting
p.000534: Regardless of whether the trial is completed or completed early, the client should ensure that clinical trial reports are prepared and
p.000534: submitted to the competent authorities in accordance with applicable legal regulations. The client should also ensure that clinical trial reports which
p.000534: are an integral part of the marketing request, satisfy the ICH Guidelines for the preparation and content of clinical trial reports.
p.000534: (NOTE: In some cases, ICH Guidelines for the compilation and content of clinical trial reports allow for summary reports of
p.000534: clinical trial).
p.000534: 5.23. Multicenter trials
p.000534: In the case of multicenter testing, the contracting authority should ensure that:
p.000534: 5.23.1. all examiners carry out the examination strictly adhering to the Examination Plan approved by the contracting authority, the Commission and, where prescribed,
p.000534:
p.000534: 5.23.2. the test lists are designed to contain the necessary data from all sites where a multicenter test is conducted. They also are
p.000534: examiners collecting additional data submitted to the supplementary test lists for the purpose of recording additional data.
p.000534: 5.23.3. the responsibilities of the coordinator and examiner were documented prior to the start of the examination.
p.000534: 5.23.4. all examiners received instructions on adherence to the Clinical Trial Plan, adherence to unique standards for clinical and laboratory evaluation
p.000534: results and the completion of the test sheet.
p.000534: 5.23.5. is simplified communication between examiners.
p.000534: 6. CLINICAL TESTING PLAN AND ITS AMENDMENTS AND APPENDICES
p.000534: The clinical trial plan typically covers the contents listed below. However, it may also include site-specific information on separate pages
p.000534: tests, that is, a specific agreement may be invoked, and some of the information below may be found in other documents referenced by
p.000534: A call test plan, such as the Examiner's Guide.
p.000534: 6.1. General information
p.000534: 6.1.1. Name, number and date of the Test Plan. Modifications and additions to the Test Plan should also have a number and a date.
p.000534: 6.1.2. Name and address of the contracting authority and observer (if different from the contracting authority).
p.000534: 6.1.3. Name and title of person authorized to sign the Test Plan and its amendments and supplements on behalf of the contracting authority.
p.000534: 6.1.4. Name, title, address and telephone number of the contracting authority's expert advisor (Doctor of Medicine or Doctor of Dental Medicine for examination).
p.000534: 6.1.5. The name and title of the examiner responsible for conducting the test and the address and telephone number of the test site.
p.000534: 6.1.6. The name, title, address and telephone number of the qualified medical or dental doctor responsible for all health decisions
p.000534: related to the examination (if it is a person other than the examiner).
p.000534: 6.1.7. Name and address of the clinical laboratory and other participating health / technical departments and / or institutions.
p.000534: 6.2. Basic information
p.000534: 6.2.1. Name and description of the product under test.
p.000534: 6.2.2. Summary of clinically relevant findings from preclinical studies and relevant clinical trials.
p.000534: 6.2.3. Summary of known potential risks and benefits to respondents.
p.000534: 6.2.4. Description and rationale for the particular route of administration, its dosage regimen and duration of treatment.
p.000534: 6.2.5. A statement that the trial will be conducted in accordance with the Clinical Trial Plan, Good Clinical Practice and applicable legal requirements.
p.000534: 6.2.6. Description of the respondent population.
p.000534: 6.2.7. Literature references and dates relevant to the examination that provide basic information about the examination.
p.000534: 6.3. Purpose (s) and purpose of the test
p.000534: A detailed description of the objectives and purpose of the test.
p.000534: 6.4. Test plan
p.000534: The scientific value of the test and the reliability of the test data depend significantly on the Test Plan. Description of the Test Plan should
p.000534: contain:
p.000534: 6.4.1. Specific definition of primary and secondary test parameters.
...
p.000534: need to be modified in accordance with the client's written procedures. More frequent changes may also be needed depending on the stage of development and new important ones
p.000534: knowledge. However, new findings may be so important that - keeping with good clinical practice - the examiners, the Committee and / or
p.000534: competent authorities before their inclusion in the Guidelines.
p.000534: The Principal Investigator's instructions are up-to-date in principle, and the examiners are responsible for submitting the updated Instructions to the committee. If so
p.000534: the test is ordered by the examiner, the client-examiner should determine if instructions can be obtained from the manufacturer. If the tested product is supplied by the customer,
p.000534: the examiner is then obliged to provide the required information to the staff participating in the examination. In cases where it is not possible to produce official Instructions,
p.000534: the client-examiner should, in return, extend the basic information in the Test Plan that contains the minimum of current data described in these
p.000534: Guidelines.
p.000534: 7.2. General questions
p.000534: The instructions should include:
p.000534: 7.2.1. Front page
p.000534: The cover should show the name of the customer, the identification of each product tested (ie research number, chemical or approved generic name
p.000534: and, if the client so wishes, the protected name where permitted by law) and the date of issue. It is also recommended that the cover also contain a number
p.000534: editions and a reference to the previous issue number and date. Appendix 1 provides an example of a cover.
p.000534: 7.2.2. Privacy Statement
p.000534: The contracting authority may enter an instruction requiring the examiner to consider the instruction a confidential document which may be made available for inspection and use.
p.000534: exclusively to his staff and the Commission.
p.000534: 7.3. Contents of Instructions for the Examiner
p.000534: The instructions should include the following sections, accompanied by references, where appropriate:
p.000534: 7.3.1. Content
p.000534: An example of the content is in Appendix 2.
p.000534: 7.3.2. Summary
p.000534: A short summary (preferably no longer than two pages) should be provided, listing the most important available information on chemical, chemical,
p.000534: the pharmaceutical, pharmacological, toxic, pharmacokinetic, metabolic and clinical properties of the test product for a particular phase of its
p.000534: clinical development.
p.000534: 7.3.3. Introduction
p.000534: The chemical name of the test product (as well as the generic and protected name where permitted), all active ingredients, pharmacological information should be provided
p.000534: the group to which these anticipated indications for proxy, treatment, and diagnosis belong. Finally, a general approach to assessing the subject should be introduced in the introduction
p.000534: product.
p.000534: 7.3.4. Physical, chemical and pharmaceutical properties and product formulation
p.000534: The substances that make up the test product (including chemical and / or structural formulas) should be described and a brief overview of the main chemical, chemical and / or chemical formulas.
p.000534: pharmaceutical properties.
p.000534: In order to be able to take appropriate precautionary measures during testing, formulations, including excipients, must be provided and explained
p.000534: their use where clinically relevant. Care and handling instructions should also be provided.
p.000534: Any structural similarity to other known compounds should be noted.
...
p.000534: testing.
p.000534: Where appropriate, published reports of related products should be discussed. This may help the examiner to anticipate the side effects of the drug or others
p.000534: clinical trial difficulties.
p.000534: The ultimate goal of this section of the Instruction is to provide the examiner with clear insight into the potential risks and side effects, specific tests, observations and precautions that may be taken
p.000534: be required in the conduct of the clinical trial. The insight should be based on available chemical, pharmaceutical, pharmacological,
p.000534: toxicological and clinical data on the product tested. The examiner should also be given guidelines for identifying and treating overdose and
p.000534: side effects based on previous experience with humans and the pharmacological profile of the product under study.
p.000534: The ultimate goal of this section of the Instruction is to provide the examiner with clear insight into the potential risks and side effects, specific tests, observations and precautions that may be taken
p.000534: be required in the conduct of the clinical trial. The insight should be based on available chemical, pharmaceutical, pharmacological,
p.000534: toxicological and clinical data on the product tested. The examiner should also be given guidelines for identifying and treating overdose and
p.000534: side effects based on previous experience with humans and the pharmacological profile of the product under study.
