Drug administration and clinical pharmacy column
 
Brief introductionfor search and determination of the comparator product for generic medicinal product application in the EU           
Jianzhao Niu, Dongsheng Yang, Mingdi Xu*           
National Institutes for Food and Drug Control, Beijing 100050, China
 
 
Abstract: It is vital segment to choose the right comparator product during the development and study of generic medicinal product, and this is also definitely specified in the relevant documents from the China Food and Drug Administration (CFDA) that the comparator product should be innovator product or internationally recognized same medicinal product, which is used in the re-evaluation of generic medicinal product or marketed authorization application of the generic medicinal product. To facilitate the domestic and foreign pharmaceutical enterprises to choose and determine comparator product, four medicinal product evaluation procedures, as well as the corresponding marketed medicinal product list, are detailed elaborated in this paper. At the same time, by taking the Mifepristone Tablet (200 mg) as example, the search and determination process of the comparator product for generic medicinal product application in the EU is illustrated with the combination of different marketed medicinal product lists.   
Keywords: Comparator product; Re-evaluation of generic medicinal product; Marketing authorization application; Mifepristone tablet    
CLC number: R951                Document code: A                 Article ID: 10031057(2018)1180508
 
 
1. Introduction
The suitable selection of the comparator product is an important segment during the development and research of generic medicinal product. In China, the comparator product is the reference product used in the re-evaluation of generic medicinal product, which is usually the object to be imitated. As described in the documents, guidelines for selection and determination of comparator product for Immediate Release Solid Oral Dosage Forms[1] and Announcement on the issuance on filing and recommendation procedures for the comparator product used in the re-evaluation of generic medicinal product[2], published by the China Food and Drug Administration (CFDA), the innovator product, or the  comparator product approved to be marketed in EuropeanUnion (EU), the United States of America (USA) or Japan as the internationally recognized same medicinal product can be used as comparator product. As of April 27, 2018, 14 batches of Chinese comparator product directories for generic medicinal product have been published[3]. In USA or Japan, the Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book)[4] and Japanese Orange Book English Version[5] can be used for the search of comparator product. While in EU, no unified and clear list of comparator product can be used due to a variety of reasons. In this paper, the method and procedure were introduced for search and determination of the comparatorproduct, which is named as Reference Medicinal Product (RMP) in EU, during the Marketing Authorization Application (MAA) of generic medicinal product. Moreover, it is expected to give reference for the Chinese or foreign pharmaceutical enterprises to choose and determine comparator product in the process of their Generic Applications in EU or re-evaluation of generic medicinal product in China. 
2. Regulatory basis and relevant definitions
The EU was developed from the European Community and now has 28 Member States. The legal system of the EU consists of Treaties, Regulations, Directives, Decisions, Recommendations and Opinions. Among them, the European Union Directive on medicines for human use and its revised edition (Directive, 2001/83/EC,as amended)[6] is one of the most relevant laws related to drug product regulation. The directive was promulgated in 2001, and so far, 12 revisions have been made. It is a comprehensive Directive including the all aspects of the medicinal product for human use, such as MAA, manufacturing, distribution and regulation. In EU, the comparator product is composed of RMP and European Reference Medicinal Product (ERP)[7], and the detailed definitions are as follows. 
2.1. Generic medicinal product
In accordance with article 10 (2) (b) of the European Union Directive on medicines for human use and its revised edition (Directive, 2001/83/EC, as amended), generic medicinal product means a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the RMP, and whose bioequivalence with the RMP has been demonstrated by appropriate bioavailability studies. The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance should be considered to be the same active substance, unless they significantly differ in properties with regard to safety and/or efficacy.
2.2. RMP
In accordance with article 10 (2) (a) of the EU Directive on medicines for human use and its revised edition (Directive, 2001/83/EC, as amended), RMP means a medicinal product authorized under Article 6 (application submitted to the European Medicines Agency (EMA)), or in accordance with the provisions of Article 8 (application submitted to the competent authority of the Member State), and its submitted document should conform to the requirements of CommonTechnical Document (CTD), which include the contents of pharmaceutical (physico-chemical, biological or microbiological) tests, pre-clinical (toxicological and pharmacological) tests, and clinical trials. Therefore, according to its approval procedure, the RMP may be approved either by the European Commission (EC), or by the competent authority of the Member State.
2.3. ERP
In the case of an RMP which has never been authorizedin the chosen Reference Member State (RMS) orthe chosen Concerned Member State (s) (CMS), an RMP authorized by another national competent authority of the Member State or by the EC can be chosen. This RMP is the so-called ERP. With generic application of Lacidipine Tablets in the Netherlands as example[8], three strengths (2, 4 and 6 mg) are scheduled to be submitted in the application. However, in the Netherlands,there are only two strengths (2 and 4 mg) of the innovator product approved for market. Therefore, for those two strengths, it may choose corresponding strengths approved in the Netherlands as RMP, and for 6 mg strength, it can only choose that approved in other Member State, such as Portugal, with the same strength as comparator product, namely the ERP.
At the request of the competent authority of the Member State in which the application is submitted, the competent authority of the other Member State should transmit, within a period of one month, a confirmation that the RMP is or has been authorized together with the full composition of the reference product and if necessary other relevant documentation. 
3. Procedures for MAA in EU
A medicinal product may only be placed on the market in the EU when a marketing authorization has been issued by the competent authority of a Member State for its own territory (national authorization) or when an authorization has been granted by EC for the entire Union (Union authorization). The union authorization is for drugs intended to be marketed across the EU, and it includes the Centralized Procedure (CP); and national authorization composed of Decentralised Procedure (DCP), Mutual Recognized Procedure (MRP), and National Authorization Procedure (NP)[9].
