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Regulations for registration and expertise of drugs in the Eurasian Economic Union (EAEU)

Table of Contents

  1. Regulations for registration and examination of drugs for medical use
    1. General provisions
    2. Definitions
    3. General principles of registration of drugs
    4. General principles of expertise of drugs
    5. The procedure for registration and expertise of drugs under the mutual recognition procedure
      1. Registration and examination of drugs in the reference state
      2. Registration and expertise of a drug under the mutual recognition procedure in the state (states) of recognition
    6. The registration and expertise sequence of a drug under the decentralized procedure in the reference state and in the states of recognition
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Rules for Registration and Expertise of Medicinal Products for Medical Use in EAEU

General provisions

These Rules determine the procedure for registering, confirming registration (re-registration), amending the registration dossier and examining drugs for medical use with the aim of forming a common market for medicines within the Eurasian Economic Union (hereinafter - the Union), as well as the other procedures related to the registration of drugs (hereinafter referred to as procedures related to registration),
including:

  • Bringing the registration dossier of a drug registered in the Member States of the Union (hereinafter referred to as the Member States) before the entry into force of the Agreement on Uniform Principles and Regulation for the circulation of medicinal products within the Eurasian Economic Union from December 23, 2014 (hereinafter referred to as the Agreement) until December 31, 2020, in compliance with these rules (hereinafter referred to as bringing to conformity with the requirements of the Union);
  • Suspension and cancellation of registration of drugs or application limitation of a medicinal product;
  • Issuance of duplicates of the registration certificate of a drug.

The requirements of these Rules apply to developers and manufacturers of drugs, holders of drug registration certificates, their proxies, authorized bodies (expert organizations) of Member States in the field of medicinal products circulation.

Registration in accordance with these Regulations shall be applied to the drugs intended for circulation in the common market of pharmaceutical products within the framework of the Eurasian Economic Union or in the territory of one of the Member States.

Registration under one trade name of medicines having different qualitative composition of active substances is prohibited.

One drug with different trade names may be registered in different Member States in the following cases:

  • Use of the proposed trade name may be contrary to the norms of law and morals or otherwise does not take into account the national cultural and (or) linguistic properties ;
  • intellectual rights to a trade name in the form of a trademark belong to a person who is different from the person who applied for the registration of the medicinal product (hereinafter referred to as the applicant) or the holder of the registration certificate, and the applicant or holder of the registration certificate can not provide the relevant license agreement on granting of the right Use of the trademark;
  • the drug has been registered under different trade names in accordance with the legislation of Member States until December 31, 2020.

Registration of a pharmaceutical product, confirmation of registration (re-registration), introduction of changes to the registration dossier, as well as procedures related to registration, are carried out by authorized bodies.

Expert examination of a medicinal product is carried out by an expert organization determined in accordance with the legislation of a Member State.

Authorized bodies and expert organizations ensure the confidentiality of information contained in the registration dossier of the drug in the process of registration and examination of medicinal products, including information contained in the closed part of the master file for active pharmaceutical substance.

The applicant, in accordance with the legislation of a Member State, incurs expenses on registration, confirmation of registration (re-registration), changes to the registration dossier and examination of drugs, procedures related to registration, and inspections in order to determine compliance with the requirements of appropriate pharmaceutical practices initiated due to the implementation of these procedures.

The authorized body (expert organization) of the reference state upon receipt of the application for registration, confirmation of registration (re-registration), modification of the registration dossier and procedures related to drug registration, assigns to it a unique number via the integrated information system of the Union (hereinafter referred to as the integrated system), and informs the applicant.

The authorized body (expert organization) of the Member State shall provide information related to drug registration, confirmation of registration (re-registration), amendments to the registration dossier, as well as procedures related to registration, authorized bodies (expert organizations) of other Member States, and To the Commission using the integrated system according to the application number in accordance with the formation and maintenance procedure of the Unified Register of Registered Medicines (hereinafter - the Register).

The authorized body (expert organization) of the reference state shall in no later than 5 working days from the date the applicant submits the registration dossier electronically provide access to the registration dossier information upon the request of the authorized bodies (expert organizations) of the recognition states through the use of the means of the integrated system.