p.000534: ____________________________ 7.4. APPENDIX 1:
p.000534: HOME (Example)
p.000534: TITLE OF THE TEST ORDER
p.000534: Product:
p.000534: Number of Surveys:
p.000534: Product name (s): Chemical name, (approved) generic name, protected name (if authorized by the contracting authority and permitted by law):
p.000534: INSTRUCTIONS TO THE TESTOR
p.000534: Issue Number:
p.000534: Release Date:
p.000534: Previous issue number:
p.000534: Previous issue date:
p.000534: ____________________________ 7.5. APPENDIX 2:
p.000534: TABLE OF CONTENTS OF EXAMINER INSTRUCTIONS (Example)
p.000534: 8. BASIC DOCUMENTS FOR CONDUCTING A CLINICAL TEST
p.000534: 8.1. Introduction
p.000534: Basic documents are those documents which, individually or together, enable the assessment of the performance of the tests and the quality of the data obtained. These documents
p.000534: serve as evidence that the examiner, client and observer have complied with the Good Clinical Practice standards and all applicable legal requirements.
p.000534: In addition, basic documents have a broad and important purpose. Timely storage of basic documents with examiners / institutions and contracting authorities may
p.000534: significantly contribute to the successful conduct of the examination by examiners, contracting authorities and observers.
p.000534: In addition, these documents are the most common subject to control and inspection as part of the validation process of testing and completeness
p.000534: of the data collected.
p.000534: The following is a list of the most essential basic documents. The different documents are divided into three groups according to the test phase in which they are usually created. 1) before
p.000534: the beginning of the clinical phase of the trial, 2) during the clinical phase of the trial, and 3) after the conclusion or termination of the study. It is listed
p.000534: the purpose of each document and whether it should be stored by the examiner / institution, the contracting authority or both. Some documents can be merged provided that
p.000534: they can immediately recognize the separate parts.
p.000534: At the beginning of the examination, the main examination archive should be established both with the examiner / institution and with the client.
p.000534: Final closing of the examination is possible only after the observer examines all the stored documents both with the examiner / institution and with the client and confirm
p.000534: that all basic documents are properly stored.
p.000534: All documents referred to in these Guidelines are subject to the supervision of the contracting authority and the inspection of the competent authorities.
p.000534: 8.2. Before the clinical trial phase begins
p.000534: The following documents should be prepared at this stage of planning, which must be stored before the official start of the examination.
p.000534: Stored with the Client
p.000534: Document name Purpose
p.000534: examiner / testing institution
p.000534: Document that relevant topicals have been provided to the examiner
p.000534: 8.2.1. TEST INSTRUCTIONS X X
p.000534: scientific knowledge of the product tested.
p.000534: Document that the examiner and the contracting authority agreed on the issue
p.000534: 8.2.2. SIGNED TEST PLAN AND EVENTUAL CHANGE I
p.000534: Test Plan and any amendments to the Test Plan, X X
p.000534: ADDITIONS TO THIS TEST LIST
p.000534: as well as Test Lists
p.000534: 8.2.3. NOTICE TO THE RESPONDENTS
p.000534: - CONSENT STATEMENT FORM (including all relevant translations) Document interviewee consent X X
p.000534: Document that respondent will receive appropriate written notice
p.000534: - OTHER WRITTEN NOTES on the basis of which he or she may choose to participate in X X
p.000534: examination
p.000534: - ADVERTISING TO INCLUDE THE RESPONDENTS (if advertising is planned) Document that the inclusion of the respondents is appropriate and without coercion X
p.000534: Document the financial agreement on conducting the test between
p.000534: 8.2.4. FINANCIAL ASPECTS OF TESTING X X
p.000534: the examiner / institution and the contracting authority
p.000534: Document that the respondent will be compensated for any damages
p.000534: 8.2.5. INSURANCE STATEMENT (where applicable) X X
p.000534: injuries resulting from his participation in the examination.
p.000534: 8.2.6. SIGNED AGREEMENTS BETWEEN TEST PARTICIPANTS, eg: Document the said agreements
p.000534: - examiner / institution and contracting authority X X
p.000534: X
p.000534: - the examiner / institution and the contracting research organization X
p.000534: (where necessary)
p.000534: - the contracting authority and the contracting research organization X
p.000534: - examiner / institution and competent authorities (where applicable) X X
p.000534: 8.2.7. DATED AND DOCUMENTED APPROVAL / POSITIVE Document that examination was considered by the Committee and provided its
p.000534: OPINION OF THE HEALTHCARE MEDICINE COMMITTEE / approval / positive opinion. Identify version number and date X X
p.000534: INDEPENDENT ETHICAL COMMITTEE ON THE FOLLOWING: document (s).
p.000534: - Test plan and amendments thereto
p.000534: - Test sheets
p.000534: - Consent form
p.000534: - other written notices intended for the respondents
p.000534: - Respondent recruitment ad (if scheduled)
p.000534: - Respondent's fees (if any):
p.000534: - other approved documents
p.000534: 8.2.8. COMPOSITION OF THE CLINICAL TRIAL / INDEPENDENT COUNCIL Document that the composition of the committee is consistent with good clinical X (where
p.000534: X
p.000534: ETHICAL TRUSTEE practice. needed)
p.000534: Document that an authorization / approval / notification has been obtained from X
p.000534: 8.2.9. AUTHORIZATION / APPROVAL / NOTICE OF TEST PLAN X (where is
p.000534: of the competent authority before the commencement of the examination and in accordance with the applicable one
p.000534: COMPETENT AUTHORITY (where applicable) required)
p.000534: legal regulations. (where necessary)
p.000534: 8.2.10. BIOGRAPHY AND / OR OTHER EVIDENCE DOCUMENTS Document the qualifications and suitability for conducting the tests and / or
p.000534: X X
p.000534: QUALIFICATIONS OF THE TESTIGATORS AND PERSONS WHO CONDUCT THE TESTING OF THE HEALTH MONITORING OF THE RESPONDENTS.
p.000534: 8.2.11. NORMAL VALUES / VALUES FOR
p.000534: MEDICAL / LABORATORY / TECHNICAL PROCEDURES AND / OR TESTS Document normal values and / or ranges of test values. X X
p.000534: PROVIDED FOR TESTING PLAN
p.000534: X
p.000534: Document the suitability of the department / laboratory for implementation
p.000534: 8.2.12. MEDICAL / LABORATORY / TECHNICAL PROCEDURES / TESTS X
p.000534: predicted tests and confirm the reliability of the findings.
p.000534: (where necessary)
p.000534: - confirmation or
p.000534: - authorization or
p.000534: - established quality control and / or external quality assessment
p.000534: - other forms of validation (where appropriate)
p.000534: Document compliance with applicable labeling regulations and
p.000534: 8.2.13. SAMPLE MARK ON TANK OF TESTED PRODUCT X
p.000534: the appropriateness of the instructions for the respondents.
p.000534: 8.2.14. INSTRUCTIONS FOR THE MANAGEMENT OF THE TESTED PRODUCT I Document the instructions necessary for proper storage, packaging,
p.000534: TEST MATERIALS (if not included in Test Plan or Distribution and Removal of Tested Product and Material for X X
p.000534: Instructions for the examiner) examination.
p.000534: Document the date of dispatch, batch number and shipping method of the subject
p.000534: 8.2.15. RECORD OF DELIVERY OF THE TESTED PRODUCT I
p.000534: products and test materials. Lets track the X X series
p.000534: TEST MATERIAL
p.000534: products, checking shipping conditions, and logging inputs and outputs
p.000534: 8.2.16. CERTIFICATES ON ANALYSIS OF SHIPPED TESTED
...
p.000534: (see 8.2.16.) X
p.000534: PRODUCTS
p.000534: 8.3.10. MONITORING REPORTS AFTER VISIT TO DOCUMENT Documentation of observation findings during site visit
p.000534: X
p.000534: CONDUCTING TESTING TESTING.
p.000534: Document agreements and important discussions regarding administration, breach
p.000534: 8.3.11. COMMUNICATION OUTSIDE THE VISIT OF THE PLACE
p.000534: provision of Test Plan, Test Execution, Reporting of Harmful X X
p.000534: TESTING
p.000534: events.
p.000534: - letters / letters
p.000534: - meeting notes
p.000534: - telephone conversation notes
p.000534: Document that the respondent gave his or her consent in accordance with Good Clinical
p.000534: 3/8/12 SIGNATURE DECLARATIONS CONCERNED with the practice and the Examination Plan prior to its participation in the examination. With that X
p.000534: document permission for direct access to data (see 8.2.3).
