Drug Development in Asia - kitasato
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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
•
•
•
•
•
•
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
–
–
–
–
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
•
•
•
•
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