Jan. 26, 2011 Meir-Chyun Tzou, Ph.D. Director, Division of Drugs & New

1. Sharing Assessment of Regulatory Approval or Assessment Reports – Could This be an Effective Way for Agencies in Asia Pacific to Use Regulatory Resources? Jan. 26, 2011 Meir-Chyun Tzou, Ph.D. Director, Division of Drugs & New Biotechnology Products, Taiwan FDA

2. Outline • Organization and regulation of TFDA • Challenge for regulatory agency • Advantage of sharing assessment report • APEC “Best Regulatory Practice Project” • A pilot case report • Action Plan for Taiwan APEC Project • Conclusion/ Future Perspectives

3. Establishment of Taiwan FDA (TFDA) • TFDA was inaugurated on Jan. 1, 2010 • TFDA supersedes the following 4 bureaus of Department of Health • Bureau of Food Safety • Bureau of Pharmaceutical Affairs • Bureau of Food and Drug Analysis • Bureau of Controlled Drugs

4. TFDA Organization Chart 4 4

5. Division of Drugs and New Biotechnology Products Cooperation Institute Drug Safety and Evaluation Center for Drug Evaluation, CDE New Drugs Generic Drugs Medical and Pharmaceutical Industry Technology and Development Center, PITDC Director Deputy Director Biologics and New Biotechnology Products Clinical Trial Management Taiwan Drug Relief Foundation, TDRF Pharmaceutical Management

6. Pharmaceuticals Regulation in Taiwan Post-Market Management Pre-Market Approval Research & Discovery Preclinical Testing IND/IDE NDA/ PMA Market GPvP GLP IRB/GCP ADR/AE Reporting Quality ADR/AE ★ Reporting Drug Injury Relief Insurance GTP cGMP ★ADR/AE: adverse drug reaction/adverse event 6 6

7. Review Process for INDImplement Fast Track First-in Human、 Ethnic and Ethical concern etc. Hospitals、Sponsors、CRO Application TFDA Review Team Archives Technical and Administrative Document IRB/ J-IRB Assessment Report Consultation with AC Experts if needed Advisory Committee TFDA Decision Hospitals、sponsors、CRO 7 7

8. Review Process for NDA Sponsor Application TFDA Review Team (TFDA Staff+ CDE) Archives GMP /PMF Technical and administrative document, GMP/PMF Global New, Botanical product, Biosimilar product, etc. Assessment report Consult with AC experts for special concern Advisory Committee Decision ★GMP: Good manufacturing practice PMF: Plant master file Sponsor 8 8

9. Challenge for Regulatory Agency • Limited regulatory resources with overwhelming workload and increasing complexity and expectation from all stakeholders • Build-in uncertainty for drug safety – “Drug Lag” vs “Drug Withdrawal” • Safety beyond the boarder – global drug development, supply chain, ethnicity, safety signal

10. Potential Solution to Avoid Duplicate Assessment • Standardization: ICH, GHTF, PIC/S • Mutual recognition: EMA, ASEAN • Bilateral agreement among countries • Partnership in Harmonization: APEC, Tripartite, ICH GCG • Administration requirement: CPP

11. Non-CPP 1-CPP 2-CPP 1. Early phase clinical trials in Taiwan 2. REMS/RMP 1. Pivotal clinical trials in Taiwan 2. REMS/RMP if necessary 1. REMS/RMP if necessary ★CPP: Certificate for Pharmaceutical Product from 10 advanced countries ★REMS/RMP: Risk Evaluation and Mitigation Strategy/ Risk management plan ★expected review time does not include the time for document supplementation and bridging study Current NDA Review Strategy in Taiwan

12. Review verification Future with MOU Priority review Unmet medical needs: 1.Severe diseases 2.Urgent medical needs Streamlined review Approved by FDA + EMA No ethnic sensitivity Fast-track review Innovative domestic Products aiming at International markets Priority review: Full documents Partial review, focused on bridging data, REMS, PSUR, etc. Accelerated Review: Full documents Verification based on reference agencies’ assessment reports MOU: Memorandum of Understanding To Establish Accelerated NDA Review Mechanism

13. Why not Sharing Assessment Report? • Confidentiality data of company esp. CMC data • Different review approach, template and regulatory consideration • “Lack of confidence” or “Strong ego” in assessment

14. Why not Just use FDA/EMA/PMDA Assessment Report on the Web Site? • Good reference but can be better – Ethnic sensitivity, accumulated safety data, different indication approved, life cycle management of drug

15. Advantage of Sharing Assessment Report • Transparency, Efficiency, Predictability, Consistence • Improve Good Review Practice – Review quality, template, process, peer group interactions • “Compare and Contrast” from different agenies, spot check the concerns risk/benefit decision • Share responsibility and liability via public private partnership

16. APEC “Best Regulatory Practice Project” (I) • A 2-year APEC project leaded by Taiwan cosponsored by Canada, China, Indonesia, Korea, Malaysia, Mexico, Peru, Philippine, Thailand and US • “Partnership in Harmonization” is the key • Build up capacity of regulatory science via GRP workshop on drug and medical device targeting on regulators

