DECISION OF COUNCIL OF THE EURASIAN ECONOMIC COMMISSION

of November 3, 2016 No. 79

About approval of Rules of proper clinical practice of the Eurasian Economic Union

According to article 30 of the Agreement on the Eurasian Economic Union of May 29, 2014, article 6 of the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union of December 23, 2014, Item 83 of appendix No. 1 to the Regulations of work of the Eurasian economic commission approved by the Decision of the Supreme Eurasian economic council of December 23, 2014 No. 98, and the Decision of the Supreme Eurasian economic council of December 23, 2014 "About implementation of the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union" Council of the Eurasian economic commission solved No. 108:

1. Approve the enclosed Rules of proper clinical practice of the Eurasian Economic Union.

2. This Decision becomes effective after 10 calendar days from the effective date of the Protocol signed on December 2, 2015 on accession of the Republic of Armenia to the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union of December 23, 2014, but not earlier than after 10 calendar days from the date of official publication of this Decision.

Members of council of the Eurasian economic commission: From the Republic of Armenia

V. Gabriyelyan

From the Republic of Belarus

V. Matyushevsky

From the Republic of Kazakhstan

A. Mamin

From the Kyrgyz Republic

O. Pankratov

From the Russian Federation

I. Shuvalov

Approved by the Decision of Council of the Eurasian economic commission of November 3, 2016 No. 79

Rules of proper clinical practice of the Eurasian Economic Union

I. General provisions

These rules represent the international ethical and scientific standard of planning and carrying out researches with participation of the person as the subject of researches, and also documentary registration and representation of results of such researches.

Observance of provisions of these rules serves as guarantee that the rights, safety and wellbeing of subjects of research are protected for society, accord with the principles underlain by the Helsinki declaration adopted at the XVII session of the World association of health care in 1964 and that these researches are reliable.

The purpose of these rules is establishment of single procedure for conduct of clinical trials (testing) (further – researches) medicines that shall promote ensuring functioning of the total market of medicines within the Eurasian Economic Union (further – the Union), to mutual recognition of these clinical trials (testing) of state members of the Union by authorized bodies (further – state members), and also to recognition of clinical trials (testing) executed in the territory of the Union and beyond its limits.

The numbering used in the text the Section II of these rules corresponds to the numbering applied in the international edition of proper clinical practice (Good Clinical Practice; GCP), regarding all subsections, except for subsection 1, in which concepts are located in alphabetical order.

These rules are prepared on the basis of ICH GCP – the Management on proper clinical practice (Guideline for Good Clinical Practice) which is the document E6 (R 1) of version 4 of the International conference on harmonization of technical requirements to registration of the pharmaceutical products intended for use by the person (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use; ICH).

These rules need to be followed when performing any clinical trials (testing) data of which are represented to authorized bodies of state members.

The principles established by these rules are applicable as well to other researches which can exert impact on safety and wellbeing of the person acting as the subject of research.

These rules are subject to revision on regular basis taking into account experience of their use in state members, and also in case of change of the international standards of carrying out researches (with introduction of necessary changes).

II. Main part

1. Determinations

For the purposes of these rules concepts which mean the following are used:

"audit" (audit) – systematic and independent check belonging to research of activities and documentation, carried out for confirmation of conformity of these activities, and also procedures of collection, the analysis and data presentation to the protocol, standard operational procedures of the sponsor ought to clinical practice and applicable requirements;

"wellbeing of subjects of research (patients)" (well-being (of the trial subjects (patients))) – physical and mental health of the subjects participating in research;

"the brochure of the researcher" (investigator "s brochure) – summary statement of the clinical and preclinical data on the researched medicine relating to its research at the person;

"design of research" (study design) – the general plan of research, the description of method of carrying out research depending on selection and forming of groups of subjects of research, masking of data;

"agreement" (contract) – the dated and signed agreement between two or more parties which establishes the arrangements concerning distribution of amount of works and obligations when carrying out research, and also, if necessary, financial questions. The protocol of research shall form basis of the agreement;

"preclinical trials" (nonclinical study)" – the biomedical researches conducted without participation of the person as the subject researches;

"documentary trace" (audit trail) – documentation allowing to recover the course of events;

