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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

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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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