badrul a. chowdhury, md, phd
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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)
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.
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)
Spray 2 sp BID (n=54)
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)
Spray 2 sp BID (n=54)
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)
Spray 2 sp BID (n=54)
Major Symptoms Complex Score after Treatment
05
101520253035404550
Mea
n %
Cha
nge
from
Bas
elin
e
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)
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)
Spray 2 sp BID (n=54)
Major Symptoms Complex Score after Treatment
05
101520253035404550
Mea
n %
Cha
nge
from
Bas
elin
e
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)
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.
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)
Spray 256 mcg (n=82)
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)
Spray 256 mcg (n=82)
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)
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
Rhinorrhea Sneezing Congestion
Sym
ptom
Sco
res Placebo (n=83)
Spray 32 mcg (n=78)
Spray 64 mcg (n=79)
Spray 128 mcg (n=83)
Spray 256 mcg (n=82)
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)
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
Rhinorrhea Sneezing Congestion
Sym
ptom
Sco
res Placebo (n=83)
Spray 32 mcg (n=78)
Spray 64 mcg (n=79)
Spray 128 mcg (n=83)
Spray 256 mcg (n=82)
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.
Change in Symptom Scores
010203040506070
Adju
sted
Mea
n %
Cha
nge
from
Bas
ellin
e
Placebo (n=82)
Spray 256 mcg QD (n=81)
Spray 400 mcg QD (n=82)
Aerosol 200 mcg BID (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
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)
Spray 256 mcg QD (n=81)
Spray 400 mcg QD (n=82)
Aerosol 200 mcg BID (n=79)
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.
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)
Spray 50 mcg QD (n=95)
Spray 100 mcg QD (n=95)
Spray 200 mcg QD (n=98)
Spray 800 mcg QD (n=95)
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 3 Day 7 Day 14 Day 21 Day 28
Mea
n %
Cha
nge
from
Bas
elin
e
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)
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 3 Day 7 Day 14 Day 21 Day 28
Mea
n %
Cha
nge
from
Bas
elin
e
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 3 Day 7 Day 14 Day 21 Day 28
Mea
n %
Cha
nge
from
Bas
elin
e
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)
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 3 Day 7 Day 14 Day 21 Day 28
Mea
n %
Cha
nge
from
Bas
elin
e
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 3 Day 7 Day 14 Day 21 Day 28
Mea
n %
Cha
nge
from
Bas
elin
e
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)
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.
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
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 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