"documentation" (documentation) – all records in any form (including records on paper, electronic, magnetic or optical media, skanogramma, x-ray films, electrocardiograms, etc.) which describe or register methods, the organization and (or) results of research, and also factors influencing research and the taken measures;

"the conclusion of independent ethical committee (council on ethics, the commission on questions of ethics)" (opinion (in relation to Independent Ethics Committee (Ethical Council))) – the document in writing which contains the conclusion and (or) recommendations of independent ethical committee concerning participation of the person in research;

"legal representative" (legally acceptable representative)" – physical person or legal entity or other person of law which, according to the legislation of state member which research centers are involved in research are given the right of making the informed consent on behalf of the subject of the research which is incapacitated or minor;

"identification code of the subject" (subject identification code) – the unique code assigned by the researcher for each subject of research for ensuring confidentiality of its personal data and used instead of name of the subject of research in reports on the undesirable phenomena and (or) other data relating to research;

"the individual registration card, IRK" (Case Report Form; CRF)" – the document on the paper, electronic or optical medium intended for introduction all to the transfer to the sponsor of information on each subject of research provided by the protocol and subject;

"inspection (check)" (inspection) – the action of authorized body consisting in conducting official check of documents, infrastructures, records, agreements on quality assurance and any other sources which are regarded by authorized body as belonging to research and which can be located in the research center, on objects of the sponsor and (or) the contractual research organization or in other organizations which, according to authorized body, require inspection;

"informed consent" (informed consent) – free and voluntary declaration of will of the subject about the desire to participate in specific research after receipt of data on all aspects of this research, significant for decision making by the subject about participation, and in case with minor and incapacitated subjects – permission or the consent of their legal representatives on inclusion of such subjects in research. The informed consent is documented by means of signing and dating of form of the informed consent;

"researcher" (investigator) – the physical person who is responsible for carrying out research in the research center. In case of carrying out research in the research center group of persons by the researcher (the chief researcher) is the head of group;

"researcher-coordinator" (coordinating investigator) – the researcher who is responsible for coordination of activities of researchers of all research centers participating in multicenter clinical trial;

"the researcher (medical institution)" (investigator (institution))" – the researcher and (or) the organization (depending on use of concept);

"the research center" (trial site) – the actual venue of research;

"the researched medicine" (investigational medicinal product) – medicine which in research is subjected to test or is applied to comparison including placebo, including the registered medicine (if its route of administration differs from approved, and also in case of its use according to the new indication or for more information according to the approved indication);

"clinical trial (testing)" (clinical trial) – the clinical studying satisfying at least to one of the following conditions: appointment to the subject of research of specific therapeutic strategy (intervention) happens in advance and is not routine clinical practice in state member which research centers take part in this clinical trial; the decision on purpose of the researched medicine is made together with the decision on inclusion of the subject in clinical studying; to subjects of research, in addition to procedures of routine clinical practice, supplementary procedures of diagnosis or monitoring are performed;

"the contractual research organization" (contract research organization; CRO) – physical person or the organization (commercial, research or other) which within the contract with the sponsor carries out one or more of its obligations and functions connected with conduct of clinical trial;

"quality control" (quality control; QC)" – the methods and measures which are part of system of quality assurance and used for check of compliance of the procedures performed when carrying out research to qualifying standards to their quality;

"coordinating committee" (coordinating committee) – committee which can be organized by the sponsor for coordination of performing multicenter clinical trial;

"confidentiality" (confidentiality) – preserving unknown to unauthorized persons of information belonging to the sponsor or information allowing to identify the subject of research;

"multicenter clinical trial" (multicentre trial) – the clinical trial conducted under the single protocol more than in 1 research center and, more than 1 researcher;

"monitor" (monitor) – the physical person designated by the sponsor or the contractual research organization which works together with the researcher-coordinator or coordinating committee and controls conduct of clinical trial according to the protocol, estimates extent of its accomplishment, renders assistance to the researcher in the analysis, interpretation and extrapolation of data;

"monitoring" (monitoring) – the activities consisting in control of the course of clinical trial, ensuring its carrying out, data collection and representation of results according to the protocol, standard operational procedures, proper clinical practice and applicable requirements;

