ICH E-5Overview and Current Topics

Mamoru Narukawa

World Drug Sales in11 leading countries

(IMS 2001)

North America

Japan

Europe (leading 5)

Latin America(leading 3)

Origin of New Drugsin the World Market

(Med Ad News vol.18 No.5 1999)

49%

36%

14%1%

US Europe Japan others

Reorganization of Pharmaceutical Industry

GlaxoSmithKline (1) GlaxoWellcomeSmithKline Beecham

Pfizer (2) Warner-LambertAstraZeneca (4) Zeneca, AstraAventis (5) Hoechst, Rhone-PoulaneBristol-Myers Squibb (6) DupontNovartis (7) Ciba-Geigy, SandozJohnson & Johnson (8) ALZAPharmacia (9) Pharmacia & Upjohn

Monsanto(Economist 2001.9.11)

ICH

• Europe (EU, EFPIA), Japan (MHLW, JPMA), and US (FDA, PhRMA)

• Discuss scientific and technical aspects of requirements for pharmaceuticals

• Eliminate unnecessary delay in the global development and availability of new drugs

ICH Topics – Efficacy (1)

• E1: The extent of population exposure to assess clinical safety

• E2A: Definitions and standards for expedited reporting

• E2B: Data elements for transmission of ADR reports

• E2C: Periodic safety update reports• E3: Structure and content of clinical study

reports• E4: Dose-response information to support

drug registration

ICH Topics – Efficacy (2)

• E5E5: Ethnic factors in the acceptability of Ethnic factors in the acceptability of foreign clforeign clinical datainical data

• E6: Good clinical practice• E7: Clinical trials in special population – Geriatric

s• E8: General considerations• E9: Statistical principles• E10: Choice of control group• E11: Clinical investigation in the pediatrics• E12A: Clinical trials on antihypertensives

History of ICH E-5

• 1992.3 Discussion started

• 1997.3 Draft Guideline agreed• 1997.5 Draft Guideline circulated• 1998.2 Final Guideline agreed• 1998.8 Guideline adopted by the

MHW

Before E-5 Guideline

Types of Study Acceptance ofForeign Data

ADME ◎Tolerance ○Dose setting ◎Clinical pharmacology ○Open trials ○Confirmative controlled trials ◎

○: accept◎: accept, but domestic data also needed

After E-5 Guideline

• Necessity/Type of domestic clinical study (Bridging study) data is judged scientifically based on the E-5 Guideline

Intrinsic & ExtrinsicEthnic Factors

Intrinsic Factors Extrinsic Factors

Race

Genetic polymorphism

Receptor sensitivity

Age, Gender, Weight

・・・

Medical practice

(Disease definition, Therapeutic approach)

Methodology of clinical trial

・・・

What is “Bridging Study” ?

• A supplemental study performed in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen in the new region that will allow extrapolation of the foreign clinical data to the new region.

(E5 Guideline)

Types of Bridging Studyand Ethnic Factors

• No Bridging Study (PK study)

Intrinsic Factors

• Study using pharmacological endpoint

Intrinsic (+ Extrinsic) Factors

• Study using clinical endpoint

Intrinsic and Extrinsic Factors

Diagram of Bridging (1)

Domestic data Foreign data

PK data PK data

PD data

Clinical dataExtrapolation

similar

Diagram of Bridging (2)

Domestic data Foreign data

PK data PK data

PD data

Clinical dataExtrapolation

similarPD data

Diagram of Bridging (3)

Domestic data Foreign data

PK data PK data

PD data

Clinical dataExtrapolation

similar

PD data

Clinical dataClinical data

Recommended Bridging Study

• Similar study design

• Proper number of patients

• Quality of data

Race

“Census: US diversity on rise - The nation

is much more diverse, and that diversity is

much more complex.”(USA TODAY: March 13, 2001)

“Racial categorization may be only a surrogate

marker for genetic or other factors.”(NEJM: May 3, 2001)

Intrinsic Ethnic Factors

Race

Individual

Sequence of the Genome

Extrinsic Ethnic Factors

Medical PracticeClinical Trial Methodology・・・

Region

Harmonization of Medical Practice/Clinical Trial

Methodology

Can E-5 Guideline be a solution

to the “drug-lag” in Japan?

Types of worldwide development of new drugs

Types No. of Drugs

Precede in Japan 14 (18.4%)

Simultaneously 16 (21.1%)

Precede in the US 39 (51.3%)

Precede in EU 7 ( 9.2%)

Total 76(JETRO 2001)

International multi-center cooperative study

• Use the same protocol

• Progress simultaneously worldwide

Stratification by Region/Race

Circumstances of Clinical Trial in Japan

• Infrastructure of medical institutions has been improving (CRC, clinical research center, etc)

• Information dissemination activities by sponsors/medical institutions to recruit patients began to take effect

• Motivation of Investigators/Trial Staff ?

Number of Clinical Trials Started in Japan

(YAKUMU-KOUHOU)

0

20

40

60

80

100

120

'95 '96 '97 '98 '99 '00

NCE

Future Perspectives

• International Competitiveness of New Drug Development

• Clinical Trials with– Quality– Speed