Building the “in-House Review” Competence of GRP via an Innovative Review Model in Chinese Taipei

1. Building the “in-House Review” Competence of GRP via an Innovative Review Model in Chinese Taipei Meir-Chyun Tzou, Ph.D. Director, Divisionof Drugs & New Biotechnology Products, TFDA

2. Outline • Organization of TFDA • Reform of Taiwan Drug Review System • Implementation of Good Review Practice • Key elements of GRP • Template and tools • Reviewer training • Qualification of reviewer • Case study

3. Taiwan FDA (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 Establishment of Taiwan FDA 3 3

4. TFDA Organization Chart 4 4

5. Organization chart of Division of Drugs and New Biotechnology Products 5 5

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 6 6

7. Reform of Taiwan Drug Review System • Rationalization of the Review System Transparent , Unified, Fast • Regulation Strategies • post-marketing surveillance

8. Transparencyof the Review System 2000: Present to AC meeting for Appeal Case 2001: Use bar code to trace review status 2005: Announce AC meeting schedule on website 2006: Release of AC meeting results to applicants 2009: Announce AC members/experts name on website Aug. 2010 : announce the NCE assessment report on website 8 8

9. Transparencyand Quality Assurance • Implementation of Good Review Practice (GRP) • Review quality assurance: QA/QC task force • On-line Roadmap : for tracking review progress, starting from May 2010

10. UnifiedDrug Review System TFDA Review Team TFDA staff + CDE ★ reviewers Responsible for drugs and medical devices review General cases & fast-track review process Advisory Committee (AC) Committee members from academics, research organizations and health institutes Provides TFDA related consultation and advices Special cases review ★Center of Drug Evaluation (CDE) was Established by the DOH (Department of Health) in1998 as a NGO, NPO. Its mission is to assist DOH to evaluate new drugs and new medical devices for regulatory requirements and offer related consultation services. 10 10

11. Reform of the Advisory Committee Duties of the Advisory Committee Special case review Clinical Trial ：First in human, Ethnic and Ethical Concern and etc. NDA：Global New, NCE not approve by US FDA and EMA, Botanical product, Biosimilar and etc. Ethics, Public Health and Public awareness issues 11 11

12. Innovative Review Model of TFDA/CDE/AC • Create a functional “TFDA office for Evaluation” with part of CDE reviewers sit into the TFDA office building-”In HouseReview” and joint training program • Flexibility of CDE: funding resource, salary, head count, science based technical support from regulatory consultation to review • Authority of TFDA: legal, policy position • Streamline the review process

13. In-house Review Capacity ofTFDA TFDA AC AC Medical Device Drug TFDA Office for Evaluation Biological product PMA、IDE IVD PMA、IDE Class II and III Genetic product IND、BABE New drug NDA Class I Application

14. 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 14 14

15. Bridging Evaluation (2010.3) Different opinion Submission CCDP ★ Fee Review team Review Meeting Q&A Assessment Report Consultation with Experts Same opinion ★ CCDP: complete clinical data package Administrative process Advisory Committee TFDA Decision Require bridging study: PK, PD or clinical trials, etc. Grant bridging waiver 15 15

16. Review Process for NDA Sponsor Application TFDA Review Team (TFDA Staff+ CDE) 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 16 16

17. Impact of CDE/TFDA/AC Model – Cases Further Discussed at AC

18. Implementation of Good Review Practice (GRP)

19. Key elements of GRP • Template and tools • Reviewer training • Qualification of reviewer

20. Review Team of NDA Executive director or division director • All section have 2 reviewers, primary and secondary reviewers. • For special cases, the division director or Executive director will make the final conclusion. Team leader (secondary medical reviewer) CMC Pharm/Tox PK/PD Statistical Medical Project manager CMC: Chemistry, Manufacture, Control Pharm/Tox: Pharmacology/toxicology

21. Template and Other Tools • Template: • points to consider • Content and format of assessment report • template for IND, BSE and NDA assessment report • CMC, Pharm/Tox, PK/PD, Clinical, Statistics • Other tools: SOP, guidelines, primary endpoint for different indication, special protocol design….

