Transcript Drug Development in Asia - kitasato

Drug Development in Asia – an
Industry perspective
Stephen Uden
Pfizer Inc.
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Industry
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Academia
MHLW
Drug Development in Asia – an
Industry perspective
• Where are we today
• Where can we go in the future
– Path 1. Ever greater contribution to
pharmaceutical and regulatory science
– Path 2. Simple bridging on the margins of
drug research
Key accomplishments
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ICH established
Adoption of GCP based on ICH
Kikoh and PMDEC consultation process
Time clock introduced
MHLW vision
Increasing interest in Clinical Research in
Asia
• Scientific progress
– Statistical methods
– Pharmacogenomics
Clinical trial activity – is it increasing?
• Clinical trials started to
decline long before ICH
was implemented
• Recently activity seems
be increasing
Clinical trial activity – is it increasing?
Clinical trial activity in Japan – patient recruitment experience
from four companies
Number of new informed consents
2500
2000
Company A
1500
Company B
Company C
1000
Company D
500
0
1993
1994
1995
1996
1997
Year
1998
1999
2000
2001
Bridging out of Asia
(Japan as an example)
Company
A
B
C
US
No
Yes
Yes
EU
No
Yes
Yes
Other Asia
No
Yes
Yes
D
E
F
Yes
No
Yes
Yes
No
Yes
No
No
Yes
G
H
Yes
No
Yes
No
Yes
Yes
PMDEC analysis
Approval Time
NCEs and LEs
As of June 2001
(Day)
800
700
Total
600
MHLW/PMDEC
500
Sponsor
400
(Median
300
）
200
100
0
1996
1997
1998
1999
2000
Increasing sophistication of
scientific methodology
• Pharmacogenomics
– Metabolic differences well understood
– Some advances in pharmacodynamics
• Preclinical assessment
– Metabolic pathways
• Statistical methodology
– Sub-population analysis
Remaining Obstacles for Enhanced
Drug Development
Remaining Obstacles for Enhanced
Drug Development
• Ambiguity in drug development
– Need for routine repetition of basic PK
Remaining Obstacles for Enhanced
Drug Development
• Ambiguity in drug development
– Need for routine repetition of basic PK
Plasma concentration (ng/mL)
14.0
Japanese subject
12.0
Western subject
10.0
8.0
6.0
4.0
2.0
0.0
0
24
48
Time post dose (h)
72
96
Japanese and Western young males (resident in Japan)
 Similar PK profiles in two populations
Remaining Obstacles for Enhanced
Drug Development
Large differences in cost between different areas
discourage investment
6
5
4
3
2
1
0
Hong Kong
Korea
Japan
US
Turkey
Argentina
Relative cost per patient for a large scale global outcomes study
Unlike Phase II/III sites Japanese
commercial Phase I units are
internationally competitive
Relative costs for a Phase I multiple dose study comparing
Japanese and Caucasian normal volunteers
2
1.5
1
0.5
0
EU - 1 EU - 2 EU - 3 EU - 4
J-1
J-2
J-3
J-4
Remaining Obstacles to
Enhanced Drug Development
• Mind set
– Unwillingness to collaborate
– Beliefs prevailing over scientific evidence
and methodology
– Sponsors unaware of changes
• Drug development expertise stagnating
– Repetition of routine work inhibits
development of new methodology
Path 1 – the improvement
trend continues
Path 1 – the improvement
trend continues
• Bridging evolves into making best use
of data generated throughout the world
Path 1 – the trend continues
• Commitment to Asia being a centre of drug
development excellence
• Regulators
• Companies
• Academics
• Costs brought under control in Japan
• Investigators/Departments reimbursed directly
• Institutional overhead costs controlled
