Development of Evaluation and ConDevelopment of Evaluation and Consultation on Bridging Studies: Thailsultation on Bridging Studies: Thail

and Experiencesand Experiences

Suchart Chongprasert, Ph.D.Suchart Chongprasert, Ph.D.Investigational New Drug Subdivision Investigational New Drug Subdivision

Food and Drug AdministrationFood and Drug Administration

ThailandThailand

Presentation

ICH E5 and Bridging Studies Historical Experiences on Local Cli

nical Trials in Thailand FDA Policy on Bridging Study Evaluation Criteria Consultation Process Way Forward Conclusions

“ Bridging Study (BS)….a supplementalsupplemental 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 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 Experiences with Local Trials in ThailandTrials in Thailand

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 Experiences with Local Trials in ThailandTrials in Thailand

No concrete guideline or criteria developed by the FDA to help determine the need for local trials

Major Reasons: hypothetical concern on dose inappr

opriate for Thai racial differences concern food and climate impacts insufficient data for judgement

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 StandpointsFirm 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 JudgementJudgement……..”

Mechanisms/approaches developed to judge such the need for BS

Details of BSDetails of BS

ConsultationConsultation

evidence-basedevidence-based

Types of Bridging Study

Bridging design: PK, PK/PD, clinical trials (safety and efficacy)

Bridging Studies for Efficacyno bridging studyBS using pharmacological endpoin

tscontrolled clinical studies

Bridging Study for Safety

Evaluation of the Need for BSEvaluation of the Need for BS

Local trials necessary?

What purposes?What purposes?

fulfil local requirements

support extrapolation (BS)

• assessment criteria • ethnic sensitivity criteria • extrapolation criteria

• consultation procedures

Bridging Schema (appendix B)

Assessment CriteriaAssessment Criteria

Criteria to assess the fulfillment of regulatory requirements

Criteria to assess drug’s ethnic sensitivity

Criteria to assess extrapolability of clinical data

CONTENTCONTENT YES NO REMARK

Assessment Criteria for FulfillmentAssessment Criteria for Fulfillment of Regulatory Requirementsof Regulatory Requirements

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

CONTENTCONTENT YES NO REMARK

4. Clinical trials generating data in 2. should

• utilize endpoints that are appropriate for assessment for treatment

• evaluate clinical disorders using medical and diagnostic definition acceptable to the new region

Assessment Criteria for FulfillmentAssessment Criteria for Fulfillment of Regulatory Requirementsof Regulatory Requirements

• comply with local regulatory requirements

• comply with GCP acceptable by the new region

• be adequate and well controlled

Assessment Criteria for Drug’s Ethnic Sensitivity

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

CONTENT Yes No Ref.Unk.

Assessment Criteria for Drug’s Ethnic Sensitivity

5. Metabolism by enzymes known to sh

ow genetic polymorphism 6. Administration as a prodrug, with the potential for ethnically variable enzymatic

conversion 7. High inter-subject variation in bioava

ilability

CONTENT Yes No Ref.Unk.

8. Low bioavailability, thus more susceptible to dietary absorption effects

Assessment Criteria for Drug’s Ethnic Sensitivity

CONTENT Yes No Ref.Unk.

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 Unk.

poor

Assessment Criteria for Extrapolability of Foreign Clinical Data

1. Comparative pharmacokinetic (PK) data among ethnic populations available adequately

• Asian vs. Caucasian

• Asian vs. Black• Black vs. Caucasian

2. Comparative pharmacokinetic (PK) data in 1. demonstrate significant differences among ethnic populations

• Asian vs. Black• Blacks vs. Caucasian

• Asian vs. Caucasian

CONTENT Yes No Ref.

Assessment Criteria for Extrapolability of Foreign Clinical Data

• Asian vs. Caucasian

• Asian vs. Black

• Black vs. Caucasian

• Asian vs. Black• Blacks vs. Caucasian

3. Comparative dose-response data among ethnic groups available

• Asian vs. Caucasian

CONTENT Yes No Ref./ Remark

4. Comparative dose-response data in 3. demonstrate significant differences among ethnic group

Assessment Criteria for Extrapolability of Foreign Clinical Data

• Asian vs. Caucasian• Asian vs. Black

• Black vs. Caucasian

CONTENT Yes No Ref.

5.. Evaluation that dose-response curve that may be shifted in the new population available

Assessment results:

1. Can a CDP be extrapolated to the new region ?

2. Is a BS necessary in the new region ?

YES NO CONSULT

Evaluation for Need for BS in Thailand

Submitted CDP including foreign clinical data meets regulatory requirements

Does CDP include clinical data generated in Asian population?

Need additional study*

NOYES

Have early phases trials or global clinical trials including bridging study been con

ducted in Thailand ?

*consultation

NOYES

Have early phases trials or global clinical trials including bridging study been conducted in Th

ailand ?

YES

BS waivedIs 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 ?

YES

BS waived

NO

Is it reasonable to extrapolate foreign clinical data that dose-response curve will be similar to Asian popu

lation?

YESNO BS waived

NO

Is it reasonable to extrapolate foreign clinical data that dose-response curve w

ill be similar to Asian population?

Are available Asian PK, PD data predictive of dose/dose regimen/efficacy of medicine

in the population?

YES

NO

Optimal dose adjustment using exist

ing data

Bridging study required

YES

BS waived

NO

Does CDP include data generated in Asi

an population?

NO

Is the drug insensitive to ethnic factors, and available safety and

efficacy profiles acceptable ?

NO

YES

BS waived

*consultation

*

In some instances where existing evidence indicates that Thai population responds differently from other Asian population, BS is needed.

Evaluation

Scheme

Applicant

CDP

Bridging Data Package

Self assessment on BS and fulfillment of regulatory requirements

Clinical Data Review Committee

Local trial needed ?

NO

consultation

Re-evaluation

YES

NO

consultation

(if inconsistent outcome results)

Details of trials

waived

1. additional study ?

2. bridging study ?

waived

+

+

Authority (FDA)

assessment

evidence

Way ForwardWay Forward

Attempt to implement the assessment cAttempt to implement the assessment criteria for the need for and if needed typriteria for the need for and if needed types of bridging studies in the futurees of bridging studies in the future

Explore statistical approaches suitable fExplore statistical approaches suitable for bridging studyor bridging study

Strengthen a consultation system to allStrengthen a consultation system to allow more discussion among involved paow more discussion among involved parties on bridging studyrties on bridging study

Seek more international partners to helSeek more international partners to help build up rational bridging strategiesp build up rational bridging strategies

Way ForwardWay Forward

Take part in a global bridging study or Take part in a global bridging study or global bridging justification developmglobal bridging justification developmentent

Continuously deregulate and promote Continuously deregulate and promote the quality conduct of GCP trials to mthe quality conduct of GCP trials to meet internationally acceptable standareet internationally acceptable standards to be able to join global drug develds to be able to join global drug developmentopment

ConclusionsConclusions

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.

ConclusionsConclusions

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 Thank you for your attention your attention