Year XIV Tuesday, January 19, 2010 Number / Number 4 Year XIV Tuesday, January 19, 2010 ISSN 1512-7486 - Bosnian Pursuant to Article 56, paragraph (4) and Article 120, paragraph 6 of the Law on Medicines and Medical Devices ("Official Gazette of BiH", no. 58/08), at the proposal of the Expert Council of the Agency for Medicinal Products and Medical Devices of Bosnia and Herzegovina, Ministry of Bosnia and Herzegovina brings civil affairs RULEBOOK ON CLINICAL TESTING OF MEDICINES AND MEDICINAL PRODUCTS PART ONE - INTRODUCTORY PART Article 1 (Subject of the Rules) (1) This Rulebook regulates the field of clinical trial of a medicinal product and a medical device in Bosnia and Herzegovina: the clinical trial procedure for the medicinal product and the medical device, the obligations of the participants in the clinical trial procedure medication and record keeping in the clinical trial procedure. In the preparation of the clinical trial, they must be determined goals, problems as a risk-benefit balance, and whether the solutions selected are scientifically and ethically justified. According to the provisions of the Declaration of Helsinki contained in Annex No. VI of these Regulations and International Ethical Guidelines biomedical testing on humans issued by the Council for International Organizations of Medical Sciences International Organizations of Medical Sciences-CIOMS), clinical trials must be conducted in accordance with baseline ethical principles: voluntariness; respect for rights; respect for the person; benevolence and harmlessness. (2) The precondition for clinical trial is preclinical trials which provide sufficient evidence of eligibility potential harm and possible clinical use of the drug. (3) Prior to testing, monitoring and control methods and standard operating procedures should be established. Article 2 (Definitions) The terms used in this Regulation shall have the following meanings: a) Good clinical practice is a set of internationally recognized ethical and professional standards related to quality planning, performing, documenting and reporting on clinical trials performed on humans, which ensure the protection of the rights, safety and well-being of the subjects as well as the credibility of the results of clinical trials; b) Respondent documentation is documentation prepared in accordance with the clinical trial plan and contains information on one subject collected during the clinical trial; c) Pharmacogenomics is a study of variations in DNA and RNA characteristics related to a given drug response; d) Pharmacogenetics is a branch of pharmacogenomics and is defined as a study of variations in DNA strand sequences related to drug response; e) Pharmacodynamics is the study of the interaction between a drug and its molecular targets; f) Genes are functional segments of genetic material that serve as a schematic blueprint for protein synthesis; g) A genome is the total genetic material of an organism; h) The Institutional Ethics Committee is an independent, advisory body whose duty is to evaluate the justification clinical trial, as well as the possibility of conducting a clinical trial according to the principles of Good Clinical Practice, and all this to ensure and protect the rights, safety and well-being of the subjects involved in the clinical trial; i) The examiner is the person responsible for conducting the clinical trial in the institution where it is conducted; j) The Principal Investigator is the investigator who is responsible for conducting the clinical trial of the medicinal product if clinical drug testing is conducted by the research team; k) The applicant is a person who participates in the clinical trial as a beneficiary of the investigational medicinal product the drug in the trial compares or placebo; l) Clinical Trial Report is a written report of the course of a clinical trial of any therapeutic, a prophylactic or diagnostic product, comprising clinical and statistical data processing, presentation, analysis and conclusions; m) Single or double blind examination means that the candidate does not know what he is receiving or that he does not the respondent, the examiner, or the competent observer do not know what anyone has received. n) Data coding categories Single-coded data and samples are marked with one specific code and do not imply any personal information identifiers. In the case of single coding, data or samples can be linked to a specific person using the encryption key. The clinical investigator is responsible for keeping the coding key. Since the samples and supporting information can be indirectly linked to the research subject, using a coding key, can be taken procedures such as drawing a sample or returning individual results at the request of the subject. Single use coded data and samples allows clinical monitoring, monitoring of the subject or supplementing of the subject's data. Single coding is currently the standard used in clinical research and offers an additional guarantee of subject identifiers, in relation to the general principles of trust in the health care system and privacy protection in daily medical practice; Duplicate encoded data and samples were originally marked with one specific code and did not carry any personal data information. The data and samples are then labeled with a second code that is first linked via the second encryption key. Data or patterns can be linked to the face using both encryption keys. The clinical researcher is responsible for safeguarding the former encryption key and has no access to another key. As samples and corresponding data can be very indirectly linked to subject to the use of both coding keys, procedures such as sample withdrawal or retrieval may be undertaken individual results at the request of the subject. However, additional electronic or technical processes may limit the ability to associate the genotype result with face. E.g. a certain computer procedure may add new data to the subject, but connection is prevented genotype data with the subject's personal information. The use of duplicate encoded data and samples is made possible clinically monitoring, monitoring the subject or supplementing the data. The use of the second code provides additional confidence and protection of the privacy of the entities, greater than that of the single code encoding. Access to both keys is required to merge any data or patterns with the subject's personal information. The anonymized data and samples were originally single or double coded, but there is a link between personal data subjects and unique codes are then deleted. Once a connection has been deleted, it is no longer possible to associate data and samples with to people via encryption keys. "Anonymization" prevents the subject from being re-identified. Since being "anonymized" samples and relevant data cannot relate to the subject. It is not possible to undertake procedures such as sample withdrawal or the return of individual results even at the request of the subject. The use of anonymized data and samples does not allow clinical monitoring, monitoring the subject or adding new data. By deleting the encryption keys that bind the data and specimens with personal information about the subject are provided with additional confidence and privacy protection as this is prevented reidentification of the subject using keys. Anonymous data and samples are never marked with personal information when they collect, nor does the coding key be generated. Therefore, there is no possibility of linking genomic data and samples with individual subjects. In some cases only limited clinical information may be associated with anonymous samples (e.g., samples from diabetic subjects, men, age 50-55 g., cholesterol> mg / dl). Because anonymous samples and relevant data cannot be associated with subjects, it is not possible to undertake procedures such as sample withdrawal, return of individual results, even at the request of the subject. The use of anonymous data and samples does not permit clinical monitoring, monitoring of the subject or supplementation of the data; o) Clinical trial of a drug is any systematic trial of a drug with the aim of finding or confirming it actions, as well as the identification of any side effects of did medication. The clinical trial of the drug includes i clinical part of the study of the bioavailability and bioequivalence of a medicinal product with the aim of determining its effectiveness i harmlessness p) Final Report, Clinical Trial Completion Report, contained in Annex No. IV to this Ordinance presents a detailed description of the test after completion and includes a description of the test methodology, method statistical data processing, description of respondents, presentation and evaluation of statistical analysis results, and critical, ethical, statistical and clinical evaluation of the whole trial; q) Quality control means operational techniques and activities undertaken within the assurance system quality, in order to confirm that all the quality requirements have been met; r) Good manufacturing practice is part of a quality assurance system that ensures that medicines are consistently and continuously produce and control according to appropriate quality standards in accordance with their purpose; s) Multicenter clinical trial is a clinical trial conducted according to a single protocol a multi-center clinical trial run by multiple examiners, with the centers where the tests are being conducted may be located in one or more countries; t) Surveillance is a systematic test conducted (as a rule on a randomly selected sample of data) by a trained person. which does not directly participate in the trial in order to determine whether the clinical trial in question is being conducted according to approved plan trials, in accordance with standard operating procedures and Good Clinical Practice. It is monitored by the monitor it has appropriate qualifications to perform clinical trial monitor jobs and have good clinical education practice; u) Competent observer is a qualified person who independently assesses the conformity of all on behalf of the contracting authority activities related to clinical trial, protocol, standard operating procedures, Good clinical practice and with applicable regulations; v) The client of the trial is the legal entity at whose request the clinical trial is conducted; w) Adverse drug action is any adverse and unintentionally triggered reaction that may occur during a therapeutic dose of the drug. A side effect of a drug can also be defined as any adverse reaction to a drug that has been administered at the usual dose for prophylactic, diagnostic or therapeutic purposes, or for modifying physiological functions, with the condition that there is a cause and effect relationship, or that relationship cannot be ruled out; x) Adverse drug reaction in a clinical trial is an undesirable and unintentionally induced reaction in a subject, which may occur in a clinical trial of a drug in connection with any dose of the drug; y) An unexpected side effect of a drug is one that has an unknown nature, severity or outcome, that is, they are not described in the Summary of Product Characteristics and Package Leaflet, or are not part of this effect current knowledge of the drug; z) Adverse event in clinical trial is an unwanted experience (any adverse and undesirable sign such as abnormal laboratory result, symptoms, or disease in the trial) that occurred during the clinical drug testing, whether or not it has a causal relationship to drug use; aa) Other respondent documentation includes hospital records, specialist examination findings and / or special information about the respondent that allows to determine the authenticity of the information in the test lists of