1.2. EAEU Pharmaceutical Market: Regulations and Guidelines, Part 1

Thus, the Agreement on the common principles and rules of medicinal products circulation within the Eurasian Economic Union envisages adoption of a number of second-level regulations which detail the requirements, rules, procedures, and guidance for development, authorization, and life-cycling of medicinal products for human use. Those documents will be considered next in the order they have been adopted by the legal bodies of the Eurasian Economic Union. In September 2015, the first two documents were adopted by the Eurasian Economic Commission: the Conception of Harmonization of Pharmacopeias of the Member States of Union and the Rules of Procedure of the Pharmacopoeial Committee. Texts of EAEU Pharmacopoeia will be predominantly imported from other sources. The main pharmacopoeia from which texts are to be imported is the European Pharmacopoeia, whereas the U.S. Pharmacopoeia, British Pharmacopoeia, and Japanese Pharmacopoeia serve as supplementary sources. Purely national texts of pharmacopoeias of the Member States also may be used, but the information contained therein is not as robust. The main principle of establishing new texts is importing them from European Pharmacopoeia with no amendments or only minor amendments (rarely). Thus, the primary purpose of the Pharmacopoeial Committee is to verify that the translation of texts into Russian is correct and to support harmonization with other legal acts of the Union. The draft Table of Contents is available, and it follows that of the European Pharmacopoeia. The Rules of procedure set procedures for the adoption of new chapters and monographs, as well as the maintenance of the existing ones. Further on, in December of 2015, another three documents were adopted: The Eurasian Economic Union pharmaceutical dose form nomenclature which is based on EDQM’s Standard Terms. However, Standard Terms have been modified to take into account some local nuances. Hopefully, the Nomenclature will be amended in the future to sort out all the inconsistencies with the EDQM’s Standard Terms. Next is the Rules of determining of supply category of medicinal products subject to prescription and not subject to prescription. The document is based on two sources: Title VI Classification of medicinal products of Directive 2001/83/EC and the Guideline on changing the classification for the supply of a medicinal product for human use issued by the European Commission. The third document is the Rules of classification of medicinal products to be available on prescription or without prescription taking into account the active substances contained thereof. This is based on the EDQM’s Resolution RESAP(2007)1 on the classification of medicines as regards their supply which was renewed in 2014. The next set of regulations was adopted a year later, in November of 2016, when all disagreements between the Member States were resolved. The main issue of disagreement concerned the interchangeability of medicinal products. The decision was postponed and will be considered in the future since the model suggested by Russia is inoperable. The adopted document forms the legal and operational environment for the Single Market to function within. The Rules lay down the legal framework for marketing authorization procedures and lifecycling procedures (including renewal and variation) for medicinal products for human use. They also envisage upgrading the MAA dossiers of medicinal products authorized via national procedures to bring those dossiers into compliance with the Union requirements. Authorization procedures somewhat resemble those of the European Union. However, only two of four EU procedures will be used in the EAEU in the near future, namely the mutual recognition and decentralized procedures. Thus, neither the national procedure nor centralized procedure is envisaged so far, but many stakeholders hope that the centralized procedure will be created in the future. The main principle of creating Union legislation is using foreign experience. The legal system which is the most relevant to the Eurasian Economic Union model is that of the European Union. This is why principles and provisions outlined in EU legislation were used to create the Rules. The main source document underlying the Rules is Directive 2001/83/EC of the EU. For instances, provisions laying down the imposition of post-marketing measures; renewal of a marketing authorization; variation to the marketing authorization; suspension or revocation of a marketing authorization were directly sourced from the Directive. The Rules have 20 appendices most of them represent the adapted translation of EU/EC/EMA legal acts and guidelines. In the following several slides, we will describe the content and the sources of the appendices to the Rules. The first Appendix outlines the requirements for a marketing authorization application dossier. It was drafted based on Annex I of Directive 2001/83/EC as amended and Annex II of Chapter 1 – Marketing Authorization, Vol. 2A, EudraLex. The second Appendix contains application templates for a marketing authorization for a medicinal product, variation applications, renewal applications, etc. It was derived from the EU Application Forms, Volume 2B – Presentation and content of the dossier, EudraLex. Appendix 3 provides guidance on drafting a normative document accompanying an application for a marketing authorization. This is a type of a document used in Belarus, Kazakhstan, and Russia only, so no foreign sources are available. Appendix 4 lays down requirements for a marketing authorization application dossier in the Common Technical Document (CTD) format. This is based on Appendix 1, so indirectly the source is the Annex I to Directive 2001/83/EC. Appendix 5 describes the Organization of the Common Technical Document for the registration of pharmaceuticals for human use, and it represents the direct translation of ICH M4 Organization of the Common Technical Document for the registration of pharmaceuticals for human use. Appendix 6 provides a template for Critical Assessment Report, Non-Clinical Aspects and was drafted based on the EMA Day 80 assessment report – Non-clinical template. Appendix 7 provides a template for Critical Assessment Report, Clinical Aspects and was drafted based on the EMA Day 80 assessment report – Clinical template. Appendix 8 provides a template for Critical Assessment Report, Quality Aspects, and it is based on EMA Day 80 assessment report – Quality template