"proper clinical practice" (Good Clinical Practice; GCP) – the code of ethical and scientific requirements to planning, carrying out, realization, monitoring, audit, documentation, the analysis and representation of results of the clinical trials providing protection of the rights, safety and wellbeing of subjects of research and obtaining within clinical trial of reliable and reliable data;

"undesirable reaction" (adverse reaction) – the inadvertent adverse reaction of organism connected using medicine (the researched drug), assuming availability, at least, of possible interrelation using the suspected medicine (the researched drug);

"the undesirable phenomenon" (adverse event) – any adverse change in the state of health of the patient or the subject of research to which medicine, irrespective of cause and effect relationship with its use is administered. The undesirable phenomenon can represent any adverse and inadvertent change (for example, variation of laboratory indicator from regulation), symptom or disease which time of origin does not exclude cause and effect relationship using medicine, regardless of availability or lack of interrelation using medicine;

"independent committee on monitoring of data, NKMD" (Independent Data-Monitoring Committee; IDMC (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee)) – independent committee which can be formed at the initiative of the sponsor for periodic consideration of the course of clinical trial, this on safety and (or) key parameters of efficiency, and also for development of recommendations to the sponsor about feasibility of continuation, termination of research or entering of changes into it;

"independent ethical committee, NEK" (Independent Ethics Committee; IEC) – independent body (the advisory council or committee operating at the level of the organization at regional, national or international level) which is founded according to the legislation of state member, consists of health workers, and also is given to persons which do not have relations to medicine the right to draw the conclusions for the purpose of implementation of these rules (in view of views of nonspecialists, in particular patients and the organizations of patients), and also ensures protection of the rights, safety and wellbeing of subjects of research and acts for society as the guarantor of such protection, in particular by consideration, approval (issue of the conclusion) of the protocol of research, candidates of researchers, the research centers, and also materials and methods which are supposed to be used for obtaining and documentation of the informed consent of subjects of research. Legal status, structure, functions and activities of independent ethical

committees, and also requirements, applicable to them, can differ in different state members, nevertheless, NEK shall function according to these rules;

"the uninterested witness" (impartial witness) is physical person which is not privy to conduct of clinical trial upon which participants of clinical trial cannot put pressure and which if the subject of research or its legal representative are not able or cannot read, is present during receipt of the informed consent, and also reads the text of the informed consent and any other researches provided to the subject written materials;

"unexpected undesirable reaction" (unexpected adverse drug reaction) – undesirable reaction, nature, severity or outcome of which does not correspond to information containing in general characteristic of medicine or in the brochure of the researcher (for the unregistered medicine);

"quality assurance" (quality assurance; QA) – set of systematic and systematic actions which aim to provide compliance of the conducted research, collection, registration and data presentation to proper clinical practice and applicable requirements;

"approval of advisory council of the organization" (approval (in relation to Institutional Review Boards))" – the conclusion accepted by the Advisory Council of the Organization (ACO), confirming the fact of conducting examination of clinical trial and which is permission to its carrying out in this organization according to instructions of ESO, regulating documents of the medical organization, and also proper clinical practice and applicable requirements;

"the medical organization" (institution (medical)) – organization (organization) of health care regardless of its form of business in which clinical trial is conducted and which has permission (license) for medical activities and also has rights to conduct of clinical trials;

"the main documents" (essential documents)" – documents which in total or separately allow to estimate the course of clinical trial and quality of the obtained data;

"the report of the monitor" (monitoring report) – the written report of the monitor to the sponsor after each visit to the research center and (or) contact with researchers according to the standard operational procedures (SOP) of the sponsor;

"the report on audit" (audit report) – the written conclusion of the auditor of the sponsor about results of audit;

"the report on clinical trial (testing)" (clinical trial (study report)) – the description in writing clinical trial provided in the format allowing to perform easy search, constituted according to appendix No. 1 to these rules and the Section 5 of part 1 of appendix No. 1 to Rules of registration and examination of medicines for medical application approved Eurasian economic the commissions in case of support of the registration application;