respondents and if necessary, allow them to be supplemented and corrected; bb) Clinical trial quality assurance includes the quality assurance systems and procedures in place conducting trials and obtaining data in accordance with Good Clinical Practice, including rules on ethical and professional implementation of standard operating procedures, reporting and qualification of professional staff; cc) A serious adverse reaction in a clinical trial is an undesirable and unintentionally induced reaction to drug in a clinical trial that results in death, imminent life-threatening, disability, hospital treatment (which was not previously required), an extension of hospital treatment or congenital anomaly, that is, birth defects and after birth; dd) A serious adverse event in a clinical trial is an adverse experience that occurred during the clinical trial drug testing, whether or not it has a causal connection with the use of the drug, resulting in death life-threatening, disability, hospital treatment (if not required before), hospital extension treatment, congenital anomalies, or defect at and after birth, or malignancy during the test; ee) Post-marketing intervention clinical trial is a prospective trial in which the drug is administered apply in accordance with the conditions specified in the marketing authorization, which requires additional diagnostic procedures as well as monitoring procedures defined by the clinical trial protocol; ff) Post-marketing non-interventional clinical trial (pharmacoepidemiological study) is a trial in which the drug is administered in accordance with the conditions set out in the marketing authorization of the choice Patients are not predetermined by the clinical trial protocol but fall into current established practice The prescribing is clearly separate from the decision to enroll the patient in the trial. Extra diagnostic or monitoring procedures are not applied and the results obtained are analyzed epidemiologically methods; gg) Test protocol is a document containing the objective, plan and methodology of the test, the method of statistical processing clinical trial data and organization, in accordance with Good Clinical Practice; hh) Respondent's consent is the written statement of the respondent, parent of a minor child, guardian or legal representative, by which he voluntarily confirms his willingness to participate in a particular clinical trial, whether orally and in writing informed of all aspects of the examination that are relevant to the decision to participate. The consent of the respondents is documents using the signed statement of consent of the interviewee with the date of signature; ii) Randomization is the process of engaging subjects in therapy or control groups using random methods election to reduce bias; jj) Standard Operating Procedures (SOPs) are detailed written instructions for implementing each specific situation throughout clinical trials, which allow all functions and activities to be performed equally during a particular clinical trial testing; kk) Certificate of Good Clinical Practice - document confirming knowledge of Good Clinical Practice; ll) Raw data are or certified copies of original observations, clinical findings and other activity data within the clinical trial required for reconstruction and evaluation of the trial. The information provided also include laboratory records, notes, accounts, data obtained through automated instruments, accurate verified copies in the form of photocopies, photographic negatives, microfilms or magnetic media; mm) An Examiner Instruction is a document containing relevant drug information, analytical information, pharmacological-toxicological testing, as well as clinical trials to date of the medicinal product concerned, including data that is relevant to clinical trial to which they refer. The guidance also includes information that justifies the nature, scope and duration tests, potential harm assessment, special warnings and are updated in accordance with new data. Article 3 (Phases of clinical trial of the drug) The clinical trial of the drug is divided into several phases as follows: a) Phase 1: Represents an examination of the first administration of the drug to humans and is conducted to establish a preliminary assessment the safety and pharmacokinetic / pharmacodynamic profile of the active substance in humans; b) Phase 2: This implies Phase 2a and Phase 2b; Phase 2a of the clinical trial represents an early phase of drug administration in a small number of selected subjects who expect beneficial side effects of did medicine. It is carried out with the aim of ascertaining the efficacy and safety of did medication as well dose range. Phase 2b of the clinical trial represents a late phase of drug administration in a large number of selected subjects, with a goal making the final decision on dosage range and pharmaceutical form. During this phase of the clinical trial, i collecting data on metabolic activities in the human body over the long term period versus phase 2a; c) Phase 3: Represents the administration of the drug to a sufficiently large number of selected subjects for determination efficacy and safety of administration of the test drug. A sufficiently large number of subjects means the number of subjects from the accepted professional examination protocol an institution conducting clinical trials for this stage to evaluate the result; d) Phase 4: Represents the release of the medicinal product in limited quantities under supervision. It is conducted for the purpose of monitoring the impact of the drug under conditions of limited marketing in selected professional clinical trial institutions medicines; e) Post-marketing phase: represents drug testing, ie monitoring and collecting additional data on its efficacy and safety, after obtaining a marketing authorization. PART TWO - CLINICAL TESTING OF MEDICINES CHAPTER I - CLINICAL TESTING PROCEDURE Article 4 (Content and method of clinical trial of the drug) (1) The clinical trial shall determine: the efficacy of the drug, the relationship between the beneficial and adverse effects of the drug, side effects, bioequivalence and bioavailability; (2) All clinical trials of medicinal products on humans must be conducted in accordance with the ethical principles laid down in Helsinki the Patient Rights Protection Declaration (hereinafter: the Declaration of Helsinki) and in accordance with the rules of good clinical practices and this Rulebook; (3) The medicinal product may be clinically tested after having received a positive evaluation of the pharmaceutical-chemical-biological and pharmacological- toxicological study of the drug. Article 5 (Investigator) (1) Clinical trials shall be performed at the request of the client of the trial: the manufacturer, that is, legal or natural persons which acts on behalf of the manufacturer and is established in Bosnia and Herzegovina, interested legal persons, individuals, or at the request of the competent ministry; (2) The test client is responsible for the reliability of the data and information made available to the examiner before the start of the clinical trial, or those that occur during the trial; (3) The investigator and the examiner are obliged to cooperate with the authorized institution where the clinical testing regarding reporting, implementation of changes to clinical trial protocols, reporting adverse events, and submission of test reports; (4) The contracting authority shall organize a quality assurance system (including independent supervision) for implementation testing; (5) The contracting authority shall prepare written detailed standard operating procedures (SOPs), in accordance with Good clinical practice; (6) The investigator and the examiner must agree and sign the clinical trial protocol, and determine the method of data entry. Article 6 (Authorization for clinical trial of a medicinal product) (1) Each clinical trial of a medicinal product must be approved by the Agency for Medicinal Products and Medical Devices of Bosnia and Herzegovina (hereinafter: the Agency); (2) Prior to granting a license to conduct a clinical trial of a medicinal product "referred to in paragraph (2) of this Article" obtain the approval of the Clinical Trials Committee for Medicinal Products and Medical Devices of Bosnia and Herzegovina (the Commission); (3) The Agency is obliged to issue a clinical trial authorization within 60 days from the date of admission a formal request, based on the Commission's opinion. Article 7 (Costs of clinical trial of the drug) (1) The costs of applying for a clinical trial and licensing shall be borne by the applicant for the trial; (2) The amount of compensation for the work of the members of the Commission shall be determined by a decision of the Agency and shall be borne by the proposer testing. Article 8 (Contents of request for clinical trial of drug) The following shall be attached to the application for authorization to conduct a clinical trial of a medicinal product and a medical device documentation: a) a cover letter with a mandatory list of documents with the date and signature of the applicant; b) the completed clinical trial authorization form for the medicinal product or medical device which is in Annex (I) of this Of the Rules and forms an integral part thereof; c) information on the sponsor of the study; d) a contractual research organization (CRO) authorization letter; logo, name and address of the examiner (logo if any); the name of the professional institution that will participate in the examination, including the approval of the Ethics Committee (s) of the professional institution certifying participation in the the present clinical trial; e) the name of the clinical trial; f) the name of the medicinal product to be tested; g) pharmaceutical form and strength; h) "ATC" - classification, if any; i) the name of the manufacturer; j) proof of payment of the costs of the proceedings; k) a statement of the purpose of the study, the indication of the test phase and the registration status of the medicinal product; l) summary of the clinical study protocol in the local language; m) the clinical trial plan (protocol) with the date and signature of the principal investigator for that clinical trial; n) booklet for the researcher in the local language; o) evidence of the subject's insurance against the potential adverse consequences of participating in the clinical trial; and a medical device that must cover the complete clinical trial period - local insurance (in which case there are data on the number of centers and the number of respondents); p) current knowledge of adverse effects; q) a form for reporting serious adverse drug reactions; r) a list of countries where a clinical trial is being conducted, including Bosnia and Herzegovina, if multicenter; s) a list of countries where the study drug is registered; t) the CRP Case Report Form test lists; u) notification for the respondent in the local language; v) Respondent's consent form with the place of signature of the patient and the principal investigator and the place for the date at local language; w) card of the patient participating in the study; x) "CV" of the researcher; y) evidence of education in the field of good clinical practice for the principal investigator. Article 9 (Appointment of Principal Investigator and Clinical Trial Investigator) (1) The principal investigator for clinical trials shall appoint a medical doctor or of dentist. (2) The principal investigator may be assigned to a maximum of three clinical studies during one calendar year. Article 10 (Contents of the documentation for the drug under study) The documentation for the drug under study contains: a) a certificate of good manufacturing practice; b) Certificate of completed drug