A New Paradigm for Pharmaceutical Regulation in Taiwan: TFDA Establishment

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A New Paradigm for Pharmaceutical Regulation in
Taiwan TFDA Establishment

• 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
• 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

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TFDA Organization Chart
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Establish Taiwan Food and Drug Safety Management
System
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Core Value of TFDA

• From Product Center to Consumer Center

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

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Pharmaceutical Regulation in Taiwan
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Statistics on Pharmaceutical Licenses(Sep. 2010)
3960
568
1752
21072

• API active pharmaceutical ingredient
• DP Drug Product

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Statistics on Pharmaceutical Licenses (Sep.
2010)
Domestic Import Total
New Drug 486 1104 1590
Generic Drug 20586 2856 23442
API 568 1752 2320
Total no. of Licenses Total no. of Licenses 21640 5712 27352
ratio ratio 1421.2 12.61.6 114.71.5
Domestic Import Total
Rx drug 13492 3323 16815
Non-Rx drug 7580 637 8217
Total 21072 3960 25032
Rx Non-RX 1.81 5.21 21
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Case numbers of IND Application in Taiwan(Sep.
2010)
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   Distribution of Clinical Trial Applicationsin
Taiwan ( Nov. 2010)
  2004 2004 2005 2005 2006 2006 2007 2007 2008 2008 2009 2009 2010 2010
  P S P S P S P S P S P S P S
Phase I 8 12 14 26 12 20 10 18 11 14 18 19 18 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 4 10 4 5 3 4 6 14 16 21 14 19 18 27
Total 119 316 120 351 133 422 168 581 205 682 187 612 181 658
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P protocol S site
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Milestones on Pharmaceutical Events

• 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 (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
2010
1990
1982 GMP
1987 BA/BE
1999 cGMP
2009 DMF
2010 PIC/S GMP
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
1983 PV/PMS
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

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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.
• NDAGlobal New, NCE not approve by US FDA and
  EMEA, Botanical product, Biosimilar, t-NCE and
  etc.
• Ethics, Public Health and Public awareness issues

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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

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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

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Key elements of GRP

• Template and tools
• Reviewer training
• Qualification of reviewer

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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.

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Reviewers 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
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Review Process for IND Implement Fast Track
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
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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)
• 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)

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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
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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

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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

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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, GCRC11 sites
• Center of Excellence5 sites
• Cancer Center of Excellence 8 sites
• Site Management Organization, SMO
• Qualified clinical trial sites for IND
• 108 teaching hospitals

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Regulation Strategies for NDA
NDA
Standard Review Non-CPP
Accelerated Review 1-CPP
Abbreviated Review 2-CPP (FDA EMA)

Full technical dossier Early development in
Taiwan GCP GLP GMP preapproval inspection REMS
Full technical dossier REMS if necessary
Full technical dossier CT in Taiwan REMS
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Regulation Strategies for NDA

• 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)

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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

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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

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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
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Post-marketing Safety and Quality
Surveillance-Risk Management
Passive
Drug Product quality defect reporting system
Quality surveillance
National Quality surveillance Program
Active
Surveillance
Post-marketing product quality and safety
surveillance
Passive
ADR reporting system
Safety surveillance
ManufacturerDrug safety report on a regular
basis
Active
GovernmentADR active Monitoring Network

• Reassessment / Inspection
• Labeling change
• Withdrawal/Recall

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Pharmacovigilance in Taiwan

• Taiwan MedWatch (http//adr.doh.gov.tw/default.as
  p )
• 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

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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
TFDA
Drug Injury Relief Review Committee
Drug Injury Relief Fund

Relief Fund Payment
Request for Review
Review and Determine Results
Levies
Taiwan Drug Injury Relief Foundation (TDRF)
Levies Collection, Verification, Request, Return
and Claim
Drug Injury Relief Application
Review Notification, Relief Fund Payment
Licensed Holders
Drug Hazard Victim
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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
PIC/S GMP
cGMP
GMP
number of domestic pharmaceutical manufacturer
21 pharmaceutical manufacturers are in compliance
with PIC/S GMP
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1982
1999
2010.11
1988
2005
Overseas Inspection since 2002
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GMP International Harmonization
1999Upgrade to Current GMP (Validation)
1982ImplementGMP
2007adopt to International GMP (PIC/S GMP)
Quality Systems
Design Quality into Product
Building Quality into Product
Control Quality by Testing
1980s
1990s
2000s
1970s
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GMP Inspectorate in TFDA

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

Taiwan FDA
Div. of Risk Management
GMP AuditBranch
GTP Audit LicensingBranch
Risk Management Branch
Laboratory managementBranch
GMP Licensing Certificate
Domestic Oversea GMP Inspection
GMP Inspectorate
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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 for Medicinal
  Products for medicinal products for human use had
  been formally adopted since Feb. 2010.
• Management Activities
• Licensing activity
• Manufacturing License
• GMP certification
• Inspection activities
• Domestic and oversea inspections (APIs factory
  only)
• New GMP Assessment, routine inspection, for-cause
  inspection
• Inspections on contract laboratory
• Other activities
• Reviewing the Plant Master File of oversea
  manufacturers, etc.

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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
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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.36)

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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

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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

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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.

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Thank You for Your Attention
http//www.fda.gov.tw
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