p.000534: Document the existence of respondents and prove the integrity of the collected
p.000534: 3/8/13 ORIGINAL DOCUMENTS of test data. Include original documents related to testing, X
p.000534: treatment and medical history of the subjects.
p.000534: Document that the examiner or the examiner's authorized staff confirmed X
p.000534: 3/8/14 FILLED, SIGNED AND DATED TEST SHEET X (copy)
p.000534: recorded observations. (original)
p.000534: Document any changes / corrections or corrections to the test sheet after entering X
p.000534: 3/8/15 TEST SHEET X DOCUMENTATION (copy)
p.000534: initial data. (original)
p.000534: 3/8/16 NOTICE OF DANGEROUS EVENTS
p.000534: ASSOCIATED REPORTS SUBMITTED BY AN EXAMINER TO NOTIFY NOTIFICATIONS OF SERIOUS ADVERSE EVENTS AND ASSOCIATED REPORTS
p.000534: X X
p.000534: shall submit to the contracting authority the examination in accordance with Section 4. 11. of the Guidelines.
p.000534: TO THE ORDERING TEST
p.000534: 3/8/17 NOTICE OF Unexpected DANGER Notices of unexpected serious side effects, or other information on
p.000534: ADVERSE REVIEWS AND OTHER INFORMATION ON THE SAFETY OF THE MEDICINAL PRODUCT The safety of the medicinal product submitted to the competent X (where
p.000534: X
p.000534: WHICH THE TEST ORDER AND / OR TESTER PROVIDES TO THE AUTHORITIES AND THE COMMISSION IN ACCORDANCE WITH SECTION 5.17. and paragraph 4.11.1, as applicable)
p.000534: TO THE COMPETENT AUTHORITIES paragraphs 5.16.2. and 4.11.2. Guideline.
p.000534: 3/8/18 SAFETY NOTES SUBMITTED BY THE CONTRACTING AUTHORITY The safety notices provided by the contracting authority to the examiner in accordance with
p.000534: X X
p.000534: TESTS THE TESTS TO THE TESTOR paragraph 5.16.2. Guideline.
p.000534: 3/8/19 PROVISIONAL OR ANNUAL COMMITTEE REPORTS Interim or annual reports to the Commission in accordance with section 4.10. and X (where
p.000534: X
p.000534: AND THE COMPETENT AUTHORITIES to the competent authorities in accordance with paragraph 5.17.3. Guideline. needed)
p.000534: X (where is
p.000534: 3/8/20 EVALUATION OF THE EXAMINER SELECTION Document the identity of the respondents who participated in the examination screening. X
p.000534: needed)
p.000534: Document that the examiner / institution keeps a confidential list of everyone's names
p.000534: 8.3.21. LIST OF RESPONDENTS 'IDENTIFICATION MARKS of the respondents with their corresponding marks which they received upon entering the examination. X
p.000534: Allows the examiner / institution to determine the identity of each respondent.
p.000534: 8.3.22. RECORD OF THE TESTAMENTS INCLUDED IN THE TESTING Chronologically document the entry of the subjects into the examination according to their mark. X
p.000534: 8.3.23. RECORD OF INPUTS AND OUTPUTS TESTED
p.000534: Document that the product under test is used in accordance with the Test Plan. X X
p.000534: PRODUCTS AT THE TEST PLACE
p.000534: Document the signatures and para- graphs of all persons authorized to enter data and / or
p.000534: 8.3.24. SIGNATURE SHEET X X
p.000534: updates to test lists.
p.000534: 8.3.25. RECORDED BODY RECORDS Document the location and identification marks of the preserved specimens in case
p.000534: X X
p.000534: TISSUE LIQUID / SAMPLE should be repeated.
p.000534: 8.4. After completion or termination of the examination
p.000534: Upon completion or termination of the examination, all documents referred to in sections 8.2. and 8.3. should be stored with the following documents:
p.000534: 8.4.1. RECORDING OF INPUTS AND OUTPUTS Document that the tested product was used in accordance with the Test Plan. Document the final
p.000534: TESTED PRODUCT ON THE INPUTS AND OUTPUTS OF THE TESTED PRODUCT: how many were delivered to the test site, how many X
p.000534: X
p.000534: LOCATION OF TESTING divided by respondents, how much returned from the respondents, how much returned to the client of the examination.
p.000534: X (if destroyed)
p.000534: 8.4.2. DOCUMENTATION
p.000534: Document the destruction of unused test products at the test site or at the site organization
p.000534: DESTRUCTION OF TESTED X
p.000534: of the contracting authority. conducting
p.000534: PRODUCTS
p.000534: testing)
p.000534: 8.4.3. COMPLETE LIST
p.000534: Provide identification of all respondents who participated in the examination for monitoring purposes. List
p.000534: IDENTIFICATION MARKS X
p.000534: should be kept confidential for the agreed duration.
p.000534: EXAMINER
p.000534: 8.4.4. CERTIFICATE OF CONTROL (where
p.000534: Document that supervision has been carried out. X
p.000534: available)
p.000534: 8.4.5. FINAL REPORT ON
p.000534: Document that all closing activities are completed and copies of basic documents
p.000534: CONCLUSION BY CLOSURE X
p.000534: stored in appropriate scriptures.
p.000534: TESTING
p.000534: 8.4.6. ALLOCATION DOCUMENTATION
p.000534: Returns to the test client to document any decryption procedures. X
p.000534: THERAPY AND DECRIPTION
p.000534: 8.4.7. FINAL REPORT WHICH
p.000534: EXPERT EXCHANGE
p.000534: Document completion of testing. X
p.000534: CONFIDENTIAL AND / OR COMPETENT
p.000534: BODIES
p.000534: X
p.000534: 8.4.8. CLINICAL REPORT
p.000534: Document test results and their interpretation. X
p.000534: TESTING / STUDY
p.000534: (where necessary)
p.000534: ANNEX II.
p.000534: European Medicines Agency
p.000534: Evaluation of medicines for human use
p.000534: London, 27 July 2000.
p.000534: CPMP / ICH / 2711/99
p.000534: ICH theme E 11
p.000534: CLINICAL TESTING OF MEDICINES IN CHILDREN
p.000534: Step 4 of the ICH Procedure
p.000534: GUIDELINES FOR CLINICAL TESTING OF MEDICINES IN CHILDREN (CPMP / ICH / 2711/99)
p.000534: Entry into force: January 2001.
p.000534: CLINICAL TESTING OF MEDICINES IN CHILDREN
p.000534: 1. INTRODUCTION
p.000534: 1.1. Objectives of the guideline
...
p.000534: The upper limit of this age group varies from country to country. Older adolescents may be involved in adult trials, though they may be
p.000534: difficulty adhering to the treatment regimen. Due to problems specific to adolescence, conducting tests may be appropriate
p.000534: (whether included in the adult test protocol or in a separate protocol) in healthcare settings with knowledge and experience in nursing
p.000534: of this patient population.
p.000534: 2.6. Ethical issues related to testing in children
p.000534: Children are a vulnerable group of respondents. It is therefore necessary to introduce specific measures to protect their rights in clinical trials and to prevent them
p.000534: exposure to unnecessary risk. The purpose of this section is to provide an ethical framework for conducting testing in children.
p.000534: For the clinical trial to be of benefit to its participants and other children, its plan must be such as to ensure the quality and clarity of the collected
p.000534: data. Respondents are also expected to benefit from the clinical trial, except in the special circumstances described in the ICH.
p.000534: document E6, section 4.8.14.
p.000534: 2.6.1. Clinical Trial Panel / Independent Ethics Committee (Committee)
p.000534: The role and authority of the Commission described in ICH document E6 is crucial in protecting the respondents. When considering protocols involving children,
p.000534: The committee among its membership must or must seek the professional opinion of persons with a good knowledge of ethical, clinical and psychosocial issues.
p.000534: related to children.
p.000534: 2.6.2. Involvement of respondents
p.000534: Respondents should be included in a way that completely excludes inappropriate prompting of respondents, or their parents / guardians, to participate in
p.000534: examination.
