drug development in asia – an industry perspective

Drug Development in Asia – an Industry perspective

Stephen Uden Pfizer Inc.

Industry Academia MHLW

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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

0

500

1000

1500

2000

2500

1993 1994 1995 1996 1997 1998 1999 2000 2001

Company A

Company B

Company C

Company D

Clinical trial activity in Japan – patient recruitment experience from four companies

Year

Nu

mb

er o

f n

ew i

nfo

rmed

co

nse

nts

Clinical trial activity – is it increasing?

Company US EU Other Asia

A No No No

B Yes Yes Yes

C Yes Yes Yes

D Yes Yes No

E No No No

F Yes Yes Yes

G Yes Yes Yes

H No No Yes

Bridging out of Asia (Japan as an example)

PMDEC analysis Approval Time

0

100

200

300

400

500

600

700

800

1996 1997 1998 1999 2000

Total

MHLW/PMDEC

Sponsor

(Day)

(Median

）

(n=43) (36) (34) (44) (10)

Year of Submission

NCEs and LEsNCEs and LEsAs of June 2001As of June 2001

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


• Ambiguity in drug development– Need for routine repetition of basic PK


• Ambiguity in drug development– Need for routine repetition of basic PK

0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

0 24 48 72 96Time post dose (h)

Pla

sma

conc

entr

atio

n (n

g/m

L) Japanese subject

Western subject

Japanese and Western young males (resident in Japan) Similar PK profiles in two populations

Large differences in cost between different areas discourage investment

0

1

2

3

4

5

6

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

0

0.5

1

1.5

2

EU - 1 EU - 2 EU - 3 EU - 4 J - 1 J - 2 J - 3 J - 4

Relative costs for a Phase I multiple dose study comparing Japanese and Caucasian normal volunteers

Re

lati

ve

co

st

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

• Bridging evolves into making best use of data generated throughout the world

Path 1 – the improvement trend continues

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

– 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 sub-populations in the global database that are useful to Asian regulators and physicians

Discovery to first in man

– 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

Clinical Pharmacology 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 JapanSolid 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 Bio-equivalence

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


US EU JapanSolid form Bio-equivalence

Elderly PK study

PK/PD study


Interaction study E



Interaction study A

Interaction study B



PK in smokers

Interaction study C

Interaction study D


New formulation BE


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 IComparative efficacy

N = 500

EU/Europe

Pivotal efficacy study IIComparative efficacy

N = 500

Japan/Asia

Pivotal efficacy study IIIComparative efficacy

N = 500

Data combined to analyse for clinically important sub-populations•Sex•Co-morbid illness•Concomitant medication•Metabolic status


Study 1Japan/other Asia/US/Canada/EU/Eastern Europe

Confirmation of efficacy

Study 2Japan/other Asia/US/Canada/EU/Eastern EuropeEfficacy comparative to different class of drug

Study 2Japan/other Asia/US/Canada/EU/Eastern Europe

Efficacy in special population

Regional specific issuesResolved through pre-Planned use of: • Pop PK• Sub Group analysis• Pharmacogenomics


Global Outcomes study in Asia, Americas, Europe

Regional specific issuesResolved through pre-Planned use of: • Pop PK• Sub Group analysis• Pharmacogenomics

Sub study A Sub study B Sub study C

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

Year 1 Year 2 Year 3 Year 4 Year 5

Phase I and II Global Development

Asia

= Phase III start

US or EU

= Filing

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


• 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 thoughtRoutine Phase I programme at Discovery site

- First in humans

- Multiple dose PK

- Fed Fasting study


US EUSolid form Bio-equivalence

Elderly PK study

PK/PD study


Interaction study E


PK in smokers

Interaction study C



Interaction study A

Interaction study B



New formulation BE

Interaction study D


Japan Phase -First in humans

- Multiple dose PK

- Fed Fasting study

Japan Pop PK


- First in humans

- Multiple dose PK

- Fed Fasting study



Elderly PK study

PK/PD study


Interaction study E


PK in smokers

Interaction study C



Interaction study A

Interaction study B



New formulation BE

Interaction study D



- Multiple dose PK

- Fed Fasting study

Japan Pop PK

EU/US dominated PK programme


- First in humans

- Multiple dose PK

- Fed Fasting study



Elderly PK study

PK/PD study


Interaction study E


PK in smokers

Interaction study C



Interaction study A

Interaction study B



New formulation BE

Interaction study D



- Multiple dose PK

- Fed Fasting study

Japan Pop PK


No new data


- First in humans

- Multiple dose PK

- Fed Fasting study



Elderly PK study

PK/PD study


Interaction study E


PK in smokers

Interaction study C



Interaction study A

Interaction study B



New formulation BE

Interaction study D



- Multiple dose PK

- Fed Fasting study

Japan Pop PK


No new dataCapability stagnates

Clinical trial activity – why invest more?

Companies continueto do minimum workfor approval

Japan Bridging StudyN = 200


Korea Bridging Study

N = 200



N = 200

China Bridging StudyN = 200



N = 200

Taiwan Bridging StudyN = 200




N = 200

Philippine Bridging StudyN = 200





N = 200




Thai Bridging StudyN = 200

Is this really the way ahead?



N = 200




Thai Bridging StudyN = 200


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drug development in asia – an industry perspective

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