Approaching Bringing the Application Dossier into Compliance with EAEU Rules
Approaching Bringing the Application Dossier into Compliance with EAEU Rules
Bringing into compliance, EAEU, Agreement, the Rules for the granting of marketing authorization and the assessment
Among the most important requisites for marketing medicines within the Single pharmaceutical market of the Eurasian Economic Union is the bringing into compliance of all pharmaceuticals authorized based on national provisions with the new requirements developed based on international principles and policies for demonstrating drug safety, efficacy, and quality. Statutory wording used to legally outline this procedure needs thorough discussion and clarification and are addressed in this paper. Moreover, we emphasize the paramount importance of ensuring that the basic goals of the Agreement on the common principles and rules of medicinal products circulation within the Eurasian Economic Union are reached. They envisage authorising only those medicines for marketing that demonstrated their safety, efficacy, and quality in accordance with state-of-the-art scientific standards, and the rules for bringing into compliance play an instrumental role here while a formalistic approach should be abandoned.
As part of the process of forming a single market for medicines of the Eurasian Economic Union (hereinafter - the Union), which should be completed on December 31, 2025, a procedure for bringing the registration dossier into compliance with the requirements of the Union is laid down. It raises perhaps the greatest number of questions, since it is aimed at updating and revising the list of drugs that were previously authorised for marketing in accordance with to national rules.
In this article, the most significant elements of this procedure is analyzed, from the point of view of holders of marketing authorisation, assessors, as well as competent authorities of the Member States of the Union. Given the expected amount of work on this procedure, it deserves a very careful attention of all stakeholders. The current rules provide the competent authorities and assessors with a wide range of tools for the implementation of the plan laid down in the Agreement on common principles and rules for the circulation of medicines within the Union. At the same time, a reasonable and pragmatic approach is necessary, which should take into account:
→ the need to keep safe, effective and high-quality drugs on the market;
→ the need for a elaborated and balanced approach to each drug, taking into account its regulatory history and its regulatory status in foreign markets;
→ the real need for medicine from the perspective of current clinical practice and taking into account the principles of evidence-based medicine / pharmacotherapy;
→ understanding the acceptability of scientific justification and of possible absence of any data while providing other information or fulfilling certain regulatory criteria;
→ operational capabilities of regulators, especially assessment resources.
■ Legislative requirement to align
The Agreement on Common Principles and Rules for the Circulation of Medicinal Products within the Eurasian Economic Union (hereinafter referred to as the Agreement), being an international agreement concluded between the Member States of the Union (Republic of Armenia, Republic of Belarus, Republic of Kazakhstan, Kyrgyz Republic and Russian Federation), serves as a legal basis for improving the regulatory system in this area. On the basis of the Agreement, a set of documents has been adopted, explaining the principles contained therein and introducing procedures for bringing the quality of both the regulation and the regulated drugs to international standards.
The main document adopted under the Agreement is the Rules for Registration and Expertise of Medicinal Products for Human Use (hereinafter referred to as the Union Registration Rules), which regulate the following procedures: marketing authorisation/registration of drugs, managing the life cycle of registered drugs and updating the application dossier of drugs registered according to national rules. Obviously, updating the registration documentation in some cases will entail the refinement of production methods and quality control, as well as conducting preclinical or clinical studies that assess the safety, quality and effectiveness of the drug to keep it on the market in accordance with the conditions of use the holder of the registration certificate wants to keep and which will be reflected in the product information.
If any indication or other conditions of use of the drug are not substantiated or do not meet current requirements for quality, safety or efficacy, then the alternative to conducting additional research may be exclusion of such indications or conditions of use from the product information while retaining only those claims which are substantiated by the documents of the registration dossier / reconciliation dossier. If the drug does not meet and will not be able to meet modern requirements in the foreseeable future, it should be removed from the market, which is in the interests of practical public health and is the ultimate goal of global changes in pharmaceutical regulation, since, in accordance with the Agreement, only high-quality, safe and effective drugs should remain on the market.