p.000534: Fees and living expenses may be included in the cost of the pediatric clinical trial. Fees should be approved by
p.000534: Committees.
p.000534: When conducting child testing, it is a good idea to include individuals who represent the demographic country / region and the disease being tested, except where
p.000534: there are valid reasons for limited participation in the examination.
p.000534: 2.6.3. Consent and consent
p.000534: As a rule, children are legally incapable of giving their consent to participate in the examination. Therefore, their participation depends on their decision
p.000534: parents or guardians to take responsibility for their participation in the clinical trial. Fully familiarize the caregiver with the examination and
...
p.000534: The Commission, as described in Section 2.6.1.
p.000534: Listed below are some practical assumptions that can contribute to a positive clinical trial experience and minimize feelings
p.000534: discomfort and suffering:
p.000534: • Staff with knowledge and experience in working with children and adjusting to their age, including experience in pediatric procedures.
p.000534: • Physical space with furniture, toys, daily activities and food adapted to the age of the children.
p.000534: • Conducting tests in a well-known environment such as a hospital or clinic where the subjects are otherwise receiving medical care.
p.000534: • Ways to reduce the discomfort associated with performing procedures such as:
p.000534: • local anesthesia before the introduction of an intravenous catheter,
p.000534: • use of permanent catheters instead of frequent veins in the blood to collect blood samples,
p.000534: • simultaneous collection of blood samples for protocol-defined purposes when routine clinical sampling is performed.
p.000534: The committee should consider how many veins in the vein are acceptable to obtain the blood samples prescribed by the protocol and make sure that
p.000534: understanding of procedures in the event that a permanent catheter becomes unusable over time. Respondent's right to refuse further participation must be respected
p.000534: in the test procedures, except in the case described in section 2.6.3.
p.000534: ANNEX III.
p.000534: APPLICATION FORM FOR THE APPROVAL OF THE MINISTER OF HEALTH CARE FOR CARRYING OUT THE CLINICAL TESTING OF MEDICINES IN THE REPUBLIC
p.000534: HRVATSKOJ
p.000534: - completed by the contracting authority or the applicant responsible for the accuracy of the information provided
p.000534: Clinical trial client:
p.000534: Applicant for clinical trial:
p.000534: * Date of receipt of the item:
p.000534: * Date of receipt of complete documentation:
p.000534: A. General information
p.000534: Test Name:
p.000534: Test Plan Designation
p.000534: EUDRACT number:
p.000534: Clinical trial phase (I, II, III, IV)
p.000534: List of countries in which clinical trials were approved and / or planned by the time the application was submitted to the ministry responsible for health
p.000534: implement
p.000534: Version and date of test plan
p.000534: Brochure for examiners
p.000534: Informed consent
p.000534: Insurance document
p.000534: Policy number, date of issue, period of insurance
p.000534: B. Information on examiners
p.000534: Chief Examiner in the Republic of Croatia
p.000534: Address:
p.000534: Phone / Fax
p.000534: e-mail
p.000534: Informed consent, version and date, signed by the Examiner
p.000534: Leaders of participating testing centers (examiners)
p.000534: C. Data on test substance
p.000534: Is the preparation approved in the Republic of Croatia
p.000534: Countries where the preparation is approved
p.000534: Generic name
p.000534: Trademark
p.000534: Manufacturer
p.000534: Dosage and administration of the drug in this study
p.000534: Results of non-clinical trials (or reasons why they were not performed)
p.000534: Primary test hypothesis (and secondary if significant)
p.000534: Ethical considerations of the trial (identify and list any possible problem, outline the potential gains of clinical knowledge
...
p.000534: Clinical trial sponsor (sponsor):
p.000534: Applicant for clinical trial:
p.000534: Name of test
p.000534: Institution (s) at which the test (s) will be conducted
p.000534: Total number of centers
p.000534: Test Plan Mark (Protocol), EUDRACT
p.000534: Clinical trial phase I. II. III. IV.
p.000534: Indication
p.000534: Primary:
p.000534: Objectives of the research
p.000534: (comparing drugs)
p.000534: Secondary objective:
p.000534: Patient population diagnosis and main criterion for inclusion
p.000534: Duration of the experiment
p.000534: Beginning and end of the experiment (in Croatia, worldwide)
p.000534: Criteria for measuring the effect of treatment
p.000534: Methodology
p.000534: open, double-blind, placebo
p.000534: controlled
p.000534: (type of test) (tick)
p.000534: Number of visits, controls
p.000534: Side effects
p.000534: Method of administration and dosage
p.000534: Special notes
p.000534: The principal investigator reviewed the translation of the informed consent (specify version and date) and a summary of the test plan, which is confirmed by the signature
p.000534: of this SEP form
p.000534: Applicant / clinical trial applicant signature and date
p.000534: ANNEX VI.
p.000534: CENTRAL ETHICAL COMMITTEE
p.000534: APPLICATION FORM AND EVALUATION OF NON-INTERVENTIONAL TEST
p.000534: Non-interventional background information (to be completed by the applicant)
p.000534: Name of non-intervention drug test in Croatian:
p.000534: Name of non-intervention drug test in English:
p.000534: Test plan designation:
p.000534: Name and address of the contracting authority:
p.000534: Applicant's name and address:
p.000534: Principal examiners and establishments where non-interventional drug testing will be conducted (number of establishments and examiners): The list is attached to this form and is an integral part of it
p.000534: Objectives of the test:
p.000534: Inclusion criteria:
p.000534: Anticipated number of patients to be monitored:
p.000534: Estimated duration of testing in the Republic of Croatia:
p.000534: Documents provided (filled in by applicant)
p.000534: Test plan (mark, version and date):
p.000534: Approved Summary of Product Characteristics in the Republic of Croatia (approval date):
p.000534: Package leaflet for the medicinal product in the Republic of Croatia (date of approval):
p.000534: Decision on marketing authorization (date):
p.000534: Informed consent for the patient in Croatian language (version and date):
p.000534: Original informed consent in English (version and date):
p.000534: Test financial plan:
p.000534: Other documentation (list, with version and date of documents):
p.000534: Certificate of payment of the costs of giving the opinion of the SPS:
p.000534: Applicant's signature and date:
p.000534: _________________________________________
p.000534: Documentation evaluation (to be completed by the rapporteur)
p.000534: Test plan YES NO
p.000534: The medicine is prescribed according to the marketing authorization: ∑ ☐ Comment:
p.000534: Involvement of patients in a particular therapeutic procedure is not determined in advance by the test plan but is carried out in accordance with normal practice: ∑ ☐ Comment:
...
p.000534: Fits test plan: ∑ ☐ Comment:
p.000534: Test Financial Plan: YES NO
p.000534: The test's financial plan is clear: ∑ ☐ Comment:
p.000534: Examiner fees match the estimated scope of work: ∑ ☐ Comment:
p.000534: Rapporteur's recommendation for the adoption of the SPS opinion at the meeting (specify date):
p.000534: (delete unnecessarily; in case b, c or d, reasons must be provided)
p.000534: a. positive thinking
p.000534: b. conditional positive thinking
p.000534: c. it is delayed
p.000534: d. negative thinking
p.000534: Reasons:
p.000534: Report date Reporter's signature:
p.000534: [1] 1 [1] In ICH's E5 Guidelines on Ethnic Factors Affecting Clinical Acceptance from Other Countries, Factors
p.000534: which may influence different drug response in different populations are divided into internal and external ethnic factors. Here you are
p.000534: categories are called internal or external factors only.
p.000534: ANNEX VII.
