1. Building the “in-House Review” Competence of GRP via an Innovative Review Model in Chinese Taipei
Meir-Chyun Tzou, Ph.D.
Director, Division of Drugs & New Biotechnology Products, TFDA

2. Outline Case study Organization of TFDA
Reform of Taiwan Drug Review System
Implementation of Good Review Practice
Key elements of GRP
Template and tools
Reviewer training
Qualification of reviewer
Case study

3. 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 3 3

4. TFDA Organization Chart4 4

5. Organization chart of Division of Drugs and New Biotechnology Products5 5 5

6. Pharmaceuticals Regulation in Taiwan
Post-Market Management
Pre-Market Approval
Research & Discovery
Preclinical
Testing
IND/IDE
NDA/
PMA
Market
GPvP
GLP
IRB/GCP
ADR/AE Reporting
Quality
ADR/AE ★ Reporting
Drug
Injury
Relief
Insurance
GTP
cGMP
★ADR/AE: adverse drug reaction/adverse event 6 6 6 6

7. Reform of Taiwan Drug Review System
Rationalization of the Review System
Transparent , Unified, Fast
Regulation Strategies
post-marketing surveillance

8. 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 : announce the NCE assessment report on website 8 8

9. 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

10. 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. 10 10

11. 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：Global New, NCE not approve by US FDA and EMA, Botanical product, Biosimilar and etc.
Ethics, Public Health and Public awareness issues 11 11

12. Innovative Review Model of TFDA/CDE/AC
Create a functional “TFDA office for Evaluation” with part of CDE reviewers sit into the TFDA office building-”In House Review” and joint training program
Flexibility of CDE: funding resource, salary, head count, science based technical support from regulatory consultation to review
Authority of TFDA: legal, policy position
Streamline the review process

13. In-house Review Capacity of TFDA
Medical Device
TFDA
Drug
Office for Evaluation
IND、BABE
New drug NDA
PMA、IDE
Biological product
Genetic product
Class II and III
IVD PMA、IDE
Class I
Application AC

14. Review Process for IND Implement Fast Track
Hospitals、Sponsors、CRO Application
TFDA
Review Team
Archives
First-in Human、
Ethnic and
Ethical concern
etc.
Technical and Administrative
Document
IRB/
J-IRB
Assessment Report
Consultation with AC Experts if needed
Advisory Committee
TFDA Decision
Hospitals、sponsors、CRO 14 14

15. Bridging Evaluation (2010.3)
Submission
Fee
CCDP ★
Review team
Review Meeting
Q&A
Different opinion
Assessment Report
Consultation with Experts
Same opinion
★ CCDP: complete clinical data package
Administrative process
Advisory Committee
TFDA Decision
Require bridging study: PK, PD or clinical trials, etc.
Grant bridging waiver 15 15

16. administrative document,
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
There is a uniform and rapid review process in TFDA, including new drug application, new medical device as well as IND and IDE
Consult with AC experts for special concern
Advisory Committee
Decision
★ GMP: Good manufacturing practice
PMF: Plant master file
Sponsor 16 16 16

17. Impact of CDE/TFDA/AC Model – Cases Further Discussed at AC
2009
2010, Jan.~Sep.
IND
11/189 (5.8%)
0/118 (0%)
BSE
62/67 (92.5%)
0/8 (0%)
NCE
100%
6/12(50%)
NDA
23/62 (37%)

18. Implementation of Good Review Practice (GRP)

19. Key elements of GRP Template and tools Reviewer training
Qualification of reviewer

20. Executive director or division director (secondary medical reviewer)
Review Team of NDA
Executive director or division director
Team leader
(secondary medical reviewer)
CMC
Pharm/Tox
PK/PD
Statistical
Medical
Project manager
All section have 2 reviewers, primary and secondary reviewers.
For special cases, the division director or Executive director will make the final conclusion.
2 biological reviewers if biological products
Secondary medical reviewer is the team leader, who makes the final conclusion.
For special cases, the division director or Executive director will make the final conclusion.
CMC: Chemistry, Manufacture, Control
Pharm/Tox: Pharmacology/toxicology

21. Template and Other Tools
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….

22. Template example- key elements in IND review-clinical section
Rationale and expected value of the study
Protection of the welfare for all subjects
Diagnosis of the subjects
Inclusion and exclusion criteria
Dose selection, administration route, and treatment duration
Consideration and protection of the safety of subjects
Limitations on concomitant medication usage
Selection of therapeutic endpoints
Sub-study
Informed consent form

