A New Paradigm for Pharmaceutical Regulation in Taiwan: TFDA Establishment

1 Taiwan Food and Drug Administration Director, Division of Drugs and New Biotechnology Products Meir-Chyun Tzou, Ph.D

Dec. 10, 2010

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Outline



Organization and Responsibility



Reform of Taiwan Drug Review System



Rationalization of Review System



Regulation Strategies



post-marketing surveillance



International Cooperation



Future Prospects

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Organization and Responsibility

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Establishment of Taiwan FDA



Taiwan FDA (TFDA) was inaugurated on Jan. 1, 2010

4 

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

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Establish Taiwan Food and Drug Safety Management System

Food Drug Medical Drvice/cosmetics Risk Management And Quality Assurance

TFDA Center for Regional Administration

Controlled Drug Research & Analysis

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Core Value of TFDA

From Product Center to Consumer Center Consumer Protection Risk Analysis Food Management

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Drug Management

Strategy of TFDA Reform

1. Consumer Protection (1) Center for Consumer Protection (2) Section of Risk Management 2. Food Safety (1) Division of FS (2) Regional Centers (3) Risk Assessment Task Force 3. Pharmaceutical Affair (1) Division of D&NBP (2) Division of MD&C (3) Division of CD

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4. Supporting Division (1)Division of P&RD (2) Division of R&A (3) Division of Risk Management

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

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Roles of Regulatory Authorities



Public Health Protection

 Gate-keeper  Prudent evaluation based on Good Review Practice  Drug quality, safety and efficacy 

Health Industry Promoter

 Consultation mechanism  Efficient and transparent review process  International harmonization 10

Pharmaceutical Regulation in Taiwan

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New Drug Discovery Preclinical Testing GLP Pre-Market Approvals IND/IDE NDA/ PMA IRB/GCP Quality ADR Reporting Insurance ICH Based GXP GMP Post Market Management Market GPvP/GPP ADR Drug Injure Relief

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Statistics on Pharmaceutical Licenses

(~Sep. 2010)

25000 20000 15000 10000 5000 0

Domestic API 2.1%

Domes t i c API

568 Import API 6.4%

I mpor t API

1752 Domestic DP 77%

Domes t i c DP

21072 Import DP 14.5%

I mpor t DP

3960

S1 •

API: active pharmaceutical ingredient

•

DP: Drug Product

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Statistics on Pharmaceutical Licenses

(~Sep. 2010) New Drug Generic Drug API Total no. of Licenses

ratio

Domestic

486 20586 568 21640 1:42:1.2

Import

1104 2856 1752 5712 1:2.6:1.6

Total

1590 23442 2320 27352 1:14.7:1.5

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Rx drug Non-Rx drug Total Rx: Non-RX Domestic

13492 7580 21072 1.8:1

Import

3323 637 3960 5.2:1

Total

16815 8217 25032 2:1

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Case numbers of IND Application in Taiwan (~Sep. 2010)

100 50 0 250 200 150 25 89 2004 46 110 27 112 2005 2006 一般案件 22 146 2007 22 183 18 169 2008 Fast track案件 2009 4 141 2010.Q3

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Distribution of Clinical Trial Applications in Taiwan (~ Nov. 2010) Phase I 2004 2005 P 8 S 12 P 14 S 26 P 12 2006 S 20 P 10 2007 S 18 2008 2009 2010 P 11 S 14 P 18 S 19 P 18 S 21 Phase II 22 57 33 78 32 98 46 158 46 120 60 167 43 135 Phase III 85 237 69 242 86 300 106 391 132 527 95 407 102 475 Phase IV/others Total 4 10 4 119 316 120 5 3 351 133 4 422 6 14 16 21 14 19 18 27 168 581 205 682 187 612 181 658 P: protocol S: site

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Milestones on Pharmaceutical Events

