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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

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

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

  2. 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

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

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

  5. Stages of CPB Review NDA Review Label Action Letter

  6. 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 ? NDA Review Are the pk dose proportional ? Label Has the drug been tested for its potential for cardiac repolarization ? Action Letter Are the in-vitro QC data appropriate ? Is the pivotal BE study needed ? Are extrinsic/intrinsic factors represented in the definitive clinical trials Stages of CPB Review: NDA Review

  7. Should there be dose adjustment due to intrinsic factors ? What doses should be approved ? NDA Review What is the optimal dosing regimen ? Label Should there be dose adjustment due to extrinsic factors ? Action Letter 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: Label

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

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

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

  11. Drug AExposure-Response Data

  12. Drug ADosing: Day 1, Day 15, Day 29, q Day 29 Trough Drug Concentrations vs Time in Days

  13. 0 10 20 30 40 50 100 0 100 0 0 10 20 30 40 50 Drug A Drug concentration at Days 29, 57, 113, 169 Day 113 Day 169 Day 29 Subject Day 57

  14. 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

  15. 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

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

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

  18. 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

  19. 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)

  20. 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

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