"primary documentation" (original medical records) (original medical record (source documents)) – initial documents, data and records (for example, case histories, out-patient cards, laboratory records, notes, diaries of subjects of research, questionnaires, magazines of issue of medicines, the records of automatic devices verified and the verified copies or statements, microfiches, photonegatives, microfilms or magnetic carriers, x-ray films, any records which are relating to the patient, including stored in the drugstore, laboratories and departments of tool diagnosis used in clinical trial);

"primary data" (source data) – all information containing in original medical records and their verified copies, on results of clinical observations, inspections and other activities, allowing to recreate the course of clinical trial and to estimate it. Primary data contain in primary documentation (originals or their verified copies);

"the amendment to the protocol" (protocol amendment) – the description of changes which is drawn up in writing, or the message on the made changes or official explanation of the protocol;

"comparison drug" (comparator (product)) – the researched or registered medicine (active control) or placebos used for control in clinical trial;

"applicable requirements" (applicable regulatory requirement(s)) – the acts constituting the right of the Union, and the legislation of state members in the field of drug circulation regulating conduct of clinical trials;

"the interim statement on clinical trial (testing)" (interim clinical trial (study report)) – the report on intermediate results and their assessment based on the data analysis which is carried out during clinical trial;

"the protocol of clinical trial" (protocol) – the document describing the purposes, design, methodology, statistical techniques and the organization of research. In addition, the protocol of clinical trial usually contains the data obtained earlier and reasons for research, however this information can be provided also in other documents to which the protocol of clinical trial refers. In relation to these rules the term "protocol" implies as all subsequent versions of the protocol of clinical trial, and the amendment to it;

"direct access" (direct access) – the permission issued by management of the research center, to interested persons on studying, the analysis, check and copying of any records and reports necessary for assessment of clinical trial. Persons having the right of direct access (for example, representatives of national or foreign authorized bodies, monitors and the sponsor's auditors), shall take all reasonable measures for observance of applicable requirements for protection of confidentiality of information allowing to identify subjects of research, and information belonging to the sponsor;

"randomization" (randomization) – the process of distribution of subjects of research on groups of treatment or control in a random way allowing to minimize subjectivity;

"routine clinical practice" (routine clinical practice) – sample (same) medical diagnostic and medical procedures, technologies or actions which are performed for this group of patients or this standard of delivery of health care;

"the certificate of audit" (audit certificate) – the document constituted by the auditor in confirmation of the fact of carrying out audit;

"serious undesirable phenomenon (SUP), serious undesirable reaction (SUR)" (serious adverse event; SAE or serious adverse drug reaction; serious ADR) – undesirable medical event which leads to death poses threat for life, requires hospitalization of the patient or its prolongation, results in the resistant or expressed disability or disability, to congenital anomalies or malformations, requires medical intervention for prevention of development of the listed conditions;

"blind method (masking)" (blinding (masking)) – method in case of which use to one or several parties participating in clinical trial is unknown what treatment is appointed to the subject of research. The simple blind method provides lack of information on the type of treatment of subjects of research appointed by it while the double blind method implies lack of information of subjects of research, researchers, monitors and in certain cases persons which are carrying out statistical data processing;

"observance of requirements (in relation to clinical trials)" (compliance (in relation to trials)) – compliance to all requirements connected with clinical trial, to proper clinical practice and other applicable requirements;

"soissledovatel (subinvestigator)" – any member of research collective appointed the researcher and performing under its control significant procedures of clinical trial in the research center (for example, the intern, the intern, the research associate);

"sponsor" (sponsor) – the physical person or legal entity which is responsible for initiation, the organization and ensuring financing of clinical trial;

"sponsor researcher" (sponsor-investigator) – person who independently or together with other persons initiates and conducts clinical trial and under whose direct management the researched drug either is appointed or is issued to the subject of research, or the last accepts it. Only the physical person can be the sponsor researcher. Obligations of the sponsor researcher include obligations of both the sponsor, and the researcher;

"standard operational procedures, SOP" (standard operating procedures; SOPs) – the detailed written instructions intended for achievement of uniformity when implementing certain activities;

"the subject (the subject of research)" (subject (trial subject)) – the physical person participating in clinical trial as a part of the group receiving the researched drug or as a part of control group;

"authorized bodies" (regulatory authorities) – the bodies having rights to perform the regulating functions. In relation to these rules instances treat authorized bodies, authorized to consider the clinical data provided to them, and also to carry out inspections. These bodies also sometimes are called competent authorities;

