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)