1. CLINICAL EFFICACY TESTING for NASAL DRUGS Mary M. Fanning, M.D., Ph.D. Associate Director for Medical Affairs Office of Generic Drugs, FDA June 4, 1999

2. Nasal Drug Products Prescription: corticosteroids antihistamines anticholinergics OTC: mast cell stabilizer cromolyn sodium

3. BA/BE for Nasal Drug Products BA Release of drug substance from drug product to the site of action cannot be measured by conventional pharmacokinetics

4. BE - comparison of a test product to a precursor product to-be-marketed product to a pivotal clinical trial material generic drug product to a reference listed drug

5. Clinical Endpoints Highly variable Relatively insensitive to detect differences between products Unequivocally establish effectiveness

6. Suspensions: Solutions: Bioequivalence studies with clinical endpoints are necessary systemic exposure studies in vitro studies In vitro studies

7. Indication to be studied: Seasonal Allergic Rhinitis Document bioequivalence for all labeled indications Treatment Study Design not prophylaxis

8. Sensitivity Evaluation Dose-response relationship Second dose may differ by 2- to 4- fold Increase sensitivity – lower dose may be below the recommended labeled dose (1/4 or 1/2)

9. Study Endpoints Before and during treatment Patient self-rated total nasal symptoms score (TNSS) Composite score runny nose, sneezing nasal itching, congestion

10. Study Endpoints (con’t) Onset of action Efficacy at the end of the dosing interval

11. Inclusion/Exclusion Criteria History of Seasonal Allergic Rhinitis Positive Allergy test for specific allergens Exclude patients with other diseases Patients with defined minimum level of symptom severity

12. Study Designs Traditional Treatment Study Day(s) in the Park Study Environment Exposure Unit Study

13. Traditional Treatment Study Two weeks of conventional therapy Randomized, double-blind, placebo- controlled, parallel group

14. Traditional Treatment Study (con’t) Symptom measurement twice a day reflective scores End of dosing interval symptom measurement - instantaneous scores Adverse Event (ADE) monitoring, Lab

15. Traditional Treatment Study (con’t) Relatively insensitive Large sample size Frequently used design

16. Day(s) in The Park Study Randomized, double-blind, placebo- controlled, parallel group Park exposure for pre-specified period, one to two days Dosing prior to or at beginning of study Safety ADE

17. Day(s) in The Park Study (con’t) Maximize exposure to allergens Shorter duration Less experience with study design Sample size? pilot study

18. Environmental Exposure Unit Study Randomized, double-blind, placebo- controlled, parallel group design Controlled indoor environment with controlled allergen release Pre-treatment exposure to relevant allergens

19. Environmental Exposure Unit Study (con’t) Screen for symptomatic responders Duration - full dosing interval Safety ADE Control allergen exposure

20. Environmental Exposure Unit Study (con’t) Select responders to specific allergens Limited experience with this model Availability of units Sample size? pilot study