Transcript Implementation of Bridging Study

Implementation of Bridging
Study-Taiwan’s Experience
Meir-Chyun Tzou, Ph.D.
Senior Officer, and Director of Section III,
Bureau of Pharmaceutical Affairs
Department of Health, The Executive Yuan
Taipei, Taiwan, R.O.C.
Outline
 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
Organization of the Department of Health,
the Executive Yuan, ROC
Secretary General
Minister
Deputy/Vice
Minister
Specialist-General
Counselor
Bureau of Medical
Affairs
National Bureau of
Controlled Drugs
Bureau of
Pharmaceutical Affairs
Center for Disease Control
Bureau of Food
Sanitation
National Institute of
Preventive Medicine
Bureau of Health
Promotion
National laboratories of
Food and Drugs
Bureau of Health
Planning
National Quarantine
Service
Bureau of National
Health Insurence
Office of Secretariat
Office of Personnel
Affairs
Committee on Chinese
Medicine and Pharmacy
Office of Anticorruption
NHI Supervisory
Committee
Office of Accounting
NHI Health Care Cost
Arbitration Committee
Office of Statistics
National Health
Research Institutes
Center for Drug Evaluation
Changing Environmental of Clinical
Trial 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
(CDE) 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
Applicant
C.D.E.
Advisory Board
(Review Committee)
Advice
Application
Approval
D.O.H.
(BPA)
DRF
Consult
BPA: Bureau of Pharmaceutical Affairs; CDE:Center for Drug Evaluation
DOH: Department of Health
DRF: Drug Relief Foundation
Parallel Review Process of
IRB/JIRB and DOH
Conducting Clinical Trials
DOH
(Regulator)
Approval
Approval
(IRB/J-IRB)
Hospital
Sponsor
CRO
Efficiency-Speedup in Review Time
in Taiwan for New Drugs
(Day)
306
1997
300
250
1998
200
150
137
1999
123
112
89
100
2000.1-2000.6
63
52
32
50
0
Imported New Drug Application
Clinical Trial Protocols
2000.7-Present
Consolidating Infrastructure for New Drug
Clinical Trials in Taiwan
(2)
• 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
Regulatory Strategies for
Implementation 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 )
Submit relevant documents
Does the drug meet DOH requirements for waiving
YES according to DOH
a bridging study and also the criteria for exempting
requirements and request
submission of information for ethnic consideration?(1)
for waiving bridging studies
NO
Does the submitted preclinical and clinical
data package meet the regulatory requirements
(ICH E5 and DOH guidance on clinical trials)?(2)
NO
Amendment
YES
NO
Does the package include clinical data
of Asian populations?(3)
Is the medicine insensitive to both
intrinsic and extrinsic factors?
efficacy and safety insignificant?
(See ICH E5 guidelines)
YES
YES
NO
Considerations for Assessing the Necessity of a
Bridging Study
( 2 of 4 )
Does the package include clinical data
of Asian populations?(3)
NO
YES
YES
Have any early phase trials or
global clinical trials that meet the
YES
DOH requirements of bridging studies
been conducted in Taiwan?
NO
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
Is the medicine insensitive to both
intrinsic and extrinsic factors?
Are the clinical differences in
efficacy and safety insignificant?
(See ICH E5 guidelines)
No bridging
study required(4)
NO
Based on the result of evaluation,
an appropriately designed
protocol of a bridging study
should be submitted to
DOH for approval(5)
YES
No bridging study required(4)
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)
YES
No bridging
study required(4)
NO
Is it reasonable to extrapolate from
foreign clinical data that the
concentration (dose)-response relationship
is similar between foreign and
Asian populations(3)?
NO
Is PK and/or PD data of Asian
populations(3) available for
estimating dosage or predicting efficacy?
YES
NO
YES
Based on the result of evaluation,
an appropriately designed protocol
of a bridging study should be
submitted to DOH for approval.(5)
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?
YES
NO
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.
Bridging Study Evaluation
--Current Status-18
8
7
No.of Bridging Study Evaluation Applications in 2001
6
5
5
4
3
3
3
3
2
2
1
1
0
0
Jan.
0
Feb. Mar. Apr. May Jun.
1
Jul.
Aug. Sep. Total
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 1999
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.
2000
The 1st workshop was held in Taipei.
2001
The 2001 symposium was held in Taipei.
The 2001 Symposium on APEC Network of
Pharmaceutical Regulatory Science- APEC Joint
Research Project on Bridging Study
Conclusion(1)
1. Bridging justification should be
based 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.
The 2001 Symposium on APEC Network of
Pharmaceutical Regulatory Science- APEC Joint
Research Project on Bridging Study
Conclusion(2)
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.