1. Difficulties in showing a dose- response with locally-acting nasal sprays and aerosols for allergic rhinitis Badrul A. Chowdhury, MD, PhD Medical Team Leader, Division of Pulmonary and Allergy Drug Products, CDER, US FDA

2. Nasal sprays and aerosols Nasal sprays - solutions –Astelin (azelastine hydrochloride) Nasal Spray 137 mcg –Atrovent (ipratropium bromide) Nasal Spray 0.03% –Atrovent (ipratropium bromide) Nasal Spray 0.06% –NasalCrom (cromolyn sodium) Nasal Spray 5.2 mcg –Nasalide (flunisolide) Nasal Spray 25 mcg –Nasarel (flunisolide) Nasal Solution 25 mcg –Tri-Nasal (triamcinolone acetonide) Spray 50 mcg Nasal sprays - suspensions –Beconase (beclomethasone dipropionate) AQ Nasal Spray 42 mcg –Flonase (fluticasone propionate) Nasal Spray 50 mcg –Nasacort AQ (triamcinolone acetonide) Nasal Spray 55 mcg –Nasonex (mometasone furoate) Nasal Spray 50 mcg –Rhinocort (budesonide) Aqua Nasal Spray 32 mcg –Vancenase (beclomethasone dipropionate) AQ Double Strength Nasal Spray 0.084% Nasal aerosols - suspensions –Beconase (beclomethasone dipropionate) Inhalation Aerosol 42 mcg –Nasacort (triamcinolone acetonide) Nasal Inhaler 55 mcg –Rhinocort (budesonide) Nasal Inhaler 32 mcg –Vancenase (beclomethasone dipropionate) PocketHaler Nasal Inhaler 42 mcg

3. Allergic rhinitis study design Types of studies –Natural exposure study In-season, outpatient, multiple day (3-7 day run-in, 14-28 days of double blind treatment), parallel-group –Day-in-the park study In-season, outpatient, single or multiple days (1-3 days), parallel-group –Environmental exposure unit study Out-of-season, single or multiple days (1-3 days) cross-over or parallel-group

4. Allergic rhinitis study design Efficacy measures –Nasal symptoms - reflective or instantaneous [0-3 scale] nasal itching, sneezing, rhinorrhea, nasal congestion –Non-nasal symptoms - reflective or instantaneous [0-3 scale] eye itching, eye redness, eye watering, itching of ears or palate Objective pharmacodynamic measures of efficacy are not currently accepted because they lack validation and established clinical correlation –Measures of nasal passage patency rhinomanometry, nasal inspiratory flow rate, etc., –Inflammatory markers of disease activity cells, cytokines, chemokines, nitric oxide, etc.,

5. Experience with three drug substances Solution nasal spray (Drug A) –Day-in-the park dose-ranging study Suspension nasal spray and aerosol (Drug B) –Natural exposure dose-ranging study with spray formulation –Natural exposure comparative study with spray and aerosol formulations Suspension nasal spray and aerosol (Drug C) –Natural exposure dose-ranging study with spray formulation –Natural exposure comparative dose-ranging study with spray and aerosol formulations

6. Drug A: Dose-ranging study with a solution nasal spray Day-in-the-park, 2-center US study conducted in fall of 1989 SAR patients ages  12 years Two days in the park, 3 doses BID at 3 dose levels Efficacy: instantaneous scoring of 6 symptoms [runny nose, sniffles, itchy nose, nose blows, sneezes, watery eyes] on 0-5 scale. Scored hourly for 6 hours after first and third dose in the park, and less frequently at other time points. Scores summed as major symptoms complex. Baseline Major Symptom Complex 9.2 9.4 9.6 9.8 10 10.2 10.4 10.6 Mean Score Placebo (n=50) Chlor 12 mg BID (n=52) Spray 1 sp BID (n=54) Spray 2 sp QD (n=54) Spray 2 sp BID (n=54) Major Symptoms Complex Score after Treatment 0 5 10 15 20 25 30 35 40 45 50 Mean % Change from Baseline Placebo (n=50) Chlor 12 mg BID (n=52) Spray 1 sp BID (n=54) Spray 2 sp QD (n=54) Spray 2 sp BID (n=54)