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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 requirement of serious ADR reporting) 2008 Good Pharmacovigilance Practice ( GPvP ) & compulsory 2008 Guideline for Biosimilar 2009 Drug Master File ( DMF ) 2010 Implementation of Product Review and Approval PIC/S GMP 2010 Amendment of Guideline for Biosimilar Product Review and Approval (in process) 2010 Develop strategies for review guidelines of tNCE and Botanical New Drug (in process) 2010 Relaxation of CPP requirement (in progress)

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Milestones on Drug Regulation

1980 2000

1982 GMP 1987 BA/BE

1990

1999 cGMP

2010

2009 DMF 2010 PIC/S GMP 1983 PV/PMS 1993 Local clinical trial 1996 GCP 1998 GLP 2000 BS * Evaluation /ICH E5 2001 Pivotal trial/ early phase trial *Bridging Study Evaluation in accordance with ICH E5 1998 CDE 2001 TDRF 2010 TFDA 1998 ADR 2008 GPvP

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Reform of Taiwan Drug Review System

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Reform of Taiwan Drug Review System



Rationalization of the Review System Unified, Transparent , Fast

 Regulation Strategies  post-marketing surveillance 19

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Unified

Drug 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.

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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 ： and etc.

Global New, NCE not approve by US FDA and EMEA, Botanical product, Biosimilar, t-NCE 21  Ethics, Public Health and Public awareness issues 21

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Transparency

of 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 22

Transparency

and 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 23

Key elements of GRP

 Template and tools  Reviewer training  Qualification of reviewer 24

Template and Other Tools of GRP

 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….

Reviewer’s Training and Quality Control

 Review team :

Primary reviewer Secondary reviewer supervisor

 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 26

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Review Process for IND

Implement Fast Track Hospitals

、

Sponsors

、

CRO Application First-in Human

、

Ethnic and Ethical concern etc.

Archives TFDA Review Team Technical and Administrative Document IRB/ J-IRB Assessment Report Advisory Committee Consultation with AC Experts if needed TFDA Decision Hospitals

、

sponsors

、

CRO

Fast-Track Review process for IND

 fast-track review process for IND is issued for those clinical trial studies that have the same FDA approved IND number as in the US. (Apr. 09, 2010) 28  fast-track review process for multi-national IND is issued for those clinical trial studies that have been approved by advanced countries. (Aug.18, 2010) 28 28

Review Process for NDA

Sponsor Application Global New, Botanical product, Biosimilar product, etc.

Advisory Committee TFDA Review Team (TFDA Staff+ CDE) GMP /PMF Technical and administrative document, GMP/PMF Assessment report Consult with AC experts for special concern

★

GMP: Good manufacturing practice PMF: Plant master file Decision Sponsor

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Fast-Track Review Process for NDA



Fast Track (Priority and Abbreviated) Review



Priority :

For Un-met medical Needs and with clinical advantages, expected to shorten the review processing time up to 2/3.



Abbreviated :

For New chemical entity (NCE) approved by USFDA and EMA , expected to shorten the review processing time up to 1/2.



Fast track :

for value added drugs, to expand global market

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Reform of Taiwan Drug Review System

 Rationalization of the Review System 

Regulation Strategies IND, NDA, New Biotechnology Products, Generics, API

 post-marketing surveillance 31

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Regulation Strategies for IND



Establishment of a Modern Clinical Trial Environment in Taiwan

 Preclinical GLP inspection  GCP inspection  Enhancement of the quality of IRB  Training for clinical trial professional, including CRO.

