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 Nasal sprays - suspensions Nasal aerosols - suspensions

3. 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

4. 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

5. 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.,

6. Experience with three drug substances Solution nasal spray (Drug A) Suspension nasal spray and aerosol (Drug B) Suspension nasal spray and aerosol (Drug C)

7. 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

8. 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

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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

24. 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.

25. 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.

26. 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.

27. 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.

28. 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.

29. 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.

30. 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.

31. 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.

32. 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