Significance of Extrapolation of Foreign Clinical Data to Asian

Countries

Masahiro TakeuchiDiv. of Biostatistics

Kitasato University Graduate SchoolThe 2nd Kitasato-Harvard Symposium, 10/22/01

Acknowledgment

Bridging Study Working Group*Div. of Biostatistics

Kitasato University Graduate School

Kazuhiro Abe, Isao Kawachi, Masahiro Takeuchi, Masako Nishikawa, Keiichiro Hirose, Yoshiharu Horie, Kazuhiro Matsui

Outline

• Introduction• E5 Guideline• Application of E5 Guideline from

Statistical Point of View• Future Application

Introduction

• ICH - General Purpose– Unification of Necessary Documentation

and its Formats for NDA Submission

• ICH - Extrapolation– Avoidance of Unnecessary Clinical Trials

Ethically Speaking

• Globalization– Good Drugs in a Faster Time

Conditions for Extrapolation

• Two factors

– Intrinsic Factors

– Extrinsic Factors

Review of Two Factors(APPENDIX A)

• Intrinsic Factors– Genetic: race, drug metabolism, genetic

diseases

– Physiological and pathological conditions: Age ( children-elderly), Liver, Kidney, Cardiovascular functions, Diseases

• Extrinsic Factors– Culture, Medical Practice, Regulatory

practice/GCP, Methodology/Endpoints

Implication of Two Factors

• Intrinsic Factors

– Do we have an clearly defined comparative population to targeted/existed foreign population?

• Extrinsic Factors

– Can we conduct a planned clinical trial ?

Application of E5 Guideline

Target Disease Population

Sample

USEUUS

Intrinsic factors

NoYes

Extrinsic FactorsNoYes

EU NR

NR

NecessaryConditions

NecessaryConditions

Part I

Part IIPart III

Part IV

Application of E5 Guideline: Part I

Target Disease Population

Sample

Clinical Trial

(y1, y2, … , yn)

Estimation of Efficacy

Two Major Concerns:

(i) high quality protocol

(ii) high quality of data

Regulatory review system

GCP

Application of E5 Guideline: Part II

Intrinsic Factors

No

EU US NR

Sample from EU

Sample from US

Sample from NR

(yEU1, yEU2, … , yEUn1)

(yUS1, yUS2, … , yUSn2)

(yNR1, yNR2, … , yNRn3)

Sample from aSame Probability

Space

EU US NR

Genetic variation

Application of E5 Guideline: Part III

Intrinsic Factors

EU

NR

US

Yes

Question: Are these samples (EU, US, and NR) derived from a same target disease population?

Answer: No

)(EUAd

US NR

Need adjustment for intrinsic factors to have a common population among three regions

EU

)(USAd )(NRAd

Genetic variation

Application of E5 Guideline: Part IV

Extrinsic Factors

NoYes

Necessary conditionsNecessary conditions

Quality Control - Protocol Review System - GCP

Safety Issues - surveillance

Conduct of suitable clinical trials subject tomedical practice, clinical trial environment

Study Design - placebo vs active - choice of endpoint

Language& culture - subsets of primary endpoint

Future Application: Past Experience

Western Data

Region 1 Region 2 Region 3

(i) No clear scientific evidence regarding racial difference(ii) No clear statistical approach - similarity, sample size (iii) No unified regulatory authority requirements

Bridging Study 1 Bridging Study 2 Bridging Study 3

(i) Scientific Evidence NEJM - Two drugs in heart failure May 3, 2001 - Two editorials

Importance of pharmacogenomics

(ii) Statistical Evidence　　　 Shih ､ Lui - Consistency among trials　　　 Ware, Morris - Empirical Bayes Akahira and Takahashi, Takeuchi - Consistency by bootstrap

Homogeneous target populationClear definition of efficacyStatistical approach/Sample size

(iii) Regulatory Requirements APEC Meeting in Taiwan in May,01

Quality control of trials - Regulatory review system - GCP

Future Application

Western Data

Similar regions

Region 1 Region 2 Region 3

Similar region: - Intrinsic factors - Extrinsic factors (medical practice, clinical trial environment,etc) - GCP

Future Challenge

EU

US Asia

(i) one global protocol - def. of target population - def. of expected efficacy - study design

(ii) modification subject to - intrinsic factors - extrinsic factors

(iii) quality control of trials - protocol review - GCP

Clear def. of probability space

Target Disease Pop.

Each sample derived from the PS

Quality assurance

Good Drugs in a Faster Time

Correctly Targeted Disease Population

Thoroughly Planned and Collected Sample

High Quality Data