日本のジェネリック医薬品開発での BMV ガイドライン対応 Implementation of the BMV Guideline for Generic Drug Development in Japan 立木 秀尚 東和薬品株式会社、日本ジェネリック製薬協会 Hidehisa Tachiki Towa Pharmaceutical Co., Ltd., Japan Generic Medicines Association (JGA) 第6回JBFシンポジウム／The 6th JBF Symposium (26 Feb. 2015, Tokyo) 2015 Outline Generic Drug Development in Japan 1. Generic Drug Development in Japan 2. Before the BMV Guideline (~March 2014) 3. Implementation of the BMV Guidelines (July 2013~) 2015 1 1. Generic Drug Development in Japan (1/4) Generic Drug Development in Japan History of Guidelines for Bioequivalence Studies 1980 「医薬品の製造又は輸入の承認申請に際し添付すべき資 料の取扱い等について」（S55年5月30日薬審718 号） 「生物学的同等性に関する試験基準」（別表２） 1997 「後発医薬品の生物学的同等性試験ガイドライン」（H9年 12月22日医薬審第487号） 2012 「後発医薬品の生物学的同等性試験ガイドライン」（H24 年1月29日薬食審査発0229第10号） English: “Guideline for Bioequivalence Studies of Generic Products” 2013 「BMV(LC)ガイドライン」 “BMV(LC)guideline” 2015 2 1. Generic Drug Development in Japan (2/4) Generic Drug Development in Japan Assessment of Bioequivalence Bioavailability: In the bioequivalence study, bioavailability should be compared for innovator and generic products. Parameters: AUCt and Cmax Criteria: The 90% confidence interval of difference in the average values of logarithmic parameters to be assessed between test and reference products is within the acceptable range of log(0.80) - log(1.25). “Guideline for Bioequivalence Studies of Generic Products”(BE Guideline) 2015 3 1. Generic Drug Development in Japan (3/4) Generic Drug Development in Japan BMV in the BE Guideline Q-27 Please describe the analytical validation in detail. • Stability of substances to be measured in samples under the storage conditions (including freeze and thaw stability) • Accuracy • Precision (repeatability and intermediate precision) etc... Reference : • V.P. Shah, et al.,Bioavailability, bioequivalence and pharmacokinetic studies. J. Pharm. Sci., 81, 309 (1992). • ISO 5725-6 Accuracy (trueness and precision) of measurement methods and results - part 6: Use in practice of accuracy values. etc… “Guideline for Bioequivalence Studies of Generic Products Q&A” 2015 4 1. Generic Drug Development in Japan (4/4) Generic Drug Development in Japan Summary 1 The latest BE guideline does not support the latest BMV guidelines. 2015 5 Outline Generic Drug Development in Japan 1. Generic Drug Development in Japan 2. Before the BMV Guideline (~March 2014) 3. Implementation of the BMV Guidelines (July 2013~) 2015 6 2. Before the BMV Guideline (1/6) Generic Drug Development in Japan Generic Drug Application in Japan Two Times of Application in A Year (February and August) Many Applications ex) Candesartan Cilexetil (Listed Dec. 2014) 144 products from 33 companies (manufacture and sales approval, sales approval) 2015 7 2. Before the BMV Guideline (2/6) Generic Drug Development in Japan Generic Drug Application in Japan (in JGA, ~Mar.2014) Without CTD (Common Technical Document) Without BMV Documents 2015 8 2. Before the BMV Guideline (3/6) Generic Drug Development in Japan The questionnaire survey (in JGA, Oct. 2011) Q1. What kind of guidelines do you adopt for BMV? (except for BE guidelines) Q2. Have you ever performed “ISR”? 2015 9 2. Before the BMV Guideline (4/6) Generic Drug Development in Japan The questionnaire survey (in JGA, Oct. 2011) Q1. What kind of guidelines do you adopt for BMV? (except for BE guidelines) > Guidance for Industry: Bioanalytical Method Validation (FDA 2001) * Some companies made this document reference. 2015 10 2. Before the BMV Guideline (5/6) 2015 Generic Drug Development in Japan 11 2. Before the BMV Guideline (6/6) Generic Drug Development in Japan Summary 2 The latest BE guideline does not support the latest BMV guidelines. Many Japanese generic drug companies had not applied latest BMV guidelines. (Oct. 2011) Most of Japanese generic drug companies had never performed ISR. (Oct. 2011) 2015 12 Outline Generic Drug Development in Japan 1. Generic Drug Development in Japan 2. Before the BMV Guideline (~March 2014) 3. Implementation of the BMV Guidelines (July 2013~) 2015 13 3. Implementation of the BMV Guideline (1/4) Generic Drug Development in Japan Problems (Oct. 2011) Many Japanese generic drug companies had not applied latest BMV guidelines. Most of Japanese generic drug companies had never performed ISR. Implementations BMV Working Group in JGA (~Aug. 2013) Lectures for Education about Bioanalysis or ISR 2015 14 3. Implementation of the BMV Guideline (2/4) Generic Drug Development in Japan Generic Drug Application (Feb. 2015) for JGA BMV Report (Validations and Study Sample Analysis) shall be attached to Clinical Study Reports. The mention points of ISR must be shown in the table of contents of the application document. CTD is also possible. 2015 15 3. Implementation of the BMV Guideline (3/4) Generic Drug Development in Japan The Common BMV Document Format for Generic Drug Application (JGA) ○○○○錠**mgの生体試料中薬物濃度分析および分析法バリデーション の結果要約（案） ※ ※ 青文字は、適宜追加項目 赤文字は注釈 「医薬品開発における生体試料中薬物濃度分析法のバリデーションに関 するガイドライン」及び「医薬品開発における生体試料中薬物濃度分 析法のバリデーションに関するガイドライン質疑応答集（Ｑ＆Ａ）」 に基づいて、以下のように血漿中○○○○濃度測定の分析法バリデー ション（※ パーシャルバリデーションもしくはクロスバリデーショ ンの場合は書き換え）および実試料分析を実施した 2015 16 3. Implementation of the BMV Guideline (4/4) Generic Drug Development in Japan Near Future Work: Implementation of CTD for Generic Drug Application (by JGA) Currently in Progress 2015 17 4. Summary Generic Drug Development in Japan The latest BE guideline does not support the latest BMV guidelines. Many Japanese generic drug companies had not applied latest BMV guidelines. (Oct. 2011) Most of Japanese generic drug companies had never performed ISR. (Oct. 2011) Implementation of the BMV Guideline Generic Drug Application (Feb. 2015) for JGA The Common BMV Document Format for Generic Drug Application Near Future: CTD 2015 18 Thank you very much for your kind attention. 2015 19
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