17. APEC “Best Regulatory Practice Project” (II) • APEC PER (Pharmaceutical Evaluation Report) Scheme for sharing of regulatory assessment report – follow the successful example of PER Scheme (1979-2000) and the EMA centralized procedure

18. EU Netherland Norway Italy Finland Austria Sweden Hungary Canada Germany Ireland Czech Republic UK Switzerland New Zealand Australia South Africa Iceland A Model in the Past: PER Scheme 1979-2000 - EFTA as secretariat

19. Current Status for Sharing Reports • X company agreed that Taiwan can share CDE’s assessment report of Y drug to regulators in the GRP workshop for drug in Nov. 2010 • Concept endorsed by PhRMA & EFPIA and presented in many regional conferences • Taiwan – China Cross-Strait Medical and Health Care Cooperation Agreement

20. Pilot Study for APEC PER Scheme Select a few marketed products approved by several regulatory agencies to exchange NDA assessment reports with the permission from the license holders Evaluate the experience of these “case studies” in GRP, review template and administrative requirement Preliminary interest from PhRMA SGD Committee, EFPIA ICH GCG Regulatory Forum, some RA (Health Canada, TGA, etc.) and Individual companies (Eli Lilly, Novartis, etc.)

21. A Pilot Case Study of APEC PER Scheme • Y drug (X company), NDA approved in 2006 • A selective norepinephrine reuptake inhibitor • Indicated for the treatment of Z disease • Letter from X company: CDE/TFDA’s regulatory information (except CMC) can share with DRAs in this workshop

22. TFDA/CDE Review Team • Project manager • CMC • Pharmacology/Toxicology • Pharmacokinetic/Pharmacodynamic • Clinical • Statistical • Primary reviewer plus secondary reviewer in each section • Supervisor

23. U.S. Germany, U.K., Canada, Australia NDA submission* Filing meeting* Supp* Reviewmeeting* Report* AC Meeting# DOH letter Approval Not recommended Approvable Approval 11.26. 2002 2004 07.25. 2005 08.15. 2005 10.15. 2005 10.17. 2005 01.11. 2006 02.15. 2006 03.29. 2006 transparentreview processfor sponsor *: searchable from CDE website #: searchable from DOH website Review Process (continue)

24. NDA supp. submission* Report* AC meeting # DOH letter Sponsor prepare dossier* 3.29 ~ 5.15 2006 05.15. 2006 06.12. 2006 07.12. 2006 09.04. 2006 Review Process (continue) Total time: 406 calendar days (licensed) 1st submission: CDE review time: 106 days: sponsor time: 62 days Supp submission: CDE review time: 28 days sponsor time: 0 days Licensed

25. Request for More Data • PSURs – FDA approved in 2002, EMA in 2004 • Trial report conducted in Taiwan – IND in Taiwan in 2002: placebo controlled, DB, RCT for 6 wks in 106 children and Adolescence in 2 hospitals  Result statistic significant for superiority

26. Any Special Issue or Local Concern • PK/PD • Y drug metabolized by CYP2D6 • Difference in the proportion of population with CYP2D6 PM status: 5-10% in Caucasians and 0-2% in Asians, but Asian have 24% IM (Intermediate Metabolizer) • The AUC of PM was 10-fold higher than EM • No dose adjustment for IM and PM in terms of safety from clinical trial

27. Any Special Issue or Local Concern? Clinical 1. Severe liver toxicity noted after drug approval in the US 2. Warning issued for severe liver toxicity (2008) 3. Black box warning issued for suicide ideation (2006) 4. QT prolongation side effect noted after drug approval

28. More Data Submitted • Liver toxicity: 373 reports received in 3,710,000 patients. Mostly mild abnormality with severe toxicity very rare. • Suicidal ideation: 669 reports from Nov 2002 to Nov 2005. The rate of 0.013% was not higher than the rate of suicidal attempt and self injury in general population. • QT prolongation: 27 cases from Nov 2002 to Nov 2004. No TDP case found.

29. Decision Made By AC • Approval recommended with warnings and data added to drug label on liver toxicity, suicide ideation, CYP2D6

30. Sharing Assessment of Regulatory Approval or Assessment Reports – Could This be an Effective Way for Agencies in Asia Pacific to Use Regulatory Resources? • Sharing Assessment report is • Save resource • better review quality • early approval • Win-win solution for all parties

31. Action Plan for Taiwan APEC Project 2011-2012 (cosponsored by 10 countries) • Survey the current status of bilateral agreement • Conduct pilot study for sharing assessment report • Involving more agencies and companies • Coordinate the procedure for sharing and set up the secretariat

32. Future Perspectives on Pharmaceutical Regulatory Issues • Sharing review experience • exchange review reports of IND/NDA/IDE/PMA/BLA • ethnic issue study by retrospective data surveillance • establish bridging study review consensus. • Fast tract review for IND/NDA, Joint IRB • Enhance pharmaceutical regulatory networking • joint training program, e.g., GRP, GCP inspections • communication and information sharing, e.g. ADR report • potentially harmonize the review process, report format, data requirement • Establish reviewer exchange program

33. Thank You for Your Attention 33