3.1. CP
A marketing authorization granted under the CP is valid for the entire EU market, which means the medicinal product may be put on the market in all Member States. The MAA is submitted to EMA, who organizes to carry out a scientific assessment of the dossiers and gives a recommendation onwhether the medicine should be marketed or not. In addition, based on the recommendation, the EC may grant the authorization, which is valid in all EU Member States. The medicinal products may fall within the mandatory scope or the optional scope in the CP. 
3.2. DCP
For medicinal products not falling within the mandatory scope of the CP, and it is scheduled to be marketed in several Member States, the applicant may request one or more concerned Member State(s) to approve MAA of medicinal product by the recommendations from the chosen RMS. The application is submitted to the competent authorities of the RMS and the concerned Member State. At the end of the DCP with a positive agreement, a national marketing authorization will be issued in the RMS and the concerned Member State.
3.3. MRP
This procedure is suitable to medicinal products not falling within the mandatory scope of the CP, and it has already been approved in EU. It is based on the mutual recognition by concerned Member State (s) of a national marketing authorization granted by the RMS. The concerned Member State refers to the RMS that issued the national marketing authorization on which the MRP is based. At the end of the MRP, a national marketing authorization will be issued in the concerned Member State (s).
3.4. NP
This procedure is suitable to medicinal products not falling within the mandatory scope of the CP, and is not to be authorized in more than one Member State. The approval of this application is mainly according to its own prescribed procedure of Member State.
4. Procedures for search and determination of the RMP  
To market a medicinal product in EU, the applicant can choose suitable submission and procedure accordingto its purpose. Therefore, there is no uniform list containing all of drugs that have been marketed in the EU. Moreover, the market status of medicinal product in the EU, as well as the determination of its RMP, may be different due to the original evaluation and approval procedure of MAA. In order to facilitate domestic or foreign pharmaceutical enterprises to select and determine the suitable RMP, three types of lists for marketed medicinal product in the EU are introduced based on the different evaluation and approval procedure, along with their retrieval methods for reference.  
4.1. Community Register of medicinal products
The Community Register of medicinal products[10] contains medicines that have been evaluated by the EMA and approved by EC since the establishment of the EMA in 1995. Clicking on the web site of Community Register, it can login its directory easily, and then by using different ways of retrieval, such as, the name of Drug Substances for theexpected medicinal product, as keyword, and search to obtain a list of all marketed product with same drug substance in this directory, and then, preliminarily select the possible RMP as candidate by integrating the approval date and other acquired product information.
4.2. MRI Product Index
The MRI Product Index[11] includes medicines approved in the Member States of the EU according to the MRP or DCP. Clicking on the web site of MRI Product Index, it can login the index easily, and with the similar operation as in Community Register of medicinal products, take the name of Drug Substances for the expected medicinal product as keyword,and search to obtain a list of all marketed product with same drug substance in this directory, and then, preliminarily select the possible RMP as candidate in this index by integrating the approval date and other acquired product information.
4.3. List of medicinal products in each Member State
The applicant can also search the possible RMP in the medicinal product list of each EU Member State. By conducting the similar operation, search with the name of Drug Substances as keyword, to obtain a list of all marketed product with same drug substance in this Member State, and then preliminarily select the possible RMP as candidate. For example, login in the website of Medicines and Healthcare Products Regulatory Agency (MHRA)[12], competent authority of United Kingdom, and click the interlinkage for the marketed authorization, and it listed all of the medicinal products approved by MHRA since 2001, which is the starting point for the implementation of EU Directive on medicines for human use and its revised edition (Directive, 2001/83/EC, as amended).
4.4. Determination of the RMP
After the RMP candidates were preliminarily selectedthrough the various ways by the applicant, it can be further determined by the communication of the correspondingcompetent authority in EU. The contact information may be obtained from the website of EMA or Member State regulatory authority, and the detailed information also can be found in the website for Co-ordination group for Mutual recognition and Decentralized procedures-human (CMDh). When receiving the consultation letter from the applicant, the competent authority may reply in several working days or weeks to determine if the proposed candidate can be used as the RMP.
5. Example
To facilitate the understanding and conducting, the searching and determination process of RMP for generic Mifepristone Tablet (200 mg), used in supporting an MAA in the EU, is illustrated by combination of the three types of directories, such as Community Register, MRI Product Index and approved medicinal products list in each member state of EU. In addition, the specific operation process is as follows.
5.1. Searching in Community Register of medicinal products
Click the website of the Community Register, and search with “Mifepristone”, the drug substance of Mifepristone Tablet (200 mg), as the keyword, no results indicated. Because the Community Register includes medicinal product evaluated by EMA since its establishment in 1995 and approved by the EC, so a preliminary judgment can be reached that the RMP of Mifepristone Tablets (200 mg) should be marketed before 1995.
5.2. Searching in MRI Product Index and MHRA
Click the MRI Product Index and the website of MHRA in the United Kingdom respectively, and take “Mifepristone”, the drug substance of Mifepristone Tablets (200 mg) as the keyword for searching. The results are shown in Table 1 and Table 2, respectively.
As shown in Table 1 and Table 2, “Mifegyne Combi”, “MEDABON” and “Mifegyne COMBIKIT” are all combination medicinal products, and the strength for “Mifegyne 600 mg” is not matched. Therefore, the preliminary summary of the Mifepristone Tablets (200 mg) marketed in the EU is compiled in Table 3.  
 