The procedure for amending the documentation of medicinal products registered under national rules, in accordance with the new scientifically based standards, provided for in the Agreement, is introduced by the Decision of the Council of the Eurasian Economic Commission No. 78 of 3 November 2016 "On the Rules for registration and examination of medicinal products for medical use" (hereinafter - Decision number 78), where in subparagraph "g" of paragraph 2 indicated that:
medicinal products registered in accordance with the laws of the Member States must be brought into compliance with the requirements of international treaties and acts constituting Union law, until December 31, 2025 ...
In the Union Registration Rules, the procedure with the difficult to pronounce name “Bringing into compliance of the registration dossier of a medicinal product registered in the Member States of the Union prior to the entry into force of the Agreement on common principles and rules for the circulation of drugs within the Eurasian Economic Union of 23 December 2014, and till 31 December 2020, in accordance with these Rules" is specified in chapter XIII consisting of 14 points (from 170th to 183rd).
Clause 170 of the Union Registration Rules states that:
170. A marketing authorization application dossier for medicinal products authorized in the Member States before the Agreement came into effect or using national procedures before 31 December 2020 shall be brought into compliance with the requirements of the Union at the latest on 31 December 2025 in accordance with this procedure.
Thus, the clause introduces deadlines for bringing the registration dossiers into compliance, and if those are not observed - on the basis of subclause “e” of clause 2 of Decision No. 78 - the validity of drug registration certificates issued in accordance with the legislation of the Member States is terminated from 1 January 2026, i.e. they are subject to withdrawal from the market in the event of failure of the bringing into compliance procedure or the refusal of the registration certificate holder to undergo this procedure.
■ Characteristics and interpretation procedures
The first paragraph of clause 171 of the Union Registration Rules establishes the format of the dossier provided in order to bring it into compliance. According to Appendix No. 1 to the Union Registration Rules, this is the format of a common technical document. At the same time, Annex No. 1, to a large extent is equal to Annex I to European Union Directive 2001/83/EC, establishes the requirements for compiling a registration dossier in terms of documentation on manufacture, quality control, safety and efficacy of a medicinal product. It is important to note that Appendix No. 1 to the Rules for Registration of the Union differentiates the requirements for the content of the registration dossier depending on the legal basis for authorisation of a drug. Among such legal bases the following can are distinguished:
→ Original medicinal products, including biological / biotechnological (part I of Annex 1);
→ generic drugs (Part II.6 of Appendix No. 1);
→ hybrid applications (Part II.7 of Annex No. 1);
→ drugs with well-studied medicinal use (part II.8 of Annex No. 1);
→ combination drugs (which are combinations of active substances previously registered as independent drugs) (Part II.9 of Appendix No. 1);
→ biosimilars (Part II.10 of Annex No. 1);
→ vaccines (Part III.11 of Annex 1);
→ blood products (part III.12 of application No. 1);
→ radiopharmaceuticals (Part III.13 of Annex No. 1);
→ homeopathic medicines (part III.14 of Annex No. 1);
→ herbal medicines (part III.15 of Annex No. 1);
→ orphan drugs (Part III.16 of Annex No. 1);
→ high-tech drugs (the Eurasian equivalent for advanced therapy medicinal products), which include gene therapy products, somatic cell products and tissue engineering products (part IV.17 of Appendix No. 1).
Consequently, depending on the category of the drug, there will be different requirements for the completeness of the application dossier. If the drug is original/new, then its file must be complete, or a justification must be provided why the absence of some of the required data can be accepted by the regulators and there will not be any uncharacterized risks that are unacceptable from the public health perspective. For example, the absence of certain preclinical data on pharmacological safety can be justified by clinical experience of drug use. If a medicinal product is classified as generic, the relevant bioequivalence data or the rationale for the absence of the need to present them in accordance with the Rules for conducting bioequivalence studies on drugs will be required, etc. (see below).
Despite the absence in Section XIII of the Union Registration Rules of a direct indication that the legal basis for authorisation of a drug acts as a basis for the bringing into compliance procedure, the need to classify it as one of the above legal bases follows from (1) the logic of the document update procedure, (2) provisions on the need to take into account the requirements of Annex No. 1 to the Rules for the Registration of the Union and (3) the application form for bringing into compliance submitted to the competent authority. The template of the application form for brining into compliance contained in Section I of Appendix No. 2 to the Union Registration Rules coincides with the template for the application form for registration, requiring, among other things, to indicate the legal basis for athorisation of the drug from the list above.
