Sharing Assessment of Regulatory Sharing Assessment of Regulatory Approval or Assessment Reports – Approval or Assessment Reports – Could This be an Effective Way for Could This be an Effective Way for

Agencies in Asia Pacific to Use Agencies in Asia Pacific to Use Regulatory Resources?Regulatory Resources?

Jan. 26, 2011

Meir-Chyun Tzou, Ph.D.Director, Division of Drugs & NewBiotechnology Products, Taiwan FDA

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OutlineOutline 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

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Establishment of Taiwan FDA (TFDA)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

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TFDA Organization ChartTFDA Organization Chart

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DeputyDirector

Director

Generic Drugs

Biologics and New Biotechnology

Products

New Drugs

Drug Safety and Evaluation

Clinical Trial Management

Pharmaceutical Management

Center for Drug Evaluation, CDE

Division of Drugs and New Biotechnology ProductsDivision of Drugs and New Biotechnology Products

Medical and Pharmaceutical Industry

Technology and Development Center,

PITDC

Taiwan Drug Relief Foundation, TDRF

Cooperation Institute

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Pharmaceuticals Regulation in TaiwanPharmaceuticals Regulation in TaiwanPost-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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Review Process for INDReview Process for IND Implement Fast TrackImplement 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 TFDA DecisionDecision

IRB/J-IRB

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Review Process for NDAReview Process for NDASponsor 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

Archives

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Challenge for Regulatory AgencyChallenge 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

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Potential Solution to Avoid Duplicate Potential Solution to Avoid Duplicate AssessmentAssessment Standardization: ICH, GHTF, PIC/S Mutual recognition: EMA, ASEAN Bilateral agreement among countries Partnership in Harmonization: APEC, Tripartite, ICH

GCG Administration requirement: CPP

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Current NDA Review Strategy in TaiwanCurrent NDA Review Strategy in Taiwan

Non-CPP 1-CPP 2-CPP

1. Pivotal clinical trials

in Taiwan

2. REMS/RMP if necessary

1. Early phase

clinical trials

in Taiwan

2. REMS/RMP

1. REMS/RMP if necessary

★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 EstablishTo Establish Accelerated NDA Review MechanismAccelerated NDA Review Mechanism

Fast-track reviewInnovative domesticProducts aiming at

International markets

Streamlined reviewApproved by

FDA + EMANo ethnic sensitivity

Review verification Future with MOU

Priority review Unmet medical needs:1.Severe diseases2.Urgent medical needs

Priority review:Full documents

Partial review,focused on bridging data, REMS, PSUR, etc.

Verification based on reference agencies’assessment reports

Accelerated Review:Full documents

MOU: Memorandum of Understanding MOU: Memorandum of Understanding

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Why not Sharing Assessment Report?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

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Why not Just use FDA/EMA/PMDA Why not Just use FDA/EMA/PMDA Assessment Report on the Web Site?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

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Advantage of Sharing Assessment ReportAdvantage 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

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APEC “Best Regulatory Practice Project” APEC “Best Regulatory Practice Project” (I)(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

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APEC “Best Regulatory Practice Project” APEC “Best Regulatory Practice Project” (II)(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 1979-2000A Model in the Past: PER Scheme 1979-2000 - - EFTA as secretariat EFTA as secretariat

ItalyItaly

SwedenSwedenAustriaAustria

NetherlandNetherland

UKUK

GermanyGermanyHungaryHungary

FinlandFinland

IrelandIreland

NorwayNorway EUEU

CanadaCanada

AustraliaAustraliaSouth AfricaSouth Africa

New ZealandNew Zealand SwitzerlandSwitzerland

IcelandIceland

Czech RepublicCzech Republic

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Current Status for Sharing ReportsCurrent 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 SchemePilot 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 SchemeA 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

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TFDA/CDE Review TeamTFDA/CDE Review Team Project manager CMC Pharmacology/Toxicology Pharmacokinetic/Pharmacodynamic Clinical Statistical Primary reviewer plus secondary reviewer in

each section Supervisor

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Review Process Review Process (continue)(continue)

Supp*Supp* Review meeting*Review meeting* Report* Report* DOH

letterDOHletterU.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

Review Process Review Process (continue)(continue)

DOHletterDOHletterReport*Report*

ACmeeting #ACmeeting #

NDA supp.submission*NDA supp.submission*

Sponsor prepare dossier*

Sponsor prepare dossier*

06.12.200606.12.2006

07.12.2006 07.12.2006

09.04.200609.04.2006

05.15.200605.15.2006

3.29 ~ 5.152006

3.29 ~ 5.152006

LicensedLicensed

Total time: 406 calendar days (licensed)

1st submission: CDE review time: 106 days: sponsor time: 62 daysSupp submission: CDE review time: 28 days sponsor time: 0 days

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Request for More Data 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

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Any Special Issue or Local ConcernAny Special Issue or Local ConcernPK/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?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

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More Data SubmittedMore 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.

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Decision Made By ACDecision 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 Sharing Assessment of Regulatory Approval or Assessment Reports – Could This be an Effective Way Assessment Reports – Could This be an Effective Way for Agencies in Asia Pacific to Use Regulatory for Agencies in Asia Pacific to Use Regulatory Resources?Resources?

Sharing Assessment report is Save resource better review quality early approval Win-win solution for all parties

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Action Plan for Taiwan APEC Project 2011-Action Plan for Taiwan APEC Project 2011-2012 (cosponsored by 10 countries)2012 (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

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Future Perspectives on Pharmaceutical Future Perspectives on Pharmaceutical Regulatory IssuesRegulatory Issues Sharing review experience

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

Enhance pharmaceutical regulatory networking 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

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Thank You for Your AttentionThank You for Your Attention

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