"vulnerable subjects of research" (vulnerable subjects) is persons on whose desire to participate in clinical trial expectation (reasonable or unreasonable) these or those benefits connected with participation in research, or the sanction of higher persons in hierarchy in case of refusal from participation can exert excessive impact. Pupils of the highest and average medical, pharmaceutical and dental educational institutions, junior staff of clinics and laboratories, employees of the pharmaceutical companies, military personnel and prisoners, and also the patients having incurable diseases, persons which are in houses on leaving, needy and jobless treat vulnerable subjects of research, the patients who are in medical emergency representatives of ethnic minorities, the homeless, tramps, refugees, minors and persons who are under guardianship or custody and also persons incapable to agree.

"advisory council of the organization, ESO" (Institutional Review Board; IRB) – independent body which consists of persons working in the field of medicine, including scientific and also the having specialties which are not relating to medicine, ensures protection of the rights, safety and wellbeing of subjects of research and provides public guarantee of such protection, including by consideration, approval (issue of the conclusion) of the protocol of clinical trial and amendments to it, and also materials and methods which are supposed to be used for obtaining and documentation of the informed consent of subjects of research. This term is applied to the clinical trials executed in the territory of the states which do not have independent ethical committees.

2. Principles of proper clinical practice

2.1. Clinical trials shall be conducted according to the ethical principles underlain by the Helsinki declaration adopted at the XVII session of the World association of health care in 1964, and reflected in these rules and applicable requirements.

2.2. Prior to the research assessment of ratio of the expected (predictable) risk and inconveniences with the expected advantage for the subject of research and society shall be carried out. The research can be begun and continued only if the expected advantage justifies risk.

2.3. The rights, safety and wellbeing of subjects of research have paramount value and shall prevail over interests of science and society.

2.4. Information (preclinical and clinical) about the researched drug shall be sufficient for reasons for expected clinical trial.

2.5. Clinical trials shall conform to scientific requirements both shall be accurate and are in detail described in the protocol of clinical trial (further – the protocol).

2.6. Clinical trial shall be conducted according to the protocol permitted (approved) advisory council of the organization (ACO) (independent ethical committee (IEC)).

2.7. Responsibility for the medical care provided to the subject and decision making of medical nature are born by the doctor.

2.8. All persons conducting research shall have the corresponding education, preparation and experience for accomplishment of the tasks assigned to them.

2.9. The voluntary informed consent shall be received at each subject before its inclusion in research.

2.10. All information obtained in clinical trial needs to be registered, transferred and stored so that to provide the accuracy and correctness of its representation, interpretation and verification.

2.11. Confidentiality of the records allowing to identify subjects of research shall be provided for the purpose of observance of the right to private life and protection of confidentiality according to applicable requirements.

2.12. Production and storage of the researched drugs, and also the treatment of them need to be performed according to rules of proper production practice. The researched drugs shall be used according to the approved protocol.

2.13. For quality assurance of each aspect of research the corresponding systems and operational procedures shall be implemented.

3. Advisory council of the organization (independent ethical committee) (ESO (NEK))

3.1. Obligations

3.1.1. The advisory council of the organization (independent ethical committee) is urged to protect the rights, safety and wellbeing of all subjects of research. Special attention shall be paid to researches with participation of vulnerable subjects.

3.1.2. ESO (NEK) shall receive the following documents for consideration:

protocol (amendment to the protocol);

written the form of the informed consent and its subsequent editions offered by the researcher for use in research;

the description of the actions directed to involvement of subjects to participation in research (for example, advertisements);

written materials which will be provided to subjects of research;

brochure of the researcher;

the known information concerning safety;

information on payments and compensations to subjects of research;

the current edition of the curriculum vitae of the researcher (curriculum vitae) and (or) other materials confirming its qualification;

other documents which can be required ESO (NEK) for accomplishment of its obligations.

ESO (NEK) shall consider question of performing the offered clinical trial in the corresponding terms and draw the conclusion in writing, accurately identifying research, the considered documents and dates in case of pronouncement of the following possible decisions:

approval (issue of the conclusion) on carrying out research;

the requirement about modification of the submitted documentation before receipt of approval (issue of the conclusion) on carrying out research;

refusal in approval (issue of the conclusion) on carrying out research;

cancellation (suspension) of the approval (the issued conclusion) made earlier on carrying out research.

