Sharing Assessment of Regulatory
Approval or Assessment Reports –
Could This be an Effective Way for
Agencies in Asia Pacific to Use
Regulatory Resources?
Jan. 26, 2011
Meir-Chyun Tzou, Ph.D.
Director, Division of Drugs & New
Biotechnology Products, Taiwan FDA
Outline
Organization and regulation of TFDA
 Challenge for regulatory agency
 Advantage of sharing assessment report
 APEC “Best Regulatory Practice Project”
 A pilot case report



Action Plan for Taiwan APEC Project
Conclusion/ Future Perspectives
2
Establishment of Taiwan FDA (TFDA)
 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
3
TFDA Organization Chart
4
4
Division of Drugs and New Biotechnology Products
Drug Safety and
Evaluation
New Drugs
Generic Drugs
Director
Deputy
Director
Biologics and New
Biotechnology
Products
Clinical Trial
Management
Pharmaceutical
Management
Cooperation Institute
Center for Drug
Evaluation, CDE
Medical and
Pharmaceutical Industry
Technology and
Development Center,
PITDC
Taiwan Drug Relief
Foundation, TDRF
5
Pharmaceuticals Regulation in Taiwan
Pre-Market Approval
Research &
Discovery
Preclinical
Testing
GLP
IND/IDE
NDA/
PMA
IRB/GCP
Post-Market
Management
Market
GPvP
ADR/AE
Reporting
Quality
ADR/AE ★
Reporting
Insurance
Drug
Injury
Relief
GTP
cGMP
★ADR/AE: adverse
drug reaction/adverse event
6
6
Review Process for IND
Implement Fast Track
Hospitals、Sponsors、CRO Application
Archives
First-in Human、
Ethnic and
Ethical concern
etc.
Advisory
Committee
TFDA
Review
Team
Technical and Administrative
Document
IRB/
J-IRB
Assessment Report
Consultation with AC
Experts if needed
TFDA
Decision
Hospitals、sponsors、CRO
7
7
Review Process for NDA
Sponsor Application
Archives
Global New,
Botanical product,
Biosimilar product,
etc.
TFDA Review Team
(TFDA Staff+ CDE)
Technical and
administrative document,
GMP/PMF
GMP
/PMF
Assessment report
Consult with AC experts for
special concern
Advisory
Committee
Decision
8
Sponsor
★ GMP: Good manufacturing practice
PMF: Plant master file
8
Challenge for Regulatory Agency
Limited regulatory resources with overwhelming
workload and increasing complexity and expectation
from all stakeholders
 Build-in uncertainty for drug safety – “Drug Lag” vs
“Drug Withdrawal”
 Safety beyond the boarder – global drug
development, supply chain, ethnicity, safety signal

9
Potential Solution to Avoid Duplicate
Assessment
Standardization: ICH, GHTF, PIC/S
 Mutual recognition: EMA, ASEAN
 Bilateral agreement among countries
 Partnership in Harmonization: APEC, Tripartite, ICH
GCG
 Administration requirement: CPP

10
Current NDA Review Strategy in Taiwan
Non-CPP
1. Early phase
1. Pivotal clinical trials
clinical trials
in Taiwan
1-CPP
in Taiwan
2-CPP
1. REMS/RMP if
necessary
2. REMS/RMP if necessary
2. REMS/RMP
★CPP: Certificate for Pharmaceutical Product from 10 advanced countries
★REMS/RMP: Risk Evaluation and Mitigation Strategy/ Risk management plan
★expected review time does not include the time for document supplementation
and bridging study
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To Establish
Accelerated NDA Review Mechanism
Priority review
Unmet medical needs:
1.Severe diseases
2.Urgent medical needs
Priority review:
Full documents
Streamlined review
Approved by
FDA + EMA
No ethnic sensitivity
Partial review,
focused on
bridging data,
REMS, PSUR, etc.
Fast-track review
Innovative domestic
Products aiming at
International markets
Accelerated Review:
Full documents
Review verification
Future with MOU
Verification based on
reference agencies’
assessment reports
MOU: Memorandum of Understanding
12
Why not Sharing Assessment Report?
Confidentiality data of company esp. CMC data
 Different review approach, template and regulatory
consideration
 “Lack of confidence” or “Strong ego” in assessment

13
Why not Just use FDA/EMA/PMDA
Assessment Report on the Web Site?

Good reference but can be better – Ethnic sensitivity,
accumulated safety data, different indication
approved, life cycle management of drug
14
Advantage of Sharing Assessment Report
Transparency, Efficiency, Predictability, Consistence
 Improve Good Review Practice – Review quality,
template, process, peer group interactions
 “Compare and Contrast” from different agenies,
spot check the concerns risk/benefit decision
 Share responsibility and liability via public private
partnership

15
APEC “Best Regulatory Practice Project”
(I)
A 2-year APEC project leaded by Taiwan cosponsored
by Canada, China, Indonesia, Korea, Malaysia,
Mexico, Peru, Philippine, Thailand and US
 “Partnership in Harmonization” is the key
 Build up capacity of regulatory science via GRP
workshop on drug and medical device targeting on
regulators