Based on the results of drug registration, the authorized body of each Member State that registered the medicinal product issues a registration certificate of the pharmaceutical product confirming the fact of its registration.

A drug registration certificate is issued in accordance with the unified form and rules for filling a medicinal product registration certificate for medical use according to Appendix No. 17 to this Regulation by the authorized body which registered the drug.

The validity period of the registration certificate for a drug registered for the first time in the referring state is 5 years. At the end of this period, a perpetual registration certificate of the medicinal product is issued, provided that the registration (re-registration) is confirmed.

In cases specified in Section VII of these Rules, as well as in cases related to the matters of pharmacovigilance, the authorized body may re-issue a registration certificate with a validity period of 5 years following the confirmation of registration (re-registration). The registration certificate of drug registered in accordance with the legislation of the Member States before December 31, 2020 and circulating for 5 years or more on the market of at least 3 member states is issued for an indefinite period in accordance with the procedure for filing it in conformity with the requirements of the Union under section XIII of these Rules.

Definitions

For the purposes of these Rules, the terms used have the following meanings:

  • "Holder of the registration certificate" is a legal entity that received the registration certificate for a drug and became responsible for the safety, effectiveness and quality of the medicinal product;
  • "Unified Register of Registered Medicinal Products of the Union" is a common information resource formed within the integrated system and containing information on drugs registered or completed the other procedures related to registration in accordance with these Regulations;
  • "Applicant" is a legal entity competent to submit an application for drug registration, confirmation of registration (re-registration), introduction of changes to the registration dossier of a pharmaceutical products, other procedures related to registration, and responsible for the reliability of information contained in the documents submitted to it and the registration dossier data;
  • "Normative document" is a document that establishes requirements for the quality control of a drug (containing the specification and description of analytical techniques and tests or references to them, as well as the relevant eligibility criteria for these quality indicators, etc.) based on the conducted expertise of a drug; it is approved by the authorized body in case of registration of a drug in the territory of the Union and designed to control the quality of the medicinal product during the post-registration period in the territory of the Union;
  • "General characteristics of the medicinal product" is a document approved by the authorized body of the Member State, in accordance with the acts issued by the bodies of the Union, containing information for the medical workers on safety and effectiveness of the drug;
  • "Representative of the registration certificate holder" is a legal entity registered in accordance with the legislation of a Member State or a separate subdivision of a legal entity located in the territory of a Member State and authorized by the holder of a registration certificate for performance of actions related to the circulation of drugs in the territory of a Member State;
  • "Registration dossier" is a set of documents (including an application), compiled in accordance with these Rules, submitted for conducting procedures related to drug registration or confirmation of registration (re-registration) of the medicinal product;
  • "Registration certificate of a medicinal product" is a document of a unified form issued by an authorized body that confirms registration of a pharmaceutical product and is a permit for its medical use in the territory of a Member State;
  • "Registration number" is the code designation assigned to the drug winning registration in the territory of a Member State;
  • "Registration of a medicinal product" is the procedure aimed at obtaining a permit for medical use of a drug in the territories of one or more Member State carried out in accordance with these Regulations;
  • "Reference state" is a member state that prepares an expert report on evaluation of safety, efficacy and quality of a drug on the basis of drug examination in accordance with these Regulations;
  • "Reference drug" is a drug used as a reference product and is the standard by which the properties of a examined medicinal product are determined (normalized);
  • "Specification" is a list of quality indicators, references to analytical techniques as well as on tests and norms that represent numerical (quantitative) limits, ranges and other criteria for the specified quality indicators;

 

General principles of registration of drugs

Registration of drugs may be performed at the request of the applicant in succession in several Member States in accordance with the mutual recognition procedure or simultaneously in several Member States in accordance with the decentralized registration procedure.

The procedure for mutual recognition is carried out by:

  • A) the reference state in accordance with these Rules with the aim of applying the pharmaceutical product in the market of that state only (national drug registration procedure);
  • B) in the states of recognition - upon request of the applicant after registration of the drug in the reference state using the procedure of mutual recognition.

