Expectation and Demands of Clinical Trial Capacity from Overseas-Status quo of Taiwan Professor Oliver Yoa-Pu Hu Ph.D. Dean Research and Development National 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
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 (NCKUH 1 & TSGH 2 ) 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 Hospital 2. Tri-Service General Hospital 1
THE TAIWAN PHARMACEUTICAL MARKET Drivers 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 Taiwan pharmaceutical market USD Billions Other Respiratory Oncology CNS Infection Metabolic CV 7% CAGR 2.5 0.6 0.2 0.1 0.3 0.4 0.4 0.5 3.0 0.7 0.2 0.3 0.4 0.4 0.5 0.6 2002 2005 Sources: IMS; Frost & Sullivan; team analysis 2
MOST OF THE TOP MEDICAL CENTERS IN TAIWAN ARE CONCENTRATED IN 3 CITIES 7 1 2 T'aichung Shih Chilung Shih Tanshui Yangmingshan Chilung T'aoyüan Taipei T'aoyüan Panch'iao T'aipei Hsinchu Shih Hsinchu Ilan Fengyüan Miaoli Hsinchu T'aichung Changhua Chunghsinghsints'un Changhua Nant'ou Yünlin Miaoli Touliu Nant'ou Chia-i Chia-i Chia-i Shih Hualien Hsin-ying T'ainan Kuanshan T'ainan Shin Kaohsiung T'ai-nan T'aitung P'ingtung Kaohsiung Chuan-Shih T'aitung P'ingtung Kaohsiung Fengshan T'aipei Chuan-Shih T'aichung Ilan Fenglin Hualien Lü Tao Suao ~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 3 Liuch'lu Yü Fangliao Hengch un Lü Yü Source: Hospital Care in Taiwan, Department of Health, Taiwan, January 2006 3
INITIATING CLINICAL TRIALS IN TAIWAN IS EFFICIENT AND RAPID 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 Source: Pacific Bridge Medical 4
REGULATORY PROCESS IN TAIWAN IS EFFICIENT AND RESPONSIVE Clinical trial approval: 20 days No Protocol CDE review Sponsor Report DOH The review process may take meeting? 3-4 months in practice Meeting Yes The CDE is open to consultation meeting with sponsors that plan to conduct clinical trials in Taiwan NDA (new drug application) 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 NDA submission Filing meeting Review meeting Assessment report DOH Drug Review Board Conclusion Reject Additional information from sponsor Source: Center for Drug Evaluation, Taiwan 5
Volume of Clinical Trials in Asia Pacific Region - Taiwan is a major site allocated by big pharma 700 600 577 500 400 300 200 100 0 488 231 219 200 157 120 95 57 55 20 22 Data accessed from www.clinicaltrials.gov on 17 Jan 2007 6 No. of Clinical Trials Singapore China Hong Kong Taiwan Thailand Korea Malaysia India Vietnam Indonesia Philippines Australia
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 7
Reduce lead time for Taiwan NDA 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. 8
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 9
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 10
APEC Network under ISTWG, since 1999 (2002, 2006) (2004) Chinese Taipei (2000, 2001, 2003, 2005, 2007) Partnership in Harmonization with ICH 3 11
GCRC of TSGH 12
Single-Bed Ward of GCRC of TSGH 13
Good Clinical Practice GCP Inspection Clinical Trials complying with GCP must be inspected. From July 1997 to October 1999 16 mock inspections and 5 formal inspections have been conducted. 14
New IND in Taiwan TW single site TW multiple sites 2004 2005 2006 2007 P S P S P S P S 32 32 24 24 11 11 21 21 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 15
NEW IND in Taiwan 1994~2007 Protocol No. 200 150 100 50 74 Local Registration Trial 67 GCP-Taiwan 100 95 90 81 CDE established 87 63 53 62 106 67 66 64 Bridging Study Evaluation 131 138 SARS IND New System 115 116 130 Qualified Site 162 Phase I~III Phase IV 16 14 0 93' 94' 95' 96' 97' 98' 99' 00' 01' 02' 03' 04' 05' 06' 07' Year 12 5 4 4 3 6 16
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 17
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 18
2007 IND Review Time Shortening 300 250 Old System New System Old New Sponsor Time (cal.d) 47.0 7.2 No Quest. asked % 25% 60% Review Time (cal.d) 54.6 43.1 200 Initial Approval % 60.7 83.8 150 100 50 0 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 2007. Feb. 19
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 20
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 21
Independent Asian Voice 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 22
Prof. Oliver Yoa-Pu Hu Ph.D. Dean, Research&Development, National Defense Medical Center Taiwan, ROC 23
MANY TAIWANESE HOSPITALS PROVIDE MULTIPLE SPECIALTIES Hospital 1. Cathay General Hospital 2. Chang-Gung Memorial Hospital 3. China Medical University Hospital 4. Chi Mei Hospital 5. Kaohsiung Medical University Chung- Ho Memorial Hospital Location Taipei Taipei Taichung city Tainan Kaohsiung Number of specialties 37 54 62 49 53 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 6. Kaohsiung Veterans General Hospital, Veterans Affairs Commission, Exec. Yuan 7. Mackay Memorial Hospital 8. National Taiwan University Hospital Kaohsiung city Taipei Taipei 43 52 52 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 9. Nonprofit Proprietary Chang-Gung Memorial Hospital 10. Taichung Veterans General Hospital 11. Taipei Medical University Municipal Wang Fang Hospital 12. Taipei Veterans General Hospital 13. Buddhist Tzu Chi General Hospital 14. Changhua Christian Hospital 15. Shin Kong Wu Ho-Su Memorial Hospital Kaohsiung Taichung city Taipei city Taipei Huahen City Tao-Yuan County Taipei City 35 52 48 61 54 51 54 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 16. Tri-Service General Hospital Taipei 83 Source: Hospital Care in Taiwan, Department of Health, Taiwan, January 2006 Teaching hospital of National Defense Medical Center; Class A teaching hospital; best hospital in quality English environment 24
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 (NCKUH 1 & TSGH 2 ) 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 Hospital 2. Tri-Service General Hospital 25
To Support FDA/EMEA IND Process Taiwan s Clinical Infrastructure is comparable with standards in US/EU 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) 26