analysis; c) drug labeling; d) evidence of completed pharmacochemical tests with a positive evaluation; e) evidence of a positive pharmacological-toxicological study; f) evidence of the registration status of the medicinal product in the manufacturer's country; g) summary of product characteristics and package leaflet. Article 11 (Contents of clinical trial protocol) (1) The clinical trial protocol shall contain: general information; random selection and "blind" testing and statistical analysis. a) general information includes the name of the clinical trial, identification number and date. Accessories must have their own number and date. The general information contains the name and address of the examiner and the competent observer, the names of the persons who will sign the clinical trial protocol and annexes on behalf of the trial sponsor and examiner responsible for conducting the trial, and the name of the institution where the trial is being conducted. The clinical trial protocol should contain the objective of the test, the measures that will be taken to avoid bias, and in particular, where appropriate important, and the methods of & quot; blind & quot; examinations and selection of respondents; b) the manner of random selection of respondents must be documented. When the examiner receives a closed code for each individual therapy, in a "blind" randomized trial, it should be archived, both at the test site and with the test proponent. In the case of a blinded trial, the clinical trial protocol must include the conditions under who are allowed to open the code and name of the person authorized to do so. It is necessary to provide a system, which will in case of urgency, provide access to information about the treatment of the individual respondent. The system must allow access treatment of only one subject at a time. If the code is open, the same should be justified and documented in test lists of respondents; c) the types of statistical analysis must be specified in the clinical trial protocol and any deviation from the clinical trial protocol must be described and justified in the final trial report. Planned Analysis i its implementation must be carried out or confirmed and identified by an educated statistician. Options or the circumstances of the inter-assay during the trial must also be specified in the clinical trial protocol. The examiner and the authorized observer must ensure that the data is of the highest quality possible at the stage of their own collection, and the statistician must ensure uniformity of data during processing. The results of the analyzes must be presented in such a way that they allow the interpretation of clinical relevance by assessing the magnitude of the difference in treatment effect and interval reliability is more than just testing for statistical significance. An estimate of the data omitted from statistical analysis. All such exclusions must be documented so that they can be repeated if necessary analysis. (2) The clinical trial should be conducted in accordance with the clinical trial protocol agreed and signed by the contracting authority and the examiner. (3) The contracting authority and the examiner must agree on any change that occurs during the examination, sign it and add it in addition to the clinical trial protocol (amendment). (4) The clinical trial protocol must describe the objectives of the trial, the procedures to be followed, the reasons why the test is conducted on humans, the nature and degree of any known risk, the groups from which they will Respondents are also selected ways to ensure adequate information before respondent agrees participates in the examination. (5) The model of the protocol for conducting the clinical trial has the prescribed content in Annex number (II) and its constituent is part of this Ordinance. Article 12 (Contents of Instructions for Examiner) (1) The Examiner Instruction is a brief overview of existing clinical and pre-clinical trial data on a examines in a clinical trial. (2) The proponent of the study must regularly obtain new knowledge of the medicinal product obtained during the clinical trial provide the examiner with supplemental instructions. (3) The examiner's instruction shall contain: a) the content of the clinical trial, b) the content of the clinical trial, c) introductory remarks, d) the physical, chemical and pharmaceutical properties of the pharmaceutical formulation and formulation, e) preclinical studies (preclinical pharmacology, pharmacokinetics and drug metabolism in animals; and toxicology); f) the effect of the test drug in humans (Pharmacokinetics, drug metabolism in humans, tolerability, effects, traffic data), g) summary of product characteristics and conclusion. (4) At the end of each section of the instruction, the examiner must provide a list of the literature used in the clinical trial drug, and the most important literature should be provided in full. Article 13 (Competence of the Commission) Upon receipt of the request and documentation for the clinical trial, the Commission shall review the request and evaluate: a) eligibility of the examiner for the proposed examination; b) the appropriateness of the clinical trial protocol with regard to the objectives of the trial and the justification of the foreseeable hazards; and risks in relation to the assumed benefit to respondents and other persons; c) the manner of inclusion of the subjects in the clinical trial; d) the comprehensibility and completeness of the information provided to the respondents; e) insurance and reimbursement in case of death, that is, treatment of clinical subjects by examining; f) eligibility of additions to the clinical trial protocol. Article 14 (Respondents' voluntary consent principles - Declaration of Helsinki) The principles of voluntary consent of the subjects must be applied in each clinical trial, in accordance with the provisions The Declaration of Helsinki, and in particular: a) the respondent is provided with information about the clinical trial in oral and written form; b) no compulsion to participate in the clinical trial is allowed; c) the respondents, their loved ones, guardians and legal representatives must be allowed to acquire knowledge of test details; d) the information "referred to in paragraph (3) of this Article" must contain a clear message that it is an examination, that participation in the clinical trial is voluntary and that refusal to participate, that is, refusal to participate in the trial freely; e) respondents must have sufficient time to decide whether or not they wish to participate in the examination; f) the subjects must be aware and agree to check the test results and be aware that it is participation in the examination protected as professional secrecy and as such made available to the public; g) the candidate must be informed about the insurance and treatment procedures for treatment in case of damage or disabilities caused by participation in a clinical trial; h) the respondent must know the circumstances under which the examiner or the applicant may terminate his examination participation in testing; i) the candidate must be fully informed of the examination, including the objective, the expected benefit for the respondent, ie other persons, control treatment / placebo, hazards and inconveniences (eg invasive procedures) and, where appropriate, interpretation of accepted alternative standard medical treatment; j) if the candidate is unable to give his or her personal consent to participate in the clinical trial of the medicinal product, if not awareness, that is, incapable of judgment, this consent can be given by parents, guardians, legal representatives, the spouse and if the examiner considers that participation may benefit the respondent's well-being and interests; k) if the candidate is a blind person, a deaf person who cannot read, a dumb person who cannot write and a deaf person A person makes a statement about participation in a clinical trial in the presence of one witness. Article 15 (Requirements for clinical trial of a drug in minors) (1) If necessary and under special precautionary measures, clinical trials of the medicinal product may also be performed on persons up to 18 years of age who are ill or are in a condition for which the drug being tested is intended. (2) A clinical trial of a medicinal product involving juvenile subjects shall be conducted under the conditions prescribed by law and by this rulebook. (3) In addition to the conditions "referred to in paragraphs (1) and (2) of this Article", a clinical trial of a drug in a juvenile subject may be implement if: a) the parent or legal guardian has given written consent (the written consent must represent the presumed one the will of the minor and may be withdrawn at any time, without prejudice to the minor); b) the minor has received information in accordance with his or her ability to understand, by a person who has experience in work with minors related to the course of the clinical trial, the risks and health benefits respondents; c) written consent given without prompting him to participate in the clinical trial of the drug or offering it either any material stimulation or other benefits; d) the ethics committee has assessed that a clinical trial of the drug on a juvenile subject has a direct benefit for to a specific group of patients, and that such research is essential for the evaluation of clinical data by questioning individuals who are capable of giving their written consent; e) a positive decision to conduct a clinical trial of a drug in a healthcare facility was made by an ethics committee on the basis of Opinions of a specialist in pediatrics, with particular reference to clinical, ethical and psychosocial problems in conducting a clinical trial of a drug. (4) During the conduct of a clinical trial of a drug, an able-bodied juvenile shall form an opinion and evaluate it The information he has received about participating in a clinical trial may make the decision to take any at the time of withdrawal or withdrawal from the clinical trial of the drug, which shall be reported to the principal investigator or member research team. (5) The applicant / client is in the process of approving a clinical trial of a medicinal product intended for children obliged to submit to the Commission the positive opinion of the Entity Ministries of Health / Health and the Department of Health Brcko District. Article 16 (Specific requirements for clinical trial of an adult drug) (1) Clinical trial of a drug by an adult respondent who is unable to obtain legally valid informed consent (unconsciousness, limited physical or mental capacity, etc.), ie on adult respondent who did not refuse consent to participate in a clinical trial of a drug prior to the onset of its incapacity shall be subject to conditions prescribed by law and this regulation. (2) In addition to the conditions "referred to in paragraph (1) of this Article", a clinical trial of a medicinal product may also be conducted if: a) legal representative of an adult respondent who is unable to give legally valid informed consent in writing consent. The written consent of the sea represents the presumed desire of the respondent and can be withdrawn at any moment, without harm to him; b) an adult candidate who is unable to give written consent has received information to the best of his or her ability to understand, by a person who has experience in working with such persons, relating to the course of the clinical examinations, risk and health benefits of respondents; c) written consent given without prompting him to participate in the clinical trial of the drug or offering it either what material or other uses; d) it is estimated that a clinical trial of the medicinal product on that face