Decentralized registration procedure is carried out simultaneously by several Member States to which an application for drug registration of has been filed, with the choice of the reference state.

The applicant independently chooses the reference state and, if necessary, the state of recognition when applying for registration of the drug.

Only one state can act as a reference state.

The requirements for documents and data of the registration dossier in the format of the general technical document submitted for drug registration have been established by Annexes 1 to 5 to these Regulations.

Prior to submission of an application for registration of a drug in EAEU, the authorized bodies or expert organizations of the Member States shall have the right, at the request of the applicant, to conduct scientific and pre-registration consultations in accordance with the legislation of the Member States on the issues related to the execution of analytical tests, preclinical and clinical studies (trials), aspects of drug Registration procedures, including the qualification issues, a variation of the application for registration of a drug for the purpose of the volume of documents and registration dossier data, the completeness of the registration dossier, the definition of affiliated persons in the states of recognition, the format for submitting the application and the drug registration dossier, the necessity  to provide samples of the drug, reference standards, materials, specific reagents, consumables required for conducting a laboratory quality examination in the expert organization or for its intended purpose, and on the other issues.

During drug registration procedures, or confirmation of registration (re-registration), or amendments to the registration dossier or procedures related to drug registration, an authorized body or an expert organization of the reference state initiates the inspection for compliance with the relevant good pharmacy practices conducted by the Pharmaceutical inspectorate of this State in case of detection facts that call into question the reliability of the information provided by the applicant in the registration dossier regarding the conducted pre-clinical (non-clinical) studies (trials) of drugs and clinical trials (trials) of drugs or production of the pharmaceutical product, including production of pharmaceutical substances or pharmacovigilance system organization. Such inspections can also be initiated in the cases specified in paragraphs 31, 33, 35, 37,38, 39 of these Rules. Responsibility for the timely initiation of appropriate unscheduled inspections, if necessary, is borne by the authorized body of the reference state.

The production of drugs must comply with the Rules of Good Manufacturing Practices of the Eurasian Economic Union.

When applying for drug registration, confirming registration (re-registration), aligning with the requirements of the Union of a medicinal product, the applicant must submit, as a part of the registration dossier,  an existing document confirming compliance with the requirements of good manufacturing practices of the Union, the production site (production sites) where the production of the finished dosage form is performed and batch release quality control of the drug claimed for registration, confirmation of registration (re-registration), brought into conformity with the requirements of the Union.

Until December 31, 2018, with regard to the production site (production sites) of the medicinal product, the applicant, instead of a document confirming compliance with the requirements of good manufacturing practice of the Union, has the right to present a document confirming compliance with the requirements of good manufacturing practices issued by the authorized body of the Member States to the manufacturer of the medicinal product, production site (sites) of a medicinal product that carries out the production of the finished dosage form and release quality control.

If it is not possible to present the current document confirming the compliance of the production site (production sites) of the drug with the requirements of the Good Manufacturing Practice of the Union, the applicant, when filing an application for registration of a drug before December 31, 2018, or to bring it in conformity with the requirements of the Union, provides the following documents and information instead of this document:

  • A) current documents confirming the compliance of the production site (production sites) that produces the finished dosage form and issues quality control of the drug to the requirements of Good Manufacturing Practices issued to the manufacturer of the drug by the competent authority of the country of production of the drug;
  • B) a copy of the report on the results of the last inspection of the production site (production sites at production stages) conducted by the authorized body of the producing country and / or other authorized body during the last 3 years;
  • C) information on the results of all inspections of this production site (production sites) for compliance with the requirements of good manufacturing practices conducted over the last 3 years;
  • D) information on complaints regarding the quality of medicinal products produced at the given production site (production sites) over the last 3 years;
  • E) consent for a pharmaceutical inspection to be conducted in accordance with the requirements of Good Manufacturing Practice of the Union;
  • F) a copy of the main dossier (site master file) of the production site (production sites).