p.000534: AGENCY FOR MEDICINAL PRODUCTS AND MEDICAL PRODUCTS
p.000534: APPLICATION FORM FOR APPLICATION AND ASSESSMENT OF NON-INTERVENTION TEST
p.000534: Non-interventional background information (to be completed by the applicant)
p.000534: Name of non-intervention test in Croatian:
p.000534: Name of the non-intervention test in English:
p.000534: Name of the active substance (INN):
p.000534: Name of drug:
p.000534: Test plan designation:
p.000534: Authorization holder name and address:
p.000534: Name and address of the contracting authority:
p.000534: Applicant's name and address:
p.000534: Name and surname of the local pharmacovigilance officer
p.000534: Principal examiners and institutions where non-intervention testing will be conducted (names of institutions and examiners' names):
p.000534: Objectives of the test:
p.000534: Inclusion criteria:
p.000534: Exclusion criteria:
p.000534: Anticipated number of patients to be monitored:
p.000534: Estimated duration of testing in the Republic of Croatia:
p.000534: Countries where the non-intervention testing in question is already underway
p.000534: Countries where a request has been made to conduct the non-intervention test in question
p.000534: EU PAS registry number *
p.000534: Shared PASS **
p.000534: * indicate whether PASS is registered in the EU PAS registry
p.000534: ** in the case where multiple marketing authorization holders participate in the planning and implementation of the PASS
p.000534: Documents provided (filled in by applicant)
p.000534: Test plan (mark, version and date):
p.000534: Test list (version and date):
p.000534: Approved Summary of Product Characteristics in the Croatian language (approval date):
p.000534: Approved package leaflet in the Croatian language (authorization date):
p.000534: Decision on marketing authorization (date):
p.000534: Informed consent for the patient in Croatian language (version and date):
p.000534: Original informed consent in English (version and date), if applicable:
p.000534: Test financial plan:
p.000534: Proposal of Notice to the Directorate of the Institution on Conducting Non-Intervention Testing
...
General/Other / Undue Influence
Searching for indicator undue influence:
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p.000534: other relevant documents requested by the Commission.
p.000534: 3.1.4. The committee should periodically review any ongoing research at intervals appropriate to the risk for the respondents, and at least
p.000534: once a year.
p.000534: 3.1.5. The Commission has the right to request that the respondent be provided with more information than the one mentioned in paragraph 4.8.10. when according to his
p.000534: in the opinion, such supplementary information may be useful in protecting the rights, safety and / or well-being of the respondents.
p.000534: 3.1.6. When it is intended to conduct a non-therapeutic trial requiring the consent of the respondent's legal representative (see 4.8.12, 4.8.14),
p.000534: The committee should determine whether the proposed Test Plan and / or other documentation has sufficiently taken into account ethical issues and meets the applicable
p.000534: legal regulations for such tests.
p.000534: 3.1.7. Where the Examination Plan indicates that it is not possible to obtain the prior consent of the respondent or his / her legal representative (ie in an emergency
p.000534: cases, see 4.8.15), the Committee should determine whether the proposed Test Plan and / or other documentation has sufficiently taken into account ethical issues and
p.000534: whether it meets the applicable legal requirements for such tests.
p.000534: 3.1.8. The Commission should consider the amount and manner of payment of the respondents' remuneration in order to eliminate any possibility of coercion and undue influence.
p.000534: to the respondents. The payment of compensation should be distributed in installments, not that it depends entirely on the respondent's participation by the end of the examination.
p.000534: 3.1.9. The Commission should ensure that notices of compensation for respondents, including the manner, amount and timing of payments, are included in the written
p.000534: the consent statement form as well as any other written notice for the respondents. The amount and schedule of payment of the installment of the compensation should be stated.
p.000534: 3.2. Composition, tasks and work
p.000534: 3.2.1. The committee should consist of a reasonable number of members, who combine the expertise and experience needed to consider and evaluate
p.000534: the scientific, health and ethical aspects of the proposed test. It is recommended that the Commission:
p.000534: (a) has at least five members;
p.000534: (b) that at least one member by his / her vocation is not from the scientific field;
p.000534: (c) at least one member is independent of the institution conducting the examination or of the place of examination.
p.000534: Only members of the Commission who are independent of the examiner and the contracting authority should have the right to vote or to express an opinion on the examination.
p.000534: testing. The list of Committee members and their qualifications should be regularly updated.
p.000534: 3.2.2. The committee should carry out its tasks in accordance with written operational procedures, document its work and draw up minutes of its
p.000534: meetings, and should adhere to good clinical practice and applicable law.
...
General/Other / participants in a control group
Searching for indicator control group:
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p.000534: Informed consent is consent to participate in a clinical trial on a voluntary basis based on received and properly documented notices
p.000534: on the nature and importance, consequences and risks of the examination, in writing, signed by the interviewee and dated. If the person is incompetent
p.000534: to give such consent or is a minor, the consent is signed by a legal representative or guardian. If the respondent is illiterate or unable to write, he gives
p.000534: oral consent in the presence of at least one witness who is not a member of the examination team.
p.000534: Inspection supervision of clinical trials is the oversight of the competent authority over the conduct of the clinical trial, review of documentation, premises, records,
p.000534: quality assurance systems and other resources related to the conduct of clinical trials that may be conducted at the test site, at the premises
p.000534: of the clinical trial client and / or the contracting authority or in other legal entities where the competent authority deems it necessary to carry out supervision.
p.000534: The respondent is an individual who participates in a clinical trial and receives the study drug or is part of a control group.
p.000534: The examiner is a doctor of medicine or a person with appropriate professional qualifications for clinical trials due to his / her professional knowledge and necessary
p.000534: experience in treating patients. The examiner is responsible for conducting the clinical trial at the test site. If a clinical trial is conducted by a group
p.000534: individuals in one examiner site, the examiner is responsible and is called the lead examiner.
p.000534: The test site is the health facility where the clinical trial is conducted.
p.000534: Test drug is a pharmaceutical formulation with an active substance or a placebo that is being tested or used as a comparison in a clinical trial and includes
p.000534: medicinal products authorized on the market but used in a different way from the one approved or different in formulation or packaging, or
p.000534: are used in unauthorized indications or used to obtain additional information on a marketing authorization form.
p.000534: Clinical trial is any human trial designed to detect or confirm clinical, pharmacological and / or other pharmacodynamic effects
p.000534: one or more test drugs and / or detection of side effects of one or more test drugs, and / or studies on absorption, distribution, metabolism and
p.000534: excretion of one or more investigational drugs for the purpose of determining the safety of administration and / or efficacy. This includes clinical trials
p.000534: conducted in one or more testing sites, in one or more Member States of the European Union.
...
p.000534: 6.1.5. The name and title of the examiner responsible for conducting the test and the address and telephone number of the test site.
p.000534: 6.1.6. The name, title, address and telephone number of the qualified medical or dental doctor responsible for all health decisions
p.000534: related to the examination (if it is a person other than the examiner).
p.000534: 6.1.7. Name and address of the clinical laboratory and other participating health / technical departments and / or institutions.
p.000534: 6.2. Basic information
p.000534: 6.2.1. Name and description of the product under test.
p.000534: 6.2.2. Summary of clinically relevant findings from preclinical studies and relevant clinical trials.
p.000534: 6.2.3. Summary of known potential risks and benefits to respondents.
p.000534: 6.2.4. Description and rationale for the particular route of administration, its dosage regimen and duration of treatment.
p.000534: 6.2.5. A statement that the trial will be conducted in accordance with the Clinical Trial Plan, Good Clinical Practice and applicable legal requirements.
p.000534: 6.2.6. Description of the respondent population.
p.000534: 6.2.7. Literature references and dates relevant to the examination that provide basic information about the examination.
p.000534: 6.3. Purpose (s) and purpose of the test
p.000534: A detailed description of the objectives and purpose of the test.
p.000534: 6.4. Test plan
p.000534: The scientific value of the test and the reliability of the test data depend significantly on the Test Plan. Description of the Test Plan should
p.000534: contain:
p.000534: 6.4.1. Specific definition of primary and secondary test parameters.
p.000534: 6.4.2. Description of test type / layout (eg, double-blind, comparator, placebo control group) and diagram of the Test Plan, Procedures and Phases.
p.000534: 6.4.3. Description of measures taken to maximize objectivity, including:
p.000534: (a) random selection;
p.000534: (b) blind technique.
p.000534: 6.4.4. Description of treatment in study with study drug doses and dose regimens. This includes a description of the form, packaging and labeling of the investigational medicinal product.
