国際共同治験の現状と民族差を考慮した情報提供のあり方国際共同治験に関する主な留意事項国際共同治験実施の前提：想定される民族差は臨床的に意義のある差

国際共同治験の現状と民族差を考慮した情報提供のあり方

宇山佳明

（独）医薬品医療機器総合機構千葉大学大学院先進医療科学専攻医療行政学講座客員教授

名古屋大学大学院医学系研究科客員教授

Disclaimer

The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to DIA, its directors, officers, employees, volunteers, members, chapters, councils, Communities or affiliates, or any organization with which the presenter is employed or affiliated.These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. DIA and the DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners.

© 2015 DIA, Inc. All rights reserved. 2

主要規制当局における審査期間

3

Center for Innovation in Regulatory Science, R&D Briefing 55, December 2014

開発ラグの現状

4

国際共同治験の現状


Japanese：http://www.pmda.go.jp/files/000157901.pdfEnglish：http://www.pmda.go.jp/files/000157520.pdf

2007 Guideline

Japanese：http://www.pmda.go.jp/files/000157000.pdfEnglish：http://www.pmda.go.jp/files/000157900.pdf

2012 Guideline

Japanese: http://www.pmda.go.jp/files/000157480.pdfEnglish: http://www.pmda.go.jp/files/000157777.pdf

2014 Guideline

6

国際共同治験に関するガイドライン

新医薬品の開発戦略

7

FY2007 FY2008 FY2009 FY2010 FY2011 FY2012 FY2013 FY2014

0

5

10

15

20

25

30%

of C

linic

al T

rials

Year

% of GCT % of Asian GCT % of Bridging

Total 81 79 107 114 130 134 138 119

MRCT 1 0 4 7 12 19 22 33Bridging 4 2 3 6 2 3 1 1

MRCTの実施は、開発ラグの短縮に寄与

Clinical development strategy

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

Lag

in d

rug

deve

lopm

ent

(day

s)

1111 days

Local

trial

(n = 69)

Local and

foreign trials

(n = 59)

Bridging

study

(n = 19)

Global

clinical

trial

(n = 18)

Foreign

trial

(n = 13)

No

efficacy/safety

trial (n = 5)

***

**

Ueno T et al, Clin Pharmacol Ther, 95, 533-41 (2014)

Drug approved in FY2007-FY2012

8

国際共同治験に関する主な留意事項

国際共同治験実施の前提：想定される民族差は臨床的に意義のある差を生じない

– 全集団での結果を評価することが主

– しかしながら、2次的な目的として、民族間における結果の一貫性を確認することが重要

• 日本人症例が極端に少ないと一貫性評価が困難

薬物動態データは、民族差を評価する上で有用

– PPK data等の収集を考慮

内因性民族的要因だけでなく、外因性の民族的要因（併用薬等）が、大きな影響を及ぼす可能性がある。

– 事前の検討が重要（アジア治験の場合も同様）

– 安全性データにおける差異はまれではない

• その原因の一部は、民族差ではなくデータ収集における分類あるいはプロセスにおける差異に起因している場合がある

9

10

ICH E17 Guideline

ICH E17ガイドラインの検討状況

11

General principle on planning/designing Multi-Regional Clinical Trials

E17 EWG: established in June 2014 Rapporteur: PMDA

Provide common points to consider in planning/designing MRCTs and minimize conflicting opinions from regulatory bodies.

E17メンバー（2016.1現在）

12

EU EMA

EFPIA

Japan PMDA

JPMA

US FDA

PhRMA

WHO WHO

GCC Saudi Food and Drug Authority ,

Chinese Taipei Center for Drug Evaluation (CDE)

Singapore Health Sciences Authority (HSA)

Brazil Brazilian Health Surveillance Agency

Korea Ministry of Food and Drug Safety (MFDS)

November 2014 1st F2F meeting in LisbonJune 2015 2nd F2F meeting in FukuokaDecember 2015 3rd F2F meeting in Jacksonville

これまでの会合

13

14

E17ガイドラインの目次（案）

1. INTRODUCTION ........................................................................................................... - 3 -

1.1 Objectives of the Guideline ................................................................................. - 3 -1.2 Background .......................................................................................................... - 3 -1.3 Scope of the Guideline ......................................................................................... - 4 -1.4 General Principles ............................................................................................... - 4 -

2. GENERAL RECOMMENDATIONS IN THE PLANNING AND DESIGN OF MRCTs .... - 5 -

2.1 Strategy-related issues ........................................................................................ - 5 -2.1.1 The value of MRCTs in drug development................................................. - 5 -2.1.2 Basic requirements and key considerations .............................................. - 7 -2.1.3 Scientific consultation meetings with regulatory authorities .................. - 8 -

2.2 Clinical trial design and protocol-related issues ............................................... - 9 -2.2.1 Pre-consideration of regional variability of efficacy and safety ............... - 9 -2.2.2 Subject selection ........................................................................................ - 10 -2.2.3 Selection of doses for use in confirmatory MRCTs .................................. - 11 -2.2.4 Choice of endpoints .................................................................................... - 12 -2.2.5 Estimation of an overall sample size and allocation to regions and countries

