1. 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

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. 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

4. 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

5. Stages of CPB Review
NDA Review
Label
Action Letter

6. 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 ?

7. 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 ?

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

11. Drug A Exposure-Response Data

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

13. Drug A Drug concentration at Days 29, 57, 113, 169 Subject Day 2910 20 30 40 50
100
Day 113
Day 169
Subject
Day 29
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. Dose Response Relationship (Phase II/III)
Drug B
Dose Response Relationship (Phase II/III)
Dose related AEs
Dose related QT effects

17. Exposure Changes: Extrinsic/Intrinsic Factors
Extrinsic factor
Concentration
Intrinsic factor
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