The reference state, based on the documents submitted by the applicant specified in clause 30 of this Regulation, taking into account the assessment of possible risks, makes a decision on whether to conduct an unscheduled pharmaceutical inspection for compliance with the GMP requirements of the Union for the time of drug registration procedures or to include of an inspection of the drug production site (sites) in the plan of inspections in the first 3 years after completion of the registration procedures.

In case of documentary justification by the authorized body of the reference state, the impossibility of conducting an unscheduled inspection of the production site (production sites) of the drug by the reference state at the time of drug registration procedures, the applicant has the right, upon agreement with the reference state, file an application to one of the Member States for conducting an inspection of this production site (production sites) on compliance with the GMP requirements of the Union.

In case of a written refusal by the authorized state agencies of recognition in conducting an unscheduled inspection of the production site (production sites) of a drug, the authorized body of the referent state is obliged to organize and conduct an unscheduled inspection within the period of this drug registration procedures.

Decision on whether to conduct an unscheduled pharmaceutical inspection for compliance with the GMP requirements of the Union is made by the authorized body of the reference state in the process of:

  • A) drug registration procedures - for pharmaceutical products produced at the sites where the finished dosage forms are manufactured and the batch release control is performed, and which were not subject to the inspection by the authorized body (organization) of at least one Member State before;
  • B) the procedures for bringing to conformity with the requirements of the Union - for medicines previously registered in Member States, in case of indication (introduction, modification) of the production site (production sites) previously not inspected by the authorized body (organization) of at least one Member State.

Pre-clinical drug safety studies conducted in non-member states are considered during the expertise of medicinal products provided that these studies are planned, conducted and described in the pre-clinical study report in accordance with the requirements of Good Laboratory Practice equivalent to the requirements of the Union (or not below).

Clinical studies of medicinal products conducted in non-member states are reviewed during the expertise of medicinal products provided that these trials are planned, conducted and described in the clinical trial report in accordance with the requirements of GCP, equivalent to the requirements of the Union (or at least equal), as well as the principles of the Helsinki Declaration of the World Medical Association "Ethical principles of medical research with human participation as an object of research".

In the process of drug registration, the reports on previously conducted clinical trials included in Module 5 of its registration dossier are reviewed during the examination in case of one of the following conditions:

  • clinical studies shall be conducted in accordance with the legislation of the Member States and in their territory before January 1, 2016 (by the date of the last visit of the last patient (volunteer)) or continued as of January 1, 2016 (with a complete set of patients (volunteers) in the study);
  • the clinical trials shall be conducted partially or completely in the territories of the countries of the region of the International Conference on Harmonization of Technical Requirements for Registration of Medicinal products for Medical Use (ICH) before January 1, 2016 (on the date of the last visit of the last patient), on the basis of which the medicinal product was registered in the territories of countries of the Region of International Conference on the Harmonization of Technical Requirements for Registration of Medicines for Medical Use (ICH);
  • clinical studies initiated after January 1, 2016, shall be conducted in accordance with the international treaties and acts constituting the law of the Union, with at least one of the clinical studies conducted in full or in part (with respect to data obtained from the subjects of the study) in the territory of the Union.

The authorized body of the reference state on the basis of the documents and information submitted by the applicant, taking into account the assessment of possible risks, decides whether it is necessary (or not necessary) to conduct an unscheduled inspection of clinical trials of the drug, including bioequivalence studies, within the period of registration of the drug for compliance with the requirements of a GCP of the Union, or on the inclusion of a clinical research inspection in the plan for conducting inspections in the first 3 years after registration of the medicinal product.

An unscheduled inspection of the pharmacovigilance system of the holder of the registration certificate as a part of the registration procedure for the medicinal product is carried out in cases stipulated by the rules of good pharmacovigilance practice approved by the Commission.

 

General principles of expertise of medicinal products


Examination of drugs is carried out to obtain a scientific assessment of the quality, safety and efficacy of drugs and the risk-benefit ratio, and may include:

  • evaluation of documents and information provided by the applicant in the registration dossier of the drug (evaluation of the dossier);
  • conducting the laboratory tests for compliance with the requirements of the Normative Document and verification of analytical quality control procedures;
  • preparation of an expert report on evaluation of the medicinal product by the reference state;
  • assessment of the expert evaluation report by the state of recognition, taking into account the documents and information contained in the registration dossier of the drug.

