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 &
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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
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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
333
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
Establishment of Taiwan FDA
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TFDA Organization Chart
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Director
DeputyDirector
Drug Safety and
Evaluation
New Drugs
GenericDrugs
Biologics and New
Biotechnology Products
Clinical Trial
Management
Pharmaceutical Management
Center for Drug Evaluation, CDE
Cooperation Institute
Medical and Pharmaceutical Industry Technology and Development Center, PITDC
Taiwan Drug Relief Foundation, TDRF
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Organization chart of Division of Drugs and New Biotechnology Products
66 66
Pharmaceuticals Regulation in Taiwan
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Post-Market Management
Quality
Drug InjuryRelief
Research & Discovery
PreclinicalTesting
NDA/PMA
GLP
ADR/AE ★ Reporting
Insurance
cGMP
Market
GPvP
ADR/AE Reporting
IRB/GCP
IND/IDE
Pre-Market Approval
GTP
★ADR/AE: adverse drug reaction/adverse event
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Reform of Taiwan Drug Review System
Rationalization of the Review SystemRationalization of the Review System
Transparent , Unified, FastTransparent , Unified, Fast
Regulation Strategies
post-marketing surveillance
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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
101010
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: 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
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
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Medical Device
TFDA
Drug
TFDAOffice for Evaluation
IND
、BABE N
ew drug
ND
A
PMA
、IDE
Biological product
Genetic
product
Class II and III
IVD PM
A
、ID
EClass I
Application
AC AC
In-house Review Capacity of TFDA
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Review Process for IND Implement Fast Track
Hospitals、 Sponsors、 CRO Application
Archives
Assessment Report
Consultation with AC Experts if neededAdvisory
Committee
Hospitals、 sponsors、 CRO
Technical and AdministrativeDocument
TFDAReview Team
First-in Human、
Ethnic and Ethical concern
etc.
TFDA DecTFDA Decisionision
IRB/J-IRB
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Bridging Evaluation (2010.3) Bridging Evaluation (2010.3) Submission
Review team
Assessment Report
Consultation with Experts
Advisory Committee
Review Meeting
Different opinion
★ CCDP: complete clinical data package
Administrative process
Same opinion
TFDA Decision
Require bridging study: PK, PD or clinical trials, etc.
Grant bridging waiver
Fee
Q&A
CCDP ★
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Review Process for NDAReview Process for NDA
Sponsor Application
Technical and administrative document,
GMP/PMF
TFDA Review Team (TFDA Staff+ CDE)
Assessment report
Consult with AC experts for special concern Advisory
Committee
Sponsor
Decision★ GMP: Good manufacturing practice PMF: Plant master file
Global New,Botanical product,
Biosimilar product, etc.
GMP/PMF
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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 100% 23/62 (37%)
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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
All section have 2 reviewers, primary and secondary reviewers.
For special cases, the division director or Executive director will make the final conclusion.
CMC Pharm/Tox PK/PD Statistical Medical
Team leader (secondary medical reviewer)
Executive director or division director
CMC: Chemistry, Manufacture, ControlPharm/Tox: Pharmacology/toxicology
Project manager
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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 example-key elements in IND review-clinical section
1. Rationale and expected value of the study 2. Protection of the welfare for all subjects 3. Diagnosis of the subjects 4. Inclusion and exclusion criteria 5. Dose selection, administration route, and treatment dur
ation 6. Consideration and protection of the safety of subjects7. Limitations on concomitant medication usage 8. Selection of therapeutic endpoints 9. Sub-study 10. Informed consent form
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Template example-key elements in IND review-statistical section
1. Primary endpoints2. Study design3. Calculation of sample size4. Rationale for selection of the margins for non-
inferiority/ equivalence study5. Execution of interim analysis6. Population for efficacy and safety analyses7. Handling of missing data8. Models of statistical analysis
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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
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Template example-Template example-key elements in NDA review-PK section(2)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
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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
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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
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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 Annual satisfactory rate survey for stakeholders in so
ft 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
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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
Supp*Supp* Review meeting*Review meeting*
Report* Report*
DOHletterDOHletterU.S.U.S.
Germany, U.K., Canada,Australia
Germany, U.K., Canada,Australia
NDA submission*
NDA submission*
Filingmeeting*Filingmeeting*
ACMeeting#
ACMeeting#
11.26.200211.26.2002 20042004
ApprovalApproval
07.25.200507.25.2005
08.15.2005 08.15.2005
10.15.200510.15.2005
10.17.200510.17.2005
01.11.200601.11.2006
02.15.200602.15.2006
03.29.200603.29.2006
ApprovalNot
recommended
ApprovalNot
recommendedApprovableApprovable
transparent review process for sponsor *: searchable from CDE website #: searchable from DOH website
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Review Process (continue)
DOHletterDOHletterReport*Report*
ACmeeting #ACmeeting #
06.12.200606.12.2006
07.12.2006 07.12.2006
09.04.200609.04.2006
NDA supp.submission*NDA supp.submission*
05.15.200605.15.2006
Sponsor prepare dossier*
Sponsor prepare dossier*
3.29 ~ 5.152006
3.29 ~ 5.152006
LicensedLicensedTotal 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
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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
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Thank you for your attention
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