1

Marketing Authorization Procedures and Quality Marketing Authorization Procedures and Quality

Management for Generics in TaiwanManagement for Generics in Taiwan

Meir-Chyun Tzou, Ph.D.

Director, Division of Drugs and New Biotechnology Products,

Taiwan Food and Drug Administration,

Department of Health,

Taiwan, R.O.C.2011.06.03

Generic Medicines in the Legal Systems of the Republic of China and the Federal Republic of Germany

2

OutlineOutline

Organization and Responsibility

Management of Drug Quality-product Life Cycle ManagementPre-Marketing ApprovalPost-Marketing Management

Issues of Intellectual Property Right for Drug Approval

Future perspectives

3333

Taiwan FDA (TFDA) was inaugurated on Jan. 1, 2010

TFDA supersedes the following 4 bureaus of Department of Health Bureau of Food SafetyBureau of Pharmaceutical AffairsBureau of Food and Drug AnalysisBureau of Controlled Drugs

Establishment of Taiwan FDAEstablishment of Taiwan FDA

4444

TFDA Organization ChartTFDA Organization Chart

5

Core Value of TFDACore Value of TFDA

From Product Centered to Consumer Centered

Risk Analysis and risk communication

Drug Management

Food Management

Consumer Protection

6

學名藥22875

84.13%原料藥23188.53%

罕見疾病藥品35 件

新藥1649件

生物藥品309 件1.14%

Statistics on Pharmaceutical LicensesStatistics on Pharmaceutical Licenses(2010)(2010)

New drugGeneric drug

API

Biologics

Orphan Drugs

22857 84.13%

777

Statistics on Pharmaceutical LicensesStatistics on Pharmaceutical Licenses (2010) (2010)

Domestic Import TotalRx drug 13449 3239 16688

Non-Rx drug 7543 619 8162

Total 20992 3858 24850

Rx: Non-RX 1.8:1 5.2:1 2:1

　 Domestic (%)

Import (%) Total (%)

New Drug 493 (30) 1156 (70) 1649 (100)

Generic Drug 20499 (90) 2358 (10) 22857 (100)

API 560 (24) 1758 (76) 2318 (100)

Total no. of Licenses 21552 (79) 5616 (21) 27168 (100)

ratio ~1:42:1.2 ~1:2.3:1.5 ~1:14:1.4

8

Domestic Import total

NCE 1 27 28non-NCE 26 80 106total 27 107 134prescription 279 60 339OTC 90 22 112total 369 82 451post-approval post-approval changeschanges

1731 1433 3164

license license extensionsextensions

815 551 1366

casescategory

NDA

ANDA

Statistics on drug registration and post-approval Statistics on drug registration and post-approval changes changes (Jan~Dec.2010)(Jan~Dec.2010)

Statistics on drug registration and post-approval Statistics on drug registration and post-approval changes changes (Jan~Dec.2010)(Jan~Dec.2010)

9

Management of Drug Quality-Management of Drug Quality-product Life Cycle Managementproduct Life Cycle Management

Management of Drug Quality-product Life Management of Drug Quality-product Life Cycle ManagementCycle Management

Basic research

Pre- clinical

ClinicalTrials

Product Launch

ProductionMarketing

& Sales

Review

Inspection

CTD ： Safety 、 Efficacy 、 Quality

GMP/GTP

GLP 、 GCP GPvP

Analysis Testing / Trial/Analysis

(審查 )

(稽查 )

(檢驗 )10

1111

1980 1990 2000 2010

Milestones on Drug RegulationMilestones on Drug Regulation

1982GMP

1982GMP

1983BA/BE

1983BA/BE

1999cGMP

1999cGMP

2009DMF

2009DMF

2010PIC/S GMP

2010PIC/S GMP

1993Local

clinical trial

1993Local

clinical trial1996 GCP

1996 GCP

1998GLP

1998GLP

*Bridging Study Evaluation in accordance with ICH E5*Bridging Study Evaluation in accordance with ICH E5

