1. Implementation of Bridging Study-Taiwans Experience Meir-Chyun Tzou, Ph.D. Senior Officer, and Director of Section III, Bureau of Pharmaceutical Affairs Department of Health, The Executive Yuan Taipei, Taiwan, R.O.C.

2. Health Organization and the Drug Regulatory Agency Changing Environment of Clinical Trial in Taiwan Regulatory Strategies for Implementation of Bridging Study Current Status of Bridging Study Evaluation APEC Joint Research Project on Bridging Study Outline

3. Secretary - General Organization of the Department of Health, the Executive Yuan, ROC Specialist-General Counselor Minister Deputy/Vice Minister Bureau of Medical Affairs Bureau of Pharmaceutical Affairs Bureau of Food Sanitation Bureau of Health Promotion Bureau of Health Planning Office of Secretariat Office of Personnel Affairs Office of Anticorruption Office of Accounting Office of Statistics National Bureau of Controlled Drugs Center for Disease Control National Institute of Preventive Medicine National laboratories of Food and Drugs National Quarantine Service Bureau of National Health Insurence Committee on Chinese Medicine and Pharmacy NHI Supervisory Committee NHI Health Care Cost Arbitration Committee Center for Drug Evaluation National Health Research Institutes

4. Changing Environmental of Clinical Trial in Taiwan

5. Regulations Update for Clinical Trials Local clinical trial required for New Drug Registration since 1993 GCP guidelines implemented in 1997 GCP inspections for INDs and NDAs in 1997 Adverse Drug Reporting system in 1998 Guidances for clinical trials

6. Impact on New Drug Development in Taiwan Local clinical trials -Improve new drug R & D in Taiwan. -Facilitate development of Biotech / Pharmaceutical Industry

7. Global Environment / Trends International Harmonization for New Drug Registration : ICH Trade Liberalization : WTO Accession Biotech / Pharmaceutical Industry Promotion Plan

8. Consolidating Infrastructure for New Drug Clinical Trials in Taiwan Improving quality and efficiency of review process for clinical trials Promoting early phase clinical trials in Taiwan Establishing Center for clinical study in Asia Pacific Promoting Biotech-pharmaceutical Industry

9. Consolidating Infrastructure for New Drug Clinical Trials in Taiwan (1) Improving quality and efficiency of review process for clinical trials Reinforcement of GCP inspection Guidances for clinical trials Establishment of the Center for Drug Evaluation (CDE) in 1998 -full time review team Parallel review process of IRBs and DOH Establishment of Joint-IRB Deregulation and streamlining the review process for clinical trials

10. Center for Drug Evaluation -expert review team for clinical trials and NDAs BPA: Bureau of Pharmaceutical Affairs; CDE:Center for Drug Evaluation DOH: Department of Health DRF: Drug Relief Foundation D.O.H. (BPA) Advice Consult Application Approval Consultation Applicant C.D.E. Advisory Board (Review Committee) DRF

11. Parallel Review Process of IRB/JIRB and DOH Hospital Sponsor CRO Hospital Sponsor CRO DOH (Regulator) ( IRB/J-IRB) Approval Conducting Clinical Trials

12. Efficiency-Speedup in Review Time in Taiwan for New Drugs Clinical Trial Protocols

13. Promoting early phase clinical trials in Taiwan Establishing general clinical research centers (GCRC) -improving the quality and performance of the CRC. Establishing insurance and ADR reporting system for clinical trials Establishing central lab. (clinical pathology unit) -assuring the quality of clinical laboratory Regulatory reform in local clinical trial-bridging study Consolidating Infrastructure for New Drug Clinical Trials in Taiwan (2)

14. Regulatory Strategies for Implementation of Bridging Study

15. Regulatory Reform in Local Clinical Trial –Bridging Study Before An approved local clinical trial study report is required for the new drug application in Taiwan --July 7 Announcement in 1993. Disadvantage: - A sample size of 40 as required would be difficult to demonstrate significant importance clinically or statistically - The study design of the local trial usually only repeated a study that has been done in the foreign countries but in a smaller sample size The study has not been designed based on the medical situation in Taiwan

16. Regulatory Reform in Local Clinical Trial –Bridging Study After Bridging Study (Double Twelve Announcement, 2000) -Follow ICH E5 guidance Advantage: - To avoid repeating unnecessary clinical study - Conducting, necessary, meaningful clinical study based on differences of disease, ethnic differences etc, and the results of study, a dosage adjustment can be done for the locals

17. Strategies for Implementation of Bridging Study To follow closely the spirit of the ICH E5 guidance To establish a sound and practical consultation and evaluation process encourage sponsor to submit complete clinical data package for the evaluation of bridging study before new drug application guidance and Q & A data base self-evaluation checking list consultation process assessment scheme

18. Double Twelve Announcement for Bridging Studies Dec. 12, 2000 Effective on January 1, 2001 One-year of transition period -Local clinical trial bridging study In accordance with ICH E5 guidance Procedure of consultation and evaluation of bridging study