The procedural logic of bringing into compliance is similar to other registration procedures (registration, renewal and variation to the registration dossier). It is performed according to the mechanism of the mutual recognition procedure, but differs from it in terms of time and scope of the assessment. In particular, parallels are traced in such moments as the choice of a reference Member State; the need to submit an application and dossier, fees payable; document flow between concerned Member States and between the reference Member State and the applicant, etc. At the same time, there is a difference from the mutual recognition procedure: in case the drug was registered according to national procedures in at least 3 Member States of the Union during 5 years or more, the issued registration certificate will immediately have indefinite validity.
As part of the bringing into compliance procedure, the reference Member State conducts a procedure for assessing the completeness of the file and its compliance with the registration application within 14 working days (the so-called “validation procedure”). If at the stage of validation questions arise regarding the completeness of the dossier, the applicant is sent a request for the submission of missing documents and data. Up to 90 calendar days are given for the applicant for response (the procedure stops at this point).
If there are questions about the quality, efficacy, or safety of the drug, the request is sent to the applicant, who, within no more than 90 calendar days, must reply or provide the necessary information. The specified period is also not included in the general term of the procedure. At the same time, the procedure is also suspended. It should be noted that the extension of the deadline for submitting the missing documents and data by the applicant, as well as in the procedure of mutual recognition, is not provided.
After receiving the applicant's response and completing the examination, the assessors of the reference Member State prepare the final assessment report on safety, efficacy and quality. After the exclusion of confidential information and placing in the open part of the unified register of registered medicinal products of the Union, the report becomes publicly available (including medical practitioners, patients, etc.). This completes the work in the reference Member State, and the applicant receives a registration certificate indicating the reference Member State.
Within 5 working days from the date of completion of work in the reference state, the modules of the registration dossier of the medicinal product and expert reports of the reference Member State become available in the recognition countries selected by the applicant. Assessors of the Member State concerned carry out an assessment of the assessment reports prepared by the reference Member State requesting, if necessary, the applicant for additional information that he must provide within 90 calendar days, after which they take 10 calendar days for decision-making on approval. The Member State concerned issues a registration certificate with the same number as issued by the reference Member State. The validity of the registration certificate in the Member State concerned is the residual period initially agreed by the reference Member State. It should be specifically emphasized that Member States concerned do not evaluate modules 2–5 of the registration dossier, but work only with module 1 and assessment reports of the reference Member State (however, Member State concerned can verify the compliance of assessment reports of the reference Member State with modules 2–5). Also, in the Member State concerned there is no laboratory quality check.
If the applicant does not immediately indicate all the Union states as Member State concerned, they are entitled to add them to the list at any time, and the mutual recognition procedure in these Member States will begin within 5 working days from the day the list is updated. If the drug was registered in these Member States before December 31, 2020, the registration certificate is issued for the remaining validity period of the registration certificate established by the reference Member State so that the renewal procedure will occur simultaneously in all Member State concerned.
Next, we turn to paragraph 175 of the Registration Rules for the Union, which characterizes the file submitted to the reference Member State in order to bring the dossier into compliance. The third subparagraph of the first paragraph and the second paragraph of this paragraph detail the requirements for the design of the dossier. Among other things, the applicant must provide:
… Modules 1 to 3 of the marketing authorization application dossier in electronic format drawn up as laid down in Appendices 1 to 5 to these Rules and Module 1 in paper format if the medicinal product is to be marketed within a Member State where it has been authorized.
All available data on non-clinical and clinical studies performed before the Agreement came into effect as laid down in paragraph 36 of these Rules shall be submitted in this case in Modules 4 and 5 of the marketing authorization application dossier in the form of appropriate reports without mandatory bringing them into compliance with the requirements of the Union.
At the same time, it is important to highligh the differences in the wording given in paragraphs 171 and 175 of the Union Registration Rules, since they determine the completeness of the dossier for compliance, which is especially important for holders of drug registration certificates registered in Member States according to national rules that in some respects differ from internationally recognized scientific requirements for demonstrating the safety, efficacy and quality of drugs. Thus, paragraph 171 of the Union Registration Rules imposes requirements for completeness, whereas paragraph 175 specifies the requirements for registration, additionally stipulating the unnecessary re-issuance of reports on preclinical and clinical studies. At the same time, paragraph 175 does not contain instructions on the uselessness of the reports themselves, since they are necessary in accordance with paragraph 171 of the Rules for the Registration of the Union.
