1. 1 Marketing Authorization Procedures and Quality Management for Generics in Taiwan Meir-Chyun Tzou, Ph.D. Director, Division of Drugs and New Biotechnology Products, Taiwan Food and Drug Administration, Department of Health, Taiwan, R.O.C. 2011.06.03 Generic Medicines in the Legal Systems of the Republic of China and the Federal Republic of Germany

2. 2 Outline Organization and Responsibility Management of Drug Quality-product Life Cycle Management Pre-Marketing Approval Post-Marketing Management Issues of Intellectual Property Right for Drug Approval Future perspectives

3. 3 3 33 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

4. 4 4 44 TFDA Organization Chart

5. 5 Core Value of TFDA From Product Centered to Consumer Centered Risk Analysis and risk communication Drug Management Food Management Consumer Protection

6. 6 Statistics on Pharmaceutical Licenses (2010) New drug Generic drug API Biologics Orphan Drugs 22857 84.13%

7. 7 7 7 Statistics on Pharmaceutical Licenses (2010) DomesticImportTotal Rx drug13449323916688 Non-Rx drug75436198162 Total20992385824850 Rx: Non-RX1.8:15.2:12:1 Domestic (%)Import (%)Total (%) New Drug 493 (30)1156 (70)1649 (100) Generic Drug 20499 (90)2358 (10)22857 (100) API 560 (24)1758 (76)2318 (100) Total no. of Licenses 21552 (79)5616 (21) 27168 (100) ratio ~1:42:1.2~1:2.3:1.5~1:14:1.4

8. 8 DomesticImporttotal NCE 12728 non-NCE 2680106 total 27107134 prescription 27960339 OTC 9022112 total 36982451 post-approval changes 173114333164 license extensions 8155511366 cases category NDA ANDA Statistics on drug registration and post-approval changes (Jan~Dec.2010)

9. 9 Management of Drug Quality- product Life Cycle Management Management of Drug Quality- product Life Cycle Management

10. Management of Drug Quality-product Life Cycle Management Basic research Pre- clinical Clinical Trials Product Launch Production Marketing & Sales Review Inspection CTD ： Safety 、 Efficacy 、 Quality GMP/GTP GLP 、 GCP GPvP Analysis Testing / Trial/Analysis ( 審查 ) ( 稽查 ) ( 檢驗 ) 10

11. 11 1980 1990 20002010 Milestones on Drug Regulation Milestones on Drug Regulation 1982 GMP 1983 BA/BE 1999 cGMP 2009 DMF 2010 PIC/S GMP 1993 Local clinical trial 1996 GCP 1998 GLP *Bridging Study Evaluation in accordance with ICH E5 2000 BS * Evaluation /ICH E5 2001 Pivotal trial/ early phase trial 1998 CDE 2001 TDRF 2010 TFDA 1983 PV/PMS 1998 ADR 2008 GPvP

12. 12 Milestones on Drug Regulation 1982 Good Manufacturing Practice (GMP) 1987 Bioavailability / Bioequivalence Guideline (BA/BE) 1993 Safety monitoring system-the requirement of local clinical trial 1996 Good Clinical Practice (GCP) 1998 Good Laboratory Practices (GLP) 1999 Establishment of Adverse Drug Reaction reporting system 1999 Amendment of current GMP (cGMP) 2004 Implementation of bridging study evaluation (BSE) 2005 Revision of Pharmaceutical Affairs Act (Data Exclusivity & compulsory requirement of serious ADR reporting) 2008 Good Pharmacovigilance Practice (GPvP) 2008 Guideline for Biosimilar Product Review and Approval 2009 Drug Master File (DMF) 2010 Implementation of PIC/S GMP 2010 Amendment of Guideline for Biosimilar Product Review and Approval 2010 Develop strategies for review guidelines of tNCE and Botanical New Drug (in process) 2010 Relaxation of CPP requirement (draft) 12