provides direct benefit to a group of patients whose illness or condition corresponds to illness or condition of the subjects; e) a positive decision to conduct a clinical trial of a drug in a healthcare facility was made by an ethics committee on the basis of the opinion of a specialist doctor for a particular area or condition of the subjects, or for the population of patients to whom clinical trial of the drug relates, with particular reference to clinical, ethical and psycho-social problems in implementation clinical trial of the drug. (3) During the conduct of the clinical trial of a medicinal product, an adult who is unable to provide an informed written person consent, which is able to form an opinion and evaluate the information it has received about participating in the clinical drug test, can be withdrawn at any time, or waived the clinical drug test, of which informs the principal investigator or member of the research team. Article 17 (Respondent's health care) The respondent must be provided with adequate health care for the duration of the examination. Health care must also be ensured after examination in a period that depends on the nature of the disease, the manner of testing and the tests done interventions. Article 18 (Clinical trial site and staff) (1) The clinical trial shall be conducted under conditions that guarantee the safety of the subjects. (2) The choice of clinical trial site depends on the degree of product development and the associated potential risks. (3) In the case of clinical trials aimed at entering the genome of subjects for exercise pharmacogenomic and pharmacogenetic knowledge, the same can only be carried out if the required samples and data are provided anonymity or anonymity. (4) The clinical trial site must have adequate personnel, facilities and equipment, including laboratories. (5) In the composition of the research team in the clinical trial of the medicinal product being carried out in the healthcare institution providing it secondary or tertiary health care must be included by a medical doctor-specialist in clinical pharmacology, when the first phase of clinical trial of the drug is being conducted. (6) In certain parts of the clinical trial of the medicinal product, in addition to the medical doctor and the doctor of dentistry, these include professionals with other relevant education (pharmacists, specialists) medical biochemists or clinical biochemists, statisticians, nurses, health technicians, and Dr.). Article 19 (Multicenter drug test) (1) In the case of a multicenter trial, the study of the drug shall be carried out simultaneously with several examiners, at different sites, based on the same clinical trial protocol. (2) Multicenter testing "referred to in paragraph (1) of this Article" requires a special administrative system whose form depends of the number of study sites, test endpoints, and available information on the drug being tested. (3) The multicenter examination protocol shall describe the functions, responsibilities, rights and obligations of all participants in the clinical trial procedure. (4) In the case of multicenter examination, it is permissible to establish a coordinating committee or coordinator s responsibility for overseeing the practical conduct and progress of testing and maintaining contacts with the Agency, a professional the institution where the clinical trial is being conducted, as well as other competent authorities in this field. Article 20 (Notification of clinical trial) The test proponent should regularly inform the Agency and the authorized institution where the flow test is being conducted and the results of the trial, at the conclusion of each phase of the clinical trial. Article 21 (Suspension and prohibition of clinical trial of the drug) (1) While conducting a clinical trial, the Agency may suspend or suspend a clinical trial at in the following cases: a) if it finds that the conditions laid down in the law, in this regulation or in the application for a permit have not been fulfilled, that is, a license to conduct a clinical trial of the drug b) if required by the safety of the subjects or the protection of health; c) if the principal investigator, sub-investigators or any other person involved in the approved clinical trials does not meet regulatory obligations and are not governed by good clinical practice; d) upon the final and enforcement decision of the pharmaceutical inspector. (2) The Agency shall issue a decision on the suspension or prohibition of further clinical trials the opinion of the Commission obtained. The decision "referred to in paragraph (2) of this Article" is finally in administrative procedure. Article 22 (Explanation of early completion of clinical trial and final report) (1) If the clinical trial of the drug is completed before the expiration of the time specified in the clinical trial protocol, the examiner must provide a justification for the early completion of the examination to the Agency and the professional institution where it is performed clinical trial. (2) Upon completion of the examination, a final report shall be prepared. The report "referred to in paragraph (2) of this Article", as correct the indicated end date of the clinical trial must be signed by the lead examiner and submitted to the Agency and the professional the institution where the clinical trial is being conducted. Article 23 (Contents of final report) (1) The final report on the clinical trial of the medicinal product shall contain: a) general information, b) the protocol, phases and standard operating procedures for conducting the technical trial according to Good Clinical Practice; c) test results including: 1. clinical pharmacology (pharmacodynamics, pharmacokinetics, interactions), 2. bioavailability / bioequivalence, 3. clinical efficacy and safety, 4. information on the use of the medicine in countries where it is authorized. (2) The contents of the form for the final report on the implementation of the clinical trial of the medicinal product are laid down in Annex No. IV and It shall form an integral part of this Regulation. CHAPTER II - OBLIGATIONS OF PARTICIPANTS IN THE CLINICAL TESTING OF MEDICINES AND DOCUMENTATION Article 24 (Obligations of test proponent) The test proponent is obliged to: a) make the choice of examiner taking into account the location of the examination, the equipment and the credibility of the qualifications the examiner and the duration of the examination; b) inform the examiner of the chemical, pharmaceutical, toxicological, pharmacological and clinical information on the medicinal product (including previous and concurrent tests) in accordance with the nature, scope and duration of the tests as a prerequisite for test planning, and provide the examiner with all relevant new information and drug information that emerges during testing; c) submit a request with all the necessary documents to the professional institution where the clinical trial of the medicinal product is performed; d) to provide and deliver appropriately labeled and appropriately coded medicines for testing prepared in accordance with principles of Good Manufacturing Practice and properly packaged in such a way as to protect the product from damage, provided that it is process blindness ensured; e) keep sufficient samples of each batch and data on the analysis and characteristics of the product under test so that they can be re-examined if necessary by an independent laboratory; f) provide the examiner with the opportunity to establish in his institution a system for proper and safe handling, storage, privacy, return and destruction of the investigational medicinal product, and appoints a responsible person to perform these affairs; g) determine and provide training for the competent observer; h) designate persons to supervise the process and to verify the statistical processing and write the test report; i) to consider with the examiner without delay all side effects and take appropriate safety measures to submit the report of adverse reaction to the Agency; j) ensure that a full final test report is prepared; k) provide adequate compensation for the treatment or treatment for the subjects in case of damage or death related to the examination except for those resulting from malpractice or negligence. Article 25 (Special obligations of test proponent) (1) In addition to the obligations "referred to in Article 24 of this Ordinance", the testing proponent shall be obliged to secure the supply of the medicinal product for test (test product or reference product, including placebo) so that they are appropriate quality and undergo quality assurance procedures. (2) The manner in which the test proponent supplies the examiner with the drugs under examination shall be described in the clinical trial protocol. (3) The proposer of the test shall supply the examiner with the drug when he has obtained the necessary clinical trial permit from Import Agencies and Consents by the Entity Ministries of Health. (4) The proponent of the test shall, when delivering the medicines "referred to in paragraph (3) of this Article," submit it to the examiner and written instructions on how to handle and store these medicines, as well as instructions on how to handle what they will after the test possibly remaining unused. (5) The proponent of the examination shall be obliged to draw up the delivery of medicines as well as the written instructions "from paragraph (4) of this Article" a written statement. (6) The test proponent must ensure the stability of the investigational medicinal product as well as its regular supply throughout the examination. (7) The proponent of the test shall be obliged to describe in detail the manner in which the investigational medicinal product will be labeled, deliver, distribute and store. (8) The notes must contain information on the transport, shipment, receipt, distribution, return and destruction of each of the remaining drug. The examiner must not administer the medication being tested to any person not designated to receive it. (9) The test proponent shall be responsible for the proper packaging and labeling of the investigational medicinal products. The mark must indicate that the product is for clinical trial use only. (10) In blind tests, the packaging must be labeled in such a way as to prevent identification. U emergency situations must be able to determine the identity of current treatment received by a particular respondent. (11) In blind studies, the drug to be tested, including the control drug and placebo, must be of equal value. appearance, taste, smell and other physical characteristics. (12) It is the responsibility of the test proponent to ensure that the packaging of the investigational medicinal product is of appropriate dimensions for testing and appropriate for the respondents and is required to provide sufficient samples of each batch used for the sake of needs for re-analysis and control in the future. (13) Should the formulation of the control drug change, the need for comparative in vivo biological consideration should be considered tests and test dissolution or other in vitro tests. Article 26 (Clinical Trial Observer) (1) The competent observer shall be determined by the contracting authority with the consent of the examiner. The number of competent observers depends on the complexity of drug testing and the number of participating centers. The competent observer must be available to the examiner. (2) The primary obligation of the competent observer is to supervise the conduct of the test and to ensure that it is conducted in accordance with that test protocol. (3) Any unjustified deviation from the test protocol and any violation of Good Clinical Practice by a competent observer must, without delay, inform the