Moreover, clause 176 of the Union Registration Rules states that:
The competent authority (assessment organization) of the reference Member State shall verify the completeness and accuracy of the format of the documents submitted in the marketing authorization application dossier within 14 days before the assessment of the marketing authorization application dossier is started. The applicant is given a maximum of 90 calendar days which are not to be counted in the medicinal product assessment period to provide missing materials to be included in the marketing authorization application dossier in response to the observations of the competent authority (assessment organization) of the reference Member State.
The competent authority (assessment organization) of the reference Member State shall refuse to accept an application for bringing a marketing authorization for a medicinal product into compliance with the requirements of the Union in case of failure to submit missing marketing authorization application dossier materials in response to the observations of the competent authority (assessment organization) of the reference Member State and/or payment of a fee (duty) for bringing a marketing authorization for a medicinal product into compliance with the requirements of the Union, as required by the reference Member State legislation, is not confirmed.
Thus, this clause defines the actions of the regulators in case of incompleteness of the dossier on bringing into conformity. In particular, if the validation of the dossier reveals missing of certain documents that should have been submitted, then the application for bringing into compliance will be rejected even before the beginning of the assessment. It should be noted that, within the framework of such a test, a distinction is made between the three characteristics of the dossier for compliance with: (1) completeness, (2) fullness, and (3) format. Completeness and fullness can be considered to some extent as synonyms, while format defines only the form of presentation of documents.
Thus, summarizing the provisions of paragraphs 171, 175 and 176 of the Registration Rules of the Union, it can be concluded that the applicant is required to submit a complete dossier in accordance with the requirements of Appendix No. 1 to the Registration Rules of the Union, including the required amount of non-clinical and clinical data depending on the legal basis for authorisation of the drug . In this case, only the documentation of modules 1-3 is subject to registration in accordance with the specified application. The dossier can be considered complete without preclinical and clinical studies, if there is an appropriate and sufficient scientific justification.
Since it will be necessary to validate a large number of files, in some cases it will not be possible to achieve full compliance with the requirements for completeness set in Annex 1, and such incomplete files will be rejected without assessment. This will enable constantly loaded assessors to focus on the assessment of the complete dossier, without being distracted by drugs with obviously insufficient extent of documents.
In addition, it should be noted that the successful completion of the initial validation phase does not prevent the refusal at any other stage of the procedure upon subsequent review of the file on the basis of inconsistency with the law or the lack of satisfactory supporting data.
■ Assessment considerations
Paragraphs 177-180 of the Union Registration Rules address assessment considerations of the complete dossier for bringing into compliance. The nature and extent of the assessment is determined by clause 178, which makes an important clarification regarding the assessment of the to be brought into compliance drugs. The second paragraph of the clause states that:
In the course of assessment of a marketing authorization application dossier for a medicinal product within the bringing a marketing authorization for a medicinal product into compliance with the requirements of the Union, reevaluation of the risk-benefit balance shall not be carried out …
For the correct interpretation of this clause, the following should be considered:
1. examination of any drug involves several types of assessments with a final decision based on a synthesis of their results;
2. assessments performed during the assessment include: (1) an assessment of administrative documents, (2) a quality assessment, (3) a safety assessment, and (4) a performance assessment.
At the same time, it is advisable to abandon the incorrect division of quality examination and examination of the ratio of expected benefits and possible risks of use, within the framework of national registration rules, since risks from the point of view of quality must be taken into account when assessing the benefits and risks of the drug and not reducing the benefits-risk balance to safety and efficacy analysis. Such an integrative approach is consistent with the definition of risk set forth in the Union Registration Rules: “risks associated with the use of a drug — any risks associated with the quality, safety or efficacy of a drug with respect to the health of patients or the public, or risks leading to an undesirable environmental impact”, and is consistent with the risk definition adopted in the European Union, the USA, Japan, Canada, a number of other countries, as well as WHO;
3. Since, in accordance with paragraph 41 of the Registration Rules of the Union, “an assessment of drugs is carried out to obtain a scientific assessment of the quality, safety and efficacy of drugs and the“ benefit-risk ”ratio of drugs ...”, despite the uselessness of re-estimating the “benefit-risk ”, an assessment of the quality, safety and efficacy of the drug should still be carried out.
