Ameeta Parekh, Ph.D. CDER/OCPB CPSC Meeting November 17/18

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Presentation transcript:

Ameeta Parekh, Ph.D. CDER/OCPB CPSC Meeting November 17/18 Benefits and Applications of Exposure Response Relationship in Drug Development and Approval Case Studies Ameeta Parekh, Ph.D. CDER/OCPB CPSC Meeting November 17/18

Presentation Outline FDA/Industry Interactions: Milestones During Drug Development Clinical Pharmacology and Biopharmaceutics Role in Drug Review and Approval : Attention to E/R Relationship Case Studies Lessons Learned: Optimizing Dose Selection

FDA/Industry Interactions Milestones Pre-IND EOP I EOP II Pre-NDA Labeling Pre-Clinical Clinical Phase I Phase II A Phase II B Phase III Finalize Package Insert Safety IND NDA Submission Action Letter NDA Review

Clinical Pharmacology and Biopharmaceutics (CPB) Role in NDA Review and Action Pre-IND EOP I EOP II Pre-NDA Labeling Pre-Clinical Clinical Phase I Phase II A Phase II B Phase III Finalize Package Insert NDA Review Action Letter Safety IND NDA Submission

Stages of CPB Review NDA Review Label Action Letter

Stages of CPB Review: NDA Review What is the effect of intrinsic factors on exposure ? How was the dose determined ? What is the effect of extrinsic factors on exposure ? What is the exposure response relationship ? Action Letter NDA Review Label Are the pk dose proportional ? Has the drug been tested for its potential for cardiac repolarization ? Are the in-vitro QC data appropriate ? Are extrinsic/intrinsic factors represented in the definitive clinical trials Is the pivotal BE study needed ?

Stages of CPB Review: Label Should there be dose adjustment due to intrinsic factors ? What doses should be approved ? Action Letter NDA Review Label What is the optimal dosing regimen ? Should there be dose adjustment due to extrinsic factors ? What should the label state regarding the QT effects of the drug ? Do the extrinsic/intrinsic factors need Precautions, Warnings or Contraindications ?

Stages of CPB Review: Recommendations and Action Letter NDA Review Label Action Letter approval, approval with Phase IV, approvable, non-approval

Case Studies Drug A : Optimizing dose and dosing regimen Drug B : Dose selection and dose adjustment

Drug A NDA: Injection formulation Dose finding over a short term period (X days) NDA primary efficacy over about 3X days Observation: Loss of efficacy over time

Drug A Exposure-Response Data

Drug A Dosing: Day 1, Day 15, Day 29, q Day 29 Trough Drug Concentrations vs Time in Days

Drug A Drug concentration at Days 29, 57, 113, 169 Subject Day 29 10 20 30 40 50 100 Day 113 Day 169 Subject Day 29 Day 57

Drug A Observation: Loss of efficacy over time Simulations suggest higher or frequent doses could achieve and maintain therapeutic drug concentrations based on E/R relationship Conclusions: Need for appropriate dose and dosing regimen selection

Drug B Mix of real issues from >1 drug……Drug B NDA: New drug Critical issues related to exposure/response: - dose selection - dose adjustment due to intrinsic/extrinsic factors

Dose Response Relationship (Phase II/III) Drug B Dose Response Relationship (Phase II/III) Dose related AEs Dose related QT effects

Exposure Changes: Extrinsic/Intrinsic Factors Extrinsic factor Concentration Intrinsic factor Time ………dose adjustment

Drug B Exposure/response analysis suggested that more than one dose should be considered to provide optimal balance between safety and efficacy Based on changes in exposure due to extrinsic and intrinsic factors, dosage adjustment was recommended in the label

Drug B Considering these outcomes early in drug development can help plan appropriate CPB studies (e.g. DDI) Based on exposure changes due to extrinsic and intrinsic factors, sponsors may consider additional strengths for marketing (e.g. lower strengths if DDI studies support lower doses)

Lessons Learned Case Studies : - dose and dosing regimen optimization - dose selection and dose adjustment Careful and timely consideration of exposure/response relationship during drug development Emphasis on exposure response analysis for both safety and efficacy, rather than efficacy alone