Implementation of Bridging Study-Taiwan’s Experience

Meir-Chyun Tzou, Ph.D. Senior Officer, and Director of Section III,

Bureau of Pharmaceutical AffairsDepartment of Health, The Executive Yuan

Taipei, Taiwan, R.O.C.

Health Organization and the Drug Regulatory Agency

Changing Environment of Clinical Trial in Taiwan

Regulatory Strategies for Implementation of Bridging Study

Current Status of Bridging Study Evaluation

APEC Joint Research Project on Bridging Study

Outline

Secretary -General

Organization of the Department of Health, the Executive Yuan, ROC

Specialist-GeneralCounselor

Minister

Deputy/ViceMinister

Bureau of MedicalAffairs

Bureau of Pharmaceutical Affairs

Bureau of FoodSanitation

Bureau of HealthPromotion

Bureau of HealthPlanning

Office of Secretariat

Office of PersonnelAffairs

Office of Anticorruption

Office of Accounting

Office of Statistics

National Bureau ofControlled Drugs

Center for Disease Control

National Institute ofPreventive Medicine

National laboratories ofFood and Drugs

National QuarantineService

Bureau of NationalHealth Insurence

Committee on ChineseMedicine and Pharmacy

NHI SupervisoryCommittee

NHI Health Care CostArbitration Committee

Center for Drug Evaluation

National HealthResearch Institutes

Changing Environmental of Clinical Changing Environmental of Clinical Trial in TaiwanTrial in Taiwan

Regulations Update for Clinical Trials

• Local clinical trial required for New Drug Registration since 1993

• GCP guidelines implemented in 1997

• GCP inspections for INDs and NDAs in 1997

• Adverse Drug Reporting system in 1998

• Guidances for clinical trials

Impact on New Drug Development in Taiwan

• Local clinical trials-Improve new drug R & D in Taiwan.

-Facilitate development of

Biotech / Pharmaceutical Industry

Global Environment / Trends

• International Harmonization for New Drug Registration : ICH

• Trade Liberalization : WTO Accession

• Biotech / Pharmaceutical Industry Promotion Plan

Consolidating Infrastructure for New Drug Clinical Trials in Taiwan

• Improving quality and efficiency of review process for clinical trials

•Promoting early phase clinical trials in Taiwan

•Establishing Center for clinical study in Asia Pacific

• Promoting Biotech-pharmaceutical Industry

Consolidating Infrastructure for New Drug Clinical Trials in Taiwan 　 (1)

• Improving quality and efficiency of review process for clinical trials

Reinforcement of GCP inspection Guidances for clinical trials Establishment of the Center for Drug Evaluation (CD

E) in 1998

-full time review team Parallel review process of IRBs and DOH Establishment of Joint-IRB Deregulation and streamlining the review process for

clinical trials

Center for Drug Evaluation-expert review team for clinical trials and NDAs

BPA: Bureau of Pharmaceutical Affairs; CDE:Center for Drug Evaluation

DOH: Department of Health DRF: Drug Relief Foundation

D.O.H. (BPA)

Advice

Consult

Application Approval

ConsultationApplicant

C.D.E.

Advisory Board(Review

Committee)

DRF

Parallel Review Process of IRB/JIRB and DOH

HospitalSponsor

CRO

HospitalSponsor

CRO

DOH (Regulator)

DOH (Regulator)

(IRB/J-IRB)(IRB/J-IRB)

Approval

Approval

Conducting Clinical TrialsConducting Clinical Trials

Efficiency-Speedup in Review Time in Taiwan for New Drugs

137

89

123

63

112

5232

306

0

50

100

150

200

250

300

Imported New Drug Application

(Day)

1997

1998

1999

2000.1-2000.6

2000.7-Present

Clinical Trial Protocols

• Promoting early phase clinical trials in Taiwan Establishing general clinical research centers (GCRC)

-improving the quality and performance of the CRC. Establishing insurance and ADR reporting

system for clinical trials Establishing central lab. (clinical pathology unit)

-assuring the quality of clinical laboratory Regulatory reform in local ／ clinical trial-bridging study

Consolidating Infrastructure for New Drug Clinical Trials in Taiwan 　 (2)

Regulatory Strategies for Regulatory Strategies for Implementation of Bridging StudyImplementation of Bridging Study

Regulatory Reform in Local ／ Clinical Trial –Bridging Study

Before －•An approved local clinical trial study report is

required for the new drug application in Taiwan--July 7 Announcement in 1993.

Disadvantage: - A sample size of 40 as required would be 　　　　　　 difficult to demonstrate significant importance 　　　　　　 clinically or statistically　　　　　 - The study design of the local trial usually only 　　　　　　 repeated a study that has been done in the 　　　　　　 foreign countries but in a smaller sample size ；　　　　　　 The study has not been designed based on the 　　　　　　 medical situation in Taiwan

Regulatory Reform in Local ／ Clinical Trial –Bridging Study

After －•Bridging Study (Double Twelve Announcement,

2000) 　　　　 -Follow ICH E5 guidance

Advantage: - To avoid repeating unnecessary clinical study　　　　 - Conducting, necessary, meaningful clinical study ；　　　　　 based on differences of disease, ethnic differences 　　　　　 etc, and the results of study, a dosage adjustment 　　　　　 can be done for the locals

Strategies for Implementation of Bridging Study

• To follow closely the spirit of the ICH E5 guidance

• To establish a sound and practical consultation and evaluation process

encourage sponsor to submit complete clinical data package for the evaluation of “bridging study” before new drug application

guidance and Q & A data base self-evaluation checking list consultation process assessment scheme

