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

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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

151515

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