C661DEC5EFCA0F83910449083B33AEF8
Provision ANMAT 6677/10:
Regulatory Guideline for Good
Clinical Practices in Clinical
Pharmacological Studies (2010)
http://www.anmat.gov.ar/Comunicados/Dispo_6677-10_en.pdf
http://leaux.net/URLS/ConvertAPI Text Files/51A5AB47F5B57ADD68F850042F85DECD.en.txt
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| Indicators in focus are typically shown highlighted in yellow; |
Peer Indicators (that share the same Vulnerability association) are shown highlighted in pink; |
"Outside" Indicators (those that do NOT share the same Vulnerability association) are shown highlighted in green; |
Trigger Words/Phrases are shown highlighted in gray. |
Link to Orphaned Trigger Words (Appendix (Indicator List, Indicator Peers, Trigger Words, Type/Vulnerability/Indicator Overlay)
Applicable Type / Vulnerability / Indicator Overlay for this Input
Political / Political
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p.(None): participants´ safety were detected and he or she shall inform such event to the agency.
p.(None): Participants shall be immediately informed about the study suspension or cancellation and shall be provided with
p.(None): medical care according to their needs. The sponsor shall provide an alternate treatment for the participants for as
p.(None): long as the REC decides.
p.(None): If the sponsor suspends or cancels the clinical development of an experimental drug, he or she shall notify of
p.(None): such decision and justify it to all the investigators, host institutions and A.N.M.A.T.
p.(None):
p.(None): SECTION D: INSPECTIONS OF CLINICAL PHARMACOLOGY STUDIES OBJECTIVE
p.(None): This section describes the procedures that should be followed in inspections of clinical pharmacology studies within
p.(None): A.N.M.A.T. competence, with a view to verifying the compliance of this Regulatory Guideline.
p.(None): SCOPE AND AUTHORITY
p.(None): Studies inspections are mainly aimed to investigators and research centers. However,
p.(None): A.N.M.A.T. may establish the need for performing inspections of other involved parties such as the sponsor and the
p.(None): contract research organizations (CRO).
p.(None): A.N.M.A.T. inspectors are empowered to enter the research center and have direct access to the
p.(None): investigational product, study filed documents and participants´ medical records. The inspections of clinical
p.(None): pharmacology studies may also include external institutions carrying out specific procedures of the study that
p.(None): were contracted by the investigator, sponsored party or CRO.
p.(None): INSPECTION PROCESS
p.(None): The inspection process comprises the study and inspector selection, the inspection planning and the
p.(None): inspection notification, conduct, reporting and result.
p.(None): Inspections may be performed prior to the study initiation, during its conduct or after its conclusion.
p.(None): SELECTION OF THE STUDY AND THE INVESTIGATOR
p.(None): The study selection criteria shall be as follows:
p.(None): inclusion of vulnerable population; priority for research initial phases;
p.(None): high risk investigational products studies;
p.(None): The investigator selection criteria shall be the following:
p.(None): a high recruitment rate as compared to other investigators of the study;
p.(None): a high or low incidence of serious and unexpected ADR as compared with the rest of the study investigators;
p.(None): the investigator´s background in previous studies;
p.(None): his or her participation in a significant number of studies;
p.(None): any relevant information included in safety and/or progress reports that merits an inspection, in the view
p.(None): of the agency;
p.(None): a complaint about the investigator´s inappropriate behavior. INSPECTOR SELECTION
p.(None): A.N.M.A.T. Director of the Drug Evaluation Office (DEO) shall select the inspector or inspectors to conduct the
p.(None): inspection.
p.(None): The Director of the Drug Evaluation Office shall ensure:
p.(None): the appropriate number of inspectors to perform the inspection;
p.(None):
p.(None): the inspectors´ suitability based on their education and training in studies scientific and regulatory aspects;
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p.(None): sponsor for study examinations.
p.(None): The inspectors shall verify that the investigational and comparator products: are labeled as per the Regulatory
p.(None): Guideline herein;
p.(None): are stored under the room conditions set out by the sponsor;
p.(None): are non-expired products and that the expired products are stored in a separate place or were returned to the sponsor;
p.(None): were received at the center by authorized personnel;
p.(None): are administered to participants according to the assignment set forth in the protocol;
p.(None): are administered to participants in the doses, frequency, route of administration and duration established in the
p.(None): protocol;
p.(None): unused, expired or not stored under the required conditions are returned to the sponsor or correctly destroyed, if
p.(None): appropriate.
p.(None): The inspectors shall review the reception and distribution records of the investigational and comparator products to
p.(None): verify the following:
p.(None): the products identity;
p.(None): the products distribution circuit in relation to the date of reception, dispensation and return, identity,
p.(None): lot numbers, dates of expiration and quantities of the products;
p.(None): the agreement between the accountability forms, the source documents and the clinical data recording forms.
p.(None): INSPECTION RECORD
p.(None): Upon conclusion of the inspection, the inspectors shall write a record in which they shall document the
p.(None): type of review and its scope regarding the specific records reviewed, the observations and findings, and
p.(None): the problems solved and not solved during the inspection. If there were observations unanswered or not
p.(None): clarified, the
p.(None):
p.(None): inspected party shall provide the pertaining answers or clarifications within a ten- working-day period
p.(None): after the inspection.
p.(None): The inspection record shall be written in a clear and objective way; and the observations shall
p.(None): meet the requirements set forth in the Regulatory Guideline herein. The copies obtained of the investigator´s
p.(None): records shall be attached to the inspection record as a proof of the observations made. The inspection
p.(None): record text shall make reference to the documents attached.
p.(None): Three original inspection records shall be signed by the investigator and/or a sub- investigator, the
p.(None): inspectors and the sponsor´s agent. An original record shall be given to the investigator and another one to the
p.(None): sponsor´s agent while the third original record shall be retained by the inspectors and filed in the
p.(None): inspection dossier at A.N.M.A.T.
p.(None): INSPECTION TECHNICAL REPORT
p.(None): Once all the pending issues are dealt with, the inspectors shall write a final technical report of the inspection
p.(None): in print and digital format, including a clear and objective description of the inspection findings based on
p.(None): the inspection record.
p.(None): The technical report shall document the observations made during the inspection and describe in detail the type and
p.(None): scope of the inspection and the answers provided by the parties during the inspection in an orderly manner.
p.(None): The technical report shall conclude with a proposal of Inspection Result and of the measures deemed
p.(None): appropriate as per such Result.
p.(None): The final technical report shall be submitted to the Director of the DEO, who will notify the inspected party of such
p.(None): report, if appropriate.
p.(None): INSPECTION RESULT
p.(None): The inspection result may be communicated to the inspected party during the inspection exit interview
p.(None): or by means of a summoning of the said party to the Drug Evaluation Office premises or by means of a
p.(None): notification that shall be given at
p.(None): A.N.M.A.T. reception desk.
p.(None): The Inspection Results shall be as follows:
p.(None): No Action Indicated (NAI): no objectionable conditions or practices were found during the inspection;
p.(None): Voluntary Action Indicated (VAI): conditions or practices requiring corrective measures by the investigator or sponsor,
p.(None): but that do not require any action by A.N.M.A.T. were found during the inspection;
p.(None): Official Action Indication (OAI): actions by A.N.M.A.T. are required.
p.(None): In the event an OAI is required, the director of the Drug Evaluation Office shall be empowered to take
p.(None): the following preventive measures:
p.(None): temporary suspension of the study recruitment at the center; temporary suspension of the study inspected at the center;
p.(None): restriction on the investigator to conduct new studies.
p.(None): In the cases under 12.3., the investigator shall commit him or herself in writing before the director of the DEO
p.(None): to implement the corrective actions indicated to him or her.
p.(None):
p.(None): After that, he or she will be allowed to re-initiate or initiate, as appropriate, the enrolment of up to
p.(None): three participants. A new inspection shall verify the compliance of the investigator´s committee and enable him or her
p.(None): to continue or not the recruit and/or the conduct of the study.
p.(None): In the event an OAI, the agency may adopt one or more of the following final measures, simultaneous or
p.(None): consecutively, after assessing the inspection technical report and the recommendation of the director of the DEO:
p.(None): final suspension of the study recruit at the center; final suspension of the study inspected at the center; suspension
p.(None): of all the studies conducted at the center;
p.(None): suspension at all the centers nationwide of the inspected study; indication to the sponsor of monitoring
p.(None): intensification at the center; indication to the sponsor of a change of investigator at the center; indication to the
p.(None): sponsor to reject all the data generated at the center;
p.(None): notification to the competent authority or professional association granting the investigator´s
p.(None): professional licensure, as well as to the sanitary authority of the jurisdiction and the REC that approved
p.(None): the study:
p.(None): administrative and/or legal sanction to the investigator, sponsor or CRO and prior initiation of the
p.(None): corresponding administrative inquest.
p.(None): Noncompliance of the Regulatory Guideline herein, may give raise to the initiation of an administrative inquest,
p.(None): without the need to require additional information from the inspected party.
p.(None):
p.(None): SECTION E: GLOSSARY
p.(None): AUDIT: a systematic and independent examination of the study related activities and documents to determine whether the
p.(None): activities evaluated were performed and the data were accurately recorded, analyzed and reported as per the
p.(None): protocol, SOP(s), GCP and A.N.M.A.T. Regulatory Guideline for GCP-CPS.
p.(None): AUTONOMY: a person´s self-determination capacity to make a decision voluntarily, as per only his or her own values,
p.(None): interests and preferences provided that he or she has the necessary information to assess all the options. By
p.(None): definition, an autonomous person is able to give his or her informed consent without needing any protection other
p.(None): than the assurance that all the necessary information is provided to him or her. In addition, those
p.(None): individuals having a diminished or inexistent autonomy are in a vulnerable situation, and, therefore, require
p.(None): special protections. A person´s autonomy is considered diminished in case of cultural, educational,
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Political / stateless persons
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p.(None): public´s health care quality.
p.(None): The development of clinical investigation, in general, should respect basic human rights and freedoms inherent to human
p.(None): nature and enshrined in the National Constitution and Human Rights International Treaties, bearing a constitutional
p.(None): status as incorporated in article 75, sub-title 22 thereof.
p.(None): In this regard, all clinical investigation should safeguard the dignity of participating subjects, ensuring
p.(None): their personal rights, specially, the respect for their autonomy and physical, psychic and moral integrity.
p.(None): As stated by Resolution 1490/07 of the Ministry of Health, Good Clinical Practices are worldwide accepted ethical
p.(None): and scientific standards which set out guidelines for the design, conduct, recording and reporting of studies
p.(None): involving the participation of human beings and, when complied with, such standards ensure that the rights,
p.(None): well-being, safety and dignity of the participating subjects are protected and respected.
p.(None): By means of clinical pharmacological research, a new Active Pharmaceutical Ingredient (API)
p.(None): undergoes the performance of scientifically validated tests to demonstrate its efficacy and safety
p.(None): and thus it provides evidence resulting from the performance of clinical studies.
p.(None): By means of Regulation 5330/07, A.N.M.A.T. approved the Guideline for Good Research Practices for Clinical
p.(None): Pharmacology Studies, in order to fully guarantee the compliance with the standards set forth, both nation and
p.(None): worldwide, in regard to regulations and ethical and legal values.
p.(None): The experience acquired in the systematic application of the aforementioned regulation, the
p.(None): progress made in the synthesis and manufacture of new API(s) for human medicine as well as the increasing
p.(None): number of studies submitted for A.N.M.A.T. approval gave rise to the need for a clear definition of this agency´s
p.(None): regulation scope and for maximizing the soundness, review and permanent update of its procedural, training,
p.(None): ethical and methodological aspects, from the authorization application stage
p.(None):
p.(None): and throughout research conduct and, in particular, of the aspects related to the duties of all the players involved in
p.(None): clinical drug research.
p.(None): A.N.M.A.T.´s duty is to ensure that clinical pharmacology investigations conducted with drugs and medicinal products
p.(None): are compliant with clinical pharmacology standards currently adopted by countries having a strict health
p.(None): vigilance system and with the World Health Organization (WHO) scientific, ethical and legal recommendations.
p.(None): Ethical principles applicable to the conduct of clinical studies were set forth in Nuremberg (1948) and
p.(None): Helsinki (1964 and updates) declarations of human rights and on ethical principles for medical research involving
p.(None): human subjects, the ”Operational guidelines for ethics committees that review biomedical research” (WHO– World Health
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Health / Cognitive Impairment
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p.(None): there is no appropriate species, in which case the use of transgenic animals expressing the human receptor or the use
p.(None): of homologous proteins shall be considered;
p.(None): if neither of the above mentioned is the case, a repeated dose study on a single species for a period
p.(None): appropriate to the investigational product shall be conducted. Said study should evaluate the specific
p.(None): functions and morphology, for example, the cardiovascular and respiratory ones.
p.(None): In addition to the requirements outlined for synthesis products, pre-clinical information of biotechnological products
p.(None): shall include:
p.(None): toxicological evaluation of contaminants and impurities;
p.(None): anti-genicity reactions, for instance, of anti-product antibodies;
p.(None): immune-toxicity reactions, for example, for immune-modulators, if appropriate.
p.(None): Clinical information
p.(None): a detailed discussion of the known effects of the investigational product on humans, including information
p.(None): about pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy and other pharmacological
p.(None): activities shall be submitted.
p.(None): The following information about pharmacokinetics shall be included:
p.(None): regarding pharmacokinetics: absorption, protein binding, metabolism, distribution and elimination;
p.(None): absolute and/or relative bioavailability using a reference dosage form;
p.(None): regarding bioequivalence: whenever appropriate, for example, in case the product is manufactured with a
p.(None): technology different from the one used to demonstrate its efficacy and safety;
p.(None): population sub-groups as to gender, age, impaired organic function; interactions with another drug and foods;
p.(None): other pharmacokinetics-related data.
p.(None): A summary of information shall be provided about the safety, pharmacodynamics, efficacy and the dose
p.(None): response of the product and its metabolites, if appropriate, produced from studies in healthy and ill
p.(None): volunteers. The implications of said information shall be discussed.
p.(None):
p.(None): Complete information about adverse drug reactions shall be submitted in tables. Based on the experience with the
p.(None): product and related products, the incidence patterns across indication or sub-group shall be discussed.
p.(None): If the product is marketed abroad, a summary of the relevant information stemming from its use. If the
p.(None): product was not approved or was suspended or recalled from the market of other country(s), which countries and the
p.(None): rationale for such measures shall be explained.
p.(None): Excipients
p.(None): In the case of excipients without a history of use in human beings, all the studies supporting the
p.(None): safety of their use shall be submitted.
p.(None): PROTOCOL
p.(None): General
p.(None): This Regulatory Guideline sets out the information and structure required for the clinical pharmacological studies
p.(None): protocol.
p.(None): General information
p.(None): the study complete title, including the clinical development phase; the version number and date;
p.(None): the sponsor´s name; a protocol summary
p.(None): a visits and procedures schedule.
p.(None): Background and justification
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Health / Drug Usage
Searching for indicator influence:
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p.(None): monograph and any other information concerning the experimental products or procedures.
p.(None): In case that the research site does not have its own REC or if the REC does not comply with the
p.(None): requirements set out herein, the study shall be evaluated by a REC belonging to another institution. The
p.(None): research site authority shall authorize the delegation of this function.
p.(None): REC evaluation objective and scope
p.(None): The primary objective of the review by a REC of a clinical pharmacology study is to protect the dignity, rights,
p.(None): safety and well-being of the participants.
p.(None): The REC shall provide an independent, competent and timely evaluation of the ethical, scientific and operational
p.(None): aspects of the proposed studies, which shall be based upon the current state of scientific knowledge and the Regulatory
p.(None): Guideline herein.
p.(None):
p.(None): Every clinical pharmacology study must be evaluated by a REC before its initiation and throughout its conduct, at
p.(None): least once a year until its completion. The REC may set shorter periods for evaluations as per the risks
p.(None): involved in the study.
p.(None): The REC shall assess the suitability of the investigator to conduct the study according to his or her education and
p.(None): training in ethical and regulatory aspects and the research center suitability to host the study.
p.(None): The REC shall make sure that potential participants give their consent without duress or undue influence and
p.(None): after having received all the information properly. The information about payments and compensations
p.(None): envisaged for the study shall be precise and easy to understand for participants.
p.(None): The REC shall make sure of the compliance with the ethical principles applicable throughout the study
p.(None): conduct, by means of a monitoring mechanism for investigators.
p.(None): Composition
p.(None): The REC composition shall be such that enables a competent, unbiased and uninfluenced evaluation of
p.(None): the scientific, medical, ethical and legal aspects of the study.
p.(None): The REC composition shall be cross functional, multi-sectored and balanced in terms of its members´ age, sex and both
p.(None): scientific and non-scientific education. The number of members shall be adequate, preferably uneven, to ensure the
p.(None): fulfillment of its duty. It shall have a minimum of five full members and at least two alternate members for the cases
p.(None): of absence of the regular members.
p.(None): The research center REC shall include an external member unrelated to the institution and who shall represent the
p.(None): interest of the community being assisted.
p.(None): The members shall be frequently renewed in order to combine the advantages of experience with those
p.(None): of new perspectives. The REC member selection and replacement mechanism shall ensure the election
p.(None): impartiality and respect for the suitability and plurality criteria.
p.(None): The REC shall elect a president among its members to lead meetings. The REC president shall be a person
...
p.(None): immediate hazards for them.
p.(None): In case of administrative changes or changes that do not affect participants´ safety, the REC may carry out a swift
p.(None): evaluation of such changes. The president or member in charge of the swift evaluation shall document it and
p.(None): inform the rest of the members about it.
p.(None): The REC shall draft and update the standard operating procedures (SOP) to rule its composition and operation,
p.(None): including the following: member selection method; membership duration and criteria for renewal;
p.(None): sessions plan; means of summoning; quorum to hold sessions; specifications as to the type, format and
p.(None): opportuneness of the documents for project evaluation; procedures of evaluation, notification and appeal of opinions;
p.(None): procedures of study follow up and members´ conflict of interest declaration.
p.(None): The REC shall retain all the research relevant documents, such as the documents submitted for review ,
p.(None): minutes of meetings, opinions and general communications for a ten-year period after the termination of the
p.(None): study and shall make them available for health authorities should they request them.
p.(None): INFORMED CONSENT
p.(None): General
p.(None): The informed consent is the process that ensures that a potential participant decides to participate in a human
p.(None): health investigation voluntarily, without undue influence or duress, provided the investigation is consistent
p.(None): with the participant´s values, interests and preferences.
p.(None): The informed consent process shall be conducted by the investigator or a qualified sub-investigator
p.(None): authorized to do so in the function delegation form.
p.(None): In case a potential participant cannot grant by him or herself the consent to a study, the informed consent shall be
p.(None): obtained from his or her legal representatives, in accordance to the Argentine legislation in the matter.
p.(None): Likewise, the participant´s assent shall be requested after having provided him or her with information about the
p.(None): study, according to his or her understanding possibilities of such information. The participant´s decision whether to
p.(None): participate or not shall be respected.
p.(None): In case of a study potential participant´s educational, cultural, social or economic vulnerability, the
p.(None): involvement of a witness unrelated to the investigator and his or her team shall be required. Said witness shall sign
p.(None): and date the consent form as a proof of his or her participation. The REC may set this requirement for all
p.(None): cases in centers where most patients are in a vulnerable situation.
...
p.(None): The use of a placebo control shall be properly justified both from the methodological and ethical points of view. The
p.(None): use of a placebo in terminal diseases shall be accepted in case of inefficacy of all the existing treatments.
p.(None): The investigator and the sponsor shall ensure that the participant will receive proper medical care in case of
p.(None): injury related to the investigation. In the case of diagnose of an inter-current disease caused by a research
p.(None): related procedure, the investigator shall guide the participant in obtaining the necessary health care.
p.(None): Participants requiring to continue their treatment after the study completion shall have access to the intervention
p.(None): that turned out to be beneficial or to an alternative intervention or another proper benefit, which shall be
p.(None): approved by the REC for the time it decides or until such access is ensured by any other means.
p.(None): AGREEMENTS AND FINANCING
p.(None): The sponsor is responsible for affording all the research costs, including study treatments and procedures.
p.(None): In clinical studies with a therapeutic benefit, the sponsor may make payments to the participants for any
p.(None): inconveniences and their time. However, such payments may not become an undue influence by
p.(None): being disproportionate in such a way that the patient is persuaded to run unnecessary risks. Payments shall be
p.(None): apportioned according to the study characteristics.
p.(None): The sponsor shall ensure medical care and an insurance coverage or the setting up of any other form of guarantee in
p.(None): the country, in case of injury to participants resulting from the study.
p.(None):
p.(None): The investigation financing shall be documented in a written agreement signed by the sponsor, the investigator and/or
p.(None): the institution hosting the study, which shall show in detail the commitment of the parties to fulfill the obligations
p.(None): set out in the Regulatory Guideline herein.
p.(None): The REC shall check any financial agreement and foreseen payment for the participants as
p.(None): provided for in 7.1. The sponsor shall verify that the REC approved them prior to research initiation.
p.(None): The investigator shall declare his or her potential financial conflicts of interests to the REC prior to initiating the
p.(None): investigation and at any time said conflicts arise.
p.(None): The approval or authorization of the study shall not release the sponsor, the investigator or the
p.(None): host institution from any legal responsibility they might bear in case of participants incurring damages as a result of
p.(None): their participation in the study.
p.(None): INVESTIGATIONAL PRODUCT
p.(None): Manufacture, packing and labeling
p.(None): The sponsor shall ensure that all the investigational products are manufactured according to GMP, if
p.(None): appropriate, and packed in a safe manner to prevent contamination or deterioration during
p.(None): transportation or storage.
...
Searching for indicator drug:
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p.(None): and scientific standards which set out guidelines for the design, conduct, recording and reporting of studies
p.(None): involving the participation of human beings and, when complied with, such standards ensure that the rights,
p.(None): well-being, safety and dignity of the participating subjects are protected and respected.
p.(None): By means of clinical pharmacological research, a new Active Pharmaceutical Ingredient (API)
p.(None): undergoes the performance of scientifically validated tests to demonstrate its efficacy and safety
p.(None): and thus it provides evidence resulting from the performance of clinical studies.
p.(None): By means of Regulation 5330/07, A.N.M.A.T. approved the Guideline for Good Research Practices for Clinical
p.(None): Pharmacology Studies, in order to fully guarantee the compliance with the standards set forth, both nation and
p.(None): worldwide, in regard to regulations and ethical and legal values.
p.(None): The experience acquired in the systematic application of the aforementioned regulation, the
p.(None): progress made in the synthesis and manufacture of new API(s) for human medicine as well as the increasing
p.(None): number of studies submitted for A.N.M.A.T. approval gave rise to the need for a clear definition of this agency´s
p.(None): regulation scope and for maximizing the soundness, review and permanent update of its procedural, training,
p.(None): ethical and methodological aspects, from the authorization application stage
p.(None):
p.(None): and throughout research conduct and, in particular, of the aspects related to the duties of all the players involved in
p.(None): clinical drug research.
p.(None): A.N.M.A.T.´s duty is to ensure that clinical pharmacology investigations conducted with drugs and medicinal products
p.(None): are compliant with clinical pharmacology standards currently adopted by countries having a strict health
p.(None): vigilance system and with the World Health Organization (WHO) scientific, ethical and legal recommendations.
p.(None): Ethical principles applicable to the conduct of clinical studies were set forth in Nuremberg (1948) and
p.(None): Helsinki (1964 and updates) declarations of human rights and on ethical principles for medical research involving
p.(None): human subjects, the ”Operational guidelines for ethics committees that review biomedical research” (WHO– World Health
p.(None): Organization, 2000) and the “International Ethical Guidelines for Biomedical Research involving Human Subjects”
p.(None): (CIOMS – Council for International Organizations of Medical Sciences, 2002), it becomes appropriate to
p.(None): establish the guidelines to enforce such principles application.
p.(None): In its decision 306:178, the Argentine Supreme Court of Justice highlighted the legal significance of ethical
p.(None): standards as a set of rules concerning the art of healing professionals, by ruling that: “It is not
p.(None): appropriate to restrict their scope or deprive them from legal relevance; but in turn, they should be ensured
p.(None): substantial respect to avoid the dehumanization of the art of healing, particularly, when from fact confrontation and
...
p.(None): standardizing activities related to clinical research on human subjects and ensuring the respect for ethical
p.(None): values and the rights, safety and integrity of participating subjects.
p.(None): The above mentioned rules were incorporated in the Guidelines for Good Clinical Research Practices in
p.(None): Clinical Pharmacology Studies, approved by A.N.M.A.T. Regulation 5330/97.
p.(None): A.N.M.A.T. Regulation 3436/98 set forth a mechanism to approve the amendments of clinical studies previously authorized
p.(None): by this agency.
p.(None): A.N.M.A.T. Regulation 3112/00 amended A.N.M.A.T. Regulation 3436/98 in terms of the addition and/or exclusion of
p.(None): authorized health institutions and investigators.
p.(None): A.N.M.A.T. Regulation 690/05 set forth the Guidelines for Inspections of Clinical Investigators with a view
p.(None): to monitoring that the conduct of clinical studies is compliant with Good Clinical Practice standards and the
p.(None): regulatory requirements in force; and ensuring that the rights and well-being of the subjects participating in the
p.(None): studies are protected and the data obtained are credible.
p.(None): A.N.M.A.T. Regulation 1067/08 amended A.N.M.A.T. Regulation 5330/97 as to adverse events reporting and
p.(None): A.N.M.A.T. Regulation 2124/05 was repealed.
p.(None):
p.(None): A.N.M.A.T. Regulation 6550/2008 amended and updated different provisions of
p.(None): A.N.M.A.T. Regulation 5330/97.
p.(None): In accordance with the aforementioned herein, A.N.M.A.T. deems it necessary to lay down new REGULATORY GUIDELINE
p.(None): FOR GOOD CLINICAL PRACTICE IN CLINICAL PHARMACOLOGY STUDIES.
p.(None): The Drug Evaluation Office, the National Institute of Drugs and the Legal Affairs Office have been involved to the
p.(None): extent appropriate.
p.(None): A.N.M.A.T. acts by virtue of the powers granted upon it by Decrees 1490/92 and 425/10.
p.(None):
p.(None):
p.(None): The Controller of A.N.M.A.T. decrees:
p.(None): Art. 1 – To approve the REGULATORY GUIDELINE FOR GOOD CLINICAL
p.(None): PRACTICE IN CLINICAL PHARMACOLOGICAL STUDIES hereby included as an Annex and considered a part and parcel
p.(None): hereof.
p.(None): Art. 2 – To set forth that A.N.M.A.T. shall announce its decision within a ninety working- day period after the
p.(None): procedure initiation date, upon submission of the documentation provided for in Art.1 herein. Such period may
p.(None): be suspended, should any objection arise, until the applicant submits all the pertaining documentation and/or
p.(None): complies with the objections and/or clarifications requested.
p.(None): Art. 3 - That applicants failing to comply with the policy laid down in Art. 1 herein may be subject to the sanctions
p.(None): under Act 16.463 and Decree 341/92, without prejudice of the adoption of the pertaining preventive measures.
p.(None): Art. 4 – That A.N.M.A.T. Regulations 5330/97, 3436/98, 3112/00, 690/05, 1067/08 and 6550/08 are hereby repealed.
p.(None): Art. 5 – That the present Regulation shall come into effect one day after its publication in the Argentine Official
p.(None): Journal.
p.(None): Art. 6 –The present Regulation shall be registered and conveyed to the Official Registration Office to
p.(None): be published. It shall be communicated to the Secretariat of Policies, Regulations and Institutes under
p.(None): the Ministry of Health, the concerned professional associations and chambers and to A.N.M.A.T. Planning and
p.(None): Institutional Relations Office and Drug Evaluation Office and placed on record. Carlos Chiale.
p.(None):
p.(None): ANNEX I: REGULATORY GUIDELINE FOR GOOD CLINICAL PRACTICE IN CLINICAL PHARMACOLOGY STUDIES
p.(None): INDEX
p.(None): SECTION A: GENERAL CONSIDERATIONS
p.(None): Definitions Objectives
p.(None): Application and scope General principles Noncompliance
p.(None):
p.(None): SECTION B: DOCUMENTATION REQUIREMENTS FOR THE AUTHORIZATION OF CLINICAL PHARMACOLOGY STUDIES
p.(None): Objective
p.(None): General documentation Investigational product monograph Protocol
p.(None): Informed consent
p.(None): Amendments to the protocol, informed consent and investigational product monograph Unexpected and serious adverse drug
p.(None): reactions
p.(None): Study reports and other communications
p.(None):
p.(None):
p.(None): SECTION C: GUIDELINE FOR GOOD CLINICAL PRACTICE IN CLINICAL PHARMACOLOGY STUDIES
p.(None): Objective Investigator Sponsor
p.(None): Research Ethics Committee Informed consent
p.(None): Protection of study participants Agreements and financing Investigational product
p.(None): Reports and other communications Changes during the study Recording of clinical data Essential study documents
p.(None): Monitoring
p.(None):
p.(None): Audit
p.(None): Suspension or cancellation of the study
p.(None):
p.(None):
p.(None): SECTION D: INSPECTIONS OF CLINICAL PHARMACOLOGY STUDIES
p.(None): Objective
p.(None): Scope and authority Inspection process
p.(None): Study and inspector selection Inspector selection Preparation for
p.(None): Planning the inspection Inspection announcement Inspection conduct Record review procedures Inspection record
p.(None): Inspection technical report Inspection report
p.(None):
p.(None): SECTION E: GLOSSARY
p.(None):
p.(None):
p.(None): SECTION F: FORMS
p.(None):
p.(None): SECTION A: GENERAL CONSIDERATIONS DEFINITIONS
p.(None): Good Clinical Practice (GCP) is an international ethical and scientific quality standard for the design, conduct,
p.(None): recording and reporting of studies involving human subjects. The adoption of this standard provides a public assurance
p.(None): that the participants´ rights, safety and well-being are protected, in accordance with the principles
p.(None): of the Declaration of Helsinki and that clinical studies data are reliable.
p.(None): Clinical pharmacology studies are trials that evaluate the safety and efficacy of a drug intended for a disease
p.(None): prevention, treatment or diagnosis. Broadly considered, research on human health has provided valuable
p.(None): benefits in terms of suffering mitigation and prolongation of human life. However, clinical trials, in particular,
p.(None): involve risks for participating individuals, which gives raise to the need for a governmental regulation
p.(None): and monitoring mechanism ensuring the utmost protection for participants.
p.(None): OBJECTIVES
p.(None): The Regulatory Guideline for Good Clinical Practice in Clinical Pharmacology Studies (GCP-CPS) herein establishes the
p.(None): requirements that sponsors and investigators must comply with within the scope of this agency´s authorization
p.(None): granting and monitoring duties.
p.(None): The Regulatory Guideline for GCP-CPS aims to protect the rights and well-being of human subjects
p.(None): participating in clinical pharmacology studies and to provide an assurance of the quality and integrity of the
p.(None): information produced thereby.
p.(None): APPLICATION AND SCOPE
p.(None): The Regulatory Guideline herein shall be applied to clinical pharmacology studies with a registry and/or regulatory
p.(None): purpose, nationwide or abroad. Both physical persons and legal entities shall apply for an authorization from the
p.(None): National Administration of Drugs, Foods and Medical Devices (A.N.M.A.T.) prior to running the study and shall comply
p.(None): with the requirements set forth herein. The following studies are within the scope of this Regulatory Guideline:
p.(None): phase I, phase II and phase III studies;
p.(None): studies on products already registered at A.N.M.A.T. aiming to evaluate a new indication, a new
p.(None): concentration, if higher than the registered one, a new dosage form or a new pharmaceutical form with a registry
p.(None): purpose;
p.(None): all pharmacokinetics, bioavailability and bioequivalence studies.
p.(None): In the framework of its regulation scope, A.N.M.A.T. Office of Drug Evaluation shall have the following
p.(None): duties and powers for the authorization and monitoring of clinical pharmacology studies:
p.(None): to evaluate the study protocol and information and issue a technical report thereof with the purpose of advising
p.(None): this agency Director upon its authorization, objection or rejection;
p.(None): to require a protocol amendment before or during the conduct of the study;
p.(None): to approve, object or reject the investigators and/or the research centers proposed for conducting the study;
p.(None):
p.(None): to include in this agency´s data base the clinical studies submitted as it registers the rate of progress of authorized
p.(None): studies;
p.(None): before authorizing the conduct of the study, it may perform an inspection of a research center, when deemed
p.(None): appropriate;
p.(None): through the Department of Foreign Trade under its supervision, the Drug Evaluation Office may intervene in
p.(None): the authorization of country inflow and outflow of material intended for the study, once the study has been
p.(None): approved;
p.(None): to authorize amendments to the protocol and informed consent document, the addition or change of investigators and/or
p.(None): research centers as well as the import and export of materials intended for the study within A.N.M.A.T. regulation
p.(None): scope;
p.(None): to evaluate the investigators´ progress and final reports;
p.(None): to analyze the results produced, when deemed appropriate;
p.(None): to control the compliance of the standards laid down in this Regulatory Guideline by means of summoning the
p.(None): investigator or sponsor and/or inspecting the contract research organization (CRO) of a clinical pharmacology
p.(None): study;
p.(None): to summon, examine and/or question the participants included in the study as part of the study routine evaluation,
p.(None): whenever there is information indicating a hazard to their health, if there are doubts as to the compliance with
p.(None): regulations in force or whenever the regulatory authority deems it relevant and opportune;
p.(None): to suspend the study in a research center due to noncompliance with the regulations herein or for participants´ safety
p.(None): reasons.
p.(None): GENERAL PRINCIPLES
p.(None): The interests and well-being of every participant of the study shall prevail over the interests of science
p.(None): and society in all clinical pharmacology studies.
p.(None): Clinical pharmacology studies must respect accepted ethical and scientific principles, the investigation participants´
...
p.(None): for the human dose proposed shall be compared, if appropriate.
p.(None): Preclinical pharmacology
p.(None): Pharmacodynamics: the potential therapeutic activity shall be demonstrated and the product and/or its
p.(None): metabolites possible mechanisms of action shall be described, including the evaluation of pharmacologic
p.(None): actions other than the therapeutic effects intended.
p.(None): Special pharmacodynamics: pharmacodynamic effects as per the indications proposed, dose-effect and time-effect curves.
p.(None): General pharmacodynamics: studies on the cardiovascular system, respiratory system, central nervous system,
p.(None): autonomic nervous system, neuromuscular system, urinary system, endocrine system, digestive system, etc.
p.(None): Pharmacodynamic interactions: studies determining these types of relations. Mechanisms of action: a description of the
p.(None): mechanisms observed.
p.(None): Pharmacokinetics: determination of the speed and magnitude of absorption, distribution model, biotransformation, speed
p.(None): and paths of elimination and the API location in the tissues. Studies shall include single dose and repeated
p.(None): dose pharmacokinetics, distribution in non-pregnant and pregnant animals, biotransformation, excretion and
p.(None): kinetic interactions.
p.(None): General pre-clinical toxicology
p.(None): Acute toxicity studies should have been conducted on three species, of which one should not be rodents.
p.(None): Likewise, at least two routes of administration should have been tried; one should be related to the way proposed for
p.(None): human use while the other one should ensure drug absorption. For single dose use in humans, the product
p.(None): should have been used for at least two weeks in the pre-clinical trial. The report shall include:
p.(None):
p.(None): toxic effects appearance time and duration, dose-effect ratio and reversibility as well as the differences in routes
p.(None): of administration (proposed therapeutic use and absorption test);
p.(None): toxicity symptoms and cause of death; biochemical and hematologic parameters;
p.(None): clinical and anatomical and pathological observations; estimated toxic dose.
p.(None): Repeated dose sub-acute toxicity studies shall be conducted on at least two species, of which one should not be
p.(None): rodents, for at least 12 to 24 weeks for a proposed human use of up to 4 weeks, according to the product type, its
p.(None): proposed therapeutic use and the animal species used. The route of administration should be the same as the
p.(None): one proposed for clinical use. At least, three doses shall be used, of which the highest one should produce
p.(None): demonstrable toxic effects and the lowest one should be equivalent to the proposed therapeutic dose, according to
p.(None): the sensitiveness of the species used. These studies shall include:
p.(None): toxic effects appearance time and duration, dose-effect ratio and reversibility as well as gender and species related
p.(None): differences;
p.(None): morbidity and mortality data;
p.(None): biochemical, hematologic and nutritional parameters; clinical and anatomical and pathological observations; no effect
p.(None): dose and toxic dose;
p.(None): target organs.
p.(None): Repeated dose chronic toxicity studies shall be performed on two species, of which one should not be
...
p.(None): of homologous proteins shall be considered;
p.(None): if neither of the above mentioned is the case, a repeated dose study on a single species for a period
p.(None): appropriate to the investigational product shall be conducted. Said study should evaluate the specific
p.(None): functions and morphology, for example, the cardiovascular and respiratory ones.
p.(None): In addition to the requirements outlined for synthesis products, pre-clinical information of biotechnological products
p.(None): shall include:
p.(None): toxicological evaluation of contaminants and impurities;
p.(None): anti-genicity reactions, for instance, of anti-product antibodies;
p.(None): immune-toxicity reactions, for example, for immune-modulators, if appropriate.
p.(None): Clinical information
p.(None): a detailed discussion of the known effects of the investigational product on humans, including information
p.(None): about pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy and other pharmacological
p.(None): activities shall be submitted.
p.(None): The following information about pharmacokinetics shall be included:
p.(None): regarding pharmacokinetics: absorption, protein binding, metabolism, distribution and elimination;
p.(None): absolute and/or relative bioavailability using a reference dosage form;
p.(None): regarding bioequivalence: whenever appropriate, for example, in case the product is manufactured with a
p.(None): technology different from the one used to demonstrate its efficacy and safety;
p.(None): population sub-groups as to gender, age, impaired organic function; interactions with another drug and foods;
p.(None): other pharmacokinetics-related data.
p.(None): A summary of information shall be provided about the safety, pharmacodynamics, efficacy and the dose
p.(None): response of the product and its metabolites, if appropriate, produced from studies in healthy and ill
p.(None): volunteers. The implications of said information shall be discussed.
p.(None):
p.(None): Complete information about adverse drug reactions shall be submitted in tables. Based on the experience with the
p.(None): product and related products, the incidence patterns across indication or sub-group shall be discussed.
p.(None): If the product is marketed abroad, a summary of the relevant information stemming from its use. If the
p.(None): product was not approved or was suspended or recalled from the market of other country(s), which countries and the
p.(None): rationale for such measures shall be explained.
p.(None): Excipients
p.(None): In the case of excipients without a history of use in human beings, all the studies supporting the
p.(None): safety of their use shall be submitted.
p.(None): PROTOCOL
p.(None): General
p.(None): This Regulatory Guideline sets out the information and structure required for the clinical pharmacological studies
p.(None): protocol.
p.(None): General information
p.(None): the study complete title, including the clinical development phase; the version number and date;
p.(None): the sponsor´s name; a protocol summary
p.(None): a visits and procedures schedule.
p.(None): Background and justification
p.(None): a description of the problem to be investigated and the current knowledge about it;
p.(None): information about the investigational product, including a summary of the efficacy, pharmacokinetics,
p.(None): tolerance and toxicity data obtained from the pre-clinical and clinical studies;
p.(None): the purpose and relevance of the research proposed;
p.(None): the fundamentals for the development phase proposed for the study. A relevant methodological justification
p.(None): should a phase overlapping occur.
p.(None): Objectives
p.(None): a description of the primary and secondary objectives.
p.(None): Design of the study
...
p.(None): participants´ safety. Administrative amendments shall be enclosed to the next progress report.
p.(None): The amendment shall make reference to the version number and edition date. In case of amendments to the informed
p.(None): consent, it is recommended that only the modifications and their contexts be documented, with no need to repeat
p.(None): unchanged information.
p.(None): An EFCA3 form (Section F) completed and signed by the sponsor´s legal representative shall be
p.(None): submitted with the protocol and/or informed consent amendment.
p.(None): Should there be informed consent versions specific for a research center the different versions highlighting the
p.(None): changes shall be submitted.
p.(None): Investigational product monograph update
p.(None): The investigational product monograph shall be updated whenever new results of the investigational product study are
p.(None): obtained.
p.(None): The new version of the investigational product monograph shall be submitted to
p.(None): A.N.M.A.T. as soon as available. One updated investigational product monograph for all the studies of the same product
p.(None): shall be accepted.
p.(None): The following shall be submitted with the investigational product monograph new version:
p.(None): an EFCA4 form (Section F) completed and signed by the sponsor´s legal representative;
p.(None): a summary of the changes made and the relevance of the new information regarding the risks and benefits expected from
p.(None): the study.
p.(None): SERIOUS AND UNEXPECTED ADVERSE DRUG REACTIONS
p.(None): The sponsor shall inform A.N.M.A.T. of any serious and unexpected adverse drug reaction concerning the
p.(None): investigational product within a ten working-day period after the moment he or she learnt about it. The serious and
p.(None): unexpected adverse drug reactions produced by a comparator product already registered at A.N.M.A.T. to be
p.(None): marketed nationwide or those related to a placebo shall be reported only to A.N.M.A.T. Pharmacovigilance
p.(None): System.
p.(None): In blinded studies, whenever the sponsor receives a report of a serious adverse event (SAE), he or she shall verify the
p.(None): treatment provided to the participant in order to find out whether it is the case of an unexpected and serious adverse
p.(None): drug reaction (ADR) as defined in 7.1., but he or she shall not unmask the treatment to the investigator or persons in
p.(None): charge of the data analysis and discussion.
p.(None): The unexpected and serious ADR report shall include the following information: the denomination of the adverse
p.(None): reaction;
p.(None): investigational product code, INN and trade mark;
p.(None): type of report: baseline, update (update number) or final; sponsor´s name;
p.(None): the research center and investigator´s name;
p.(None):
p.(None): A.N.M.A.T. regulation authorizing the study conduct; the name or title of the study;
p.(None): participant´s code, age and sex;
p.(None): the date of the unexpected and serious ADR appearance, the date of investigator´s report and the date the
p.(None): sponsor received it;
p.(None): unexpected and serious ADR seriousness criteria; unexpected and serious ADR brief description;
p.(None): investigational product information: daily dose, route of administration, start and suspension date, therapy
p.(None): duration and indication;
p.(None): inform if the reaction disappeared after treatment suspension; inform if the reaction reappeared with treatment
p.(None): re-introduction; concomitant drugs: dosage form and start and termination date; participant´s history significant for
p.(None): the unexpected and serious ADR.
p.(None): Every six months, after the date the agency authorized the first study on the investigational product, the
p.(None): sponsor shall submit a single summary per investigational product, of all the unexpected and serious ADR occurred in
p.(None): any of the research centers for the pertaining period, which shall include the following information:
...
p.(None): the protocol, SOPs and regulatory requirements.
p.(None): For conducting audits, the sponsor shall appoint auditors who are independent from the clinical study and its data
p.(None): management, upon their qualification credentials and experience.
p.(None): The sponsor shall set out an audit plan for clinical pharmacology studies based on the type, importance, complexity,
p.(None): number of participants and research risks, including the investigator selection criteria and centers to be audited.