2000BS *

Evaluation /ICH E5

2000BS *

Evaluation /ICH E5

2001Pivotal trial/

early phase trial

2001Pivotal trial/

early phase trial

1998CDE

1998CDE

2001TDRF

2001TDRF

2010TFDA

2010TFDA

1983PV/PMS

1983PV/PMS

1998ADR

1998ADR

2008GPvP

2008GPvP

121212

Milestones on Drug RegulationMilestones on Drug Regulation1982 Good Manufacturing Practice (GMP)1987 Bioavailability / Bioequivalence Guideline (BA/BE)1993 Safety monitoring system-the requirement of local clinical trial1996 Good Clinical Practice (GCP) 1998 Good Laboratory Practices (GLP)1999 Establishment of Adverse Drug Reaction reporting system 1999 Amendment of current GMP (cGMP) 2004 Implementation of bridging study evaluation (BSE) 2005 Revision of Pharmaceutical Affairs Act (Data Exclusivity & compulsory requirement of serious ADR reporting)2008 Good Pharmacovigilance Practice (GPvP)2008 Guideline for Biosimilar Product Review and Approval2009 Drug Master File (DMF)2010 Implementation of PIC/S GMP2010 Amendment of Guideline for Biosimilar Product Review and Approval

2010 Develop strategies for review guidelines of tNCE and Botanical New Drug (in process)

2010 Relaxation of CPP requirement (draft)

12

13

Pre-Marketing ApprovalPre-Marketing Approval

14

Pre-marketing reviewPre-marketing review

New Drug Generic drug

Safety

Efficacy

Pharm / Tox

PK/PD/BA/BE

Clinical trials

Bioequivalence (BE) as a surrogate to clinical trial

Quality Chemistry, Manufacturing and Controls, CMC Including Active Pharmaceutical Ingredient (API) ,

excipients, process control, validation, stability, etc.

GLP, GCP, cGMP Labeling （ direction of use）

15

Regulatory requirement on BE studiesRegulatory requirement on BE studies

Regulations Guideline of Bioavailability and Bioequivalence

(BA/BE) studies (1987) Regulations of BA/BE Studies (2009)

Drug ApplicationNew drugs Generic drugs

—Since 1983—Retrospectively request BE studies for drugs approved before

1983 with BE concerne.g., Diltiazem 、 Glyburide 、 Furosemide 、 Isosorbide

dinitrate 、 Atenolol 、 Nifedipine 、 Rifampin 、 Digoxin 、 Carbamazepine

BA/BEBA/BE studies inspectionstudies inspection

Implement inspection from 2002Clinical phase should follow GCPLaboratory phase should follow GLPOther Regulations of BA/BE Studies Reviewer initiated inspection

16

17

PIC/S GMP

1982◆

1999◆

cGMPGMP

◆

2010.11◆

1988◆

2005

211 230163

165

550

0

100

200

300

400

500

600

21 pharmaceutical manufacturers are in

compliance with PIC/S GMP

Milestones of Pharmaceutical GMP Development Milestones of Pharmaceutical GMP Development in Taiwanin Taiwan

number of domestic pharmaceutical manufacturer

Overseas Inspection since 2002

Regulatory requirement on Active Regulatory requirement on Active Pharmaceutical Ingredients (API)Pharmaceutical Ingredients (API)

DMF for API of NDA and biological products

2002 GMP Guide for Active Pharmaceutical Ingredients

2009 Announced DMF technical information review form and application notes for API.

18

19

Post-marketing ManagementPost-marketing Management

20

Regulation on post-approval changesRegulation on post-approval changes

Types of Post-approval Changes Scale of manufacturing, Manufacturing process,

equipment, site, manufacturer, etc.Particle size, crystalline form, polymorphs, in-process,

controls, product release specification, etc.Synthetic procedures, source of API and excipients,

supplier, etc.Regulation Requirement

Scale-Up and Post Approval Changes (SUPAC) （ 2001 public Announcement ）

For products that have passed the BE testing and registered for marketing, any changes, depending on the level and extent of change are required to submit Bioequivalence testing report or Dissolution Rate Profile to assure and verify its quality.