.................................................................................................................... - 14 -2.2.6 Collecting and handling efficacy and safety information ....................... - 17 -2.2.7 Statistical analysis plans addressing specific features of MRCTs ......... - 18 -2.2.8 Selection of comparators ........................................................................... - 21 -2.2.9 Handling concomitant medications .......................................................... - 22 -

3. GLOSSARY ................................................................................................................. - 24 -

4. ABBREVIATIONS ....................................................................................................... - 24 -

15

Objectives & Scope

The purpose of this guideline is to facilitate the acceptance of MRCTs by regulatory authorities. This guideline describes general principles for the planning and design of MRCTs with the aim of encouraging the use of MRCTs in global regulatory submissions.

E17ガイドラインに記載予定の主な事項（１）

16

Promoting conduct of MRCTs

MRCTs are generally the preferred option for investigating a new drug, which is planned to be approved for use in multiple regions and countries. – The rationale for conducting the MRCT rather than

single-region or -country trials is based on the assumption that there is a global treatment effect that is applicable to all regions and/or countries being studied, while also acknowledging that some regional and/or national variation is expected.

– This assumption should be based on a priori knowledge about intrinsic and extrinsic factors and their potential impact on drug response in each region as well as any data available from early exploratory trials of the therapy.

E17ガイドラインに記載予定の主な事項（２）

17

Careful consideration

To increase an acceptability of MRCT data in the review by multiple regulatory agencies for drug approval, a sponsor should carefully consider the planning and design of MRCTs in advance.– The MRCT should be designed to provide sufficient

information for an evaluation of whether the overall treatment effect applies to subjects from different regions, which will likely include both regulatory and geographic regions.

– The amount of information needs to provide for each region will depend on the extent of prior information and its credibility.

– Ethnic factors are a major point of consideration when planning MRCTs.

E17ガイドラインに記載予定の主な事項（３）

18

Pooled PopulationIntroduce a new use of “pooled population” to help regulatory decision making– Subpopulations in an MRCT may be defined by one or more

of intrinsic and/or extrinsic factors, and these subpopulations may span multiple regions.

– Some regions may be pooled, if subjects in those regions are thought to be similar with respect to intrinsic and/or extrinsic factors which are relevant to the disease area and/or drug under study.

– Both subpopulations and pooled regions should be specified at the study planning stage and may provide a basis for regulatory decision making for relevant regulatory authorities.

E17ガイドラインに記載予定の主な事項（４）

19

Sample size allocationThe guiding principle for determining the overall sample size in MRCTs is that the test of the primary hypothesis based on combining data from all regions in the trial, is of primary importance.Without increasing the overall sample size for the primary hypothesis, allocation to regions should ensure that clinically meaningful differences among regions can be described.

E17ガイドラインに記載予定の主な事項（５）

20

MRCTs in an exploratory stage

Encourage to conduct MRCTs in an exploratory stage as well as a confirmatory stage– MRCTs can play an important role in a drug

development program beyond their contribution at the confirmatory stage.

– For example, conducting MRCTs in the exploratory phase to gather scientific data regarding the impact of extrinsic and intrinsic factors on PK/PD and other drug properties can enable better designs of confirmatory MRCTs.

– MRCTs may also serve as the basis for approval in regions or countries not studied at the confirmatory stage through the extrapolation of study results.

E17ガイドラインに記載予定の主な事項（６）

21

Discussions with regulatory agencies

Encourage discussions with regulatory authorities in the planning stage– In the planning and design of MRCTs, it is

important to understand the different regulatory requirements in the concerned regions and countries. Efficient communication among sponsors and regulatory authorities at a global level can facilitate future development of the drug. These discussions are encouraged at the planning stage, before the MRCT begins.

E17ガイドラインに記載予定の主な事項（７）

22

Avoid duplication – Reduce the need to conduct standalone regional or national

studies including bridging studies.

Promote international harmonization– A globally harmonized approach to drug development should be

considered first.

Provide better evidences for drug approval in each region– Encourage better planning and design of MRCTs based on the

latest scientific knowledge and experiences• By implementing new use of “pooled population”

E17ガイドラインの発出で期待される成果

現状でのスケジュール

First face-to-face EWG Meeting in November 2014 in Lisbon

Discussion by e-mail and web-based conference: 4Q 2014 - 1Q 2015

Second F2F EWG Meeting in June 2015 in Fukuoka

Third F2F EWG meeting in December 2015

Finalizing draft guideline and Postal sign-off procedure 1Q 2016

Public consultation: 2Q 2016 - 3Q 2016

Fourth face-to-face EWG Meeting in 4Q 2016 (in Japan) to revise the guideline based on comments received on the public consultation.