Double Twelve Announcement for Bridging Studies 　 （ Dec. 12,

2000 ） 　 　• Effective on January 1, 2001

•One-year of transition period

-Local clinical trial bridging study

•In accordance with ICH E5 guidance

• Procedure of consultation and evaluation of bridging study

Considerations for Assessing the Necessity of a Bridging Study ( 1of 4 )

Does the drug meet DOH requirements for waivinga bridging study and also the criteria for exempting submission of information for ethnic consideration?(1)

Does the package include clinical data of Asian populations?(3)

Does the submitted preclinical and clinical data package meet the regulatory requirements (ICH E5 and DOH guidance on clinical trials)?(2)

Amendment

Is the medicine insensitive to both intrinsic and extrinsic factors? Are the clinical differences in efficacy and safety insignificant?(See ICH E5 guidelines)

Submit relevant documents according to DOH requirements and request for waiving bridging studies

YES

NO

NO

NO

YES

YES NO

YES

Does the package include clinical data of Asian populations?(3)

Considerations for Assessing the Necessity of a Bridging Study ( 2 of 4 )

Is the medicine insensitive to both intrinsic and extrinsic factors? Are the clinical differences in efficacy and safety insignificant?(See ICH E5 guidelines)

Have any early phase trials or global clinical trials that meet the DOH requirements of bridging studies been conducted in Taiwan?

Is it reasonable to extrapolate from foreign clinical data that the medicine is insensitive to both intrinsic and extrinsic factors in Asians(3) and that its clinical differences in efficacy and safety are acceptable?(See ICH E5 guidelines)

No bridging study required(4)

Based on the result of evaluation, an appropriately designed protocol of a bridging study should be submitted to DOH for approval(5)

No bridging study required(4)

YES

YES

NOYES

NO

NO

YES

NO

Considerations for Assessing the Necessity of a Bridging Study ( 3 of 4 )

Is it reasonable to extrapolate from foreign clinical data that the medicine is insensitive to both intrinsic and extrinsic factors in Asians(3) and that its clinical differences in efficacy and safety are acceptable?(See ICH E5 guidelines)

No bridging study required(4)

Is it reasonable to extrapolate from foreign clinical data that the concentration (dose)-response relationship is similar between foreign and Asian populations(3)?

Is PK and/or PD data of Asian populations(3) available for estimating dosage or predicting efficacy?

Based on the result of evaluation, an appropriately designed protocol of a bridging study should be

submitted to DOH for approval.(5)

NO

YES

YES

NO

NO

YES

Considerations for Assessing the Necessity of a Bridging Study ( 4 of 4 )

Is PK and/or PD data of Asian populations(3) available for estimating dosage or predicting efficacy?

Based on the result of evaluation, an appropriately designed protocol of a bridging study should be

submitted to DOH for approval.(5)

Using available data for

dose determination

(1) Apply for waiving bridging studies with reference to DOH announcements of waiving clinical trials. If the drug falls within the category that “requires submission of information proving no existence of ethnic differences”, it should be evaluated following this flowchart after the one year phase-in period.(2) Under circumstances when evidence indicating potential intrinsic/extrinsic differences between Chinese and other Asian populations, a bridging study in Chinese population is a must.(3) A bridging study will be required when there exists any safety concern.1(4) Under circumstances when evidence indicating potential intrinsic/extrinsic differences between Chinese and other Asian populations, a bridging study in Chinese population is a must.(5) A bridging study can be a PK and/or PD study or any clinical study that can demonstrate the efficacy and safety of the medicine.

NO

YES

0 0

1

3 3 3

2

5

1

18

0

1

2

3

4

5

6

7

8

Jan. Feb. Mar. Apr. May Jun. Jul. Aug. Sep. Total

No.of Bridging Study Evaluation Applications in 2001

Bridging Study Evaluation--Current Status--

Bridging Study Evaluation--Current Status--

• Bridging study evaluation : 18 cases applied. (2001-present)

8/11 (73%) waived (including 4 without complete Asian data).

Out of 3 not waived, 1 has safety concern, 2 did not have enough information.

Impact of Bridging Study on Clinical Trials

• Promoting early phase / global clinical trials in Taiwan

• Conducting necessary, meaningful clinical study based on scientific and medical circumstances (intrinsic/ extrinsic factors)

Establish Network of Pharmaceutical Regulatory Science

- APEC Joint Research Project -

Objectives:

To establish an APEC network of pharmaceutical

regulatory science

To promote regulatory consensus through regional

educational seminar, or APEC conference

To develop a sound and practical methodology for

implementing bridging study in accordance with ICH

E5 by APEC members for the global new drug

development

Establish Network of Pharmaceutical Regulatory Science

- APEC Joint Research Project -

At the 17th APEC ISTWG Meeting, all of the

APEC economies have reached consensus on

this project proposed and sponsored by

Chinese Taipei and co-sponsored by

Singapore, Philippines, Mexico, Malaysia,

and Australia.

The 1st workshop was held in Taipei.

The 2001 symposium was held in Taipei.

19991999

20002000

20012001

The 2001 Symposium on APEC Network of Pharmaceutical Regulatory Science- APEC Joint Research Project on Bridging Study Conclusion(1)

1. Bridging justification should bebased on sound science and intrinsic /extrinsic factors,not based on citizenship and nationality.

2. The regulatory agency should consider existing data and various factors (scientific and medical circumstances ) for drug approval.

3. Criteria for the similarity of efficacy,safety and quality between regions is needed.

4. Bridging: Multi-directional Input and output between ICH/ Non ICH region should be involved

5. ICH E5- Identifying the questions from APEC region, elaboration/supplement is needed.

6. Consolidate the networking of pharmaceutical regulatory science within APEC is obviously.

The 2001 Symposium on APEC Network of Pharmaceutical Regulatory Science- APEC Joint Research Project on Bridging Study Conclusion(2)