23. Template example- key elements in IND review-statistical section
Primary endpoints
Study design
Calculation of sample size
Rationale for selection of the margins for non-inferiority/ equivalence study
Execution of interim analysis
Population for efficacy and safety analyses
Handling of missing data
Models of statistical analysis

24. Template example- key elements in NDA review-PK section(1)
Absorption
Cmax, tmax, AUC
Dose proportionality
Bioavailability
Singe dose vs. multiple dose (except single use)
Healthy subjects vs. target patients
Food effect
Formulation effect (e.g. clinical batch vs. commercial batch, different strength)
Distribution
Protein binding (concentration dependent?)
Volume of distribution
Tissue distribution in animals (e.g. Whole-body autoradiography)
RBC distribution
Placenta transfer and milk secretion in animals
Metabolism
Metabolic pathway
Enzyme identification
Metabolite identification and activity
Metabolic profile in animal and human

25. Template example- key elements in NDA review-PK section(2)
Excretion
Mass balance study
Clearance and half-life
PK/PD correlation
Special populations
Gender
Age
Renal impairment
Hepatic impairment
Others
Dose recommendation for special population
Drug-drug interaction
Displacement-based (in vivo and iv vitro)
Metabolism-based (in vivo and iv vitro)
Transporter-based (in vivo and iv vitro)
Clinical co-medication
Dose recommendation for drug-durg interaction
Bridging study
Ethnic sensitivity from PK perspective

26. Reviewer’s 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

27. Orientation course for new reviewer
Basic course
Advanced course
Basic introduction for new drug development, CMC, pharmacology/toxicology, PK/PD, Statistics, Biologics, key element for IND review
Computer skill, soft skill for consultation and communication
Consultation process, IND process, NDA process, BSE process
Review SOP
Each new reviewer must complete the orientation course within 3 months

28. On- Job training
Real case training- supervised mainly under secondary reviewer
Learn how to set the approval criteria
Case discussion with senior Advisory committee member once every week since 2005
Lectures from experts
CDER-101 training course
CBER-101 training course
DIA meeting in USA, Japan, and Europe
Optional training course
Presentation skill in English
Communication skill

29. Qualification of secondary reviewer
At least 2 years’ experience as reviewer
Logic thinking, decision making, quality of assessment report, communication skill, leadership in team work are key elements to evaluate the qualification of secondary reviewer
Division Director and Executive Director are responsible to evaluate the secondary reviewer

30. External QA/QC for GRP of TFDA/CDE’s Assessment Reports
Annual satisfactory rate survey for stakeholders in soft skill and professional performance via independent CRO
Stakeholders meeting with representatives from industry association. Give meeting minutes and follow up action report
Consultation/IND/NDA assessment reports of all disciplines rountinely scrutinized in written by contracted external consultants with FDA experience in clinical, statistics, PK, Pharm/Tox., CMC sections followed by face to face group discussion sessions

31. For consistence in regulatory requirement
Pivotal Trial Study Design and Primary Endpoints Selection for Different Cancer Indication – An Internal Review for NDA
For consistence in regulatory requirement
Review by cancer type, stage, with control group or not, effect size, endpoint selection like overall survival, progression free survival, disease free survival, time to progression, objective tumor response rate, surrogate endpoints, new indication, new formulation and approval or not

32. Case study

33. Review Process transparent review process for sponsor
Supp*
Review meeting*
Report*
DOH
letter
U.S.
Germany, U.K., Canada,
Australia
NDA submission*
Filing
meeting* AC
Meeting#
11.26.
2002
2004
Approval
07.25.
2005
08.15.
10.15.
10.17.
01.11.
2006
02.15.
03.29.
Not recommended
Approvable
transparent review process for sponsor
*: searchable from CDE website
#: searchable from DOH website

34. Review Process (continue)
DOH
letter
Report* AC
meeting #
06.12.
2006
07.12.
09.04.
NDA supp.
submission*
05.15.
Sponsor prepare dossier*
3.29 ~ 5.15
Licensed
Total time: 406 calendar days (licensed)
1st submission: CDE review time: 106 days:
sponsor time: 62 days
Supp submission: CDE review time: 28 days
sponsor time: 0 days

35. IF NDA Atomoxetine Submitted in 2010 in Stead of 2005….
Early submission with 1 CPP after FDA approval - 2 years
Shorter CDE/TFDA review time, administrative time:  30%
Better interactions with CDE/TFDA in scientific advice, supplement information, labeling discussion, REMS
Possibility of better drug price for clinical trial conduct in Chinese Taipei

36. Thank you for your attention