# Presentation: 590194

## 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

## Nasal sprays and aerosols

- Nasal sprays - solutions
- Nasal sprays - suspensions
- Nasal aerosols - suspensions

## 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

## 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

## 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.,

## Experience with three drug substances

- Solution nasal spray (Drug A)
- Suspension nasal spray and aerosol (Drug B)
- Suspension nasal spray and aerosol (Drug C)

## 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

## 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

## 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.

## 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.

## 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.

## 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.

## 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.

## 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

## 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.

**Notes:**
Adjusted = Center, Baseline NIS or Nasal component score

## 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.

**Notes:**
Adjusted = Center, Baseline NIS or Nasal component score

## 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.

**Notes:**
Adjusted = Center, Baseline NIS or Nasal component score

## 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.

**Notes:**
Adjusted = Center, Baseline NIS or Nasal component score

## 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.

**Notes:**
Adjusted = Center, Baseline NIS or Nasal component score

## 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.

## 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.

## 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.

## 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

## 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.

## 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.

## 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.

## 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.

## 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.

## 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.

**Notes:**
Test for dose response using a linear contrast of treatment means with a two-way ANOVA failed for MFNA (placebo excluded) but won for MFNS (placebo excluded).

## 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.

**Notes:**
Test for dose response using a linear contrast of treatment means with a two-way ANOVA failed for MFNA (placebo excluded) but won for MFNS (placebo excluded).

## 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.

**Notes:**
Test for dose response using a linear contrast of treatment means with a two-way ANOVA failed for MFNA (placebo excluded) but won for MFNS (placebo excluded).

## 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