Study Design and Efficacy Results for Tinea Pedis Clinical Trials

1. Study Design and Efficacy Results for Tinea Pedis Clinical Trials Kathleen Fritsch, Ph.D. Division of Biometrics III, FDA

2. Part I: Clinical Trial Design for Tinea Pedis Trials

3. Trial Characteristics • Trial Design • Randomized, double-blind, vehicle controlled, multicenter • Indications • tinea pedis (athlete’s foot) • evaluate “all-comers” or multiple sub-types • interdigital tinea pedis (athlete’s foot between the toes) • evaluate interdigital variant only

4. Patient Populations • Randomized & treated population • positive KOH • clinical signs and symptoms • Efficacy analysis population (MITT) • must also have positive baseline culture (cultures take up to 4 weeks—treatment may be completed before baseline culture results are known) • only ~2/3 of randomized patients have positive baseline culture

5. 3 Nested Efficacy EndpointsInvolving Mycological & Clinical Outcomes

6. Efficacy Endpoints • Negative Mycology • negative KOH & culture • Effective Treatment (Sometimes Primary) • negative KOH & culture + mild or no signs & symptoms (typically at most mild erythema and scaling, but definition varies) • Complete Cure (Often Primary) • negative KOH & culture + no signs & symptoms Signs and symptoms: at a minimum--erythema, pruritus, scaling (may include others)

7. Study Phases • Treatment period • Typical treatment duration is 1-4 weeks • Post-treatment follow-up Primary timepoint for efficacy evaluation at least 2 weeks after completing treatment • 5 to 8 weeks post-treatment for 1 week Tx • 2 to 4 weeks post-treatment for 4 week Tx • In both cases, primary timepoint is 6 to 9 weeks after starting treatment

8. Why is efficacy assessed during post-treatment follow-up? • epidermal turnover may take several weeks • may not expect clearance of some signs until at least 6 weeks after start of treatment, even if fungus is eradicated →May be significant time lag (weeks or months) between end of treatment and assessment of cure

9. Part II: Data Presentation Efficacy results from selected clinical trials

10. Selected Drug Products Criteria for dataset selection: • NDA reviews available (oldest from 1988) • vehicle controlled trials The 9 products/formulations/regimens identified represent: • 6 active ingredients • 4 Rx and 5 OTC products/regimens • 4 one-week and 5 four-week regimens • 7 “interdigital tinea pedis” and 2 “tinea pedis”

11. Sample Sizes *Data from 2 studies

12. CAUTION! • Data do NOT represent head-to-head comparisons of products! • Success rates are influenced by • Patient populations (e.g. concomitant disease, baseline severity) • Clinical study procedures (e.g. sample collection, timing) • Endpoint definitions (e.g. assessment scales, evaluations) which can vary substantially from trial to trial

13. Efficacy Outcomes (9 Drug Products) Negative Mycology Effective Treatment Complete Cure

14. Negative Mycology(End of Treatment)

15. Negative Mycology(Primary Timepoint – Week 6-9)

16. Effective Treatment(End of Treatment)

17. Effective Treatment(Primary Timepoint – Week 6-9)

18. Complete Cure(End of Treatment)

19. Complete Cure(Primary Timepoint – Week 6-9)

20. Clearance of Signs and Symptoms over Time (2 Drug Products) Erythema Scaling Pruritus

21. Erythema(Percent of Subjects Clear)

22. Scaling(Percent of Subjects Clear)

23. Pruritus(Percent of Subjects Clear)

24. Summary of Efficacy Results • May be a time lag of several weeks between end of treatment and clearance of signs and symptoms (particularly for 1-week products) • Most subjects have some signs and symptoms remaining post-treatment • Typical cure rates at primary post-treatment timepoint (Week 6-9) are Complete cure: 20% Effective Treatment: 50% Negative Mycology: 70%