p.000534: 6.4.5. Expected duration of participation of respondents in the examination and description of the sequence and duration of all parts of the examination, including monitoring (where it is
p.000534: needed).
p.000534: 6.4.6. Description of criteria for termination or termination of part / entire examination, or for exclusion of individual respondents from the examination.
p.000534: 6.4.7. Procedures for recording the inputs and outputs of the test product, placebo and comparator drugs.
p.000534: 6.4.8. Description of storing random selection codes and procedures for decrypting them.
p.000534: 6.4.9. A description of all the data that should be entered directly into the test list of respondents (ie, those not previously recorded in an electronic or written document) and
p.000534: information considered original.
p.000534: 6.5. Selection of respondents and their withdrawal from examination
p.000534: 6.5.1. Criteria for inclusion of respondents in the examination.
p.000534: 6.5.2. Exclusion criteria for respondents.
p.000534: 6.5.3. Criteria for withdrawal of test subjects (ie discontinuation of treatment with test product) and procedures specifying the following:
p.000534: (a) when and how subjects may withdraw from testing / treatment with the product tested;
...
p.000534: Step 4 of the ICH Procedure
p.000534: GUIDELINES FOR CLINICAL TESTING OF MEDICINES IN CHILDREN (CPMP / ICH / 2711/99)
p.000534: Entry into force: January 2001.
p.000534: CLINICAL TESTING OF MEDICINES IN CHILDREN
p.000534: 1. INTRODUCTION
p.000534: 1.1. Objectives of the guideline
p.000534: The choice of medicines registered for use in children is currently limited. The aim of this guideline is to encourage and facilitate the timely development of medicines for children
p.000534: internationally. This guideline gives a brief overview of key issues related to the development of medicines for children and the different approaches to achieving them
p.000534: safe, successful and ethically sound drug trials in children.
p.000534: 1.2. Starting point
p.000534: ICH documents relevant to child testing include:
p.000534: E2: Manage innocuous data
p.000534: E3: Compilation and content of clinical trial reports
p.000534: E4: Dose efficacy data on drug registration
p.000534: E5: Ethnic factors affecting the acceptance of clinical data from other countries
p.000534: E6: Good clinical practice: integrated guidelines
p.000534: E8: General considerations related to clinical trials
p.000534: E9: Statistical principles applicable in clinical trials
p.000534: E10: Selection of control group for clinical trial
p.000534: M3: Preclinical safety testing of pharmaceutical products for clinical trials in humans
p.000534: Q1: Stability testing
p.000534: Q2: Validation of analytical procedures
p.000534: Q3: Impurity testing
p.000534: 1.3. Scope of the Guidelines
p.000534: This guideline covers the following issues related to clinical trials in children: (1) considerations regarding the introduction of a drug testing program in children
p.000534: children; (2) planning the start of testing in children with respect to the developmental phase of the drug; (3) types of testing (pharmacokinetics,
p.000534: pharmacokinetics / pharmacodynamics, efficacy, safety); (4) age groups and (5) ethical justification for clinical trials in children. The intention
p.000534: these guidelines do not provide a detailed overview of all issues; these are further elaborated in other ICH guidance and regulatory documents
p.000534: bodies and pediatric associations of individual countries.
p.000534: 1.4. General principles
p.000534: Children should only receive medicines that have been properly tested and evaluated for use in children. For safe and effective treatment
...
Searching for indicator placebo:
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p.000534: oral consent in the presence of at least one witness who is not a member of the examination team.
p.000534: Inspection supervision of clinical trials is the oversight of the competent authority over the conduct of the clinical trial, review of documentation, premises, records,
p.000534: quality assurance systems and other resources related to the conduct of clinical trials that may be conducted at the test site, at the premises
p.000534: of the clinical trial client and / or the contracting authority or in other legal entities where the competent authority deems it necessary to carry out supervision.
p.000534: The respondent is an individual who participates in a clinical trial and receives the study drug or is part of a control group.
p.000534: The examiner is a doctor of medicine or a person with appropriate professional qualifications for clinical trials due to his / her professional knowledge and necessary
p.000534: experience in treating patients. The examiner is responsible for conducting the clinical trial at the test site. If a clinical trial is conducted by a group
p.000534: individuals in one examiner site, the examiner is responsible and is called the lead examiner.
p.000534: The test site is the health facility where the clinical trial is conducted.
p.000534: Test drug is a pharmaceutical formulation with an active substance or a placebo that is being tested or used as a comparison in a clinical trial and includes
p.000534: medicinal products authorized on the market but used in a different way from the one approved or different in formulation or packaging, or
p.000534: are used in unauthorized indications or used to obtain additional information on a marketing authorization form.
p.000534: Clinical trial is any human trial designed to detect or confirm clinical, pharmacological and / or other pharmacodynamic effects
p.000534: one or more test drugs and / or detection of side effects of one or more test drugs, and / or studies on absorption, distribution, metabolism and
p.000534: excretion of one or more investigational drugs for the purpose of determining the safety of administration and / or efficacy. This includes clinical trials
p.000534: conducted in one or more testing sites, in one or more Member States of the European Union.
p.000534: An observer is a person who performs monitoring during a clinical trial and ensures that it is conducted, documented and recorded in accordance with the test plan,
p.000534: standard operating procedures, good clinical practice and specific regulations.
p.000534: Non-interventional drug testing is any trial in which the drug is prescribed in accordance with the marketing authorization. Involvement of patients in
p.000534: a particular therapeutic procedure is not predetermined by the test plan but is carried out in accordance with normal practice, and prescribing is
p.000534: regardless of the decision to enroll the patient in the trial. Additional diagnostic and patient follow-up procedures are not performed, but performed
p.000534: use epidemiological methods to analyze the data collected.
...
p.000534: 1.9. Documenting surveillance
p.000534: Documentation to track the sequence of events.
p.000534: 1.10. Clinical trial blindness / masking
p.000534: A process in which one or more parties participating in a clinical trial do not know how treatment is assigned. Single blind trial
p.000534: usually refers to a patient who does not know the division of treatment, and double-blind to a respondent, examiner, observer, and in some cases,
p.000534: data analysts.
p.000534: 1.11. Test list
p.000534: Printed, optical or electronic document intended to record all data required by the Clinical Trial Plan used by the trial client
p.000534: reports on each respondent.
p.000534: 1.12. Clinical trial / clinical study
p.000534: Any human study intended to detect or confirm the clinical, pharmacological and / or other pharmacodynamic effects of the subject
p.000534: product, and / or the determination of side effects and / or the study of absorption, distribution, metabolism and excretion, with a view to determining the safety and / or
p.000534: the effectiveness of the test product. The terms clinical trial and clinical study are ambiguous.
p.000534: 1.13. Clinical Trial / Clinical Study Report
p.000534: Description of the clinical trial / study in writing of any therapeutic, pro-lactic or diagnostic agent administered in humans, and
p.000534: clinical and statistical description, presentation and analysis form a single report (see ICH Guidelines for the Structure and Content of the Clinical Report
p.000534: examination).
p.000534: 1.14. Product of comparison
p.000534: Tested or marketed product (ie active control), or placebo, used in the clinical trial as a comparison product.
p.000534: 1.15. Compliance (applies to clinical trial procedures)
p.000534: Compliance with all clinical trial requirements, good clinical practices and applicable legal requirements.
p.000534: 1.16. Confidentiality
p.000534: Preventing the disclosure, except to authorized persons, of the protected data of the test client, or the identity of the respondents.
p.000534: 1.17. The contract
p.000534: A written, dated and signed agreement between two or more parties specifying the delegation and distribution of tasks and obligations, and nancial matters there
p.000534: where necessary. The contract may be based on a Clinical Trial Plan.
p.000534: 1.18. Commission for Coordination
p.000534: A committee that may be set up by a trial client to coordinate the implementation of a multicenter clinical trial.
p.000534: 1.19. Examiner Coordinator
p.000534: Examiner responsible for coordinating examiners at different centers participating in multicenter testing.
p.000534: 1.20. Contracting research organization
p.000534: Person or organization (commercial, academic or otherwise) with whom the contracting authority has contracted to perform one or more duties and activities
p.000534: related to the clinical trial.
