Badrul A. Chowdhury, MD, PhD

Difficulties in showing a dose-response with locally-acting

nasal sprays and aerosols for allergic rhinitis

Badrul A. Chowdhury, MD, PhDMedical 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)


• 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.






Baseline Major Symptom Complex

9.2

9.4

9.6

9.8

10

10.2

10.4

10.6

Mea

n S

core

Placebo (n=50)

Chlor 12 mg BID (n=52)

Spray 1 sp BID (n=54)

Spray 2 sp QD (n=54)







Baseline Major Symptom Complex

9.2

9.4

9.6

9.8

10

10.2

10.4

10.6

Mea

n S

core

Placebo (n=50)





Major Symptoms Complex Score after Treatment

05

101520253035404550

Mea

n %

Cha

nge

from

Bas

elin

e

Placebo (n=50)






• 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


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

Baseline Treatment Change

Nas

al In

dex

Sco

re Placebo (n=83)

Spray 32 mcg (n=78)

Spray 64 mcg (n=79)

Spray 128 mcg (n=83)








Adjusted Mean Nasal Index Score

0

1

2

3

4

5

6

Baseline Treatment Change

Nas

al In

dex

Sco

re Placebo (n=83)

Spray 32 mcg (n=78)

Spray 64 mcg (n=79)



Adjusted Mean Change in Individual Nasal Symptom Scores

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Rhinorrhea Sneezing Congestion

Sym

ptom

Sco

res Placebo (n=83)

Spray 32 mcg (n=78)

Spray 64 mcg (n=79)



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

010203040506070

Adju

sted

Mea

n %

Cha

nge

from

Bas

ellin

e

Placebo (n=82)

Spray 256 mcg QD (n=81)


Aerosol 200 mcg BID (n=79)







Change in Symptom Scores

010203040506070

Rhinorrh

ea

Sneez

ing

Conge

stion

Nasal

Sympto

ms

Eye S

ympto

msAd

just

ed M

ean

% C

hang

e fro

m B

asel

line

Placebo (n=82)



Aerosol 200 mcg BID (n=79)


• 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


Drug C: Dose-ranging study with a suspension nasal spray


• 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 3 Day 7 Day 14 Day 21 Day 28

Mea

n %

Cha

nge

from

Bas

elin

e

Placebo (n=95)











Physician Rated Total Symptom Score

0

10

20

30

40

50

60

70


Mea

n %

Cha

nge

from

Bas

elin

e

Placebo (n=95)





Patient Rated Total Symptom Score

0

10

20

30

40

50

60

70


Mea

n %

Cha

nge

from

Bas

elin

e

Placebo (n=95)





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

05

1015202530354045

Day 1 to 8 Day 9 to 15 Day 1 to 15

Mea

n %

Cha

nge

from

Bas

elin

e

Placebo

Aerosol 25mcg QD

Aerosol 50mcg QD

Aerosol 200mcg QD

Spray 25mcg QD

Spray 50mcg QD

Spray 200mcg QD






Change in Total Nasal Symptom Score

05

1015202530354045

Day 1 to 8 Day 9 to 15 Day 1 to 15M

ean

% C

hang

e fro

m B

asel

ine

Placebo

Aerosol 25mcg QD

Aerosol 50mcg QD

Aerosol 200mcg QD

Spray 25mcg QD

Spray 50mcg QD

Spray 200mcg QD

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

Badrul A. Chowdhury, MD, PhD

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