21

Post-approval commitmentPost-approval commitment

Surveillance on Safety, Efficacy and Quality Post-marketing Surveillance, Phase-IV trialADR/quality defect reporting and investigationREMS/RMP

Maintenance for Drug Quality-Life Cycle Management (industry’s role)Well controlled process and quality system

— batch to batch releaseOn-going stability protocolPost-approval changes, annual report Inspection

22

The role of Government and IndustryThe role of Government and Industry in ensuring in ensuring Drug qualityDrug quality

Government’s role Industry’s role

Review Review to ensure S 、 E&Q Provide data for S 、 E&Qnon-clinical, clinical trial, CMC

Testing Batch release for biologics

No testing for other drugs (with exceptions)

In process control and batch to batch release for drugs and biologics

Inspection Inspection to assure compliance

Comply with GXP-

to assure data integrity and honest communication

It is mainly the industry’s responsibility, not the government’s,to ensure product quality throughout product life cycle

232323

Post-marketing Post-marketing ManagementManagement System System

23

Post-marketing Management systemPost-marketing Management system

Post-approval changes

Post-approval changes

Post-approvalcommitment

Post-approvalcommitment

ADR reporting system

ADR reporting system

Product quality defect reporting

system

Product quality defect reporting

system

Compliance Compliance

GMPGMPSafety

PharmacovigilanceSafety

Pharmacovigilance

ReviewReview ReviewReviewReview/Testing

Review/Testing

InspectionInspection

Quality surveillance

Quality surveillance

24

Post-marketing product quality

and safety surveillance

Post-marketing product quality

and safety surveillance

Quality surveillance

Quality surveillance

Safety surveillance

Safety surveillance

Drug Product quality defect reporting system

Drug Product quality defect reporting system

ActiveActive

ActiveActive

National Quality surveillance Program

National Quality surveillance Program

National ADR reporting system

National ADR reporting system

Manufacturer ： Drug safety report on a regular

basis(PSUR)

Manufacturer ： Drug safety report on a regular

basis(PSUR)

Government ： ADR active Monitoring Network

Government ： ADR active Monitoring Network

Reassessment / InspectionLabeling change

Withdrawal/Recall

Reassessment / InspectionLabeling change

Withdrawal/Recall

SurveillanceSurveillance

Post-marketing Safety and Quality Post-marketing Safety and Quality Surveillance-Risk ManagementSurveillance-Risk Management

PassivePassive

PassivePassive

Therapeutic Inequivalence Reporting System

Therapeutic Inequivalence Reporting System

24

Issues of Intellectual Property Right Issues of Intellectual Property Right for Drug Approvalfor Drug Approval

25

26

Issues of Patent

Issues of Exclusivity

Issues of Research ExemptionIssues ofIntellectual

Property Right for Drug Approval

Issues of Copyright

Issues of PatentIssues of Patent

Disclosure of patent

Declaration of patent non-infringement

The review of generic drug and the information of patents are normally linked

Review of patent infringement cases- Intellectual Property Court

27

28

Issues of PatentIssues of Patent

Disclosure of patentDisclosure of patent Pharmaceutical Affairs Act Article 40-2 (since 2005 Pharmaceutical Affairs Act Article 40-2 (since 2005

)) While granting the certificate of pharmaceutical product,

the central health competent authority shall announce the disclosed patent number or patent application number provided by the applicant.

-DOH made an announcement on October, 2005 notifying applicants who are applying or have been granted marketing approval for pharmaceutical products after Feb. 2005, to submit registered patent number/ affidavit of patent.

These information are available on website.(http://

www.fda.gov.tw/Bgradation_index.aspx?site_content_sn=38)

29

Issues of PatentIssues of Patent

Declaration of patent non-infringement Review Regulations for Registration and Market

Approval of Pharmaceuticals Article 19Applicants should submit an affidavit to declare that the

applicant has full legal responsibility if the applied product infringe the patent of others.