13. 13 Pre-Marketing Approval

14. 14 Pre-marketing review New DrugGeneric drug Safety Efficacy Pharm / Tox PK/PD/BA/BE Clinical trials Bioequivalence (BE) as a surrogate to clinical trial Quality Chemistry, Manufacturing and Controls, CMC Including Active Pharmaceutical Ingredient (API), excipients, process control, validation, stability, etc. GLP, GCP, cGMP Labeling （ direction of use ）

15. 15 Regulatory requirement on BE studies Regulations Guideline of Bioavailability and Bioequivalence (BA/BE) studies (1987) Regulations of BA/BE Studies (2009) Drug Application New drugs Generic drugs — Since 1983 — Retrospectively request BE studies for drugs approved before 1983 with BE concern e.g., Diltiazem 、 Glyburide 、 Furosemide 、 Isosorbide dinitrate 、 Atenolol 、 Nifedipine 、 Rifampin 、 Digoxin 、 Carbamazepine

16. BA/BE studies inspection Implement inspection from 2002 Clinical phase should follow GCP Laboratory phase should follow GLP Other Regulations of BA/BE Studies Reviewer initiated inspection 16

17. 17 PIC/S GMP 1982 ◆ 1999 ◆ cGMPGMP ◆ 2010.11 ◆ 1988 ◆ 2005 21 pharmaceutical manufacturers are in compliance with PIC/S GMP Milestones of Pharmaceutical GMP Development in Taiwan number of domestic pharmaceutical manufacturer Overseas Inspection since 2002

18. Regulatory requirement on Active Pharmaceutical Ingredients (API) DMF for API of NDA and biological products 2002 GMP Guide for Active Pharmaceutical Ingredients 2009 Announced DMF technical information review form and application notes for API. 18

19. 19 Post-marketing Management

20. 20 Regulation on post-approval changes Types of Post-approval Changes Scale of manufacturing, Manufacturing process, equipment, site, manufacturer, etc. Particle size, crystalline form, polymorphs, in-process, controls, product release specification, etc. Synthetic procedures, source of API and excipients, supplier, etc. Regulation Requirement Scale-Up and Post Approval Changes (SUPAC) （ 2001 public Announcement ） For products that have passed the BE testing and registered for marketing, any changes, depending on the level and extent of change are required to submit Bioequivalence testing report or Dissolution Rate Profile to assure and verify its quality.

21. 21 Post-approval commitment Surveillance on Safety, Efficacy and Quality Post-marketing Surveillance, Phase-IV trial ADR/quality defect reporting and investigation REMS/RMP Maintenance for Drug Quality-Life Cycle Management (industry’s role) Well controlled process and quality system — batch to batch release On-going stability protocol Post-approval changes, annual report Inspection

22. 22 The role of Government and Industry in ensuring Drug quality Government’s roleIndustry’s role Review Review to ensure S 、 E&QProvide data for S 、 E&Q non-clinical, clinical trial, CMC Testing Batch release for biologics No testing for other drugs (with exceptions) In process control and batch to batch release for drugs and biologics Inspection Inspection to assure compliance Comply with GXP- to assure data integrity and honest communication It is mainly the industry’s responsibility, not the government’s, to ensure product quality throughout product life cycle

23. 23 Post-marketing Management System 23 Post-marketing Management system Post-approval changes Post-approval changes Post-approval commitment Post-approval commitment ADR reporting system ADR reporting system Product quality defect reporting system Product quality defect reporting system Compliance GMP Safety Pharmacovigilance Safety Pharmacovigilance Review Review/ Testing Review/ Testing Inspection Quality surveillance Quality surveillance

24. 24 Post-marketing product quality and safety surveillance Quality surveillance Safety surveillance Drug Product quality defect reporting system Active National Quality surveillance Program National ADR reporting system Manufacturer ： Drug safety report on a regular basis(PSUR) Government ： ADR active Monitoring Network Reassessment / Inspection  Labeling change  Withdrawal/Recall Reassessment / Inspection  Labeling change  Withdrawal/Recall Surveillance Post-marketing Safety and Quality Surveillance-Risk Management Passive Therapeutic Inequivalence Reporting System 24

