Transcript ICH E-5 Overview and Current Topics

ICH E-5
Overview and Current Topics
Mamoru Narukawa
World Drug Sales in
11 leading countries
North America
Japan
Europe (leading 5)
Latin America
(leading 3)
(IMS 2001)
Origin of New Drugs
in the World Market
14%
1%
49%
36%
US
Europe
Japan
others
(Med Ad News vol.18 No.5 1999)
Reorganization of
Pharmaceutical Industry
GlaxoSmithKline
(1)
Pfizer (2)
AstraZeneca (4)
Aventis (5)
Bristol-Myers Squibb (6)
Novartis (7)
Johnson & Johnson (8)
Pharmacia (9)
GlaxoWellcome
SmithKline Beecham
Warner-Lambert
Zeneca, Astra
Hoechst, Rhone-Poulane
Dupont
Ciba-Geigy, Sandoz
ALZA
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)
• E5: Ethnic factors in the acceptability of
foreign clinical data
• E6: Good clinical practice
• E7: Clinical trials in special population –
Geriatrics
• 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
•
•
•
•
Draft Guideline agreed
Draft Guideline circulated
Final Guideline agreed
Guideline adopted by the
MHW
1997.3
1997.5
1998.2
1998.8
Before E-5 Guideline
Types of Study
Acceptance of
Foreign 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 & Extrinsic
Ethnic 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 Study
and 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
similar
PK data
PK data
PD data
Extrapolation
Clinical data
Diagram of Bridging (2)
Domestic data
Foreign data
PK data
PK data
PD data
Extrapolation
similar
PD data
Clinical data
Diagram of Bridging (3)
Domestic data
Foreign data
PK data
PK data
PD data
PD data
Clinical data
Extrapolation
similar
Clinical data
Clinical 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 Practice
Clinical 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
Total
7 ( 9.2%)
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
120
100
80
60
NCE
40
20
0
'95
'96
'97
'98
'99
'00
(YAKUMU-KOUHOU)
Future Perspectives
• International Competitiveness of New
Drug Development
• Clinical Trials with
– Quality
– Speed