16
APEC “Best Regulatory Practice Project”
(II)

APEC PER (Pharmaceutical Evaluation Report)
Scheme for sharing of regulatory assessment
report – follow the successful example of PER
Scheme (1979-2000) and the EMA centralized
procedure
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A Model in the Past: PER Scheme 1979-2000
- EFTA as secretariat
Netherland
Norway
Italy
EU
Finland Austria
Sweden
Hungary
Canada
Germany
Ireland
UK
Czech Republic
Switzerland
New Zealand
Iceland
South Africa
Australia
18
Current Status for Sharing Reports
X company agreed that Taiwan can share CDE’s
assessment report of Y drug to regulators in the GRP
workshop for drug in Nov. 2010
 Concept endorsed by PhRMA & EFPIA and presented
in many regional conferences
 Taiwan – China Cross-Strait Medical and Health Care
Cooperation Agreement

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Pilot Study for APEC PER Scheme



Select a few marketed products approved by several
regulatory agencies to exchange NDA assessment
reports with the permission from the license holders
Evaluate the experience of these “case studies” in GRP,
review template and administrative requirement
Preliminary interest from PhRMA SGD Committee,
EFPIA ICH GCG Regulatory Forum, some RA (Health
Canada, TGA, etc.) and Individual companies (Eli Lilly,
Novartis, etc.)
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A Pilot Case Study of APEC PER Scheme
Y drug (X company), NDA approved in 2006
 A selective norepinephrine reuptake inhibitor
 Indicated for the treatment of Z disease
 Letter from X company: CDE/TFDA’s regulatory
information (except CMC) can share with DRAs in
this workshop

21
TFDA/CDE Review Team
Project manager
 CMC
 Pharmacology/Toxicology
 Pharmacokinetic/Pharmacodynamic
 Clinical
 Statistical
 Primary reviewer plus secondary reviewer in
each section
 Supervisor

22
Review Process (continue)
U.S.
Germany,
U.K.,
Canada,
Australia
NDA
submis
sion*
Review
Filing
meeting
*
Supp*
meeting
*
2004
AC
Meeting#
Approval
Not
recommended
Approval
11.26.
2002
Report
*
07.25.
2005
08.15.
2005
10.15.
2005
10.17.
2005
01.11.
2006
DOH
letter
Approvable
02.15.
2006
03.29.
2006
transparent review process for sponsor
*: searchable from CDE website
#: searchable from DOH website
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Review Process (continue)
Sponsor
prepare
dossier*
NDA supp.
submission*
Report*
AC
meeting #
DOH
letter
Total time: 406 calendar days (licensed)
Licensed
1st submission: CDE review time: 106 days:
sponsor time: 62 days
Supp submission: CDE review time: 28 days
sponsor time: 0 days
3.29 ~ 5.15
2006
05.15.
2006
06.12.
2006
07.12.
2006
09.04.
2006
Request for More Data
PSURs – FDA approved in 2002, EMA in 2004
 Trial report conducted in Taiwan – IND in Taiwan in
2002: placebo controlled, DB, RCT for 6 wks in 106
children and Adolescence in 2 hospitals  Result
statistic significant for superiority

25
Any Special Issue or Local Concern
 PK/PD
Y drug metabolized by CYP2D6
 Difference in the proportion of population with
CYP2D6 PM status: 5-10% in Caucasians and 0-2% in
Asians, but Asian have 24% IM (Intermediate
Metabolizer)
 The AUC of PM was 10-fold higher than EM
 No dose adjustment for IM and PM in terms of
safety from clinical trial

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Any Special Issue or Local Concern?
Clinical
1. Severe liver toxicity noted after drug
approval in the US
2. Warning issued for severe liver toxicity (2008)
3. Black box warning issued for suicide ideation
(2006)
4. QT prolongation side effect noted after drug
approval
27
More Data Submitted
Liver toxicity: 373 reports received in 3,710,000
patients. Mostly mild abnormality with severe
toxicity very rare.
 Suicidal ideation: 669 reports from Nov 2002 to Nov
2005. The rate of 0.013% was not higher than the
rate of suicidal attempt and self injury in general
population.
 QT prolongation: 27 cases from Nov 2002 to Nov
2004. No TDP case found.

28
Decision Made By AC

Approval recommended with warnings and data
added to drug label on liver toxicity, suicide ideation,
CYP2D6
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Sharing Assessment of Regulatory Approval or
Assessment Reports – Could This be an Effective Way
for Agencies in Asia Pacific to Use Regulatory
Resources?

Sharing Assessment report is
 Save resource
 better review quality
 early approval
 Win-win solution for all parties
30
Action Plan for Taiwan APEC Project 20112012 (cosponsored by 10 countries)
Survey the current status of bilateral agreement
 Conduct pilot study for sharing assessment report
 Involving more agencies and companies
 Coordinate the procedure for sharing and set up the
secretariat

31
Future Perspectives on Pharmaceutical
Regulatory Issues

Sharing review experience





Enhance pharmaceutical regulatory networking




exchange review reports of IND/NDA/IDE/PMA/BLA
ethnic issue study by retrospective data surveillance
establish bridging study review consensus.
Fast tract review for IND/NDA, Joint IRB
joint training program, e.g., GRP, GCP inspections
communication and information sharing, e.g. ADR report
potentially harmonize the review process, report format,
data requirement
Establish reviewer exchange program
32
Thank You for Your Attention
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