p.000534: 1.21. Direct access
p.000534: Approval to review, analyze, verify and transmit all data and reports relevant to the evaluation of the clinical trial. Any side that has a direct
p.000534: access to documentation (eg domestic or foreign competent authorities, observers, and supervisors of the contracting authority) is obliged to take all reasonable steps
...
p.000534: the form on which the signature and date are entered.
p.000534: 1.29. Inspection
p.000534: Procedure by the competent authority to review documents, assets, equipment and premises, records and all other matters that the body considers related to
p.000534: clinical trial and can be found at the site of the clinical trial, at the trial sponsor and / or contracting research organization, or
p.000534: to other institutions that the competent authority deems appropriate.
p.000534: 1.30. Institution (medical)
p.000534: Any public or private entity, institute or medical or dental institution where clinical trials are conducted.
p.000534: 1.31. Clinical Trials Board
p.000534: An independent body composed of medical professionals and non-medical members whose responsibility is to ensure the protection of rights,
p.000534: the safety and well-being of the people participating in the clinical trial, including by reviewing, approving and ensuring ongoing review of the Plan
p.000534: clinical trial and its appendices are used to obtain and document the informed consent of the clinical trial investigator.
p.000534: 1.32. Clinical trial / study interim report
p.000534: Report on intermediate results and their evaluation based on analysis performed during the clinical trial.
p.000534: 1.33. Tested product
p.000534: Pharmaceutical form of the active substance or placebo to be tested in a clinical trial for comparison, including a product approved on the market if
p.000534: its use or method (formulation or packaging) differ from the approved one, or, if used for an indication that is not approved, or used for
p.000534: collecting further information on approved application.
p.000534: 1.34. Examiner
p.000534: The person responsible for conducting the clinical trial at the place where it is conducted. If a group of individuals conducts a site survey,
p.000534: the examiner is the person responsible for leading the group and is also referred to as the lead examiner. See also Assistant Examiner.
p.000534: 1.35. Examiner / Institution
p.000534: A term that designates "examiner and / or institution in accordance with applicable law."
p.000534: 1.36. Instructions for the examiner
p.000534: A set of clinical and preclinical data on an investigational product that is relevant to its human test (see 7. Test Guideline).
p.000534: 1.37. Legal representative
p.000534: An individual or legal entity or other body authorized by applicable law to consent to participate in a clinical trial on behalf of the respondent.
p.000534: 1.38. Observation
p.000534: The act of monitoring the progress of the clinical trial and ensuring that its implementation, documentation and reporting are consistent with the Clinical Trial Plan,
p.000534: standard operating procedures, good clinical practice and applicable legal requirements.
p.000534: 1.39. Observation report
p.000534: A written report submitted by the observer to the contracting authority after each visit to the examination site and / or upon new knowledge relating to
p.000534: testing in accordance with standard operating procedures of the test client.
p.000534: 1.40. Multicenter testing
...
p.000534: fees to respondents and other documents requested by the Commission.
p.000534: 5.11.2. If the Committee gives its approval / positive opinion changes to any aspect of the examination such as changes to the Plan
p.000534: Examination, Consent Statement Form, Other Written Notices Intended for Respondents and / or Other Procedures
p.000534: the examiner / institution must receive a copy of the modification document and the date of approval / positive opinion of the Commission.
p.000534: 5.11.3. The contracting authority shall obtain from the examiner / institution the documentation and dates of re-approvals / supervision of the Commission, as well as
p.000534: withdrawal / revocation of approval / positive opinion.
p.000534: 5.12. Data on the product tested
p.000534: 5.12.1. When planning a test, the test client should make sure that sufficient safety and performance information is available
p.000534: from preclinical and / or clinical trials related to route of administration, dose, duration and appropriate population of subjects.
p.000534: 5.12.2. As soon as it becomes aware of the new data, the test client is obliged to update the Testing Instructions.
p.000534: 5.13. Production, packaging and labeling and coding of the product under test
p.000534: 5.13.1. The test client shall ensure that the test product (including, if applicable, comparative active drug and placebo) is labeled in accordance with
p.000534: the stage of its development, that it has been manufactured in accordance with all applicable good manufacturing practices, that it has been coded and labeled in such a way that
p.000534: if necessary, it protects the blind process. In addition, labeling should be in accordance with applicable legal regulations.
p.000534: 5.13.2. The contracting authority shall state the appropriate storage conditions for the medicinal product such as temperature, light protection, storage time,
p.000534: then, if necessary, fluid reconstitution procedures and accessories used for infusion of the test product. The contracting authority should inquire about this
p.000534: inform all interested parties (ie observers, examiners, pharmacists, warehouse managers).
p.000534: 5.13.3. The packaging of the test product should be such as to prevent its contamination and unacceptable changes in transport and storage.
p.000534: 5.13.4. In blind studies, the labeling system of the product under test should also include a mechanism that allows for rapid identification of the drug in the
p.000534: emergency but which does not allow identity disclosure to go unnoticed.
p.000534: 5.13.5. If there are any significant changes in the formulation of the test product or comparator at the clinical stage of development,
p.000534: testing new formulations to obtain the results of additional testing (eg stability, dissolution rate, bioavailability) required for evaluation
p.000534: can these changes significantly alter the pharmacokinetics of the drug.
...
p.000534: 6.1.5. The name and title of the examiner responsible for conducting the test and the address and telephone number of the test site.
p.000534: 6.1.6. The name, title, address and telephone number of the qualified medical or dental doctor responsible for all health decisions
p.000534: related to the examination (if it is a person other than the examiner).
p.000534: 6.1.7. Name and address of the clinical laboratory and other participating health / technical departments and / or institutions.
p.000534: 6.2. Basic information
p.000534: 6.2.1. Name and description of the product under test.
p.000534: 6.2.2. Summary of clinically relevant findings from preclinical studies and relevant clinical trials.
p.000534: 6.2.3. Summary of known potential risks and benefits to respondents.
p.000534: 6.2.4. Description and rationale for the particular route of administration, its dosage regimen and duration of treatment.
p.000534: 6.2.5. A statement that the trial will be conducted in accordance with the Clinical Trial Plan, Good Clinical Practice and applicable legal requirements.
p.000534: 6.2.6. Description of the respondent population.
p.000534: 6.2.7. Literature references and dates relevant to the examination that provide basic information about the examination.
p.000534: 6.3. Purpose (s) and purpose of the test
p.000534: A detailed description of the objectives and purpose of the test.
p.000534: 6.4. Test plan
p.000534: The scientific value of the test and the reliability of the test data depend significantly on the Test Plan. Description of the Test Plan should
p.000534: contain:
p.000534: 6.4.1. Specific definition of primary and secondary test parameters.
p.000534: 6.4.2. Description of test type / layout (eg, double-blind, comparator, placebo control group) and diagram of the Test Plan, Procedures and Phases.
p.000534: 6.4.3. Description of measures taken to maximize objectivity, including:
p.000534: (a) random selection;
p.000534: (b) blind technique.
p.000534: 6.4.4. Description of treatment in study with study drug doses and dose regimens. This includes a description of the form, packaging and labeling of the investigational medicinal product.
p.000534: 6.4.5. Expected duration of participation of respondents in the examination and description of the sequence and duration of all parts of the examination, including monitoring (where it is
p.000534: needed).
p.000534: 6.4.6. Description of criteria for termination or termination of part / entire examination, or for exclusion of individual respondents from the examination.
p.000534: 6.4.7. Procedures for recording the inputs and outputs of the test product, placebo and comparator drugs.
p.000534: 6.4.8. Description of storing random selection codes and procedures for decrypting them.
p.000534: 6.4.9. A description of all the data that should be entered directly into the test list of respondents (ie, those not previously recorded in an electronic or written document) and
p.000534: information considered original.
p.000534: 6.5. Selection of respondents and their withdrawal from examination
p.000534: 6.5.1. Criteria for inclusion of respondents in the examination.
p.000534: 6.5.2. Exclusion criteria for respondents.
p.000534: 6.5.3. Criteria for withdrawal of test subjects (ie discontinuation of treatment with test product) and procedures specifying the following:
p.000534: (a) when and how subjects may withdraw from testing / treatment with the product tested;
p.000534: (b) the type of data and the timetable for collecting it from the withdrawing respondents;
p.000534: (c) whether these respondents replace each other and how;
p.000534: (d) monitoring of subjects who withdraw from testing / treatment with the product under examination.
p.000534: 6.6. Treatment of subjects
p.000534: 6.6.1. Planned treatment, including the names of all products, their doses and dosage schedules, route / route of administration and periods of administration, including
p.000534: the follow-up period of respondents from each group who received the product under test.
p.000534: 6.6.2. Description of medicines / treatments that are (including emergency medicines), that is, not allowed before and / or during the test.
p.000534: 6.6.3. Observation procedures designed to determine whether a respondent adheres to the prescribed treatment.
p.000534: 6.7. Performance evaluation
p.000534: 6.7.1. List of drug efficacy parameters.
