implementation of bridging study-taiwans experience meir-chyun tzou, ph.d. senior officer, and...
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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)