The guideline will be finalized as Step 4 possibly in 2Q 2017

23

24

今後の情報提供のあり方

25

Nomura Research Institute, Survey on promotion of accepting foreign patients in hospitals in Japan (2013)

日本の病院で治療を受ける外国人は増加しつつある

Tanaka A et al, Clin Pharmacol Ther. 2015;98(5):480-2

国際化する社会において、医薬品の民族差に関する情報をどのように提供することが、適正使用に役立つか？

26

27

民族差データ：有効性に関する日米比較

日本では、全集団での結果だけでなく、日本人集団での結果が多く記載

米国では、全集団のみの結果が多く、白人以外の集団（黒人、アジア人など）での結果が記載されている場合もある。


Generic name Target disease

Category of focused

population Japan US

Japan USSummary of

descriptions on ethnic similarities/differences

Category of conclusion

Summary of descriptions on ethnic similarities/differences


apixaban

Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular

Atrial Fibrillation

Major(+ All)

Minor(+ All + Major)

Results in Japanese population had similar trend to those in the overall population.

no difference

The efficacy profile of the drug was generally consistent across subgroups of interest for this indication (e.g., age, gender, race, etc.).

no difference

everolimus Breast Cancer Overall(All)

Overall(All) ― ―

PFS results were also consistent across the subgroups of age, race, etc.

no difference

pramipexole Parkinson’s disease

Major(+ All)

Overall(All)

Results in Japanese population were consistent with those in the overall population.

no difference ― ―

riociguatPulmonaryArterialHypertension

Major(+ All)

Overall(All)

Effect on improvement of hemodynamics in Japanese population were similar to those in the overall population.

no difference ― ―

suvorexant Insomnia Overall(All)

Overall(All) ― ―

The efficacy was similar between women and men and, based on limited data, between Caucasians and non-Caucasians.

no difference

－: no descriptions on the label

有効性に関する記載例

28

29

日本では、全集団でのデータとともに、日本人集団での発現率が記載されている場合が多数ある。

米国では、全集団のみでの結果が多いが、白人以外の集団（黒人、アジア人など）での結果が記述されている場合もある。

民族差データ：安全性に関する日米比較


Generic name Target disease

Category of focused

population for safety data

shown on the label

Japan US

Japan US

Summary of descriptions

on ethnic similarities/differences

Category of

conclusion

Summary of descriptions on ethnic similarities/differences


afatinib Non-Small Cell Lung Cancer

Overall(All)

All + Minor ― ―

The incidence of ILD appeared to be higher in patients of Asian ethnicity as compared to non-Asians.

difference

apixaban

Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular

Atrial Fibrillation

Major(+ All)

Minor(+ All

+ Major)

― ―

The results for major bleeding were generally consistent across most major subgroups including age, weight, geographic region, etc.

no difference

pertuzumab Breast Cancer Overall(All)

All + Minor ― ―

Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group compared with the placebo-treated group.

difference

－: no descriptions on the label

安全性に関する記載例

30

民族差データの記載例：アピキサバン：日本

日本人集団においては、．．．．．中略．．．．．、日本人集団においてもアピキサバン群はワルファリン群に比べ、大出血の年間イベント発現率は低かった。また、これらの結果は、全体の結果と比較して同様の傾向がみられた。

非弁膜症性心房細動患者における虚血性脳卒中及び全身性塞栓症の発症抑制

31

民族差データの記載例：アピキサバン：米国

In ARISTOTLE, the results for major bleeding were generally consistent across most major subgroups including age, weight, CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk), prior warfarin use, geographic region, and aspirin use at randomization (Figure 1).

32

どのようなデータを提供すべきか

提供すべきデータとは？

有効性あるいは安全性において、臨床的に意義のある差を生じうるか否か

– 民族差がないことが明らかな場合

– 用量変更の必要性がある場合

– 異なる安全性プロファイルが予測される場合

33© 2015 DIA, Inc. All rights reserved.

検討事項

民族あるいは地理的地域（国）は、一つの層別因子と考えられるが、常に最適な因子とは限らない

医薬品の有効性・安全性と関連が深い因子で分類した方がより臨床的に意義があるかもしれない

– 遺伝子プロファイル、標準治療等


提供方法

文字だけでなく図等による理解しやすい情報提供

– フォレストプロットなどの活用

添付文書だけでなく、他の資材を活用した情報提供

– 添付文書では紙面が限られており、優先度の高い情報に限定

– 参考情報については、他の資材で記載することも考慮


何が最適な提供方法であるのか、今後、関係者で検討していく必要がある。

注目する民族は各国で異なるものの、記載すべき事項やそのフォーマットについては、国際的にも標準化できる可能性がある。


PMDA web site (English) http://www.pmda.go.jp/english/index.html

E-mail:[email protected]

Thank you for your attentionNiyodo-river, Kouchi, Japan

37

Documents

国際共同治験の現状と民族差 を考慮した情報提供のあり方国際共同治験に関する主な留意事項 国際共同治験実施の前提：想定される民族差は臨床的に意義のある差

国際共同治験の現状と民族差を考慮した情報提供のあり方国際共同治験に関する主な留意事項国際共同治験実施の前提：想定される民族差は臨床的に意義のある差