Transcript Development of Evaluation and Consultation on Bridging

Development of Evaluation and
Consultation on Bridging Studies:
Thailand Experiences
Suchart Chongprasert, Ph.D.
Investigational New Drug Subdivision
Food and Drug Administration
Thailand
Presentation
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ICH E5 and Bridging Studies
Historical Experiences on Local
Clinical Trials in Thailand
FDA Policy on Bridging Study
Evaluation Criteria
Consultation Process
Way Forward
Conclusions
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“Bridging Study (BS)….a supplemental
study performed in the new region to provide
pharmacodynamic or clinical data on efficacy,
safety, dosage, and dose regimen in the new
region that will allow extrapolation of foreign
clinical data to the new region”
Facilitate the use
of clinical data
across the regions
Potential impact of
ethnicity on drug
response well-addressed
Increased awareness among
nations regarding the need
for local trials?
Experiences with Local
Trials in Thailand
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Local registration trial not mandatory
required by the FDA for New Drug
Application (NDA)
About 5% of applications
experienced a request for local trials
with various reasons (~40 cases
from 742 applications)
Recommendations mostly based
solely on expert’s judgment for such
a request
Experiences with Local
Trials in Thailand
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No concrete guideline or criteria
developed by the FDA to help
determine the need for local trials
Major Reasons:
hypothetical concern on dose
inappropriate for Thai
 racial differences concern
 food and climate impacts
 insufficient data for judgement
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Definitely an urgent need to develop
rational criteria and guideline to
evaluate whether drug’s ethnic
sensitivity exists and significantly
affects clinical outcomes
Need for Local Trials ???
Promote an efficient and
transparent NDA Process
Our Goal!
FDA Policy on Bridging Study
“ ..take advantages of the conceptual
framework of a bridging study
established in the ICH E5 to further
develop into practical criteria and
operational guideline to determine
the need for and types of local
trials, if necessary.”
Firm Standpoints
“….Bridging study not lead to
delay or obstruction of the
registration of new drug, thus
impeding accessibility of new
drug to the public”
Rationally developed criteria and
guideline for bridging justification
and bridging study a definite need !!
“the type of bridging study needed is
ultimately a matter of evidence-based
Judgement……..”
Mechanisms/approaches
developed to judge such the
need for BS
Consultation
Details of BS
Types of Bridging
Study
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Bridging design: PK, PK/PD,
clinical trials (safety and efficacy)
Bridging Studies for Efficacy
 no
bridging study
 BS using pharmacological
endpoints
 controlled clinical studies
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Bridging Study for Safety
Evaluation of the Need for BS
Local trials necessary?
What purposes?
fulfil local
requirements
• assessment criteria
support extrapolation
(BS)
• ethnic sensitivity criteria
• extrapolation criteria
• consultation procedures
Bridging Schema (appendix B)
Assessment Criteria
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Criteria to assess the
fulfillment of regulatory
requirements
Criteria to assess drug’s
ethnic sensitivity
Criteria to assess
extrapolability of clinical
data
Assessment Criteria for Fulfillment
of Regulatory Requirements
CONTENT
1. CDP submitted contains all
information required by authority in the
new region (FDA)
2. Available PK, PD, dose-response,
safety, and efficacy data adequately
characterized in population in foreign
regions
3. Such characterizations in 2. include
trials conducted in population of the new
regions or people representative of the
new region
YES
NO
REMARK
Assessment Criteria for Fulfillment
of Regulatory Requirements
CONTENT
4.
Clinical trials generating data in 2.
should
• comply with local regulatory requirements
• comply with GCP acceptable by the new
region
• be adequate and well controlled
• utilize endpoints that are appropriate
for assessment for treatment
• evaluate clinical disorders using
medical and diagnostic definition
acceptable to the new region
YES
NO
REMARK
Assessment Criteria for Drug’s Ethnic
Sensitivity
CONTENT
1.
Non-linear pharmacokinetics (PK)
2. A steep pharmacodynamic (PD)
(effect-concentration) curve for both
efficacy and safety in the range of the
recommended dosage and dose regimen
3.
A narrow therapeutic dose range
4. Highly metabolized, especially
through a single pathway, thereby
increasing the potential for drug-drug
interaction
Yes No Unk.
Ref.
Assessment Criteria for Drug’s Ethnic
Sensitivity
CONTENT
5.
Metabolism by enzymes known to
show genetic polymorphism
6. Administration as a prodrug, with the
potential for ethnically variable enzymatic
conversion
7. High inter-subject variation in
bioavailability
8. Low bioavailability, thus more
susceptible to dietary absorption effects
Yes No Unk.
