The June 1999 Draft BA/BE Guidance for Nasal Aerosols and Nasal Sprays: Recommendations of the OINDP Subcommittee

1. The June 1999 Draft BA/BE Guidance for Nasal Aerosols and Nasal Sprays:Recommendations of the OINDP Subcommittee Wallace P. Adams, Ph.D. OPS/CDER/FDA Advisory Committee for Pharmaceutical Science OINDP Subcommittee Report Rockville, MD 19 July 2001

2. OUTLINE • Introduction to the two questions • The two questions • Recommendations/conclusions of the OINDP subcommittee

3. INTRODUCTION TOTHE TWO QUESTIONS To establish BE of suspension formulation nasal aerosols and nasal sprays for allergic rhinitis, the June 1999 draft guidance BA and BE Studies for Nasal Aerosols and Nasal Sprays for Local Action recommends equivalence of formulation, both qualitatively and quantitatively; device; in vitro studies; and systemic exposure or systemic absorption. The in vitro studies, however, do not assure equivalence of particle size of the suspended drug. Because particle size differences between test and reference products have the potential to alter the rate and extent of delivery of drug to local sites of action in the nose,differences in clinical effectiveness could result. For this reason, the draft guidance also recommends the conduct of a clinical study for allergic rhinitis to confirm equivalent local delivery. Providing equivalence of each of the items in the first sentence exists:

4. THE TWO QUESTIONS 1. Does the committee believe that a placebo-controlled traditional two-week rhinitis study conducted at the lowest active dose is sufficient to confirm equivalent local delivery of suspension formulation nasal sprays and nasal aerosols for allergic rhinitis?

5. THE TWO QUESTIONS 2. Does the committee believe that a placebo-controlled park study or an EEU study conducted at the lowest active dose is an acceptable option to confirm equivalent local delivery of suspension formulation nasal sprays and nasal aerosols for allergic rhinitis?

6. Conclusions of the OINDP Subcommittee Regarding the Clinical BE Studies - 7-17-01 • Based on current technology and methods, demonstration of dose-response may not be possible for locally acting drug products for allergic rhinitis

7. Conclusions of the OINDP Subcommittee Regarding the Clinical BE Studies - 7-17-01 • A clinical study is needed in the comparison of suspension nasal products • Note that the subcommittee was not in consensus on this issue, but the majority agreed with the above

8. Conclusions of the OINDP Subcommittee Regarding the Clinical BE Studies - 7-17-01 • A clinical rhinitis study would be useful to confirm that whatever unknowns remain after establishing equivalence through in vitro performance and pharmacokinetic metrics are not clinically important.

9. Conclusions of the OINDP Subcommittee Regarding the Clinical BE Studies - 7-17-01 • Of the 3 study designs in the draft guidance, the traditional, placebo-controlled two week rhinitis study is most appropriate • A single dose level of test and reference products should be used, at the lowest labeled dose

10. THE END

11. Response Equivalence DOSE-RESPONSE Reduced safety Reducedefficacy Adapted from JN Pritchard, ANZSRS Annual Meeting, Brisbane, 16-19 Mar 2001