During development of the pharmaceutical product, execution of pre-clinical (non-clinical) and clinical trials (trials) of the drug, its production, pharmacovigilance and preparation of documents for drug registration procedure, confirmation of registration (re-registration), changes in the registration dossier or other procedures related to registration , Developers, manufacturers and Marketing Authorization Holders and their authorized persons must comply with legislation of Member States, international treaties and acts constituting the right of the Union, as well as to be guided by the best approaches, the implementation of which will ensure the fulfillment of such requirements, and which are set out in decisions and recommendations adopted by the Commission. In case of non-compliance with these recommendations, the applicant must provide a rationale for the admissibility of the chosen approach in terms of ensuring the quality, efficacy and safety of the drug. The presented rationale must be evaluated when examining the medicinal products.

Examination of the drug is not interrupted for the period of conducting unscheduled pharmaceutical inspections for compliance with the requirements of the Union's proper practices (production, laboratory, clinical, pharmacovigilance), but the final expert evaluation report can be drawn up by the authorized body (expert organization) of the reference state only taking into account the results of unscheduled pharmaceutical inspections (if conducted). These inspections should be carried out within a period not exceeding 180 calendar days from the date of the authorized body's decision to initiate the inspection.

 

The procedure for registration and examination of medicinal products under the procedure of mutual recognition

Registration and examination of medicinal product in the reference state

The period of drug registration and examination in a reference state shall not exceed 210 calendar days from the date of filing an application for registration of a drug until the day of issuing a registration certificate.

For the purpose of a drug registration (Marketing Authorization Application), the applicant shall submit the following documents and materials to the authorized body (expert organization) of the reference state:

  • Application for registration of a drug in the established form on paper and (or) electronic media in accordance with Appendix no. 2 of these Regulations;
  • Documents confirming the payment of the fee (toll) for registration and examination of the pharmaceutical product according to the procedure established by the legislation of the reference state;
  • Drug Registration dossier in accordance with Annexes 1 to 5 to these Regulations on electronic media (in addition module 1 of the registration dossier is submitted on paper (except for the risk management plan, the main dossier (master file) of the production site (production sites) and the master file on pharmacovigilance));
  • Samples of medicinal products.

In the cases specified in the eighth paragraph of clause 47 of these Regulations, laboratory tests are carried out in the laboratory of quality control of the manufacturer of the medicinal product in the presence of representatives of the expert organization or in the contract laboratory used by the manufacturer in the presence of representatives of the expert organization.

Examination of a medicinal product in a reference state includes:

  • evaluation of completeness and correctness of the documents submitted in the drug registration dossier;
  • evaluation of documents and information on safety, efficacy and quality of the drug provided by the applicant in the registration dossier;
  • execution of the laboratory tests for compliance with the requirements of the normative document on quality and reproducibility of the declared quality control procedures carried out in the accredited testing laboratories;
  • initiation, if necessary, of an unscheduled or planned pharmaceutical inspection in the cases specified in these Regulations;
  • preparation of an expert report on evaluation of the drug by the reference state.

The authorized body (expert organization) of the reference state shall, within 14 working days from the date of submission of the application for drug registration, assess the completeness, contents and correctness of registration of the documents submitted in the registration dossier before sending the registration dossier materials for expertise. The applicant is granted 90 calendar days maximum not included in the registration and examination period of the pharmaceutical product, for submission of materials missing in the drug registration dossier, according to the comments of the authorized body (expert organization) of the reference state.

The authorized body (expert organization) of the reference state rejects the application for drug registration in the event of failure to submit the registration dossier materials on the remarks of the authorized body (expert organization) of the reference state and (or) failure to confirm payment of the fee (fee) for registration and examination of the medicinal product in cases and order Established by the legislation of the reference state.