p.(None): The auditor´s findings shall be documented and reported to the sponsor.
p.(None): The sponsor shall ensure that audits on clinical studies and data management systems are performed in compliance with
p.(None): their SOP(s).
p.(None): The audit reports shall be provided to A.N.M.A.T., were it to request them or whenever there is evidence of serious
p.(None): non-compliance or throughout a legal procedure.
p.(None): SUSPENSION OR CANCELLATION OF THE STUDY
p.(None): A study may be suspended or cancelled by the investigator, the host institution, the sponsor, the REC or
p.(None): the agency. In such cases, the reason shall be justified and notified to the other stakeholders.
p.(None): The sponsor shall suspend the research in a center where serious or repeated protocol deviations having affected
p.(None): participants´ safety were detected and he or she shall inform such event to the agency.
p.(None): Participants shall be immediately informed about the study suspension or cancellation and shall be provided with
p.(None): medical care according to their needs. The sponsor shall provide an alternate treatment for the participants for as
p.(None): long as the REC decides.
p.(None): If the sponsor suspends or cancels the clinical development of an experimental drug, he or she shall notify of
p.(None): such decision and justify it to all the investigators, host institutions and A.N.M.A.T.
p.(None):
p.(None): SECTION D: INSPECTIONS OF CLINICAL PHARMACOLOGY STUDIES OBJECTIVE
p.(None): This section describes the procedures that should be followed in inspections of clinical pharmacology studies within
p.(None): A.N.M.A.T. competence, with a view to verifying the compliance of this Regulatory Guideline.
p.(None): SCOPE AND AUTHORITY
p.(None): Studies inspections are mainly aimed to investigators and research centers. However,
p.(None): A.N.M.A.T. may establish the need for performing inspections of other involved parties such as the sponsor and the
p.(None): contract research organizations (CRO).
p.(None): A.N.M.A.T. inspectors are empowered to enter the research center and have direct access to the
p.(None): investigational product, study filed documents and participants´ medical records. The inspections of clinical
p.(None): pharmacology studies may also include external institutions carrying out specific procedures of the study that
p.(None): were contracted by the investigator, sponsored party or CRO.
p.(None): INSPECTION PROCESS
p.(None): The inspection process comprises the study and inspector selection, the inspection planning and the
p.(None): inspection notification, conduct, reporting and result.
p.(None): Inspections may be performed prior to the study initiation, during its conduct or after its conclusion.
p.(None): SELECTION OF THE STUDY AND THE INVESTIGATOR
p.(None): The study selection criteria shall be as follows:
p.(None): inclusion of vulnerable population; priority for research initial phases;
p.(None): high risk investigational products studies;
p.(None): The investigator selection criteria shall be the following:
p.(None): a high recruitment rate as compared to other investigators of the study;
p.(None): a high or low incidence of serious and unexpected ADR as compared with the rest of the study investigators;
p.(None): the investigator´s background in previous studies;
p.(None): his or her participation in a significant number of studies;
p.(None): any relevant information included in safety and/or progress reports that merits an inspection, in the view
p.(None): of the agency;
p.(None): a complaint about the investigator´s inappropriate behavior. INSPECTOR SELECTION
p.(None): A.N.M.A.T. Director of the Drug Evaluation Office (DEO) shall select the inspector or inspectors to conduct the
p.(None): inspection.
p.(None): The Director of the Drug Evaluation Office shall ensure:
p.(None): the appropriate number of inspectors to perform the inspection;
p.(None):
p.(None): the inspectors´ suitability based on their education and training in studies scientific and regulatory aspects;
p.(None): the absence of potential financial conflicts of interest with the study investigators, research sites or
p.(None): sponsor;
p.(None): the supply of a proper identification document for inspectors;
p.(None): inspectors´ access to all the study information needed to carry out the inspection, including at least,
p.(None): the protocol, amendments, informed consents and serious and unexpected ADRs reports as well as the study
p.(None): progress and previous inspections reports.
p.(None): PLANNING AN INSPECTION
p.(None): When planning an inspection, the designated inspectors shall: analyze the information provided by the Drug Evaluation
p.(None): Office ;
p.(None): thoroughly know the study objectives, inclusion and exclusion criteria, foreseen visits and analytical procedures,
p.(None): investigational product information, its safety data and special handling and storage requirements as well
p.(None): as the allowed and unallowed concomitant drugs;
p.(None): consider the observations made during the study evaluation prior to the authorization and/or the study and investigator
p.(None): selection criteria;
p.(None): create an inspection plan specific for the study and the investigator to be inspected , which shall be approved by the
p.(None): Inspections Coordinator and the DEO;
p.(None): create an inspection form including the list of study documents to be reviewed, the guidelines to obtain
p.(None): the informed consent, the verification of clinical records, the investigational product circuit and the
p.(None): facilities of the research center to be visited.
p.(None): INSPECTION ANNOUNCEMENT
p.(None): Inspections shall be announced to the sponsor and/or principal investigator at least fifteen running days
p.(None): before it is conducted, in order to ensure the availability of the research team and documentation at the
p.(None): time of the inspection conduct.
p.(None): The previous inspection announcement may not be made if the visit is decided upon relevant information included in
p.(None): the safety reports and/or progress reports or upon a complaint about the investigator´s inappropriate behavior.
p.(None): The inspection shall be announced by means of a certified return receipt letter. INSPECTION CONDUCT
p.(None): General considerations
p.(None): Inspectors shall appear at the site to be inspected and get in contact with the investigator or his or
p.(None): her delegate at the announced date and time.
p.(None): Inspectors shall:
p.(None): verify the compliance with the protocol and its amendments authorized by A.N.M.A.T.; verify that participants´ rights
p.(None): and safety were protected;
p.(None): evaluate data quality and integrity.
p.(None):
p.(None): The documents obtained or produced from the inspections of clinical investigators shall be available only for
p.(None): A.N.M.A.T. and, when appropriate, for the investigators and sponsor involved.
p.(None): Both inspector and any other A.N.M.A.T. personnel related to clinical investigators activities shall
p.(None): maintain confidential the information they access to during the inspections.
p.(None): Initial interview
p.(None): In the initial interview the inspector shall show his or her official identification and explain the
p.(None): type and scope of the inspection as well as the procedures that will be conducted therein.
p.(None): The investigator´s team members and the sponsor´s agents may be present at the initial interview.
p.(None): The inspectors shall request information (who, what, when, where, how) about the delegation of the following
p.(None): functions to the investigator´s team members:
p.(None): informed consent obtainment; prospective participants assessment;
p.(None): participants´ selection and random assignment; clinical data obtainment and evaluation;
p.(None): clinical data forms filing out;
p.(None): study drug reception, return and management.
p.(None): The inspector may interview the investigator´s team members and, if appropriate, participants at the
p.(None): beginning of or during the inspection.
p.(None): Inspection conduct
p.(None): The inspectors shall identify and review all the source documents and other documents essential for the study.
p.(None): Likewise, the inspectors may inspect the facilities of the research center or those of the external institutions where
p.(None): study-related procedures are performed.
p.(None): The handwritten or electronic notes taken by the inspectors during the inspection shall be filed in the inspection
p.(None): dossier at the agency and shall serve as a support for inspection report accuracy.
p.(None): The inspectors shall request and take copies of the study records or investigational product samples, if
p.(None): they deem it appropriate.
p.(None): The inspectors may interview the study participants, should they find it necessary. Such interviews shall be
p.(None): documented in records different from the inspection records. The interview records shall contain the
p.(None): participant´s identification, the interview objective, the questions made and the answers provided by
p.(None): the participants. The interview records shall be filed in the inspection dossier at the agency and the
p.(None): investigators shall access them upon previous justified request to and express authorization by the
p.(None): agency.
p.(None):
p.(None): The inspectors may interrupt the study and shall immediately communicate such decision to the DEO, if they
p.(None): were to identify serious deviations from the regulations or serious risks for the participants.
p.(None): RECORD REVIEW PROCEDURES
...
p.(None): record text shall make reference to the documents attached.
p.(None): Three original inspection records shall be signed by the investigator and/or a sub- investigator, the
p.(None): inspectors and the sponsor´s agent. An original record shall be given to the investigator and another one to the
p.(None): sponsor´s agent while the third original record shall be retained by the inspectors and filed in the
p.(None): inspection dossier at A.N.M.A.T.
p.(None): INSPECTION TECHNICAL REPORT
p.(None): Once all the pending issues are dealt with, the inspectors shall write a final technical report of the inspection
p.(None): in print and digital format, including a clear and objective description of the inspection findings based on
p.(None): the inspection record.
p.(None): The technical report shall document the observations made during the inspection and describe in detail the type and
p.(None): scope of the inspection and the answers provided by the parties during the inspection in an orderly manner.
p.(None): The technical report shall conclude with a proposal of Inspection Result and of the measures deemed
p.(None): appropriate as per such Result.
p.(None): The final technical report shall be submitted to the Director of the DEO, who will notify the inspected party of such
p.(None): report, if appropriate.
p.(None): INSPECTION RESULT
p.(None): The inspection result may be communicated to the inspected party during the inspection exit interview
p.(None): or by means of a summoning of the said party to the Drug Evaluation Office premises or by means of a
p.(None): notification that shall be given at
p.(None): A.N.M.A.T. reception desk.
p.(None): The Inspection Results shall be as follows:
p.(None): No Action Indicated (NAI): no objectionable conditions or practices were found during the inspection;
p.(None): Voluntary Action Indicated (VAI): conditions or practices requiring corrective measures by the investigator or sponsor,
p.(None): but that do not require any action by A.N.M.A.T. were found during the inspection;
p.(None): Official Action Indication (OAI): actions by A.N.M.A.T. are required.
p.(None): In the event an OAI is required, the director of the Drug Evaluation Office shall be empowered to take
p.(None): the following preventive measures:
p.(None): temporary suspension of the study recruitment at the center; temporary suspension of the study inspected at the center;
p.(None): restriction on the investigator to conduct new studies.
p.(None): In the cases under 12.3., the investigator shall commit him or herself in writing before the director of the DEO
p.(None): to implement the corrective actions indicated to him or her.
p.(None):
p.(None): After that, he or she will be allowed to re-initiate or initiate, as appropriate, the enrolment of up to
p.(None): three participants. A new inspection shall verify the compliance of the investigator´s committee and enable him or her
p.(None): to continue or not the recruit and/or the conduct of the study.
p.(None): In the event an OAI, the agency may adopt one or more of the following final measures, simultaneous or
p.(None): consecutively, after assessing the inspection technical report and the recommendation of the director of the DEO:
p.(None): final suspension of the study recruit at the center; final suspension of the study inspected at the center; suspension
p.(None): of all the studies conducted at the center;
p.(None): suspension at all the centers nationwide of the inspected study; indication to the sponsor of monitoring
p.(None): intensification at the center; indication to the sponsor of a change of investigator at the center; indication to the
p.(None): sponsor to reject all the data generated at the center;
p.(None): notification to the competent authority or professional association granting the investigator´s
...
p.(None): social or economic disadvantage, for example, in the case of ethnic minorities, refugees or illiterate,
p.(None): subdued, homeless or impoverished persons. For such cases, the additional protection is the presence of an impartial
p.(None): witness who assures that all the rights and interests of those persons are respected during the informed consent
p.(None): obtainment process. The absence of autonomy takes place when a person is legally or mentally incapable of
p.(None): giving his or her consent voluntarily. In said cases, the consent shall be obtained from his or her legal
p.(None): representative pursuant to the Argentine legislation in the matter.
p.(None): BIOAVAILABILITY: the capacity of a pharmaceutical form of releasing an API in the site of action at the proper
p.(None): speed to obtain a sufficient concentration, and at the timely moment to enable it to exert its action. Since,
p.(None): generally, the concentration cannot be determined in bio-phase in human beings and assuming the existence of balance in
p.(None): the concentrations in serum and bio-phase, the fraction of a drug reaching the systemic circulation of the
p.(None): extravascularly administered dose of a given pharmaceutical form, shall be accepted as bioavailability.
p.(None): BIOEQUIVALENCE: two drugs or medicinal products are biologically equivalent when, upon the existence of chemical
p.(None): equivalence, they have a similar bioavailability if administered to the same person in an equal dosage regimen.
p.(None): GOOD CLINICAL PRACTICE (GCP): an international ethical and scientific quality standard for the design,
p.(None): conduct, recording and reporting of the trials involving the participation of human subjects. Compliance
p.(None): with this standard provides a public assurance that the participants´ rights, safety and well-being
p.(None): are protected, in accordance with the Declaration of Helsinki; and that the trials data are reliable.
p.(None): GOOD MANUFACTURING PRACTICE (GMP): a standard to assure a uniform manufacture that meets the
p.(None): requirements of product identity, activity and purity.
p.(None): GOOD LABORATORY PRACTICE (GLP): a laboratory organization and activity related standard under which studies are
p.(None): planned, conducted, recorded, controlled and presented. It aims at assuring the quality and integrity of all the
p.(None): data produced during a given study as well as to tighten the study related safety.
p.(None): RESEARCH ETHICS COMMITTEE (REC): a body acting within its competence scope, which is independent from the sponsor and
p.(None): investigator and is constituted by medical or scientific professionals and non-medical or non-scientific members
p.(None): and whose function is to provide public assurance of the protection of the rights, dignity, safety and
p.(None):
...
p.(None): CLINICAL STUDY: a set of activities with the purpose of obtaining generalizable knowledge about human
p.(None): health to be applied in medicine, sciences of life and their related technologies. Clinical studies may be
p.(None): observational or experimental, according to whether the investigator intervenes or not in the variable under study.
p.(None): EXPERIMENTAL CLINICAL STUDY (synonym: clinical trial): a study in which the investigator selects
p.(None): participants upon inclusion and exclusion criteria, actively intervenes on the independent or predicting
p.(None): variable and observes and analyzes the changes made in the dependent or outcome variable as a consequence
p.(None): of the
p.(None):
p.(None): intervention. Controlled clinical trials entail the concept of hypotheses contrast with a null hypothesis. The
p.(None): interventions may encompass synthesis drugs, biological products, medical devices, surgical techniques, etc.
p.(None): Said studies are considered as of “major risk” to participants.
p.(None): CLINICAL PHARMACOLOGY STUDY: a systematic scientific study conducted with drugs or biological products in
p.(None): volunteer, healthy or unhealthy human subjects, with the purpose of discovering or verifying their therapeutic effects
p.(None): and/or identifying adverse reactions and/or studying the absorption, distribution, metabolism
p.(None): (biotransformation) and excretion of their active principles in order to determine their efficacy and safety.
p.(None): PHASE I STUDY: an initial introduction of a new drug researched in human subjects to determine its metabolism,
p.(None): pharmacological actions, secondary effects with increasing doses and, if possible, to obtain early evidence about its
p.(None): efficacy. It includes the study of variations among sub-populations and interactions with other drugs and the intake of
p.(None): food. These studies must justify the use of the product in Phase II. Typically, Phase I studies are closely monitored
p.(None): and may be conducted in volunteer healthy subjects or, occasionally, in patients.
p.(None): PHASE II STUDY: the efficacy and safety of the dose ranges are determined in this phase. Likewise, the
p.(None): dose-response ratio is determined, whenever possible, in order to obtain a broad background for the design of widened
p.(None): therapeutic studies (Phase III).
p.(None): PHASE III STUDY: a study conducted in large and varied groups of participants in order to determine both
p.(None): short-term and long-term risk-benefit balance of the proposed formulation(s) and the relative therapeutic value, in
p.(None): general.
p.(None): PHASE IV STUDY: a study conducted after the drug and/or medicinal product is marketed in order to determine
p.(None): its therapeutic value, the appearance of new adverse reactions and/or the confirmation of the already known adverse
p.(None): reactions frequency as well as the treatment strategies.
p.(None): VACCINE CLINICAL STUDY: a systematic and scientific study conducted in volunteer, healthy or unhealthy human
p.(None): subjects in order to determine the tolerance, safety, immunogenicity and/or efficacy of a vaccine. It has
p.(None): three phases: (a) Phase I: first study conducted in human beings to evaluate the tolerance, safety and biologic
p.(None): effects;
p.(None): (b) Phase II: a study determining the immunogenicity caused by a vaccine; and (c) Phase III: a controlled
p.(None): clinical study, with a high number of volunteer participants which aims to assess the effectiveness of a vaccine for
p.(None): the prevention of a disease and its safety in a more thorough way.
p.(None): MULTI-CENTER STUDY: a clinical study conducted according to only one protocol but in more than one place or
p.(None): institution and, therefore, conducted by more than one investigator.
p.(None): ADVERSE EVENT (AE): any adverse medical occurrence in a patient or subject of a clinical study of a health intended
p.(None): product or therapeutic procedure and which does not have a necessary causal relation with this treatment. An
p.(None): adverse event may be any unfavorable and unintended sign, including laboratory abnormal findings and
p.(None): symptoms or diseases temporally associated with the use of the investigational product, whether related or
p.(None): not with it.
...
p.(None): with the aim of acting as a comparator in a clinical
p.(None):
p.(None): pharmacological study, as long as the ethical criteria of participant protection is respected.
p.(None): VULNERABLE POPULATION: an individual or a group of individuals whose wish to participate in a clinical
p.(None): trial may be unduly influenced by the justified or unjustified expectation of the benefits associated with his
p.(None): or her participation (undue influence) or by the threat by the investigators or any other unequal relation in case the
p.(None): individual refuses to participate (duress).
p.(None): COMPARATOR PRODUCT: a marketed or investigational product or a placebo used as a reference in a clinical study.
p.(None): INVESTIGATIONAL PRODUCT: a pharmaceutical form of an active substance under investigation, including products
p.(None): holding a marketing authorization when used or combined in the formulation in a form other than the authorized
p.(None): one or for the treatment of an unauthorized indication.
p.(None): PROTOCOL: a document describing the history, fundamentals, objectives, design, methodology ethical
p.(None): considerations, statistical aspects and organization of a study.
p.(None): ADVERSE DRUG REACTION (ADR): an untoward and unintended response to a medicinal product at any dose. In
p.(None): clinical experience and before the approval of a new medicinal product or of its new uses, particularly, when the
p.(None): therapeutic dose cannot be determined, any reaction implying causal relation between a medicinal product and an adverse
p.(None): event as a reasonable possibility, that is to say, that the relation may not be ruled out, must be considered an
p.(None): adverse drug reaction.
p.(None): UNEXPECTED AND SERIOUS ADVERSE DRUG REACTION (UNEXPECTED
p.(None): SADR): an adverse reaction that results in death, is life-threatening, requires in-patient hospitalization or
p.(None): prolongation of the existent hospitalization, results in persistent or significant incapacity or disability
p.(None): and whose nature of seriousness is not consistent with the product information written in the
p.(None): investigational product monograph or any other documentation.
p.(None): LEGAL REPRESENTATIVE: a person authorized under the Argentine Civil Code or the applicable laws, who acts as the
p.(None): representative of a prospective participant in a clinical study to grant the informed consent to the study.
p.(None): IMPARTIAL WITNESS: a person independent from the investigator and his or her team who participates in the informed
p.(None): consent obtainment process as an assurance that such process respects the rights and interests of a
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p.(None): product or therapeutic procedure and which does not have a necessary causal relation with this treatment. An
p.(None): adverse event may be any unfavorable and unintended sign, including laboratory abnormal findings and
p.(None): symptoms or diseases temporally associated with the use of the investigational product, whether related or
p.(None): not with it.
p.(None): SERIOUS ADVERSE EVENT (SAE): any unfavorable occurrence throughout and within the research of a diagnostic or
p.(None): therapeutic product or procedure that results in death, is life-threatening, requires in-patient hospitalization
p.(None): or prolongation of the
p.(None):
p.(None): existent hospitalization, results in persistent or significant incapacity or disability or that is a congenital anomaly
p.(None): or a birth defect or that is medically significant as per medical criteria. The above mentioned is applicable
p.(None): without the need for an alleged causal relation existence between the product or treatment administered
p.(None): and the adverse event.
p.(None): CLINICAL DATA FORM (CDF): a printed, digital or optical document designed to keep record of all the clinical data
p.(None): required as per protocol, about each participant of the study and that shall be reported to the sponsor.
p.(None): CONTROL GROUP: a group used as a comparator that indicates what happens when the treatment under study is not applied.
p.(None): ACTIVE PHARMACEUTICAL INGREDIENT: a natural, biological or synthetic chemical substance having a specific
p.(None): pharmacological effect and that is used in human medicine.
p.(None): INSPECTION: an official review conducted by the competent authority of the documents, facilities,
p.(None): records and any resource considered as related to the clinical study and that may be located in the research
p.(None): center, sponsor´s or contract research organization (CRO) facilities or in other sites deemed appropriate.
p.(None): INSPECTOR: a person designated by the competent health and/or regulatory authority to conduct the study-related
p.(None): inspections.
p.(None): INSTITUTION OR RESEARCH CENTER: any government or privately owned agency or medical or dental facility where clinical
p.(None): studies are conducted.
p.(None): INVESTIGATOR: a professional responsible for conducting the clinical trial at the research center. If the
p.(None): trial is conducted by a team, the investigator is responsible for the team and is denominated the principal
p.(None): investigator. The principal investigator may delegate functions to his or her team, but not his or her
p.(None): responsibilities. The investigator-sponsor is the physical person initiating, managing financing and
p.(None): conducting, on his or her own or together with others, a clinical study, having under his or her responsibility the
p.(None): management, dispensation and use of the investigational product.
p.(None): INVESTIGATIONAL PRODUCT MONOGRAPH: (Synonym: Investigator´s brochure) a compilation of clinical and non-clinical data
p.(None): of drugs, investigational medical products or procedures relevant for their study in human beings.
p.(None): MONITORING: action of overseeing the process of a clinical study and ensuring that it is conducted, recorded and
p.(None): reported in accordance with the protocol, SPO(s), GCP and applicable regulatory requirements.
p.(None): CONTRACT RESEARCH ORGANIZATION (CRO): a physical person or legal entity contracted by the sponsor to perform
p.(None): one or more of his or her functions or activities related to the study.
p.(None): STUDY PARTICIPANT: a healthy or unhealthy individual participating in a clinical pharmacology study as a
p.(None): research subject.
p.(None): SPONSOR: a physical person or legal entity responsible for initiating, managing, controlling and financing a
p.(None): clinical study.
p.(None): PLACEBO: a pharmacologically inert substance used as a substitute of the investigational product
p.(None): with the aim of acting as a comparator in a clinical
p.(None):
p.(None): pharmacological study, as long as the ethical criteria of participant protection is respected.
p.(None): VULNERABLE POPULATION: an individual or a group of individuals whose wish to participate in a clinical
p.(None): trial may be unduly influenced by the justified or unjustified expectation of the benefits associated with his
p.(None): or her participation (undue influence) or by the threat by the investigators or any other unequal relation in case the
p.(None): individual refuses to participate (duress).
p.(None): COMPARATOR PRODUCT: a marketed or investigational product or a placebo used as a reference in a clinical study.
p.(None): INVESTIGATIONAL PRODUCT: a pharmaceutical form of an active substance under investigation, including products
p.(None): holding a marketing authorization when used or combined in the formulation in a form other than the authorized
p.(None): one or for the treatment of an unauthorized indication.
p.(None): PROTOCOL: a document describing the history, fundamentals, objectives, design, methodology ethical
p.(None): considerations, statistical aspects and organization of a study.
p.(None): ADVERSE DRUG REACTION (ADR): an untoward and unintended response to a medicinal product at any dose. In
p.(None): clinical experience and before the approval of a new medicinal product or of its new uses, particularly, when the
p.(None): therapeutic dose cannot be determined, any reaction implying causal relation between a medicinal product and an adverse
p.(None): event as a reasonable possibility, that is to say, that the relation may not be ruled out, must be considered an
p.(None): adverse drug reaction.
p.(None): UNEXPECTED AND SERIOUS ADVERSE DRUG REACTION (UNEXPECTED
p.(None): SADR): an adverse reaction that results in death, is life-threatening, requires in-patient hospitalization or
p.(None): prolongation of the existent hospitalization, results in persistent or significant incapacity or disability
p.(None): and whose nature of seriousness is not consistent with the product information written in the
p.(None): investigational product monograph or any other documentation.
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p.(None): regulations in force or whenever the regulatory authority deems it relevant and opportune;
p.(None): to suspend the study in a research center due to noncompliance with the regulations herein or for participants´ safety
p.(None): reasons.
p.(None): GENERAL PRINCIPLES
p.(None): The interests and well-being of every participant of the study shall prevail over the interests of science
p.(None): and society in all clinical pharmacology studies.
p.(None): Clinical pharmacology studies must respect accepted ethical and scientific principles, the investigation participants´
p.(None): physical and mental integrity as well as their privacy and personal data protection, pursuant to Act 25.326 or any law
p.(None): replacing it.
p.(None): According to the type of active pharmaceutical ingredient (API) under study, clinical pharmacology studies
p.(None): shall be conducted after running pre-clinical studies which prove that the investigational product has a potential
p.(None): therapeutic advantage and that the risks participants are exposed to are justified by the benefits expected.
p.(None): Pre-clinical studies shall be conducted in accordance to Good Laboratory Practice (GLP) standards and
p.(None): investigational products shall be manufactured, handled and stored under the Good Manufacturing Practice
p.(None): (GMP) standards. In studies of undefined or not GLP or GMP governed products, for instance, biological
p.(None): products, the sponsor shall set the guidelines for development, control and usage procedures, which shall require
p.(None): A.N.M.A.T. approval.
p.(None): The sponsor and investigators of clinical pharmacology studies within the scope of this Regulatory Guideline shall
p.(None): fulfill the obligations established herein.
p.(None): Clinical pharmacology studies shall be described in a clear and detailed protocol and require a Research Ethics
p.(None): Committee assessment and approval as well as an
p.(None): A.N.M.A.T. authorization prior to the enrollment of participants in a research center.
p.(None):
p.(None): Clinical pharmacology studies shall be conducted by investigators holding credited qualification and
p.(None): training to perform them, as set forth in 2.2. (c) and 2.2. (d) of SECTION B.
p.(None): Investigators shall obtain a free and voluntary informed consent from the prospective participants or their legal
p.(None): representatives before entering the study.
p.(None): Treatments and procedures related to the study shall be free of charge for all participants.
p.(None): The transport of the biological samples obtained in the studies shall comply with applicable international
p.(None): and domestic regulations.
p.(None): NONCOMPLIANCE
p.(None): Investigators and sponsors failing to comply with the Regulatory Guideline herein shall be subject to the sanctions
p.(None): and preventive measures provided for in Act 16.463 and Decree 341/92 or the regulations replacing them, without
p.(None): prejudice of the criminal actions which may take place and/or the relevant report to the authorities governing the
p.(None): pertaining professional practice.
p.(None): SECTION B: DOCUMENTS REQUIREMENTS FOR A CLINICAL PHARMACOLOGY STUDY AUTHORIZATION APPLICATION
p.(None): OBJECTIVE
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p.(None): NATIONAL ADMINISTRATION OF DRUGS, FOODS AND MEDICAL DEVICES REGULATION 6677/10
p.(None):
p.(None): The Regulatory Guideline for Good Clinical Practices in Clinical Pharmacology Studies is hereby approved.
p.(None): Some A.N.M.A.T. (the agency) regulations are hereby repealed.
p.(None):
p.(None):
p.(None): Buenos Aires City, November 1, 2010.
p.(None): Having regard to A.N.M.A.T. Regulation 5330/97, as amended and supplemented by Regulations 3436/98, 3112/00, 690/05,
p.(None): 1067/08 and 6550/08, Dossier Nr 1-47-20664- 10-0 of the Registry Office of the National Administration of Drugs, Foods
p.(None): and Medical Devices, and
p.(None):
p.(None):
p.(None): Whereas,
p.(None): Clinical Pharmacological Investigation is necessary to obtain strong scientific evidence which enables to improve the
p.(None): public´s health care quality.
p.(None): The development of clinical investigation, in general, should respect basic human rights and freedoms inherent to human
p.(None): nature and enshrined in the National Constitution and Human Rights International Treaties, bearing a constitutional
p.(None): status as incorporated in article 75, sub-title 22 thereof.
p.(None): In this regard, all clinical investigation should safeguard the dignity of participating subjects, ensuring
p.(None): their personal rights, specially, the respect for their autonomy and physical, psychic and moral integrity.
p.(None): As stated by Resolution 1490/07 of the Ministry of Health, Good Clinical Practices are worldwide accepted ethical
p.(None): and scientific standards which set out guidelines for the design, conduct, recording and reporting of studies
p.(None): involving the participation of human beings and, when complied with, such standards ensure that the rights,
p.(None): well-being, safety and dignity of the participating subjects are protected and respected.
p.(None): By means of clinical pharmacological research, a new Active Pharmaceutical Ingredient (API)
p.(None): undergoes the performance of scientifically validated tests to demonstrate its efficacy and safety
p.(None): and thus it provides evidence resulting from the performance of clinical studies.
p.(None): By means of Regulation 5330/07, A.N.M.A.T. approved the Guideline for Good Research Practices for Clinical
p.(None): Pharmacology Studies, in order to fully guarantee the compliance with the standards set forth, both nation and
p.(None): worldwide, in regard to regulations and ethical and legal values.
p.(None): The experience acquired in the systematic application of the aforementioned regulation, the
p.(None): progress made in the synthesis and manufacture of new API(s) for human medicine as well as the increasing
p.(None): number of studies submitted for A.N.M.A.T. approval gave rise to the need for a clear definition of this agency´s
p.(None): regulation scope and for maximizing the soundness, review and permanent update of its procedural, training,
p.(None): ethical and methodological aspects, from the authorization application stage
p.(None):
p.(None): and throughout research conduct and, in particular, of the aspects related to the duties of all the players involved in
p.(None): clinical drug research.
p.(None): A.N.M.A.T.´s duty is to ensure that clinical pharmacology investigations conducted with drugs and medicinal products
p.(None): are compliant with clinical pharmacology standards currently adopted by countries having a strict health
p.(None): vigilance system and with the World Health Organization (WHO) scientific, ethical and legal recommendations.
p.(None): Ethical principles applicable to the conduct of clinical studies were set forth in Nuremberg (1948) and
p.(None): Helsinki (1964 and updates) declarations of human rights and on ethical principles for medical research involving
p.(None): human subjects, the ”Operational guidelines for ethics committees that review biomedical research” (WHO– World Health
p.(None): Organization, 2000) and the “International Ethical Guidelines for Biomedical Research involving Human Subjects”
p.(None): (CIOMS – Council for International Organizations of Medical Sciences, 2002), it becomes appropriate to
p.(None): establish the guidelines to enforce such principles application.
p.(None): In its decision 306:178, the Argentine Supreme Court of Justice highlighted the legal significance of ethical
p.(None): standards as a set of rules concerning the art of healing professionals, by ruling that: “It is not
p.(None): appropriate to restrict their scope or deprive them from legal relevance; but in turn, they should be ensured
p.(None): substantial respect to avoid the dehumanization of the art of healing, particularly, when from fact confrontation and
p.(None): professional behavior demands, as currently ruled, a judgment of reproach bearing the capacity of affecting the
p.(None): responsibility of the stakeholders may arise” (translation of “… no cabe restringir su alcance ni privarlos de
p.(None): toda relevancia jurídica, sino que se impone garantizarles un respeto para evitar la deshumanización del
p.(None): arte de curar, particularmente cuando de la confrontación de los hechos y de las exigencias de la conducta
p.(None): profesional así reglada,podría eventualmente surgir un juicio de reproche con entidad para comprometer la
p.(None): responsabilidad de los interesados”).
p.(None): The GUIDELINES FOR GOOD CLINICAL PRACTICE IN RESEARCH ON HUMAN
p.(None): SUBJECTS was approved by means of Resolution Nr 1490/07 of the Ministry of Health, with a view to
p.(None): standardizing activities related to clinical research on human subjects and ensuring the respect for ethical
p.(None): values and the rights, safety and integrity of participating subjects.
p.(None): The above mentioned rules were incorporated in the Guidelines for Good Clinical Research Practices in
p.(None): Clinical Pharmacology Studies, approved by A.N.M.A.T. Regulation 5330/97.
p.(None): A.N.M.A.T. Regulation 3436/98 set forth a mechanism to approve the amendments of clinical studies previously authorized
p.(None): by this agency.
p.(None): A.N.M.A.T. Regulation 3112/00 amended A.N.M.A.T. Regulation 3436/98 in terms of the addition and/or exclusion of
p.(None): authorized health institutions and investigators.
p.(None): A.N.M.A.T. Regulation 690/05 set forth the Guidelines for Inspections of Clinical Investigators with a view
p.(None): to monitoring that the conduct of clinical studies is compliant with Good Clinical Practice standards and the
p.(None): regulatory requirements in force; and ensuring that the rights and well-being of the subjects participating in the
p.(None): studies are protected and the data obtained are credible.
p.(None): A.N.M.A.T. Regulation 1067/08 amended A.N.M.A.T. Regulation 5330/97 as to adverse events reporting and
p.(None): A.N.M.A.T. Regulation 2124/05 was repealed.
p.(None):
p.(None): A.N.M.A.T. Regulation 6550/2008 amended and updated different provisions of
p.(None): A.N.M.A.T. Regulation 5330/97.
p.(None): In accordance with the aforementioned herein, A.N.M.A.T. deems it necessary to lay down new REGULATORY GUIDELINE
p.(None): FOR GOOD CLINICAL PRACTICE IN CLINICAL PHARMACOLOGY STUDIES.
p.(None): The Drug Evaluation Office, the National Institute of Drugs and the Legal Affairs Office have been involved to the
p.(None): extent appropriate.
p.(None): A.N.M.A.T. acts by virtue of the powers granted upon it by Decrees 1490/92 and 425/10.
p.(None):
p.(None):
p.(None): The Controller of A.N.M.A.T. decrees:
p.(None): Art. 1 – To approve the REGULATORY GUIDELINE FOR GOOD CLINICAL
p.(None): PRACTICE IN CLINICAL PHARMACOLOGICAL STUDIES hereby included as an Annex and considered a part and parcel
p.(None): hereof.
p.(None): Art. 2 – To set forth that A.N.M.A.T. shall announce its decision within a ninety working- day period after the
p.(None): procedure initiation date, upon submission of the documentation provided for in Art.1 herein. Such period may
p.(None): be suspended, should any objection arise, until the applicant submits all the pertaining documentation and/or
p.(None): complies with the objections and/or clarifications requested.
p.(None): Art. 3 - That applicants failing to comply with the policy laid down in Art. 1 herein may be subject to the sanctions
p.(None): under Act 16.463 and Decree 341/92, without prejudice of the adoption of the pertaining preventive measures.
p.(None): Art. 4 – That A.N.M.A.T. Regulations 5330/97, 3436/98, 3112/00, 690/05, 1067/08 and 6550/08 are hereby repealed.
p.(None): Art. 5 – That the present Regulation shall come into effect one day after its publication in the Argentine Official
p.(None): Journal.
p.(None): Art. 6 –The present Regulation shall be registered and conveyed to the Official Registration Office to
p.(None): be published. It shall be communicated to the Secretariat of Policies, Regulations and Institutes under
p.(None): the Ministry of Health, the concerned professional associations and chambers and to A.N.M.A.T. Planning and
p.(None): Institutional Relations Office and Drug Evaluation Office and placed on record. Carlos Chiale.
p.(None):
p.(None): ANNEX I: REGULATORY GUIDELINE FOR GOOD CLINICAL PRACTICE IN CLINICAL PHARMACOLOGY STUDIES
p.(None): INDEX
p.(None): SECTION A: GENERAL CONSIDERATIONS
p.(None): Definitions Objectives
p.(None): Application and scope General principles Noncompliance
p.(None):
p.(None): SECTION B: DOCUMENTATION REQUIREMENTS FOR THE AUTHORIZATION OF CLINICAL PHARMACOLOGY STUDIES
p.(None): Objective
p.(None): General documentation Investigational product monograph Protocol
p.(None): Informed consent
p.(None): Amendments to the protocol, informed consent and investigational product monograph Unexpected and serious adverse drug
p.(None): reactions
p.(None): Study reports and other communications
p.(None):
p.(None):
p.(None): SECTION C: GUIDELINE FOR GOOD CLINICAL PRACTICE IN CLINICAL PHARMACOLOGY STUDIES
p.(None): Objective Investigator Sponsor
p.(None): Research Ethics Committee Informed consent
p.(None): Protection of study participants Agreements and financing Investigational product
p.(None): Reports and other communications Changes during the study Recording of clinical data Essential study documents
p.(None): Monitoring
p.(None):
p.(None): Audit
p.(None): Suspension or cancellation of the study
p.(None):
p.(None):
p.(None): SECTION D: INSPECTIONS OF CLINICAL PHARMACOLOGY STUDIES
p.(None): Objective
p.(None): Scope and authority Inspection process
p.(None): Study and inspector selection Inspector selection Preparation for
p.(None): Planning the inspection Inspection announcement Inspection conduct Record review procedures Inspection record
p.(None): Inspection technical report Inspection report
p.(None):
p.(None): SECTION E: GLOSSARY
p.(None):
p.(None):
p.(None): SECTION F: FORMS
p.(None):
p.(None): SECTION A: GENERAL CONSIDERATIONS DEFINITIONS
p.(None): Good Clinical Practice (GCP) is an international ethical and scientific quality standard for the design, conduct,
p.(None): recording and reporting of studies involving human subjects. The adoption of this standard provides a public assurance
p.(None): that the participants´ rights, safety and well-being are protected, in accordance with the principles
p.(None): of the Declaration of Helsinki and that clinical studies data are reliable.
p.(None): Clinical pharmacology studies are trials that evaluate the safety and efficacy of a drug intended for a disease
p.(None): prevention, treatment or diagnosis. Broadly considered, research on human health has provided valuable
p.(None): benefits in terms of suffering mitigation and prolongation of human life. However, clinical trials, in particular,
p.(None): involve risks for participating individuals, which gives raise to the need for a governmental regulation
p.(None): and monitoring mechanism ensuring the utmost protection for participants.
p.(None): OBJECTIVES
p.(None): The Regulatory Guideline for Good Clinical Practice in Clinical Pharmacology Studies (GCP-CPS) herein establishes the
p.(None): requirements that sponsors and investigators must comply with within the scope of this agency´s authorization
p.(None): granting and monitoring duties.
p.(None): The Regulatory Guideline for GCP-CPS aims to protect the rights and well-being of human subjects
p.(None): participating in clinical pharmacology studies and to provide an assurance of the quality and integrity of the
p.(None): information produced thereby.
p.(None): APPLICATION AND SCOPE
p.(None): The Regulatory Guideline herein shall be applied to clinical pharmacology studies with a registry and/or regulatory
p.(None): purpose, nationwide or abroad. Both physical persons and legal entities shall apply for an authorization from the
p.(None): National Administration of Drugs, Foods and Medical Devices (A.N.M.A.T.) prior to running the study and shall comply
p.(None): with the requirements set forth herein. The following studies are within the scope of this Regulatory Guideline:
p.(None): phase I, phase II and phase III studies;
p.(None): studies on products already registered at A.N.M.A.T. aiming to evaluate a new indication, a new
p.(None): concentration, if higher than the registered one, a new dosage form or a new pharmaceutical form with a registry
p.(None): purpose;
...
p.(None): to require a protocol amendment before or during the conduct of the study;
p.(None): to approve, object or reject the investigators and/or the research centers proposed for conducting the study;
p.(None):
p.(None): to include in this agency´s data base the clinical studies submitted as it registers the rate of progress of authorized
p.(None): studies;
p.(None): before authorizing the conduct of the study, it may perform an inspection of a research center, when deemed
p.(None): appropriate;
p.(None): through the Department of Foreign Trade under its supervision, the Drug Evaluation Office may intervene in
p.(None): the authorization of country inflow and outflow of material intended for the study, once the study has been
p.(None): approved;
p.(None): to authorize amendments to the protocol and informed consent document, the addition or change of investigators and/or
p.(None): research centers as well as the import and export of materials intended for the study within A.N.M.A.T. regulation
p.(None): scope;
p.(None): to evaluate the investigators´ progress and final reports;
p.(None): to analyze the results produced, when deemed appropriate;
p.(None): to control the compliance of the standards laid down in this Regulatory Guideline by means of summoning the
p.(None): investigator or sponsor and/or inspecting the contract research organization (CRO) of a clinical pharmacology
p.(None): study;
p.(None): to summon, examine and/or question the participants included in the study as part of the study routine evaluation,
p.(None): whenever there is information indicating a hazard to their health, if there are doubts as to the compliance with
p.(None): regulations in force or whenever the regulatory authority deems it relevant and opportune;
p.(None): to suspend the study in a research center due to noncompliance with the regulations herein or for participants´ safety
p.(None): reasons.
p.(None): GENERAL PRINCIPLES
p.(None): The interests and well-being of every participant of the study shall prevail over the interests of science
p.(None): and society in all clinical pharmacology studies.
p.(None): Clinical pharmacology studies must respect accepted ethical and scientific principles, the investigation participants´
p.(None): physical and mental integrity as well as their privacy and personal data protection, pursuant to Act 25.326 or any law
p.(None): replacing it.
p.(None): According to the type of active pharmaceutical ingredient (API) under study, clinical pharmacology studies
p.(None): shall be conducted after running pre-clinical studies which prove that the investigational product has a potential
p.(None): therapeutic advantage and that the risks participants are exposed to are justified by the benefits expected.
p.(None): Pre-clinical studies shall be conducted in accordance to Good Laboratory Practice (GLP) standards and
p.(None): investigational products shall be manufactured, handled and stored under the Good Manufacturing Practice
p.(None): (GMP) standards. In studies of undefined or not GLP or GMP governed products, for instance, biological
p.(None): products, the sponsor shall set the guidelines for development, control and usage procedures, which shall require
p.(None): A.N.M.A.T. approval.
...
p.(None): the investigator´s abridged Curriculum Vitae which shall be signed and dated by him or her;
p.(None): a certified copy of the investigator´s degree certification and professional license awarded by the
p.(None): sanitary authority of the jurisdiction where the study shall be conducted. Likewise, a certified copy of
p.(None): his or her proofs of training and/or experience in clinical research shall be required;
p.(None): for Phase II and Phase III studies, a certified copy of the certificate of specialist or the certificate of residency
p.(None): completion or the certificate of graduate specialization in the disease under study;
p.(None): an original letter stating the commitment to comply with the study protocol (indicating its title), the Declaration of
p.(None): Helsinki and A.N.M.A.T. Regulatory Guideline for GMP-CFS;
p.(None): a certified copy of the study approval by a Research Ethics Committee (REC), with a detail of the documents
p.(None): reviewed, for example, protocol, informed consent, and investigational product monograph. Only one approval by a
p.(None): REC shall be accepted per each research center;
p.(None): a dated list of the members of each REC, including name, birth date, gender, profession and
p.(None): occupation, position in the committee and relationship with the institution;
p.(None): a certified copy of the study authorization issued by the highest authority of the host institution. Should the
p.(None): jurisdiction health authority require the registration of health research studies, a certified copy of the proof
p.(None): of the study registration in the jurisdiction shall be submitted;
p.(None): a certified copy of the authorization by the institution authority for the study review by an external REC, if
p.(None): appropriate;
p.(None): a certified proof of the research center operating license in force;
p.(None): an informed consent document specific for the research center, if appropriate; General documents shall be submitted in
p.(None): the above mentioned order.
p.(None): All the documents submitted to the agency shall be in Spanish, except for the investigational product
p.(None): monograph since it shall be used only as study background information. The protocol, informed consent and EFCA
p.(None): forms shall be submitted both in print and digital format (the latter shall be enclosed.)
p.(None):
p.(None): In the event that an amendment to any of the documents, including the protocol, informed consent and
p.(None): investigational product monograph already submitted is needed, the original document with the document amended and a
p.(None): letter explaining the mistake and identifying the original submission file number shall be submitted.
p.(None): The following documents shall not be submitted to the agency but they shall be requested should an
p.(None): inspection of the research center be conducted:
p.(None): clinical data forms (CDF);
p.(None): participants´ enrolment forms and clinical follow-up diaries, excluding questionnaires of the study primary objectives
p.(None): assessment;
p.(None): material to be used in informative meetings with potential participants; a monitoring plan.
