Expectation and Demands of Clinical Trial Capacity from

Overseas-Status quo of Taiwan

Professor Oliver Yoa-Pu Hu Ph.D.Dean

Research and DevelopmentNational Defense Medical Center

Taipei, Taiwan, ROC.(Former Director-General of Bureau of Pharmaceutical Affairs,

Department of Health, Taiwan)

2008.02.26. 7.5 Kitasato-Harvard symposium Tokyo

1

CONDUCTING TRIALS IN TAIWAN CAN SUPPORT FDA/EMEA IND PROCESS

Taiwan’s Clinical Infrastructure is comparable with standards in US/EU• High Level Compliance with ICH GCP- Two study sites (NCKUH1 & TSGH2)

have been successfully inspected by US FDA

• Experienced Clinical Research Professionals-Qualified Investigators, Study Nurse and Clinical Research Associate in all phase of clinical trial

• Sufficient Patient Pool for all therapeutic fields for clinical study, Taiwan’s population is about 23 million

• Study Cost-comparing with US/EU/JP, the cost can be reduced up to 30%~50%

• Global KOL/Expertise in Specific Therapeutic Area eg. Hepatitis B• Simplified IRB Process-In selected hospitals, clinical trial application

was reviewed biweekly through Joint Institutional Review Board (JIRB) • Improved and Supportive Regulatory Environment for Clinical Trial-

Improved regulatory review process and professional review unit -Center of Drug Evaluation (CDE)

1. National Chen Kung University Hospital2. Tri-Service General Hospital

2

THE TAIWAN PHARMACEUTICAL MARKET

0.5 0.6

0.40.5

0.40.40.3

0.40.1

0.30.2

0.20.6

0.72.5

2002

3.0

2005

Other

RespiratoryOncologyCNS

Infection

Metabolic

CV

Taiwan pharmaceutical marketUSD BillionsDrivers

• Bureau of National Health Insurance recently raised health budget to 4.6% of GDP

• Developed economy and aging population may drive increased demand for drugs to treat chronic conditions

Barriers

• Multinational companies (MNCs) already control roughly 70% of the Taiwan market, with 30% served by local generics producers

• Increasing pressure from BNHI on hospitals to keep drug costs low favors generics

• Reimbursement policies favor local generics through high reimbursement compared to novel drugs

Sources: IMS; Frost & Sullivan; team analysis

7%CAGR

3

MOST OF THE TOP MEDICAL CENTERS IN TAIWAN ARE CONCENTRATED IN 3 CITIES

Source: “Hospital Care in Taiwan,” Department of Health, Taiwan, January 2006

• ~40% doctors work at the top 15 hospitals in Taiwan.

• 126 teaching hospitals can conduct clinical trails in Taiwan

• Most of these hospitals are multispecialty hospitals with hundreds of beds and very high-class infrastructure

• These hospitals also invest a lot in research, training, and exchange/visits to Western countries

1

3

Yangmingshan

Fenglin

Kuanshan

Hengch’un

Fangliao

Chunghsinghsints'un

Suao

Tanshui Chilung

Panch'iao T'aoyüan

Hsinchu Ilan

Miaoli

Fengyüan

T'aichung Changhua

Hualien Nant'ou

Touliu

Chia-i

Hsin-ying

T'ai-nan

P'ingtung Fengshan Kaohsiung

T'aitung

Hsinchu Shih

Taipei T'aoyüan

T'aipei Chuan-Shih

Chilung Shih

Hsinchu Ilan

Miaoli

T'aichung

Changhua

Nant'ou

Hualien

Yünlin

Chia-i

T'ainan

T'aitung Kaohsiung

P'ingtung Kaohsiung Chuan-Shih

T'ainan Shin

T'aipei

T'aichung Shih

Chia-i Shih

Liuch'lu Yü

Lü Yü

Lü Tao

2

7

4

INITIATING CLINICAL TRIALS IN TAIWAN IS EFFICIENT AND RAPID

Source: Pacific Bridge Medical

Regulatory approval IRB approval Clinical trial conduct

• Trial protocols are submitted to the Bureau of Pharmaceutical Affairs of the Department of Health (DOH), which is assisted by the Center for Drug Evaluation, a non-profit organization

• DOH protocol review typically takes 30 days

• Fast-track approval is available for INDs that have already been approved in the U.S.

• Total clinical trial review time, including IRB review, averages 2-4 months

• Taiwan instituted a Joint Institutional Review Board (JIRB) in 1997 to provide a single entity for ethics review

• JIRB decisions are widely accepted by Taiwanese hospitals, although individual IRBs can request an independent review

• JIRB response takes approximately 25 working days

• Submissions to DOH and JIRB may be done simultaneously

• Adhere to ICH Good Clinical Practice guidelines, implemented in 1997

• DOH inspects nearly all trials to ensure compliance

5

REGULATORY PROCESS IN TAIWAN IS EFFICIENT AND RESPONSIVE

Protocol CDE review • The review process may take 3-4 months in practice

• The CDE is open to consultation meeting with sponsors that plan to conduct clinical trials in Taiwan

• The government wishes to make the environment friendly for multinational companies to conduct clinical trials, in an effort to establish Taiwan as the center for clinical research in Asia

Report DOHSponsor meeting?