and the EMA Active substance master file (ASMF) assessment report template. Appendix 9 provides a New active substance status template for Critical assessment report on the claim of new active substance status, and it is based on the EMA Day 80 assessment report – New active substance status template. Appendix 10 outlines the Active Substance Master File Procedure which was adapted from the EMA Guideline on Active Substance Master File Procedure. Appendix 11 provides Preliminary summary report template and is based on the EMA Day 120 list of questions template. Appendix 12 provides a test report template. The template is to be completed by the reference Member State’s control laboratory carrying out verification of test method included in the specification of the finished product. This does not have any sources as it pertains to local aspects of authorization procedures. All the templates are for use by the regulatory authorities. Appendix 13, 14, and 15 represent the guidance documents on the content of the critical assessment report on non-clinical, clinical, and quality aspects. They are intended to complement the appropriate template and are based on the appropriate EMA guidance documents. Appendix 16 provides an overview template for Critical assessment report on Safety, Efficacy, and Quality and is based on the EMA Day 80 assessment report – Overview template. Appendix 17 provides a template for a Certificate of marketing authorization for a medicinal product for human use. No foreign sources were used to draft the document. Appendix 18 provides a Member State concerned comments template, and it is adapted from the CMDh Concerned Member State Comments on Day 70 Preliminary Assessment Report. Appendix 19 outlines the Rules concerning the processing of variations to the terms of marketing authorizations for medicinal products for human use and is adapted from the European Commission Regulation (EC) #1234/2008 as amended and the Annex to the European Commission Guidelines on the details of the various categories of variations. Appendix 20 is complementary to Appendix 19 and outlines the Rules concerning the examination of variations to the terms of marketing authorizations for medicinal products for human use. The Appendix is based on the main text of the European Commission Guidelines on the details of the various categories of variations. Appendix 21 provides a template for type I Variation Critical Assessment Report and is based on the EMA template for rapporteur Type II variation assessment report. Appendices 22 and 23 provide a template and a guidance complementary to the template on the content of critical assessment report for non-clinical and clinical aspects of generic medicinal products. The appendices are adapted from the EMA Day 80 assessment report – Generic clinical and non-clinical template and guidance, respectively. The Rules of good manufacturing practice were enacted together with the Rules of authorization and assessment. The GMP rules are based on those provided in the EudraLex – Volume 4 – Good Manufacturing Practice guidelines of the European Union. Namely, the Glossary, Parts I to III, as well as Annexes to Part I were translated. However, several, albeit minor, amendments were introduced making the EAEU rules somewhat different from the EU guidelines. It is worth noting that when drafting the Union pharmaceutical law, the Member States paid attention mostly to the technical aspects of good practices while procedural aspects were largely ignored. This created procedural vagueness and needs to be addressed in the near future. For instance, GMP rules lack the provisions similar to those laid down in Titles IV and XI of Directive 2001/83/EC, Directive 2003/94/EC of the European Union, as well as national provisions of EU Member States, such as contained in the UK Human Medicines Regulations of 2012. The Rules of good distribution practice, approved together with other documents, are based on the European Commission Guidelines on Good Distribution Practice of Medicinal Products for Human Use. Similar to GMP rules, almost no procedural aspects were included in the document such as envisaged by Titles IV, VII, and XI of Directive 2001/83/EC or national provisions of EU Member States, such as contained in the UK Human Medicines Regulations of 2012. Thus, only technical provisions are included in the EAEU GDP Rules so far. Moreover, the EU Guidelines on GDP of active substances were not also taken into account. Similar to other GxP rules of the Eurasian Economic Union, the Rules of good laboratory practice were adapted from a foreign source. For GLP, these are OECD GLP guidelines. Thus, the GLP of the Union does not contain any regulatory procedures such as those outlined in the EU Directives 2004/9/EC and 2004/10/EC and national legislation of the EU Member States, such as the Good Laboratory Practice Regulations of 1999 of the UK. In addition, the Rules are limited only to medicinal products. Rules of good clinical practice of the Eurasian Economic Union also became effective on November 3rd, 2016. Union GCP rules are based on several ICH and EU documents pertaining to clinical trials: The main text is a translation of ICH E6(R1) GCP guideline. Upgrade to ICH E6(R2) is forthcoming. Appendix 1 is sourced from ICH E3 Structure and Content of CSR. Appendices 2 to 9 represent annexes to ICH E3. Appendix 10 contains a list of amendments to a Clinical Trial Application considered substantial, which is based on the MHRA Substantial Protocol Amendments List. Appendix 11 contains Rules of safety reporting for ongoing clinical trials which have no formal source. Appendix 12 lays down the Requirements for Development Safety Update Report. These are based on ICH E2F. As in the case of other GxP, GCP rules lack procedural aspects, such as contained in EU Regulation (EU) N 536/2014 or the UK Medicines for Human Use (Clinical Trials) Regulations 2004. Rules of Good Pharmacovigilance Practice conclude the GxP rules of the Union enacted in November 3rd, 2016. The main source of the rules is the appropriate chapters of the EU GVP guidelines. Yet, GVP rules of the EAEU have the same drawback as other Union GxP rules. In this case, provisions similar to those of Titles IX and XI of Directive 2001/83/EC, Commission Implementing Regulation (EU) No 520/2012 and national provisions of the EU Member States, such as contained in the UK Human Medicines Regulations of 2012, have not been taken into account.

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