• Adoption of robust scientific methodologies to
cope with inevitable differences
• Statistical
• Pharmacogenomics
• Clinical technology
Discovery to first in man
– Asian development centres identify critical
issues for global development
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–
–
–
Opportunities for special population work in Asia
Sub populations prevalent in Asia
Metabolic groups
Patterns of medical practice
– End points validated in Asian patients
– Statistical methodologies to analyse subpopulations in the global database that are
useful to Asian regulators and physicians
Clinical Pharmacology Programme
– Pre-clinical assessment to determine
likelihood of significant PK issues
– Application of statistical methodology to
generate data relevant to Asians as part of
global development programme
Integrated global PK programme
Routine Phase I programme at Discovery site
- First in humans
- Multiple dose PK
- Fed Fasting study
- Surrogate efficacy/Phase IIa
US
EU
Solid form Bio-equivalence
Elderly PK study
PK/PD study
Special study e.g. end point
validation
Interaction study E
Hepatic Impairment study
Renal Impairment study
Interaction study A
Interaction study B
Commercial Form Bioequivalence
Japan
Poor metaboliser study
PK in smokers
Interaction study C
Interaction study D
Special Study e.g. cognitive
function
New formulation BE
Phase II/III population PK programme
Integrated global PK programme
Routine Phase I programme at Discovery site
- First in humans
- Multiple dose PK
- Fed Fasting study
- Surrogate efficacy/Phase IIa
US
EU
Solid form Bio-equivalence
Elderly PK study
PK/PD study
Special study e.g. end point
validation
Interaction study E
Hepatic Impairment study
Renal Impairment study
Interaction study A
Interaction study B
Commercial Form Bioequivalence
Japan
Poor metaboliser study
PK in smokers
Interaction study C
Interaction study D
Special Study e.g. cognitive
function
New formulation BE
Phase II/III population PK programme
Statistical methodology applied to
characterise PK in Japanese/Asians
Phase III
• Basic Efficacy accepted as relevant to all
regions
• Integrated global strategy to determine how
drug can best be used in individual patients
– Best doses in sub-populations
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•
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Sex
Co-morbid illness
Concomitant medication
Metabolic status
Integrated Phase III strategy - 1
US/Canada
Pivotal efficacy study I
Comparative efficacy
N = 500
EU/Europe
Japan/Asia
Pivotal efficacy study II
Comparative efficacy
Pivotal efficacy study III
Comparative efficacy
N = 500
N = 500
Data combined to analyse for clinically important sub-populations
•Sex
•Co-morbid illness
•Concomitant medication
•Metabolic status
Integrated Phase III strategy - 2
Study 1
Japan/other Asia/US/Canada/EU/Eastern Europe
Confirmation of efficacy
Study 2
Japan/other Asia/US/Canada/EU/Eastern Europe
Efficacy comparative to different class of drug
Study 2
Japan/other Asia/US/Canada/EU/Eastern Europe
Efficacy in special population
Regional specific issues
Resolved through prePlanned use of:
• Pop PK
• Sub Group analysis
• Pharmacogenomics
Integrated Phase III strategy - 3
Global Outcomes study in Asia, Americas, Europe
Sub study A
Sub study B
Sub study C
Regional specific issues
Resolved through prePlanned use of:
• Pop PK
• Sub Group analysis
• Pharmacogenomics
Clinical trial activity – definitely increases?
• Return to 1993 level?
• Studies more complex
and “value added”?