...
p.(None): 8.10. The sponsor shall submit the final result within one-year period after the study termination.
p.(None): SECTION C: GOOD CLINICAL PRACTICE GUIDE FOR CLINICAL PHARMACOLOGY STUDIES
p.(None): OBJECTIVE
p.(None): With a view to enabling the agency to exercise its monitoring authority, this section sets forth the procedures that
p.(None): clinical pharmacology studies investigators and sponsors shall conduct pursuant to this regulation.
p.(None): INVESTIGATOR
p.(None): The investigator is the person responsible for conducting a clinical pharmacology study in a research center.
p.(None): Whenever the investigator, plans, initiates and conducts an investigation on his or her own, he or she becomes
p.(None): the study sponsor and takes all the responsibilities implied thereby.
p.(None): The investigator shall be suitably trained and experienced to conduct a clinical pharmacology study, as
p.(None): detailed in his or her Curriculum Vitae and proofs attached thereto.
p.(None): The investigator may set up a team of qualified collaborators who are trained in all the applicable requirements to
p.(None): conduct the investigation, and may therefore, delegate some of his or her functions to them; but not
p.(None): his or her responsibilities. The collaborators´ qualifications shall be documented in their updated Curricula
p.(None): Vitae.
p.(None): The investigator shall maintain an updated list of his or her collaborators, indicating their name,
p.(None): delegated function, activities initiation date and signature registry.
p.(None):
p.(None): The investigator and his or her collaborators shall know and respect the outlines set out in this Regulatory
p.(None): Guideline as well as the competent Health Authority requirements and the study protocol. The investigator and his
p.(None): or her collaborators shall be familiar with the information available concerning the investigational products.
p.(None): The investigator shall verify and ensure that the research site is licensed to operate, that its infrastructure
p.(None): adjusts to the study requirements and that all the equipment, instruments and supplies to be used
p.(None): operate properly. Phase I, pharmacokinetics, bioavailability and bioequivalence studies may only be
p.(None): conducted in second or third level health institutions (for hospitalization), according to the regulation
p.(None): in effect set forth by the Ministry of Health. The level of each institution may be verified in its
p.(None): operating license.
p.(None): In case of advertising in communication media for participant recruit purposes, the advertisements used
p.(None): shall be approved by the REC and submitted to the agency. The investigational product may not, implicitly or
p.(None): explicitly, be referred to as efficacious, safe or equivalent to or better than existing products in such
p.(None): advertisements.
p.(None): The investigator and the research site shall be subject to monitoring, audit or inspection of the clinical study by the
p.(None): REC, sponsor and competent authorities.
p.(None): SPONSOR
p.(None): The sponsor of the study is the physical person or legal entity that initiates, manages, controls and finances the
p.(None): study and takes all the responsibilities laid down in this regulatory guideline.
p.(None): The sponsor shall count on qualified professionals for the design, planning, conduct, analysis and reporting of the
p.(None): clinical study, as well as on medical advisors to pursue matters concerning the investigational products and
p.(None): participants´ safety.
p.(None): The sponsor is responsible for selecting qualified investigators according to their education, training and
p.(None): experience; and research centers having all the resources needed for the proper conduct of the clinical
p.(None): pharmacology study.
p.(None): The sponsor shall furnish the investigator with all the documents necessary to perform the study properly, such as,
p.(None): the protocol and investigational product monograph, among others. Likewise, the sponsor shall be responsible for
p.(None): training the investigator and his or her team on the study procedures, investigational products and applicable
p.(None): requirements.
...
p.(None): conduct, by means of a monitoring mechanism for investigators.
p.(None): Composition
p.(None): The REC composition shall be such that enables a competent, unbiased and uninfluenced evaluation of
p.(None): the scientific, medical, ethical and legal aspects of the study.
p.(None): The REC composition shall be cross functional, multi-sectored and balanced in terms of its members´ age, sex and both
p.(None): scientific and non-scientific education. The number of members shall be adequate, preferably uneven, to ensure the
p.(None): fulfillment of its duty. It shall have a minimum of five full members and at least two alternate members for the cases
p.(None): of absence of the regular members.
p.(None): The research center REC shall include an external member unrelated to the institution and who shall represent the
p.(None): interest of the community being assisted.
p.(None): The members shall be frequently renewed in order to combine the advantages of experience with those
p.(None): of new perspectives. The REC member selection and replacement mechanism shall ensure the election
p.(None): impartiality and respect for the suitability and plurality criteria.
p.(None): The REC shall elect a president among its members to lead meetings. The REC president shall be a person
p.(None): holding the experience, competence and qualifications to deal with and evaluate all the aspects of the investigations.
p.(None): Operation
p.(None): The REC holds the authority to approve, request amendments to, disapprove, discontinue or cancel
p.(None): an investigation on human health. The REC shall report its opinions in writing to the investigator, including
p.(None): the reasons for its decisions.
p.(None): The REC shall make a list and keep it updated of its members, indicating their names, age, sex, profession or
p.(None): occupation, position at the REC and relationship with the institution.
p.(None): The REC shall place in record its meetings, consultations and decisions, including the participating members and their
p.(None): voting results.
p.(None): The REC shall request and make available for its members all the research documents necessary for a comprehensive
p.(None): evaluation including: the protocol and its amendments, the informed consent and its amendments, other
p.(None): information for participants, the investigator´s updated curriculum vitae, enrolment mechanisms, a
p.(None): detail of the payments and insurance coverage envisaged for the participants and financing source of the study.
p.(None):
p.(None): A member of the REC who is, in turn, an investigator in a project may not participate in any evaluations, consultations
p.(None): or decisions about such project.
p.(None): The REC shall consult experts as to specific subject matters but they shall not have a right to decide on the project.
p.(None): The experts requested participation and opinion shall be documented.
p.(None): The REC shall demand from the investigator the immediate report on all the relevant information about safety or
p.(None): protocol amendments increasing the risk for participants or those changes made with the purpose of eliminating the
p.(None): immediate hazards for them.
p.(None): In case of administrative changes or changes that do not affect participants´ safety, the REC may carry out a swift
p.(None): evaluation of such changes. The president or member in charge of the swift evaluation shall document it and
p.(None): inform the rest of the members about it.
p.(None): The REC shall draft and update the standard operating procedures (SOP) to rule its composition and operation,
p.(None): including the following: member selection method; membership duration and criteria for renewal;
p.(None): sessions plan; means of summoning; quorum to hold sessions; specifications as to the type, format and
p.(None): opportuneness of the documents for project evaluation; procedures of evaluation, notification and appeal of opinions;
p.(None): procedures of study follow up and members´ conflict of interest declaration.
p.(None): The REC shall retain all the research relevant documents, such as the documents submitted for review ,
p.(None): minutes of meetings, opinions and general communications for a ten-year period after the termination of the
p.(None): study and shall make them available for health authorities should they request them.
p.(None): INFORMED CONSENT
p.(None): General
p.(None): The informed consent is the process that ensures that a potential participant decides to participate in a human
p.(None): health investigation voluntarily, without undue influence or duress, provided the investigation is consistent
p.(None): with the participant´s values, interests and preferences.
p.(None): The informed consent process shall be conducted by the investigator or a qualified sub-investigator
p.(None): authorized to do so in the function delegation form.
p.(None): In case a potential participant cannot grant by him or herself the consent to a study, the informed consent shall be
p.(None): obtained from his or her legal representatives, in accordance to the Argentine legislation in the matter.
p.(None): Likewise, the participant´s assent shall be requested after having provided him or her with information about the
p.(None): study, according to his or her understanding possibilities of such information. The participant´s decision whether to
p.(None): participate or not shall be respected.
p.(None): In case of a study potential participant´s educational, cultural, social or economic vulnerability, the
p.(None): involvement of a witness unrelated to the investigator and his or her team shall be required. Said witness shall sign
p.(None): and date the consent form as a proof of his or her participation. The REC may set this requirement for all
...
p.(None): was authorized to perform that action.
p.(None): Since exposure to an investigational product during pregnancy implies risks for the embryo or fetus, the
p.(None): following measures shall be taken:
p.(None): women of fertile age shall be warned about such risks, before giving their consent to participate in the study and
p.(None): about the need to immediately inform the investigator should they suspect of being pregnant at any time of the
p.(None): study;
p.(None): the investigator shall run a pregnancy test prior to the admission to the study of every women of fertile age; and then
p.(None): regularly throughout the study;
p.(None): a positive result pregnancy test shall imply the exclusion of the prospective participant or the preventive
p.(None): discontinuation of the investigational product administration, if appropriate. In case of pregnancy, the
p.(None): investigator shall guide the participant in obtaining proper care;
p.(None): the sponsor and the investigator shall ensure the access to the necessary contraceptive methods
p.(None): for all the study participants.
p.(None): An investigator who is a doctor of medicine or a dentist, as appropriate, shall be responsible for all
p.(None): the participants´ health care related decisions throughout the study.
p.(None): Should the study put at risk the integrity or health of the participants, for example, due to an adverse reaction
p.(None): or a therapeutic failure, the investigator shall take all the precautions to halt the exposure to the risk.
p.(None): The use of a placebo control shall be properly justified both from the methodological and ethical points of view. The
p.(None): use of a placebo in terminal diseases shall be accepted in case of inefficacy of all the existing treatments.
p.(None): The investigator and the sponsor shall ensure that the participant will receive proper medical care in case of
p.(None): injury related to the investigation. In the case of diagnose of an inter-current disease caused by a research
p.(None): related procedure, the investigator shall guide the participant in obtaining the necessary health care.
p.(None): Participants requiring to continue their treatment after the study completion shall have access to the intervention
p.(None): that turned out to be beneficial or to an alternative intervention or another proper benefit, which shall be
p.(None): approved by the REC for the time it decides or until such access is ensured by any other means.
p.(None): AGREEMENTS AND FINANCING
p.(None): The sponsor is responsible for affording all the research costs, including study treatments and procedures.
p.(None): In clinical studies with a therapeutic benefit, the sponsor may make payments to the participants for any
p.(None): inconveniences and their time. However, such payments may not become an undue influence by
p.(None): being disproportionate in such a way that the patient is persuaded to run unnecessary risks. Payments shall be
p.(None): apportioned according to the study characteristics.
p.(None): The sponsor shall ensure medical care and an insurance coverage or the setting up of any other form of guarantee in
p.(None): the country, in case of injury to participants resulting from the study.
p.(None):
p.(None): The investigation financing shall be documented in a written agreement signed by the sponsor, the investigator and/or
p.(None): the institution hosting the study, which shall show in detail the commitment of the parties to fulfill the obligations
p.(None): set out in the Regulatory Guideline herein.
p.(None): The REC shall check any financial agreement and foreseen payment for the participants as
p.(None): provided for in 7.1. The sponsor shall verify that the REC approved them prior to research initiation.
...
p.(None): etc., for the proper conservation of investigational products and any other supply necessary for its
p.(None): administration. The protocol shall also indicate procedures for handling, storing and returning the unused
p.(None): products to the sponsor and/or their final disposition at the research center, pursuant to the regulations in
p.(None): effect.
p.(None): The sponsor shall set forth the development and control guidelines and use procedures to be applied to studies of
p.(None): products not defined or governed by GMP or GLP standards, for example, biological products. Said guidelines and
p.(None): procedures shall be subject to approval by the agency.
p.(None): Supply and handling
p.(None): The sponsor shall be responsible for handling the investigational product from the moment it departs from
p.(None): the manufacturing site or when it is cleared from Customs until it is delivered to the research site and from the time
p.(None): he or she takes away the unused or expired product until its destruction. The investigator shall be
p.(None): responsible for managing the product domestically and shall be supervised by the sponsor who shall be jointly and
p.(None): severally liable.
p.(None): The sponsor shall be responsible for providing study participants with free-of-charge investigational products
p.(None): throughout all the study and for ensuring their timely delivery and the retrieval of failed, expired or unused
p.(None): products.
p.(None): Before delivering the investigational products to the investigator, the sponsor shall make sure that the
p.(None): REC has approved it and the agency and jurisdictional health authority have authorized it.
p.(None): The investigator shall be responsible for the investigational products to be used as per the protocol. The investigator
p.(None): or his or her delegate shall instruct every participant on the rightful use of the investigational product(s),
p.(None): make sure participants understand such instructions and then verify in every clinical visit that the instructions
p.(None): are followed.
p.(None):
p.(None): If a blinding method is used in the study, the sponsor shall set out a decoding procedure for emergency
p.(None): situations and the investigator shall do his or her utmost to preserve the blind, unless it becomes necessary to
p.(None): identify the product for participant´s safety reasons. In such case, the investigator shall document and justify the
p.(None): procedure and immediately report it to the sponsor and the REC.
p.(None): The investigator shall have an inventory of the investigational products documenting the following: reception
p.(None): from the sponsor, dispensation to participants, reception of the remains and return of unused products to the sponsor.
p.(None): Said function may be delegated to a BSc in Pharmacy or any other team member qualified and authorized to do so.
p.(None): The inventory of investigational products at the center shall indicate the participant´s code, product name or code,
p.(None): lot or serial number, expiry date, delivery and reception date and the respective quantities. The inventory
p.(None): shall enable to verify that the products were dispensed only to participants and that they used the products
p.(None): according to the protocol. Final accountability shall show a coincidence among the products received, the
...
p.(None): planned, conducted, recorded, controlled and presented. It aims at assuring the quality and integrity of all the
p.(None): data produced during a given study as well as to tighten the study related safety.
p.(None): RESEARCH ETHICS COMMITTEE (REC): a body acting within its competence scope, which is independent from the sponsor and
p.(None): investigator and is constituted by medical or scientific professionals and non-medical or non-scientific members
p.(None): and whose function is to provide public assurance of the protection of the rights, dignity, safety and
p.(None):
p.(None): well-being of a study participants, by means of, among other things, the review of the study protocol, informed consent
p.(None): process and the investigator´s suitability.
p.(None): INDEPENDENT DATA MONITORING COMMITTEE (IDMC): an external board set up by the sponsor to evaluate, at set time
p.(None): intervals, a clinical study progress, safety data and critical points for efficacy assessment, in such a way that it
p.(None): may recommend the study continuation, modification or suspension.
p.(None): CONFLICT OF INTEREST: a conflict of interest takes place when a professional primary interest such as the
p.(None): patients´ well-being or the validity of a scientific research study may be affected by a secondary interest such
p.(None): as economic gain, professional prestige or personal rivalries.
p.(None): INFORMED CONSENT: a process by means of which a person confirms his or her decision to participate in a human
p.(None): health research study, after having been informed of all its relevant aspects. The informed consent is documented
p.(None): by means of signing a specific form to such purpose.
p.(None): SOURCE DATA: the information about clinical findings, observations or other activities, which is necessary for the
p.(None): reconstruction and evaluation of the clinical study. Said information is documented in original records or
p.(None): their copies certified by the person responsible for them, which are called source documents. The source
p.(None): data must be attributable, readable, accurate and contemporary.
p.(None): PERSONAL DATA: information of any type related to certain or ascertainable physical persons or legal entities.
p.(None): ESSENTIAL DOCUMENTS: documents that individually or collectively enable the evaluation of a study conduct and
p.(None): of the quality of the data produced thereby.
p.(None): SOURCE DOCUMENTS: original documents and records of the clinical data used in a study, such as the medical records,
p.(None): laboratory or pharmacy records, imaging reports and images, participants´ diaries, data recorded on automated
p.(None): instruments, magnetic devices or microfilm and photographic negatives. The certified exact copies of the
p.(None): above mentioned documents are included in this definition.
p.(None): INFORMED CONSENT AMENDMENT: a written description of the formal changes or clarifications of the documents or consent
p.(None): form. The changes of expected benefits and risks envisaged for participants or that may affect their decision to
p.(None): continue with the study require approval by the REC and A.N.M.A.T.
p.(None): PROTOCOL AMENDMENT: a document of changes or clarifications of a study protocol. The amendments may be: (a)
p.(None): substantial, when they describe changes in the design, population, procedures or investigational product and require
p.(None): approval by the REC and A.N.M.A.T.; or (b) unsubstantial or administrative when they reflect, for example,
p.(None): only changes of the contact data.
p.(None): CLINICAL STUDY: a set of activities with the purpose of obtaining generalizable knowledge about human
p.(None): health to be applied in medicine, sciences of life and their related technologies. Clinical studies may be
p.(None): observational or experimental, according to whether the investigator intervenes or not in the variable under study.
p.(None): EXPERIMENTAL CLINICAL STUDY (synonym: clinical trial): a study in which the investigator selects
p.(None): participants upon inclusion and exclusion criteria, actively intervenes on the independent or predicting
p.(None): variable and observes and analyzes the changes made in the dependent or outcome variable as a consequence
p.(None): of the
p.(None):
p.(None): intervention. Controlled clinical trials entail the concept of hypotheses contrast with a null hypothesis. The
p.(None): interventions may encompass synthesis drugs, biological products, medical devices, surgical techniques, etc.
p.(None): Said studies are considered as of “major risk” to participants.
p.(None): CLINICAL PHARMACOLOGY STUDY: a systematic scientific study conducted with drugs or biological products in
p.(None): volunteer, healthy or unhealthy human subjects, with the purpose of discovering or verifying their therapeutic effects
p.(None): and/or identifying adverse reactions and/or studying the absorption, distribution, metabolism
p.(None): (biotransformation) and excretion of their active principles in order to determine their efficacy and safety.
p.(None): PHASE I STUDY: an initial introduction of a new drug researched in human subjects to determine its metabolism,
p.(None): pharmacological actions, secondary effects with increasing doses and, if possible, to obtain early evidence about its
...
p.(None): PHASE III STUDY: a study conducted in large and varied groups of participants in order to determine both
p.(None): short-term and long-term risk-benefit balance of the proposed formulation(s) and the relative therapeutic value, in
p.(None): general.
p.(None): PHASE IV STUDY: a study conducted after the drug and/or medicinal product is marketed in order to determine
p.(None): its therapeutic value, the appearance of new adverse reactions and/or the confirmation of the already known adverse
p.(None): reactions frequency as well as the treatment strategies.
p.(None): VACCINE CLINICAL STUDY: a systematic and scientific study conducted in volunteer, healthy or unhealthy human
p.(None): subjects in order to determine the tolerance, safety, immunogenicity and/or efficacy of a vaccine. It has
p.(None): three phases: (a) Phase I: first study conducted in human beings to evaluate the tolerance, safety and biologic
p.(None): effects;
p.(None): (b) Phase II: a study determining the immunogenicity caused by a vaccine; and (c) Phase III: a controlled
p.(None): clinical study, with a high number of volunteer participants which aims to assess the effectiveness of a vaccine for
p.(None): the prevention of a disease and its safety in a more thorough way.
p.(None): MULTI-CENTER STUDY: a clinical study conducted according to only one protocol but in more than one place or
p.(None): institution and, therefore, conducted by more than one investigator.
p.(None): ADVERSE EVENT (AE): any adverse medical occurrence in a patient or subject of a clinical study of a health intended
p.(None): product or therapeutic procedure and which does not have a necessary causal relation with this treatment. An
p.(None): adverse event may be any unfavorable and unintended sign, including laboratory abnormal findings and
p.(None): symptoms or diseases temporally associated with the use of the investigational product, whether related or
p.(None): not with it.
p.(None): SERIOUS ADVERSE EVENT (SAE): any unfavorable occurrence throughout and within the research of a diagnostic or
p.(None): therapeutic product or procedure that results in death, is life-threatening, requires in-patient hospitalization
p.(None): or prolongation of the
p.(None):
p.(None): existent hospitalization, results in persistent or significant incapacity or disability or that is a congenital anomaly
p.(None): or a birth defect or that is medically significant as per medical criteria. The above mentioned is applicable
p.(None): without the need for an alleged causal relation existence between the product or treatment administered
p.(None): and the adverse event.
p.(None): CLINICAL DATA FORM (CDF): a printed, digital or optical document designed to keep record of all the clinical data
p.(None): required as per protocol, about each participant of the study and that shall be reported to the sponsor.
p.(None): CONTROL GROUP: a group used as a comparator that indicates what happens when the treatment under study is not applied.
p.(None): ACTIVE PHARMACEUTICAL INGREDIENT: a natural, biological or synthetic chemical substance having a specific
p.(None): pharmacological effect and that is used in human medicine.
p.(None): INSPECTION: an official review conducted by the competent authority of the documents, facilities,
p.(None): records and any resource considered as related to the clinical study and that may be located in the research
p.(None): center, sponsor´s or contract research organization (CRO) facilities or in other sites deemed appropriate.
p.(None): INSPECTOR: a person designated by the competent health and/or regulatory authority to conduct the study-related
p.(None): inspections.
p.(None): INSTITUTION OR RESEARCH CENTER: any government or privately owned agency or medical or dental facility where clinical
p.(None): studies are conducted.
p.(None): INVESTIGATOR: a professional responsible for conducting the clinical trial at the research center. If the
p.(None): trial is conducted by a team, the investigator is responsible for the team and is denominated the principal
p.(None): investigator. The principal investigator may delegate functions to his or her team, but not his or her
p.(None): responsibilities. The investigator-sponsor is the physical person initiating, managing financing and
p.(None): conducting, on his or her own or together with others, a clinical study, having under his or her responsibility the
p.(None): management, dispensation and use of the investigational product.
p.(None): INVESTIGATIONAL PRODUCT MONOGRAPH: (Synonym: Investigator´s brochure) a compilation of clinical and non-clinical data
p.(None): of drugs, investigational medical products or procedures relevant for their study in human beings.
p.(None): MONITORING: action of overseeing the process of a clinical study and ensuring that it is conducted, recorded and
p.(None): reported in accordance with the protocol, SPO(s), GCP and applicable regulatory requirements.
p.(None): CONTRACT RESEARCH ORGANIZATION (CRO): a physical person or legal entity contracted by the sponsor to perform
p.(None): one or more of his or her functions or activities related to the study.
p.(None): STUDY PARTICIPANT: a healthy or unhealthy individual participating in a clinical pharmacology study as a
p.(None): research subject.
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Searching for indicator mentally:
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p.(None): than the assurance that all the necessary information is provided to him or her. In addition, those
p.(None): individuals having a diminished or inexistent autonomy are in a vulnerable situation, and, therefore, require
p.(None): special protections. A person´s autonomy is considered diminished in case of cultural, educational,
p.(None): social or economic disadvantage, for example, in the case of ethnic minorities, refugees or illiterate,
p.(None): subdued, homeless or impoverished persons. For such cases, the additional protection is the presence of an impartial
p.(None): witness who assures that all the rights and interests of those persons are respected during the informed consent
p.(None): obtainment process. The absence of autonomy takes place when a person is legally or mentally incapable of
p.(None): giving his or her consent voluntarily. In said cases, the consent shall be obtained from his or her legal
p.(None): representative pursuant to the Argentine legislation in the matter.
p.(None): BIOAVAILABILITY: the capacity of a pharmaceutical form of releasing an API in the site of action at the proper
p.(None): speed to obtain a sufficient concentration, and at the timely moment to enable it to exert its action. Since,
p.(None): generally, the concentration cannot be determined in bio-phase in human beings and assuming the existence of balance in
p.(None): the concentrations in serum and bio-phase, the fraction of a drug reaching the systemic circulation of the
p.(None): extravascularly administered dose of a given pharmaceutical form, shall be accepted as bioavailability.
p.(None): BIOEQUIVALENCE: two drugs or medicinal products are biologically equivalent when, upon the existence of chemical
p.(None): equivalence, they have a similar bioavailability if administered to the same person in an equal dosage regimen.
p.(None): GOOD CLINICAL PRACTICE (GCP): an international ethical and scientific quality standard for the design,
p.(None): conduct, recording and reporting of the trials involving the participation of human subjects. Compliance
p.(None): with this standard provides a public assurance that the participants´ rights, safety and well-being
p.(None): are protected, in accordance with the Declaration of Helsinki; and that the trials data are reliable.
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p.(None): three phases: (a) Phase I: first study conducted in human beings to evaluate the tolerance, safety and biologic
p.(None): effects;
p.(None): (b) Phase II: a study determining the immunogenicity caused by a vaccine; and (c) Phase III: a controlled
p.(None): clinical study, with a high number of volunteer participants which aims to assess the effectiveness of a vaccine for
p.(None): the prevention of a disease and its safety in a more thorough way.
p.(None): MULTI-CENTER STUDY: a clinical study conducted according to only one protocol but in more than one place or
p.(None): institution and, therefore, conducted by more than one investigator.
p.(None): ADVERSE EVENT (AE): any adverse medical occurrence in a patient or subject of a clinical study of a health intended
p.(None): product or therapeutic procedure and which does not have a necessary causal relation with this treatment. An
p.(None): adverse event may be any unfavorable and unintended sign, including laboratory abnormal findings and
p.(None): symptoms or diseases temporally associated with the use of the investigational product, whether related or
p.(None): not with it.
p.(None): SERIOUS ADVERSE EVENT (SAE): any unfavorable occurrence throughout and within the research of a diagnostic or
p.(None): therapeutic product or procedure that results in death, is life-threatening, requires in-patient hospitalization
p.(None): or prolongation of the
p.(None):
p.(None): existent hospitalization, results in persistent or significant incapacity or disability or that is a congenital anomaly
p.(None): or a birth defect or that is medically significant as per medical criteria. The above mentioned is applicable
p.(None): without the need for an alleged causal relation existence between the product or treatment administered
p.(None): and the adverse event.
p.(None): CLINICAL DATA FORM (CDF): a printed, digital or optical document designed to keep record of all the clinical data
p.(None): required as per protocol, about each participant of the study and that shall be reported to the sponsor.
p.(None): CONTROL GROUP: a group used as a comparator that indicates what happens when the treatment under study is not applied.
p.(None): ACTIVE PHARMACEUTICAL INGREDIENT: a natural, biological or synthetic chemical substance having a specific
p.(None): pharmacological effect and that is used in human medicine.
p.(None): INSPECTION: an official review conducted by the competent authority of the documents, facilities,
p.(None): records and any resource considered as related to the clinical study and that may be located in the research
p.(None): center, sponsor´s or contract research organization (CRO) facilities or in other sites deemed appropriate.
p.(None): INSPECTOR: a person designated by the competent health and/or regulatory authority to conduct the study-related
p.(None): inspections.
p.(None): INSTITUTION OR RESEARCH CENTER: any government or privately owned agency or medical or dental facility where clinical
p.(None): studies are conducted.
...
p.(None): individual refuses to participate (duress).
p.(None): COMPARATOR PRODUCT: a marketed or investigational product or a placebo used as a reference in a clinical study.
p.(None): INVESTIGATIONAL PRODUCT: a pharmaceutical form of an active substance under investigation, including products
p.(None): holding a marketing authorization when used or combined in the formulation in a form other than the authorized
p.(None): one or for the treatment of an unauthorized indication.
p.(None): PROTOCOL: a document describing the history, fundamentals, objectives, design, methodology ethical
p.(None): considerations, statistical aspects and organization of a study.
p.(None): ADVERSE DRUG REACTION (ADR): an untoward and unintended response to a medicinal product at any dose. In
p.(None): clinical experience and before the approval of a new medicinal product or of its new uses, particularly, when the
p.(None): therapeutic dose cannot be determined, any reaction implying causal relation between a medicinal product and an adverse
p.(None): event as a reasonable possibility, that is to say, that the relation may not be ruled out, must be considered an
p.(None): adverse drug reaction.
p.(None): UNEXPECTED AND SERIOUS ADVERSE DRUG REACTION (UNEXPECTED
p.(None): SADR): an adverse reaction that results in death, is life-threatening, requires in-patient hospitalization or
p.(None): prolongation of the existent hospitalization, results in persistent or significant incapacity or disability
p.(None): and whose nature of seriousness is not consistent with the product information written in the
p.(None): investigational product monograph or any other documentation.
p.(None): LEGAL REPRESENTATIVE: a person authorized under the Argentine Civil Code or the applicable laws, who acts as the
p.(None): representative of a prospective participant in a clinical study to grant the informed consent to the study.
p.(None): IMPARTIAL WITNESS: a person independent from the investigator and his or her team who participates in the informed
p.(None): consent obtainment process as an assurance that such process respects the rights and interests of a
...
Health / Mentally Incapacitated
Searching for indicator incapable:
(return to top)
p.(None): than the assurance that all the necessary information is provided to him or her. In addition, those
p.(None): individuals having a diminished or inexistent autonomy are in a vulnerable situation, and, therefore, require
p.(None): special protections. A person´s autonomy is considered diminished in case of cultural, educational,
p.(None): social or economic disadvantage, for example, in the case of ethnic minorities, refugees or illiterate,
p.(None): subdued, homeless or impoverished persons. For such cases, the additional protection is the presence of an impartial
p.(None): witness who assures that all the rights and interests of those persons are respected during the informed consent
p.(None): obtainment process. The absence of autonomy takes place when a person is legally or mentally incapable of
p.(None): giving his or her consent voluntarily. In said cases, the consent shall be obtained from his or her legal
p.(None): representative pursuant to the Argentine legislation in the matter.
p.(None): BIOAVAILABILITY: the capacity of a pharmaceutical form of releasing an API in the site of action at the proper
p.(None): speed to obtain a sufficient concentration, and at the timely moment to enable it to exert its action. Since,
p.(None): generally, the concentration cannot be determined in bio-phase in human beings and assuming the existence of balance in
p.(None): the concentrations in serum and bio-phase, the fraction of a drug reaching the systemic circulation of the
p.(None): extravascularly administered dose of a given pharmaceutical form, shall be accepted as bioavailability.
p.(None): BIOEQUIVALENCE: two drugs or medicinal products are biologically equivalent when, upon the existence of chemical
p.(None): equivalence, they have a similar bioavailability if administered to the same person in an equal dosage regimen.
p.(None): GOOD CLINICAL PRACTICE (GCP): an international ethical and scientific quality standard for the design,
p.(None): conduct, recording and reporting of the trials involving the participation of human subjects. Compliance
p.(None): with this standard provides a public assurance that the participants´ rights, safety and well-being
p.(None): are protected, in accordance with the Declaration of Helsinki; and that the trials data are reliable.
p.(None): GOOD MANUFACTURING PRACTICE (GMP): a standard to assure a uniform manufacture that meets the
...
Health / Physically Ill
Searching for indicator ill:
(return to top)
p.(None): functions and morphology, for example, the cardiovascular and respiratory ones.
p.(None): In addition to the requirements outlined for synthesis products, pre-clinical information of biotechnological products
p.(None): shall include:
p.(None): toxicological evaluation of contaminants and impurities;
p.(None): anti-genicity reactions, for instance, of anti-product antibodies;
p.(None): immune-toxicity reactions, for example, for immune-modulators, if appropriate.
p.(None): Clinical information
p.(None): a detailed discussion of the known effects of the investigational product on humans, including information
p.(None): about pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy and other pharmacological
p.(None): activities shall be submitted.
p.(None): The following information about pharmacokinetics shall be included:
p.(None): regarding pharmacokinetics: absorption, protein binding, metabolism, distribution and elimination;
p.(None): absolute and/or relative bioavailability using a reference dosage form;
p.(None): regarding bioequivalence: whenever appropriate, for example, in case the product is manufactured with a
p.(None): technology different from the one used to demonstrate its efficacy and safety;
p.(None): population sub-groups as to gender, age, impaired organic function; interactions with another drug and foods;
p.(None): other pharmacokinetics-related data.
p.(None): A summary of information shall be provided about the safety, pharmacodynamics, efficacy and the dose
p.(None): response of the product and its metabolites, if appropriate, produced from studies in healthy and ill
p.(None): volunteers. The implications of said information shall be discussed.
p.(None):
p.(None): Complete information about adverse drug reactions shall be submitted in tables. Based on the experience with the
p.(None): product and related products, the incidence patterns across indication or sub-group shall be discussed.
p.(None): If the product is marketed abroad, a summary of the relevant information stemming from its use. If the
p.(None): product was not approved or was suspended or recalled from the market of other country(s), which countries and the
p.(None): rationale for such measures shall be explained.
p.(None): Excipients
p.(None): In the case of excipients without a history of use in human beings, all the studies supporting the
p.(None): safety of their use shall be submitted.
p.(None): PROTOCOL
p.(None): General
p.(None): This Regulatory Guideline sets out the information and structure required for the clinical pharmacological studies
p.(None): protocol.
p.(None): General information
p.(None): the study complete title, including the clinical development phase; the version number and date;
p.(None): the sponsor´s name; a protocol summary
p.(None): a visits and procedures schedule.
p.(None): Background and justification
p.(None): a description of the problem to be investigated and the current knowledge about it;
p.(None): information about the investigational product, including a summary of the efficacy, pharmacokinetics,
p.(None): tolerance and toxicity data obtained from the pre-clinical and clinical studies;
p.(None): the purpose and relevance of the research proposed;
...
Health / Pregnant
Searching for indicator pregnant:
(return to top)
p.(None): reversibility of the pharmacologic and toxic effects and dose response, as well as the statistical analysis of
p.(None): such results.
p.(None): Discussion of the most significant findings and conclusions, including the dose response of the effects
p.(None): observed, the relevance for human beings and any other aspect intended to be studied in human beings. The
p.(None): findings of the effective and non toxic doses (therapeutic index) in the same animal species and their ratio
p.(None): for the human dose proposed shall be compared, if appropriate.
p.(None): Preclinical pharmacology
p.(None): Pharmacodynamics: the potential therapeutic activity shall be demonstrated and the product and/or its
p.(None): metabolites possible mechanisms of action shall be described, including the evaluation of pharmacologic
p.(None): actions other than the therapeutic effects intended.
p.(None): Special pharmacodynamics: pharmacodynamic effects as per the indications proposed, dose-effect and time-effect curves.
p.(None): General pharmacodynamics: studies on the cardiovascular system, respiratory system, central nervous system,
p.(None): autonomic nervous system, neuromuscular system, urinary system, endocrine system, digestive system, etc.
p.(None): Pharmacodynamic interactions: studies determining these types of relations. Mechanisms of action: a description of the
p.(None): mechanisms observed.
p.(None): Pharmacokinetics: determination of the speed and magnitude of absorption, distribution model, biotransformation, speed
p.(None): and paths of elimination and the API location in the tissues. Studies shall include single dose and repeated
p.(None): dose pharmacokinetics, distribution in non-pregnant and pregnant animals, biotransformation, excretion and
p.(None): kinetic interactions.
p.(None): General pre-clinical toxicology
p.(None): Acute toxicity studies should have been conducted on three species, of which one should not be rodents.
p.(None): Likewise, at least two routes of administration should have been tried; one should be related to the way proposed for
p.(None): human use while the other one should ensure drug absorption. For single dose use in humans, the product
p.(None): should have been used for at least two weeks in the pre-clinical trial. The report shall include:
p.(None):
p.(None): toxic effects appearance time and duration, dose-effect ratio and reversibility as well as the differences in routes
p.(None): of administration (proposed therapeutic use and absorption test);
p.(None): toxicity symptoms and cause of death; biochemical and hematologic parameters;
p.(None): clinical and anatomical and pathological observations; estimated toxic dose.
p.(None): Repeated dose sub-acute toxicity studies shall be conducted on at least two species, of which one should not be
p.(None): rodents, for at least 12 to 24 weeks for a proposed human use of up to 4 weeks, according to the product type, its
p.(None): proposed therapeutic use and the animal species used. The route of administration should be the same as the
p.(None): one proposed for clinical use. At least, three doses shall be used, of which the highest one should produce
p.(None): demonstrable toxic effects and the lowest one should be equivalent to the proposed therapeutic dose, according to
p.(None): the sensitiveness of the species used. These studies shall include:
...
p.(None): or her decision to continue participating in the study shall be communicated verbally an in writing
p.(None): in order to obtain the consent. The new consent document shall be previously approved by the REC and the
p.(None): agency, unless the changes require swift implementation for safety reasons.
p.(None): PROTECTION OF STUDY PARTICIPANTS
p.(None):
p.(None): The investigator and the sponsor shall ensure that every participant will have access to their own information and
p.(None): to the study results once available and that their right to confidentiality will be protected at all times.
p.(None): The investigator is responsible for obtaining the consent of all the participants, even when a sub-investigator
p.(None): was authorized to perform that action.
p.(None): Since exposure to an investigational product during pregnancy implies risks for the embryo or fetus, the
p.(None): following measures shall be taken:
p.(None): women of fertile age shall be warned about such risks, before giving their consent to participate in the study and
p.(None): about the need to immediately inform the investigator should they suspect of being pregnant at any time of the
p.(None): study;
p.(None): the investigator shall run a pregnancy test prior to the admission to the study of every women of fertile age; and then
p.(None): regularly throughout the study;
p.(None): a positive result pregnancy test shall imply the exclusion of the prospective participant or the preventive
p.(None): discontinuation of the investigational product administration, if appropriate. In case of pregnancy, the
p.(None): investigator shall guide the participant in obtaining proper care;
p.(None): the sponsor and the investigator shall ensure the access to the necessary contraceptive methods
p.(None): for all the study participants.
p.(None): An investigator who is a doctor of medicine or a dentist, as appropriate, shall be responsible for all
p.(None): the participants´ health care related decisions throughout the study.
p.(None): Should the study put at risk the integrity or health of the participants, for example, due to an adverse reaction
p.(None): or a therapeutic failure, the investigator shall take all the precautions to halt the exposure to the risk.
p.(None): The use of a placebo control shall be properly justified both from the methodological and ethical points of view. The
...
Health / Terminally Ill
Searching for indicator terminal:
(return to top)
p.(None): study;
p.(None): the investigator shall run a pregnancy test prior to the admission to the study of every women of fertile age; and then
p.(None): regularly throughout the study;
p.(None): a positive result pregnancy test shall imply the exclusion of the prospective participant or the preventive
p.(None): discontinuation of the investigational product administration, if appropriate. In case of pregnancy, the
p.(None): investigator shall guide the participant in obtaining proper care;
p.(None): the sponsor and the investigator shall ensure the access to the necessary contraceptive methods
p.(None): for all the study participants.
p.(None): An investigator who is a doctor of medicine or a dentist, as appropriate, shall be responsible for all
p.(None): the participants´ health care related decisions throughout the study.
p.(None): Should the study put at risk the integrity or health of the participants, for example, due to an adverse reaction
p.(None): or a therapeutic failure, the investigator shall take all the precautions to halt the exposure to the risk.
p.(None): The use of a placebo control shall be properly justified both from the methodological and ethical points of view. The
p.(None): use of a placebo in terminal diseases shall be accepted in case of inefficacy of all the existing treatments.
p.(None): The investigator and the sponsor shall ensure that the participant will receive proper medical care in case of
p.(None): injury related to the investigation. In the case of diagnose of an inter-current disease caused by a research
p.(None): related procedure, the investigator shall guide the participant in obtaining the necessary health care.
p.(None): Participants requiring to continue their treatment after the study completion shall have access to the intervention
p.(None): that turned out to be beneficial or to an alternative intervention or another proper benefit, which shall be
p.(None): approved by the REC for the time it decides or until such access is ensured by any other means.
p.(None): AGREEMENTS AND FINANCING
p.(None): The sponsor is responsible for affording all the research costs, including study treatments and procedures.
p.(None): In clinical studies with a therapeutic benefit, the sponsor may make payments to the participants for any
p.(None): inconveniences and their time. However, such payments may not become an undue influence by
p.(None): being disproportionate in such a way that the patient is persuaded to run unnecessary risks. Payments shall be
p.(None): apportioned according to the study characteristics.
p.(None): The sponsor shall ensure medical care and an insurance coverage or the setting up of any other form of guarantee in
p.(None): the country, in case of injury to participants resulting from the study.
p.(None):
...
Health / volunteers
Searching for indicator volunteers:
(return to top)
p.(None): In addition to the requirements outlined for synthesis products, pre-clinical information of biotechnological products
p.(None): shall include:
p.(None): toxicological evaluation of contaminants and impurities;
p.(None): anti-genicity reactions, for instance, of anti-product antibodies;
p.(None): immune-toxicity reactions, for example, for immune-modulators, if appropriate.
p.(None): Clinical information
p.(None): a detailed discussion of the known effects of the investigational product on humans, including information
p.(None): about pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy and other pharmacological
p.(None): activities shall be submitted.
p.(None): The following information about pharmacokinetics shall be included:
p.(None): regarding pharmacokinetics: absorption, protein binding, metabolism, distribution and elimination;
p.(None): absolute and/or relative bioavailability using a reference dosage form;
p.(None): regarding bioequivalence: whenever appropriate, for example, in case the product is manufactured with a
p.(None): technology different from the one used to demonstrate its efficacy and safety;
p.(None): population sub-groups as to gender, age, impaired organic function; interactions with another drug and foods;
p.(None): other pharmacokinetics-related data.
p.(None): A summary of information shall be provided about the safety, pharmacodynamics, efficacy and the dose
p.(None): response of the product and its metabolites, if appropriate, produced from studies in healthy and ill
p.(None): volunteers. The implications of said information shall be discussed.
p.(None):
p.(None): Complete information about adverse drug reactions shall be submitted in tables. Based on the experience with the
p.(None): product and related products, the incidence patterns across indication or sub-group shall be discussed.
p.(None): If the product is marketed abroad, a summary of the relevant information stemming from its use. If the
p.(None): product was not approved or was suspended or recalled from the market of other country(s), which countries and the
p.(None): rationale for such measures shall be explained.
p.(None): Excipients
p.(None): In the case of excipients without a history of use in human beings, all the studies supporting the
p.(None): safety of their use shall be submitted.
p.(None): PROTOCOL
p.(None): General
p.(None): This Regulatory Guideline sets out the information and structure required for the clinical pharmacological studies
p.(None): protocol.
p.(None): General information
p.(None): the study complete title, including the clinical development phase; the version number and date;
p.(None): the sponsor´s name; a protocol summary
p.(None): a visits and procedures schedule.
p.(None): Background and justification
p.(None): a description of the problem to be investigated and the current knowledge about it;
p.(None): information about the investigational product, including a summary of the efficacy, pharmacokinetics,
p.(None): tolerance and toxicity data obtained from the pre-clinical and clinical studies;
p.(None): the purpose and relevance of the research proposed;
p.(None): the fundamentals for the development phase proposed for the study. A relevant methodological justification
p.(None): should a phase overlapping occur.
p.(None): Objectives
...