 Improvement of clinical trial Infrastructure

Regulation Strategies for IND

Improvement of Clinical Trial Infrastructure



Goal

 Establishment of software and hardware to meet international standard   Promote early phase multi-national multi-center trial, global drug development Strengthen quality of clinical trial 

Government funding Research Centers

 Grant $22 million (2010)     Good Clinical Research Center, GCRC ： 11 sites Center of Excellence ： 5 sites Cancer Center of Excellence ： 8 sites Site Management Organization, SMO 33 

Qualified clinical trial sites for IND

：  108 teaching hospitals 33

Regulation Strategies for NDA

Standard Review Non-CPP NDA Accelerated Review 1-CPP Abbreviated Review 2-CPP (FDA + EMA)

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Full technical dossier Early development in Taiwan GCP GLP GMP preapproval inspection REMS Full technical dossier + CT in Taiwan + REMS Full technical dossier + REMS if necessary

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Regulation Strategies for NDA

35  Relaxation of the requirement of Certificate of Pharmaceutical Product (CPP)  Risk Evaluation and Mitigation Strategy (REMS) or Risk Management Plan (RMP)  Strategies for Special Categories of New Drugs  Botanical product   Biosimilar T-NCE ★ approved the first domestic botanical product (Apr. 2010) 35

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Regulation Strategies for New Biotechnology Products

 Regulation strategy in supporting the development of new biomedical innovation: 

stem and somatic cells



engineered tissue products, and etc.



biosimilar medicine

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Regulation Strategies for Biosimilar medicine

 Regulation Strategies for Biosimilar medicine  Points to consider for common technical document (CTD) in review and approval of biosimilar medicine (Draft announced on Aug. 27. 2010 ) including CMC, Non-clinical, Clinical, RMP ★ Incentive : abridged data submission if NDA application before Dec.31.2013

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Regulation Strategies for Generic Drug and API

 Establishing the review strategies for DMF of API and CTD of Generic Drugs  Time-line and action plans for DMF and CTD  Communication with the industry association  Training /Education 38

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Regulation Strategies for Post-Approval Changes

 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)  Regulation Strategy for management of product license 39

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Reform of Taiwan Drug Review System

 Rationalizeation of the Review System  Regulation Strategies 

post-marketing surveillance

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

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Post-marketing Safety and Quality Surveillance

-Risk Management Passive Post-marketing product quality and safety surveillance Surveillance Quality surveillance Safety surveillance Reassessment / Inspection



Labeling change



Withdrawal/Recall Active Passive Active Drug Product quality defect reporting system National Quality surveillance Program ADR reporting system Manufacturer

：

Drug safety report on a regular basis Government

：

ADR active Monitoring Network

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Pharmacovigilance in Taiwan

 Taiwan MedWatch (

http://adr.doh.gov.tw/default.asp

)  Website of Pharmacovigilance in Taiwan ( http://adr.doh.gov.tw

)   Drug Safety information for Consumer Product Quality Defect Reporting System  From Voluntary reporting to Active surveillance  Establish Taiwan VAERS for Vaccine Safety 43

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Taiwan MedWatch



http://adr.doh.gov.tw/default.asp



Provide update safety information to the public



On-line report an ADR

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Website of Pharmacovigilance in Taiwan (http://adr.doh.gov.tw)

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Drug Safety information for Consumer

http://drug.doh.gov.tw/

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Product Quality Defect Reporting System http://recall.doh.gov.tw

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Taiwan Drug Injury Relief System

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TFDA

Drug Injury Relief Review Committee Request for Review Review and Determine Results Drug Injury Relief Fund

Relief Fund Payment Levies

Taiwan Drug Injury Relief Foundation (TDRF) Drug Injury Relief Application Review Notification, Relief Fund Payment Drug Hazard Victim Levies Collection, Verification, Request, Return and Claim Licensed Holders

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Quality Assurance for Drug Manufacturing



Good Manufactory Practice (GMP)

 Documentations, SOP, QC, QA  

Current GMP (c-GMP)

 Validations- analytical method, process, data treatment

PIC/S GMP by 2014

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Milestones of Pharmaceutical GMP Development in Taiwan GMP cGMP PIC/S GMP

600 500 400 300 200 100 0

number of domestic pharmaceutical manufacturer

550 ◆ 1982 211 ◆ 1988 230 ◆ 1999 163 ◆ 2005 165 ◆ 2010.