25. Issues of Intellectual Property Right for Drug Approval 25

26. 26 Issues of Patent Issues of Exclusivity Issues of Research Exemption Issues of Intellectual Property Right for Drug Approval Issues of Copyright

27. Issues of Patent Disclosure of patent Declaration of patent non-infringement The review of generic drug and the information of patents are normally linked Review of patent infringement cases- Intellectual Property Court 27

28. 28 Issues of Patent Disclosure of patent  Pharmaceutical Affairs Act Article 40-2 (since 2005 ) While granting the certificate of pharmaceutical product, the central health competent authority shall announce the disclosed patent number or patent application number provided by the applicant. - DOH made an announcement on October, 2005 notifying applicants who are applying or have been granted marketing approval for pharmaceutical products after Feb. 2005, to submit registered patent number/ affidavit of patent. These information are available on website. (http://www.fda.gov.tw/Bgradation_index.aspx?site_content_s n=38)http://www.fda.gov.tw/Bgradation_index.aspx?site_content_s n=38

29. 29 Issues of Patent Declaration of patent non-infringement  Review Regulations for Registration and Market Approval of Pharmaceuticals Article 19 Applicants should submit an affidavit to declare that the applicant has full legal responsibility if the applied product infringe the patent of others. The review of generic drug and the information of patents are normally linked.

30. Issues of Patent Review of patent infringement cases- Intellectual Property Court  According to Taiwan’s Patent Act, within valid patent protection period, generic drug cannot enter the market or be sold.  Patent infringement will be granted by the patentee if the generic drug applicants violate the rule.  Patent-related litigation and the quality of review had been enhanced and accelerated since the Intellectual Property Court was established on July 1st, 2008. 30

31. 31 Issues of Exemption Issues of Research Exemption Exemption for Research use  Pharmaceutical Affairs Act Article 40-2 Paragraph 5 The patent right of the new drug shall not be applicable to researches, teachings, or testing prior to the application for registration by the pharmaceutical firms.  Patent Act Article 60(Amending)

32. 32 Issues of Exclusivity Historical exclusivity analogy  1993 Safety monitoring system-the requirement of local clinical trial for NDA (Taiwan-US Intellectual Property Right Agreement) Pipeline protection of new drug before the Patent Act was amended in 1986. Barrier for generic drug application Within five years after the issuance of a license for new drug, the second applicant is required to submit the same scale of clinical trial data as the first applicant.  1997 New indication  2004 Implementation of bridging study evaluation (BSE)

33. 33 Issues of Data exclusivity Within five years after the issuance of a license for new drug of new chemical entity, any other pharmaceutical firm may not apply for evaluation and registration of the same items by citing the data submitted by the licensee without such licensee’s authorization. After three years of the issuance of a license for new drug of new chemical entity, other pharmaceutical firm may apply for registration of drugs of the same substance, the same dosage form, the same dose, and the same dose unit according to this Act and related laws or regulations; the drug license may be issued on the next day to the expiration of five years after the issuance of license to such new drug of new chemical entity. Pharmaceutical Affairs Act Article 40-2

34. 34 Issues of Data exclusivity Pharmaceutical Affairs Act Article 40-2 The second paragraph hereof can only be applicable with the compliance that application for registration of a new drug of new chemical entity shall be made to the Central Competent Health Authority within three years after it is first approved for marketing in any country.