Meeting

No

Yes

NDA submission

Filing meeting

Reviewmeeting

Assess-ment report

DOHDrug Review Board

Conclusion

Additional information from sponsor

Clinical trial approval: 20 days

NDA (new drug application)

Reject

Source: Center for Drug Evaluation, Taiwan

6

Volume of Clinical Trials in Asia Pacific Region- Taiwan is a major site allocated by big pharma

Data accessed from www.clinicaltrials.gov on 17 Jan 2007

120

231

157

488

95

200

57

219

20 2255

577

0

100

200

300

400

500

600

700

Singap

ore

China

Hong K

ong

Taiw

anTh

ailan

d

Korea

Malays

ia

India

Vietna

mInd

ones

iaPhil

ippine

sAus

tralia

No. o

f Clin

ical

Tria

ls

7

To Facilitate Japan IND Process

Kazuhiko Mori of PMDA mentioned Japan’s acceptance of Taiwan, Korea and Singapore’s data at 2nd Japan-Taiwan joint regulatory seminar on 3 Aug 2006

Faster drug registration in Japan could be exploited through Pan-Asia trials including Taiwan & Korea.

MNCs such as Pfizer, Eli-Lilly have conducted clinical trials in Taiwan to facilitate Japan’s subject recruitment and IND process

8

Reduce lead time for TaiwanNDA Process

Can get local drug license within 3~6 months after getting FDA & EMEA approval if Taiwan join same protocol for the FDA/EMEA Phase IIIa pivotal clinical study for NDA or Phase I/II Binging study.

Taiwan’s early involvement in multinational Phase I, II & IIIb can also facilitate local NDA process to get local drug license within 12 months after getting FDA & EMEA approval

Without participating in SPRI clinical trials, the lead time for Taiwan IND/NDA is unpredictable.

9

Pattern of Approach in Accepting Foreign clinical Data among Asian

Countries (I)

Japan, Korea and Taiwan: Bridging Study Evaluation based on ICH E5, Active players of APEC Network of Pharmaceutical Regulatory Science – Joint Research Project on Bridging Study

Thailand, Malaysia, Indonesia, Vietnam and Singapore: ASEAN mutual recognition in the future, accepting foreign clinical data now

10

Pattern of Approach in Accepting Foreign clinical Data among Asian

Countries (II)

China: Administrative Requirement for additional local clinical data

Hong Kong: Accepting foreign clinical data, discuss with China for accepting H.K. data

11

APEC Network under ISTWG, since 1999

33

Chinese Taipei (2000, 2001, 2003, 2005, 2007)

(2004)

(2002, 2006)

Partnership inPartnership inHarmonizationHarmonization

with ICHwith ICH

12

GCRC of TSGH

13

Single-Bed Ward of GCRC of TSGH

14

Good Clinical Practice

GCP Inspection

Clinical Trials complying with GCP must be inspected.

From July 1997 to October 199916 mock inspections and 5 formal

inspections have been conducted.

15

New IND in Taiwan

2004 2005 2006 2007

P S P S P S P S

TW single site

32 32 24 24 11 11 21 21

TW multiple

sites

25 88 10 43 22 74 20 69

MN trials 62 196 86 284 100 337 127 415

% of MN trials, P

52.1% 71.7% 75% 75.6%

Total 119 316 120 351 133 422 168 505

* P: protocol S: site

16

NEW IND in Taiwan 1994~2007

Year

0

50

100

150

200

94' 95' 96' 97' 98' 99' 00' 01' 02' 03' 04' 05' 06' 07'

Phase I~IIIPhase IV

Protocol No.

93'

BridgingStudyEvaluation

Qualified Site

SARS

CDE established

16 14

90

95 87

63

106

64

131138

115 116130

162

7467

100

81

53 6267

66

125 4 4 3 6

Local Registration Trial

GCP-Taiwan

IND New System

17

Evolving Concept for IND Assessment (I)

I. ~1993: Some small postmarketing “listing trial” only

II. 1993~1996: “Local registration trial”, >40 cases, Ph. IV >> III

III. 1996~2000: Registration trial with GCP inspection, Ph. III > IV

18

Evolving Concept for IND Assessment (II)

IV. 2000~2007: Bridging Study evaluation replace local registration trial, Ph. III >>> IV, rarely done with China and Japan

V. 2007~ : New “IND process” concept by CDE, Safe to proceed with recommendation, Ph. III, some done with China and Japan