investigator, the Agency and the professional institution where the clinical is performed examination. Article 27 (Special Obligations of Clinical Trial Observer) (1) In addition to the basic obligation "referred to in Article 26 of this Ordinance", the competent observer shall also have the obligation: a) supervise the implementation of the test protocol and ensure that all test data is kept orderly and complete recorded; b) determine whether adequate space, personnel and equipment, laboratories, and assess the availability of an adequate number of subjects during the examination; c) ensure that staff assisting the examiner in the examination are informed of the examination and that all details are respected testing; d) ensure liaison between the examiner and the proposer of the test during the conduct of the test; e) ensure that the test lists of respondents are filled in correctly; f) examine whether the supplies, distribution and refund of the investigational medicinal product have been secured and documented at appropriate manner in accordance with regulations; g) submit a written report to the examiner after each visit and every other contact with the examiner. (2) During the visit to the examiner, the competent observer must check: a) whether the test drug is used solely for the purposes specified in the clinical trial protocol; b) that there is information on the quantities of the drug being tested; b. c) storage conditions of the investigational medicinal product; d) treatment with returned or unused drug. Article 28 (Side effects, side effects and adverse events during clinical trial of the drug) (1) The occurrence of any undesirable effect, adverse reaction or adverse event of a did drug must be taken carefully monitor and record in detail throughout the examination. (2) The clinical trial protocol shall specify the method by which adverse reactions, adverse reactions or adverse events "referred to in paragraph (1) of this Article". (3) The investigator shall make available to the Agency questionnaires for reporting adverse reactions. (4) The client must report all adverse reactions to the Agency and the ethical committee of the institution where the clinical is performed. examination. (5) The reports "referred to in paragraph (4) of this Article” must contain evaluations of causation and possible impact on the examination and future use of the product being tested, as well as the identification of the subjects and methods of testing. (6) Upon completion of the study, any recorded adverse reactions of did drug or medical devices must be determined and evaluated in the final report. (7) The contracting authority shall, without delay, inform the examiner of any trial of the same medicinal product, anywhere and discontinued at any time, as well as withdrawal of that medicine for lack of safety. Article 29 (Notes and information during the clinical trial of the medicine) (1) The purpose of keeping notes in the drug test procedure is to register information, transfer information, effective and proper modification of information obtained from respondents into data that can be used in the report.Svi test procedures must be documented. (2) The basic feature of the uniqueness of the data is to ensure a "blind" test with respect to species determination treatment, which begins with the randomization of subjects into different groups and is maintained throughout the data processing until the decision to open the code is made. (3) In the case of electronic data processing, the confidentiality of the database must be specifically ensured as well as its accuracy. Article 30 (Method and time limit for keeping clinical trial records) (1) The contracting authority shall ensure that the respondents' identification codes are archived for security reasons and efficiency. (2) The contracting authority shall take appropriate measures to keep the other documentation relating to examination. (3) The information "referred to in paragraph (2) of this Article" may be stored on a microfilm or electronically, provided that there is a copy on paper. (4) The trial contracting authority must keep the clinical trial protocol, documentation, permit and all other documents concerning the tests, including certificates on how to perform the procedures 5 years after the end of the clinical trials, that is, even after the said deadline, if other applicable criteria or agreements between the contracting authorities so require examiners and examiners. Article 31 (Examiner's obligations) (1) The examiner shall be responsible for strictly implementing the clinical trial protocol as follows: a) The examiner may not make any changes to the approved test except in the case of a direct procedure if necessary to eliminate the obvious imminent risk or danger to the respondents by obligatory notifying the Agency thereof; b) in the case of annexes to the clinical trial protocol, the prior approval of the Commission shall be obtained; c) the form of the annexes to the protocol related to the conduct of the clinical trial of the medicinal product has the prescribed contents in Annex no. (III) and is an integral part of this Regulation; d) the examiner must provide appropriate information to the subjects in the clinical trial and comply with the provisions The Declaration of Helsinki and the International Ethical Guidelines for Human Biomedical Testing; e) The nature of the information to be communicated to the subjects depends on the complexity of the clinical trial and the type of drug being examined; f) the information "referred to in point e) of this paragraph" shall, as a rule, be given both verbally and in writing and in a language which is understandable to the respondent; g) the examiner is obliged to inform the subjects about their participation in the clinical trial, to mark the persons from whom may request assistance in an emergency, and alert to the need to keep the said information with them; h) the examiner must be aware of the properties and effects, including information obtained prior to the clinical trial, o the product being tested clinically; i) the examiner must be aware of all relevant new product information that appears during the clinical course testing; j) in the case of a serious undesirable effect, the examiner must inform the proposer of the test without delay, the professional institution where the clinical trial is conducted and through the applicant the Agency; k) the examiner must be available at periodic visits by the competent observer and during the supervision the pharmaceutical inspector as well as the persons designated by the test proponent for quality assurance. (2) The examiner must ensure that: a) safe treatment with the medicinal product being tested during and after the test; b) that the investigational medicinal product is used only in accordance with the clinical trial protocol and is being tested include respondents who are responsible to the examiner; c) the dose and instructions for use are appropriate and understood by each subject; d) that the unused drug under test be returned or destroyed and the notes made on it keep activities according to the test protocol. Article 32 (Obligations of the contracting authority) (1) The contracting authority shall be responsible for the implementation of the quality assurance system with regard to site verification the conduct of the examination, all data and records relating thereto. (2) All observations and findings must be available for verification to ensure the credibility of all information, and that the conclusions drawn from the processing of the raw data obtained are correct. (3) Verification procedures must be justified and specified. (4) Sampling should be controlled by a statistically acceptable method of verification in testing. (5) Quality control must be applied at every stage of data processing, to ensure that all data be safe and properly handled. PART THREE - CLINICAL TESTING OF MEDICAL AGENT Article 33 (Purpose of clinical trial of medical device) Testing of a medical device is performed to determine or confirm its effectiveness, safety and quality, in agreement declared use specified by the manufacturer. Article 34 (Medical drug classes and clinical trial) (1) A clinical trial of a medical device is the determination or confirmation of the safety of a medical device, its effectiveness and compliance with the general and specific requirements as specified by the manufacturer. (2) A clinical trial shall be conducted for a Class IIa, IIb and Class III medical device, until a Class I medical device, except for a medical device that is sterile or that contains a radiation source. (3) For the clinical trial "referred to in paragraph (2) of this Article", the license shall be issued by the Agency. (4) The clinical trial procedure of a medical device must correspond to current scientific and technical achievements and principles of good clinical practice in clinical trial and medical ethics. Clinical trial results must capture the results of all available clinical trials of the medical device, whether positive or negative. (5) The documentation of the clinical trial of a medical device must include the test results that are detailed and objectively described and available to enable an objective assessment of the benefit-risk relationship for the patient an assessment of its safety, efficacy and an opinion on whether the medical device is general and specific the requirements of the Act and the purpose specified by the manufacturer. Article 35 (Contents of clinical trial requirements for medical devices) (1) The following must be attached to the application for authorization to conduct a clinical trial of a medical device the documentation referred to in Annex number (V) which forms an integral part of this Regulation: a) the clinical trial plan, which contains the objectives, methods, control system, organization and statistical method processing; b) proof of insurance in the event of possible damage to the person or persons under examination or participants tests resulting from testing; c) written consent of the respondents; d) a report on the harmful or undesirable effects of the medical device so far (if any); e) an excerpt from the medical examination plan in official languages; f) information on the medical device: name, type, model, designation, size; g) documentation relating to input materials; h) documentation relating to the manufacturing process of the medical device; i) documentation relating to the final product in relation to its intended use and risk; j) the proposal for the labeling of the medical device and the package leaflet; k) documentation or confirmation of compliance with general and specific requirements; l) documentation of clinical trials to date (if any); m) a brief biography of the principal investigator; n) proof of payment of costs for the application and authorization of the clinical trial. (2) The Agency may require additional documentation if it concerns the preservation of public health. Article 36 (Competence of the Agency) (1) If the applicant for a clinical trial of a medical device does not receive a negative response from the Agency Within 30 days from the date of submission of the request, it shall be deemed that the clinical trial of the medical device may commence. (2) If the clinical trial is refused, the Agency shall be obliged not later than 30 days from the receipt of the complete to request a permit for clinical trial of a medical device to make a decision with the justified reasons why the request is denied. The decision is finally in administrative procedure and no appeal is allowed, but it can be initiated administrative dispute before a competent court. (3) The time limit referred to in "paragraph (2) of this Article" shall expire on the