In particular, it will be necessary to confirm the safety and efficacy of each indication for use included in the summary of product characteristics (SmPC) for the drug that is to be brought into compliance.
In addition, the need for documentation and confirmation of safety and efficacy arises from the need for submission and designation provided for by the same paragraph 175 in accordance with module 2. One should keep in mind that, among other things, module 2 includes sections 2.4 Non-clinical review, 2.5 Clinical review, 2.6 Preclinical summaries and 2.7 Clinical summaries. At the same time, in accordance with Annex No. 1 to the Rules for Registration of the Union, reviews should contain a critical assessment / analysis of preclinical and clinical data and research (own and literary data, depending on the registration group), as well as the rationale for the research strategy if necessary to deviate from the relevant requirements. It is necessary to answer all questions regarding the effectiveness and safety that have arisen in the development process and which have not been explained. The summaries (sections 2.6 and 2.7) should be actual summaries of their own preclinical and clinical information included in module 4 or 5. This once again confirms the thesis that it is necessary to submit a complete dossier in accordance with the requirements of Annex 1 to the Union Registration Rules, but without the need for re-writing of documents in the case of studies conducted in the period preceding the introduction of good practices, into the regulation.
It is important to bear in mind that Appendix No. 1 to the Rules for the Registration of the Union contains only general requirements for compiling a registration dossier. Detailed requirements for the type and scope of research, assessment criteria, goals to be achieved, etc. are contained in numerous documents that constitute the Union’s law, including documents that are under development. Moreover, given that in the near future it is not possible to transpose all applicable ICH, WHO, EMA, FDA, etc. documents containing the scientific criteria adopted by the regulatory community for safety, efficacy and quality, drug developers and regulators should also refer to the original sources to meet modern scientific requirements for the development of appropriate groups of drugs, since scientific standards for safety, efficacy and quality do not have national borders, are universal in nature and are based on current scientific knowledge in the field of human biology, pharmacology, materials and production processes. This approach is fully in line with the spirit of the Agreement, which enshrines the use of international approaches in developing policies for regulating the circulation of drugs (Article 3). Moreover, the scientific provisions of Union documents based on ICH, EMA, FDA, WHO, other organizations that draft scientific standards for development, production and quality assurance, as well as confirmation of the safety and efficacy of drugs, should be correlated with the original text and its meaning, despite the possible errors that have arisen during the transfer of regulatory norms to the Union documents, since the Union documents are developed on the basis of the principle of harmonization.
Since the alignment procedure is a point character, it is not possible to solve all the accumulated problems with it. That is why the Union Registration Rules provide for additional legal instruments.
■ Complementary Powers
Union Pharmaceutical Law provides regulators with a wide range of tools to ensure acceptable safety, efficacy, and quality of drugs entering the Union market throughout their life cycle. Regulators can also use such tools as part of the alignment procedure.
In particular, Section VII “Establishment of Post-Registration Measures (Registration on Conditions)” of the Union Registration Rules gives regulators the authority to introduce additional conditions for entering the market and staying on it above those set out in Appendix 1 to the Union Registration Rules Union, and beyond the standard pharmacovigilance requirements. Thus, clause 116 of the Union Registration Rules permits regulators, within the framework of registration and the implementation of procedures related to registration, to put forward one or more additional requirements. These requirements are:
to take certain measures for ensuring the safe use of the medicinal product to be included in the risk management system;
to conduct post-authorization safety studies of the medicinal product;
to introduce additional obligations on the marketing authorization for the medicinal product or reporting of suspected adverse reactions;
to conduct post-authorization efficacy studies and where necessary studies of some aspects of the efficacy of the medicinal product which can be resolved only after the medicinal product has been marketed;
other conditions or restrictions to ensure safe and efficacious use of the medicinal product in accordance with the requirements of the Good Pharmacovigilance Practice of the Eurasian Economic Union.