35. 35 Generic drug labeling  Review Regulations for Registration and Market Approval of Pharmaceuticals Article 20 Generic drug labeling of the surveillance drugs*, should follow the first approved labeling; labeling of the non- surveillance drugs** should be translated according to the innovator’s labeling.  But drug labeling has not been excluded from the copyright act, which might cause the lawsuit. * surveillance drugs: chemical entity first approved after 1983. ** non-surveillance drugs : chemical entity first approved before 1983. Issues of Copyright

36. 36 Drug labeling – fair use for public benefit  Copyright Act Article 65 Fair use of a work shall not constitute infringement on economic rights in the work. In determining whether the exploitation of a work complies with the provisions of Articles 44 through 63, or other conditions of fair use, all circumstances shall be taken into account, and in particular the following facts shall be noted as the basis for determination.  The court decision for lawsuit cases : Drug labeling should refer to Copyright Act Article 52 “Within a reasonable scope, it may be used for necessary or other legitimate purposes” Drug labeling excluding from copyright Pharmaceutical Affairs Act Article 48-2 TFDA is planning to amend the Pharmaceutical Affairs Act Article 48-2, to stipulates the suitability of excluding drug labeling from Copyright Act. Issues of Copyright

37. Future perspectives of Intellectual Property Right for Drug Approval Exemption for research use -amendment of Patent Act -amendment of Patent Act Drug labeling excluding from copyright -amendment of Pharmaceutical Affairs Act -amendment of Pharmaceutical Affairs Act Data exclusivity for new indication? 37

38. 38 Future perspectives

39. 39 Future perspectives in Enhancing Drug Quality Strategies for API and Generic Drug Strategies for GMP regulation Strategies for Post-Approval Changes

40. 40 Establishing the review strategies for DMF of API and CTD of Generic Drugs Time-line and action plans to implement API’s DMF and CTD for Generic Drug Implement DMF and CTD by stages. Stage 1: With NHI drug price incentives, encouraging companies to implement DMF, starting from Oct. 1st, 2009 Stage 2: Compulsory implementation of DMF and CTD -Implement by stages, by items Strategies for API and Generic Drug

41. 41 New chemical entities New biologic New indication New dosage forms New route of administration Generics OTC EUFDAMHLW included included* included not included * with the exception of blood and blood components Common Technical Document (CTD) Implementation Coordination Group presented in June 13 `02 General Information on the CTD organized by: Implementation Coordination Group Members plus members in CTD-Q, CTD-S, CTD-E & eCTD Implement Common Technical Document for generic drug

42. 42 Regulation strategies for post-approval changes Establish DMF database of API Monitor and inspect API changes Revise guideline for Scale-Up and Post Approval Changes (SUPAC) Strengthen regulation on Post-Approval Changes-Product Quality Review Regulation Strategy for management of product license Strategies for Post-Approval Changes

43. 43 Strategies for GMP regulation Quality Assurance for Drug Manufacturing Good Manufactory Practice (GMP) Documentations, SOP, QC, QA Current GMP (cGMP) Validations- analytical method, process, data treatment PIC/S GMP by 2014

44. 44 PIC/S GMP 1982 ◆ 1999 ◆ cGMPGMP ◆ 2010.11 ◆ 1988 ◆ 2005 21 pharmaceutical manufacturers are in compliance with PIC/S GMP Milestones of Pharmaceutical GMP Development in Taiwan number of domestic pharmaceutical manufacturer Overseas Inspection since 2002

45. 45 Internationalize quality guidelines Implementation status of ICH quality Guidelines in Taiwan Q1StabilityAdopt Q2Analytical ValidationAdopt Q3ImpuritiesAccept Q4PharmacopoeiasAccept Q5Quality of Biotechnological productsAccept Q6SpecificationsAccept Q7 Good Manufacturing Practice( 原料藥 GMP) Adopt Q8Pharmaceutical DevelopmentAccept Q9Risk Management systemAccept Q10Pharmaceutical Quality systemAccept

46. 46 Quality by Testing- Quality Control Quality by Manufacturing - Quality Assurance 1970s 1980s1990s2000s Quality by Design Quality Systems Evolution of Quality concept

47. 47 New Quality Initiative How to doWhat to do Product -1970s Quality Control Process 1980s~1990s Systems 21 st Century Quality Systems Quality Assurance Fixed controls state Dynamic controls state

48. 48 The three-way win Consumer IndustryGovernment Ensure Drug quality, safety& efficacy International harmonization on drug management Increase international competitiveness Goal

49. 49