ich e-5 overview and current topics mamoru narukawa
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ICH E-5Overview and Current Topics
Mamoru Narukawa
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World Drug Sales in11 leading countries
(IMS 2001)
North America
Japan
Europe (leading 5)
Latin America(leading 3)
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Origin of New Drugsin the World Market
(Med Ad News vol.18 No.5 1999)
49%
36%
14%1%
US Europe Japan others
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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)
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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
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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
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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
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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
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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
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After E-5 Guideline
• Necessity/Type of domestic clinical study (Bridging study) data is judged scientifically based on the E-5 Guideline
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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
・・・
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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)
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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
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Diagram of Bridging (1)
Domestic data Foreign data
PK data PK data
PD data
Clinical dataExtrapolation
similar
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Diagram of Bridging (2)
Domestic data Foreign data
PK data PK data
PD data
Clinical dataExtrapolation
similarPD data
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Diagram of Bridging (3)
Domestic data Foreign data
PK data PK data
PD data
Clinical dataExtrapolation
similar
PD data
Clinical dataClinical data
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Recommended Bridging Study
• Similar study design
• Proper number of patients
• Quality of data
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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)
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Intrinsic Ethnic Factors
Race
Individual
Sequence of the Genome
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Extrinsic Ethnic Factors
Medical PracticeClinical Trial Methodology・・・
Region
Harmonization of Medical Practice/Clinical Trial
Methodology
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Can E-5 Guideline be a solution
to the “drug-lag” in Japan?
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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)
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International multi-center cooperative study
• Use the same protocol
• Progress simultaneously worldwide
Stratification by Region/Race
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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 ?
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Number of Clinical Trials Started in Japan
(YAKUMU-KOUHOU)
0
20
40
60
80
100
120
'95 '96 '97 '98 '99 '00
NCE
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Future Perspectives
• International Competitiveness of New Drug Development
• Clinical Trials with– Quality– Speed