Table 1. Summary of medicinal product containing mifepristone as drug substance in theMRI Product Index.
 
 
 
Table 2. Summary of medicinal product containing mifepristone as drug substance in United Kingdom.
 
 
 
Table 3. Summary of Mifepristone Tablets (200 mg) marketed in EU.
  
 
5.3. Further supplement of product marketed in other Member States
It can be seen from Table 1 that the RMS of “Mifepristone Linepharma” is Sweden. Therefore, the RMP may be marketed in Sweden. At the same time, the manufacturers of the four products listed in Table 3 are all in France. Therefore, the RMP may be also marketed in France. As a result, the further searching is carried out to the marketed products of Mifepristone Tablets (200 mg) in Sweden and France, and specific results as shown in Table 4 and Table 5, respectively.
 
 
Table 4. Summary of Mifepristone Tablets (200 mg) marketed in Sweden.
 
 
 
 
Table 5. Summary of Mifepristone Tablets (200 mg) marketed inFrance.
  
 
 
5.4. Determination of the RMP
According to the results listed in Table 3, Table 4 and Table 5, the approval date for the “Mifegyne 200 mg” held by “EXELGYN” in France is December 28, 1988, which is the earliest marketing time. Therefore, this product is initially determined as the RMP of Mifepristone Tablets (200 mg) in the market of the EU. For the further verification, the email was sent to the regulatory authority in France, United Kingdom and Sweden, respectively, and positive replies were received in a few weeks. The “Mifegyne 200 mg” can be used as RMP of Mifepristone Tablets (200 mg) in the market of the EU. 
5.5. Conclusions
In a whole, the search and determination process of the comparator product for generic medicinal product application in the EU is illustrated as following Figure 1.
 
 
 