Social / Access to Social Goods
Searching for indicator access:
(return to top)
p.(None): a study hypothesis with a specification of the null and alternative hypothesis; specification of descriptive methods
p.(None): and statistical tests for variables; criteria for managing missing, excluded and false data;
p.(None): criteria for inclusion or exclusion of participants in the analysis; information technology tools to be used;
p.(None): criteria for processing safety information; interim analysis schedule, if appropriate.
p.(None): Efficacy evaluation
p.(None): efficacy parameters to be assessed, including measurement instruments and methods; efficacy criteria.
p.(None): Investigational products
p.(None): a description of the investigational products indicating API, formulation, dose, route of administration and treatment
p.(None): and follow-up frequency and duration;
p.(None): In the case of biological products trials, a detail of the identification and assessment methodology ensuring
p.(None): the preparation uniformity or the consistency of the lots under study;
p.(None): allowed and un-allowed drugs; criteria for treatment discontinuation;
p.(None): foreseen rescue treatment and follow up in case of failure or adverse events.
p.(None): Adverse events
p.(None): adverse events recording and reporting procedures; emergency blind breaking procedure, if appropriate;
p.(None): Ethical aspect
p.(None): specific mention that the investigation shall be reviewed by a REC; informed consent obtainment procedures;
p.(None): protection of participants´ information and identity confidentially; details of participants´ coverage and compensation
p.(None): for injuries;
p.(None): justification for available payments or compensation for expenses for participants;
p.(None): access for participants to the intervention identified as beneficial in the trial or to an appropriate
p.(None): alternative or benefit upon completion of the trial;
p.(None): justification for using a placebo, if appropriate
p.(None): justification for conducting the research in a vulnerable group, if appropriate; possible conflicts of interest.
p.(None): Administrative and other aspects
p.(None):
p.(None): investigational products maintenance and storage procedures; clinical data record keeping and reports;
p.(None): trial documents handling; monitoring and audit procedures; criteria for trial discontinuation; results publication
p.(None): plan.
p.(None): INFORMED CONSENT
p.(None): The information document used to obtain the consent of a potential participant or of his or her legal representative,
p.(None): pursuant to legal provisions, shall include the following:
p.(None): research title, objective or purpose;
p.(None): sponsor´s data in the country: name or denomination and company name and address; approximate number of participants
p.(None): intended for the study;
p.(None): study experimental aspects;
p.(None): study treatments, assignment method and probability for each treatment;
p.(None): all the procedures to which the participant shall be submitted, the visits schedule they are expected to fulfill and
p.(None): their envisaged participation duration;
p.(None): a statement that all the investigational products and procedures will be free-of-charge for the participants;
p.(None): the reasonably expected benefits from participants´ involvement in the study. A clear remark must be made if the
...
p.(None): pursuant to the Argentine Civil Code and laws concerning civil
p.(None):
p.(None): liability for damages” (translation of: “Con la firma de este consentimiento informado Usted no renuncia a los
p.(None): derechos que posee de acuerdo con el Código Civil y las leyes argentinas en materia de responsabilidad civil por
p.(None): daños”).
p.(None): special mention shall be made as to the fact that the sponsor finances the investigators´
p.(None): fees and the study procedures costs through an agreement with the investigator and/or the institution;
p.(None): the possible conflict of interest and the investigator´s institutional membership;
p.(None): an assurance that the participant´s involvement in the investigation is voluntary and that the candidate may
p.(None): refuse to participate or may abandon the study at any time with no need to explain his or her reason to do so and with
p.(None): no loss of the benefits he or she is entitled to;
p.(None): an assurance that the participant´s personal data shall remain confidential, even when the investigation results are
p.(None): published, pursuant to Law 25.326;
p.(None): the commitment to provide timely answers to questions, clarifications or doubts about the procedures, risks and
p.(None): benefits concerning the investigation;
p.(None): the commitment to timely communicate to the participant or his or her legal representative all
p.(None): the new information that might change his or her decision to continue participating in the study;
p.(None): the envisaged situations by which the investigation or a person´s participation could be prematurely discontinued;
p.(None): a description of the rights a person is entitled to as a participant of a research study, including the access to his
p.(None): or her study-related information and his or her right to have it available;
p.(None): the permission the participant shall give to the sponsor´s representative, REC and the Regulatory Authority to access
p.(None): his or her medical records, which shall contain its scope and a special mention to the fact that such
p.(None): authorization is granted by signing the informed consent form;
p.(None): contact information of the investigator and the REC that approved the study;
p.(None): the following phrase shall be included: “This clinical pharmacology study was authorized by
p.(None): A.N.M.A.T. Should you have any doubt about the investigation treatment, call toll free A.N.M.A.T. Responde at
p.(None): 0800-333-1234.” [translation of: “Este estudio de farmacología clínica ha sido autorizado por A.N.M.A.T. Si usted
p.(None): tuviera alguna duda sobre el tratamiento de la investigación, puede consultar a A.N.M.A.T. responde al
p.(None): 0800-333-1234 (línea gratutita)”].
p.(None): a signature page, with a space for the date, signature and print name of the participant, legal representative and
p.(None): witness, if appropriate, and of the investigator who led the process.
p.(None): AMENDMENTS TO THE PROTOCOL, INFORMED CONSENT AND INVESTIGATIONAL PRODUCT MONOGRAPH
p.(None): Amendments to the protocol and informed consent
p.(None): The objections to the protocol made by the agency in the baseline evaluation shall be changed and submitted as an
p.(None): amendment before its final authorization.
p.(None):
p.(None): Amendments to the protocol and informed consent require an approval by the REC and the authorization by A.N.M.A.T.
p.(None): before their implementation; unless it is necessary to implement them immediately to protect
...
p.(None): following shall be mentioned: date and time of initiation, that the participant was given sufficient time to
p.(None): reflect on and make questions, that the participant´s understanding of the information was verified, that two
p.(None): original signature pages were signed and that one of them was given to the participant or his or her legal
p.(None): representative.
p.(None): When the consent is given by a participant´s legally acceptable representative or when a witness is required to
p.(None): carry out the process, the participant´s medical record shall document the reasons for such situation and
p.(None): the fulfillment of the requirements applicable thereto. Likewise, the medical record shall inform both the
p.(None): presence and absence of the prospective participant´s vulnerable condition.
p.(None): All the new information or changes in the protocol that may affect the participant´s safety or his
p.(None): or her decision to continue participating in the study shall be communicated verbally an in writing
p.(None): in order to obtain the consent. The new consent document shall be previously approved by the REC and the
p.(None): agency, unless the changes require swift implementation for safety reasons.
p.(None): PROTECTION OF STUDY PARTICIPANTS
p.(None):
p.(None): The investigator and the sponsor shall ensure that every participant will have access to their own information and
p.(None): to the study results once available and that their right to confidentiality will be protected at all times.
p.(None): The investigator is responsible for obtaining the consent of all the participants, even when a sub-investigator
p.(None): was authorized to perform that action.
p.(None): Since exposure to an investigational product during pregnancy implies risks for the embryo or fetus, the
p.(None): following measures shall be taken:
p.(None): women of fertile age shall be warned about such risks, before giving their consent to participate in the study and
p.(None): about the need to immediately inform the investigator should they suspect of being pregnant at any time of the
p.(None): study;
p.(None): the investigator shall run a pregnancy test prior to the admission to the study of every women of fertile age; and then
p.(None): regularly throughout the study;
p.(None): a positive result pregnancy test shall imply the exclusion of the prospective participant or the preventive
p.(None): discontinuation of the investigational product administration, if appropriate. In case of pregnancy, the
p.(None): investigator shall guide the participant in obtaining proper care;
p.(None): the sponsor and the investigator shall ensure the access to the necessary contraceptive methods
p.(None): for all the study participants.
p.(None): An investigator who is a doctor of medicine or a dentist, as appropriate, shall be responsible for all
p.(None): the participants´ health care related decisions throughout the study.
p.(None): Should the study put at risk the integrity or health of the participants, for example, due to an adverse reaction
p.(None): or a therapeutic failure, the investigator shall take all the precautions to halt the exposure to the risk.
p.(None): The use of a placebo control shall be properly justified both from the methodological and ethical points of view. The
p.(None): use of a placebo in terminal diseases shall be accepted in case of inefficacy of all the existing treatments.
p.(None): The investigator and the sponsor shall ensure that the participant will receive proper medical care in case of
p.(None): injury related to the investigation. In the case of diagnose of an inter-current disease caused by a research
p.(None): related procedure, the investigator shall guide the participant in obtaining the necessary health care.
p.(None): Participants requiring to continue their treatment after the study completion shall have access to the intervention
p.(None): that turned out to be beneficial or to an alternative intervention or another proper benefit, which shall be
p.(None): approved by the REC for the time it decides or until such access is ensured by any other means.
p.(None): AGREEMENTS AND FINANCING
p.(None): The sponsor is responsible for affording all the research costs, including study treatments and procedures.
p.(None): In clinical studies with a therapeutic benefit, the sponsor may make payments to the participants for any
p.(None): inconveniences and their time. However, such payments may not become an undue influence by
p.(None): being disproportionate in such a way that the patient is persuaded to run unnecessary risks. Payments shall be
p.(None): apportioned according to the study characteristics.
p.(None): The sponsor shall ensure medical care and an insurance coverage or the setting up of any other form of guarantee in
p.(None): the country, in case of injury to participants resulting from the study.
p.(None):
p.(None): The investigation financing shall be documented in a written agreement signed by the sponsor, the investigator and/or
p.(None): the institution hosting the study, which shall show in detail the commitment of the parties to fulfill the obligations
p.(None): set out in the Regulatory Guideline herein.
p.(None): The REC shall check any financial agreement and foreseen payment for the participants as
p.(None): provided for in 7.1. The sponsor shall verify that the REC approved them prior to research initiation.
p.(None): The investigator shall declare his or her potential financial conflicts of interests to the REC prior to initiating the
p.(None): investigation and at any time said conflicts arise.
p.(None): The approval or authorization of the study shall not release the sponsor, the investigator or the
p.(None): host institution from any legal responsibility they might bear in case of participants incurring damages as a result of
...
p.(None): make sure participants understand such instructions and then verify in every clinical visit that the instructions
p.(None): are followed.
p.(None):
p.(None): If a blinding method is used in the study, the sponsor shall set out a decoding procedure for emergency
p.(None): situations and the investigator shall do his or her utmost to preserve the blind, unless it becomes necessary to
p.(None): identify the product for participant´s safety reasons. In such case, the investigator shall document and justify the
p.(None): procedure and immediately report it to the sponsor and the REC.
p.(None): The investigator shall have an inventory of the investigational products documenting the following: reception
p.(None): from the sponsor, dispensation to participants, reception of the remains and return of unused products to the sponsor.
p.(None): Said function may be delegated to a BSc in Pharmacy or any other team member qualified and authorized to do so.
p.(None): The inventory of investigational products at the center shall indicate the participant´s code, product name or code,
p.(None): lot or serial number, expiry date, delivery and reception date and the respective quantities. The inventory
p.(None): shall enable to verify that the products were dispensed only to participants and that they used the products
p.(None): according to the protocol. Final accountability shall show a coincidence among the products received, the
p.(None): products used and the products returned to the sponsor. Otherwise, differences shall be accounted for in
p.(None): writing.
p.(None): Investigational products shall be stored in a locked safe place, with the exclusive access of authorized
p.(None): personnel and in the room conditions set out by the sponsor and the applicable regulations.
p.(None): The sponsor shall keep an analysis and description record of every investigational product batch and
p.(None): reserve an adequate quantity of samples for an eventual re- confirmation of specifications until the
p.(None): study data analysis is completed or until the regulatory authority decides that should be the case.
p.(None): Investigational products destruction shall be carried out according to the legislation in force concerning hazardous
p.(None): residues. The sponsor shall be primarily responsible for the destruction of unused products and shall retain the
p.(None): destruction certificate.
p.(None): REPORTS AND NOTIFICATIONS
p.(None): The investigator shall immediately notify the sponsor of all the serious adverse events (SAE), including relevant
p.(None): laboratory abnormalities, as per the procedures and terms established by the sponsor. Additional
p.(None): information enabling to determine the SAE relation with the investigational product shall be furnished, as soon as
p.(None): available.
p.(None): The investigator shall notify the REC, within the period set out by the latter, of all the SAEs and other events
p.(None): significantly affecting the study and/or the risk for participants.
p.(None): The investigator shall report the study progress to the REC at least once a year. The progress report shall contain,
p.(None): at least, the number of enrolled, followed up and withdrawn participants, the encoded list of
p.(None): participants, serious adverse events and their alleged relation with the investigational product as well as the
...
p.(None): of the informed consent, pre-study evaluation, inclusion in the study, randomized assignment result, instructions for
p.(None): using the investigational product, treatment initiation and termination, control of product delivery and return, as
p.(None): well as the information provided to the participant, shall be documented in the same format as are the medical notes
p.(None): used for the rest of the patients receiving medical care at the center.
p.(None): The investigator shall be responsible for preserving the confidentiality of every participant´s
p.(None): identity. No data of the participant´s identity shall be contained in any document transmitted, reported or
p.(None): taken away from the host institution.
p.(None): The changes or corrections of any of the study records shall not conceal or delete the original datum. Corrections
p.(None): shall be dated and signed with their author´s initials.
p.(None): In case of using electronic direct data transmission automated devices to perform study-related exams such
p.(None): as an electrocardiogram and a spirometry, an identifiable printed source document of the process shall
p.(None): be obtained and filed in the medical record.
p.(None): In case of using an electronic format for clinical data record-keeping and transmission, the system used shall
p.(None): comply with integrity, accuracy, reliability, confidentiality and consistency requirements.
p.(None): Electronic record-keeping systems shall enable:
p.(None): the recording of all the editions of individual data, including the author and the edition date and without eliminating
p.(None): the original data;
p.(None): a restricted access to enter or edit data;
p.(None):
p.(None): the obtainment of a data back-up copy;
p.(None): the protection of treatment blind during data entry and processing, if appropriate.
p.(None): The sponsor shall use an SOP to manage electronic systems and a list of the persons authorized to discharge such
p.(None): function.
p.(None): The study final results must be always related to the study clinical data, even when the variables were transformed at
p.(None): processing.
p.(None): ESSENTIAL DOCUMENTS OF THE STUDY
p.(None): Documents file and retention
p.(None): Document filing shall be set out from the beginning of the study, both at the research center and the sponsor´s
p.(None): office. All the documents mentioned in the Regulatory Guideline herein are subject to monitoring and
p.(None): auditing by the sponsor and to inspection by the agency and shall be available whenever required by them.
p.(None): The investigator and the sponsor shall retain the study documents in a locked safe place with access
p.(None): limited to authorized personnel and shall take the necessary steps to prevent their accidental loss or destruction.
p.(None): All the study documents shall be retained for ten years after the date of the last visit of the last patient enrolled
p.(None): in the center.
p.(None): Essential documents required prior to the study initiation:
p.(None): a copy of A.N.M.A.T. Regulatory Guideline herein; a current version of the Declaration of Helsinki;
p.(None): a valid investigational product monograph and other safety information; a protocol approved by the REC and the agency;
p.(None): amendments prior to the study initiation approved by the REC and A.N.M.A.T., if any; blank copies of the clinical data
p.(None): forms;
p.(None): an informed consent document approved by the REC and the agency; a model of recruitment advertisements approved by the
p.(None): REC, if any;
p.(None): a letter of commitment from the investigator and his or her team to comply with the protocol (study
p.(None): title) and to abide by the Declaration of Helsinki and A.N.M.A.T. Regulatory Guideline for GMP-CPS;
p.(None): a proof of approval by the REC of the study indicating the approved documents: protocol and which
p.(None): version, informed consent and which version, recruitment advertisements and others;
p.(None): a dated list of the REC members and positions;
p.(None): the Regulation or note whereby A.N.M.A.T. authorizes the study and research center;
p.(None): the notes whereby the agency authorizes the protocol or informed consent amendments;
p.(None): the proof whereby the agency was informed about the recruitment advertisements; an investigator´s function delegation
...
p.(None): SUSPENSION OR CANCELLATION OF THE STUDY
p.(None): A study may be suspended or cancelled by the investigator, the host institution, the sponsor, the REC or
p.(None): the agency. In such cases, the reason shall be justified and notified to the other stakeholders.
p.(None): The sponsor shall suspend the research in a center where serious or repeated protocol deviations having affected
p.(None): participants´ safety were detected and he or she shall inform such event to the agency.
p.(None): Participants shall be immediately informed about the study suspension or cancellation and shall be provided with
p.(None): medical care according to their needs. The sponsor shall provide an alternate treatment for the participants for as
p.(None): long as the REC decides.
p.(None): If the sponsor suspends or cancels the clinical development of an experimental drug, he or she shall notify of
p.(None): such decision and justify it to all the investigators, host institutions and A.N.M.A.T.
p.(None):
p.(None): SECTION D: INSPECTIONS OF CLINICAL PHARMACOLOGY STUDIES OBJECTIVE
p.(None): This section describes the procedures that should be followed in inspections of clinical pharmacology studies within
p.(None): A.N.M.A.T. competence, with a view to verifying the compliance of this Regulatory Guideline.
p.(None): SCOPE AND AUTHORITY
p.(None): Studies inspections are mainly aimed to investigators and research centers. However,
p.(None): A.N.M.A.T. may establish the need for performing inspections of other involved parties such as the sponsor and the
p.(None): contract research organizations (CRO).
p.(None): A.N.M.A.T. inspectors are empowered to enter the research center and have direct access to the
p.(None): investigational product, study filed documents and participants´ medical records. The inspections of clinical
p.(None): pharmacology studies may also include external institutions carrying out specific procedures of the study that
p.(None): were contracted by the investigator, sponsored party or CRO.
p.(None): INSPECTION PROCESS
p.(None): The inspection process comprises the study and inspector selection, the inspection planning and the
p.(None): inspection notification, conduct, reporting and result.
p.(None): Inspections may be performed prior to the study initiation, during its conduct or after its conclusion.
p.(None): SELECTION OF THE STUDY AND THE INVESTIGATOR
p.(None): The study selection criteria shall be as follows:
p.(None): inclusion of vulnerable population; priority for research initial phases;
p.(None): high risk investigational products studies;
p.(None): The investigator selection criteria shall be the following:
p.(None): a high recruitment rate as compared to other investigators of the study;
p.(None): a high or low incidence of serious and unexpected ADR as compared with the rest of the study investigators;
p.(None): the investigator´s background in previous studies;
p.(None): his or her participation in a significant number of studies;
p.(None): any relevant information included in safety and/or progress reports that merits an inspection, in the view
p.(None): of the agency;
p.(None): a complaint about the investigator´s inappropriate behavior. INSPECTOR SELECTION
p.(None): A.N.M.A.T. Director of the Drug Evaluation Office (DEO) shall select the inspector or inspectors to conduct the
p.(None): inspection.
p.(None): The Director of the Drug Evaluation Office shall ensure:
p.(None): the appropriate number of inspectors to perform the inspection;
p.(None):
p.(None): the inspectors´ suitability based on their education and training in studies scientific and regulatory aspects;
p.(None): the absence of potential financial conflicts of interest with the study investigators, research sites or
p.(None): sponsor;
p.(None): the supply of a proper identification document for inspectors;
p.(None): inspectors´ access to all the study information needed to carry out the inspection, including at least,
p.(None): the protocol, amendments, informed consents and serious and unexpected ADRs reports as well as the study
p.(None): progress and previous inspections reports.
p.(None): PLANNING AN INSPECTION
p.(None): When planning an inspection, the designated inspectors shall: analyze the information provided by the Drug Evaluation
p.(None): Office ;
p.(None): thoroughly know the study objectives, inclusion and exclusion criteria, foreseen visits and analytical procedures,
p.(None): investigational product information, its safety data and special handling and storage requirements as well
p.(None): as the allowed and unallowed concomitant drugs;
p.(None): consider the observations made during the study evaluation prior to the authorization and/or the study and investigator
p.(None): selection criteria;
p.(None): create an inspection plan specific for the study and the investigator to be inspected , which shall be approved by the
p.(None): Inspections Coordinator and the DEO;
p.(None): create an inspection form including the list of study documents to be reviewed, the guidelines to obtain
p.(None): the informed consent, the verification of clinical records, the investigational product circuit and the
p.(None): facilities of the research center to be visited.
p.(None): INSPECTION ANNOUNCEMENT
p.(None): Inspections shall be announced to the sponsor and/or principal investigator at least fifteen running days
p.(None): before it is conducted, in order to ensure the availability of the research team and documentation at the
p.(None): time of the inspection conduct.
p.(None): The previous inspection announcement may not be made if the visit is decided upon relevant information included in
p.(None): the safety reports and/or progress reports or upon a complaint about the investigator´s inappropriate behavior.
p.(None): The inspection shall be announced by means of a certified return receipt letter. INSPECTION CONDUCT
p.(None): General considerations
p.(None): Inspectors shall appear at the site to be inspected and get in contact with the investigator or his or
p.(None): her delegate at the announced date and time.
p.(None): Inspectors shall:
p.(None): verify the compliance with the protocol and its amendments authorized by A.N.M.A.T.; verify that participants´ rights
p.(None): and safety were protected;
p.(None): evaluate data quality and integrity.
p.(None):
p.(None): The documents obtained or produced from the inspections of clinical investigators shall be available only for
p.(None): A.N.M.A.T. and, when appropriate, for the investigators and sponsor involved.
p.(None): Both inspector and any other A.N.M.A.T. personnel related to clinical investigators activities shall
p.(None): maintain confidential the information they access to during the inspections.
p.(None): Initial interview
p.(None): In the initial interview the inspector shall show his or her official identification and explain the
p.(None): type and scope of the inspection as well as the procedures that will be conducted therein.
p.(None): The investigator´s team members and the sponsor´s agents may be present at the initial interview.
p.(None): The inspectors shall request information (who, what, when, where, how) about the delegation of the following
p.(None): functions to the investigator´s team members:
p.(None): informed consent obtainment; prospective participants assessment;
p.(None): participants´ selection and random assignment; clinical data obtainment and evaluation;
p.(None): clinical data forms filing out;
p.(None): study drug reception, return and management.
p.(None): The inspector may interview the investigator´s team members and, if appropriate, participants at the
p.(None): beginning of or during the inspection.
p.(None): Inspection conduct
p.(None): The inspectors shall identify and review all the source documents and other documents essential for the study.
p.(None): Likewise, the inspectors may inspect the facilities of the research center or those of the external institutions where
p.(None): study-related procedures are performed.
p.(None): The handwritten or electronic notes taken by the inspectors during the inspection shall be filed in the inspection
p.(None): dossier at the agency and shall serve as a support for inspection report accuracy.
p.(None): The inspectors shall request and take copies of the study records or investigational product samples, if
p.(None): they deem it appropriate.
p.(None): The inspectors may interview the study participants, should they find it necessary. Such interviews shall be
p.(None): documented in records different from the inspection records. The interview records shall contain the
p.(None): participant´s identification, the interview objective, the questions made and the answers provided by
p.(None): the participants. The interview records shall be filed in the inspection dossier at the agency and the
p.(None): investigators shall access them upon previous justified request to and express authorization by the
p.(None): agency.
p.(None):
p.(None): The inspectors may interrupt the study and shall immediately communicate such decision to the DEO, if they
p.(None): were to identify serious deviations from the regulations or serious risks for the participants.
p.(None): RECORD REVIEW PROCEDURES
p.(None): The inspectors shall review the investigator´s essential documents under Section C of the Regulatory Guideline herein.
p.(None): The inspectors shall verify the recruit mechanisms in the medical record of each participant and the
p.(None): absence of duress and undue influence in the recruit.
p.(None): The inspectors shall verify the following in the informed consent process: that the consent obtainment process fulfills
p.(None): all the rules set forth herein; that the informed consent used was approved by the REC and A.N.M.A.T.;
p.(None): that all the informed consent forms were signed and dated by the participants or their legal representative and the
p.(None): investigator or authorized sub-investigator;
p.(None): that the empowerment to represent the participant is documented in the medical record, had the
p.(None): informed consent been obtained from the participant´s legal representative;
p.(None): that a written assent was obtained in the case of persons under age and within the lower age limit
p.(None): determined by the REC;
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p.(None): shall be submitted for Phase I, Phase II and Phase III clinical pharmacology studies.
p.(None): A patient´s information leaflet shall be accepted as an investigational product monograph for
p.(None): studies conducted with API(s) already registered at A.N.M.A.T.
p.(None): General information
p.(None): General information shall include:
p.(None): sponsor´s name
p.(None): investigational product monograph number and edition date;
p.(None): generic name(s) as per the International Non-proprietary Name (INN) or similar code or investigational product code, if
p.(None): no generic name is available yet;
p.(None): ATC (Anatomical Therapeutic Chemical) classification, if appropriate; CAS (Chemical Abstract Service) classification;
p.(None): physical-chemical properties; qualitative and quantitative formula;
p.(None): pharmaceutical form to be studied, including excipients;
p.(None): investigational product pharmacologic properties, therapeutic potential and its qualitative and
p.(None): quantitative relation with the study therapeutic indication;
p.(None): pharmacokinetic characteristics;
p.(None): the safety margin and envisaged adverse effects in the doses proposed. Pre-clinical information
p.(None):
p.(None): Pre-clinical information shall account for the nature, scale and duration of the trial. The description of each
p.(None): pre-clinical study shall be submitted with the following sections:
p.(None): Materials and methods which shall include:
p.(None): a detailed and justified plan indicating the GLP it is governed by;
p.(None): the product used and information concerning its origin, composition, lot number, quality control protocol number and
p.(None): expiry date;
p.(None): the animals or substitutive models used and information indicating their number, species, strain, gender, age
p.(None): and weight;
p.(None): the experimental conditions and information about dose, frequency, route of administration, duration,
p.(None): type of feeding and environmental conditions.
p.(None): A summary of the results produced, including nature, time of appearance, frequency, intensity, duration and
p.(None): reversibility of the pharmacologic and toxic effects and dose response, as well as the statistical analysis of
p.(None): such results.
p.(None): Discussion of the most significant findings and conclusions, including the dose response of the effects
p.(None): observed, the relevance for human beings and any other aspect intended to be studied in human beings. The
p.(None): findings of the effective and non toxic doses (therapeutic index) in the same animal species and their ratio
p.(None): for the human dose proposed shall be compared, if appropriate.
p.(None): Preclinical pharmacology
p.(None): Pharmacodynamics: the potential therapeutic activity shall be demonstrated and the product and/or its
p.(None): metabolites possible mechanisms of action shall be described, including the evaluation of pharmacologic
p.(None): actions other than the therapeutic effects intended.
p.(None): Special pharmacodynamics: pharmacodynamic effects as per the indications proposed, dose-effect and time-effect curves.
p.(None): General pharmacodynamics: studies on the cardiovascular system, respiratory system, central nervous system,
p.(None): autonomic nervous system, neuromuscular system, urinary system, endocrine system, digestive system, etc.
p.(None): Pharmacodynamic interactions: studies determining these types of relations. Mechanisms of action: a description of the
p.(None): mechanisms observed.
p.(None): Pharmacokinetics: determination of the speed and magnitude of absorption, distribution model, biotransformation, speed
...
p.(None): shall be accepted;
p.(None): there is no appropriate species, in which case the use of transgenic animals expressing the human receptor or the use
p.(None): of homologous proteins shall be considered;
p.(None): if neither of the above mentioned is the case, a repeated dose study on a single species for a period
p.(None): appropriate to the investigational product shall be conducted. Said study should evaluate the specific
p.(None): functions and morphology, for example, the cardiovascular and respiratory ones.
p.(None): In addition to the requirements outlined for synthesis products, pre-clinical information of biotechnological products
p.(None): shall include:
p.(None): toxicological evaluation of contaminants and impurities;
p.(None): anti-genicity reactions, for instance, of anti-product antibodies;
p.(None): immune-toxicity reactions, for example, for immune-modulators, if appropriate.
p.(None): Clinical information
p.(None): a detailed discussion of the known effects of the investigational product on humans, including information
p.(None): about pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy and other pharmacological
p.(None): activities shall be submitted.
p.(None): The following information about pharmacokinetics shall be included:
p.(None): regarding pharmacokinetics: absorption, protein binding, metabolism, distribution and elimination;
p.(None): absolute and/or relative bioavailability using a reference dosage form;
p.(None): regarding bioequivalence: whenever appropriate, for example, in case the product is manufactured with a
p.(None): technology different from the one used to demonstrate its efficacy and safety;
p.(None): population sub-groups as to gender, age, impaired organic function; interactions with another drug and foods;
p.(None): other pharmacokinetics-related data.
p.(None): A summary of information shall be provided about the safety, pharmacodynamics, efficacy and the dose
p.(None): response of the product and its metabolites, if appropriate, produced from studies in healthy and ill
p.(None): volunteers. The implications of said information shall be discussed.
p.(None):
p.(None): Complete information about adverse drug reactions shall be submitted in tables. Based on the experience with the
p.(None): product and related products, the incidence patterns across indication or sub-group shall be discussed.
p.(None): If the product is marketed abroad, a summary of the relevant information stemming from its use. If the
p.(None): product was not approved or was suspended or recalled from the market of other country(s), which countries and the
p.(None): rationale for such measures shall be explained.
p.(None): Excipients
p.(None): In the case of excipients without a history of use in human beings, all the studies supporting the
p.(None): safety of their use shall be submitted.
p.(None): PROTOCOL
p.(None): General
p.(None): This Regulatory Guideline sets out the information and structure required for the clinical pharmacological studies
p.(None): protocol.
p.(None): General information
p.(None): the study complete title, including the clinical development phase; the version number and date;
p.(None): the sponsor´s name; a protocol summary
p.(None): a visits and procedures schedule.
...
p.(None): the study.
p.(None): SERIOUS AND UNEXPECTED ADVERSE DRUG REACTIONS
p.(None): The sponsor shall inform A.N.M.A.T. of any serious and unexpected adverse drug reaction concerning the
p.(None): investigational product within a ten working-day period after the moment he or she learnt about it. The serious and
p.(None): unexpected adverse drug reactions produced by a comparator product already registered at A.N.M.A.T. to be
p.(None): marketed nationwide or those related to a placebo shall be reported only to A.N.M.A.T. Pharmacovigilance
p.(None): System.
p.(None): In blinded studies, whenever the sponsor receives a report of a serious adverse event (SAE), he or she shall verify the
p.(None): treatment provided to the participant in order to find out whether it is the case of an unexpected and serious adverse
p.(None): drug reaction (ADR) as defined in 7.1., but he or she shall not unmask the treatment to the investigator or persons in
p.(None): charge of the data analysis and discussion.
p.(None): The unexpected and serious ADR report shall include the following information: the denomination of the adverse
p.(None): reaction;
p.(None): investigational product code, INN and trade mark;
p.(None): type of report: baseline, update (update number) or final; sponsor´s name;
p.(None): the research center and investigator´s name;
p.(None):
p.(None): A.N.M.A.T. regulation authorizing the study conduct; the name or title of the study;
p.(None): participant´s code, age and sex;
p.(None): the date of the unexpected and serious ADR appearance, the date of investigator´s report and the date the
p.(None): sponsor received it;
p.(None): unexpected and serious ADR seriousness criteria; unexpected and serious ADR brief description;
p.(None): investigational product information: daily dose, route of administration, start and suspension date, therapy
p.(None): duration and indication;
p.(None): inform if the reaction disappeared after treatment suspension; inform if the reaction reappeared with treatment
p.(None): re-introduction; concomitant drugs: dosage form and start and termination date; participant´s history significant for
p.(None): the unexpected and serious ADR.
p.(None): Every six months, after the date the agency authorized the first study on the investigational product, the
p.(None): sponsor shall submit a single summary per investigational product, of all the unexpected and serious ADR occurred in
p.(None): any of the research centers for the pertaining period, which shall include the following information:
p.(None): A.N.M.A.T. dossier or regulation number concerning the investigational product;
p.(None): a list of unexpected and serious ADR classified by organic system and reaction type, including the participant
p.(None): code, denomination of the adverse reaction, date of appearance and country of occurrence.
p.(None): the investigational product overall risk-benefit assessment and a particular assessment per type of reaction, including
p.(None): all the cases in which the same reaction occurred.
p.(None): The agency shall be informed of any risk increase over benefits in any of the studies on an investigational product
...
p.(None): The REC shall provide an independent, competent and timely evaluation of the ethical, scientific and operational
p.(None): aspects of the proposed studies, which shall be based upon the current state of scientific knowledge and the Regulatory
p.(None): Guideline herein.
p.(None):
p.(None): Every clinical pharmacology study must be evaluated by a REC before its initiation and throughout its conduct, at
p.(None): least once a year until its completion. The REC may set shorter periods for evaluations as per the risks
p.(None): involved in the study.
p.(None): The REC shall assess the suitability of the investigator to conduct the study according to his or her education and
p.(None): training in ethical and regulatory aspects and the research center suitability to host the study.
p.(None): The REC shall make sure that potential participants give their consent without duress or undue influence and
p.(None): after having received all the information properly. The information about payments and compensations
p.(None): envisaged for the study shall be precise and easy to understand for participants.
p.(None): The REC shall make sure of the compliance with the ethical principles applicable throughout the study
p.(None): conduct, by means of a monitoring mechanism for investigators.
p.(None): Composition
p.(None): The REC composition shall be such that enables a competent, unbiased and uninfluenced evaluation of
p.(None): the scientific, medical, ethical and legal aspects of the study.
p.(None): The REC composition shall be cross functional, multi-sectored and balanced in terms of its members´ age, sex and both
p.(None): scientific and non-scientific education. The number of members shall be adequate, preferably uneven, to ensure the
p.(None): fulfillment of its duty. It shall have a minimum of five full members and at least two alternate members for the cases
p.(None): of absence of the regular members.
p.(None): The research center REC shall include an external member unrelated to the institution and who shall represent the
p.(None): interest of the community being assisted.
p.(None): The members shall be frequently renewed in order to combine the advantages of experience with those
p.(None): of new perspectives. The REC member selection and replacement mechanism shall ensure the election
p.(None): impartiality and respect for the suitability and plurality criteria.
p.(None): The REC shall elect a president among its members to lead meetings. The REC president shall be a person
p.(None): holding the experience, competence and qualifications to deal with and evaluate all the aspects of the investigations.
p.(None): Operation
p.(None): The REC holds the authority to approve, request amendments to, disapprove, discontinue or cancel
p.(None): an investigation on human health. The REC shall report its opinions in writing to the investigator, including
p.(None): the reasons for its decisions.
p.(None): The REC shall make a list and keep it updated of its members, indicating their names, age, sex, profession or
p.(None): occupation, position at the REC and relationship with the institution.
p.(None): The REC shall place in record its meetings, consultations and decisions, including the participating members and their
p.(None): voting results.
p.(None): The REC shall request and make available for its members all the research documents necessary for a comprehensive
p.(None): evaluation including: the protocol and its amendments, the informed consent and its amendments, other
p.(None): information for participants, the investigator´s updated curriculum vitae, enrolment mechanisms, a
p.(None): detail of the payments and insurance coverage envisaged for the participants and financing source of the study.
p.(None):
p.(None): A member of the REC who is, in turn, an investigator in a project may not participate in any evaluations, consultations
p.(None): or decisions about such project.
p.(None): The REC shall consult experts as to specific subject matters but they shall not have a right to decide on the project.
p.(None): The experts requested participation and opinion shall be documented.
p.(None): The REC shall demand from the investigator the immediate report on all the relevant information about safety or
p.(None): protocol amendments increasing the risk for participants or those changes made with the purpose of eliminating the
p.(None): immediate hazards for them.
p.(None): In case of administrative changes or changes that do not affect participants´ safety, the REC may carry out a swift
p.(None): evaluation of such changes. The president or member in charge of the swift evaluation shall document it and
...
p.(None): the fulfillment of the requirements applicable thereto. Likewise, the medical record shall inform both the
p.(None): presence and absence of the prospective participant´s vulnerable condition.
p.(None): All the new information or changes in the protocol that may affect the participant´s safety or his
p.(None): or her decision to continue participating in the study shall be communicated verbally an in writing
p.(None): in order to obtain the consent. The new consent document shall be previously approved by the REC and the
p.(None): agency, unless the changes require swift implementation for safety reasons.
p.(None): PROTECTION OF STUDY PARTICIPANTS
p.(None):
p.(None): The investigator and the sponsor shall ensure that every participant will have access to their own information and
p.(None): to the study results once available and that their right to confidentiality will be protected at all times.
p.(None): The investigator is responsible for obtaining the consent of all the participants, even when a sub-investigator
p.(None): was authorized to perform that action.
p.(None): Since exposure to an investigational product during pregnancy implies risks for the embryo or fetus, the
p.(None): following measures shall be taken:
p.(None): women of fertile age shall be warned about such risks, before giving their consent to participate in the study and
p.(None): about the need to immediately inform the investigator should they suspect of being pregnant at any time of the
p.(None): study;
p.(None): the investigator shall run a pregnancy test prior to the admission to the study of every women of fertile age; and then
p.(None): regularly throughout the study;
p.(None): a positive result pregnancy test shall imply the exclusion of the prospective participant or the preventive
p.(None): discontinuation of the investigational product administration, if appropriate. In case of pregnancy, the
p.(None): investigator shall guide the participant in obtaining proper care;
p.(None): the sponsor and the investigator shall ensure the access to the necessary contraceptive methods
p.(None): for all the study participants.
p.(None): An investigator who is a doctor of medicine or a dentist, as appropriate, shall be responsible for all
p.(None): the participants´ health care related decisions throughout the study.
p.(None): Should the study put at risk the integrity or health of the participants, for example, due to an adverse reaction
p.(None): or a therapeutic failure, the investigator shall take all the precautions to halt the exposure to the risk.
p.(None): The use of a placebo control shall be properly justified both from the methodological and ethical points of view. The
p.(None): use of a placebo in terminal diseases shall be accepted in case of inefficacy of all the existing treatments.
p.(None): The investigator and the sponsor shall ensure that the participant will receive proper medical care in case of
...
p.(None): investigators shall access them upon previous justified request to and express authorization by the
p.(None): agency.
p.(None):
p.(None): The inspectors may interrupt the study and shall immediately communicate such decision to the DEO, if they
p.(None): were to identify serious deviations from the regulations or serious risks for the participants.
p.(None): RECORD REVIEW PROCEDURES
p.(None): The inspectors shall review the investigator´s essential documents under Section C of the Regulatory Guideline herein.
p.(None): The inspectors shall verify the recruit mechanisms in the medical record of each participant and the
p.(None): absence of duress and undue influence in the recruit.
p.(None): The inspectors shall verify the following in the informed consent process: that the consent obtainment process fulfills
p.(None): all the rules set forth herein; that the informed consent used was approved by the REC and A.N.M.A.T.;
p.(None): that all the informed consent forms were signed and dated by the participants or their legal representative and the
p.(None): investigator or authorized sub-investigator;
p.(None): that the empowerment to represent the participant is documented in the medical record, had the
p.(None): informed consent been obtained from the participant´s legal representative;
p.(None): that a written assent was obtained in the case of persons under age and within the lower age limit
p.(None): determined by the REC;
p.(None): that the informed consent was obtained by the investigator or sub-investigator authorized in the
p.(None): function delegation form; that the informed consent was obtained prior to evaluating the eligibility criteria or any
p.(None): other study specific procedure;
p.(None): that the consent obtainment is documented in the participant´s medical record, including the initiation date
p.(None): and time, that they were provided with time to reflect on and make questions, which the questions made were, that the
p.(None): participant´s understanding of the information was verified and that two originals were signed and one of them was
p.(None): given to the participant;
p.(None): that in the case of a participant being in a situation of cultural, educational, social or economic vulnerability,
p.(None): the consent was obtained in the presence and with the signature of an impartial witness and that the
p.(None): mechanism was documented in the participant´s medical record.
p.(None): The inspectors shall verify that the participants gave their consent to all the informed consent amendments and the
...
Social / Child
Searching for indicator children:
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p.(None): host institution from any legal responsibility they might bear in case of participants incurring damages as a result of
p.(None): their participation in the study.
p.(None): INVESTIGATIONAL PRODUCT
p.(None): Manufacture, packing and labeling
p.(None): The sponsor shall ensure that all the investigational products are manufactured according to GMP, if
p.(None): appropriate, and packed in a safe manner to prevent contamination or deterioration during
p.(None): transportation or storage.
p.(None): The label shall be written in Spanish and contain, at least, the following printed information or,
p.(None): whenever appropriate, there shall be space left to complete said information on it:
p.(None): study identification, sponsor and investigator; product name, or if blinded, the corresponding code;
p.(None): dosage form, route of administration (may be excluded in solid forms) and concentration or
p.(None): potency per unit, were it the case of an open study;
p.(None): lot number or code to identify the manufacturing and packing process; participant´s code and number of visit or date of
p.(None): product administration.
p.(None): The following information shall be included in the label whenever the primary packing size allows for it, or otherwise,
p.(None): in the secondary packing or a leaflet attached:
p.(None): the name, address and telephone number of the person who should be contacted for information about the product, the
p.(None): study and the emergency decoding (sponsor, CRO or investigator);
p.(None): basic storage conditions; expiry date (month/year);
p.(None): special instructions for the product administration; a “clinical investigation exclusive use” statement;
p.(None): a “keep away from the reach of children” statement if the product is given to the participant.
p.(None): In case of updating the investigational product expiration date, an additional label shall be placed on the packing
p.(None): which shall contain the lot number, the old expiration date and the new one. The re-labeling process may be
p.(None): carried out at the authorized manufacturing site or at the research center, in which case, the study
p.(None): monitor shall
p.(None):
p.(None): perform said procedure and a sponsor representative shall review its result. Such process shall be
p.(None): documented on the sponsor´s lot record and the research center product accountability records.
p.(None): If the formulation of the investigational product or its comparators were modified during the study, the new
p.(None): pharmacokinetics or dissolution studies, according to the pharmaceutical form, shall be available prior to
p.(None): using the new the formulation, in order to ensure therapeutic equivalence. Topical and gaseous drugs are exempted from
p.(None): said requirement, provided the API concentration is the same. All product modifications require a protocol
p.(None): amendment and approval by the REC and A.N.M.A.T.
p.(None): Information
p.(None): All clinical studies shall be based on safety and efficacy information obtained from clinical and
p.(None): non-clinical studies. Such information shall support the product proposed use as to its indication, pharmaceutical
p.(None): form, route of administration, dose and population to be treated.
p.(None): The sponsor shall submit an investigation product monograph updated with complete data concerning the safety, efficacy,
p.(None): route of administration and treated population of pre-clinical or previous clinical studies on the investigational
...