19

2007 IND Review Time Shortening

0

50

100

150

200

250

300

1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61 64 67 70 73 76 79 82 85 88 91 94 97 100

103

106

109

CDE_Time Sponsor_Time BPA_TIME

Old System

New SystemOld New

Sponsor Time (cal.d) 47.0 7.2

No Quest. asked % 25% 60%

Review Time (cal.d) 54.6 43.1

Initial Approval % 60.7 83.8

2007. Feb.

20

How to Accept Foreign Clinical Data

Self-identification for some obvious drug categories to be ethnic insensitive – no review

Clinical Trial Waiver application for some drug categories – a simplified review

Bridging Study Evaluation for ethnic sensitivity based on ICH E5 – a comprehensive review

21

Regulatory Challenge ICH-E5

Japan-need phase I, II Japanese data plus Multi-national trial, ideally “Pan-Asian Study”

Korea: at least 1 Korean study

Taiwan: Bridging study Evaluation for all products, 60% judged as ethnic insensitive

ASEAN: No special ICH-E5 requirement

22

• Gefitinib : effective for Asian in ISEL trial• Rosuvastatin : half the initial and max. dose• Aspirin + dipyridamole : half the initial dose

for headache• Alosetron disapproved before • Mibefradil worldwide withdrawal• Carbamazepine: HLA-B*1502 and Steven-

Johnson syndrome labeling warning first in Taiwan, followed by FDA

Independent Asian Voice

23

Prof. Oliver Yoa-Pu Hu Ph.D.Dean,

Research＆Development,National Defense Medical Center

Taiwan, ROC

24

MANY TAIWANESE HOSPITALS PROVIDE MULTIPLE SPECIALTIES

Source: “Hospital Care in Taiwan,” Department of Health, Taiwan, January 2006

Hospital1. Cathay General Hospital2. Chang-Gung Memorial Hospital3. China Medical University Hospital4. Chi Mei Hospital5. Kaohsiung Medical University Chung-

Ho Memorial Hospital6. Kaohsiung Veterans General Hospital,

Veterans Affairs Commission, Exec. Yuan

7. Mackay Memorial Hospital8. National Taiwan University Hospital

9. Nonprofit Proprietary Chang-Gung Memorial Hospital

10. Taichung Veterans General Hospital11. Taipei Medical University Municipal

Wang Fang Hospital12. Taipei Veterans General Hospital13. Buddhist Tzu Chi General Hospital

14. Changhua Christian Hospital

15. Shin Kong Wu Ho-Su Memorial Hospital

16. Tri-Service General Hospital

LocationTaipeiTaipeiTaichung cityTainanKaohsiung

Kaohsiung city

TaipeiTaipei

Kaohsiung

Taichung cityTaipei city

TaipeiHuahen City

Tao-Yuan CountyTaipei City

Taipei

Number of specialties3754624953

43

5252

35

5248

6154

51

54

83

Comments• Young investigator award for investigation in RA• Strong research team that has published many papers• Oncology department has tie with U.S. center• Investigators with research experience and publications• Emphasis on continuing education and training

• Passed ISO 9001 certification• Published many research papers

• Focus on family care • Published 808 papers in SCI journals in 2004; cancer treatment

and clinical trials are areas of focus

• Extensive international exchange program for physicians including U.S. and China

• Program for international experience for personnel• Experience with large diabetes education program

• Has research centers of excellence• Received medical center classification in 2002,

ISO 9001 certification in 2001• Hospitals in 4 locations; 14 research units on-site

• Between 2002 and 2004, 149 staff (including 86 physicians) went to study abroad and hosted 318 foreign medical specialists

• Teaching hospital of National Defense Medical Center; Class A teaching hospital; best hospital in quality English environment

25

To Support FDA/EMEA IND Process

Taiwan’s Clinical Infrastructure is comparable with standards in US/EU

High Level Compliance with ICH GCP-Two study sites (NCKUH1 & TSGH2) have been successfully inspected by US FDA

Experienced Clinical Research Professionals-Qualified Investigators, Study Nurse and Clinical Research Associate in all phase of clinical trial

Sufficient Patient Pool for all therapeutic fields for clinical study, Taiwan’s population is about 23 million

1. National Chen Kung University Hospital2. Tri-Service General Hospital

26

To Support FDA/EMEA IND Process

Taiwan’s Clinical Infrastructure is comparable with standards in US/EUStudy Cost-comparing with US/EU/JP, the cost can be reduced up to 30%~50%Global KOL/Expertise in Specific Therapeutic Area eg. Hepatitis BSimplified IRB Process-In selected hospitals, clinical trial application was reviewed biweekly through Joint Institutional Review Board (JIRB) Improved and Supportive Regulatory Environment for Clinical Trial-Improved regulatory review process and professional review unit - Center of Drug Evaluation (CDE)