7. Drug B: Dose-ranging study with a suspension nasal spray Natural exposure, 14-center US study conducted in fall of 1994 Subjects: Ragweed sensitive SAR patients ages  6 years Design: one-week baseline period, followed by four-week double-blind treatment period Treatment: QD dosing of 4 dose levels over an 8-fold range Efficacy: 12-hour reflective recording of 3 nasal symptoms [runny nose, nasal congestion, sneezing] scored on 0-3 scale every morning. Sum of the 3 symptoms is nasal index score. Adjusted Mean Nasal Index Score 0 1 2 3 4 5 6 BaselineTreatmentChange Nasal Index Score Placebo (n=83) Spray 32 mcg (n=78) Spray 64 mcg (n=79) Spray 128 mcg (n=83) Spray 256 mcg (n=82) Adjusted Mean Change in Individual Nasal Symptom Scores 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 RhinorrheaSneezingCongestion Symptom Scores Placebo (n=83) Spray 32 mcg (n=78) Spray 64 mcg (n=79) Spray 128 mcg (n=83) Spray 256 mcg (n=82)

8. Drug B: Comparative study with a suspension nasal spray and aerosol Natural exposure, 7-center Canadian study conducted in fall of 1994 Subjects: ragweed sensitive SAR patients ages  12 years Design: one-week baseline period, followed by three-week double-blind treatment period QD dosing of 3 dose levels Efficacy: 12-hour reflective recording of of 3 nasal symptoms [runny nose, sneezing, nasal congestion] and eye symptoms on 0-3 scale twice daily. Change in Symptom Scores 0 10 20 30 40 50 60 70 Rhinorrhea Sneezing Congestion Nasal Symptoms Eye Symptoms Adjusted Mean % Change from Baselline Placebo (n=82) Spray 256 mcg QD (n=81) Spray 400 mcg QD (n=82) Aerosol 200 mcg BID (n=79)

9. Drug C: Dose-ranging study with a suspension nasal spray Natural exposure, 15-center US study conducted in fall of 1992 SAR patients ages  18 years Design: one-week baseline period, followed by four-week double-blind treatment period QD dosing of four dose levels over a 16-fold range Efficacy: 12-hour reflective recording of 8 symptoms [runny nose, nasal congestion, nasal itching, sneezing, eye itching and burning, tearing of eyes, eye redness, itching of ears and/or palate] scored on 0-6 scale every morning. Physician Rated Total Symptom Score 0 10 20 30 40 50 60 70 Day 3Day 7Day 14Day 21Day 28 Mean % Change from Baseline Placebo (n=95) Spray 50 mcg QD (n=95) Spray 100 mcg QD (n=95) Spray 200 mcg QD (n=98) Spray 800 mcg QD (n=95) Patient Rated Total Symptom Score 0 10 20 30 40 50 60 70 Day 3Day 7Day 14Day 21Day 28 Mean % Change from Baseline Placebo (n=95) Spray 50 mcg QD (n=95) Spray 100 mcg QD (n=95) Spray 200 mcg QD (n=98) Spray 800 mcg QD (n=95)

10. Drug C: Comparative dose-ranging study with a suspension nasal spray and aerosol Natural exposure, 32-center US study conducted in 1999 spring SAR patients ages  12 years Design: one-week baseline period, followed by two-week double-blind treatment period QD dosing of 3 dose levels from 2 devices over an 8-fold range Efficacy: 12-hour reflective recording of 4 nasal symptoms [rhinorrhea, nasal congestion, sneezing, nasal itching] scored on 0-3 scale twice daily. Sum of the 4 symptoms is total nasal symptom score. Change in Total Nasal Symptom Score 0 5 10 15 20 25 30 35 40 45 Day 1 to 8Day 9 to 15Day 1 to 15 Mean % Change from Baseline Placebo Aerosol 25mcg QD Aerosol 50mcg QD Aerosol 200mcg QD Spray 25mcg QD Spray 50mcg QD Spray 200mcg QD

11. Summary comments Rhinitis studies of nasal sprays and aerosols do not consistently show dose-response relationship Reasons of failure to show dose-response –Symptom score is not a sensitive discriminative measure –The approved doses of some drugs may be at the upper flat portion of the dose-response curve