Social / Educational
Searching for indicator education:
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p.(None): adjusts to the study requirements and that all the equipment, instruments and supplies to be used
p.(None): operate properly. Phase I, pharmacokinetics, bioavailability and bioequivalence studies may only be
p.(None): conducted in second or third level health institutions (for hospitalization), according to the regulation
p.(None): in effect set forth by the Ministry of Health. The level of each institution may be verified in its
p.(None): operating license.
p.(None): In case of advertising in communication media for participant recruit purposes, the advertisements used
p.(None): shall be approved by the REC and submitted to the agency. The investigational product may not, implicitly or
p.(None): explicitly, be referred to as efficacious, safe or equivalent to or better than existing products in such
p.(None): advertisements.
p.(None): The investigator and the research site shall be subject to monitoring, audit or inspection of the clinical study by the
p.(None): REC, sponsor and competent authorities.
p.(None): SPONSOR
p.(None): The sponsor of the study is the physical person or legal entity that initiates, manages, controls and finances the
p.(None): study and takes all the responsibilities laid down in this regulatory guideline.
p.(None): The sponsor shall count on qualified professionals for the design, planning, conduct, analysis and reporting of the
p.(None): clinical study, as well as on medical advisors to pursue matters concerning the investigational products and
p.(None): participants´ safety.
p.(None): The sponsor is responsible for selecting qualified investigators according to their education, training and
p.(None): experience; and research centers having all the resources needed for the proper conduct of the clinical
p.(None): pharmacology study.
p.(None): The sponsor shall furnish the investigator with all the documents necessary to perform the study properly, such as,
p.(None): the protocol and investigational product monograph, among others. Likewise, the sponsor shall be responsible for
p.(None): training the investigator and his or her team on the study procedures, investigational products and applicable
p.(None): requirements.
p.(None): The investigator is responsible for obtaining the authorization from the research site or institution authority before
p.(None): initiating the study; while the sponsor shall be responsible for obtaining the authorization from the agency before
p.(None): starting the study conduct.
p.(None): For multi-site research studies, the investigator shall lay out a plan to validate and standardize all the
p.(None): measurement procedures in the various research sites.
p.(None): The sponsor may summon an Independent Data Monitoring Committee (IDMC) composed of experts in the clinical
p.(None): study subject matter to review safety and efficacy partial results and evaluate and recommend whether the study
p.(None): should be continued, modified or cancelled. The IDMC members cannot be investigators of the study or
p.(None): sponsor´s employees.
p.(None): The sponsor shall implement and maintain a quality control and assurance process throughout the study
p.(None): stages, which shall be based upon standardized operational
p.(None):
p.(None): procedures (SOPs), in order to ensure the study is being conducted and documented according to the protocol and
...
p.(None): protocol and its amendments, informed consent documents and their amendments, other information to be
p.(None): provided to potential participants, participant enrolment method, last version of the investigational product
p.(None): monograph and any other information concerning the experimental products or procedures.
p.(None): In case that the research site does not have its own REC or if the REC does not comply with the
p.(None): requirements set out herein, the study shall be evaluated by a REC belonging to another institution. The
p.(None): research site authority shall authorize the delegation of this function.
p.(None): REC evaluation objective and scope
p.(None): The primary objective of the review by a REC of a clinical pharmacology study is to protect the dignity, rights,
p.(None): safety and well-being of the participants.
p.(None): The REC shall provide an independent, competent and timely evaluation of the ethical, scientific and operational
p.(None): aspects of the proposed studies, which shall be based upon the current state of scientific knowledge and the Regulatory
p.(None): Guideline herein.
p.(None):
p.(None): Every clinical pharmacology study must be evaluated by a REC before its initiation and throughout its conduct, at
p.(None): least once a year until its completion. The REC may set shorter periods for evaluations as per the risks
p.(None): involved in the study.
p.(None): The REC shall assess the suitability of the investigator to conduct the study according to his or her education and
p.(None): training in ethical and regulatory aspects and the research center suitability to host the study.
p.(None): The REC shall make sure that potential participants give their consent without duress or undue influence and
p.(None): after having received all the information properly. The information about payments and compensations
p.(None): envisaged for the study shall be precise and easy to understand for participants.
p.(None): The REC shall make sure of the compliance with the ethical principles applicable throughout the study
p.(None): conduct, by means of a monitoring mechanism for investigators.
p.(None): Composition
p.(None): The REC composition shall be such that enables a competent, unbiased and uninfluenced evaluation of
p.(None): the scientific, medical, ethical and legal aspects of the study.
p.(None): The REC composition shall be cross functional, multi-sectored and balanced in terms of its members´ age, sex and both
p.(None): scientific and non-scientific education. The number of members shall be adequate, preferably uneven, to ensure the
p.(None): fulfillment of its duty. It shall have a minimum of five full members and at least two alternate members for the cases
p.(None): of absence of the regular members.
p.(None): The research center REC shall include an external member unrelated to the institution and who shall represent the
p.(None): interest of the community being assisted.
p.(None): The members shall be frequently renewed in order to combine the advantages of experience with those
p.(None): of new perspectives. The REC member selection and replacement mechanism shall ensure the election
p.(None): impartiality and respect for the suitability and plurality criteria.
p.(None): The REC shall elect a president among its members to lead meetings. The REC president shall be a person
p.(None): holding the experience, competence and qualifications to deal with and evaluate all the aspects of the investigations.
p.(None): Operation
p.(None): The REC holds the authority to approve, request amendments to, disapprove, discontinue or cancel
p.(None): an investigation on human health. The REC shall report its opinions in writing to the investigator, including
p.(None): the reasons for its decisions.
p.(None): The REC shall make a list and keep it updated of its members, indicating their names, age, sex, profession or
p.(None): occupation, position at the REC and relationship with the institution.
p.(None): The REC shall place in record its meetings, consultations and decisions, including the participating members and their
p.(None): voting results.
...
p.(None): INSPECTION PROCESS
p.(None): The inspection process comprises the study and inspector selection, the inspection planning and the
p.(None): inspection notification, conduct, reporting and result.
p.(None): Inspections may be performed prior to the study initiation, during its conduct or after its conclusion.
p.(None): SELECTION OF THE STUDY AND THE INVESTIGATOR
p.(None): The study selection criteria shall be as follows:
p.(None): inclusion of vulnerable population; priority for research initial phases;
p.(None): high risk investigational products studies;
p.(None): The investigator selection criteria shall be the following:
p.(None): a high recruitment rate as compared to other investigators of the study;
p.(None): a high or low incidence of serious and unexpected ADR as compared with the rest of the study investigators;
p.(None): the investigator´s background in previous studies;
p.(None): his or her participation in a significant number of studies;
p.(None): any relevant information included in safety and/or progress reports that merits an inspection, in the view
p.(None): of the agency;
p.(None): a complaint about the investigator´s inappropriate behavior. INSPECTOR SELECTION
p.(None): A.N.M.A.T. Director of the Drug Evaluation Office (DEO) shall select the inspector or inspectors to conduct the
p.(None): inspection.
p.(None): The Director of the Drug Evaluation Office shall ensure:
p.(None): the appropriate number of inspectors to perform the inspection;
p.(None):
p.(None): the inspectors´ suitability based on their education and training in studies scientific and regulatory aspects;
p.(None): the absence of potential financial conflicts of interest with the study investigators, research sites or
p.(None): sponsor;
p.(None): the supply of a proper identification document for inspectors;
p.(None): inspectors´ access to all the study information needed to carry out the inspection, including at least,
p.(None): the protocol, amendments, informed consents and serious and unexpected ADRs reports as well as the study
p.(None): progress and previous inspections reports.
p.(None): PLANNING AN INSPECTION
p.(None): When planning an inspection, the designated inspectors shall: analyze the information provided by the Drug Evaluation
p.(None): Office ;
p.(None): thoroughly know the study objectives, inclusion and exclusion criteria, foreseen visits and analytical procedures,
p.(None): investigational product information, its safety data and special handling and storage requirements as well
p.(None): as the allowed and unallowed concomitant drugs;
p.(None): consider the observations made during the study evaluation prior to the authorization and/or the study and investigator
p.(None): selection criteria;
p.(None): create an inspection plan specific for the study and the investigator to be inspected , which shall be approved by the
p.(None): Inspections Coordinator and the DEO;
p.(None): create an inspection form including the list of study documents to be reviewed, the guidelines to obtain
p.(None): the informed consent, the verification of clinical records, the investigational product circuit and the
p.(None): facilities of the research center to be visited.
p.(None): INSPECTION ANNOUNCEMENT
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Searching for indicator educational:
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p.(None): minutes of meetings, opinions and general communications for a ten-year period after the termination of the
p.(None): study and shall make them available for health authorities should they request them.
p.(None): INFORMED CONSENT
p.(None): General
p.(None): The informed consent is the process that ensures that a potential participant decides to participate in a human
p.(None): health investigation voluntarily, without undue influence or duress, provided the investigation is consistent
p.(None): with the participant´s values, interests and preferences.
p.(None): The informed consent process shall be conducted by the investigator or a qualified sub-investigator
p.(None): authorized to do so in the function delegation form.
p.(None): In case a potential participant cannot grant by him or herself the consent to a study, the informed consent shall be
p.(None): obtained from his or her legal representatives, in accordance to the Argentine legislation in the matter.
p.(None): Likewise, the participant´s assent shall be requested after having provided him or her with information about the
p.(None): study, according to his or her understanding possibilities of such information. The participant´s decision whether to
p.(None): participate or not shall be respected.
p.(None): In case of a study potential participant´s educational, cultural, social or economic vulnerability, the
p.(None): involvement of a witness unrelated to the investigator and his or her team shall be required. Said witness shall sign
p.(None): and date the consent form as a proof of his or her participation. The REC may set this requirement for all
p.(None): cases in centers where most patients are in a vulnerable situation.
p.(None): A summary of the written information for the patient approved by the REC and the agency may be used in
p.(None): case of serious situations requiring immediate medical care. Spoken information shall be provided in the presence of
p.(None): an impartial witness, who shall
p.(None):
p.(None): sign the written summary of the information and the consent signature page, together with the investigator.
p.(None): Guidelines for obtaining the informed consent
p.(None): The information consent documents include at least two sections: information pages for the participant and the
p.(None): signatures page. Any document intended to be used in the process shall be approved by the REC and the agency.
p.(None): The information section shall contain all the elements described in section B.5.1.
p.(None): The informed consent shall be obtained prior to initiating the assessment of eligibility criteria or any other
p.(None): specific procedure of the study.
...
p.(None): that all the informed consent forms were signed and dated by the participants or their legal representative and the
p.(None): investigator or authorized sub-investigator;
p.(None): that the empowerment to represent the participant is documented in the medical record, had the
p.(None): informed consent been obtained from the participant´s legal representative;
p.(None): that a written assent was obtained in the case of persons under age and within the lower age limit
p.(None): determined by the REC;
p.(None): that the informed consent was obtained by the investigator or sub-investigator authorized in the
p.(None): function delegation form; that the informed consent was obtained prior to evaluating the eligibility criteria or any
p.(None): other study specific procedure;
p.(None): that the consent obtainment is documented in the participant´s medical record, including the initiation date
p.(None): and time, that they were provided with time to reflect on and make questions, which the questions made were, that the
p.(None): participant´s understanding of the information was verified and that two originals were signed and one of them was
p.(None): given to the participant;
p.(None): that in the case of a participant being in a situation of cultural, educational, social or economic vulnerability,
p.(None): the consent was obtained in the presence and with the signature of an impartial witness and that the
p.(None): mechanism was documented in the participant´s medical record.
p.(None): The inspectors shall verify that the participants gave their consent to all the informed consent amendments and the
p.(None): latter had been approved by the REC and the agency at the time of using them and that all the process requirements were
p.(None): fulfilled.
p.(None): The inspectors shall compare the protocol and amendments approved by the REC and the agency with the protocol filed by
p.(None): the investigator in relation to:
p.(None): inclusion and exclusion criteria;
p.(None): clinical data type and obtainment frequency; treatment dose, frequency and route of administration; randomized
p.(None): assignment and blinding procedures.
p.(None): The inspectors shall review the source documents and verify the following:
p.(None):
p.(None): that participants exist and that all the procedures under the protocol were performed to them;
p.(None): that participants met the eligibility criteria at the time of their inclusion in the study; that participants were
p.(None): administered the study treatments per the protocol;
p.(None): that all SAE were notified to the sponsor;
p.(None): that clinical data were obtained and notified correctly and completely. According to the inspection plan set out, the
p.(None): inspectors shall verify: the informed consents;
...
p.(None): without the need to require additional information from the inspected party.
p.(None):
p.(None): SECTION E: GLOSSARY
p.(None): AUDIT: a systematic and independent examination of the study related activities and documents to determine whether the
p.(None): activities evaluated were performed and the data were accurately recorded, analyzed and reported as per the
p.(None): protocol, SOP(s), GCP and A.N.M.A.T. Regulatory Guideline for GCP-CPS.
p.(None): AUTONOMY: a person´s self-determination capacity to make a decision voluntarily, as per only his or her own values,
p.(None): interests and preferences provided that he or she has the necessary information to assess all the options. By
p.(None): definition, an autonomous person is able to give his or her informed consent without needing any protection other
p.(None): than the assurance that all the necessary information is provided to him or her. In addition, those
p.(None): individuals having a diminished or inexistent autonomy are in a vulnerable situation, and, therefore, require
p.(None): special protections. A person´s autonomy is considered diminished in case of cultural, educational,
p.(None): social or economic disadvantage, for example, in the case of ethnic minorities, refugees or illiterate,
p.(None): subdued, homeless or impoverished persons. For such cases, the additional protection is the presence of an impartial
p.(None): witness who assures that all the rights and interests of those persons are respected during the informed consent
p.(None): obtainment process. The absence of autonomy takes place when a person is legally or mentally incapable of
p.(None): giving his or her consent voluntarily. In said cases, the consent shall be obtained from his or her legal
p.(None): representative pursuant to the Argentine legislation in the matter.
p.(None): BIOAVAILABILITY: the capacity of a pharmaceutical form of releasing an API in the site of action at the proper
p.(None): speed to obtain a sufficient concentration, and at the timely moment to enable it to exert its action. Since,
p.(None): generally, the concentration cannot be determined in bio-phase in human beings and assuming the existence of balance in
...
p.(None): therapeutic dose cannot be determined, any reaction implying causal relation between a medicinal product and an adverse
p.(None): event as a reasonable possibility, that is to say, that the relation may not be ruled out, must be considered an
p.(None): adverse drug reaction.
p.(None): UNEXPECTED AND SERIOUS ADVERSE DRUG REACTION (UNEXPECTED
p.(None): SADR): an adverse reaction that results in death, is life-threatening, requires in-patient hospitalization or
p.(None): prolongation of the existent hospitalization, results in persistent or significant incapacity or disability
p.(None): and whose nature of seriousness is not consistent with the product information written in the
p.(None): investigational product monograph or any other documentation.
p.(None): LEGAL REPRESENTATIVE: a person authorized under the Argentine Civil Code or the applicable laws, who acts as the
p.(None): representative of a prospective participant in a clinical study to grant the informed consent to the study.
p.(None): IMPARTIAL WITNESS: a person independent from the investigator and his or her team who participates in the informed
p.(None): consent obtainment process as an assurance that such process respects the rights and interests of a
...
Social / Ethnicity
Searching for indicator ethnic:
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p.(None): activities evaluated were performed and the data were accurately recorded, analyzed and reported as per the
p.(None): protocol, SOP(s), GCP and A.N.M.A.T. Regulatory Guideline for GCP-CPS.
p.(None): AUTONOMY: a person´s self-determination capacity to make a decision voluntarily, as per only his or her own values,
p.(None): interests and preferences provided that he or she has the necessary information to assess all the options. By
p.(None): definition, an autonomous person is able to give his or her informed consent without needing any protection other
p.(None): than the assurance that all the necessary information is provided to him or her. In addition, those
p.(None): individuals having a diminished or inexistent autonomy are in a vulnerable situation, and, therefore, require
p.(None): special protections. A person´s autonomy is considered diminished in case of cultural, educational,
p.(None): social or economic disadvantage, for example, in the case of ethnic minorities, refugees or illiterate,
p.(None): subdued, homeless or impoverished persons. For such cases, the additional protection is the presence of an impartial
p.(None): witness who assures that all the rights and interests of those persons are respected during the informed consent
p.(None): obtainment process. The absence of autonomy takes place when a person is legally or mentally incapable of
p.(None): giving his or her consent voluntarily. In said cases, the consent shall be obtained from his or her legal
p.(None): representative pursuant to the Argentine legislation in the matter.
p.(None): BIOAVAILABILITY: the capacity of a pharmaceutical form of releasing an API in the site of action at the proper
p.(None): speed to obtain a sufficient concentration, and at the timely moment to enable it to exert its action. Since,
p.(None): generally, the concentration cannot be determined in bio-phase in human beings and assuming the existence of balance in
p.(None): the concentrations in serum and bio-phase, the fraction of a drug reaching the systemic circulation of the
p.(None): extravascularly administered dose of a given pharmaceutical form, shall be accepted as bioavailability.
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Social / Fetus/Neonate
Searching for indicator fetus:
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p.(None): justification for conducting the research in a vulnerable group, if appropriate; possible conflicts of interest.
p.(None): Administrative and other aspects
p.(None):
p.(None): investigational products maintenance and storage procedures; clinical data record keeping and reports;
p.(None): trial documents handling; monitoring and audit procedures; criteria for trial discontinuation; results publication
p.(None): plan.
p.(None): INFORMED CONSENT
p.(None): The information document used to obtain the consent of a potential participant or of his or her legal representative,
p.(None): pursuant to legal provisions, shall include the following:
p.(None): research title, objective or purpose;
p.(None): sponsor´s data in the country: name or denomination and company name and address; approximate number of participants
p.(None): intended for the study;
p.(None): study experimental aspects;
p.(None): study treatments, assignment method and probability for each treatment;
p.(None): all the procedures to which the participant shall be submitted, the visits schedule they are expected to fulfill and
p.(None): their envisaged participation duration;
p.(None): a statement that all the investigational products and procedures will be free-of-charge for the participants;
p.(None): the reasonably expected benefits from participants´ involvement in the study. A clear remark must be made if the
p.(None): participant is not intended to obtain any clinical benefit from the study;
p.(None): the risks and discomforts foreseen for the participants and; in case of pregnancy and breastfeeding, for the embryo,
p.(None): fetus or infant;
p.(None): a description of pregnancy prevention and protection methods;
p.(None): study alternative procedures or treatments and their potential benefits;
p.(None): the commitments undertaken by the participants should they accept to participate in the study;
p.(None): the intended use of all the samples obtained, if appropriate;
p.(None): the available compensation for participants for the expenses arising from their participation. In case
p.(None): a compensation for participating in the study were allowed, its amount and payment form;
p.(None): medical assistance and coverage for the participants which shall be afforded by the sponsor in case of
p.(None): damage, injury or adverse event related to the study as well as contact information for such cases;
p.(None): the proof of an insurance policy or any other form of guarantee in Argentina for the coverage of the
p.(None): risks or potential damages that may arise from participating in the study;
p.(None): the following phrase shall be included: “By signing this informed consent you do not waiver your rights
p.(None): pursuant to the Argentine Civil Code and laws concerning civil
p.(None):
p.(None): liability for damages” (translation of: “Con la firma de este consentimiento informado Usted no renuncia a los
p.(None): derechos que posee de acuerdo con el Código Civil y las leyes argentinas en materia de responsabilidad civil por
p.(None): daños”).
p.(None): special mention shall be made as to the fact that the sponsor finances the investigators´
...
p.(None): carry out the process, the participant´s medical record shall document the reasons for such situation and
p.(None): the fulfillment of the requirements applicable thereto. Likewise, the medical record shall inform both the
p.(None): presence and absence of the prospective participant´s vulnerable condition.
p.(None): All the new information or changes in the protocol that may affect the participant´s safety or his
p.(None): or her decision to continue participating in the study shall be communicated verbally an in writing
p.(None): in order to obtain the consent. The new consent document shall be previously approved by the REC and the
p.(None): agency, unless the changes require swift implementation for safety reasons.
p.(None): PROTECTION OF STUDY PARTICIPANTS
p.(None):
p.(None): The investigator and the sponsor shall ensure that every participant will have access to their own information and
p.(None): to the study results once available and that their right to confidentiality will be protected at all times.
p.(None): The investigator is responsible for obtaining the consent of all the participants, even when a sub-investigator
p.(None): was authorized to perform that action.
p.(None): Since exposure to an investigational product during pregnancy implies risks for the embryo or fetus, the
p.(None): following measures shall be taken:
p.(None): women of fertile age shall be warned about such risks, before giving their consent to participate in the study and
p.(None): about the need to immediately inform the investigator should they suspect of being pregnant at any time of the
p.(None): study;
p.(None): the investigator shall run a pregnancy test prior to the admission to the study of every women of fertile age; and then
p.(None): regularly throughout the study;
p.(None): a positive result pregnancy test shall imply the exclusion of the prospective participant or the preventive
p.(None): discontinuation of the investigational product administration, if appropriate. In case of pregnancy, the
p.(None): investigator shall guide the participant in obtaining proper care;
p.(None): the sponsor and the investigator shall ensure the access to the necessary contraceptive methods
p.(None): for all the study participants.
p.(None): An investigator who is a doctor of medicine or a dentist, as appropriate, shall be responsible for all
p.(None): the participants´ health care related decisions throughout the study.
p.(None): Should the study put at risk the integrity or health of the participants, for example, due to an adverse reaction
...
Social / Homeless Persons
Searching for indicator homeless:
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p.(None): protocol, SOP(s), GCP and A.N.M.A.T. Regulatory Guideline for GCP-CPS.
p.(None): AUTONOMY: a person´s self-determination capacity to make a decision voluntarily, as per only his or her own values,
p.(None): interests and preferences provided that he or she has the necessary information to assess all the options. By
p.(None): definition, an autonomous person is able to give his or her informed consent without needing any protection other
p.(None): than the assurance that all the necessary information is provided to him or her. In addition, those
p.(None): individuals having a diminished or inexistent autonomy are in a vulnerable situation, and, therefore, require
p.(None): special protections. A person´s autonomy is considered diminished in case of cultural, educational,
p.(None): social or economic disadvantage, for example, in the case of ethnic minorities, refugees or illiterate,
p.(None): subdued, homeless or impoverished persons. For such cases, the additional protection is the presence of an impartial
p.(None): witness who assures that all the rights and interests of those persons are respected during the informed consent
p.(None): obtainment process. The absence of autonomy takes place when a person is legally or mentally incapable of
p.(None): giving his or her consent voluntarily. In said cases, the consent shall be obtained from his or her legal
p.(None): representative pursuant to the Argentine legislation in the matter.
p.(None): BIOAVAILABILITY: the capacity of a pharmaceutical form of releasing an API in the site of action at the proper
p.(None): speed to obtain a sufficient concentration, and at the timely moment to enable it to exert its action. Since,
p.(None): generally, the concentration cannot be determined in bio-phase in human beings and assuming the existence of balance in
p.(None): the concentrations in serum and bio-phase, the fraction of a drug reaching the systemic circulation of the
p.(None): extravascularly administered dose of a given pharmaceutical form, shall be accepted as bioavailability.
p.(None): BIOEQUIVALENCE: two drugs or medicinal products are biologically equivalent when, upon the existence of chemical
p.(None): equivalence, they have a similar bioavailability if administered to the same person in an equal dosage regimen.
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Social / Incarcerated
Searching for indicator restricted:
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p.(None): of the informed consent, pre-study evaluation, inclusion in the study, randomized assignment result, instructions for
p.(None): using the investigational product, treatment initiation and termination, control of product delivery and return, as
p.(None): well as the information provided to the participant, shall be documented in the same format as are the medical notes
p.(None): used for the rest of the patients receiving medical care at the center.
p.(None): The investigator shall be responsible for preserving the confidentiality of every participant´s
p.(None): identity. No data of the participant´s identity shall be contained in any document transmitted, reported or
p.(None): taken away from the host institution.
p.(None): The changes or corrections of any of the study records shall not conceal or delete the original datum. Corrections
p.(None): shall be dated and signed with their author´s initials.
p.(None): In case of using electronic direct data transmission automated devices to perform study-related exams such
p.(None): as an electrocardiogram and a spirometry, an identifiable printed source document of the process shall
p.(None): be obtained and filed in the medical record.
p.(None): In case of using an electronic format for clinical data record-keeping and transmission, the system used shall
p.(None): comply with integrity, accuracy, reliability, confidentiality and consistency requirements.
p.(None): Electronic record-keeping systems shall enable:
p.(None): the recording of all the editions of individual data, including the author and the edition date and without eliminating
p.(None): the original data;
p.(None): a restricted access to enter or edit data;
p.(None):
p.(None): the obtainment of a data back-up copy;
p.(None): the protection of treatment blind during data entry and processing, if appropriate.
p.(None): The sponsor shall use an SOP to manage electronic systems and a list of the persons authorized to discharge such
p.(None): function.
p.(None): The study final results must be always related to the study clinical data, even when the variables were transformed at
p.(None): processing.
p.(None): ESSENTIAL DOCUMENTS OF THE STUDY
p.(None): Documents file and retention
p.(None): Document filing shall be set out from the beginning of the study, both at the research center and the sponsor´s
p.(None): office. All the documents mentioned in the Regulatory Guideline herein are subject to monitoring and
p.(None): auditing by the sponsor and to inspection by the agency and shall be available whenever required by them.
p.(None): The investigator and the sponsor shall retain the study documents in a locked safe place with access
p.(None): limited to authorized personnel and shall take the necessary steps to prevent their accidental loss or destruction.
p.(None): All the study documents shall be retained for ten years after the date of the last visit of the last patient enrolled
p.(None): in the center.
p.(None): Essential documents required prior to the study initiation:
p.(None): a copy of A.N.M.A.T. Regulatory Guideline herein; a current version of the Declaration of Helsinki;
p.(None): a valid investigational product monograph and other safety information; a protocol approved by the REC and the agency;
p.(None): amendments prior to the study initiation approved by the REC and A.N.M.A.T., if any; blank copies of the clinical data
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Social / Infant
Searching for indicator infant:
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p.(None): Administrative and other aspects
p.(None):
p.(None): investigational products maintenance and storage procedures; clinical data record keeping and reports;
p.(None): trial documents handling; monitoring and audit procedures; criteria for trial discontinuation; results publication
p.(None): plan.
p.(None): INFORMED CONSENT
p.(None): The information document used to obtain the consent of a potential participant or of his or her legal representative,
p.(None): pursuant to legal provisions, shall include the following:
p.(None): research title, objective or purpose;
p.(None): sponsor´s data in the country: name or denomination and company name and address; approximate number of participants
p.(None): intended for the study;
p.(None): study experimental aspects;
p.(None): study treatments, assignment method and probability for each treatment;
p.(None): all the procedures to which the participant shall be submitted, the visits schedule they are expected to fulfill and
p.(None): their envisaged participation duration;
p.(None): a statement that all the investigational products and procedures will be free-of-charge for the participants;
p.(None): the reasonably expected benefits from participants´ involvement in the study. A clear remark must be made if the
p.(None): participant is not intended to obtain any clinical benefit from the study;
p.(None): the risks and discomforts foreseen for the participants and; in case of pregnancy and breastfeeding, for the embryo,
p.(None): fetus or infant;
p.(None): a description of pregnancy prevention and protection methods;
p.(None): study alternative procedures or treatments and their potential benefits;
p.(None): the commitments undertaken by the participants should they accept to participate in the study;
p.(None): the intended use of all the samples obtained, if appropriate;
p.(None): the available compensation for participants for the expenses arising from their participation. In case
p.(None): a compensation for participating in the study were allowed, its amount and payment form;
p.(None): medical assistance and coverage for the participants which shall be afforded by the sponsor in case of
p.(None): damage, injury or adverse event related to the study as well as contact information for such cases;
p.(None): the proof of an insurance policy or any other form of guarantee in Argentina for the coverage of the
p.(None): risks or potential damages that may arise from participating in the study;
p.(None): the following phrase shall be included: “By signing this informed consent you do not waiver your rights
p.(None): pursuant to the Argentine Civil Code and laws concerning civil
p.(None):
p.(None): liability for damages” (translation of: “Con la firma de este consentimiento informado Usted no renuncia a los
p.(None): derechos que posee de acuerdo con el Código Civil y las leyes argentinas en materia de responsabilidad civil por
p.(None): daños”).
p.(None): special mention shall be made as to the fact that the sponsor finances the investigators´
p.(None): fees and the study procedures costs through an agreement with the investigator and/or the institution;
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Social / Linguistic Proficiency
Searching for indicator language:
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p.(None): and date the consent form as a proof of his or her participation. The REC may set this requirement for all
p.(None): cases in centers where most patients are in a vulnerable situation.
p.(None): A summary of the written information for the patient approved by the REC and the agency may be used in
p.(None): case of serious situations requiring immediate medical care. Spoken information shall be provided in the presence of
p.(None): an impartial witness, who shall
p.(None):
p.(None): sign the written summary of the information and the consent signature page, together with the investigator.
p.(None): Guidelines for obtaining the informed consent
p.(None): The information consent documents include at least two sections: information pages for the participant and the
p.(None): signatures page. Any document intended to be used in the process shall be approved by the REC and the agency.
p.(None): The information section shall contain all the elements described in section B.5.1.
p.(None): The informed consent shall be obtained prior to initiating the assessment of eligibility criteria or any other
p.(None): specific procedure of the study.
p.(None): Oral or written information provided to the potential participant or his or her representative,
p.(None): in the cases under legal provisions, shall be submitted in a clear, precise, complete and truthful way; and
p.(None): in a practical language which shall be easily understandable for the participant, without including any expression that
p.(None): might lead the participant to believe he or she is not entitled to or waivers any of his or her legal rights or that
p.(None): the investigator, institution or sponsor is released from liability by signing the consent. The written document
p.(None): shall guide the oral explanation.
p.(None): The investigator or authorized sub-investigator shall provide the prospective participant or his or her legal
p.(None): representative with sufficient time and opportunity to assess all the options and make all the questions they might
p.(None): wish and receive satisfactory answers; and shall then verify through questions to the participant or legal
p.(None): representative that he or she fully understands the information provided.
p.(None): After fulfilling the information process, the participant or his or her legal representative, in the cases legally
p.(None): foreseen, the investigator or authorized sub-investigator and the witness, if appropriate, shall sign and date
p.(None): two original consent signature pages, as a declaration of having been provided with the information and having
p.(None): understood it and made the decision to participate in the study freely and voluntarily. The participant or his or her
p.(None): legal representative shall receive one of the original signature pages and a copy of the written information section.
p.(None): The process for obtaining the consent shall be documented in the participant´s medical record, for which end the
p.(None): following shall be mentioned: date and time of initiation, that the participant was given sufficient time to
...
Social / Marital Status
Searching for indicator single:
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p.(None): A summary of the results produced, including nature, time of appearance, frequency, intensity, duration and
p.(None): reversibility of the pharmacologic and toxic effects and dose response, as well as the statistical analysis of
p.(None): such results.
p.(None): Discussion of the most significant findings and conclusions, including the dose response of the effects
p.(None): observed, the relevance for human beings and any other aspect intended to be studied in human beings. The
p.(None): findings of the effective and non toxic doses (therapeutic index) in the same animal species and their ratio
p.(None): for the human dose proposed shall be compared, if appropriate.
p.(None): Preclinical pharmacology
p.(None): Pharmacodynamics: the potential therapeutic activity shall be demonstrated and the product and/or its
p.(None): metabolites possible mechanisms of action shall be described, including the evaluation of pharmacologic
p.(None): actions other than the therapeutic effects intended.
p.(None): Special pharmacodynamics: pharmacodynamic effects as per the indications proposed, dose-effect and time-effect curves.
p.(None): General pharmacodynamics: studies on the cardiovascular system, respiratory system, central nervous system,
p.(None): autonomic nervous system, neuromuscular system, urinary system, endocrine system, digestive system, etc.
p.(None): Pharmacodynamic interactions: studies determining these types of relations. Mechanisms of action: a description of the
p.(None): mechanisms observed.
p.(None): Pharmacokinetics: determination of the speed and magnitude of absorption, distribution model, biotransformation, speed
p.(None): and paths of elimination and the API location in the tissues. Studies shall include single dose and repeated
p.(None): dose pharmacokinetics, distribution in non-pregnant and pregnant animals, biotransformation, excretion and
p.(None): kinetic interactions.
p.(None): General pre-clinical toxicology
p.(None): Acute toxicity studies should have been conducted on three species, of which one should not be rodents.
p.(None): Likewise, at least two routes of administration should have been tried; one should be related to the way proposed for
p.(None): human use while the other one should ensure drug absorption. For single dose use in humans, the product
p.(None): should have been used for at least two weeks in the pre-clinical trial. The report shall include:
p.(None):
p.(None): toxic effects appearance time and duration, dose-effect ratio and reversibility as well as the differences in routes
p.(None): of administration (proposed therapeutic use and absorption test);
p.(None): toxicity symptoms and cause of death; biochemical and hematologic parameters;
p.(None): clinical and anatomical and pathological observations; estimated toxic dose.
p.(None): Repeated dose sub-acute toxicity studies shall be conducted on at least two species, of which one should not be
p.(None): rodents, for at least 12 to 24 weeks for a proposed human use of up to 4 weeks, according to the product type, its
p.(None): proposed therapeutic use and the animal species used. The route of administration should be the same as the
p.(None): one proposed for clinical use. At least, three doses shall be used, of which the highest one should produce
p.(None): demonstrable toxic effects and the lowest one should be equivalent to the proposed therapeutic dose, according to
p.(None): the sensitiveness of the species used. These studies shall include:
p.(None): toxic effects appearance time and duration, dose-effect ratio and reversibility as well as gender and species related
p.(None): differences;
p.(None): morbidity and mortality data;
p.(None): biochemical, hematologic and nutritional parameters; clinical and anatomical and pathological observations; no effect
p.(None): dose and toxic dose;
p.(None): target organs.
p.(None): Repeated dose chronic toxicity studies shall be performed on two species, of which one should not be
p.(None): rodents, for over 24 weeks according to the type of product, the proposed therapeutic use and the
...
p.(None): than two species, of which one shall not be rodents, with at least three doses, of which the higher one should be
p.(None): sub-toxic.
p.(None): In vivo and in vitro mutagenic activity with or without metabolic activation. In vitro trials results shall be
p.(None): available before the first exposure of human subjects. The standard battery of tests shall be available before
p.(None): Phase II studies.
p.(None): In vivo and in vitro carcinogenicity data.
p.(None): According to the type of product, the results of studies on animal local irritation or sensitization,
p.(None): among others, shall be submitted upon request.
p.(None):
p.(None): Biological products
p.(None): Biological products include vaccines, blood and blood products, allergens, gene therapies, recombinant
p.(None): proteins and other animal or cellular products with a specific therapeutic activity. As these products
p.(None): are more difficult to characterize than the synthetic ones, a more detailed description of their
p.(None): structure and manufacturing or obtaining process is required to demonstrate their safety, quality and efficacy.
p.(None): As a general rule, biological products toxicity studies should be performed on two animal species
p.(None): appropriate for the type of product, unless:
p.(None): the study to be conducted is a long term study or there is only one appropriate species, in which case one species
p.(None): shall be accepted;
p.(None): there is no appropriate species, in which case the use of transgenic animals expressing the human receptor or the use
p.(None): of homologous proteins shall be considered;
p.(None): if neither of the above mentioned is the case, a repeated dose study on a single species for a period
p.(None): appropriate to the investigational product shall be conducted. Said study should evaluate the specific
p.(None): functions and morphology, for example, the cardiovascular and respiratory ones.
p.(None): In addition to the requirements outlined for synthesis products, pre-clinical information of biotechnological products
p.(None): shall include:
p.(None): toxicological evaluation of contaminants and impurities;
p.(None): anti-genicity reactions, for instance, of anti-product antibodies;
p.(None): immune-toxicity reactions, for example, for immune-modulators, if appropriate.
p.(None): Clinical information
p.(None): a detailed discussion of the known effects of the investigational product on humans, including information
p.(None): about pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy and other pharmacological
p.(None): activities shall be submitted.
p.(None): The following information about pharmacokinetics shall be included:
p.(None): regarding pharmacokinetics: absorption, protein binding, metabolism, distribution and elimination;
p.(None): absolute and/or relative bioavailability using a reference dosage form;
p.(None): regarding bioequivalence: whenever appropriate, for example, in case the product is manufactured with a
p.(None): technology different from the one used to demonstrate its efficacy and safety;
p.(None): population sub-groups as to gender, age, impaired organic function; interactions with another drug and foods;
p.(None): other pharmacokinetics-related data.
p.(None): A summary of information shall be provided about the safety, pharmacodynamics, efficacy and the dose
...
p.(None): treatment provided to the participant in order to find out whether it is the case of an unexpected and serious adverse
p.(None): drug reaction (ADR) as defined in 7.1., but he or she shall not unmask the treatment to the investigator or persons in
p.(None): charge of the data analysis and discussion.
p.(None): The unexpected and serious ADR report shall include the following information: the denomination of the adverse
p.(None): reaction;
p.(None): investigational product code, INN and trade mark;
p.(None): type of report: baseline, update (update number) or final; sponsor´s name;
p.(None): the research center and investigator´s name;
p.(None):
p.(None): A.N.M.A.T. regulation authorizing the study conduct; the name or title of the study;
p.(None): participant´s code, age and sex;
p.(None): the date of the unexpected and serious ADR appearance, the date of investigator´s report and the date the
p.(None): sponsor received it;
p.(None): unexpected and serious ADR seriousness criteria; unexpected and serious ADR brief description;
p.(None): investigational product information: daily dose, route of administration, start and suspension date, therapy
p.(None): duration and indication;
p.(None): inform if the reaction disappeared after treatment suspension; inform if the reaction reappeared with treatment
p.(None): re-introduction; concomitant drugs: dosage form and start and termination date; participant´s history significant for
p.(None): the unexpected and serious ADR.
p.(None): Every six months, after the date the agency authorized the first study on the investigational product, the
p.(None): sponsor shall submit a single summary per investigational product, of all the unexpected and serious ADR occurred in
p.(None): any of the research centers for the pertaining period, which shall include the following information:
p.(None): A.N.M.A.T. dossier or regulation number concerning the investigational product;
p.(None): a list of unexpected and serious ADR classified by organic system and reaction type, including the participant
p.(None): code, denomination of the adverse reaction, date of appearance and country of occurrence.
p.(None): the investigational product overall risk-benefit assessment and a particular assessment per type of reaction, including
p.(None): all the cases in which the same reaction occurred.
p.(None): The agency shall be informed of any risk increase over benefits in any of the studies on an investigational product
p.(None): within a ten day-period after the finding occurred.
p.(None): STUDY PROGRESS REPORTS AND OTHER REPORTS
p.(None): The sponsor shall submit a complete progress report EFCA5 form (Section 5) per each investigator filled out with
p.(None): information about the study progress in his or her center, which shall be signed and dated by the
p.(None): investigator and the sponsor´s legal representative, at least once a year as from the date of authorization
p.(None): by the agency.
p.(None): For clinical trials on narcotic drugs, progress reports shall be submitted every six months as from the
p.(None): date of authorization by the agency.
p.(None): The IDMC reports, if appropriate, shall be submitted with the progress reports, except when a change in the study
p.(None): conditions and risks takes place, in which case the reports shall be submitted within ten working days after obtaining
p.(None): them.
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Social / Occupation
Searching for indicator occupation:
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p.(None): Application for authorization of the investigator and the research center: for authorizing each principal investigator
p.(None): and research center, the sponsor shall submit the following documents:
p.(None): an EFCA2 form completed and signed (Section F);
p.(None): a copy of the authorization to conduct the clinical pharmacology study;
p.(None): the investigator´s abridged Curriculum Vitae which shall be signed and dated by him or her;
p.(None): a certified copy of the investigator´s degree certification and professional license awarded by the
p.(None): sanitary authority of the jurisdiction where the study shall be conducted. Likewise, a certified copy of
p.(None): his or her proofs of training and/or experience in clinical research shall be required;
p.(None): for Phase II and Phase III studies, a certified copy of the certificate of specialist or the certificate of residency
p.(None): completion or the certificate of graduate specialization in the disease under study;
p.(None): an original letter stating the commitment to comply with the study protocol (indicating its title), the Declaration of
p.(None): Helsinki and A.N.M.A.T. Regulatory Guideline for GMP-CFS;
p.(None): a certified copy of the study approval by a Research Ethics Committee (REC), with a detail of the documents
p.(None): reviewed, for example, protocol, informed consent, and investigational product monograph. Only one approval by a
p.(None): REC shall be accepted per each research center;
p.(None): a dated list of the members of each REC, including name, birth date, gender, profession and
p.(None): occupation, position in the committee and relationship with the institution;
p.(None): a certified copy of the study authorization issued by the highest authority of the host institution. Should the
p.(None): jurisdiction health authority require the registration of health research studies, a certified copy of the proof
p.(None): of the study registration in the jurisdiction shall be submitted;
p.(None): a certified copy of the authorization by the institution authority for the study review by an external REC, if
p.(None): appropriate;
p.(None): a certified proof of the research center operating license in force;
p.(None): an informed consent document specific for the research center, if appropriate; General documents shall be submitted in
p.(None): the above mentioned order.
p.(None): All the documents submitted to the agency shall be in Spanish, except for the investigational product
p.(None): monograph since it shall be used only as study background information. The protocol, informed consent and EFCA
p.(None): forms shall be submitted both in print and digital format (the latter shall be enclosed.)
p.(None):
p.(None): In the event that an amendment to any of the documents, including the protocol, informed consent and
p.(None): investigational product monograph already submitted is needed, the original document with the document amended and a
...
p.(None): scientific and non-scientific education. The number of members shall be adequate, preferably uneven, to ensure the
p.(None): fulfillment of its duty. It shall have a minimum of five full members and at least two alternate members for the cases
p.(None): of absence of the regular members.
p.(None): The research center REC shall include an external member unrelated to the institution and who shall represent the
p.(None): interest of the community being assisted.
p.(None): The members shall be frequently renewed in order to combine the advantages of experience with those
p.(None): of new perspectives. The REC member selection and replacement mechanism shall ensure the election
p.(None): impartiality and respect for the suitability and plurality criteria.
p.(None): The REC shall elect a president among its members to lead meetings. The REC president shall be a person
p.(None): holding the experience, competence and qualifications to deal with and evaluate all the aspects of the investigations.
p.(None): Operation
p.(None): The REC holds the authority to approve, request amendments to, disapprove, discontinue or cancel
p.(None): an investigation on human health. The REC shall report its opinions in writing to the investigator, including
p.(None): the reasons for its decisions.
p.(None): The REC shall make a list and keep it updated of its members, indicating their names, age, sex, profession or
p.(None): occupation, position at the REC and relationship with the institution.
p.(None): The REC shall place in record its meetings, consultations and decisions, including the participating members and their
p.(None): voting results.
p.(None): The REC shall request and make available for its members all the research documents necessary for a comprehensive
p.(None): evaluation including: the protocol and its amendments, the informed consent and its amendments, other
p.(None): information for participants, the investigator´s updated curriculum vitae, enrolment mechanisms, a
p.(None): detail of the payments and insurance coverage envisaged for the participants and financing source of the study.
p.(None):
p.(None): A member of the REC who is, in turn, an investigator in a project may not participate in any evaluations, consultations
p.(None): or decisions about such project.
p.(None): The REC shall consult experts as to specific subject matters but they shall not have a right to decide on the project.
p.(None): The experts requested participation and opinion shall be documented.
p.(None): The REC shall demand from the investigator the immediate report on all the relevant information about safety or
p.(None): protocol amendments increasing the risk for participants or those changes made with the purpose of eliminating the
p.(None): immediate hazards for them.
p.(None): In case of administrative changes or changes that do not affect participants´ safety, the REC may carry out a swift
p.(None): evaluation of such changes. The president or member in charge of the swift evaluation shall document it and
p.(None): inform the rest of the members about it.