The authorized body and (or) the expert organization of the reference state when conducting drug registration and (or) examination of the medicinal product has the right to send a request to the applicant in written and (or) electronic form concerning submission of missing additional information, and request necessary explanations or document clarifications and data presented in the registration dossier.

The period for submitting a response to the request specified in paragraph 52 of these Rules shall not exceed 90 calendar days from the date of receipt of the request.

If necessary, the period established in paragraph 53 of these Rules may be extended by the authorized body (expert organization) of the reference state on the basis of the relevant justification of the applicant. The total response time for inquiries should not exceed 180 calendar days.

The period for documents submission for the applicant upon the request of the authorized body or expert organization during expertise of the drug is not included in the period of examination and registration of the pharmaceutical product.

If the applicant fails to submit the requested documents and information within the prescribed period, examination and registration of the drug shall be terminated. The authorized body (expert organization) notifies the applicant in writing and (or) by e-mail services within 14 working days from the date of adoption of this decision.

The interaction of the authorized body (expert organization) with the applicant when sending requests is carried out electronically using an integrated system.

Expertise of the medicinal product in case of initiating a pharmaceutical inspection for compliance with the proper pharmaceutical practices of the Union shall not be suspended. Wherein preparation of an expert evaluation report is completed by the reference state only after the expert organization of the reference state receives the results of the inspection. An unscheduled pharmaceutical inspection with a report on the completed inspection must be conducted within the time of registration of the medicinal product not exceeding 180 calendar days from the date the decision to conduct the inspection was adopted by the authorized body or an expert organization. The applicant organizes a visit to the production site and / or the research center and / or the inspection of the pharmacovigilance system of the Marketing Authorization holder within 30 calendar days after receiving a request to hold an inspection or offers the dates of visits, but no later than 90 calendar days after receiving the notification that the inspection shall be performed.

To prepare an expert evaluation report, the expert organization of the reference state prepares the expert reports on the forms in accordance with Appendices no.  6, 7, 8,9, 10, 12  and 22 to these Regulations.

Based on the results of the expert examination of the drug, the expert organization of the reference state prepares the final expert report on evaluation of the drug submitted for registration, including an assessment of the explanations received from the applicant, documents and information submitted in response to the request of the expert organization or authorized body, in accordance with Appendix no. 16 to these Regulations.

Expert reports on quality aspects, preclinical, clinical aspects, and final expert evaluation report are compiled in accordance with appendices No. 13, 14, 15 and 23 to this Regulation.

The expert evaluation report should be updated by the expert organization of the reference state with the appearance of new information that is important for assessing the quality, safety or efficacy of the drug and may affect the benefit-risk ratio of the medicinal product as part of the procedure for amending the registration dossier.

If, based on the results of the examination of the pharmaceutical product, the authorized body of the reference state takes a positive decision on registration of the drug, the authorized body of the reference state within a period not exceeding 10 working days shall:

  • issue a drug registration certificate to the applicant in the form in accordance with Appendix No. 17 to these Regulations;
  • place information about the medicinal product and its active pharmaceutical substances in a single registry with the application of approved summary of product characteristics, instructions for medical use, package mock-ups, the quality standard document, and the final expert evaluation report compiled in accordance with Appendix No. 16 to these Regulations, after confiscation of confidential data and data on experts, the agreed risk management plan for the use of the drug (if necessary) in accordance with the procedure for the formation and maintenance of a unified register.

The authorized body of the reference state refuses to register the drug based on the results of the examination in the following cases:

  • the expected risk-benefit ratio  associated with the use of the medicinal product is not favorable;
  • the effectiveness of the drug is not confirmed by the information provided by the applicant;
  • the quality of the drug is not confirmed;
  • the proposed quality control methods and techniques  are impracticable;
  • the applicant provided false information;
  • according to the results of the appointed inspection during drug registration, its compliance with the relevant pharmaceutical practices of the Union is not confirmed.

In case the authorized body of the reference state adopts a decision to refuse to register a drug, the authorized body (expert organization) of the reference state shall notify the applicant about it in electronic and / or written form within 10 working days from the date of adoption of such decision.

 

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