day on which the Agency submits the applicant for clinical trial request the necessary additional information or explanations and the interruption of the deadline will continue until the request of the Agency is fulfilled. (4) For the purpose of protecting the health of the population, the Agency may determine the temporary or permanent termination of a clinical trial. (5) The Agency may determine the supervision of the conduct of the clinical trial of the medical device and the observance of the principles good practice in clinical trial in accordance with the Law. Article 37 (Conditions for clinical testing of a medicinal product by specific persons) (1) A clinical trial of a medical device may be performed only with the written consent-consent of the person on whom the test is performed. (2) Clinical testing of a medical device on children may be performed only if the examination in adults is personal can provide appropriate results. (3) In exceptional cases, for a person who is not conscious, with severe mental disability, for a business incapable person or a minor, written consent is given by the legal representative or legal guardian of the person. (4) A clinical trial must not be performed if the potential risk of using a medical device is greater than the health justification for testing the medical device, as assessed by the Commission or the Director of the Agency. (5) Clinical trials should not be carried out on prisoners and on persons who may be influenced by coercion consent to participate in a clinical trial of a medical device. Article 38 (Costs and persons authorized to report clinical trial of medical device) (1) Prior to the commencement of the clinical trial of a medical device in the territory of BiH, the intended clinical trial the medical device must be reported to the Agency. (2) The applicant for the clinical trial of a medical device may be a sponsor, manufacturer or importer or on his behalf the principal investigator of a clinical trial of a medical device. (3) It shall bear the costs of the clinical trial and consideration of the application of the clinical trial of the medical device the applicant for the clinical trial. (4) Agency or Entity Ministries of Health or Department of Health of the Brcko District, other state or the entity ministry or other legal entity may require a clinical trial of the medical device for use protection of population health. (5) The costs of testing shall be borne by the proponent of the clinical trial only if it is demonstrated that the safety is effective and the compliance of the medical device with the general and special requirements is in accordance with the provisions of the Act and the regulations adopted on based on it. (6) If it is proved that the safety, efficacy and compliance of the medical device with the general and specific requirements do not in accordance with the provisions of the Act and the regulations adopted thereunder, the costs of the clinical trial shall be borne by the manufacturer that is, the importer of the medical device. Article 39 (Changes, final report and notification of clinical trial of medical device) (1) The manufacturer shall submit to the Agency any amendments or modifications to an already approved medical test plan funds. (2) The report signed by the principal investigator must contain a critical appraisal of all information obtained and collected during the clinical trial of the medical device. (3) The applicant for the clinical trial request shall notify the competent authorities of the Member States concerned of the completion of the clinical trial of the medical device, and in the event of early termination, the notification must be followed by reasoning. PART FOUR - TRANSITIONAL AND FINAL PROVISIONS Article 40 (Amendments to the Rules) Amendments to this Ordinance shall be made in the manner and by the procedure for its adoption. Article 41 (Termination of regulations) With the entry into force of this Rulebook, the Rulebook on Good Clinical Practice and Clinical Trials ("Official Gazette of the Federation of Bosnia and Herzegovina", No. 61/04), Rulebook on Amendments to the Rulebook on Good Clinical Practice and clinical trials of the medicinal product (Official Gazette of the Federation of Bosnia and Herzegovina, No. 56/05), Rulebook on Clinical drug testing ("Official Gazette of the Republika Srpska", no. 64/05) and Rulebook on Amendments to the Rulebook on clinical trial of the medicinal product (Official Gazette of the Republika Srpska, No. 23/07). Article 42 (Entry into Force and Publication) This Rulebook shall enter into force on the day of its adoption and shall be published in the Official Gazette of BiH. No. 08-02-2-1172-2-JD / 09 December 10, 2009 Minister Mr. Sredoje Novic, s. r. Annex (1) Medicines Agency of Bosnia and Herzegovina Address: Veljka Mlađenovića b.b. ; 78000 Banja Luka, Bosnia and Herzegovina, Phones: +387 (0) 51 456040; +387 (0) 51 456050 Fax +387 (0) 51 450301; E-mail: klinicka@alims.gov.ba Number: Received by: Date of receipt: Request date with additional documentation: Date of receipt of additional documentation: Date when the request is formally complete: To be completed by the Medicines Agency of Bosnia and Herzegovina APPLICATION FOR A CLINICAL TESTING AUTHORIZATION / CLINICAL TEST APPLICATION Request for Clinical Trial Authorization Application for Clinical Trial Test Name: Clinical trial plan (protocol) number, including number of amendments, if required: Proposer (name, address): Applicant, authorized by the contracting authority to cooperate with the Agency during the examination, if not ordering authority (name, address): Contact address (name, address, telephone, fax, e-mail): Applicant: test proponent Test drug, name, form (s) of drug, strength (s) contract research organization examiner Drug manufacturer (name, address): Medication registered in BiH: yes License number: no Marketing Authorization Holder (name, address): The approval procedure in Bosnia and Herzegovina is ongoing: yes Number of requests: no The drug has been tested in Bosnia and Herzegovina: Registered in other countries Study number and date licensing: no Country, year and approval number: Yes no Shelf life: Storage conditions: Method of administration: Dosage in clinical trial: Active substance (s), name (for radiopharmaceuticals - radionuclide): Substance contained in a drug already registered in the world: no yes Countries where it is registered and year of registration: Active substance manufacturer (name, address): Amount of active substance per unit dosage unit, per unit volume or per unit mass: the drug in question contains more active substances: yes Type of medicine: no Specify total number: Radiopharmaceutical drug Drug containing synthetic active substance Herbal drug A drug for dental use A drug containing a narcotic or psychotropic substance Other medicines intended for use in testing Name of the drug, form (s), strength (s): Immunological Drug Blood Derivative Biotechnological Drug Others Specify: Yes no Drug manufacturer (name, address): Medication registered in BiH: no yes License number: Holder of Marketing Authorization (name, address): The procedure for issuing a license in BiH is to: no Number of requests: The drug has been tested in Bosnia and Herzegovina: The medicine is registered in another country: Expiration date: Method of administration: yes Study number and date no license: yes Earth, year and number do not allow: Storage conditions: Dosage in clinical trial: Active substance (s), name (for radiopharmaceuticals - radionuclide) Substance contained in a drug already registered in the world: no yes Countries where the medicine is registered, Registration year: Active substance manufacturer (name, address): Amount of active substance per unit dosage unit, per unit volume or per unit mass: The drug contains several active substances: yes Specify total number: no Comparative administration of another, registered medicinal product is permitted as standard for therapy: no Testing characteristics: Main Test Objective: Other Objectives: Therapeutic area: Cardiovascular CNS Respiratory Antiinfective Oncology Gastrointestinal Endocrinology Dermatology Others Test Phases: I II III IV Bioequivalence Test Types of testing: New indications Pharmacokinetic studies Dose determination New group patients New drug combination New pharmaceutical shape Increase the number of respondents Second tests Post-marketing testing Specify: If therapeutic effect is tested, provide indications: Test mode: Randomized Cross-Comparative Placebo Controlled Open Other Respondents: Single blind Specify: Healthy volunteers Double blind Patients Double dummy Number of patients: Total in all centers Total in BiH: Total number of respondents: Total number of respondents in BiH Single-center testing In multiple centers in BiH International multicenter in countries: Duration of drug administration: Single dose Repeated dose Specify number of days: Sunday: month: The period of thought after last take of the drug no yes Estimated test duration: Specify the monitoring period: Patient Involvement Criterion: Gender: Age: Disease: Institution at which the examination is carried out Name: Address (including postcode): Name of examiner: Laboratory tests shall be carried out in the laboratories of the institutions where the tests are carried out that not only in some Names and addresses of laboratories not part of the testing institutions Test quality control: yes no Monitor Oditor Other Specify: Indicative starting date of the test: The test is related to obtaining a marketing authorization in BiH: yes Clinical trial is already approved in other countries: yes country, license number, date of issue: ,, Clinical trial of the active substance Reported in BiH yes no Rejected in BiH yes Submitted documentation Part / page: from to Clinical trial protocol Documentation of the investigational medicinal product no no no Part / Side: from-to Researcher brochure / summary of product characteristics Sample Test List Ethics Committee (s) approval Statement of the Professional Collegium / Institution Director GMP certificate Biography of Principal Investigator Proof of Paid Compensation Other documents Number of pages added by the applicant due to lack of space on the form: I declare that the information in the request and the supporting documentation is true and that no important fact that may affect the safety of the participants in the examination and the credibility of the conclusions are not hidden. Name and surname of the responsible person Date Signature of responsible person Appendix to Annex (I) Guidance for Applicants for Clinical Trial Authorization / Application for a Clinical Trial The application for a clinical trial license shall be submitted for each clinical trial of the unlicensed medicinal product for the marketing of the medicinal product in Bosnia and Herzegovina (clinical trial: Phase I - III and bioequivalence testing); the application for a clinical trial shall be submitted in the case of a medicinal product authorized to be placed on the market traffic in Bosnia and Herzegovina, when the drug is used in accordance with the marketing authorization traffic in Bosnia and Herzegovina, e.g. in accordance with the approved summary of product characteristics. Form to apply must be typed on a typewriter or computer. In the event that in any part of the form does not have enough space for data, additional pages are used, which become an integral part of the form with note that there is an add-on for the part in question. Documentation references are not recommended. 