Transcript 投影片 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
Outline
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
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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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Organization chart of Division of
Drugs and New Biotechnology Products
Cooperation Institute
Director
Medical and
Pharmaceutical Industry
Technology and
Development Center,
PITDC
Center for Drug
Evaluation, CDE
Deputy
Director
Drug Safety
and
Evaluation
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New
Drugs
Generic
Drugs
Biologics and
New
Biotechnology
Products
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Taiwan Drug Relief
Foundation, TDRF
Clinical
Trial
Management
Pharmaceutical
Management
Pharmaceuticals Regulation in Taiwan
Pre-Market Approval
Research &
Discovery
Preclinical
Testing
IND/IDE
NDA/
PMA
IRB/GCP
ADR/AE
Reporting
Quality
ADR/AE ★
Reporting
Insurance
GTP
cGMP
★ADR/AE: adverse drug reaction/adverse event
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Market
GPvP
GLP
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Post-Market
Management
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Drug
Injury
Relief
Reform of Taiwan Drug Review System

Rationalization of the Review System
Transparent , Unified, Fast
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
Regulation Strategies

post-marketing surveillance
Transparency of the Review System
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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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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
★
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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：Global New, NCE not approve by US
FDA and EMA, Botanical product, Biosimilar
and etc.
Ethics, Public Health and Public awareness
issues
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Innovative Review Model of TFDA/CDE/AC
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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
In-house Review Capacity of TFDA
TFDA
AC
AC
Medical Device
Drug
TFDA
Office for Evaluation
、
New drug NDA
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IND BABE
Application
Genetic product
Biological product
PMA IDE
Class II and III
IVD PMA IDE
Class I
、
、
Review Process for IND
Implement Fast Track
Hospitals、Sponsors、CRO Application
Archives
First-in Human、
Ethnic and
Ethical concern
etc.
Advisory
Committee
Technical and Administrative
Document
Assessment Report
Consultation with AC
Experts if needed
TFDA
Decision
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TFDA
Review
Team
Hospitals、sponsors、CRO
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IRB/
J-IRB
Bridging Evaluation (2010.3)
Submission
CCDP ★
Fee
Review team
Review Meeting
Q&A
Assessment Report
Different opinion
Consultation with Experts
Same opinion
Advisory Committee
Administrative process
TFDA Decision
Require bridging
study: PK, PD or
clinical trials, etc.
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Grant bridging
waiver
★ CCDP: complete
clinical data package
Review Process for NDA
Sponsor Application
TFDA Review Team
(TFDA Staff+ CDE)
Global New,
Botanical product,
Biosimilar product,
etc.
Technical and
administrative document,
GMP/PMF
Assessment report
Consult with AC experts for
special concern
Advisory
Committee
Decision
16 ★ GMP: Good manufacturing practice
PMF: Plant master file
GMP
/PMF
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Sponsor
Impact of CDE/TFDA/AC Model –
Cases Further Discussed at AC
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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
100%
23/62 (37%)
Implementation of Good Review
Practice (GRP)
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Key elements of GRP
Template and tools
 Reviewer training
 Qualification of reviewer
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Review Team of NDA
Executive director
or division director
Team leader
(secondary medical reviewer)
CMC
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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.
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CMC: Chemistry, Manufacture, Control
Pharm/Tox: Pharmacology/toxicology
Template and Other Tools
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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Template examplekey elements in IND review-clinical section
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10.
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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
Template examplekey elements in IND review-statistical section
1.
2.
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Primary endpoints
Study design
Calculation of sample size
Rationale for selection of the margins for noninferiority/ equivalence study
Execution of interim analysis
Population for efficacy and safety analyses
Handling of missing data
Models of statistical analysis
Template examplekey 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
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Template examplekey 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
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Reviewer’s Training and Quality Control
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Review team :
Primary
reviewer
Secondary
reviewer
supervisor
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Consultation with a group of 100 domestic experts and 5
oversea contracted consultants with FDA experience
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Regular case discussion, review guidance discussion and
drafting
Structured training and evaluation program for primary and
secondary reviewers
Internal/external QA/QC task force
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Orientation course for new reviewer
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Basic course
Advanced course
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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
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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
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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
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External QA/QC for GRP of
TFDA/CDE’s Assessment Reports
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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
Pivotal Trial Study Design and Primary Endpoints
Selection for Different Cancer Indication – An
Internal Review for NDA 2004-2008
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

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Case study
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Review Process
U.S.
Germany,
U.K.,
Canada,
Australia
NDA
submi
ssion*
Review
Filing
meeting
*
Supp*
2004
07.25.
2005
08.15.
2005
10.15.
2005
transparent review process for sponsor
*: searchable from CDE website
#: searchable from DOH website
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AC
Meeting
#
Approval
Not
recommended
Approval
11.26.
2002
meeting
*
Report
*
10.17.
2005
01.11.
2006
DOH
letter
Approvable
02.15.
2006
03.29.
2006
Review Process (continue)
Sponsor
prepare
dossier*
NDA supp.
submission
*
Report*
AC
meeting #
Total time: 406 calendar days (licensed)
DOH
letter
Licensed
1st submission: CDE review time: 106 days:
sponsor time: 62 days
Supp submission: CDE review time: 28 days
3.29 ~ 5.15
05.15.
06.12.
sponsor
time: 0 days07.12.
2006
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2006
2006
2006
09.04.
2006
IF NDA Atomoxetine Submitted in
2010 in Stead of 2005….
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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
Thank you for your attention
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