1. 1 Asthma Stability Model for Inhaled Corticosteroid Dose-Response Wallace P. Adams, PhD OGD/OPS/CDER/US FDA Advisory Committee for Pharmaceutical Science and Clinical Pharmacology 23 July 2008

2. 2 Outline of the Presentation Methods to establish BE Challenges to ICS BE Asthma stability model: Pilot study –crossover vs parallel design –estimates of sample size for a BE study Asthma stability model: FDA research Pharmacodyamic study data analysis

3. 3 Methods for Establishment 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 BE Comparative in vitro studies 21 CFR 320.24(b)

4. 4 DOSE-RESPONSE Reduced efficacy Reduced safety Response Equivalence Adapted from JN Pritchard, ANZSRS Annual Meeting, Brisbane, 16-19 Mar 2001

5. 5 Inhaled Corticosteroids (ICS) Dose-response * –Differences from placebo for each active dose are statistically significant –A dose-response generally exists shallow –Lack of statistical significance in response between adjacent doses high variability of response –4-fold or greater dose differences generally required to detect statistical significance Carryover between treatment periods is a concern for crossover study designs –Unequal carryover can bias the estimate of difference between treatment means *PJ Barnes et al, AJRCCM 1998;157:S1-53

6. 6 Subjects age >18 yrs with asthma 50-75% of predicted N=50-59 per treatment WW Busse et al, JACI 1999;104:1215-22 Dose-Response (D-R): CFC vs HFA Beclomethasone Dipropionate Treatments BDP for 6 weeks Parallel group design Up to 28 day ICS washout with placebo MDI 100, 400 or 800 mcg daily (BID dosing), blinded to dose

7. 7 Dose-Response (D-R): CFC-BDP and HFA-BDP WW Busse et al, JACI 1999;104:1215-22

8. 8 WW Busse et al, JACI 1999;104:1215-22, cited in JA Vanden Burgt et al, JACI 2000;106:1209-1226 Relative Potency of CFC-BDP and HFA-BDP (Finney Bioassay Method)

9. 9 Asthma Stability after Oral Prednisone Model Pilot study in 12 adult asthmatics Randomized two period crossover study Oral prednisone (40 mg BID) wash-in, 4-7 days Two doses of HFA-BDP; 100, 800 mcg/day 21 day treatment period with ICS Periodic measurement of pulmonary function Repeat wash-in (4-7 day), crossover ICS (21 day) RC Ahrens et al, AJRCCM, 2001;164:1138-45

10. 10 Sample Size Estimates (based on the Ahrens Pilot Study) Assume –2 by 2 study design (2 doses of each preparation) –Finney bioassay –90% confidence interval –BE interval on the dose scale is 50 - 200% –power = 80% –parallel or crossover study design Sample size estimates –based on ‘s’ and ‘b’ at end of treatment period –‘s’ is SD for responses from ANOVA –‘b’ is dose-response slope –low s/b ratio increases study power RC Ahrens et al, AJRCCM, 2001;164:1138-45

11. 11 Mean AM FEV1 Responses/b ratios RC Ahrens et al, AJRCCM, 2001;164:1138-45 Mean Responses by Study Treatment Day

12. 12 RC Ahrens et al, AJRCCM, 2001;164:1138-45 Study Design: Parallel vs Crossover

13. 13 Asthma Stability Model: FDA Study Objectives Oral prednisone versus high dose ICS –Effect on maximum FEV1 value during high dose run-in of each crossover treatment –Effect on observed D-R Characterize D-R based on three treatment levels Study efficiency of screening process for identifying subjects demonstrating sufficient D-R (study enrichment) Examine D-R of primary and secondary outcome variables Characterize D-R using linear, nonlinear and Emax modeling

14. 14 Design and Conduct of the FDA Study Subjects –Persistent asthma, non-smoking –Exhibit dose-response during run-in Run-In Study Periods –14 day high-dose ICS run-in (220 mcg x 4 actuations BID) –28 day low-dose ICS run-in (44 mcg x 1 actuation BID) Study Treatment Periods –high dose corticosteroid burst oral prednisone on two periods, or ICS randomly assigned –4 randomized crossover periods double-blind, double-dummy 28 days per period 44 mcg (1 actuation), 88 mcg (2 actuations), 88 mcg, and 352 (8 actuations) mcg BID

15. 15 Design and Conduct of the Study HDCB 7 day prednisone or 14 day FP Home spirometry: AM FEV 1 and PM FEV 1 every day Office spirometry at each clinical visit eNO at each clinic visit N = 30N = up to 120 (est.) Pre-study 7 day28 day Low dose run-in High dose run-in 14 day FP treatment 28 day N = 24 44, 88, 88, 352 mcg BID

16. 16 BE Criteria on the Dose Scale: Theory W Gillespie, ACPS Meeting, 16 Aug 1996

17. 17 Dose Scale Approach to Estimate Relative BA Drug X (hypothetical example) Revised from W Gillespie, ACPS Meeting, 16 Aug 1996 RLD MDI Dose (mcg) for RLD 2 (180 mcg) puffs of RLD RLD Dose of RLD that would result in a

18. 18 Acknowledgments Project Advisory Group –Badrul Chowdhury, MD, PhD, Division of Pulmonary and Allergy Products, OND –Sally Seymour, MD, DPAD –Robert Lionberger, PhD, OGD/OPS –Bing Li, PhD, OGD/OPS –Wallace Adams, PhD, OGD/OPS Lawrence Yu, PhD, OGD/OPS