1) List all drug forms and all potencies of the investigational medicinal product to be used in the clinical setting in Bosnia and Herzegovina. Strength indicates the amount of active substance per unit of individual dosage, per unit volume or per unit mass and this is indicated if the drug contains one active substance. In case the active substance is in the form of salts, hydrates, etc. it must be clarified whether strength refers to the whole molecule of the substance or only its active part. 2) Indicate if the medicinal product has a marketing authorization in Bosnia and Herzegovina. 3) If there are multiple forms or strengths of the medicinal product used in the clinical trial, provide information for each shape and strength. 4) In the case of medicinal products not authorized for marketing in Bosnia and Herzegovina, state the proposed deadline of use. 5) In the case where there are several forms of medicine or more ways of administration of the drug, provide all the necessary information. 6) Where the active substance is in the form of salts, hydrates, etc., it must be clearly stated whether the amount refers to the whole molecule of the substance or only its active part. 7) If the medicinal product contains more than one active substance, list all active substances on the additional page with all information as well as for the first active substance. 8) Narcotics and Psychotropic Substances are the substances listed in the Narcotics Production and Trafficking Act establishing a list of narcotic drugs. 9) List the medicines to be used in the trial in Bosnia and Herzegovina and which are explicitly stated in the plan (protocol) testing, e.g. comparative drugs or drugs specifically suggested for basic or auxiliary use treatment. If more than one medication is available, an additional side is used, which becomes an integral part of the claim. 10) List all drug forms and all strengths of the drug to be used in the trial in Bosnia and Herzegovina. 11) If the test cannot be classified into just one of the stages, indicate that it has multiple options or list them. 12) Tests are classified in Phase IV if the drug has been used in accordance with an approved summary of the main characteristics of the drug. Tests exploring new indications, new modes of administration, new fixed ones combinations, trials with much higher doses than previously approved and trials that are funnels on patient groups not previously approved are not considered for phase IV trials. 13) Multiple types of testing can be characterized. 14) In the case of large-scale trials, indicate approximately the number of respondents. 15) List all the institutions where the examination is being conducted in Bosnia and Herzegovina. In case of space shortage, state this on the additional page that becomes an integral part of the request. 16) In the case of multiple examiners, indicate the lead examiner responsible for conducting the test. 17) The laboratory testing facility is considered to be part of the facility where it is conducted examination of the drug in case it is within the same health institution and is at the same address perform all biochemical and haematological tests, and determine plasma drug levels or drug concentrations in urine, feces, etc. 18) Indicate if the same clinical trial, or trial of the same drug or the same active substance was approved. 19) Mark those parts of the documentation that are submitted with the application. 20) In accordance with the Clinical Trial Regulations, the applicant is required to reimburse all costs of the evaluation clinical trial permit applications or clinical trial application costs at filing a claim. The amount to be paid and the payment procedure will subsequently be determined and invoiced to the applicant. Annex (II) MODEL OF THE CLINICAL TESTING PROTOCOL The clinical trial plan (protocol) must include the following: 1. Name and justification for conducting the test; 2. The meaning, purpose and purpose of the examination; 3. Venue of the test, name and address of the test client; 4. Name, address and qualifications of each examiner; 5. Description of the type of test; 6. Ethical side examination and measures to ensure ethical aspects (interviewee consent); 7. Description of the respondents. Criteria for inclusion and non-inclusion of potential respondents and how they are collected, types, methods and time of assignment of respondents. Exclusion criteria for previously included respondents; 8. Number of respondents required to achieve the objective of the examination based on statistical considerations; 9. Description and justification of the route of administration, the dose, the interval between doses and the period of administration of the investigational medicinal product and that used as a control; 10. Any other treatment that may or may be used at the same time as the treatment testing; 11. Clinical and laboratory tests during the course of pharmacokinetic analysis and others which are approved during the study plan (protocol) tests must be carried out; 12. Description of how the reactions to the administration of the drug will be recorded. Description and evaluation of measurement methods, measurement time, method monitoring; 13. Instructions for completing the whole or part of the test; 14. Methods of registering and reporting adverse events, adverse reactions and adverse events. Procedure in case of complications; 15. Method of archiving the list of subjects with the codes of the subjects, data on the use of the drug, the list of randomization and / or the test list. The records must allow for easy identification of individual respondents or participants as well as surveillance data and reconstruction (data); 16. Information on the test code of where it will be archived and when, how and by whom in case of emergency open; 17. Measures to be taken to ensure the safe handling and storage of pharmaceutical products and measures to ensure encourage and control adherence to all clinical trial guidelines; 18. Description of methodology and evaluation of results (eg statistical methods) as well as description of patients / participants who have dropped out testing 19. Time until completion of examination; 20. Information to be provided to the respondents including information on how they will be notified of the examination and how and where will give consent; 21. Instructions for persons, e.g. how the persons will be informed of the manner in which the examination will be conducted and its application; 22. Definition of medical care for the subjects after the examination including the method of treatment; 23. Data on financing, insurance, liability and transfer / distribution of responsibilities; 24. List of references referred to in the test plan. Annex (III) Medicines Agency of Bosnia and Herzegovina Address: Veljka Mlađenovića b.b. ; 78000 Banja Luka, Bosnia and Herzegovina, Phones: +387 (0) 51 456040; +387 (0) 51 456050 Fax +387 (0) 51 450301; E-mail: klinicka@alims.gov.ba Number: Received by: Date of receipt: Request date with additional documentation: Date of receipt of additional documentation: Date when the request is formally complete: To be completed by the Medicines Agency of Bosnia and Herzegovina APPLICATION FOR AUTHORIZATION FOR AMENDMENT OF THE CLINICAL TEST Amendments to the clinical trial plan (protocol) Amendments to the original clinical trial request Test Name: Clinical trial plan (protocol) number, including number of amendments, if required: Proposer (name, address): Applicant, authorized by the proponent of the examination to cooperate with the Agency during the examination, if not ordering authority (name, address): Contact address (name, address, telephone, fax, e-mail): Applicant: trial proponent Type of clinical trial modification contract research organization examiner These amendments mainly relate to the precautionary measures already in place that do not clinical trial amendments: Changes made in the safety and integrity of the respondents yes no Changes made in the interpretation of the professional documentation / test results yes no Changes made in the quality of the investigated medical product yes no Changes in the management or management of the clinical trial: Amendments or inclusion of additional examination site, change of principal examiner yes no Changes to the trial client, legal representative, applicant for the clinical trial Yes no Changes in the Transfer of Major Assignments and Obligations in the Clinical Trial Not to Specify: Other changes Yes no Specify: Second: Yes no Specify: Content of clinical trial amendments: Amendments to the information provided in the clinical trial request yes no additions to the clinical trial plan (protocol) yes no Amendments to other documents Yes no Specify: Second: Yes no Specify: Reasons for amendments: Short description of the amendments: Submitted documentation Part / page: from to Proof of Paid List of Changed Documents Part / Side: from-to Review proposed changes Other documents Supporting documentation I declare that the information in the request and the supporting documentation is true and that no important fact that may affect the safety of the participants in the examination and the credibility of the conclusions are not hidden. Name and surname of the responsible person Date Signature of responsible person Annex (IV) Medicines Agency of Bosnia and Herzegovina Address: Veljka Mlađenovića b.b. ; 78000 Banja Luka, Bosnia and Herzegovina, Phones: +387 (0) 51 456040; +387 (0) 51 456050 Fax +387 (0) 51 450301; E-mail: klinicka@alims.gov.ba Number: Received by: Date of receipt: Request date with additional documentation: Date of receipt of additional documentation: Date when the request is formally complete: To be completed by the Medicines Agency of Bosnia and Herzegovina CLINICAL TEST COMPLETION NOTICE Test Name: Clinical trial plan (protocol) number, including number of amendments, if required: Proposer (name, address): Applicant, authorized by the proponent of the examination to cooperate with the Agency during the examination, if not ordering authority (name, address): Contact address (name, address, telephone, fax, e-mail): Applicant: proponent of the examination Completion of examination contract research organization examiner Completion of examination in Bosnia and Herzegovina yes no Date:. . .year. Completion of testing in all countries where the test was conducted yes no Date:. . .year. Premature examination completed yes Suspension yes Reason for provisionally ending the test: Security yes Inefficiency yes Testing not started yes Second yes no Date:. . .year. no Date:. . .year. no no no no Specify: Number of subjects still receiving therapy at the time of discontinuation or suspension of a clinical trial at Bosnia and Herzegovina In case of interruption of the clinical trial or its early termination, briefly describe in the Appendix: - justification for termination or early termination of the examination - the proposed treatment of subjects receiving therapy at the time of early termination or suspension - the consequences of prematurely discontinuing the trial to evaluate the results and analyze the benefit-risk balance of the test drug I declare that the information given in the notice is correct and that clinical trial reports will be submitted The Agency and the responsible ethics committee within 90 days of the completion of the examination in all countries in which it was conducted examination. Name and surname of the responsible person Date Signature of responsible person Annex (V) Medicines Agency of Bosnia and Herzegovina Address: Veljka Mlađenovića b.b. ; 78000 Banja Luka, Bosnia and Herzegovina, Phones: +387 (0) 51 456040; +387 (0) 51 456050 Fax +387 (0) 51 450301; E-mail: klinicka@alims.gov.ba Number: Received by: Date of receipt: Request date with additional documentation: Date of receipt of additional documentation: Date when the request is formally complete: To be completed by the Agency for Medicinal