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Social / Social
Searching for indicator social:
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p.(None): study and shall make them available for health authorities should they request them.
p.(None): INFORMED CONSENT
p.(None): General
p.(None): The informed consent is the process that ensures that a potential participant decides to participate in a human
p.(None): health investigation voluntarily, without undue influence or duress, provided the investigation is consistent
p.(None): with the participant´s values, interests and preferences.
p.(None): The informed consent process shall be conducted by the investigator or a qualified sub-investigator
p.(None): authorized to do so in the function delegation form.
p.(None): In case a potential participant cannot grant by him or herself the consent to a study, the informed consent shall be
p.(None): obtained from his or her legal representatives, in accordance to the Argentine legislation in the matter.
p.(None): Likewise, the participant´s assent shall be requested after having provided him or her with information about the
p.(None): study, according to his or her understanding possibilities of such information. The participant´s decision whether to
p.(None): participate or not shall be respected.
p.(None): In case of a study potential participant´s educational, cultural, social or economic vulnerability, the
p.(None): involvement of a witness unrelated to the investigator and his or her team shall be required. Said witness shall sign
p.(None): and date the consent form as a proof of his or her participation. The REC may set this requirement for all
p.(None): cases in centers where most patients are in a vulnerable situation.
p.(None): A summary of the written information for the patient approved by the REC and the agency may be used in
p.(None): case of serious situations requiring immediate medical care. Spoken information shall be provided in the presence of
p.(None): an impartial witness, who shall
p.(None):
p.(None): sign the written summary of the information and the consent signature page, together with the investigator.
p.(None): Guidelines for obtaining the informed consent
p.(None): The information consent documents include at least two sections: information pages for the participant and the
p.(None): signatures page. Any document intended to be used in the process shall be approved by the REC and the agency.
p.(None): The information section shall contain all the elements described in section B.5.1.
p.(None): The informed consent shall be obtained prior to initiating the assessment of eligibility criteria or any other
p.(None): specific procedure of the study.
p.(None): Oral or written information provided to the potential participant or his or her representative,
...
p.(None): that all the informed consent forms were signed and dated by the participants or their legal representative and the
p.(None): investigator or authorized sub-investigator;
p.(None): that the empowerment to represent the participant is documented in the medical record, had the
p.(None): informed consent been obtained from the participant´s legal representative;
p.(None): that a written assent was obtained in the case of persons under age and within the lower age limit
p.(None): determined by the REC;
p.(None): that the informed consent was obtained by the investigator or sub-investigator authorized in the
p.(None): function delegation form; that the informed consent was obtained prior to evaluating the eligibility criteria or any
p.(None): other study specific procedure;
p.(None): that the consent obtainment is documented in the participant´s medical record, including the initiation date
p.(None): and time, that they were provided with time to reflect on and make questions, which the questions made were, that the
p.(None): participant´s understanding of the information was verified and that two originals were signed and one of them was
p.(None): given to the participant;
p.(None): that in the case of a participant being in a situation of cultural, educational, social or economic vulnerability,
p.(None): the consent was obtained in the presence and with the signature of an impartial witness and that the
p.(None): mechanism was documented in the participant´s medical record.
p.(None): The inspectors shall verify that the participants gave their consent to all the informed consent amendments and the
p.(None): latter had been approved by the REC and the agency at the time of using them and that all the process requirements were
p.(None): fulfilled.
p.(None): The inspectors shall compare the protocol and amendments approved by the REC and the agency with the protocol filed by
p.(None): the investigator in relation to:
p.(None): inclusion and exclusion criteria;
p.(None): clinical data type and obtainment frequency; treatment dose, frequency and route of administration; randomized
p.(None): assignment and blinding procedures.
p.(None): The inspectors shall review the source documents and verify the following:
p.(None):
p.(None): that participants exist and that all the procedures under the protocol were performed to them;
p.(None): that participants met the eligibility criteria at the time of their inclusion in the study; that participants were
p.(None): administered the study treatments per the protocol;
p.(None): that all SAE were notified to the sponsor;
p.(None): that clinical data were obtained and notified correctly and completely. According to the inspection plan set out, the
p.(None): inspectors shall verify: the informed consents;
p.(None): the serious adverse events and the serious and unexpected ADR; the participants withdrawn from the study;
...
p.(None):
p.(None): SECTION E: GLOSSARY
p.(None): AUDIT: a systematic and independent examination of the study related activities and documents to determine whether the
p.(None): activities evaluated were performed and the data were accurately recorded, analyzed and reported as per the
p.(None): protocol, SOP(s), GCP and A.N.M.A.T. Regulatory Guideline for GCP-CPS.
p.(None): AUTONOMY: a person´s self-determination capacity to make a decision voluntarily, as per only his or her own values,
p.(None): interests and preferences provided that he or she has the necessary information to assess all the options. By
p.(None): definition, an autonomous person is able to give his or her informed consent without needing any protection other
p.(None): than the assurance that all the necessary information is provided to him or her. In addition, those
p.(None): individuals having a diminished or inexistent autonomy are in a vulnerable situation, and, therefore, require
p.(None): special protections. A person´s autonomy is considered diminished in case of cultural, educational,
p.(None): social or economic disadvantage, for example, in the case of ethnic minorities, refugees or illiterate,
p.(None): subdued, homeless or impoverished persons. For such cases, the additional protection is the presence of an impartial
p.(None): witness who assures that all the rights and interests of those persons are respected during the informed consent
p.(None): obtainment process. The absence of autonomy takes place when a person is legally or mentally incapable of
p.(None): giving his or her consent voluntarily. In said cases, the consent shall be obtained from his or her legal
p.(None): representative pursuant to the Argentine legislation in the matter.
p.(None): BIOAVAILABILITY: the capacity of a pharmaceutical form of releasing an API in the site of action at the proper
p.(None): speed to obtain a sufficient concentration, and at the timely moment to enable it to exert its action. Since,
p.(None): generally, the concentration cannot be determined in bio-phase in human beings and assuming the existence of balance in
p.(None): the concentrations in serum and bio-phase, the fraction of a drug reaching the systemic circulation of the
...
p.(None): event as a reasonable possibility, that is to say, that the relation may not be ruled out, must be considered an
p.(None): adverse drug reaction.
p.(None): UNEXPECTED AND SERIOUS ADVERSE DRUG REACTION (UNEXPECTED
p.(None): SADR): an adverse reaction that results in death, is life-threatening, requires in-patient hospitalization or
p.(None): prolongation of the existent hospitalization, results in persistent or significant incapacity or disability
p.(None): and whose nature of seriousness is not consistent with the product information written in the
p.(None): investigational product monograph or any other documentation.
p.(None): LEGAL REPRESENTATIVE: a person authorized under the Argentine Civil Code or the applicable laws, who acts as the
p.(None): representative of a prospective participant in a clinical study to grant the informed consent to the study.
p.(None): IMPARTIAL WITNESS: a person independent from the investigator and his or her team who participates in the informed
p.(None): consent obtainment process as an assurance that such process respects the rights and interests of a
...
Social / Threat of Stigma
Searching for indicator threat:
(return to top)
p.(None): of drugs, investigational medical products or procedures relevant for their study in human beings.
p.(None): MONITORING: action of overseeing the process of a clinical study and ensuring that it is conducted, recorded and
p.(None): reported in accordance with the protocol, SPO(s), GCP and applicable regulatory requirements.
p.(None): CONTRACT RESEARCH ORGANIZATION (CRO): a physical person or legal entity contracted by the sponsor to perform
p.(None): one or more of his or her functions or activities related to the study.
p.(None): STUDY PARTICIPANT: a healthy or unhealthy individual participating in a clinical pharmacology study as a
p.(None): research subject.
p.(None): SPONSOR: a physical person or legal entity responsible for initiating, managing, controlling and financing a
p.(None): clinical study.
p.(None): PLACEBO: a pharmacologically inert substance used as a substitute of the investigational product
p.(None): with the aim of acting as a comparator in a clinical
p.(None):
p.(None): pharmacological study, as long as the ethical criteria of participant protection is respected.
p.(None): VULNERABLE POPULATION: an individual or a group of individuals whose wish to participate in a clinical
p.(None): trial may be unduly influenced by the justified or unjustified expectation of the benefits associated with his
p.(None): or her participation (undue influence) or by the threat by the investigators or any other unequal relation in case the
p.(None): individual refuses to participate (duress).
p.(None): COMPARATOR PRODUCT: a marketed or investigational product or a placebo used as a reference in a clinical study.
p.(None): INVESTIGATIONAL PRODUCT: a pharmaceutical form of an active substance under investigation, including products
p.(None): holding a marketing authorization when used or combined in the formulation in a form other than the authorized
p.(None): one or for the treatment of an unauthorized indication.
p.(None): PROTOCOL: a document describing the history, fundamentals, objectives, design, methodology ethical
p.(None): considerations, statistical aspects and organization of a study.
p.(None): ADVERSE DRUG REACTION (ADR): an untoward and unintended response to a medicinal product at any dose. In
p.(None): clinical experience and before the approval of a new medicinal product or of its new uses, particularly, when the
p.(None): therapeutic dose cannot be determined, any reaction implying causal relation between a medicinal product and an adverse
p.(None): event as a reasonable possibility, that is to say, that the relation may not be ruled out, must be considered an
p.(None): adverse drug reaction.
p.(None): UNEXPECTED AND SERIOUS ADVERSE DRUG REACTION (UNEXPECTED
p.(None): SADR): an adverse reaction that results in death, is life-threatening, requires in-patient hospitalization or
...
Social / Women
Searching for indicator women:
(return to top)
p.(None): the fulfillment of the requirements applicable thereto. Likewise, the medical record shall inform both the
p.(None): presence and absence of the prospective participant´s vulnerable condition.
p.(None): All the new information or changes in the protocol that may affect the participant´s safety or his
p.(None): or her decision to continue participating in the study shall be communicated verbally an in writing
p.(None): in order to obtain the consent. The new consent document shall be previously approved by the REC and the
p.(None): agency, unless the changes require swift implementation for safety reasons.
p.(None): PROTECTION OF STUDY PARTICIPANTS
p.(None):
p.(None): The investigator and the sponsor shall ensure that every participant will have access to their own information and
p.(None): to the study results once available and that their right to confidentiality will be protected at all times.
p.(None): The investigator is responsible for obtaining the consent of all the participants, even when a sub-investigator
p.(None): was authorized to perform that action.
p.(None): Since exposure to an investigational product during pregnancy implies risks for the embryo or fetus, the
p.(None): following measures shall be taken:
p.(None): women of fertile age shall be warned about such risks, before giving their consent to participate in the study and
p.(None): about the need to immediately inform the investigator should they suspect of being pregnant at any time of the
p.(None): study;
p.(None): the investigator shall run a pregnancy test prior to the admission to the study of every women of fertile age; and then
p.(None): regularly throughout the study;
p.(None): a positive result pregnancy test shall imply the exclusion of the prospective participant or the preventive
p.(None): discontinuation of the investigational product administration, if appropriate. In case of pregnancy, the
p.(None): investigator shall guide the participant in obtaining proper care;
p.(None): the sponsor and the investigator shall ensure the access to the necessary contraceptive methods
p.(None): for all the study participants.
p.(None): An investigator who is a doctor of medicine or a dentist, as appropriate, shall be responsible for all
p.(None): the participants´ health care related decisions throughout the study.
p.(None): Should the study put at risk the integrity or health of the participants, for example, due to an adverse reaction
p.(None): or a therapeutic failure, the investigator shall take all the precautions to halt the exposure to the risk.
p.(None): The use of a placebo control shall be properly justified both from the methodological and ethical points of view. The
p.(None): use of a placebo in terminal diseases shall be accepted in case of inefficacy of all the existing treatments.
p.(None): The investigator and the sponsor shall ensure that the participant will receive proper medical care in case of
...
Social / Youth/Minors
Searching for indicator minor:
(return to top)
p.(None): a list of unexpected and serious ADR classified by organic system and reaction type, including the participant
p.(None): code, denomination of the adverse reaction, date of appearance and country of occurrence.
p.(None): the investigational product overall risk-benefit assessment and a particular assessment per type of reaction, including
p.(None): all the cases in which the same reaction occurred.
p.(None): The agency shall be informed of any risk increase over benefits in any of the studies on an investigational product
p.(None): within a ten day-period after the finding occurred.
p.(None): STUDY PROGRESS REPORTS AND OTHER REPORTS
p.(None): The sponsor shall submit a complete progress report EFCA5 form (Section 5) per each investigator filled out with
p.(None): information about the study progress in his or her center, which shall be signed and dated by the
p.(None): investigator and the sponsor´s legal representative, at least once a year as from the date of authorization
p.(None): by the agency.
p.(None): For clinical trials on narcotic drugs, progress reports shall be submitted every six months as from the
p.(None): date of authorization by the agency.
p.(None): The IDMC reports, if appropriate, shall be submitted with the progress reports, except when a change in the study
p.(None): conditions and risks takes place, in which case the reports shall be submitted within ten working days after obtaining
p.(None): them.
p.(None): The sponsor shall inform A.N.M.A.T. about the following deviations from the protocol within a ten-day period after
p.(None): learning about them:
p.(None): major deviations having affected participants´ rights or safety;
p.(None): repeated minor deviations despite having warned the investigator about their occurrence.
p.(None):
p.(None): The application for the addition or exclusion of an investigator or research center shall be submitted with the
p.(None): EFCA2 form (Section F) completed and signed and other supporting documents. Whenever an exclusion is requested,
p.(None): the reason for it shall be explained.
p.(None): The study premature cancellation in one given center or in the country shall be immediately informed to
p.(None): A.N.M.A.T. including the pertaining justification.
p.(None): The following changes throughout the study shall be informed to the agency with the study progress report:
p.(None): changes in the REC member composition;
p.(None): administrative changes, for example, the person responsible for the study or his or her contact data or the
p.(None): investigator´s contact data.
p.(None): The following changes or updates may not be informed to the agency:
p.(None): start, duration and completion of the enrolment or random assignment period; extension of the investigational product
p.(None): lot expiry date;
p.(None): changes in the sponsor´s monitoring program;
p.(None): REC monitoring report, except for the case of major deviations (as described in 8.4).
p.(None): 8.9. Upon trial completion, the sponsor shall submit a complete final report EFCA5 form (Section F) per each
p.(None): investigator.
p.(None): 8.10. The sponsor shall submit the final result within one-year period after the study termination.
p.(None): SECTION C: GOOD CLINICAL PRACTICE GUIDE FOR CLINICAL PHARMACOLOGY STUDIES
p.(None): OBJECTIVE
p.(None): With a view to enabling the agency to exercise its monitoring authority, this section sets forth the procedures that
...
Social / embryo
Searching for indicator embryo:
(return to top)
p.(None): rodents, for at least 12 to 24 weeks for a proposed human use of up to 4 weeks, according to the product type, its
p.(None): proposed therapeutic use and the animal species used. The route of administration should be the same as the
p.(None): one proposed for clinical use. At least, three doses shall be used, of which the highest one should produce
p.(None): demonstrable toxic effects and the lowest one should be equivalent to the proposed therapeutic dose, according to
p.(None): the sensitiveness of the species used. These studies shall include:
p.(None): toxic effects appearance time and duration, dose-effect ratio and reversibility as well as gender and species related
p.(None): differences;
p.(None): morbidity and mortality data;
p.(None): biochemical, hematologic and nutritional parameters; clinical and anatomical and pathological observations; no effect
p.(None): dose and toxic dose;
p.(None): target organs.
p.(None): Repeated dose chronic toxicity studies shall be performed on two species, of which one should not be
p.(None): rodents, for over 24 weeks according to the type of product, the proposed therapeutic use and the
p.(None): animal species used. The route of administration shall be the same as the one proposed for clinical use. At
p.(None): least, three doses shall be used, of which the highest one should produce demonstrable toxic effects and
p.(None): the lowest one should be equivalent to the proposed therapeutic dose for human use, according to the
p.(None): sensitiveness of the species used. The concerning report shall contain the same requirements applicable to sub-acute
p.(None): toxicity.
p.(None): Special pre-clinical toxicity
p.(None): The effects on fertility shall be determined before initiating Phase III.
p.(None): Embryo-toxicity, teratogenicity and prenatal and postnatal toxicity studies shall be performed on not less
p.(None): than two species, of which one shall not be rodents, with at least three doses, of which the higher one should be
p.(None): sub-toxic.
p.(None): In vivo and in vitro mutagenic activity with or without metabolic activation. In vitro trials results shall be
p.(None): available before the first exposure of human subjects. The standard battery of tests shall be available before
p.(None): Phase II studies.
p.(None): In vivo and in vitro carcinogenicity data.
p.(None): According to the type of product, the results of studies on animal local irritation or sensitization,
p.(None): among others, shall be submitted upon request.
p.(None):
p.(None): Biological products
p.(None): Biological products include vaccines, blood and blood products, allergens, gene therapies, recombinant
p.(None): proteins and other animal or cellular products with a specific therapeutic activity. As these products
p.(None): are more difficult to characterize than the synthetic ones, a more detailed description of their
p.(None): structure and manufacturing or obtaining process is required to demonstrate their safety, quality and efficacy.
p.(None): As a general rule, biological products toxicity studies should be performed on two animal species
p.(None): appropriate for the type of product, unless:
p.(None): the study to be conducted is a long term study or there is only one appropriate species, in which case one species
p.(None): shall be accepted;
p.(None): there is no appropriate species, in which case the use of transgenic animals expressing the human receptor or the use
p.(None): of homologous proteins shall be considered;
...
p.(None): justification for conducting the research in a vulnerable group, if appropriate; possible conflicts of interest.
p.(None): Administrative and other aspects
p.(None):
p.(None): investigational products maintenance and storage procedures; clinical data record keeping and reports;
p.(None): trial documents handling; monitoring and audit procedures; criteria for trial discontinuation; results publication
p.(None): plan.
p.(None): INFORMED CONSENT
p.(None): The information document used to obtain the consent of a potential participant or of his or her legal representative,
p.(None): pursuant to legal provisions, shall include the following:
p.(None): research title, objective or purpose;
p.(None): sponsor´s data in the country: name or denomination and company name and address; approximate number of participants
p.(None): intended for the study;
p.(None): study experimental aspects;
p.(None): study treatments, assignment method and probability for each treatment;
p.(None): all the procedures to which the participant shall be submitted, the visits schedule they are expected to fulfill and
p.(None): their envisaged participation duration;
p.(None): a statement that all the investigational products and procedures will be free-of-charge for the participants;
p.(None): the reasonably expected benefits from participants´ involvement in the study. A clear remark must be made if the
p.(None): participant is not intended to obtain any clinical benefit from the study;
p.(None): the risks and discomforts foreseen for the participants and; in case of pregnancy and breastfeeding, for the embryo,
p.(None): fetus or infant;
p.(None): a description of pregnancy prevention and protection methods;
p.(None): study alternative procedures or treatments and their potential benefits;
p.(None): the commitments undertaken by the participants should they accept to participate in the study;
p.(None): the intended use of all the samples obtained, if appropriate;
p.(None): the available compensation for participants for the expenses arising from their participation. In case
p.(None): a compensation for participating in the study were allowed, its amount and payment form;
p.(None): medical assistance and coverage for the participants which shall be afforded by the sponsor in case of
p.(None): damage, injury or adverse event related to the study as well as contact information for such cases;
p.(None): the proof of an insurance policy or any other form of guarantee in Argentina for the coverage of the
p.(None): risks or potential damages that may arise from participating in the study;
p.(None): the following phrase shall be included: “By signing this informed consent you do not waiver your rights
p.(None): pursuant to the Argentine Civil Code and laws concerning civil
p.(None):
p.(None): liability for damages” (translation of: “Con la firma de este consentimiento informado Usted no renuncia a los
p.(None): derechos que posee de acuerdo con el Código Civil y las leyes argentinas en materia de responsabilidad civil por
p.(None): daños”).
p.(None): special mention shall be made as to the fact that the sponsor finances the investigators´
...
p.(None): carry out the process, the participant´s medical record shall document the reasons for such situation and
p.(None): the fulfillment of the requirements applicable thereto. Likewise, the medical record shall inform both the
p.(None): presence and absence of the prospective participant´s vulnerable condition.
p.(None): All the new information or changes in the protocol that may affect the participant´s safety or his
p.(None): or her decision to continue participating in the study shall be communicated verbally an in writing
p.(None): in order to obtain the consent. The new consent document shall be previously approved by the REC and the
p.(None): agency, unless the changes require swift implementation for safety reasons.
p.(None): PROTECTION OF STUDY PARTICIPANTS
p.(None):
p.(None): The investigator and the sponsor shall ensure that every participant will have access to their own information and
p.(None): to the study results once available and that their right to confidentiality will be protected at all times.
p.(None): The investigator is responsible for obtaining the consent of all the participants, even when a sub-investigator
p.(None): was authorized to perform that action.
p.(None): Since exposure to an investigational product during pregnancy implies risks for the embryo or fetus, the
p.(None): following measures shall be taken:
p.(None): women of fertile age shall be warned about such risks, before giving their consent to participate in the study and
p.(None): about the need to immediately inform the investigator should they suspect of being pregnant at any time of the
p.(None): study;
p.(None): the investigator shall run a pregnancy test prior to the admission to the study of every women of fertile age; and then
p.(None): regularly throughout the study;
p.(None): a positive result pregnancy test shall imply the exclusion of the prospective participant or the preventive
p.(None): discontinuation of the investigational product administration, if appropriate. In case of pregnancy, the
p.(None): investigator shall guide the participant in obtaining proper care;
p.(None): the sponsor and the investigator shall ensure the access to the necessary contraceptive methods
p.(None): for all the study participants.
p.(None): An investigator who is a doctor of medicine or a dentist, as appropriate, shall be responsible for all
p.(None): the participants´ health care related decisions throughout the study.
...
Social / illiterate
Searching for indicator illiterate:
(return to top)
p.(None): protocol, SOP(s), GCP and A.N.M.A.T. Regulatory Guideline for GCP-CPS.
p.(None): AUTONOMY: a person´s self-determination capacity to make a decision voluntarily, as per only his or her own values,
p.(None): interests and preferences provided that he or she has the necessary information to assess all the options. By
p.(None): definition, an autonomous person is able to give his or her informed consent without needing any protection other
p.(None): than the assurance that all the necessary information is provided to him or her. In addition, those
p.(None): individuals having a diminished or inexistent autonomy are in a vulnerable situation, and, therefore, require
p.(None): special protections. A person´s autonomy is considered diminished in case of cultural, educational,
p.(None): social or economic disadvantage, for example, in the case of ethnic minorities, refugees or illiterate,
p.(None): subdued, homeless or impoverished persons. For such cases, the additional protection is the presence of an impartial
p.(None): witness who assures that all the rights and interests of those persons are respected during the informed consent
p.(None): obtainment process. The absence of autonomy takes place when a person is legally or mentally incapable of
p.(None): giving his or her consent voluntarily. In said cases, the consent shall be obtained from his or her legal
p.(None): representative pursuant to the Argentine legislation in the matter.
p.(None): BIOAVAILABILITY: the capacity of a pharmaceutical form of releasing an API in the site of action at the proper
p.(None): speed to obtain a sufficient concentration, and at the timely moment to enable it to exert its action. Since,
p.(None): generally, the concentration cannot be determined in bio-phase in human beings and assuming the existence of balance in
p.(None): the concentrations in serum and bio-phase, the fraction of a drug reaching the systemic circulation of the
p.(None): extravascularly administered dose of a given pharmaceutical form, shall be accepted as bioavailability.
p.(None): BIOEQUIVALENCE: two drugs or medicinal products are biologically equivalent when, upon the existence of chemical
...
Social / philosophical differences/differences of opinion
Searching for indicator opinion:
(return to top)
p.(None): Operation
p.(None): The REC holds the authority to approve, request amendments to, disapprove, discontinue or cancel
p.(None): an investigation on human health. The REC shall report its opinions in writing to the investigator, including
p.(None): the reasons for its decisions.
p.(None): The REC shall make a list and keep it updated of its members, indicating their names, age, sex, profession or
p.(None): occupation, position at the REC and relationship with the institution.
p.(None): The REC shall place in record its meetings, consultations and decisions, including the participating members and their
p.(None): voting results.
p.(None): The REC shall request and make available for its members all the research documents necessary for a comprehensive
p.(None): evaluation including: the protocol and its amendments, the informed consent and its amendments, other
p.(None): information for participants, the investigator´s updated curriculum vitae, enrolment mechanisms, a
p.(None): detail of the payments and insurance coverage envisaged for the participants and financing source of the study.
p.(None):
p.(None): A member of the REC who is, in turn, an investigator in a project may not participate in any evaluations, consultations
p.(None): or decisions about such project.
p.(None): The REC shall consult experts as to specific subject matters but they shall not have a right to decide on the project.
p.(None): The experts requested participation and opinion shall be documented.
p.(None): The REC shall demand from the investigator the immediate report on all the relevant information about safety or
p.(None): protocol amendments increasing the risk for participants or those changes made with the purpose of eliminating the
p.(None): immediate hazards for them.
p.(None): In case of administrative changes or changes that do not affect participants´ safety, the REC may carry out a swift
p.(None): evaluation of such changes. The president or member in charge of the swift evaluation shall document it and
p.(None): inform the rest of the members about it.
p.(None): The REC shall draft and update the standard operating procedures (SOP) to rule its composition and operation,
p.(None): including the following: member selection method; membership duration and criteria for renewal;
p.(None): sessions plan; means of summoning; quorum to hold sessions; specifications as to the type, format and
p.(None): opportuneness of the documents for project evaluation; procedures of evaluation, notification and appeal of opinions;
p.(None): procedures of study follow up and members´ conflict of interest declaration.
p.(None): The REC shall retain all the research relevant documents, such as the documents submitted for review ,
p.(None): minutes of meetings, opinions and general communications for a ten-year period after the termination of the
p.(None): study and shall make them available for health authorities should they request them.
p.(None): INFORMED CONSENT
p.(None): General
p.(None): The informed consent is the process that ensures that a potential participant decides to participate in a human
...
Economic / Economic/Poverty
Searching for indicator economic:
(return to top)
p.(None): INFORMED CONSENT
p.(None): General
p.(None): The informed consent is the process that ensures that a potential participant decides to participate in a human
p.(None): health investigation voluntarily, without undue influence or duress, provided the investigation is consistent
p.(None): with the participant´s values, interests and preferences.
p.(None): The informed consent process shall be conducted by the investigator or a qualified sub-investigator
p.(None): authorized to do so in the function delegation form.
p.(None): In case a potential participant cannot grant by him or herself the consent to a study, the informed consent shall be
p.(None): obtained from his or her legal representatives, in accordance to the Argentine legislation in the matter.
p.(None): Likewise, the participant´s assent shall be requested after having provided him or her with information about the
p.(None): study, according to his or her understanding possibilities of such information. The participant´s decision whether to
p.(None): participate or not shall be respected.
p.(None): In case of a study potential participant´s educational, cultural, social or economic vulnerability, the
p.(None): involvement of a witness unrelated to the investigator and his or her team shall be required. Said witness shall sign
p.(None): and date the consent form as a proof of his or her participation. The REC may set this requirement for all
p.(None): cases in centers where most patients are in a vulnerable situation.
p.(None): A summary of the written information for the patient approved by the REC and the agency may be used in
p.(None): case of serious situations requiring immediate medical care. Spoken information shall be provided in the presence of
p.(None): an impartial witness, who shall
p.(None):
p.(None): sign the written summary of the information and the consent signature page, together with the investigator.
p.(None): Guidelines for obtaining the informed consent
p.(None): The information consent documents include at least two sections: information pages for the participant and the
p.(None): signatures page. Any document intended to be used in the process shall be approved by the REC and the agency.
p.(None): The information section shall contain all the elements described in section B.5.1.
p.(None): The informed consent shall be obtained prior to initiating the assessment of eligibility criteria or any other
p.(None): specific procedure of the study.
p.(None): Oral or written information provided to the potential participant or his or her representative,
...
p.(None): investigator or authorized sub-investigator;
p.(None): that the empowerment to represent the participant is documented in the medical record, had the
p.(None): informed consent been obtained from the participant´s legal representative;
p.(None): that a written assent was obtained in the case of persons under age and within the lower age limit
p.(None): determined by the REC;
p.(None): that the informed consent was obtained by the investigator or sub-investigator authorized in the
p.(None): function delegation form; that the informed consent was obtained prior to evaluating the eligibility criteria or any
p.(None): other study specific procedure;
p.(None): that the consent obtainment is documented in the participant´s medical record, including the initiation date
p.(None): and time, that they were provided with time to reflect on and make questions, which the questions made were, that the
p.(None): participant´s understanding of the information was verified and that two originals were signed and one of them was
p.(None): given to the participant;
p.(None): that in the case of a participant being in a situation of cultural, educational, social or economic vulnerability,
p.(None): the consent was obtained in the presence and with the signature of an impartial witness and that the
p.(None): mechanism was documented in the participant´s medical record.
p.(None): The inspectors shall verify that the participants gave their consent to all the informed consent amendments and the
p.(None): latter had been approved by the REC and the agency at the time of using them and that all the process requirements were
p.(None): fulfilled.
p.(None): The inspectors shall compare the protocol and amendments approved by the REC and the agency with the protocol filed by
p.(None): the investigator in relation to:
p.(None): inclusion and exclusion criteria;
p.(None): clinical data type and obtainment frequency; treatment dose, frequency and route of administration; randomized
p.(None): assignment and blinding procedures.
p.(None): The inspectors shall review the source documents and verify the following:
p.(None):
p.(None): that participants exist and that all the procedures under the protocol were performed to them;
p.(None): that participants met the eligibility criteria at the time of their inclusion in the study; that participants were
p.(None): administered the study treatments per the protocol;
p.(None): that all SAE were notified to the sponsor;
p.(None): that clinical data were obtained and notified correctly and completely. According to the inspection plan set out, the
p.(None): inspectors shall verify: the informed consents;
p.(None): the serious adverse events and the serious and unexpected ADR; the participants withdrawn from the study;
p.(None): the eligibility and treatment evaluation criteria in a relevant sample;
...
p.(None):
p.(None): SECTION E: GLOSSARY
p.(None): AUDIT: a systematic and independent examination of the study related activities and documents to determine whether the
p.(None): activities evaluated were performed and the data were accurately recorded, analyzed and reported as per the
p.(None): protocol, SOP(s), GCP and A.N.M.A.T. Regulatory Guideline for GCP-CPS.
p.(None): AUTONOMY: a person´s self-determination capacity to make a decision voluntarily, as per only his or her own values,
p.(None): interests and preferences provided that he or she has the necessary information to assess all the options. By
p.(None): definition, an autonomous person is able to give his or her informed consent without needing any protection other
p.(None): than the assurance that all the necessary information is provided to him or her. In addition, those
p.(None): individuals having a diminished or inexistent autonomy are in a vulnerable situation, and, therefore, require
p.(None): special protections. A person´s autonomy is considered diminished in case of cultural, educational,
p.(None): social or economic disadvantage, for example, in the case of ethnic minorities, refugees or illiterate,
p.(None): subdued, homeless or impoverished persons. For such cases, the additional protection is the presence of an impartial
p.(None): witness who assures that all the rights and interests of those persons are respected during the informed consent
p.(None): obtainment process. The absence of autonomy takes place when a person is legally or mentally incapable of
p.(None): giving his or her consent voluntarily. In said cases, the consent shall be obtained from his or her legal
p.(None): representative pursuant to the Argentine legislation in the matter.
p.(None): BIOAVAILABILITY: the capacity of a pharmaceutical form of releasing an API in the site of action at the proper
p.(None): speed to obtain a sufficient concentration, and at the timely moment to enable it to exert its action. Since,
p.(None): generally, the concentration cannot be determined in bio-phase in human beings and assuming the existence of balance in
p.(None): the concentrations in serum and bio-phase, the fraction of a drug reaching the systemic circulation of the
...
p.(None): GOOD MANUFACTURING PRACTICE (GMP): a standard to assure a uniform manufacture that meets the
p.(None): requirements of product identity, activity and purity.
p.(None): GOOD LABORATORY PRACTICE (GLP): a laboratory organization and activity related standard under which studies are
p.(None): planned, conducted, recorded, controlled and presented. It aims at assuring the quality and integrity of all the
p.(None): data produced during a given study as well as to tighten the study related safety.
p.(None): RESEARCH ETHICS COMMITTEE (REC): a body acting within its competence scope, which is independent from the sponsor and
p.(None): investigator and is constituted by medical or scientific professionals and non-medical or non-scientific members
p.(None): and whose function is to provide public assurance of the protection of the rights, dignity, safety and
p.(None):
p.(None): well-being of a study participants, by means of, among other things, the review of the study protocol, informed consent
p.(None): process and the investigator´s suitability.
p.(None): INDEPENDENT DATA MONITORING COMMITTEE (IDMC): an external board set up by the sponsor to evaluate, at set time
p.(None): intervals, a clinical study progress, safety data and critical points for efficacy assessment, in such a way that it
p.(None): may recommend the study continuation, modification or suspension.
p.(None): CONFLICT OF INTEREST: a conflict of interest takes place when a professional primary interest such as the
p.(None): patients´ well-being or the validity of a scientific research study may be affected by a secondary interest such
p.(None): as economic gain, professional prestige or personal rivalries.
p.(None): INFORMED CONSENT: a process by means of which a person confirms his or her decision to participate in a human
p.(None): health research study, after having been informed of all its relevant aspects. The informed consent is documented
p.(None): by means of signing a specific form to such purpose.
p.(None): SOURCE DATA: the information about clinical findings, observations or other activities, which is necessary for the
p.(None): reconstruction and evaluation of the clinical study. Said information is documented in original records or
p.(None): their copies certified by the person responsible for them, which are called source documents. The source
p.(None): data must be attributable, readable, accurate and contemporary.
p.(None): PERSONAL DATA: information of any type related to certain or ascertainable physical persons or legal entities.
p.(None): ESSENTIAL DOCUMENTS: documents that individually or collectively enable the evaluation of a study conduct and
p.(None): of the quality of the data produced thereby.
p.(None): SOURCE DOCUMENTS: original documents and records of the clinical data used in a study, such as the medical records,
p.(None): laboratory or pharmacy records, imaging reports and images, participants´ diaries, data recorded on automated
p.(None): instruments, magnetic devices or microfilm and photographic negatives. The certified exact copies of the
p.(None): above mentioned documents are included in this definition.
...
p.(None): event as a reasonable possibility, that is to say, that the relation may not be ruled out, must be considered an
p.(None): adverse drug reaction.
p.(None): UNEXPECTED AND SERIOUS ADVERSE DRUG REACTION (UNEXPECTED
p.(None): SADR): an adverse reaction that results in death, is life-threatening, requires in-patient hospitalization or
p.(None): prolongation of the existent hospitalization, results in persistent or significant incapacity or disability
p.(None): and whose nature of seriousness is not consistent with the product information written in the
p.(None): investigational product monograph or any other documentation.
p.(None): LEGAL REPRESENTATIVE: a person authorized under the Argentine Civil Code or the applicable laws, who acts as the
p.(None): representative of a prospective participant in a clinical study to grant the informed consent to the study.
p.(None): IMPARTIAL WITNESS: a person independent from the investigator and his or her team who participates in the informed
p.(None): consent obtainment process as an assurance that such process respects the rights and interests of a
...
General/Other / Dependent
Searching for indicator dependent:
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p.(None): instruments, magnetic devices or microfilm and photographic negatives. The certified exact copies of the
p.(None): above mentioned documents are included in this definition.
p.(None): INFORMED CONSENT AMENDMENT: a written description of the formal changes or clarifications of the documents or consent
p.(None): form. The changes of expected benefits and risks envisaged for participants or that may affect their decision to
p.(None): continue with the study require approval by the REC and A.N.M.A.T.
p.(None): PROTOCOL AMENDMENT: a document of changes or clarifications of a study protocol. The amendments may be: (a)
p.(None): substantial, when they describe changes in the design, population, procedures or investigational product and require
p.(None): approval by the REC and A.N.M.A.T.; or (b) unsubstantial or administrative when they reflect, for example,
p.(None): only changes of the contact data.
p.(None): CLINICAL STUDY: a set of activities with the purpose of obtaining generalizable knowledge about human
p.(None): health to be applied in medicine, sciences of life and their related technologies. Clinical studies may be
p.(None): observational or experimental, according to whether the investigator intervenes or not in the variable under study.
p.(None): EXPERIMENTAL CLINICAL STUDY (synonym: clinical trial): a study in which the investigator selects
p.(None): participants upon inclusion and exclusion criteria, actively intervenes on the independent or predicting
p.(None): variable and observes and analyzes the changes made in the dependent or outcome variable as a consequence
p.(None): of the
p.(None):
p.(None): intervention. Controlled clinical trials entail the concept of hypotheses contrast with a null hypothesis. The
p.(None): interventions may encompass synthesis drugs, biological products, medical devices, surgical techniques, etc.
p.(None): Said studies are considered as of “major risk” to participants.
p.(None): CLINICAL PHARMACOLOGY STUDY: a systematic scientific study conducted with drugs or biological products in
p.(None): volunteer, healthy or unhealthy human subjects, with the purpose of discovering or verifying their therapeutic effects
p.(None): and/or identifying adverse reactions and/or studying the absorption, distribution, metabolism
p.(None): (biotransformation) and excretion of their active principles in order to determine their efficacy and safety.
p.(None): PHASE I STUDY: an initial introduction of a new drug researched in human subjects to determine its metabolism,
p.(None): pharmacological actions, secondary effects with increasing doses and, if possible, to obtain early evidence about its
p.(None): efficacy. It includes the study of variations among sub-populations and interactions with other drugs and the intake of
p.(None): food. These studies must justify the use of the product in Phase II. Typically, Phase I studies are closely monitored
p.(None): and may be conducted in volunteer healthy subjects or, occasionally, in patients.
p.(None): PHASE II STUDY: the efficacy and safety of the dose ranges are determined in this phase. Likewise, the
...
General/Other / Diminished Autonomy
Searching for indicator diminished:
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p.(None): professional licensure, as well as to the sanitary authority of the jurisdiction and the REC that approved
p.(None): the study:
p.(None): administrative and/or legal sanction to the investigator, sponsor or CRO and prior initiation of the
p.(None): corresponding administrative inquest.
p.(None): Noncompliance of the Regulatory Guideline herein, may give raise to the initiation of an administrative inquest,
p.(None): without the need to require additional information from the inspected party.
p.(None):
p.(None): SECTION E: GLOSSARY
p.(None): AUDIT: a systematic and independent examination of the study related activities and documents to determine whether the
p.(None): activities evaluated were performed and the data were accurately recorded, analyzed and reported as per the
p.(None): protocol, SOP(s), GCP and A.N.M.A.T. Regulatory Guideline for GCP-CPS.
p.(None): AUTONOMY: a person´s self-determination capacity to make a decision voluntarily, as per only his or her own values,
p.(None): interests and preferences provided that he or she has the necessary information to assess all the options. By
p.(None): definition, an autonomous person is able to give his or her informed consent without needing any protection other
p.(None): than the assurance that all the necessary information is provided to him or her. In addition, those
p.(None): individuals having a diminished or inexistent autonomy are in a vulnerable situation, and, therefore, require
p.(None): special protections. A person´s autonomy is considered diminished in case of cultural, educational,
p.(None): social or economic disadvantage, for example, in the case of ethnic minorities, refugees or illiterate,
p.(None): subdued, homeless or impoverished persons. For such cases, the additional protection is the presence of an impartial
p.(None): witness who assures that all the rights and interests of those persons are respected during the informed consent
p.(None): obtainment process. The absence of autonomy takes place when a person is legally or mentally incapable of
p.(None): giving his or her consent voluntarily. In said cases, the consent shall be obtained from his or her legal
p.(None): representative pursuant to the Argentine legislation in the matter.
p.(None): BIOAVAILABILITY: the capacity of a pharmaceutical form of releasing an API in the site of action at the proper
p.(None): speed to obtain a sufficient concentration, and at the timely moment to enable it to exert its action. Since,
...
