Marketing Authorization Procedures and Quality Management for Generics

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 1

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

Establishment of Taiwan FDA (TFDA) was inaugurated on Jan. 1, 2010 TFDA supersedes the following 4 bureaus of Department of Health ü Bureau of Food Safety ü Bureau of Pharmaceutical Affairs ü Bureau of Food and Drug Analysis ü Bureau of Controlled Drugs 33 3

TFDA Organization Chart 44 4

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

Statistics on Pharmaceutical Licenses (2010) Generic drug New drug API 22857 84. 13% Biologics Orphan Drugs 6

Statistics on Pharmaceutical Licenses (2010) Domestic (%) Import (%) Total (%) 493 (30) 1156 (70) 1649 (100) 20499 (90) 2358 (10) 22857 (100) 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 　 New Drug Generic Drug API Domestic 13449 Import 3239 Total 16688 Non-Rx drug 7543 619 8162 Total Rx: Non-RX 20992 1. 8: 1 3858 5. 2: 1 24850 2: 1 Rx drug 77 7

Statistics on drug registration and post-approval ch (Jan~Dec. 2010) category NCE NDA cases Domestic non-NCE total prescription ANDA OTC total post-approval changes license extensions Import total 1 26 27 279 90 369 1731 27 80 107 60 22 82 1433 28 106 134 339 112 451 3164 815 551 1366 8

Management of Drug Qualityproduct Life Cycle Management 9

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

Milestones on Drug Regulation 1980 1982 GMP 2000 1999 c. GMP 1983 BA/BE 1993 1996 Local clinical trial GCP 1998 GLP 2000 BS * Evaluation /ICH E 5 2010 2009 DMF 2010 PIC/S GMP 2001 Pivotal trial/ early phase trial *Bridging Study Evaluation in accordance with ICH E 5 1983 PV/PMS 1998 ADR 1998 CDE 2008 GPv. P 2001 TDRF 2010 TFDA 11 11

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 (c. GMP) 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 (GPv. P) 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 t. NCE and Botanical New Drug (in process) 2010 Relaxation of CPP requirement (draft) 12 12 12

Pre-Marketing Approval 13

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

Regulatory requirement on BE studies Regulations ü Guideline of Bioavailability and Bioequivalence (BA/BE) studies (1987) ü Regulations of BA/BE Studies (2009) Drug Application ü New drugs ü 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 15

BA/BE studies inspection Implement inspection from 2002 üClinical phase should follow GCP üLaboratory phase should follow GLP üOther Regulations of BA/BE Studies üReviewer initiated inspection 16

Milestones of Pharmaceutical GMP Development in Taiwan GMP c. GMP PIC/S GMP number of domestic pharmaceutical manufacturer 21 pharmaceutical manufacturers are in compliance with PIC/S GMP ◆ ◆ 1982 1988 1999 2005 ◆ 2010. 11 Overseas Inspection since 2002 17

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

Post-marketing Management 19

Regulation on post-approval changes Types of Post-approval Changes ü Scale of manufacturing, Manufacturing process, equipment, site, manufacturer, etc. ü Particle size, crystalline form, polymorphs, in-process, controls, product release specification, etc. ü Synthetic procedures, source of API and excipients, supplier, etc. Regulation Requirement Scale-Up and Post Approval Changes (SUPAC) （2001 public Announcement ） ü 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. 20

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

The role of Government and Industry in ensuring Drug quality It is mainly the industry’s responsibility, not the government’s, to ensure product quality throughout product life cycle Government’s role Industry’s role Review • Review to ensure S、 E&Q 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 to assure compliance • Comply with GXPto assure data integrity and honest communication Inspection • Provide data for S、 E&Q ünon-clinical, clinical trial, CMC 22

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

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

Issues of Intellectual Property Right for Drug Approval 25

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

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

Issues of Patent Disclosure of patent Ø Pharmaceutical Affairs Act Article 40 -2 (since 2005 ) ü 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. ü These information are available on website. (http: //www. fda. gov. tw/Bgradation_index. aspx? site_content_ sn=38) 28

Issues of Patent Declaration of patent non-infringement Ø Review Regulations for Registration and Market Approval of Pharmaceuticals Article 19 ü 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. 29

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

Issues of Research Exemption for Research use Ø 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. Ø Patent Act Article 60(Amending) 31

Issues of Exclusivity Historical exclusivity analogy Ø 1993 Safety monitoring system-the requirement of local clinical trial for NDA (Taiwan-US Intellectual Property Right Agreement) ü Pipeline protection of new drug before the Patent Act was amended in 1986. ü Barrier for generic drug application ü 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. Ø 1997 New indication Ø 2004 Implementation of bridging study evaluation (BSE) 32

Issues of Data exclusivity Pharmaceutical Affairs Act Article 40 -2 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. 33

Issues of Data exclusivity Pharmaceutical Affairs Act Article 40 -2 ü 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. 34

Issues of Copyright Generic drug labeling Ø 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 nonsurveillance drugs** should be translated according to the innovator’s labeling. Ø 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. 35

Issues of Copyright Drug labeling – fair use for public benefit ØCopyright 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. Ø 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 TFDA is planning to amend the Pharmaceutical Affairs Act Article 48 -2, to stipulates the 48 -2 suitability of excluding drug labeling from Copyright Act. 36

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

Future perspectives 38

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

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

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

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

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

Milestones of Pharmaceutical GMP Development in Taiwan GMP c. GMP PIC/S GMP number of domestic pharmaceutical manufacturer 21 pharmaceutical manufacturers are in compliance with PIC/S GMP ◆ ◆ 1982 1988 1999 2005 ◆ 2010. 11 Overseas Inspection since 2002 44

Internationalize quality guidelines Implementation status of ICH quality Guidelines in Taiwan Q 1 Stability Adopt Q 2 Analytical Validation Adopt Q 3 Impurities Accept Q 4 Pharmacopoeias Accept Q 5 Quality of Biotechnological products Accept Q 6 Specifications Accept Q 7 Good Manufacturing Practice(原料藥GMP) Adopt Q 8 Pharmaceutical Development Accept Q 9 Risk Management system Accept Q 10 Pharmaceutical Quality system Accept 45

Evolution of Quality concept Quality Systems Quality by Testing- Quality by Manufacturing - Quality by Design Assurance Quality Control 1970 s 1980 s 1990 s 2000 s 46

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

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

49