Ref.
Assessment Criteria for Drug’s Ethnic
Sensitivity
CONTENT
Yes No Unk.
Ref.
9. High likelihood of use in a setting of
multiple co-medications
10. High likelihood for inappropriate
use, e.g., analgesic and tranquilizers
11. Other defined ethnic factors sensitive
to to Thai population
Assessment results:
Is a medicine sensitive to ethnic
factors ?
high
fair poor Unk
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Assessment Criteria for Extrapolability of
Foreign Clinical Data
CONTENT
1. Comparative pharmacokinetic (PK)
data among ethnic populations available
adequately
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Asian vs. Caucasian
Asian vs. Black
• Black vs. Caucasian
2. Comparative pharmacokinetic (PK) data
in 1. demonstrate significant differences
among ethnic populations
• Asian vs. Caucasian
• Asian vs. Black
• Blacks vs. Caucasian
Yes
No
Ref.
Assessment Criteria for Extrapolability of
Foreign Clinical Data
CONTENT
3. Comparative dose-response data
among ethnic groups available
•
•
Asian vs. Caucasian
Asian vs. Black
•
Black vs. Caucasian
4. Comparative dose-response data in 3.
demonstrate significant differences among
ethnic group
• Asian vs. Caucasian
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Asian vs. Black
Blacks vs. Caucasian
Yes
No
Ref./
Remark
Assessment Criteria for Extrapolability of
Foreign Clinical Data
CONTENT
Yes
No
YES
NO CONSULT
Ref.
5.. Evaluation that dose-response curve
that may be shifted in the new population
available
• Asian vs. Caucasian
• Asian vs. Black
•
Black vs. Caucasian
Assessment results:
1. Can a CDP be extrapolated to the new
region ?
2. Is a BS necessary in the new region ?
Evaluation for Need for BS in Thailand
Submitted CDP including foreign clinical
data meets regulatory requirements
YES
Does CDP include clinical
data generated in Asian
population?
NO
**
Need additional study
YES
NO
Have early phases trials or
global clinical trials
including bridging study
been conducted in
Thailand ?
consultation
Have early phases trials or global clinical trials
including bridging study been conducted in
Thailand ?
NO
YES
Is it reasonable to extrapolate foreign
clinical data by regarding that drug is
insensitive to ethnic factors to Asian
population and that safety and efficacy
profiles acceptable ?
NO
YES
Is it reasonable to extrapolate
foreign clinical data that doseresponse curve will be similar to
Asian population?
BS waived
YES
NO
BS waived
BS waived
Does CDP include
data generated in
Asian population?
Is it reasonable to extrapolate foreign
clinical data that dose-response curve
will be similar to Asian population?
YES
NO
Are available Asian PK, PD data predictive
of dose/dose regimen/efficacy of medicine
in the population?
NO
NO
YES
Bridging study
required
Is the drug insensitive to ethnic
factors, and available safety and
efficacy profiles acceptable ?
YES
BS waived
BS waived
NO
*
Optimal dose
adjustment using
existing data
*
consultation
In some instances where existing
evidence indicates that Thai
population responds differently from
other Asian population, BS is needed.
E
v
a
Applicant
l
u
a
CDP
t
i
+
Bridging Data Package o
n
+
Self assessment on
BS and fulfillment of
regulatory
requirements
S
c
h
e
m
e
Authority (FDA)
Clinical Data Review Committee
assessment
Local trial needed ?
1. additional study ?
2. bridging study ?
NO
Re-evaluation
consultation
(if inconsistent
outcome results)
NO
waived
waived
evidence
YES
consultation
Details of trials
Way Forward
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Attempt to implement the assessment
criteria for the need for and if needed
types of bridging studies in the future
Explore statistical approaches
suitable for bridging study
Strengthen a consultation system to
allow more discussion among
involved parties on bridging study
Seek more international partners to
help build up rational bridging
strategies
Way Forward
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Take part in a global bridging study or
global bridging justification
development
Continuously deregulate and promote
the quality conduct of GCP trials to
meet internationally acceptable
standards to be able to join global
drug development
Conclusions
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The Thai FDA is developing rational
criteria and operational guidelines to
assess the influences of ethnic
factors to drug’s effects and to
determine the need for and types of
local clinical studies, if needed.
The concept of bridging study in the
ICH E5 is our template for such
derivation of the criteria.
Conclusions
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We are seeking to implement the
bridging study criteria for new drug
application in the FDA by 2002.
Information exchange is still
expected to be a key mechanism to
improve our understanding for a
bridging study.
We are looking forward to joining
international efforts for bridging
strategies development.
Thank you for your attention