A successful simultaneous
development bridging strategy with
simultaneous filing/approval
Global Development
Phase I and II
Year 1
Year 2
US or EU
Asia
= Phase III start
= Filing
Year 3
Year 4
Year 5
A successful simultaneous
development bridging strategy with
simultaneous filing/approval
Global Development
Phase I and II
Year 1
Year 2
US or EU
Asia
= Phase III start
= Filing
Year 3
Year 4
Year 5
Path 2 – stagnation or reversal
Path 2 – stagnation or reversal
• Bridging degenerates into multiple
repetitive studies throughout Asia
• Japan destined to perform basic PK
studies and routine (Phase II) Bridging
studies
Path 2 – stagnation or reversal
• Nationality seen as more important than physiological or
pathological status
• Only nationally produced data is seen as relevant
• Costs continue to escalate particularly in Japan
Investigators demotivated as not rewarded for their
efforts
• Advances in scientific methodology ignored or rejected
• Sponsor companies maintain prejudices about difficulty of
work in Asia
Phase I – a routine after thought
Routine Phase I programme at Discovery site
- First in humans
- Multiple dose PK
- Fed Fasting study
- Surrogate efficacy/Phase IIa
US
Solid form Bio-equivalence
Elderly PK study
PK/PD study
Special study e.g. end point
validation
Interaction study E
Poor metaboliser study
PK in smokers
Interaction study C
EU
Hepatic Impairment study
Renal Impairment study
Interaction study A
Interaction study B
Commercial Form Bio-equivalence
Special Study e.g. cognitive function
New formulation BE
Interaction study D
Phase II/III population PK programme
Japan Phase
-First in humans
- Multiple dose PK
- Fed Fasting study
Japan Pop PK
Phase I – a routine after thought
Routine Phase I programme at Discovery site
- First in humans
- Multiple dose PK
- Fed Fasting study
- Surrogate efficacy/Phase IIa
US
Solid form Bio-equivalence
Elderly PK study
PK/PD study
Special study e.g. end point
validation
Interaction study E
Poor metaboliser study
PK in smokers
Interaction study C
EU
Hepatic Impairment study
Renal Impairment study
Interaction study A
Interaction study B
Commercial Form Bio-equivalence
Special Study e.g. cognitive function
New formulation BE
Interaction study D
Phase II/III population PK programme
EU/US dominated PK programme
Japan Phase
-First in humans
- Multiple dose PK
- Fed Fasting study
Japan Pop PK
Phase I – a routine after thought
Routine Phase I programme at Discovery site
- First in humans
- Multiple dose PK
- Fed Fasting study
- Surrogate efficacy/Phase IIa
US
Solid form Bio-equivalence
Elderly PK study
PK/PD study
Special study e.g. end point
validation
Interaction study E
Poor metaboliser study
PK in smokers
Interaction study C
No new data
EU
Hepatic Impairment study
Renal Impairment study
Interaction study A
Interaction study B
Commercial Form Bio-equivalence
Special Study e.g. cognitive function
New formulation BE
Interaction study D
Phase II/III population PK programme
EU/US dominated PK programme
Japan Phase
-First in humans
- Multiple dose PK
- Fed Fasting study
Japan Pop PK
Phase I – a routine after thought
Routine Phase I programme at Discovery site
- First in humans
- Multiple dose PK
- Fed Fasting study
- Surrogate efficacy/Phase IIa
US
Solid form Bio-equivalence
Elderly PK study
PK/PD study
Special study e.g. end point
validation
Interaction study E
Poor metaboliser study
PK in smokers
Interaction study C
No new data
Capability stagnates
EU
Hepatic Impairment study
Renal Impairment study
Interaction study A
Interaction study B
Commercial Form Bio-equivalence
Special Study e.g. cognitive function
New formulation BE
Interaction study D
Phase II/III population PK programme
EU/US dominated PK programme
Japan Phase
-First in humans
- Multiple dose PK
- Fed Fasting study
Japan Pop PK
Clinical trial activity – why invest
more?
Companies continue
to do minimum work
for approval
Japan Bridging Study
N = 200
Japan Bridging Study
N = 200
Korea Bridging Study
N = 200
China Bridging Study
N = 200
Japan Bridging Study
N = 200
Korea Bridging Study
N = 200
Japan Bridging Study
N = 200
China Bridging Study
N = 200
Korea Bridging Study
N = 200
Taiwan Bridging Study
N = 200
Japan Bridging Study
N = 200
China Bridging Study
N = 200
Korea Bridging Study
N = 200
Philippine Bridging Study
N = 200
Taiwan Bridging Study
N = 200
Japan Bridging Study
N = 200
China Bridging Study
N = 200
Korea Bridging Study
N = 200
Thai Bridging Study
N = 200
Philippine Bridging Study
N = 200
Taiwan Bridging Study
N = 200
Is this really the way ahead?
Japan Bridging Study
N = 200
China Bridging Study
N = 200
Korea Bridging Study
N = 200
Thai Bridging Study
N = 200
Philippine Bridging Study
N = 200
Taiwan Bridging Study
N = 200
?
Industry
?
?
Academia
MHLW
Industry
Academia
MHLW