1. History and Overview of OTC Topical Antifungal Drug Products Houda Mahayni, R. Ph., Ph.D. Division of Over-the-Counter Drug Products

2. Outline Introduction OTC Drug Monograph System History of OTC Topical Antifungal Monograph

3. Mechanisms By Which OTC Drug Products Are Regulated NDA  Drug product-specific  Pre-market approval  Confidential OTC Drug Monograph  Active ingredient-specific  GRASE (generally recognized as safe and effective)  No pre-market approval  Public

4. OTC Drug Monograph System

5. OTC drug review began in 1972 FDA established therapeutic category of OTC drug products List GRASE conditions of use

6. What is included in an OTC Drug Monograph? Active ingredients  dosage strength  dosage form Labeling requirements  uses  directions for use  warnings Final formulation testing Conditions of Use

7. OTC Drug Review Four step public rulemaking process 1.Advisory Review Panel 2.Advance Notice of Proposed Rulemaking (ANPR) 3.Tentative Final Monograph (TFM) 4.Final Monograph (FM)

8. OTC Drug Review Category I: GRASE Category II: not GRASE Category III: cannot determine if safe and effective Advisory Review Panel

9. OTC Drug Review Category I: GRASE Category II: not GRASE Category III: cannot determine if safe and effective ANPR

10. OTC Drug Review ANPR TFM Comments

11. OTC Drug Review TFM Comments Data FM

12. History of OTC Topical Antifungal Monograph

13. Advance Notice of Proposed Rulemaking Published March 1982 Concerned about curing the condition  “An OTC product must provide more than temporary symptomatic relief of athlete’s foot, jock itch, and ringworm” Required at least one well-designed clinical study Recommended an ingredient as GRASE if it was significantly more effective than vehicle

14. Advance Notice of Proposed Rulemaking (cont.) Criteria for well-designed study are: (1) double-blinded and randomized (2) vehicle-controlled (3) test groups of adequate size (4) sign and symptoms verified by positive KOH and culture (5) standardized dosing regimen (i.e., four week treatment for athlete’s foot) (6) follow-up examinations at the end of treatment and two weeks after treatment ends

15. Advanced Notice of Proposed Rulemaking (cont.) 50 clinical studies for 35 ingredients 10 studies evaluated active ingredient(s) in treating athlete’s foot, but most poorly designed  Enrollment bias  Treatment duration  Efficacy assessment  Criteria for cure Recommended 6 GRASE active ingredients

16. Advance Notice of Proposed Rulemaking (cont.) Labeling Indication: “should enable the consumers to clearly understand the results that can be anticipated from the use of the product” Warning: “if irritation occurs or if there is no improvement within 4 weeks, discontinue use and consult a doctor or pharmacist” Direction: “should be clear and direct. They should provide the user with sufficient information to enable safe and effective use of the product”  Apply twice a day for 4 weeks

17. Tentative Final Monograph Published December 1989 25 clinical studies submitted following ANPR  6 studies addressed athlete’s foot FDA agreed with the Panel’s recommended conditions of use except for two ingredients  Nystatin: not GRASE  Povidone-iodine: GRASE

18. Final Monograph Published September 1993 FDA reviewed 10 studies submitted after TFM GRASE active ingredients:  Clinoquinol 3%  Haloprogin 1%  Miconazole nitrate 2%  Povidone-iodine 10%  Tolnaftate 1%  Undecylenic acid and its salts (calcium, copper, and zinc) for a total undecylenate concentration of 10-25%

19. Final Monograph Amendments cures “most” indication August 2000 Rationale for amendment:  Varying percentages of subjects were clinically and mycologically cured  Consistent with OTC vaginal antifungal drug products Adding clotrimazole February 2002 FDA reviewed 8 studies submitted after the FM

20. Summary OTC drug monograph system: safety and effectiveness for entire therapeutic class OTC topical antifungal monograph  GRASE active ingredients and labeling  for treatment of athlete’s foot, jock itch and ringworm Difficult to compare athlete’s foot cure rates for monograph drug products Monograph requires labeling of expected outcome: “cures most athlete’s foot”