Implementation of Bridging Study-Taiwan’s Experience

1. Implementation of Bridging Study-Taiwan’s 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. Outline • 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

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

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

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

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

13. Consolidating Infrastructure for New Drug Clinical Trials in Taiwan(2) • 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

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

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

22. Considerations for Assessing the Necessity of a Bridging Study ( 4 of 4 ) Based on the result of evaluation, an appropriately designed protocol of a bridging study should be submitted to DOH for approval.(5) Is PK and/or PD data of Asian populations(3) available for estimating dosage or predicting efficacy? NO YES 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. • (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.

23. Bridging Study Evaluation--Current Status--

24. Bridging Study Evaluation--Current Status-- • 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 APECmembers for the global new drug development

27. Establish Network of Pharmaceutical Regulatory Science - APEC Joint Research Project - 1999 2000 2001 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 1st workshop was held in Taipei. The 2001 symposium was held in Taipei.

28. The 2001 Symposium on APEC Network of Pharmaceutical Regulatory Science- APEC Joint Research Project on Bridging StudyConclusion(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. The 2001 Symposium on APEC Network of Pharmaceutical Regulatory Science- APEC Joint Research Project on Bridging StudyConclusion(2) 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.

30. Thank you very much