Development of Evaluation and Consultation on Bridging Studies: Thailand Experiences Suchart Chongprasert, Ph.D. Investigational New Drug Subdivision Food and Drug Administration Thailand

Presentation n ICH E5 and Bridging Studies n Historical Experiences on Local Clinical Trials in Thailand n FDA Policy on Bridging Study n Evaluation Criteria n Consultation Process n Way Forward n Conclusions

supplemental extrapolation “ 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 n Local registration trial not mandatory required by the FDA for New Drug Application (NDA) n About 5% of applications experienced a request for local trials with various reasons (~40 cases from 742 applications) n Recommendations mostly based solely on expert’s judgment for such a request

Experiences with Local Trials in Thailand n No concrete guideline or criteria developed by the FDA to help determine the need for local trials n Major Reasons: u hypothetical concern on dose inappropriate for Thai u racial differences concern u food and climate impacts u 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 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 !!

Judgement “the type of bridging study needed is ultimately a matter of Judgement……..” Mechanisms/approaches developed to judge such the need for BS Details of BS Consultation evidence-based

Types of Bridging Study Bridging design: PK, PK/PD, clinical trials (safety and efficacy) n Bridging Studies for Efficacy  no bridging study  BS using pharmacological endpoints  controlled clinical studies n Bridging Study for Safety

Evaluation of the Need for BS Local trials necessary? What purposes? fulfil local requirements support extrapolation (BS) assessment criteria ethnic sensitivity criteria extrapolation criteria consultation procedures

Bridging Schema (appendix B)

Assessment Criteria n Criteria to assess the fulfillment of regulatory requirements n Criteria to assess drug’s ethnic sensitivity n Criteria to assess extrapolability of clinical data

CONTENT YES NO REMARK Assessment Criteria for Fulfillment of Regulatory Requirements of 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

CONTENT 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 Fulfillment of Regulatory Requirements of 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 YesNo Ref. Unk.

Assessment Criteria for Drug’s Ethnic Sensitivity 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 CONTENT YesNo Ref. Unk. 8. Low bioavailability, thus more susceptible to dietary absorption effects

Assessment Criteria for Drug’s Ethnic Sensitivity CONTENT YesNo 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 * NO YES Have early phases trials or global clinical trials including bridging study been conducted in Thailand ? * consultation NO YES

Have early phases trials or global clinical trials including bridging study been conducted in Thailand ? 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 population? YES NO BS waived NO

Is it reasonable to extrapolate foreign clinical data that dose-response curve will 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 existing data Bridging study required YES BS waived NO Does CDP include data generated in Asian 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 SchemeEvaluation 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 Forward n Attempt to implement the assessment criteria for the need for and if needed types of bridging studies in the future n Explore statistical approaches suitable for bridging study n Strengthen a consultation system to allow more discussion among involved parties on bridging study n Seek more international partners to help build up rational bridging strategies

Way Forward n Take part in a global bridging study or global bridging justification development n Continuously deregulate and promote the quality conduct of GCP trials to meet internationally acceptable standards to be able to join global drug development

Conclusions n 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. n The concept of bridging study in the ICH E5 is our template for such derivation of the criteria.

Conclusions n We are seeking to implement the bridging study criteria for new drug application in the FDA by n 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