The June 1999 Draft BA/BE Guidance for Nasal Aerosols and Nasal Sprays: History, Recommendations and Local Delivery Issu

1. The June 1999 Draft BA/BE Guidance for Nasal Aerosols and Nasal Sprays:History, Recommendations and Local Delivery Issues Wallace P. Adams, Ph.D. OPS/CDER/FDA Orally Inhaled and Nasal Drug Products (OINDP) Subcommittee of Advisory Committee for Pharmaceutical Science Rockville, MD 17 July 2001

2. NASAL AEROSOLS (MDIs) AND NASAL SPRAYS* Corticosteroids Anticholinergics Antihistamines Cromones *Draft FDA Guidance for Industry: BA and BE Studies for Nasal Aerosols and Nasal Sprays for Local Action, June 1999

3. OUTLINE • History • Guidance Recommendations for BE • formulation and device • in vitro studies • in vivo studies • Local Delivery BE Issues

4. History (a) • Patent or exclusivity expiration dates • Beconase AQ (Glaxo)- 27 July 1990 • September 1993 • GDAC with PADAC Representation meeting • BE of nasal solution formulations may be established with in vitro testing only • April 1995 • CDER internal memo • For BE of generic aqueous suspension nasal sprays • Q1 and Q2 sameness • comparative in vitro data • multiple dose PK study

5. History (b) • December 1996 letter to FDA • OGD requirements for BE of aqueous suspension nasal sprays do not require data on drug PSD, thus are inadequate to assure BE • Drug PSD affects rate and extent of dissolution and absorption from aqueous suspension nasal sprays to sites of action • May 1997 • OINDP Technical Committee organized • June 1999 • Issuance of draft guidance, BA and BE Studies for Nasal Aerosols and Nasal Sprays for Local Action • AAPS Workshop on Regulatory Issues Related to Drug Products for Oral Inhalation and Nasal Delivery

6. History (c) • November 1999 • OINDP Expert Panel organizational meeting • April 2000 • OINDP Subcommittee of ACPS meeting • November 2000 • OINDP Subcommittee report to ACPS

7. METHODS FOR DOCUMENTATION OF BE* • In vivo studies in humans comparing drug or active metabolite in an accessible biologic fluid • In vivo studies in humans comparing a pharmacodynamic endpoint • Comparative clinical trials to demonstrate bioequivalence • Comparative in vitro studies • See 21 CFR 320.24 for details

8. APPLICATION OF BE STUDIES • FOR NDA’s • To-be-marketed product comparable to clinical trial product • FOR ANDA’S • Generic product BE to innovator product • FOR NDA’s and ANDA’s • Certain postapproval changes

9. BE RECOMMENDATIONSFormulation Equivalence • Qualitative sameness (Q1) • identical active and inactive ingredients as in the RLD • Quantitative sameness (Q2) • inactive ingredients within ± 5% of the concentrations in the RLD

10. BE RECOMMENDATIONSThe Device • Assurance of equivalence: • is greatest when T uses the same brand and model (particularly the metering valve or pump and actuator) as used in R. • if not feasible, valve or pump, and actuator designs should be as close as possible in all critical dimensions (e.g., metering chamber volume, actuator orifice diameter)

11. BE RECOMMENDATIONS Comparable In Vitro Performance (a) • Dose content uniformity through container life • Droplet and particle size distribution

12. BE RECOMMENDATIONS: Comparable In Vitro Performance (b) • Spray pattern • Plume geometry • Priming and repriming • Tailoff characteristics

13. LOCAL DELIVERYClinical Endpoint in SAR Patients • Dose-response • To document sensitivity • Traditional treatment study • Day(s) in the park study • Environmental Exposure Unit (EEU) study

14. SYSTEMIC EXPOSURE STUDY (PK) • Randomized, two-way crossover • Healthy (non-SAR) subjects • Single or multiple dose • Multiple actuations per dose to achieve measurable plasma concentrations, if necessary • minimize drug loss from fluid drainage • AUC and Cmax measures • Two one-sided tests procedure (ANOVA)

15. SYSTEMIC ABSORPTION STUDY (PD) • When PK study is not feasible -HPA axis suppression study for nasal corticosteroids • Healthy, nonallergic subjects • Randomized, placebo-controlled, parallel group study • Conduct at maximum labeled dose for 14 days • 24-hr urinary free cortisol or 24-hr serum cortisol, data baseline-adjusted

16. BE RECOMMENDATIONS(OVERVIEW) • Q1 and Q2 sameness • Device recommendations • Comparable in vitro performance • Comparable in vivo performance for local delivery • suspension formulation nasal sprays and nasal aerosols only • Comparable in vivo performance for systemic exposure or absorption • suspension formulation nasal sprays and nasal aerosols only

17. THE LOCAL DELIVERY ISSUES* • Clinical study may be crucial to establish BE for local delivery • Dose-response relationship • may not be possible to show • may not be consistently reproducible • Clinical study should document sensitivity • between different doses • doses may differ by two to fourfold • minimum dose not less than one spray per nostril daily • *Draft FDA Guidance for Industry: BA and BE Studies for Nasal Aerosols and Nasal Sprays for Local Action, June 1999

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

19. PROPOSAL FOR BE STUDYNASAL SUSPENSION AEROSOLS AND SPRAYS • Formulation recommendations • Device recommendations • In vitro studies • In vivo studies • rhinitis study (lowest active dose) • PK study (high dose) • alternate: PD study

20. ACKNOWLEDGMENTS FDA/CDER OINDP Technical Committee Helen Winkle Ajaz Hussain, Ph.D. Roger Williams, M.D.

21. BCC and CMC CC Locally Acting Drug Products Oral Inhalation and Nasal Drug Products Wallace Adams (Chair) Working Groups Badrul Chowdhury Mary Fanning Lydia Gilbert-McClain Robert Meyer Gur Jai Pal Singh (Chair) Wallace Adams Dale Conner Stella Machado Robert Meyer Donald Schuirmann Sandra Suarez Eugene Sullivan Wallace Adams (Chair) James Allgire Charles Brownell Dale Conner Moheb Nasr Rabindra Patnaik Pradeep Sathe Gur Jai Pal Singh Yi Tsong Guirag Poochikian (Chair) Craig Bertha Timothy McGovern Robert Meyer Michael Smela Donald Hare Debra Birenbaum Tien-Mien (Albert) Chen Young Moon Choi Dale Conner Robert Meyer Gur Jai Pal Singh Sandra Suarez Comparative Clinical Pharmacodynamic In Vitro Bioavailability/ Bioequivalence Inhalation Drug Products* Comparability of Inactive Ingredients Comparative Systemic Absorption (Safety) Study * A CMC CC Working Group 23 April 2001

22. THE END

23. PROPOSED BE CRITERION FOR NONPROFILE DATA • Evaluates • mean performance of T and R products • variability of R product • variability of T product • Based on • difference between T and R means • difference between T and R variances • scaling of BE boundaries to RLD variance • Uses one-sided 95% upper confidence bound • alpha = 0.05

24. PROPOSED BE CRITERION FOR NONPROFILE DATA: In Vitro Population BE Criterion and BE Limit

25. RELATIVE BIOAVAILABILITY "RESPONSE SCALE" vs "DOSE SCALE” (PHARMACODYNAMIC STUDIES) GJPS 3/30/2000

26. DATA ANALYSIS • Clinical Study (Rhinitis) • Under discussion • Change from baseline data have continuous and noncontinuous (categorical) aspects • HPA Suppression Study (PD) • To be drafted • Systemic Exposure Study (PK) • Two one-sided tests procedure (ANOVA) GJPS 3/30/2000