3.1.3. ESO (NEK) shall estimate compliance of qualification of the researcher to the offered research based on the current edition of the curriculum vitae of the researcher (curriculum vitae) and (or) other corresponding documentation requested by ESO (NEK).

3.1.4. ESO (NEK) shall consider periodically documentation on each current research with the frequency depending on risk degree to which subjects of research, but at least 1 time a year are exposed.

3.1.5. ESO (NEK) can demand that additional data on research were provided to subjects of research in addition to information specified in Item 4.8.10 of these rules if, according to ESO (NEK), it is necessary for protection of the rights and health of subjects of research, and also for guarantee of their safety.

3.1.6. If consent to participation of the subject in the research which is not connected with treatment the legal representative according to Items 4.8.12 and 4.8.14 of these rules gives it), ESO (NEK) shall be convinced that the provided protocol and (or) other documentation completely reflect clinical questions and conforms to ethical and other applicable requirements to similar clinical trials.

3.1.7. If in the protocol it is specified impossibility of receipt of consent to participation in research at the subject of research or his (her) legal representative according to Item 4.8.15 of these rules until inclusion of the subject in research (for example, in case of medical emergency), ESO (NEK) shall be convinced that the provided protocol and (or) other documentation completely reflects clinical questions and conforms to ethical and other applicable requirements to similar clinical trials.

3.1.8. ESO (NEK) considers the size and payment procedure to the subject of research to be convinced of lack of unreasonable interest or compulsion of subjects of research. The amount of payments to subjects of research can be pro rata to their participation in testing, but shall not depend only on whether the subject completed research completely or not.

3.1.9. ESO (NEK) shall be convinced that information concerning payments to subjects of research including methods, the size and payment procedure, is reflected in writing the informed consent and in any other materials provided to subjects of research. It shall be specified how the amount of payments will be determined.

3.2. Structure, functions and operating procedure

3.2.1. The sufficient number of persons having in total necessary qualification and experience for consideration and carrying out expert evaluation of scientific, medical and ethical aspects of the planned research shall be part of ESO (NEK).

Inclusion in structure of ESO (NEK) is recommended:

at least 5 people;

at least 1 person who is not specializing in the field of scientific research (activities);

at least 1 person who is not the employee of medical institution (the research center) in whom the research is conducted.

Only the members of ESO (NEK) who are not employees of the researcher or the sponsor of research and not having personal interest in performing specific clinical trial can take part in vote (discussion) of the questions connected with conduct of clinical trial. The list of members with indication of their qualification shall conduct ESO (NEK).

3.2.2. ESO (NEK) shall perform activities according to documentary drawn up working procedures, document the work and keep protocols of meetings. Its activities shall conform to these rules and applicable requirements of the legislation of state members.

3.2.3. ESO (NEK) makes decisions at the announced meetings with the quorum determined by working procedures.

3.2.4. Only the members of ESO (NEK) who were directly involved in consideration of documentation on research and discussion can participate in vote (to express the opinion) and (or) to make recommendations.

3.2.5. The researcher can provide information on any aspects of research, but cannot participate in debate or in vote (opinion development) of ESO (NEK).

3.2.6. ESO (NEK) can resort to the help of independent experts with special questions.

3.3. Procedures

ESO (NEK) shall develop, documentary draw up and observe the standard working procedures regulating:

3.3.1. Its structure (surnames and qualification of members) and the body which founded it.

3.3.2. Procedure for purpose of meetings, notifications of his members about the forthcoming meetings, and also the organization of meetings.

3.3.3. Procedure for primary and subsequent consideration of documentation on research.

3.3.4. Frequency of the subsequent consideration of documentation on research.

3.3.5. Procedure for accelerated prosecution of documentation, according to applicable requirements for approval (issue of the conclusion) in case of minor change in the current researches which already got approval (conclusion) of ESO (NEK).

3.3.6. Inadmissibility of inclusion of subjects in research before ESO (NEK) is issued by written approval (conclusion) on carrying out research.

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