...
p.000534: Clinical trial client:
p.000534: Applicant for clinical trial:
p.000534: SEP - Registration number
p.000534: EUDRACT number
p.000534: Date of receipt of complete documentation
p.000534: A. General information
p.000534: Test name, label
p.000534: Clinical trial phase (I, II, III, IV.)
p.000534: version and date of test plan
p.000534: Examiner brochure (version and date)
p.000534: Informed Consent ((Version and Date)
p.000534: Insurance document Policy number, date of issue, duration of insurance
p.000534: Certificate of payment of the fee
p.000534: Test Summary (Version and Date) According to the SEP Special Form
p.000534: B. Information on examiners
p.000534: Chief Examiner in the Republic of Croatia
p.000534: Address *
p.000534: Phone and fax
p.000534: e-mail
p.000534: Chief Examiner
p.000534: reviewed the translation of informed consent
p.000534: specify version and date -
p.000534: which is confirmed by the signature of this section
p.000534: Leaders of participating testing centers (examiners),
p.000534: (addresses, tel, fax, e-mail)
p.000534: C. Data on test substance
p.000534: Is the preparation approved in the Republic of Croatia
p.000534: Countries where the preparation is approved
p.000534: Generic name
p.000534: Trademark
p.000534: Manufacturer
p.000534: Dosage and administration of the drug in this study
p.000534: Summary of non-clinical trials (Phase I and Phase II trials only)
p.000534: Known side effects
p.000534: Known contraindications
p.000534: Known interactions
p.000534: D. Use of placebo Yes No
p.000534: If yes: information on existing accepted effective treatment options for this condition or disease.
p.000534: Danger of untreated or placebo use in this disease or condition
p.000534: E. Drug Supply
p.000534: Will the patient and / or institution receive the drug for free for clinical trial purposes
p.000534: Is the continuation of the open-label study scheduled, whether participants will receive the drug at no charge, and for how long
p.000534: * The address of the lead examiner, which is also the address for all communications between the SEP and the researcher in the project
p.000534: ANNEX V.
p.000534: Clinical trial summary
p.000534: (filled in by the client or applicant responsible for accuracy of information)
p.000534: Clinical trial sponsor (sponsor):
p.000534: Applicant for clinical trial:
p.000534: Name of test
p.000534: Institution (s) at which the test (s) will be conducted
p.000534: Total number of centers
p.000534: Test Plan Mark (Protocol), EUDRACT
p.000534: Clinical trial phase I. II. III. IV.
p.000534: Indication
p.000534: Primary:
p.000534: Objectives of the research
p.000534: (comparing drugs)
p.000534: Secondary objective:
p.000534: Patient population diagnosis and main criterion for inclusion
p.000534: Duration of the experiment
p.000534: Beginning and end of the experiment (in Croatia, worldwide)
p.000534: Criteria for measuring the effect of treatment
p.000534: Methodology
p.000534: open, double-blind, placebo
p.000534: controlled
p.000534: (type of test) (tick)
p.000534: Number of visits, controls
p.000534: Side effects
p.000534: Method of administration and dosage
p.000534: Special notes
p.000534: The principal investigator reviewed the translation of the informed consent (specify version and date) and a summary of the test plan, which is confirmed by the signature
p.000534: of this SEP form
p.000534: Applicant / clinical trial applicant signature and date
p.000534: ANNEX VI.
p.000534: CENTRAL ETHICAL COMMITTEE
p.000534: APPLICATION FORM AND EVALUATION OF NON-INTERVENTIONAL TEST
p.000534: Non-interventional background information (to be completed by the applicant)
p.000534: Name of non-intervention drug test in Croatian:
p.000534: Name of non-intervention drug test in English:
p.000534: Test plan designation:
p.000534: Name and address of the contracting authority:
p.000534: Applicant's name and address:
p.000534: Principal examiners and establishments where non-interventional drug testing will be conducted (number of establishments and examiners): The list is attached to this form and is an integral part of it
p.000534: Objectives of the test:
p.000534: Inclusion criteria:
p.000534: Anticipated number of patients to be monitored:
p.000534: Estimated duration of testing in the Republic of Croatia:
p.000534: Documents provided (filled in by applicant)
p.000534: Test plan (mark, version and date):
p.000534: Approved Summary of Product Characteristics in the Republic of Croatia (approval date):
p.000534: Package leaflet for the medicinal product in the Republic of Croatia (date of approval):
...
Orphaned Trigger Words
Appendix
Indicator List
| Indicator | Vulnerability |
|---|
| access | Access to Social Goods |
| access to information | Access to information |
| age | Age |
| another country | Other Country |
| authority | Relationship to Authority |
| child | Child |
| children | Child |
| coerce | Presence of Coercion |
| cognitive | Cognitive Impairment |
| control group | participants in a control group |
| dependence | Drug Dependence |
| dependency | Drug Dependence |
| dependent | Dependent |
| disability | Mentally Disabled |
| drug | Drug Usage |
| education | education |
| elderly | Elderly |
| embryo | embryo |
| emergency | Public Emergency |
| ethnic | Ethnicity |
| family | Motherhood/Family |
| fetus | Fetus/Neonate |
| healthy volunteers | Healthy People |
| home | Property Ownership |
| homeless | Homeless Persons |
| ill | ill |
| illiterate | Literacy |
| illness | Physically Disabled |
| impaired | Cognitive Impairment |
| incapable | Mentally Incapacitated |
| incapacity | Incapacitated |
| infant | Infant |
| influence | Drug Usage |
| institutionalized | Institutionalized |
| job | Occupation |
| laboratory staff | Laboratory Staff |
| language | Linguistic Proficiency |
| linguistic | Linguistic Proficiency |
| mentally | Mentally Disabled |
| military | Soldier |
| minor | Youth/Minors |
| nomads | nomad |
| opinion | philosophical differences/differences of opinion |
| parent | parents |
| parents | parents |
| placebo | participants in a control group |
| poor | Economic/Poverty |
| prison | Incarcerated |
| restricted | Incarcerated |
| sick | Physically Ill |
| single | Marital Status |
| student | Student |
| substance | Drug Usage |
| undue influence | Undue Influence |
| unemployed | Unemployment |
| union | Trade Union Membership |
| vulnerable | vulnerable |
Indicator Peers (Indicators in Same Vulnerability)
| Indicator | Peers |
|---|
| child | ['children'] |
| children | ['child'] |
| cognitive | ['impaired'] |
| control group | ['placebo'] |
| dependence | ['dependency'] |
| dependency | ['dependence'] |
| disability | ['mentally'] |
| drug | ['influence', 'substance'] |
| impaired | ['cognitive'] |
| influence | ['drug', 'substance'] |
| language | ['linguistic'] |
| linguistic | ['language'] |
| mentally | ['disability'] |
| parent | ['parents'] |
| parents | ['parent'] |
| placebo | ['controlXgroup'] |
| prison | ['restricted'] |
| restricted | ['prison'] |
| substance | ['drug', 'influence'] |
Trigger Words
coercion
consent
developing
ethics
harm
protect
protection
risk
sensitive
welfare
Applicable Type / Vulnerability / Indicator Overlay for this Input