Products and Medical Devices of Bosnia and Herzegovina APPLICATION FOR A CLINICAL TESTING OF A MEDICAL MEDICINE / APPLICATION OF A CLINICAL TEST Request for Clinical Trial Authorization Application for Clinical Trial Test Name: Clinical trial plan (protocol) number, including number of amendments, if required: Investigator (name, address): Applicant, authorized by the contracting authority to cooperate with the Agency during the examination, if not ordering authority (name, address): Contact address (name, address, telephone, fax, e-mail): Applicant: Investigator contract research organization examiner Tested medical device, name, form (s) of medical device, packaging (s) Manufacturer of medical device (name, address): Medical device registered in BiH: yes Certificate number: no Holder of certificate for registration of the register of medical devices (name, address): The procedure for certification in Bosnia and Herzegovina is underway: yes Number of requests: no The medical device has been tested in BiH: Registered in other countries Study number and date yes licensing: no Country, year and certificate number: Yes no Shelf life: Storage conditions: Method of administration of medical device: Active substance (s), name (for medicinal products containing the medicinal product or medicinal substances): Amount of active substance per unit dosage unit, per unit volume or per unit mass: Countries where the medical device is registered and year of registration: no yes the medicinal product being tested contains more active substances: Type of medical device: Class I Class IIa Class IIb Class III In vitro diagnostic medical devices Medical Information: Name, type, model: Label, size, packaging: Proposal for the labeling of the medical device and instructions for use: Clinical trial plan: Yes no Specify the total number: Main objective of the test: Methods: Control system: Organization and method of statistical processing: Other goals: Types of testing: Specify: If therapeutic effect is tested, provide indications: Test mode: Respondents: Healthy volunteers Number of patients: Total number of respondents: Patients Total number of examinees in BiH One center testing In several centers in BiH International multicenter in countries: Length of administration of the tested medical device: Specify the monitoring period: Estimated test duration: Criteria for patient involvement: Gender: Age: Disease: Institution at which the examination is carried out Name: Address (including zip code): Name of researcher: Laboratory tests shall be carried out in the laboratories of the institutions where the tests are carried out that not only in some Names and addresses of laboratories not part of the testing institutions Test quality control: yes no Monitor Oditor Other Specify: Indicative starting date of the test: The examination is related to obtaining a certificate for entry in the medical registry funds in BiH: Yes no Clinical trial already approved in other countries: yes no Earth, license number, date of issue: ,, Certificate of Compliance with General and Specific Requirements Submitted documentation Part / page: from to Positive opinion of the Commission for Clinical Trials of BiH Proof of insurance in the event of damage to the person or persons under examination Respondent Information Form and Written Consent yes Proof of paid compensation Excerpt from medical device test plan Researcher's brochure / MS characteristics summary no Part / Side: from-to Report to date harmful or Documentation related to side effects MS input materials Documentation relating to the final product of MS regarding intent and risk Documentation related to the MS drafting process Biography of the principal investigator (s) Other documents I declare that the information given in the request and the supporting documentation is true and that no important fact exists may affect the safety of the test participants and the credibility of the conclusions is not hidden. Name, first name and title of the responsible person Date Signature of responsible person Number of pages added by the applicant due to lack of space on the form: Annex (VI) WORLD DOCTORS ASSOCIATION - DECLARATION OF HELSIN It contains recommendations for conducting biomedical research on humans It was adopted in Helsinki in June 1964. by the 18th World Medical Assembly (WMA), as amended on the 29th WMA meeting in October 1975 in Tokyo, the 35th WMA meeting in October 1983. in Venice, the 41st WMA meeting September 1989 in Hong Kong, the 48th WMA meeting in Somerset West, South Africa and the 52nd WMA meeting in Edinburgh 2000. Last clarification in Tokyo 2004. Introduction The task of physicians is to ensure the health of the people, their knowledge or awareness must be dedicated to accomplishing that task. The Geneva Declaration of the World Association of Physicians obliges doctors in these words: "The health of my patients will be my first concern," and the International Medical Ethics Code says: "A doctor will only act in the interests of the patient when he provides medical assistance that can improve the physical and mental state of the patient. " The purpose of biomedical testing in humans must be to repair diagnostic, therapeutic and prophylactic activity and understanding of the etiology and pathogenesis of the disease. In today's medical practice, most diagnostic therapeutic and prophylactic procedures involve risk. That in particular biomedical testing. Medical progress is based on testing, which ultimately rests partly on human testing. In biomedical testing one should be aware of the basic difference between a medical trial with a diagnostic or therapeutic goal for the patient and medical examination where the primary goal is only scientific without containing direct diagnostic or therapeutic values ​​for the person who is the subject of the test. In conducting tests that may affect the environment and welfare of animals that are used for testing should be especially careful. Given that it is unusually important that the results of laboratory testing be applied to people for the improvement of knowledge and assistance to humanity suffering from the World Association of Physicians has prepared the following recommendations as guidelines to every physician in biomedical testing on humans. Recommendations should be constantly refined. It has to emphasize that these standards must only serve as a guide for the world's physicians. Their doctors are not exempt from criminal, civil or ethical liability within the law of their countries. I Basic principles 1. Biomedical testing on humans must be in accordance with generally accepted scientific principles and must be be based on appropriate laboratory and animal testing and good testing knowledge of scientific literature. 2. The design and conduct of any human test must be clearly formulated in a test plan to be subjected to analysis, discussion and guidance by a specially appointed commissioner independent of the examiner with provided that such an independent commission complies with the laws and regulations of the country where the examination is being conducted. 3. Biomedical testing on humans must only be carried out by scientifically qualified personnel and under clinical supervision competent medical professional. Responsibility for the respondent must always lie with the medically qualified person, never to the respondent even though he gave his consent. 4. Medical testing on humans should not be conducted until the importance of its goal is proportionate to the danger to respondents. 5. Each biomedical human test must be preceded by an assessment of foreseeable hazards giving birth with predictable benefits to the respondent or others. Respondent care must always take priority over interests of science and society. 6. The right of the respondent to protect his or her integrity must always be respected. Every precaution should be taken for protecting the subject and reducing the impact of the examination on his physical and mental integrity and his personality in as a whole. 7. Doctors are not allowed to undertake scientific projects on humans until they are convinced that they can be trusted predictability of possible risks. Doctors must stop any testing if the dangers are found to be greater than potential benefits. 8. When publishing the results of their examination, doctors are obliged to respect the accuracy of the results. Report on examination which does not comply with the principles of this declaration should not be accepted for publication. 9. In each human test, each individual respondent must be adequately informed of goals, methods, perceived benefit and potential testing risks as well as inconvenience which it may cause. The respondent should be informed of the freedom to withdraw from the examination and yes he comes out of questioning whenever he wants. Thereafter, the physician should be given the testimony freely given consent, preferably in writing. 10. When obtaining a test consent, the physician must be especially careful if the subject is dependent on it position or give consent under pressure. In this case, consent should be given to a physician who is not involved into the examination and which is completely independent. 11. If the respondent is not legally competent consent should be obtained from his legal representative in accordance with national legislation. Whenever a minor is in a position to give consent, it must be obtained with his consent legal representative. 12. The test plan must always include a statement of ethical elements and indicate that they are the principles of this declaration were respected. II Medical examination combined with professional supervision (clinical trial) 1. In treating a patient, the physician must be able to use new diagnostic and therapeutic measures, if any in his view, they offer hope for saving lives, restoring health and reducing suffering. 2. The potential benefits, dangers and inconveniences of the new method must be weighed against the benefits the best standard diagnostic and therapeutic methods. 3. In each clinical study, each patient, including one in the control group, should have, if available, the best, most proven diagnostic and therapeutic method available. That, in cases where there is no proven diagnostic or therapeutic methods, does not exclude the use of placebo. 4. A patient's refusal to participate in the examination should never affect his or her relationship with the physician. 5. If the doctor deems it necessary not to obtain consent, the specific reasons for this must be stated in the plan (protocol) tests, to be submitted to an independent representative. 6. The physician may combine medical examination with professional supervision in order to acquire new medical knowledge only to the extent that the test is justified in terms of its potential diagnostic or therapeutic values ​​for the patient. III Non-therapeutic biomedical testing in humans (non-clinical biomedical testing) 1. In the purely scientific application of medical examination to humans, it is the duty of the physician to remain a protector the life and health of the person to be tested. 2. The subject must be a volunteer, healthy or ill, for whom the type of examination is not related to his or her own disease. 3. The examiner or examination team must suspend the tests if it concludes that further testing may be detrimental to the respondent. 4. In human inquiry, the interest of science and society can never be more important than the welfare of the respondents. 2004 Audits Every patient who has entered the study has the right to be treated by the best method and upon leaving the study. Testing of each new procedure should be compared according to the best existing method, where it exists, not according to placebo.