Figure 1. The search and determination process of the comparator product for generic medicinal product application in the EU.  
6. Discussion
Different from the simple way in the USA or Japan, the search and determination process of the comparator product for Generic Medicinal Product in EU is a complexprocedure due to its history and development. To facilitatethe Chinese or foreign pharmaceutical enterprises choose and determine the suitable comparator product used for the process of Re-evaluation of Generic Medicinal Product in China or the application for Generic Medicinal Product in EU, the detailed description of the search and determination process of the comparator product, RMP or ERP in EU, is provided in this paper. By reference to the marketed medicinal product list in different ways, and as directed in the provided example, Mifepristone Tablets (200 mg), it is expected to give the inspiration and help for practitioner in pharmaceutical field, as well as the decision maker in regulatory authority in China in their determination of the comparator product.
Acknowledgements
This research was supported by National Science and Technology Major Projects for ‘Major New Drugs Innovation and Development’ (Grant No. 2017ZX09101001, Beijing, China). 
References
[1] China Food and Drug Administration. Guidelines for selection and determination of Comparator Product for Immediate Release Solid Oral Dosage Forms (No. 61 in 2016) [EB/OL]. [2016-03-18]. http://www.sda.gov.cn/WS01/CL1751/147583.html
[2] China Food and Drug Administration. Announcement on the issuance on filing and recommendation procedures for the Comparator Product used in the Re-evaluation of Generic Medicinal Product (No. 99 in 2016) [EB/OL]. [2016-05-19].http://www.sda.gov.cn/WS01/CL1757/153485.html
[3] CFDA center for drug evaluation. State Food and Drug Administration’s announcement on the release of 14th batch of Chinese Comparator Product directories for generic medicinal product (No. 20 in 2018) [EB/OL]. [2018-04-27]. http://www.cde.org.cn/news.do?method=viewInfoCommon&id=314453
[4] US FDA. Approved Drug Products with TherapeuticEquivalence Evaluations (Orange Book) [EB/OL]. [2017-01-01]. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/UCM071436.pdf
[5] MHLW. Jp-orangebook home page. [EB/OL]. [2018-06-30]. http://www.jp-orangebook.gr.jp/english/
[6] EMA. Directive 2001 /83 /EC of the European parliament and of the council of 6 November 2001 on the communitycode relating to medicinal products for human use [EB/OL]. 2001[2012-11-16]. http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02001L0083-20121116&qid= 1488777888862&from=EN
[7] Coordination Group for Mutual Recognition and DecentralisedProcedure (human). CMDh WORKING DOCUMENT - INFORMATION TO BE SUBMITTED BY THE MEMBER STATE OF THE EUROPEAN REFERENCE MEDICINAL PRODUCT [EB/OL]. [2016-10]. http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/procedural_guidance/Generics/CMDh_088_2006_Rev03_2016_10_clean.pdf
[8] HMA. Public Assessment Report: Lacidipine Double-e Pharma 2 mg,4 mg and 6 mg film-coated tablets. [EB/OL]. [2016-07-28]. http://mri.cts-mrp.eu/download/NL_H_2992_001_PAR.pdf 
[9] European Commission. NOTICE TO APPLICANTS, VOLUME 2A Procedures for marketing authorisation CHAPTER 1 MARKETING AUTHORISATION [EB/OL]. [2016-12]. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-2/vol2a_chap1_rev6_201612.pdf
[10] European Commission. Community Register of medicinal products [EB/OL]. [2017-02-23].http://ec.europa.eu/health/documents/community-register/html/index_en.htm
[11] Coordination Group for Mutual Recognition and Decentralised Procedure (human). MRI Product Index [EB/OL]. [2018-08-29]. https://mri.cts-mrp.eu/Human/
[12] United Kingdom. Marketing authorisations: lists ofgranted licences [EB/OL]. [2014-12-18]. https://www.gov.uk/government/collections/marketing-authorisations-lists-of-granted-licences
 
 
 
 
欧盟仿制药参比制剂检索与确认简介
牛剑钊, 杨东升, 许鸣镝*
中国食品药品检定研究院, 北京100050       
摘要: 参比制剂的选择是仿制药开发和研究的一个重要环节。国家食品药品监督管理总局相关公告明确了用于仿制药质量与疗效一致性评价或仿制药申请时的参比制剂应为原研药品或国际公认的同种药物。为了帮助国内外仿制药企业正确检索和确定欧盟的参比制剂, 本文详细介绍了欧盟药品的四种审评方式及相应的上市产品目录。同时以检索仿制药米非司酮片(200 mg)在欧盟上市申请时须选用的参比制剂为例, 结合不同的上市产品目录详细介绍了检索和确定欧盟仿制药的参比制剂过程。 
关键词: 参比制剂; 仿制药质量与疗效一致性评价; 上市许可申请; 米非司酮片
  
 
 
Received: 2018-08-30, Revised: 2018-10-16, Accepted: 2018-10-23.
Foundation item: National Science and Technology Major Projects for ‘Major New Drugs Innovation and Development’ (Grant No. 2017ZX09101001, Beijing, China).
*Corresponding author. Tel.: +86-010-67095371, E-mail: xumingdi@nifdc.org.cn       
 
  
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