At the same time, such requirements/conditions are to be reflected in the product information and the Unified Register of the registered medicinal products of the Union, which increases the transparency of the decisions made by the competent authorities and allows better tracking of the drugs on the market subject to the observance of additional requirements.
Further to the provisions of clause 116, paragraph 117 of the Registration Rules of the Union obliges the MA holder to annually confirm compliance with the additional requirements put forward on the basis of clause 116. Such confirmation shall be carried out by the holder through an annual reassessment of the benefit-risk balance, under which the authorized body is obliged to overestimate ratio under the terms agreed in the SmPC. Thus, despite the fact that the regulator did not have the right to overestimate the “benefit-risk” ratio in the framework of the adjustment procedure, even if there are grounds for that, a year later - in the case of a decision within the framework of harmonization about registration on conditions - he can do this within the framework of the procedures of Section VII of the Registration Rules of the Union or cancel the registration certificate altogether if the established additional requirements have not been met by the holder of the registration certificate.
Moreover, within the framework of the aforementioned revaluation - in accordance with paragraph 118 of the Union Registration Rules - the regulator has the right to oblige the holder of the registration certificate to:
а) to conduct a post-authorization safety studies if there are concerns about the risks of such a medicinal product. If the same concerns apply to more than one medicinal product, the competent authorities of the Member States shall encourage the marketing authorization holders of such medicinal products to conduct a joint post-authorization safety study;
b) to conduct a post-authorization efficacy study when the understanding of the disease or the clinical methodology indicate that previous efficacy evaluations might have to be revised significantly.
Thus, paragraph 118 of the Registration Rules for the Union gives regulators the opportunity to review not only safety, but also the effectiveness of a drug for one, several, or all indications for use, including on the basis that “an understanding of the disease or clinical methodology shows that previous performance evaluations require substantial revision. This rule is particularly relevant for old drugs, the effectiveness of which, with many indications from the standpoint of current knowledge in the field of clinical medicine, is questioned.
At the same time, the annual procedure for reassessing the “benefit-risk” relationship must be carried out in accordance with the procedure described in detail in Section VIII “Confirmation of registration (renewal) of a medicinal product” of the Union Registration Rules. Paragraph 146 of this section provides grounds for refusing to maintain registration, including:
а) the following serious risks of the medicinal product are remaining at the moment of confirmation (renewal) of a marketing authorization:
the risk-benefit balance proves to be unfavorable or the therapeutic efficacy proves to be lacking when the medicinal product is used according to the SmPC;
false or obsolete information in the marketing authorization application dossier accompanying the application for the confirmation (renewal) of the marketing authorization;
c) the marketing authorization holder fails to comply with the pharmacovigilance obligations or obligations of the conditional marketing authorization.
Finally, Section X “Suspension, revocation of a registration certificate, or restriction of use, or amending the conditions of a registration certificate” of the Union Registration Rules closes the regulatory cycle. Thus, paragraph 159 provides that:
Member States shall suspend the marketing authorization or restrict the supply of the medicinal product, if the view is taken that:
the favorable risk-benefit balance is not shown within the reassessment of the risk-benefit balance carried out annually by the competent authority (assessment organization) as laid down in paragraph 117 of these Rules;
the marketing authorization holder has not fulfilled the obligations imposed by the competent authority (assessment organization) as laid down in the paragraphs 116 and 118 of these Rules.
At the same time, following the suspension, on the basis of clause 160 of the Union Registration Rules, a revocation of the registration certificate may follow, if the holder of the registration certificate does not fulfill the requirements for correcting the situation.
Thus, a full-fledged regulatory cycle is formed, and the authorized bodies receive an effective instrument with respect to drugs with unproved safety or efficacy. At the same time, the rules for registering the Union are balanced, since they give the holders of registration certificates the opportunity to react appropriately to the additional requirements and to defend their interests within the framework of regulated dispute resolution procedures.
Agreement on the Common Principles and Rules of Medicinal Products Circulation within the Eurasian Economic Union (available in English)
Rules for granting a marketing authorization and assessment of medicinal products for human use as adopted by Decision of the Council of the Eurasian Economic Commission No 78 of 3 November 2016 (available in English)
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