19. Considerations for Assessing the Necessity of a Bridging Study ( 1of 4 ) Does the drug meet DOH requirements for waiving a bridging study and also the criteria for exempting submission of information for ethnic consideration? (1) Does the package include clinical data of Asian populations? (3) Does the submitted preclinical and clinical data package meet the regulatory requirements (ICH E5 and DOH guidance on clinical trials)? (2) Amendment Is the medicine insensitive to both intrinsic and extrinsic factors? Are the clinical differences in efficacy and safety insignificant? (See ICH E5 guidelines) Submit relevant documents according to DOH requirements and request for waiving bridging studies YES NO YES NO YES

20. Does the package include clinical data of Asian populations? (3) Considerations for Assessing the Necessity of a Bridging Study ( 2 of 4 ) Is the medicine insensitive to both intrinsic and extrinsic factors? Are the clinical differences in efficacy and safety insignificant? (See ICH E5 guidelines) Have any early phase trials or global clinical trials that meet the DOH requirements of bridging studies been conducted in Taiwan? Is it reasonable to extrapolate from foreign clinical data that the medicine is insensitive to both intrinsic and extrinsic factors in Asians (3) and that its clinical differences in efficacy and safety are acceptable?(See ICH E5 guidelines) No bridging study required (4) Based on the result of evaluation, an appropriately designed protocol of a bridging study should be submitted to DOH for approval (5) No bridging study required (4) YES NO YES NO YES NO

21. Considerations for Assessing the Necessity of a Bridging Study ( 3 of 4 ) Is it reasonable to extrapolate from foreign clinical data that the medicine is insensitive to both intrinsic and extrinsic factors in Asians (3) and that its clinical differences in efficacy and safety are acceptable?(See ICH E5 guidelines) No bridging study required (4) Is it reasonable to extrapolate from foreign clinical data that the concentration (dose)-response relationship is similar between foreign and Asian populations (3) ? Is PK and/or PD data of Asian populations (3) available for estimating dosage or predicting efficacy? Based on the result of evaluation, an appropriately designed protocol of a bridging study should be submitted to DOH for approval. (5) NO YES NO YES

22. Considerations for Assessing the Necessity of a Bridging Study ( 4 of 4 ) Is PK and/or PD data of Asian populations (3) available for estimating dosage or predicting efficacy? Based on the result of evaluation, an appropriately designed protocol of a bridging study should be submitted to DOH for approval. (5) Using available data for dose determination (1) Apply for waiving bridging studies with reference to DOH announcements of waiving clinical trials. If the drug falls within the category that requires submission of information proving no existence of ethnic differences, it should be evaluated following this flowchart after the one year phase-in period. (2) Under circumstances when evidence indicating potential intrinsic/extrinsic differences between Chinese and other Asian populations, a bridging study in Chinese population is a must. (3) A bridging study will be required when there exists any safety concern. 1 (4) Under circumstances when evidence indicating potential intrinsic/extrinsic differences between Chinese and other Asian populations, a bridging study in Chinese population is a must. (5) A bridging study can be a PK and/or PD study or any clinical study that can demonstrate the efficacy and safety of the medicine. NO YES

23. Bridging Study Evaluation --Current Status--

24. Bridging study evaluation : 18 cases applied. (2001-present) 8/11 (73%) waived (including 4 without complete Asian data). Out of 3 not waived, 1 has safety concern, 2 did not have enough information.

25. Impact of Bridging Study on Clinical Trials Promoting early phase / global clinical trials in Taiwan Conducting necessary, meaningful clinical study based on scientific and medical circumstances (intrinsic/ extrinsic factors)

26. Establish Network of Pharmaceutical Regulatory Science - APEC Joint Research Project - Objectives: To establish an APEC network of pharmaceutical regulatory science To promote regulatory consensus through regional educational seminar, or APEC conference To develop a sound and practical methodology for implementing bridging study in accordance with ICH E5 by APEC members for the global new drug development

27. Establish Network of Pharmaceutical Regulatory Science - APEC Joint Research Project - At the 17th APEC ISTWG Meeting, all of the APEC economies have reached consensus on this project proposed and sponsored by Chinese Taipei and co-sponsored by Singapore, Philippines, Mexico, Malaysia, and Australia. The 1 st workshop was held in Taipei. The 2001 symposium was held in Taipei. 199920002001

28. The 2001 Symposium on APEC Network of Pharmaceutical Regulatory Science- APEC Joint Research Project on Bridging Study Conclusion(1) 1.Bridging justification should be based on sound science and intrinsic /extrinsic factors, not based on citizenship and nationality. 2. The regulatory agency should consider existing data and various factors (scientific and medical circumstances ) for drug approval. 3.Criteria for the similarity of efficacy,safety and quality between regions is needed.

29. 4.Bridging: Multi-directional Input and output between ICH/ Non ICH region should be involved 5.ICH E5- Identifying the questions from APEC region, elaboration/supplement is needed. 6.Consolidate the networking of pharmaceutical regulatory science within APEC is obviously. The 2001 Symposium on APEC Network of Pharmaceutical Regulatory Science- APEC Joint Research Project on Bridging Study Conclusion(2)