The review of generic drug and the information of patents are normally linked.

Issues of PatentIssues of Patent

Review of patent infringement cases- Intellectual Property Court According to Taiwan’s Patent Act, within valid patent

protection period, generic drug cannot enter the market or be sold.

Patent infringement will be granted by the patentee if the generic drug applicants violate the rule.

Patent-related litigation and the quality of review had been enhanced and accelerated since the Intellectual Property Court was established on July 1st, 2008.

30

31

Issues of Issues of Research Exemption Exemption

Exemption for Research useExemption for Research use Pharmaceutical Affairs Act Article 40-2 Paragraph 5Pharmaceutical Affairs Act Article 40-2 Paragraph 5

The patent right of the new drug shall not be applicable to researches, teachings, or testing prior to the application for registration by the pharmaceutical firms.

Patent Act Article 60(Amending)

32

Issues of Exclusivity Issues of Exclusivity

Historical exclusivity analogyHistorical exclusivity analogy 1993 Safety monitoring system-the requirement of local

clinical trial for NDA (Taiwan-US Intellectual Property Right Agreement) Pipeline protection of new drug before the Patent Act was amended

in 1986.Barrier for generic drug applicationWithin five years after the issuance of a license for new drug , the

second applicant is required to submit the same scale of clinical trial data as the first applicant.

1997 New indication2004 Implementation of bridging study evaluation (BSE)

33

Issues of Data exclusivityIssues of Data exclusivity

Within five years after the issuance of a license for new drug of new chemical entity, any other pharmaceutical firm may not apply for evaluation and registration of the same items by citing the data submitted by the licensee without such licensee’s authorization.

After three years of the issuance of a license for new drug of new chemical entity, other pharmaceutical firm may apply for registration of drugs of the same substance, the same dosage form, the same dose, and the same dose unit according to this Act and related laws or regulations; the drug license may be issued on the next day to the expiration of five years after the issuance of license to such new drug of new chemical entity.

Pharmaceutical Affairs Act Article 40-2Pharmaceutical Affairs Act Article 40-2

34

Issues of Data exclusivityIssues of Data exclusivity

Pharmaceutical Affairs Act Article 40-2Pharmaceutical Affairs Act Article 40-2The second paragraph hereof can only be applicable

with the compliance that application for registration of a new drug of new chemical entity shall be made to the Central Competent Health Authority within three years after it is first approved for marketing in any country.

35

Generic drug labeling Review Regulations for Registration and Market

Approval of Pharmaceuticals Article 20Generic drug labeling of the surveillance drugs*, should

follow the first approved labeling; labeling of the non-surveillance drugs** should be translated according to the innovator’s labeling.

But drug labeling has not been excluded from the copyright act, which might cause the lawsuit.

*surveillance drugs: chemical entity first approved after 1983.

**non-surveillance drugs : chemical entity first approved before 1983.

Issues of Copyright Issues of Copyright

36

Drug labeling – fair use for public benefitDrug labeling – fair use for public benefit Copyright Act Article 65Copyright Act Article 65

Fair use of a work shall not constitute infringement on economic rights in the work. In determining whether the exploitation of a work complies with the provisions of Articles

44 through 63, or other conditions of fair use, all circumstances shall be taken into account, and in particular the following facts shall be noted as the basis for determination.

The court decision for lawsuit cases : Drug labeling should refer to Copyright Act Article 52 “Within a reasonable scope, it may be used for necessary or other legitimate purposes”Drug labeling excluding from copyright

TFDA is planning to amend the Pharmaceutical Affairs Act Article 48-2Pharmaceutical Affairs Act Article 48-2, to stipulates the suitability of excluding drug labeling from Copyright Act.