11 21 pharmaceutical manufacturers are in compliance with PIC/S GMP Overseas Inspection since 2002 50

GMP International Harmonization 1982 Implement GMP 1999 Upgrade to Current GMP (Validation) 2007 adopt to International GMP (PIC/S GMP)

Control Quality by Testing

1970s

Building Quality into Product

1980s

Design Quality into Product

1990s

Quality Systems

2000s

GMP Inspectorate in TFDA

• The Pharmaceutical GMP Inspectorate and Licensing Quality System had been established.

Taiwan FDA Div. of Risk Management Risk Management Branch GMP Audit Branch Domestic & Oversea GMP Inspection GTP Audit & Licensing Branch GMP Licensing & Certificate

GMP Inspectorate

Laboratory management Branch

GMP Regulation in Taiwan

• Legal System – Pharmaceutical Affairs Act • The pharmaceutical manufacturers shall comply with GMP and be approved and registered after meeting inspection standards of the competent health authority (i.e. TFDA) – GMP standards PIC/S GMP Guide – Licensing activity – Other activities: for Medicinal Products for medicinal products for human use had been formally adopted since Feb. 2010.

• Management Activities • Manufacturing License • GMP certification – Inspection activities • Domestic and oversea inspections (API’s factory only) • New GMP Assessment, routine inspection, for-cause inspection • Inspections on contract laboratory • Reviewing the Plant Master File of oversea manufacturers, etc.

The distribution of Domestic Pharmaceutical Manufacturers in Taiwan

• 166 pharmaceutical manufacturers • 9 pharmaceutical distributors involved in packaging activities • 19 of 166 pharmaceutical manufacturers are in compliance with PIC/S GMP.

Data collection until Sep. 15, 2010

4 14 11 1 3 3 18 7 2 1 25 +6 3 19 +2 14 4 20 +1 1 3 1 3

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International Cooperation

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International Cooperation

 Continuous international cooperation i.e. APEC (LSIF, ISTWG), ICH-GCG, DIA, etc.

– Initiation of APEC Industrial Science and Technology Working Group (ISTWG) project: • APEC Network on Pharmaceutical Regulatory Science since 2000 – Engage in APEC Life Science Innovation Forum (LSIF) • Initiation of APEC LSIF project: Best Regulatory Practice of Medical Products • Hosted the 2010 APEC Good Review Practice Workshop on Pharmaceuticals (Nov.3~6) 56

International Cooperation

 Harmonization on regulation and review process with international standard  Application of PIC/S membership  Observership  USP  WHA

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International Cooperation

 Bilateral Cooperation  Taiwan-:Australia  Pharmaceutical bilateral video-conference  Memorandum of Understanding (2010)   Taiwan-Japan  The 5th Joint Seminar of Taiwan & Japan Taiwan-EU  Pharmaceutical bilateral video-conference     Pre-notification of GCP, GMP inspections Taiwan-US  Pre-notification of GCP, GMP inspections Taiwan-Korea, Singapore  (Pharmaceutical bilateral video-conference) Cross strait cooperation on new drug research and clinical trial 58

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Future Prospects

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Initiatives



Pharmaceutical Affair Reform

 Regulation harmonization  Modern Review System  Quality assurance 

Cross Strait Cooperation

 Food Safety Management  New Drug Development and Clinical Trial Cooperation 60

Action Plans of TFDA



Action plan to Reform Pharmaceutical Affairs



Action plan for International affairs



Action plan for Cross-strait affairs



Action Plan to Reform Food Safety management



Action Plan for Anti-counterfeiting



Action Plan for Information Integration

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Future Prospects

 Continuous efforts in:  Promoting public health  Enhancing review quality , efficiency , and transparency .

 Improving consultation mechanism to facilitate industrial development and increase international competitiveness.

 Promoting international, regional and cross-strait drug regulatory harmonization and cooperation .

Quality Efficiency International Harmonization Transparency

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Thank You for Your Attention

http://www.fda.gov.tw

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