22. Template example-key elements in IND review-clinical section • Rationale and expected value of the study • Protection of the welfare for all subjects • Diagnosis of the subjects • Inclusion and exclusion criteria • Dose selection, administration route, and treatment duration • Consideration and protection of the safety of subjects • Limitations on concomitant medication usage • Selection of therapeutic endpoints • Sub-study • Informed consent form

23. Template example-key elements in IND review-statistical section • Primary endpoints • Study design • Calculation of sample size • Rationale for selection of the margins for non-inferiority/ equivalence study • Execution of interim analysis • Population for efficacy and safety analyses • Handling of missing data • Models of statistical analysis

24. Template example-key elements in NDA review-PK section(1) • Absorption • Cmax, tmax, AUC • Dose proportionality • Bioavailability • Singe dose vs. multiple dose (except single use) • Healthy subjects vs. target patients • Food effect • Formulation effect (e.g. clinical batch vs. commercial batch, different strength) • Distribution • Protein binding (concentration dependent?) • Volume of distribution • Tissue distribution in animals (e.g. Whole-body autoradiography) • RBC distribution • Placenta transfer and milk secretion in animals • Metabolism • Metabolic pathway • Enzyme identification • Metabolite identification and activity • Metabolic profile in animal and human

25. Template example-key elements in NDA review-PK section(2) • Excretion • Mass balance study • Clearance and half-life • PK/PD correlation • Special populations • Gender • Age • Renal impairment • Hepatic impairment • Others • Dose recommendation for special population • Drug-drug interaction • Displacement-based (in vivo and iv vitro) • Metabolism-based (in vivo and iv vitro) • Transporter-based (in vivo and iv vitro) • Clinical co-medication • Dose recommendation for drug-durg interaction • Bridging study • Ethnic sensitivity from PK perspective

26. Reviewer’s Training and Quality Control • Review team : • Consultation with a group of 100 domestic experts and 5 oversea contracted consultants with FDA experience • Regular case discussion, review guidance discussion and drafting • Structured training and evaluation program for primary and secondary reviewers • Internal/external QA/QC task force Primary reviewer Secondary reviewer supervisor

27. Orientation course for new reviewer • Basic course • Advanced course • Basic introduction for new drug development, CMC, pharmacology/toxicology, PK/PD, Statistics, Biologics, key element for IND review • Computer skill, soft skill for consultation and communication • Consultation process, IND process, NDA process, BSE process • Review SOP Each new reviewer must complete the orientation course within 3 months

28. On- Job training • Real case training- supervised mainly under secondary reviewer • Learn how to set the approval criteria • Case discussion with senior Advisory committee member once every week since 2005 • Lectures from experts • CDER-101 training course • CBER-101 training course • DIA meeting in USA, Japan, and Europe • Optional training course • Presentation skill in English • Communication skill

29. Qualification of secondary reviewer • At least 2 years’ experience as reviewer • Logic thinking, decision making, quality of assessment report, communication skill, leadership in team work are key elements to evaluate the qualification of secondary reviewer • Division Director and Executive Director are responsible to evaluate the secondary reviewer

30. External QA/QC for GRP of TFDA/CDE’s Assessment Reports • Annual satisfactory rate survey for stakeholders in soft skill and professional performance via independent CRO • Stakeholders meeting with representatives from industry association. Give meeting minutes and follow up action report • Consultation/IND/NDA assessment reports of all disciplines rountinely scrutinized in written by contracted external consultants with FDA experience in clinical, statistics, PK, Pharm/Tox., CMC sections followed by face to face group discussion sessions

31. Pivotal Trial Study Design and Primary Endpoints Selection for Different Cancer Indication – An Internal Review for NDA 2004-2008 • For consistence in regulatory requirement • Review by cancer type, stage, with control group or not, effect size, endpoint selection like overall survival, progression free survival, disease free survival, time to progression, objective tumor response rate, surrogate endpoints, new indication, new formulation and approval or not

32. Case study

33. 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 transparent review processfor sponsor *: searchable from CDE website #: searchable from DOH website Review Process

34. NDA supp. submission* Report* AC meeting # DOH letter Sponsor prepare dossier* Licensed 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

35. IF NDA Atomoxetine Submitted in 2010 in Stead of 2005…. • Early submission with 1 CPP after FDA approval - 2 years • Shorter CDE/TFDA review time, administrative time:  30% • Better interactions with CDE/TFDA in scientific advice, supplement information, labeling discussion, REMS • Possibility of better drug price for clinical trial conduct in Chinese Taipei

36. Thank you for your attention