General/Other / Impaired Autonomy
Searching for indicator autonomy:
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p.(None): NATIONAL ADMINISTRATION OF DRUGS, FOODS AND MEDICAL DEVICES REGULATION 6677/10
p.(None):
p.(None): The Regulatory Guideline for Good Clinical Practices in Clinical Pharmacology Studies is hereby approved.
p.(None): Some A.N.M.A.T. (the agency) regulations are hereby repealed.
p.(None):
p.(None):
p.(None): Buenos Aires City, November 1, 2010.
p.(None): Having regard to A.N.M.A.T. Regulation 5330/97, as amended and supplemented by Regulations 3436/98, 3112/00, 690/05,
p.(None): 1067/08 and 6550/08, Dossier Nr 1-47-20664- 10-0 of the Registry Office of the National Administration of Drugs, Foods
p.(None): and Medical Devices, and
p.(None):
p.(None):
p.(None): Whereas,
p.(None): Clinical Pharmacological Investigation is necessary to obtain strong scientific evidence which enables to improve the
p.(None): public´s health care quality.
p.(None): The development of clinical investigation, in general, should respect basic human rights and freedoms inherent to human
p.(None): nature and enshrined in the National Constitution and Human Rights International Treaties, bearing a constitutional
p.(None): status as incorporated in article 75, sub-title 22 thereof.
p.(None): In this regard, all clinical investigation should safeguard the dignity of participating subjects, ensuring
p.(None): their personal rights, specially, the respect for their autonomy and physical, psychic and moral integrity.
p.(None): As stated by Resolution 1490/07 of the Ministry of Health, Good Clinical Practices are worldwide accepted ethical
p.(None): and scientific standards which set out guidelines for the design, conduct, recording and reporting of studies
p.(None): involving the participation of human beings and, when complied with, such standards ensure that the rights,
p.(None): well-being, safety and dignity of the participating subjects are protected and respected.
p.(None): By means of clinical pharmacological research, a new Active Pharmaceutical Ingredient (API)
p.(None): undergoes the performance of scientifically validated tests to demonstrate its efficacy and safety
p.(None): and thus it provides evidence resulting from the performance of clinical studies.
p.(None): By means of Regulation 5330/07, A.N.M.A.T. approved the Guideline for Good Research Practices for Clinical
p.(None): Pharmacology Studies, in order to fully guarantee the compliance with the standards set forth, both nation and
p.(None): worldwide, in regard to regulations and ethical and legal values.
p.(None): The experience acquired in the systematic application of the aforementioned regulation, the
p.(None): progress made in the synthesis and manufacture of new API(s) for human medicine as well as the increasing
p.(None): number of studies submitted for A.N.M.A.T. approval gave rise to the need for a clear definition of this agency´s
p.(None): regulation scope and for maximizing the soundness, review and permanent update of its procedural, training,
p.(None): ethical and methodological aspects, from the authorization application stage
p.(None):
...
p.(None): consecutively, after assessing the inspection technical report and the recommendation of the director of the DEO:
p.(None): final suspension of the study recruit at the center; final suspension of the study inspected at the center; suspension
p.(None): of all the studies conducted at the center;
p.(None): suspension at all the centers nationwide of the inspected study; indication to the sponsor of monitoring
p.(None): intensification at the center; indication to the sponsor of a change of investigator at the center; indication to the
p.(None): sponsor to reject all the data generated at the center;
p.(None): notification to the competent authority or professional association granting the investigator´s
p.(None): professional licensure, as well as to the sanitary authority of the jurisdiction and the REC that approved
p.(None): the study:
p.(None): administrative and/or legal sanction to the investigator, sponsor or CRO and prior initiation of the
p.(None): corresponding administrative inquest.
p.(None): Noncompliance of the Regulatory Guideline herein, may give raise to the initiation of an administrative inquest,
p.(None): without the need to require additional information from the inspected party.
p.(None):
p.(None): SECTION E: GLOSSARY
p.(None): AUDIT: a systematic and independent examination of the study related activities and documents to determine whether the
p.(None): activities evaluated were performed and the data were accurately recorded, analyzed and reported as per the
p.(None): protocol, SOP(s), GCP and A.N.M.A.T. Regulatory Guideline for GCP-CPS.
p.(None): AUTONOMY: a person´s self-determination capacity to make a decision voluntarily, as per only his or her own values,
p.(None): interests and preferences provided that he or she has the necessary information to assess all the options. By
p.(None): definition, an autonomous person is able to give his or her informed consent without needing any protection other
p.(None): than the assurance that all the necessary information is provided to him or her. In addition, those
p.(None): individuals having a diminished or inexistent autonomy are in a vulnerable situation, and, therefore, require
p.(None): special protections. A person´s autonomy is considered diminished in case of cultural, educational,
p.(None): social or economic disadvantage, for example, in the case of ethnic minorities, refugees or illiterate,
p.(None): subdued, homeless or impoverished persons. For such cases, the additional protection is the presence of an impartial
p.(None): witness who assures that all the rights and interests of those persons are respected during the informed consent
p.(None): obtainment process. The absence of autonomy takes place when a person is legally or mentally incapable of
p.(None): giving his or her consent voluntarily. In said cases, the consent shall be obtained from his or her legal
p.(None): representative pursuant to the Argentine legislation in the matter.
p.(None): BIOAVAILABILITY: the capacity of a pharmaceutical form of releasing an API in the site of action at the proper
p.(None): speed to obtain a sufficient concentration, and at the timely moment to enable it to exert its action. Since,
p.(None): generally, the concentration cannot be determined in bio-phase in human beings and assuming the existence of balance in
p.(None): the concentrations in serum and bio-phase, the fraction of a drug reaching the systemic circulation of the
p.(None): extravascularly administered dose of a given pharmaceutical form, shall be accepted as bioavailability.
p.(None): BIOEQUIVALENCE: two drugs or medicinal products are biologically equivalent when, upon the existence of chemical
p.(None): equivalence, they have a similar bioavailability if administered to the same person in an equal dosage regimen.
p.(None): GOOD CLINICAL PRACTICE (GCP): an international ethical and scientific quality standard for the design,
p.(None): conduct, recording and reporting of the trials involving the participation of human subjects. Compliance
p.(None): with this standard provides a public assurance that the participants´ rights, safety and well-being
...
General/Other / Incapacitated
Searching for indicator incapacity:
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p.(None): subjects in order to determine the tolerance, safety, immunogenicity and/or efficacy of a vaccine. It has
p.(None): three phases: (a) Phase I: first study conducted in human beings to evaluate the tolerance, safety and biologic
p.(None): effects;
p.(None): (b) Phase II: a study determining the immunogenicity caused by a vaccine; and (c) Phase III: a controlled
p.(None): clinical study, with a high number of volunteer participants which aims to assess the effectiveness of a vaccine for
p.(None): the prevention of a disease and its safety in a more thorough way.
p.(None): MULTI-CENTER STUDY: a clinical study conducted according to only one protocol but in more than one place or
p.(None): institution and, therefore, conducted by more than one investigator.
p.(None): ADVERSE EVENT (AE): any adverse medical occurrence in a patient or subject of a clinical study of a health intended
p.(None): product or therapeutic procedure and which does not have a necessary causal relation with this treatment. An
p.(None): adverse event may be any unfavorable and unintended sign, including laboratory abnormal findings and
p.(None): symptoms or diseases temporally associated with the use of the investigational product, whether related or
p.(None): not with it.
p.(None): SERIOUS ADVERSE EVENT (SAE): any unfavorable occurrence throughout and within the research of a diagnostic or
p.(None): therapeutic product or procedure that results in death, is life-threatening, requires in-patient hospitalization
p.(None): or prolongation of the
p.(None):
p.(None): existent hospitalization, results in persistent or significant incapacity or disability or that is a congenital anomaly
p.(None): or a birth defect or that is medically significant as per medical criteria. The above mentioned is applicable
p.(None): without the need for an alleged causal relation existence between the product or treatment administered
p.(None): and the adverse event.
p.(None): CLINICAL DATA FORM (CDF): a printed, digital or optical document designed to keep record of all the clinical data
p.(None): required as per protocol, about each participant of the study and that shall be reported to the sponsor.
p.(None): CONTROL GROUP: a group used as a comparator that indicates what happens when the treatment under study is not applied.
p.(None): ACTIVE PHARMACEUTICAL INGREDIENT: a natural, biological or synthetic chemical substance having a specific
p.(None): pharmacological effect and that is used in human medicine.
p.(None): INSPECTION: an official review conducted by the competent authority of the documents, facilities,
p.(None): records and any resource considered as related to the clinical study and that may be located in the research
p.(None): center, sponsor´s or contract research organization (CRO) facilities or in other sites deemed appropriate.
p.(None): INSPECTOR: a person designated by the competent health and/or regulatory authority to conduct the study-related
p.(None): inspections.
p.(None): INSTITUTION OR RESEARCH CENTER: any government or privately owned agency or medical or dental facility where clinical
p.(None): studies are conducted.
...
p.(None): individual refuses to participate (duress).
p.(None): COMPARATOR PRODUCT: a marketed or investigational product or a placebo used as a reference in a clinical study.
p.(None): INVESTIGATIONAL PRODUCT: a pharmaceutical form of an active substance under investigation, including products
p.(None): holding a marketing authorization when used or combined in the formulation in a form other than the authorized
p.(None): one or for the treatment of an unauthorized indication.
p.(None): PROTOCOL: a document describing the history, fundamentals, objectives, design, methodology ethical
p.(None): considerations, statistical aspects and organization of a study.
p.(None): ADVERSE DRUG REACTION (ADR): an untoward and unintended response to a medicinal product at any dose. In
p.(None): clinical experience and before the approval of a new medicinal product or of its new uses, particularly, when the
p.(None): therapeutic dose cannot be determined, any reaction implying causal relation between a medicinal product and an adverse
p.(None): event as a reasonable possibility, that is to say, that the relation may not be ruled out, must be considered an
p.(None): adverse drug reaction.
p.(None): UNEXPECTED AND SERIOUS ADVERSE DRUG REACTION (UNEXPECTED
p.(None): SADR): an adverse reaction that results in death, is life-threatening, requires in-patient hospitalization or
p.(None): prolongation of the existent hospitalization, results in persistent or significant incapacity or disability
p.(None): and whose nature of seriousness is not consistent with the product information written in the
p.(None): investigational product monograph or any other documentation.
p.(None): LEGAL REPRESENTATIVE: a person authorized under the Argentine Civil Code or the applicable laws, who acts as the
p.(None): representative of a prospective participant in a clinical study to grant the informed consent to the study.
p.(None): IMPARTIAL WITNESS: a person independent from the investigator and his or her team who participates in the informed
p.(None): consent obtainment process as an assurance that such process respects the rights and interests of a
...
General/Other / Natural Hazards
Searching for indicator hazard:
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p.(None): this agency Director upon its authorization, objection or rejection;
p.(None): to require a protocol amendment before or during the conduct of the study;
p.(None): to approve, object or reject the investigators and/or the research centers proposed for conducting the study;
p.(None):
p.(None): to include in this agency´s data base the clinical studies submitted as it registers the rate of progress of authorized
p.(None): studies;
p.(None): before authorizing the conduct of the study, it may perform an inspection of a research center, when deemed
p.(None): appropriate;
p.(None): through the Department of Foreign Trade under its supervision, the Drug Evaluation Office may intervene in
p.(None): the authorization of country inflow and outflow of material intended for the study, once the study has been
p.(None): approved;
p.(None): to authorize amendments to the protocol and informed consent document, the addition or change of investigators and/or
p.(None): research centers as well as the import and export of materials intended for the study within A.N.M.A.T. regulation
p.(None): scope;
p.(None): to evaluate the investigators´ progress and final reports;
p.(None): to analyze the results produced, when deemed appropriate;
p.(None): to control the compliance of the standards laid down in this Regulatory Guideline by means of summoning the
p.(None): investigator or sponsor and/or inspecting the contract research organization (CRO) of a clinical pharmacology
p.(None): study;
p.(None): to summon, examine and/or question the participants included in the study as part of the study routine evaluation,
p.(None): whenever there is information indicating a hazard to their health, if there are doubts as to the compliance with
p.(None): regulations in force or whenever the regulatory authority deems it relevant and opportune;
p.(None): to suspend the study in a research center due to noncompliance with the regulations herein or for participants´ safety
p.(None): reasons.
p.(None): GENERAL PRINCIPLES
p.(None): The interests and well-being of every participant of the study shall prevail over the interests of science
p.(None): and society in all clinical pharmacology studies.
p.(None): Clinical pharmacology studies must respect accepted ethical and scientific principles, the investigation participants´
p.(None): physical and mental integrity as well as their privacy and personal data protection, pursuant to Act 25.326 or any law
p.(None): replacing it.
p.(None): According to the type of active pharmaceutical ingredient (API) under study, clinical pharmacology studies
p.(None): shall be conducted after running pre-clinical studies which prove that the investigational product has a potential
p.(None): therapeutic advantage and that the risks participants are exposed to are justified by the benefits expected.
p.(None): Pre-clinical studies shall be conducted in accordance to Good Laboratory Practice (GLP) standards and
p.(None): investigational products shall be manufactured, handled and stored under the Good Manufacturing Practice
p.(None): (GMP) standards. In studies of undefined or not GLP or GMP governed products, for instance, biological
p.(None): products, the sponsor shall set the guidelines for development, control and usage procedures, which shall require
p.(None): A.N.M.A.T. approval.
...
General/Other / Other Country
Searching for indicator other country:
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p.(None): activities shall be submitted.
p.(None): The following information about pharmacokinetics shall be included:
p.(None): regarding pharmacokinetics: absorption, protein binding, metabolism, distribution and elimination;
p.(None): absolute and/or relative bioavailability using a reference dosage form;
p.(None): regarding bioequivalence: whenever appropriate, for example, in case the product is manufactured with a
p.(None): technology different from the one used to demonstrate its efficacy and safety;
p.(None): population sub-groups as to gender, age, impaired organic function; interactions with another drug and foods;
p.(None): other pharmacokinetics-related data.
p.(None): A summary of information shall be provided about the safety, pharmacodynamics, efficacy and the dose
p.(None): response of the product and its metabolites, if appropriate, produced from studies in healthy and ill
p.(None): volunteers. The implications of said information shall be discussed.
p.(None):
p.(None): Complete information about adverse drug reactions shall be submitted in tables. Based on the experience with the
p.(None): product and related products, the incidence patterns across indication or sub-group shall be discussed.
p.(None): If the product is marketed abroad, a summary of the relevant information stemming from its use. If the
p.(None): product was not approved or was suspended or recalled from the market of other country(s), which countries and the
p.(None): rationale for such measures shall be explained.
p.(None): Excipients
p.(None): In the case of excipients without a history of use in human beings, all the studies supporting the
p.(None): safety of their use shall be submitted.
p.(None): PROTOCOL
p.(None): General
p.(None): This Regulatory Guideline sets out the information and structure required for the clinical pharmacological studies
p.(None): protocol.
p.(None): General information
p.(None): the study complete title, including the clinical development phase; the version number and date;
p.(None): the sponsor´s name; a protocol summary
p.(None): a visits and procedures schedule.
p.(None): Background and justification
p.(None): a description of the problem to be investigated and the current knowledge about it;
p.(None): information about the investigational product, including a summary of the efficacy, pharmacokinetics,
p.(None): tolerance and toxicity data obtained from the pre-clinical and clinical studies;
p.(None): the purpose and relevance of the research proposed;
p.(None): the fundamentals for the development phase proposed for the study. A relevant methodological justification
p.(None): should a phase overlapping occur.
p.(None): Objectives
p.(None): a description of the primary and secondary objectives.
p.(None): Design of the study
p.(None): the study design and justification of its choice; method for random assignment, if appropriate; other bias reducing
p.(None): methods.
p.(None): Population under study
p.(None): envisaged number of participants, including the calculation of potency and its justification;
p.(None): criteria for inclusion and exclusion of participants including diagnose based criteria;
p.(None):
p.(None): criteria for participant withdrawal.
p.(None): Statistical analysis
...
General/Other / Public Emergency
Searching for indicator emergency:
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p.(None): Objectives
p.(None): a description of the primary and secondary objectives.
p.(None): Design of the study
p.(None): the study design and justification of its choice; method for random assignment, if appropriate; other bias reducing
p.(None): methods.
p.(None): Population under study
p.(None): envisaged number of participants, including the calculation of potency and its justification;
p.(None): criteria for inclusion and exclusion of participants including diagnose based criteria;
p.(None):
p.(None): criteria for participant withdrawal.
p.(None): Statistical analysis
p.(None): a study hypothesis with a specification of the null and alternative hypothesis; specification of descriptive methods
p.(None): and statistical tests for variables; criteria for managing missing, excluded and false data;
p.(None): criteria for inclusion or exclusion of participants in the analysis; information technology tools to be used;
p.(None): criteria for processing safety information; interim analysis schedule, if appropriate.
p.(None): Efficacy evaluation
p.(None): efficacy parameters to be assessed, including measurement instruments and methods; efficacy criteria.
p.(None): Investigational products
p.(None): a description of the investigational products indicating API, formulation, dose, route of administration and treatment
p.(None): and follow-up frequency and duration;
p.(None): In the case of biological products trials, a detail of the identification and assessment methodology ensuring
p.(None): the preparation uniformity or the consistency of the lots under study;
p.(None): allowed and un-allowed drugs; criteria for treatment discontinuation;
p.(None): foreseen rescue treatment and follow up in case of failure or adverse events.
p.(None): Adverse events
p.(None): adverse events recording and reporting procedures; emergency blind breaking procedure, if appropriate;
p.(None): Ethical aspect
p.(None): specific mention that the investigation shall be reviewed by a REC; informed consent obtainment procedures;
p.(None): protection of participants´ information and identity confidentially; details of participants´ coverage and compensation
p.(None): for injuries;
p.(None): justification for available payments or compensation for expenses for participants;
p.(None): access for participants to the intervention identified as beneficial in the trial or to an appropriate
p.(None): alternative or benefit upon completion of the trial;
p.(None): justification for using a placebo, if appropriate
p.(None): justification for conducting the research in a vulnerable group, if appropriate; possible conflicts of interest.
p.(None): Administrative and other aspects
p.(None):
p.(None): investigational products maintenance and storage procedures; clinical data record keeping and reports;
p.(None): trial documents handling; monitoring and audit procedures; criteria for trial discontinuation; results publication
p.(None): plan.
p.(None): INFORMED CONSENT
p.(None): The information document used to obtain the consent of a potential participant or of his or her legal representative,
p.(None): pursuant to legal provisions, shall include the following:
p.(None): research title, objective or purpose;
p.(None): sponsor´s data in the country: name or denomination and company name and address; approximate number of participants
p.(None): intended for the study;
...
p.(None): The investigator shall declare his or her potential financial conflicts of interests to the REC prior to initiating the
p.(None): investigation and at any time said conflicts arise.
p.(None): The approval or authorization of the study shall not release the sponsor, the investigator or the
p.(None): host institution from any legal responsibility they might bear in case of participants incurring damages as a result of
p.(None): their participation in the study.
p.(None): INVESTIGATIONAL PRODUCT
p.(None): Manufacture, packing and labeling
p.(None): The sponsor shall ensure that all the investigational products are manufactured according to GMP, if
p.(None): appropriate, and packed in a safe manner to prevent contamination or deterioration during
p.(None): transportation or storage.
p.(None): The label shall be written in Spanish and contain, at least, the following printed information or,
p.(None): whenever appropriate, there shall be space left to complete said information on it:
p.(None): study identification, sponsor and investigator; product name, or if blinded, the corresponding code;
p.(None): dosage form, route of administration (may be excluded in solid forms) and concentration or
p.(None): potency per unit, were it the case of an open study;
p.(None): lot number or code to identify the manufacturing and packing process; participant´s code and number of visit or date of
p.(None): product administration.
p.(None): The following information shall be included in the label whenever the primary packing size allows for it, or otherwise,
p.(None): in the secondary packing or a leaflet attached:
p.(None): the name, address and telephone number of the person who should be contacted for information about the product, the
p.(None): study and the emergency decoding (sponsor, CRO or investigator);
p.(None): basic storage conditions; expiry date (month/year);
p.(None): special instructions for the product administration; a “clinical investigation exclusive use” statement;
p.(None): a “keep away from the reach of children” statement if the product is given to the participant.
p.(None): In case of updating the investigational product expiration date, an additional label shall be placed on the packing
p.(None): which shall contain the lot number, the old expiration date and the new one. The re-labeling process may be
p.(None): carried out at the authorized manufacturing site or at the research center, in which case, the study
p.(None): monitor shall
p.(None):
p.(None): perform said procedure and a sponsor representative shall review its result. Such process shall be
p.(None): documented on the sponsor´s lot record and the research center product accountability records.
p.(None): If the formulation of the investigational product or its comparators were modified during the study, the new
p.(None): pharmacokinetics or dissolution studies, according to the pharmaceutical form, shall be available prior to
p.(None): using the new the formulation, in order to ensure therapeutic equivalence. Topical and gaseous drugs are exempted from
p.(None): said requirement, provided the API concentration is the same. All product modifications require a protocol
p.(None): amendment and approval by the REC and A.N.M.A.T.
p.(None): Information
p.(None): All clinical studies shall be based on safety and efficacy information obtained from clinical and
p.(None): non-clinical studies. Such information shall support the product proposed use as to its indication, pharmaceutical
...
p.(None): procedures shall be subject to approval by the agency.
p.(None): Supply and handling
p.(None): The sponsor shall be responsible for handling the investigational product from the moment it departs from
p.(None): the manufacturing site or when it is cleared from Customs until it is delivered to the research site and from the time
p.(None): he or she takes away the unused or expired product until its destruction. The investigator shall be
p.(None): responsible for managing the product domestically and shall be supervised by the sponsor who shall be jointly and
p.(None): severally liable.
p.(None): The sponsor shall be responsible for providing study participants with free-of-charge investigational products
p.(None): throughout all the study and for ensuring their timely delivery and the retrieval of failed, expired or unused
p.(None): products.
p.(None): Before delivering the investigational products to the investigator, the sponsor shall make sure that the
p.(None): REC has approved it and the agency and jurisdictional health authority have authorized it.
p.(None): The investigator shall be responsible for the investigational products to be used as per the protocol. The investigator
p.(None): or his or her delegate shall instruct every participant on the rightful use of the investigational product(s),
p.(None): make sure participants understand such instructions and then verify in every clinical visit that the instructions
p.(None): are followed.
p.(None):
p.(None): If a blinding method is used in the study, the sponsor shall set out a decoding procedure for emergency
p.(None): situations and the investigator shall do his or her utmost to preserve the blind, unless it becomes necessary to
p.(None): identify the product for participant´s safety reasons. In such case, the investigator shall document and justify the
p.(None): procedure and immediately report it to the sponsor and the REC.
p.(None): The investigator shall have an inventory of the investigational products documenting the following: reception
p.(None): from the sponsor, dispensation to participants, reception of the remains and return of unused products to the sponsor.
p.(None): Said function may be delegated to a BSc in Pharmacy or any other team member qualified and authorized to do so.
p.(None): The inventory of investigational products at the center shall indicate the participant´s code, product name or code,
p.(None): lot or serial number, expiry date, delivery and reception date and the respective quantities. The inventory
p.(None): shall enable to verify that the products were dispensed only to participants and that they used the products
p.(None): according to the protocol. Final accountability shall show a coincidence among the products received, the
p.(None): products used and the products returned to the sponsor. Otherwise, differences shall be accounted for in
p.(None): writing.
p.(None): Investigational products shall be stored in a locked safe place, with the exclusive access of authorized
p.(None): personnel and in the room conditions set out by the sponsor and the applicable regulations.
p.(None): The sponsor shall keep an analysis and description record of every investigational product batch and
p.(None): reserve an adequate quantity of samples for an eventual re- confirmation of specifications until the
...
General/Other / Relationship to Authority
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p.(None): Institutional Relations Office and Drug Evaluation Office and placed on record. Carlos Chiale.
p.(None):
p.(None): ANNEX I: REGULATORY GUIDELINE FOR GOOD CLINICAL PRACTICE IN CLINICAL PHARMACOLOGY STUDIES
p.(None): INDEX
p.(None): SECTION A: GENERAL CONSIDERATIONS
p.(None): Definitions Objectives
p.(None): Application and scope General principles Noncompliance
p.(None):
p.(None): SECTION B: DOCUMENTATION REQUIREMENTS FOR THE AUTHORIZATION OF CLINICAL PHARMACOLOGY STUDIES
p.(None): Objective
p.(None): General documentation Investigational product monograph Protocol
p.(None): Informed consent
p.(None): Amendments to the protocol, informed consent and investigational product monograph Unexpected and serious adverse drug
p.(None): reactions
p.(None): Study reports and other communications
p.(None):
p.(None):
p.(None): SECTION C: GUIDELINE FOR GOOD CLINICAL PRACTICE IN CLINICAL PHARMACOLOGY STUDIES
p.(None): Objective Investigator Sponsor
p.(None): Research Ethics Committee Informed consent
p.(None): Protection of study participants Agreements and financing Investigational product
p.(None): Reports and other communications Changes during the study Recording of clinical data Essential study documents
p.(None): Monitoring
p.(None):
p.(None): Audit
p.(None): Suspension or cancellation of the study
p.(None):
p.(None):
p.(None): SECTION D: INSPECTIONS OF CLINICAL PHARMACOLOGY STUDIES
p.(None): Objective
p.(None): Scope and authority Inspection process
p.(None): Study and inspector selection Inspector selection Preparation for
p.(None): Planning the inspection Inspection announcement Inspection conduct Record review procedures Inspection record
p.(None): Inspection technical report Inspection report
p.(None):
p.(None): SECTION E: GLOSSARY
p.(None):
p.(None):
p.(None): SECTION F: FORMS
p.(None):
p.(None): SECTION A: GENERAL CONSIDERATIONS DEFINITIONS
p.(None): Good Clinical Practice (GCP) is an international ethical and scientific quality standard for the design, conduct,
p.(None): recording and reporting of studies involving human subjects. The adoption of this standard provides a public assurance
p.(None): that the participants´ rights, safety and well-being are protected, in accordance with the principles
p.(None): of the Declaration of Helsinki and that clinical studies data are reliable.
p.(None): Clinical pharmacology studies are trials that evaluate the safety and efficacy of a drug intended for a disease
p.(None): prevention, treatment or diagnosis. Broadly considered, research on human health has provided valuable
p.(None): benefits in terms of suffering mitigation and prolongation of human life. However, clinical trials, in particular,
p.(None): involve risks for participating individuals, which gives raise to the need for a governmental regulation
p.(None): and monitoring mechanism ensuring the utmost protection for participants.
p.(None): OBJECTIVES
p.(None): The Regulatory Guideline for Good Clinical Practice in Clinical Pharmacology Studies (GCP-CPS) herein establishes the
p.(None): requirements that sponsors and investigators must comply with within the scope of this agency´s authorization
...
p.(None):
p.(None): to include in this agency´s data base the clinical studies submitted as it registers the rate of progress of authorized
p.(None): studies;
p.(None): before authorizing the conduct of the study, it may perform an inspection of a research center, when deemed
p.(None): appropriate;
p.(None): through the Department of Foreign Trade under its supervision, the Drug Evaluation Office may intervene in
p.(None): the authorization of country inflow and outflow of material intended for the study, once the study has been
p.(None): approved;
p.(None): to authorize amendments to the protocol and informed consent document, the addition or change of investigators and/or
p.(None): research centers as well as the import and export of materials intended for the study within A.N.M.A.T. regulation
p.(None): scope;
p.(None): to evaluate the investigators´ progress and final reports;
p.(None): to analyze the results produced, when deemed appropriate;
p.(None): to control the compliance of the standards laid down in this Regulatory Guideline by means of summoning the
p.(None): investigator or sponsor and/or inspecting the contract research organization (CRO) of a clinical pharmacology
p.(None): study;
p.(None): to summon, examine and/or question the participants included in the study as part of the study routine evaluation,
p.(None): whenever there is information indicating a hazard to their health, if there are doubts as to the compliance with
p.(None): regulations in force or whenever the regulatory authority deems it relevant and opportune;
p.(None): to suspend the study in a research center due to noncompliance with the regulations herein or for participants´ safety
p.(None): reasons.
p.(None): GENERAL PRINCIPLES
p.(None): The interests and well-being of every participant of the study shall prevail over the interests of science
p.(None): and society in all clinical pharmacology studies.
p.(None): Clinical pharmacology studies must respect accepted ethical and scientific principles, the investigation participants´
p.(None): physical and mental integrity as well as their privacy and personal data protection, pursuant to Act 25.326 or any law
p.(None): replacing it.
p.(None): According to the type of active pharmaceutical ingredient (API) under study, clinical pharmacology studies
p.(None): shall be conducted after running pre-clinical studies which prove that the investigational product has a potential
p.(None): therapeutic advantage and that the risks participants are exposed to are justified by the benefits expected.
p.(None): Pre-clinical studies shall be conducted in accordance to Good Laboratory Practice (GLP) standards and
p.(None): investigational products shall be manufactured, handled and stored under the Good Manufacturing Practice
p.(None): (GMP) standards. In studies of undefined or not GLP or GMP governed products, for instance, biological
p.(None): products, the sponsor shall set the guidelines for development, control and usage procedures, which shall require
p.(None): A.N.M.A.T. approval.
p.(None): The sponsor and investigators of clinical pharmacology studies within the scope of this Regulatory Guideline shall
p.(None): fulfill the obligations established herein.
...
p.(None): a sponsor´s original sworn statement asserting that the investigational product complies with GMP
p.(None): standards. In the case of products not fully governed by GMP standards, the manufacturing conditions not
p.(None): meant to comply with such norms shall be identified;
p.(None): the study protocol;
p.(None): a general version of the informed consent; an investigational product monograph;
p.(None): an application for the import or export of study materials or samples. In the case of drugs, details as
p.(None): to the name, pharmaceutical form, strength and quantity shall be
p.(None):
p.(None): furnished. In the case of biological samples, the type and purpose shall be detailed; whereas for other
p.(None): materials, the description and quantity shall be informed;
p.(None): for the import of narcotic drugs, a sworn statement by the importing company technical director rendering the lot
p.(None): numbers of the products to be used and the list of investigators authorized to receive them shall be
p.(None): submitted;
p.(None): a copy in Spanish of the investigational product label.
p.(None): Application for authorization of the investigator and the research center: for authorizing each principal investigator
p.(None): and research center, the sponsor shall submit the following documents:
p.(None): an EFCA2 form completed and signed (Section F);
p.(None): a copy of the authorization to conduct the clinical pharmacology study;
p.(None): the investigator´s abridged Curriculum Vitae which shall be signed and dated by him or her;
p.(None): a certified copy of the investigator´s degree certification and professional license awarded by the
p.(None): sanitary authority of the jurisdiction where the study shall be conducted. Likewise, a certified copy of
p.(None): his or her proofs of training and/or experience in clinical research shall be required;
p.(None): for Phase II and Phase III studies, a certified copy of the certificate of specialist or the certificate of residency
p.(None): completion or the certificate of graduate specialization in the disease under study;
p.(None): an original letter stating the commitment to comply with the study protocol (indicating its title), the Declaration of
p.(None): Helsinki and A.N.M.A.T. Regulatory Guideline for GMP-CFS;
p.(None): a certified copy of the study approval by a Research Ethics Committee (REC), with a detail of the documents
p.(None): reviewed, for example, protocol, informed consent, and investigational product monograph. Only one approval by a
p.(None): REC shall be accepted per each research center;
p.(None): a dated list of the members of each REC, including name, birth date, gender, profession and
p.(None): occupation, position in the committee and relationship with the institution;
p.(None): a certified copy of the study authorization issued by the highest authority of the host institution. Should the
p.(None): jurisdiction health authority require the registration of health research studies, a certified copy of the proof
p.(None): of the study registration in the jurisdiction shall be submitted;
p.(None): a certified copy of the authorization by the institution authority for the study review by an external REC, if
p.(None): appropriate;
p.(None): a certified proof of the research center operating license in force;
p.(None): an informed consent document specific for the research center, if appropriate; General documents shall be submitted in
p.(None): the above mentioned order.
p.(None): All the documents submitted to the agency shall be in Spanish, except for the investigational product
p.(None): monograph since it shall be used only as study background information. The protocol, informed consent and EFCA
p.(None): forms shall be submitted both in print and digital format (the latter shall be enclosed.)
p.(None):
p.(None): In the event that an amendment to any of the documents, including the protocol, informed consent and
p.(None): investigational product monograph already submitted is needed, the original document with the document amended and a
p.(None): letter explaining the mistake and identifying the original submission file number shall be submitted.
p.(None): The following documents shall not be submitted to the agency but they shall be requested should an
p.(None): inspection of the research center be conducted:
p.(None): clinical data forms (CDF);
p.(None): participants´ enrolment forms and clinical follow-up diaries, excluding questionnaires of the study primary objectives
p.(None): assessment;
p.(None): material to be used in informative meetings with potential participants; a monitoring plan.
p.(None): INVESTIGATIONAL PRODUCT MONOGRAPH
p.(None): Introduction
p.(None): The investigational product monograph is a collection of the clinical and non-clinical data of the
...
p.(None): derechos que posee de acuerdo con el Código Civil y las leyes argentinas en materia de responsabilidad civil por
p.(None): daños”).
p.(None): special mention shall be made as to the fact that the sponsor finances the investigators´
p.(None): fees and the study procedures costs through an agreement with the investigator and/or the institution;
p.(None): the possible conflict of interest and the investigator´s institutional membership;
p.(None): an assurance that the participant´s involvement in the investigation is voluntary and that the candidate may
p.(None): refuse to participate or may abandon the study at any time with no need to explain his or her reason to do so and with
p.(None): no loss of the benefits he or she is entitled to;
p.(None): an assurance that the participant´s personal data shall remain confidential, even when the investigation results are
p.(None): published, pursuant to Law 25.326;
p.(None): the commitment to provide timely answers to questions, clarifications or doubts about the procedures, risks and
p.(None): benefits concerning the investigation;
p.(None): the commitment to timely communicate to the participant or his or her legal representative all
p.(None): the new information that might change his or her decision to continue participating in the study;
p.(None): the envisaged situations by which the investigation or a person´s participation could be prematurely discontinued;
p.(None): a description of the rights a person is entitled to as a participant of a research study, including the access to his
p.(None): or her study-related information and his or her right to have it available;
p.(None): the permission the participant shall give to the sponsor´s representative, REC and the Regulatory Authority to access
p.(None): his or her medical records, which shall contain its scope and a special mention to the fact that such
p.(None): authorization is granted by signing the informed consent form;
p.(None): contact information of the investigator and the REC that approved the study;
p.(None): the following phrase shall be included: “This clinical pharmacology study was authorized by
p.(None): A.N.M.A.T. Should you have any doubt about the investigation treatment, call toll free A.N.M.A.T. Responde at
p.(None): 0800-333-1234.” [translation of: “Este estudio de farmacología clínica ha sido autorizado por A.N.M.A.T. Si usted
p.(None): tuviera alguna duda sobre el tratamiento de la investigación, puede consultar a A.N.M.A.T. responde al
p.(None): 0800-333-1234 (línea gratutita)”].
p.(None): a signature page, with a space for the date, signature and print name of the participant, legal representative and
p.(None): witness, if appropriate, and of the investigator who led the process.
p.(None): AMENDMENTS TO THE PROTOCOL, INFORMED CONSENT AND INVESTIGATIONAL PRODUCT MONOGRAPH
p.(None): Amendments to the protocol and informed consent
p.(None): The objections to the protocol made by the agency in the baseline evaluation shall be changed and submitted as an
p.(None): amendment before its final authorization.
p.(None):
p.(None): Amendments to the protocol and informed consent require an approval by the REC and the authorization by A.N.M.A.T.
...
p.(None): repeated minor deviations despite having warned the investigator about their occurrence.
p.(None):
p.(None): The application for the addition or exclusion of an investigator or research center shall be submitted with the
p.(None): EFCA2 form (Section F) completed and signed and other supporting documents. Whenever an exclusion is requested,
p.(None): the reason for it shall be explained.
p.(None): The study premature cancellation in one given center or in the country shall be immediately informed to
p.(None): A.N.M.A.T. including the pertaining justification.
p.(None): The following changes throughout the study shall be informed to the agency with the study progress report:
p.(None): changes in the REC member composition;
p.(None): administrative changes, for example, the person responsible for the study or his or her contact data or the
p.(None): investigator´s contact data.
p.(None): The following changes or updates may not be informed to the agency:
p.(None): start, duration and completion of the enrolment or random assignment period; extension of the investigational product
p.(None): lot expiry date;
p.(None): changes in the sponsor´s monitoring program;
p.(None): REC monitoring report, except for the case of major deviations (as described in 8.4).
p.(None): 8.9. Upon trial completion, the sponsor shall submit a complete final report EFCA5 form (Section F) per each
p.(None): investigator.
p.(None): 8.10. The sponsor shall submit the final result within one-year period after the study termination.
p.(None): SECTION C: GOOD CLINICAL PRACTICE GUIDE FOR CLINICAL PHARMACOLOGY STUDIES
p.(None): OBJECTIVE
p.(None): With a view to enabling the agency to exercise its monitoring authority, this section sets forth the procedures that
p.(None): clinical pharmacology studies investigators and sponsors shall conduct pursuant to this regulation.
p.(None): INVESTIGATOR
p.(None): The investigator is the person responsible for conducting a clinical pharmacology study in a research center.
p.(None): Whenever the investigator, plans, initiates and conducts an investigation on his or her own, he or she becomes
p.(None): the study sponsor and takes all the responsibilities implied thereby.
p.(None): The investigator shall be suitably trained and experienced to conduct a clinical pharmacology study, as
p.(None): detailed in his or her Curriculum Vitae and proofs attached thereto.
p.(None): The investigator may set up a team of qualified collaborators who are trained in all the applicable requirements to
p.(None): conduct the investigation, and may therefore, delegate some of his or her functions to them; but not
p.(None): his or her responsibilities. The collaborators´ qualifications shall be documented in their updated Curricula
p.(None): Vitae.
p.(None): The investigator shall maintain an updated list of his or her collaborators, indicating their name,
p.(None): delegated function, activities initiation date and signature registry.
p.(None):
p.(None): The investigator and his or her collaborators shall know and respect the outlines set out in this Regulatory
p.(None): Guideline as well as the competent Health Authority requirements and the study protocol. The investigator and his
p.(None): or her collaborators shall be familiar with the information available concerning the investigational products.
p.(None): The investigator shall verify and ensure that the research site is licensed to operate, that its infrastructure
p.(None): adjusts to the study requirements and that all the equipment, instruments and supplies to be used
p.(None): operate properly. Phase I, pharmacokinetics, bioavailability and bioequivalence studies may only be
p.(None): conducted in second or third level health institutions (for hospitalization), according to the regulation
p.(None): in effect set forth by the Ministry of Health. The level of each institution may be verified in its
p.(None): operating license.
p.(None): In case of advertising in communication media for participant recruit purposes, the advertisements used
p.(None): shall be approved by the REC and submitted to the agency. The investigational product may not, implicitly or
p.(None): explicitly, be referred to as efficacious, safe or equivalent to or better than existing products in such
p.(None): advertisements.
p.(None): The investigator and the research site shall be subject to monitoring, audit or inspection of the clinical study by the
p.(None): REC, sponsor and competent authorities.
p.(None): SPONSOR
p.(None): The sponsor of the study is the physical person or legal entity that initiates, manages, controls and finances the
p.(None): study and takes all the responsibilities laid down in this regulatory guideline.
p.(None): The sponsor shall count on qualified professionals for the design, planning, conduct, analysis and reporting of the
p.(None): clinical study, as well as on medical advisors to pursue matters concerning the investigational products and
p.(None): participants´ safety.
p.(None): The sponsor is responsible for selecting qualified investigators according to their education, training and
p.(None): experience; and research centers having all the resources needed for the proper conduct of the clinical
p.(None): pharmacology study.
p.(None): The sponsor shall furnish the investigator with all the documents necessary to perform the study properly, such as,
p.(None): the protocol and investigational product monograph, among others. Likewise, the sponsor shall be responsible for
p.(None): training the investigator and his or her team on the study procedures, investigational products and applicable
p.(None): requirements.
p.(None): The investigator is responsible for obtaining the authorization from the research site or institution authority before
p.(None): initiating the study; while the sponsor shall be responsible for obtaining the authorization from the agency before
p.(None): starting the study conduct.
p.(None): For multi-site research studies, the investigator shall lay out a plan to validate and standardize all the
p.(None): measurement procedures in the various research sites.
p.(None): The sponsor may summon an Independent Data Monitoring Committee (IDMC) composed of experts in the clinical
p.(None): study subject matter to review safety and efficacy partial results and evaluate and recommend whether the study
p.(None): should be continued, modified or cancelled. The IDMC members cannot be investigators of the study or
p.(None): sponsor´s employees.
p.(None): The sponsor shall implement and maintain a quality control and assurance process throughout the study
p.(None): stages, which shall be based upon standardized operational
p.(None):
p.(None): procedures (SOPs), in order to ensure the study is being conducted and documented according to the protocol and
p.(None): this Regulatory Guideline and that data are being processed properly and are reliable.
p.(None): The sponsor shall transfer some or all of his or her functions concerning the study to a contract research organization
p.(None): (CRO), provided that the latter is legally incorporated in Argentina and without prejudice of the legal
p.(None): responsibility attached to the sponsor regarding participants´ care and data integrity.
p.(None): The tasks and functions transferred to and accepted by the CRO, shall be laid down in a written agreement signed by the
p.(None): parties. The functions not specified in the agreement shall be discharged by the sponsor. The CRO shall fulfill all the
p.(None): obligations established for the sponsor under this Regulatory Guideline.
