1. 1 ORALLY INHALED AND NASAL DRUG PRODUCTS FOR LOCAL ACTION Current FDA BA/BE Background and Issues Wallace P. Adams, Ph.D. OPS/CDER/FDA OINDP Subcommittee of the Advisory Committee for Pharmaceutical Science Rockville, MD 26 April 2000 This presentation represents the personal opinions of the speaker and does not necessarily represent the views or policies of US FDA

2. 2 ORALLY INHALED AND NASAL DRUG PRODUCTS FOR LOCAL ACTION Current FDA BA/BE Background and Issues Wallace P. Adams, Ph.D. OPS/CDER/FDA Orally Inhaled and Nasal Drug Products Subcommittee of the Advisory Committee for Pharmaceutical Science This presentation represents the personal opinions of the speaker and does not necessarily represent the views or policies of US FDA

3. 3 Two Product Quality Guidances BA and BE Studies for Nasal Aerosols and Nasal Sprays for Local Action –draft issued June 1999 BA and Be Studies for Orally Inhaled MDIs, DPIs and Inhalation Solutions for Local Action –in preparation

4. 4 Draft Guidances Coverage Bioavailability (BA) Measurement –May be noncomparative –Characterization (benchmark) studies –PRODUCT QUALITY BA ONLY –Additional PK/Bio studies are not covered Bioequivalence (BE) Establishment –Comparative studies Cover locally acting drug products only

5. 5 Approaches to Measure BA and Establish BE Pharmacokinetic Pharmacodynamic Clinical In vitro

6. 6 Locally Acting Drug Products (LADP) The BA and BE Challenge: Delivery to sites of action does not occur primarily after systemic absorption, hence Pharmacokinetic studies are inadequate to fully document BA and BE

7. 7 BA and BE Concepts for LADP Local delivery –relates to efficacy Systemic exposure –relates to safety –may also relate to efficacy e.g., levocabastine nasal spray

8. 8 Formulation and Container/Closure System Formulation equivalence (BE): –Q1 (excipients qualitatively the same) –Q2 (excipients quantitatively the same) Functional comparability of devices (BE)

9. 9 In Vitro BA and BE Data Apply to all MDIs, DPIs, and nasal sprays Confidence intervals for comparative data of selected in vitro BE measures Statistics under development for the selected in vitro BE measures

10. 10 In Vitro BA and BE Data: Specific Tests for MDIs and Nasal Sprays Dose or spray content uniformity through container life Droplet size distribution Drug particle size distribution Spray pattern and plume geometry Priming and repriming Tail off

11. 11 In Vitro BE: Statistical Comparisons under Development Profile comparisons –For cascade impactor data –Based on chi-square differences, or –Other possible statistics Nonprofile comparisons –For dose content uniformity through container life and other in vitro tests –Based on population BE criterion

12. 12 Proposed BE Criterion For CU Evaluate –mean performance of T and R products –variability of R product –variability of T product Criterion based on –difference between T and R means –difference between T and R variances –scaling of BE boundaries to RLD variance One-sided 95% upper confidence bound,  = 0.05

13. 13 Proposed BE Criterion for CU: In Vitro Population BE Criterion and BE Limit

14. 14 In Vivo BA and BE Data LOCAL DELIVERY based on clinical study SYSTEMIC EXPOSURE based on PK study, or SYSTEMIC ABSORPTION based on PD or clinical study In vitro data only requested for nasal solution formulations

15. 15 Clinical End Point Studies –Traditional Treatment Study: Single-blind placebo lead-in period (1-14 days), two-week treatment duration, symptom assessment twice daily and at the end of dosing interval, safety measurements (lab tests) –Day(s) in the Park Study: Baseline establishment, park exposure for specified periods over 1-2 days. Nasal symptoms assessment to characterize the onset of drug action and end-of-dosing interval efficacy. Safety assessment (adverse events reporting) –EEU study: Controlled indoor environment, Screening by repeated pretreatment exposure, EEU exposure to establish baseline, EEU exposure for specified periods over 1-2 days, Nasal symptoms assessment to characterize the onset of drug action and end-of- dosing interval efficacy. Safety assessment (adverse events reporting) BE Studies for Nasal Sprays GJPS 3/30/2000

16. 16 Equivalent Systemic Exposure –Study Design: Randomized, two-way crossover –Subjects: Generally healthy volunteers –BE Metrics PK (preferred): AUC and C max PD (if PK not feasible): Varies with the drug BE Studies for Nasal Sprays GJPS 3/30/2000

17. 17 PD Endpoints –Based on the ability of albuterol to dilate airways Forced expiratory volume in one second (FEV 1 ) –Based on the ability of albuterol to protect airways from bronchospasm induced by challenge agents Provocative dose or concentration of the agent required to reduce a given FEV 1 value by 20% (PD 20 or PC 20 ) PD BE Studies for Inhalation Aerosols (Albuterol MDI) GJPS 3/30/2000

18. 18 Study Design – Randomized, crossover studies Treatments –Minimum T1 T2, R1 R2 –Preferred T1 T2 T3, R1 R2 R3 PD-BE Studies for Inhalation Aerosols (Albuterol MDI) T = test product, R = reference product 1, 2 & 3 = Number of actuation doses GJPS 3/30/2000

19. 19 BE Studies for Inhalation Aerosols Equivalent Systemic Exposure or Systemic Absorption –Study Design:Randomized, two-way crossover –Subjects:Generally healthy volunteers –BE Metrics PK (preferred): AUC and C max PD (if PK not feasible): Varies with the drug GJPS 3/30/2000

20. 20 Data Analysis Clinical BE Studies –Study design dependent Analyses suitable for noncontinuous (categorical) data PD BE Studies –“Dose Scale” analysis Systemic Exposure Studies (PK) –Two one-sided tests procedure (ANOVA) GJPS 3/30/2000