Issues of Copyright Issues of Copyright

Future perspectivesFuture perspectives of Intellectual of Intellectual Property Right for Drug ApprovalProperty Right for Drug Approval

Exemption for research useExemption for research use

-amendment of Patent Act-amendment of Patent Act

Drug labeling excluding from copyrightDrug labeling excluding from copyright

-amendment of -amendment of Pharmaceutical Affairs ActPharmaceutical Affairs Act

Data exclusivity for new indication?Data exclusivity for new indication?

37

38

Future perspectivesFuture perspectives

39

Future perspectives in Enhancing Drug Quality

Strategies for API and Generic Drug

Strategies for GMP regulation

Strategies for Post-Approval Changes

40

Establishing the review strategies for DMF of API and CTD of Generic Drugs Time-line and action plans

to implement API’s DMF and CTD for Generic Drug

Implement DMF and CTD by stages.

Stage 1: With NHI drug price incentives, encouraging companies to

implement DMF, starting from Oct. 1st, 2009

Stage 2: Compulsory implementation of DMF and CTD

-Implement by stages, by items

Strategies for API and Generic DrugStrategies for API and Generic Drug

41

New chemical entities

New biologic

New indication

New dosage forms

New route of administration

Generics

OTC

EU FDA MHLW

included

included

included

included

included

included

included

included

included*

included

included

included

included

included

included

included

included

included

included

not included

not included

* with the exception of blood and blood components

Common Technical Document (CTD)Implementation Coordination Group

presented in June 13 `02General Information on the CTD

organized by:Implementation Coordination Group Members

plus members in CTD-Q, CTD-S, CTD-E & eCTD

Implement Common Technical Document for Implement Common Technical Document for generic druggeneric drug

4242

Regulation strategies for post-approval changes

Establish DMF database of API

Monitor and inspect API changes

Revise guideline for Scale-Up and Post

Approval Changes (SUPAC)

Strengthen regulation on Post-Approval

Changes-Product Quality ReviewRegulation Strategy for management of product

license

Strategies for Strategies for Post-Approval ChangesPost-Approval Changes

43434343

Strategies for GMP regulationStrategies for GMP regulation

Quality Assurance for Drug ManufacturingQuality Assurance for Drug Manufacturing

Good Manufactory Practice (GMP)

Documentations, SOP, QC, QACurrent GMP (cGMP)

Validations- analytical method, process, data treatment

PIC/S GMP by 2014

44

PIC/S GMP

1982◆

1999◆

cGMPGMP

◆

2010.11◆

1988◆

2005

211 230163

165

550

0

100

200

300

400

500

600

21 pharmaceutical manufacturers are in

compliance with PIC/S GMP

Milestones of Pharmaceutical GMP Development in Milestones of Pharmaceutical GMP Development in TaiwanTaiwan

number of domestic pharmaceutical manufacturer

Overseas Inspection since 2002

45

Internationalize quality guidelinesInternationalize quality guidelines

Implementation status of ICH quality Guidelines in Taiwan

Q1 Stability Adopt

Q2 Analytical Validation Adopt

Q3 Impurities Accept

Q4 Pharmacopoeias Accept

Q5 Quality of Biotechnological products Accept

Q6 Specifications Accept

Q7 Good Manufacturing Practice(原料藥GMP)

Adopt

Q8 Pharmaceutical Development Accept

Q9 Risk Management system Accept

Q10 Pharmaceutical Quality system Accept

46

Quality by

Testing- Quality Control

Quality by

Manufacturing - Quality

Assurance

1970s 1980s 1990s 2000s

Quality by

Design

Quality Systems

Evolution of Quality conceptEvolution of Quality concept

47

New Quality InitiativeNew Quality Initiative

How to do What to do

Product

-1970s

QualityControl

Process

1980s~1990s

Systems

21st Century

QualitySystems

QualityAssurance

Fixed controls state Dynamic controls state

48

The three-way winThe three-way win

Consumer

Industry Government

Ensure Drug quality,

safety& efficacy

International harmonization

on drugmanagement

Increase international

competitiveness

GoalGoal

49