...
p.(None): A clinical pharmacology study on an investigational product shall be conducted only if the sponsor takes out of an
p.(None): insurance policy or another form of guarantee set up in Argentina, in order to ensure participants´ coverage for
p.(None): risks or potential damage.
p.(None): Noncompliance of the protocol or the Regulatory Guideline herein by an investigator or sponsor´s legal representative
p.(None): shall lead to an immediate remedial action by the sponsor.
p.(None): When the sponsor identifies a repeated, persistent or serious violation of the protocol by an investigator, he or she
p.(None): shall suspend the study at the site and immediately report it to the REC and A.N.M.A.T.
p.(None): RESEARCH ETHICS COMMITTEE (REC)
p.(None): Evaluation requirement
p.(None): Prior to the research initiation, the investigator is required to have a written authorization
p.(None): by a REC. To such end, the investigator shall provide the REC with all the information it requests, including the
p.(None): protocol and its amendments, informed consent documents and their amendments, other information to be
p.(None): provided to potential participants, participant enrolment method, last version of the investigational product
p.(None): monograph and any other information concerning the experimental products or procedures.
p.(None): In case that the research site does not have its own REC or if the REC does not comply with the
p.(None): requirements set out herein, the study shall be evaluated by a REC belonging to another institution. The
p.(None): research site authority shall authorize the delegation of this function.
p.(None): REC evaluation objective and scope
p.(None): The primary objective of the review by a REC of a clinical pharmacology study is to protect the dignity, rights,
p.(None): safety and well-being of the participants.
p.(None): The REC shall provide an independent, competent and timely evaluation of the ethical, scientific and operational
p.(None): aspects of the proposed studies, which shall be based upon the current state of scientific knowledge and the Regulatory
p.(None): Guideline herein.
p.(None):
p.(None): Every clinical pharmacology study must be evaluated by a REC before its initiation and throughout its conduct, at
p.(None): least once a year until its completion. The REC may set shorter periods for evaluations as per the risks
p.(None): involved in the study.
p.(None): The REC shall assess the suitability of the investigator to conduct the study according to his or her education and
p.(None): training in ethical and regulatory aspects and the research center suitability to host the study.
p.(None): The REC shall make sure that potential participants give their consent without duress or undue influence and
p.(None): after having received all the information properly. The information about payments and compensations
p.(None): envisaged for the study shall be precise and easy to understand for participants.
p.(None): The REC shall make sure of the compliance with the ethical principles applicable throughout the study
p.(None): conduct, by means of a monitoring mechanism for investigators.
p.(None): Composition
p.(None): The REC composition shall be such that enables a competent, unbiased and uninfluenced evaluation of
p.(None): the scientific, medical, ethical and legal aspects of the study.
p.(None): The REC composition shall be cross functional, multi-sectored and balanced in terms of its members´ age, sex and both
p.(None): scientific and non-scientific education. The number of members shall be adequate, preferably uneven, to ensure the
p.(None): fulfillment of its duty. It shall have a minimum of five full members and at least two alternate members for the cases
p.(None): of absence of the regular members.
p.(None): The research center REC shall include an external member unrelated to the institution and who shall represent the
p.(None): interest of the community being assisted.
p.(None): The members shall be frequently renewed in order to combine the advantages of experience with those
p.(None): of new perspectives. The REC member selection and replacement mechanism shall ensure the election
p.(None): impartiality and respect for the suitability and plurality criteria.
p.(None): The REC shall elect a president among its members to lead meetings. The REC president shall be a person
p.(None): holding the experience, competence and qualifications to deal with and evaluate all the aspects of the investigations.
p.(None): Operation
p.(None): The REC holds the authority to approve, request amendments to, disapprove, discontinue or cancel
p.(None): an investigation on human health. The REC shall report its opinions in writing to the investigator, including
p.(None): the reasons for its decisions.
p.(None): The REC shall make a list and keep it updated of its members, indicating their names, age, sex, profession or
p.(None): occupation, position at the REC and relationship with the institution.
p.(None): The REC shall place in record its meetings, consultations and decisions, including the participating members and their
p.(None): voting results.
p.(None): The REC shall request and make available for its members all the research documents necessary for a comprehensive
p.(None): evaluation including: the protocol and its amendments, the informed consent and its amendments, other
p.(None): information for participants, the investigator´s updated curriculum vitae, enrolment mechanisms, a
p.(None): detail of the payments and insurance coverage envisaged for the participants and financing source of the study.
p.(None):
p.(None): A member of the REC who is, in turn, an investigator in a project may not participate in any evaluations, consultations
p.(None): or decisions about such project.
p.(None): The REC shall consult experts as to specific subject matters but they shall not have a right to decide on the project.
p.(None): The experts requested participation and opinion shall be documented.
p.(None): The REC shall demand from the investigator the immediate report on all the relevant information about safety or
...
p.(None): etc., for the proper conservation of investigational products and any other supply necessary for its
p.(None): administration. The protocol shall also indicate procedures for handling, storing and returning the unused
p.(None): products to the sponsor and/or their final disposition at the research center, pursuant to the regulations in
p.(None): effect.
p.(None): The sponsor shall set forth the development and control guidelines and use procedures to be applied to studies of
p.(None): products not defined or governed by GMP or GLP standards, for example, biological products. Said guidelines and
p.(None): procedures shall be subject to approval by the agency.
p.(None): Supply and handling
p.(None): The sponsor shall be responsible for handling the investigational product from the moment it departs from
p.(None): the manufacturing site or when it is cleared from Customs until it is delivered to the research site and from the time
p.(None): he or she takes away the unused or expired product until its destruction. The investigator shall be
p.(None): responsible for managing the product domestically and shall be supervised by the sponsor who shall be jointly and
p.(None): severally liable.
p.(None): The sponsor shall be responsible for providing study participants with free-of-charge investigational products
p.(None): throughout all the study and for ensuring their timely delivery and the retrieval of failed, expired or unused
p.(None): products.
p.(None): Before delivering the investigational products to the investigator, the sponsor shall make sure that the
p.(None): REC has approved it and the agency and jurisdictional health authority have authorized it.
p.(None): The investigator shall be responsible for the investigational products to be used as per the protocol. The investigator
p.(None): or his or her delegate shall instruct every participant on the rightful use of the investigational product(s),
p.(None): make sure participants understand such instructions and then verify in every clinical visit that the instructions
p.(None): are followed.
p.(None):
p.(None): If a blinding method is used in the study, the sponsor shall set out a decoding procedure for emergency
p.(None): situations and the investigator shall do his or her utmost to preserve the blind, unless it becomes necessary to
p.(None): identify the product for participant´s safety reasons. In such case, the investigator shall document and justify the
p.(None): procedure and immediately report it to the sponsor and the REC.
p.(None): The investigator shall have an inventory of the investigational products documenting the following: reception
p.(None): from the sponsor, dispensation to participants, reception of the remains and return of unused products to the sponsor.
p.(None): Said function may be delegated to a BSc in Pharmacy or any other team member qualified and authorized to do so.
p.(None): The inventory of investigational products at the center shall indicate the participant´s code, product name or code,
p.(None): lot or serial number, expiry date, delivery and reception date and the respective quantities. The inventory
p.(None): shall enable to verify that the products were dispensed only to participants and that they used the products
p.(None): according to the protocol. Final accountability shall show a coincidence among the products received, the
p.(None): products used and the products returned to the sponsor. Otherwise, differences shall be accounted for in
p.(None): writing.
p.(None): Investigational products shall be stored in a locked safe place, with the exclusive access of authorized
p.(None): personnel and in the room conditions set out by the sponsor and the applicable regulations.
p.(None): The sponsor shall keep an analysis and description record of every investigational product batch and
p.(None): reserve an adequate quantity of samples for an eventual re- confirmation of specifications until the
p.(None): study data analysis is completed or until the regulatory authority decides that should be the case.
p.(None): Investigational products destruction shall be carried out according to the legislation in force concerning hazardous
p.(None): residues. The sponsor shall be primarily responsible for the destruction of unused products and shall retain the
p.(None): destruction certificate.
p.(None): REPORTS AND NOTIFICATIONS
p.(None): The investigator shall immediately notify the sponsor of all the serious adverse events (SAE), including relevant
p.(None): laboratory abnormalities, as per the procedures and terms established by the sponsor. Additional
p.(None): information enabling to determine the SAE relation with the investigational product shall be furnished, as soon as
p.(None): available.
p.(None): The investigator shall notify the REC, within the period set out by the latter, of all the SAEs and other events
p.(None): significantly affecting the study and/or the risk for participants.
p.(None): The investigator shall report the study progress to the REC at least once a year. The progress report shall contain,
p.(None): at least, the number of enrolled, followed up and withdrawn participants, the encoded list of
p.(None): participants, serious adverse events and their alleged relation with the investigational product as well as the
p.(None): participants´ safety related relevant deviations from the protocol observed throughout the period.
p.(None): The sponsor shall notify of all the unexpected and serious ADR related to an investigational product to
p.(None): all the investigators of all the ongoing studies of the product within a fourteen-day period after learning about
p.(None): them. The investigators shall report said unexpected and serious ADR to the REC within the period it sets forth for
p.(None): such purpose.
...
p.(None): source documents such as medical records, laboratory and pharmacy records, participants´ diaries,
p.(None): imaging and technical reports, electrocardiograms, etc.
p.(None): completed and signed clinical data forms. Essential documents required at study completion
p.(None): The following documents shall be available upon study conclusion: investigational product final accountability;
p.(None): proofs of the investigational product destruction, if destroyed at the center; full list of participants´
p.(None): identification;
p.(None): final report submitted to the REC and the agency; close-out monitoring visit report;
p.(None): dated close-out notification by the sponsor. MONITORING
p.(None): The sponsor shall be responsible for implementing a regular and ongoing quality control of the clinical
p.(None): study denominated monitoring.
p.(None): The sponsor shall select monitors who have the proper scientific and/or clinical knowledge to perform the
p.(None): duty and train them on the investigational product, protocol, consent documents, sponsor´s SOP and applicable rules and
p.(None): regulations.
p.(None): The sponsor shall set out and document in a plan the type and scope of the monitoring process, based on considerations
p.(None): such as the objective, design, number of participants and variables to be assessed.
p.(None):
p.(None): The monitor shall comply with the monitoring plan and respect all the procedures established by the sponsor
p.(None): for the monitoring process.
p.(None): The monitor shall verify that:
p.(None): the rights and well-being of human subjects are protected at all times;
p.(None): the investigation is conducted per the protocol and the REC and the competent regulatory authority
p.(None): requirements;
p.(None): the investigator and his or her team are qualified to perform the study and that they have the proper resources
p.(None): throughout the study conduct;
p.(None): the approval by the REC and the authorization by the competent authority were obtained;
p.(None): the investigator uses the last version of the protocol and informed consent approved by the REC and authorized by
p.(None): A.N.M.A.T. ;
p.(None): all the participants´ written consents were obtained prior to their inclusion in the study; the investigational
p.(None): products supply and storage are appropriate and sufficient;
p.(None): the investigational products are administered to the right participants as per the conditions set forth in
p.(None): the protocol;
p.(None): participants have been provided with correct and adequate instructions for using, handling, storing and
p.(None): returning the investigational products;
p.(None): the reception, use and return of investigational products at the research site are properly controlled and
p.(None): recorded;
p.(None): the end disposition of unused investigational products complies with the sponsor´s requirements and the
p.(None): applicable regulation;
p.(None): the investigator has all the documents and supplies needed to properly conduct the investigation;
p.(None): the study personnel carry out the specific functions assigned to each of them; the participants included in the study
p.(None): meet the eligibility criteria;
p.(None): the participants rate of recruitment is adequate;
p.(None): the source documents, CDF(s) and inventories of the investigational products are precise, complete, legible,
p.(None): consistent and timely; and that participants´ confidentiality is preserved;
p.(None): the investigator submits, in due time and manner, the reports and notifications required from him or her, including the
p.(None): AE, SAE and unexpected and serious ADR;
p.(None): that deviations from protocol, REC requirements or the applicable regulation, including changes in the use of
...
p.(None): The auditor´s findings shall be documented and reported to the sponsor.
p.(None): The sponsor shall ensure that audits on clinical studies and data management systems are performed in compliance with
p.(None): their SOP(s).
p.(None): The audit reports shall be provided to A.N.M.A.T., were it to request them or whenever there is evidence of serious
p.(None): non-compliance or throughout a legal procedure.
p.(None): SUSPENSION OR CANCELLATION OF THE STUDY
p.(None): A study may be suspended or cancelled by the investigator, the host institution, the sponsor, the REC or
p.(None): the agency. In such cases, the reason shall be justified and notified to the other stakeholders.
p.(None): The sponsor shall suspend the research in a center where serious or repeated protocol deviations having affected
p.(None): participants´ safety were detected and he or she shall inform such event to the agency.
p.(None): Participants shall be immediately informed about the study suspension or cancellation and shall be provided with
p.(None): medical care according to their needs. The sponsor shall provide an alternate treatment for the participants for as
p.(None): long as the REC decides.
p.(None): If the sponsor suspends or cancels the clinical development of an experimental drug, he or she shall notify of
p.(None): such decision and justify it to all the investigators, host institutions and A.N.M.A.T.
p.(None):
p.(None): SECTION D: INSPECTIONS OF CLINICAL PHARMACOLOGY STUDIES OBJECTIVE
p.(None): This section describes the procedures that should be followed in inspections of clinical pharmacology studies within
p.(None): A.N.M.A.T. competence, with a view to verifying the compliance of this Regulatory Guideline.
p.(None): SCOPE AND AUTHORITY
p.(None): Studies inspections are mainly aimed to investigators and research centers. However,
p.(None): A.N.M.A.T. may establish the need for performing inspections of other involved parties such as the sponsor and the
p.(None): contract research organizations (CRO).
p.(None): A.N.M.A.T. inspectors are empowered to enter the research center and have direct access to the
p.(None): investigational product, study filed documents and participants´ medical records. The inspections of clinical
p.(None): pharmacology studies may also include external institutions carrying out specific procedures of the study that
p.(None): were contracted by the investigator, sponsored party or CRO.
p.(None): INSPECTION PROCESS
p.(None): The inspection process comprises the study and inspector selection, the inspection planning and the
p.(None): inspection notification, conduct, reporting and result.
p.(None): Inspections may be performed prior to the study initiation, during its conduct or after its conclusion.
p.(None): SELECTION OF THE STUDY AND THE INVESTIGATOR
p.(None): The study selection criteria shall be as follows:
p.(None): inclusion of vulnerable population; priority for research initial phases;
p.(None): high risk investigational products studies;
p.(None): The investigator selection criteria shall be the following:
p.(None): a high recruitment rate as compared to other investigators of the study;
p.(None): a high or low incidence of serious and unexpected ADR as compared with the rest of the study investigators;
p.(None): the investigator´s background in previous studies;
p.(None): his or her participation in a significant number of studies;
...
p.(None): Official Action Indication (OAI): actions by A.N.M.A.T. are required.
p.(None): In the event an OAI is required, the director of the Drug Evaluation Office shall be empowered to take
p.(None): the following preventive measures:
p.(None): temporary suspension of the study recruitment at the center; temporary suspension of the study inspected at the center;
p.(None): restriction on the investigator to conduct new studies.
p.(None): In the cases under 12.3., the investigator shall commit him or herself in writing before the director of the DEO
p.(None): to implement the corrective actions indicated to him or her.
p.(None):
p.(None): After that, he or she will be allowed to re-initiate or initiate, as appropriate, the enrolment of up to
p.(None): three participants. A new inspection shall verify the compliance of the investigator´s committee and enable him or her
p.(None): to continue or not the recruit and/or the conduct of the study.
p.(None): In the event an OAI, the agency may adopt one or more of the following final measures, simultaneous or
p.(None): consecutively, after assessing the inspection technical report and the recommendation of the director of the DEO:
p.(None): final suspension of the study recruit at the center; final suspension of the study inspected at the center; suspension
p.(None): of all the studies conducted at the center;
p.(None): suspension at all the centers nationwide of the inspected study; indication to the sponsor of monitoring
p.(None): intensification at the center; indication to the sponsor of a change of investigator at the center; indication to the
p.(None): sponsor to reject all the data generated at the center;
p.(None): notification to the competent authority or professional association granting the investigator´s
p.(None): professional licensure, as well as to the sanitary authority of the jurisdiction and the REC that approved
p.(None): the study:
p.(None): administrative and/or legal sanction to the investigator, sponsor or CRO and prior initiation of the
p.(None): corresponding administrative inquest.
p.(None): Noncompliance of the Regulatory Guideline herein, may give raise to the initiation of an administrative inquest,
p.(None): without the need to require additional information from the inspected party.
p.(None):
p.(None): SECTION E: GLOSSARY
p.(None): AUDIT: a systematic and independent examination of the study related activities and documents to determine whether the
p.(None): activities evaluated were performed and the data were accurately recorded, analyzed and reported as per the
p.(None): protocol, SOP(s), GCP and A.N.M.A.T. Regulatory Guideline for GCP-CPS.
p.(None): AUTONOMY: a person´s self-determination capacity to make a decision voluntarily, as per only his or her own values,
p.(None): interests and preferences provided that he or she has the necessary information to assess all the options. By
p.(None): definition, an autonomous person is able to give his or her informed consent without needing any protection other
p.(None): than the assurance that all the necessary information is provided to him or her. In addition, those
...
p.(None): adverse event may be any unfavorable and unintended sign, including laboratory abnormal findings and
p.(None): symptoms or diseases temporally associated with the use of the investigational product, whether related or
p.(None): not with it.
p.(None): SERIOUS ADVERSE EVENT (SAE): any unfavorable occurrence throughout and within the research of a diagnostic or
p.(None): therapeutic product or procedure that results in death, is life-threatening, requires in-patient hospitalization
p.(None): or prolongation of the
p.(None):
p.(None): existent hospitalization, results in persistent or significant incapacity or disability or that is a congenital anomaly
p.(None): or a birth defect or that is medically significant as per medical criteria. The above mentioned is applicable
p.(None): without the need for an alleged causal relation existence between the product or treatment administered
p.(None): and the adverse event.
p.(None): CLINICAL DATA FORM (CDF): a printed, digital or optical document designed to keep record of all the clinical data
p.(None): required as per protocol, about each participant of the study and that shall be reported to the sponsor.
p.(None): CONTROL GROUP: a group used as a comparator that indicates what happens when the treatment under study is not applied.
p.(None): ACTIVE PHARMACEUTICAL INGREDIENT: a natural, biological or synthetic chemical substance having a specific
p.(None): pharmacological effect and that is used in human medicine.
p.(None): INSPECTION: an official review conducted by the competent authority of the documents, facilities,
p.(None): records and any resource considered as related to the clinical study and that may be located in the research
p.(None): center, sponsor´s or contract research organization (CRO) facilities or in other sites deemed appropriate.
p.(None): INSPECTOR: a person designated by the competent health and/or regulatory authority to conduct the study-related
p.(None): inspections.
p.(None): INSTITUTION OR RESEARCH CENTER: any government or privately owned agency or medical or dental facility where clinical
p.(None): studies are conducted.
p.(None): INVESTIGATOR: a professional responsible for conducting the clinical trial at the research center. If the
p.(None): trial is conducted by a team, the investigator is responsible for the team and is denominated the principal
p.(None): investigator. The principal investigator may delegate functions to his or her team, but not his or her
p.(None): responsibilities. The investigator-sponsor is the physical person initiating, managing financing and
p.(None): conducting, on his or her own or together with others, a clinical study, having under his or her responsibility the
p.(None): management, dispensation and use of the investigational product.
p.(None): INVESTIGATIONAL PRODUCT MONOGRAPH: (Synonym: Investigator´s brochure) a compilation of clinical and non-clinical data
p.(None): of drugs, investigational medical products or procedures relevant for their study in human beings.
p.(None): MONITORING: action of overseeing the process of a clinical study and ensuring that it is conducted, recorded and
p.(None): reported in accordance with the protocol, SPO(s), GCP and applicable regulatory requirements.
p.(None): CONTRACT RESEARCH ORGANIZATION (CRO): a physical person or legal entity contracted by the sponsor to perform
p.(None): one or more of his or her functions or activities related to the study.
p.(None): STUDY PARTICIPANT: a healthy or unhealthy individual participating in a clinical pharmacology study as a
p.(None): research subject.
p.(None): SPONSOR: a physical person or legal entity responsible for initiating, managing, controlling and financing a
p.(None): clinical study.
...
General/Other / Undue Influence
Searching for indicator undue influence:
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p.(None): Likewise, the inspectors may inspect the facilities of the research center or those of the external institutions where
p.(None): study-related procedures are performed.
p.(None): The handwritten or electronic notes taken by the inspectors during the inspection shall be filed in the inspection
p.(None): dossier at the agency and shall serve as a support for inspection report accuracy.
p.(None): The inspectors shall request and take copies of the study records or investigational product samples, if
p.(None): they deem it appropriate.
p.(None): The inspectors may interview the study participants, should they find it necessary. Such interviews shall be
p.(None): documented in records different from the inspection records. The interview records shall contain the
p.(None): participant´s identification, the interview objective, the questions made and the answers provided by
p.(None): the participants. The interview records shall be filed in the inspection dossier at the agency and the
p.(None): investigators shall access them upon previous justified request to and express authorization by the
p.(None): agency.
p.(None):
p.(None): The inspectors may interrupt the study and shall immediately communicate such decision to the DEO, if they
p.(None): were to identify serious deviations from the regulations or serious risks for the participants.
p.(None): RECORD REVIEW PROCEDURES
p.(None): The inspectors shall review the investigator´s essential documents under Section C of the Regulatory Guideline herein.
p.(None): The inspectors shall verify the recruit mechanisms in the medical record of each participant and the
p.(None): absence of duress and undue influence in the recruit.
p.(None): The inspectors shall verify the following in the informed consent process: that the consent obtainment process fulfills
p.(None): all the rules set forth herein; that the informed consent used was approved by the REC and A.N.M.A.T.;
p.(None): that all the informed consent forms were signed and dated by the participants or their legal representative and the
p.(None): investigator or authorized sub-investigator;
p.(None): that the empowerment to represent the participant is documented in the medical record, had the
p.(None): informed consent been obtained from the participant´s legal representative;
p.(None): that a written assent was obtained in the case of persons under age and within the lower age limit
p.(None): determined by the REC;
p.(None): that the informed consent was obtained by the investigator or sub-investigator authorized in the
p.(None): function delegation form; that the informed consent was obtained prior to evaluating the eligibility criteria or any
p.(None): other study specific procedure;
p.(None): that the consent obtainment is documented in the participant´s medical record, including the initiation date
p.(None): and time, that they were provided with time to reflect on and make questions, which the questions made were, that the
...
p.(None): INVESTIGATIONAL PRODUCT MONOGRAPH: (Synonym: Investigator´s brochure) a compilation of clinical and non-clinical data
p.(None): of drugs, investigational medical products or procedures relevant for their study in human beings.
p.(None): MONITORING: action of overseeing the process of a clinical study and ensuring that it is conducted, recorded and
p.(None): reported in accordance with the protocol, SPO(s), GCP and applicable regulatory requirements.
p.(None): CONTRACT RESEARCH ORGANIZATION (CRO): a physical person or legal entity contracted by the sponsor to perform
p.(None): one or more of his or her functions or activities related to the study.
p.(None): STUDY PARTICIPANT: a healthy or unhealthy individual participating in a clinical pharmacology study as a
p.(None): research subject.
p.(None): SPONSOR: a physical person or legal entity responsible for initiating, managing, controlling and financing a
p.(None): clinical study.
p.(None): PLACEBO: a pharmacologically inert substance used as a substitute of the investigational product
p.(None): with the aim of acting as a comparator in a clinical
p.(None):
p.(None): pharmacological study, as long as the ethical criteria of participant protection is respected.
p.(None): VULNERABLE POPULATION: an individual or a group of individuals whose wish to participate in a clinical
p.(None): trial may be unduly influenced by the justified or unjustified expectation of the benefits associated with his
p.(None): or her participation (undue influence) or by the threat by the investigators or any other unequal relation in case the
p.(None): individual refuses to participate (duress).
p.(None): COMPARATOR PRODUCT: a marketed or investigational product or a placebo used as a reference in a clinical study.
p.(None): INVESTIGATIONAL PRODUCT: a pharmaceutical form of an active substance under investigation, including products
p.(None): holding a marketing authorization when used or combined in the formulation in a form other than the authorized
p.(None): one or for the treatment of an unauthorized indication.
p.(None): PROTOCOL: a document describing the history, fundamentals, objectives, design, methodology ethical
p.(None): considerations, statistical aspects and organization of a study.
p.(None): ADVERSE DRUG REACTION (ADR): an untoward and unintended response to a medicinal product at any dose. In
p.(None): clinical experience and before the approval of a new medicinal product or of its new uses, particularly, when the
p.(None): therapeutic dose cannot be determined, any reaction implying causal relation between a medicinal product and an adverse
p.(None): event as a reasonable possibility, that is to say, that the relation may not be ruled out, must be considered an
p.(None): adverse drug reaction.
p.(None): UNEXPECTED AND SERIOUS ADVERSE DRUG REACTION (UNEXPECTED
p.(None): SADR): an adverse reaction that results in death, is life-threatening, requires in-patient hospitalization or
...
General/Other / participants in a control group
Searching for indicator controlXgroup:
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p.(None): MULTI-CENTER STUDY: a clinical study conducted according to only one protocol but in more than one place or
p.(None): institution and, therefore, conducted by more than one investigator.
p.(None): ADVERSE EVENT (AE): any adverse medical occurrence in a patient or subject of a clinical study of a health intended
p.(None): product or therapeutic procedure and which does not have a necessary causal relation with this treatment. An
p.(None): adverse event may be any unfavorable and unintended sign, including laboratory abnormal findings and
p.(None): symptoms or diseases temporally associated with the use of the investigational product, whether related or
p.(None): not with it.
p.(None): SERIOUS ADVERSE EVENT (SAE): any unfavorable occurrence throughout and within the research of a diagnostic or
p.(None): therapeutic product or procedure that results in death, is life-threatening, requires in-patient hospitalization
p.(None): or prolongation of the
p.(None):
p.(None): existent hospitalization, results in persistent or significant incapacity or disability or that is a congenital anomaly
p.(None): or a birth defect or that is medically significant as per medical criteria. The above mentioned is applicable
p.(None): without the need for an alleged causal relation existence between the product or treatment administered
p.(None): and the adverse event.
p.(None): CLINICAL DATA FORM (CDF): a printed, digital or optical document designed to keep record of all the clinical data
p.(None): required as per protocol, about each participant of the study and that shall be reported to the sponsor.
p.(None): CONTROL GROUP: a group used as a comparator that indicates what happens when the treatment under study is not applied.
p.(None): ACTIVE PHARMACEUTICAL INGREDIENT: a natural, biological or synthetic chemical substance having a specific
p.(None): pharmacological effect and that is used in human medicine.
p.(None): INSPECTION: an official review conducted by the competent authority of the documents, facilities,
p.(None): records and any resource considered as related to the clinical study and that may be located in the research
p.(None): center, sponsor´s or contract research organization (CRO) facilities or in other sites deemed appropriate.
p.(None): INSPECTOR: a person designated by the competent health and/or regulatory authority to conduct the study-related
p.(None): inspections.
p.(None): INSTITUTION OR RESEARCH CENTER: any government or privately owned agency or medical or dental facility where clinical
p.(None): studies are conducted.
p.(None): INVESTIGATOR: a professional responsible for conducting the clinical trial at the research center. If the
p.(None): trial is conducted by a team, the investigator is responsible for the team and is denominated the principal
p.(None): investigator. The principal investigator may delegate functions to his or her team, but not his or her
p.(None): responsibilities. The investigator-sponsor is the physical person initiating, managing financing and
p.(None): conducting, on his or her own or together with others, a clinical study, having under his or her responsibility the
p.(None): management, dispensation and use of the investigational product.
...
Searching for indicator placebo:
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p.(None): criteria for processing safety information; interim analysis schedule, if appropriate.
p.(None): Efficacy evaluation
p.(None): efficacy parameters to be assessed, including measurement instruments and methods; efficacy criteria.
p.(None): Investigational products
p.(None): a description of the investigational products indicating API, formulation, dose, route of administration and treatment
p.(None): and follow-up frequency and duration;
p.(None): In the case of biological products trials, a detail of the identification and assessment methodology ensuring
p.(None): the preparation uniformity or the consistency of the lots under study;
p.(None): allowed and un-allowed drugs; criteria for treatment discontinuation;
p.(None): foreseen rescue treatment and follow up in case of failure or adverse events.
p.(None): Adverse events
p.(None): adverse events recording and reporting procedures; emergency blind breaking procedure, if appropriate;
p.(None): Ethical aspect
p.(None): specific mention that the investigation shall be reviewed by a REC; informed consent obtainment procedures;
p.(None): protection of participants´ information and identity confidentially; details of participants´ coverage and compensation
p.(None): for injuries;
p.(None): justification for available payments or compensation for expenses for participants;
p.(None): access for participants to the intervention identified as beneficial in the trial or to an appropriate
p.(None): alternative or benefit upon completion of the trial;
p.(None): justification for using a placebo, if appropriate
p.(None): justification for conducting the research in a vulnerable group, if appropriate; possible conflicts of interest.
p.(None): Administrative and other aspects
p.(None):
p.(None): investigational products maintenance and storage procedures; clinical data record keeping and reports;
p.(None): trial documents handling; monitoring and audit procedures; criteria for trial discontinuation; results publication
p.(None): plan.
p.(None): INFORMED CONSENT
p.(None): The information document used to obtain the consent of a potential participant or of his or her legal representative,
p.(None): pursuant to legal provisions, shall include the following:
p.(None): research title, objective or purpose;
p.(None): sponsor´s data in the country: name or denomination and company name and address; approximate number of participants
p.(None): intended for the study;
p.(None): study experimental aspects;
p.(None): study treatments, assignment method and probability for each treatment;
p.(None): all the procedures to which the participant shall be submitted, the visits schedule they are expected to fulfill and
p.(None): their envisaged participation duration;
p.(None): a statement that all the investigational products and procedures will be free-of-charge for the participants;
p.(None): the reasonably expected benefits from participants´ involvement in the study. A clear remark must be made if the
p.(None): participant is not intended to obtain any clinical benefit from the study;
p.(None): the risks and discomforts foreseen for the participants and; in case of pregnancy and breastfeeding, for the embryo,
...
p.(None): submitted with the protocol and/or informed consent amendment.
p.(None): Should there be informed consent versions specific for a research center the different versions highlighting the
p.(None): changes shall be submitted.
p.(None): Investigational product monograph update
p.(None): The investigational product monograph shall be updated whenever new results of the investigational product study are
p.(None): obtained.
p.(None): The new version of the investigational product monograph shall be submitted to
p.(None): A.N.M.A.T. as soon as available. One updated investigational product monograph for all the studies of the same product
p.(None): shall be accepted.
p.(None): The following shall be submitted with the investigational product monograph new version:
p.(None): an EFCA4 form (Section F) completed and signed by the sponsor´s legal representative;
p.(None): a summary of the changes made and the relevance of the new information regarding the risks and benefits expected from
p.(None): the study.
p.(None): SERIOUS AND UNEXPECTED ADVERSE DRUG REACTIONS
p.(None): The sponsor shall inform A.N.M.A.T. of any serious and unexpected adverse drug reaction concerning the
p.(None): investigational product within a ten working-day period after the moment he or she learnt about it. The serious and
p.(None): unexpected adverse drug reactions produced by a comparator product already registered at A.N.M.A.T. to be
p.(None): marketed nationwide or those related to a placebo shall be reported only to A.N.M.A.T. Pharmacovigilance
p.(None): System.
p.(None): In blinded studies, whenever the sponsor receives a report of a serious adverse event (SAE), he or she shall verify the
p.(None): treatment provided to the participant in order to find out whether it is the case of an unexpected and serious adverse
p.(None): drug reaction (ADR) as defined in 7.1., but he or she shall not unmask the treatment to the investigator or persons in
p.(None): charge of the data analysis and discussion.
p.(None): The unexpected and serious ADR report shall include the following information: the denomination of the adverse
p.(None): reaction;
p.(None): investigational product code, INN and trade mark;
p.(None): type of report: baseline, update (update number) or final; sponsor´s name;
p.(None): the research center and investigator´s name;
p.(None):
p.(None): A.N.M.A.T. regulation authorizing the study conduct; the name or title of the study;
p.(None): participant´s code, age and sex;
p.(None): the date of the unexpected and serious ADR appearance, the date of investigator´s report and the date the
p.(None): sponsor received it;
p.(None): unexpected and serious ADR seriousness criteria; unexpected and serious ADR brief description;
p.(None): investigational product information: daily dose, route of administration, start and suspension date, therapy
p.(None): duration and indication;
p.(None): inform if the reaction disappeared after treatment suspension; inform if the reaction reappeared with treatment
p.(None): re-introduction; concomitant drugs: dosage form and start and termination date; participant´s history significant for
p.(None): the unexpected and serious ADR.
...
p.(None): about the need to immediately inform the investigator should they suspect of being pregnant at any time of the
p.(None): study;
p.(None): the investigator shall run a pregnancy test prior to the admission to the study of every women of fertile age; and then
p.(None): regularly throughout the study;
p.(None): a positive result pregnancy test shall imply the exclusion of the prospective participant or the preventive
p.(None): discontinuation of the investigational product administration, if appropriate. In case of pregnancy, the
p.(None): investigator shall guide the participant in obtaining proper care;
p.(None): the sponsor and the investigator shall ensure the access to the necessary contraceptive methods
p.(None): for all the study participants.
p.(None): An investigator who is a doctor of medicine or a dentist, as appropriate, shall be responsible for all
p.(None): the participants´ health care related decisions throughout the study.
p.(None): Should the study put at risk the integrity or health of the participants, for example, due to an adverse reaction
p.(None): or a therapeutic failure, the investigator shall take all the precautions to halt the exposure to the risk.
p.(None): The use of a placebo control shall be properly justified both from the methodological and ethical points of view. The
p.(None): use of a placebo in terminal diseases shall be accepted in case of inefficacy of all the existing treatments.
p.(None): The investigator and the sponsor shall ensure that the participant will receive proper medical care in case of
p.(None): injury related to the investigation. In the case of diagnose of an inter-current disease caused by a research
p.(None): related procedure, the investigator shall guide the participant in obtaining the necessary health care.
p.(None): Participants requiring to continue their treatment after the study completion shall have access to the intervention
p.(None): that turned out to be beneficial or to an alternative intervention or another proper benefit, which shall be
p.(None): approved by the REC for the time it decides or until such access is ensured by any other means.
p.(None): AGREEMENTS AND FINANCING
p.(None): The sponsor is responsible for affording all the research costs, including study treatments and procedures.
p.(None): In clinical studies with a therapeutic benefit, the sponsor may make payments to the participants for any
p.(None): inconveniences and their time. However, such payments may not become an undue influence by
p.(None): being disproportionate in such a way that the patient is persuaded to run unnecessary risks. Payments shall be
p.(None): apportioned according to the study characteristics.
p.(None): The sponsor shall ensure medical care and an insurance coverage or the setting up of any other form of guarantee in
p.(None): the country, in case of injury to participants resulting from the study.
p.(None):
...
p.(None): inspections.
p.(None): INSTITUTION OR RESEARCH CENTER: any government or privately owned agency or medical or dental facility where clinical
p.(None): studies are conducted.
p.(None): INVESTIGATOR: a professional responsible for conducting the clinical trial at the research center. If the
p.(None): trial is conducted by a team, the investigator is responsible for the team and is denominated the principal
p.(None): investigator. The principal investigator may delegate functions to his or her team, but not his or her
p.(None): responsibilities. The investigator-sponsor is the physical person initiating, managing financing and
p.(None): conducting, on his or her own or together with others, a clinical study, having under his or her responsibility the
p.(None): management, dispensation and use of the investigational product.
p.(None): INVESTIGATIONAL PRODUCT MONOGRAPH: (Synonym: Investigator´s brochure) a compilation of clinical and non-clinical data
p.(None): of drugs, investigational medical products or procedures relevant for their study in human beings.
p.(None): MONITORING: action of overseeing the process of a clinical study and ensuring that it is conducted, recorded and
p.(None): reported in accordance with the protocol, SPO(s), GCP and applicable regulatory requirements.
p.(None): CONTRACT RESEARCH ORGANIZATION (CRO): a physical person or legal entity contracted by the sponsor to perform
p.(None): one or more of his or her functions or activities related to the study.
p.(None): STUDY PARTICIPANT: a healthy or unhealthy individual participating in a clinical pharmacology study as a
p.(None): research subject.
p.(None): SPONSOR: a physical person or legal entity responsible for initiating, managing, controlling and financing a
p.(None): clinical study.
p.(None): PLACEBO: a pharmacologically inert substance used as a substitute of the investigational product
p.(None): with the aim of acting as a comparator in a clinical
p.(None):
p.(None): pharmacological study, as long as the ethical criteria of participant protection is respected.
p.(None): VULNERABLE POPULATION: an individual or a group of individuals whose wish to participate in a clinical
p.(None): trial may be unduly influenced by the justified or unjustified expectation of the benefits associated with his
p.(None): or her participation (undue influence) or by the threat by the investigators or any other unequal relation in case the
p.(None): individual refuses to participate (duress).
p.(None): COMPARATOR PRODUCT: a marketed or investigational product or a placebo used as a reference in a clinical study.
p.(None): INVESTIGATIONAL PRODUCT: a pharmaceutical form of an active substance under investigation, including products
p.(None): holding a marketing authorization when used or combined in the formulation in a form other than the authorized
p.(None): one or for the treatment of an unauthorized indication.
p.(None): PROTOCOL: a document describing the history, fundamentals, objectives, design, methodology ethical
p.(None): considerations, statistical aspects and organization of a study.
p.(None): ADVERSE DRUG REACTION (ADR): an untoward and unintended response to a medicinal product at any dose. In
p.(None): clinical experience and before the approval of a new medicinal product or of its new uses, particularly, when the
p.(None): therapeutic dose cannot be determined, any reaction implying causal relation between a medicinal product and an adverse
p.(None): event as a reasonable possibility, that is to say, that the relation may not be ruled out, must be considered an
p.(None): adverse drug reaction.
p.(None): UNEXPECTED AND SERIOUS ADVERSE DRUG REACTION (UNEXPECTED
p.(None): SADR): an adverse reaction that results in death, is life-threatening, requires in-patient hospitalization or
p.(None): prolongation of the existent hospitalization, results in persistent or significant incapacity or disability
p.(None): and whose nature of seriousness is not consistent with the product information written in the
p.(None): investigational product monograph or any other documentation.
...
Orphaned Trigger Words
p.(None): The investigator shall report the study progress to the REC at least once a year. The progress report shall contain,
p.(None): at least, the number of enrolled, followed up and withdrawn participants, the encoded list of
p.(None): participants, serious adverse events and their alleged relation with the investigational product as well as the
p.(None): participants´ safety related relevant deviations from the protocol observed throughout the period.
p.(None): The sponsor shall notify of all the unexpected and serious ADR related to an investigational product to
p.(None): all the investigators of all the ongoing studies of the product within a fourteen-day period after learning about
p.(None): them. The investigators shall report said unexpected and serious ADR to the REC within the period it sets forth for
p.(None): such purpose.
p.(None): The sponsor shall be responsible for timely submitting the study reports and for reporting to the agency
p.(None): the unexpected and serious ADR and any other safety related
p.(None):
p.(None): information of an investigational product, within a ten-working-day period after having learnt about them.
p.(None): CHANGES DURING THE STUDY
p.(None): The changes made to an approved protocol shall be justified according to their potential impact on the
p.(None): participants and the study scientific validity. Said changes require approval by the REC and the agency prior to
p.(None): their implementation unless they were performed to preserve participants´ safety.
p.(None): The study participants or their representatives shall be informed about the changes affecting their safety
p.(None): or that may modify their decision to continue in the study and shall give their signed and dated consent prior to the
p.(None): implementation of such changes.
p.(None): Administrative amendments shall be notified to the REC and the agency, in the subsequent progress report
p.(None): and to the study participants, when appropriate; but shall not require an approval or written consent.
p.(None): CLINICAL DATA RECORD-KEEPING
p.(None): The sponsor shall set out the proper procedures for obtaining and recording participants´
p.(None): clinical data, including the encoding system that will enable to preserve their identity confidentiality.
p.(None): The investigator shall be responsible for the reliability, legibility, consistency and opportuneness of
p.(None): clinical data records both in medical records (source documents) and clinical data forms (CDF).
p.(None): Both participants´ clinical data and the description of procedures related to them, for example, the obtainment
p.(None): of the informed consent, pre-study evaluation, inclusion in the study, randomized assignment result, instructions for
p.(None): using the investigational product, treatment initiation and termination, control of product delivery and return, as
p.(None): well as the information provided to the participant, shall be documented in the same format as are the medical notes
p.(None): used for the rest of the patients receiving medical care at the center.
p.(None): The investigator shall be responsible for preserving the confidentiality of every participant´s
p.(None): identity. No data of the participant´s identity shall be contained in any document transmitted, reported or
p.(None): taken away from the host institution.
p.(None): The changes or corrections of any of the study records shall not conceal or delete the original datum. Corrections
p.(None): shall be dated and signed with their author´s initials.
p.(None): In case of using electronic direct data transmission automated devices to perform study-related exams such
p.(None): as an electrocardiogram and a spirometry, an identifiable printed source document of the process shall
...
p.(None): a proof of approval by the REC of the study indicating the approved documents: protocol and which
p.(None): version, informed consent and which version, recruitment advertisements and others;
p.(None): a dated list of the REC members and positions;
p.(None): the Regulation or note whereby A.N.M.A.T. authorizes the study and research center;
p.(None): the notes whereby the agency authorizes the protocol or informed consent amendments;
p.(None): the proof whereby the agency was informed about the recruitment advertisements; an investigator´s function delegation
p.(None): form to his or her team members;
p.(None): the investigator´s and his or her team´s curricula vitae;
p.(None):
p.(None): a proof of the investigator´s and his or her team training on the study; a list of the normal laboratory values to be
p.(None): used in the study;
p.(None): a copy of the laboratory quality accreditations and/or study findings quality control certificates;
p.(None): a curriculum vitae of the person responsible for the laboratory; the instructions for obtaining and sending samples, if
p.(None): appropriate;
p.(None): the instructions for handling and storing the investigational product, if not included in the protocol;
p.(None): the instructions for blind handling and blind breaking procedures, if not included in the protocol;
p.(None): a center monitoring plan;
p.(None): a baseline monitoring visit report;
p.(None): Essential documents required during the study
p.(None): The following documents shall be available during the study:
p.(None): the current investigational product monograph, had it been updated; amendments to the protocol approved by the REC and
p.(None): the agency, if any;
p.(None): amendments to the informed consent approved by the REC and the agency, if any; new clinical data forms, had there been
p.(None): any changes;
p.(None): new recruitment advertisements approved by the REC and the agency, if any; the REC approval notes of protocol
p.(None): amendments, if any;
p.(None): the REC approval notes of informed consent amendments, if any; the REC approval notes of new recruitment
p.(None): advertisements, if any; the REC approval notes of other documents, if appropriate;
p.(None): the agency approval notes of protocol amendments, if any;
p.(None): the agency approval notes of informed consent amendments, if any;
p.(None): the proof whereby the agency was informed about the recruitment advertisements, if any;
p.(None): the research team new members´ curricula vitae, if appropriate; research team new members´ commitment letter, if
p.(None): appropriate;
p.(None): an updated list of functions delegation, had there been any changes; updated laboratory values, had there been any
p.(None): changes;
p.(None): a copy of updated laboratory accreditation and/or its quality control certificate; updated instructions for obtaining
p.(None): and sending samples, had there been any changes; a proof of the calibration of parameter measuring instruments of the
p.(None): study;
p.(None): the notifications to the sponsor of SAEs;
p.(None): the notifications to the REC about the SAEs occurred in the center;
p.(None):
p.(None): the notifications to the REC about the unexpected and serious ADR occurred in the centers;
p.(None): the notifications to the REC about the unexpected and serious ADR occurred in other centers;
p.(None): other safety notifications;
p.(None): the progress reports submitted to the REC and A.N.M.A.T. a list of prospective, included and withdrawn participants; a
p.(None): chronologic participant enrolment list;
p.(None): a participants´ identification list;
p.(None): proofs of reception of the investigational product and a proof of its return to the sponsor;
p.(None): investigational product accountability forms;
p.(None): investigational product storage temperature control records; monitoring visit forms;
p.(None): monitor´s reports or notes;
p.(None): other relevant notifications to and from the REC, the sponsor and the agency; signed informed consents;
p.(None): source documents such as medical records, laboratory and pharmacy records, participants´ diaries,
p.(None): imaging and technical reports, electrocardiograms, etc.
...
Appendix
Indicator List
| Indicator | Vulnerability |
|---|
| access | Access to Social Goods |
| age | Age |
| authority | Relationship to Authority |
| autonomy | Impaired Autonomy |
| children | Child |
| controlXgroup | participants in a control group |
| dependent | Dependent |
| diminished | Diminished Autonomy |
| disability | Mentally Disabled |
| drug | Drug Usage |
| economic | Economic/Poverty |
| education | Educational |
| educational | Educational |
| embryo | embryo |
| emergency | Public Emergency |
| ethnic | Ethnicity |
| fetus | Fetus/Neonate |
| hazard | Natural Hazards |
| health | Health |
| homeless | Homeless Persons |
| ill | Physically Ill |
| illiterate | illiterate |
| impaired | Cognitive Impairment |
| incapable | Mentally Incapacitated |
| incapacity | Incapacitated |
| infant | Infant |
| influence | Drug Usage |
| language | Linguistic Proficiency |
| mentally | Mentally Disabled |
| minor | Youth/Minors |
| nation | stateless persons |
| occupation | Occupation |
| opinion | philosophical differences/differences of opinion |
| other country | Other Country |
| party | Political |
| placebo | participants in a control group |
| pregnant | Pregnant |
| restricted | Incarcerated |
| single | Marital Status |
| social | Social |
| substance | Drug Usage |
| terminal | Terminally Ill |
| threat | Threat of Stigma |
| undue influence | Undue Influence |
| usage | Drug Usage |
| volunteers | volunteers |
| women | Women |
Indicator Peers (Indicators in Same Vulnerability)
| Indicator | Peers |
|---|
| controlXgroup | ['placebo'] |
| disability | ['mentally'] |
| drug | ['influence', 'substance', 'usage'] |
| education | ['educational'] |
| educational | ['education'] |
| influence | ['drug', 'substance', 'usage'] |
| mentally | ['disability'] |
| placebo | ['controlXgroup'] |
| substance | ['influence', 'drug', 'usage'] |
| usage | ['influence', 'drug', 'substance'] |
Trigger Words
capacity
consent
cultural
ethics
justice
protect
protection
risk
self-determination
volunteer
vulnerability
vulnerable
Applicable Type / Vulnerability / Indicator Overlay for this Input