Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
Pulmonary and Allergy Drugs Advisory Committee Meeting
Gaithersburg, Maryland January 17, 2002
Lydia I. Gilbert-McClain, MD, FCCPMedical Reviewer, DPADP
ADVAIRADVAIRTMTM DISKUS DISKUS(R)(R)
(Fluticasone propionate/salmeterol (Fluticasone propionate/salmeterol inhalation powder)inhalation powder)
2Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
CLINICAL ISSUESCLINICAL ISSUES
• Clinical relevance of the Efficacy data
• Application of data from these ADVAIR trials to the general COPD population
• Adequacy of the Safety data
3Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
COMBINATION DRUG PRODUCTCOMBINATION DRUG PRODUCT
Not approved for use in COPD Approved 1998 - Relief of bronchospasm associated with COPD
ADVAIR DISKUS
Fluticasone propionate Salmeterol xinafoate
4Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
DEVELOPMENT PROGRAMDEVELOPMENT PROGRAM
SFCA3006 SFCA3007
*TreatmentArms
Advair 500/50 Advair 250/50
FP 500 FP 250
Salmeterol 50 Salmeterol 50
Placebo Placebo
*One inhalation twice dailyFP = fluticasone propionate
5Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
OBJECTIVESOBJECTIVES
1. Efficacy of ADVAIR 250/50 bid and ADVAIR 500/50 bid
2. Safety of ADVAIR 250/50 bid and ADVAIR 500/50 bid
3.The “ quality of life” in COPD subjects receiving ADVAIR 250/50 bid and ADVAIR 500/50 bid
6Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
FIXED COMBINATION DRUGS POLICYFIXED COMBINATION DRUGS POLICY
21 CFR 300.50 -Two or more drugs may be combined in a single dosage form when:
Each component makes a contribution to the claimed effects
The combination is safe and effective
SFCA3006, SFCA3007 adequately designed to fulfill the efficacy requirements of the policy
7Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
ENTRY CRITERIAENTRY CRITERIA
• Diagnosis of COPD [ATS definition]
• Must have a history of cough productive of sputum on most days for at least 3 months of the year for at least 2 years that was not attributable to another disease process
• Baseline FEV1 of < 65% predicted but > 0.70 L OR
• FEV1 0.70 L AND > 40% < 65% predicted
• AND FEV1/FVC ratio 70%
8Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
PATIENT POPULATION ENROLLEDPATIENT POPULATION ENROLLED
• Mean FEV1 across studies was 40% - 42% predicted
• Mean FEV1/FVC ratio across studies was 47% - 51%
• Percentage of subjects across studies with 12% improvement in FEV1 AND >200 ml absolute change was 54% - 55%
9Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
PATIENT POPULATION ENROLLEDPATIENT POPULATION ENROLLED
• All subjects had a history of chronic bronchitis
• Mean baseline symptom score on Chronic Bronchitis Symptom Questionnaire ranged 6.9 - 7.5 [maximum possible score = 16]
• Dyspnea score 2 [scale 0 - 4]
10Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
Percentage of DiscontinuationsPercentage of Discontinuations
0
20
40
60
80
100
ADVAIR 250/50 ADVAIR 500/50
% D
isco
ntin
uatio
ns
AdvairPlaceboSalmeterolFP
11Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
PRIMARY EFFICACY ENDPOINTSPRIMARY EFFICACY ENDPOINTS
• Pre-dose FEV1 Evaluate the contribution of FP in the
combination ADVAIR vs. Salmeterol
2-hr post-dose FEV1 Evaluate the contribution of salmeterol in
the combination ADVAIR vs. FP
12Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
EFFICACY: Pre-dose FEVEFFICACY: Pre-dose FEV11
ADVAIR 250/50 ADVAIR 500/50Mean FEV1 atbaseline: Advair 1.207 L 1.254 L
Mean FEV1 atbaseline: SAL 1.205 L 1.192 L
Advair - SAL atEndpoint 0.069 L 0.067 L
13Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
EFFICACY: 2-hr Post-Dose FEVEFFICACY: 2-hr Post-Dose FEV11
ADVAIR 250/50 ADVAIR 500/50Mean FEV1 atbaseline: Advair 1.207 L 1.254 L
Mean FEV1 atbaseline: FP 1.236 L 1.174 L
Advair - FP atEndpoint
0.124 L 0.129 L
14Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
EFFICACY: ADVAIR vs. Placebo EFFICACY: ADVAIR vs. Placebo (Reversible and Non-reversible populations)(Reversible and Non-reversible populations)
Pre-Dose FEVPre-Dose FEV11
Overall ITTpopulation
Reversiblepopulation
Non-Reversiblepopulation
ADVAIR250/50
0.164 L 0.211 L 0. 107 L
ADVAIR500/50
0.160 L 0.192 L 0.124 L
15Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
EFFICACY: ADVAIR vs. PlaceboEFFICACY: ADVAIR vs. Placebo(Reversible and Non-reversible populations)(Reversible and Non-reversible populations)
2- hour post- dose FEV2- hour post- dose FEV11
Overall ITTpopulation
Reversiblepopulation
Non-reversiblepopulation
ADVAIR250/50
0.223 L 0.282 L 0.150 L
ADVAIR500/50
0.233 L 0.290 L 0.167 L
16Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
PATIENT-REPORTED OUTCOMESPATIENT-REPORTED OUTCOMES
• Evaluation of patient-related outcomes may be helpful in assessing the clinical relevance of FEV1 changes
• Chronic Respiratory Disease Questionnaire [CRDQ] used in both studies
• Sponsor-defined Minimal Clinically Important change [MCIC] in Overall Score 10
17Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
Chronic Respiratory Disease QuestionnaireChronic Respiratory Disease QuestionnaireOverall Score: Treatment Difference in Change Overall Score: Treatment Difference in Change
From Baseline At EndpointFrom Baseline At Endpoint
CRDQ [Overall Score]ADVAIR250/50
ADVAIR500/50
Advair - Placebo 5 5Advair - SAL 3.6 2Advair - FP -0.4 5.2MCIC 10
18Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
CRDQ: Dyspnea DomainCRDQ: Dyspnea Domain Treatment Difference in Change from Baseline Treatment Difference in Change from Baseline
at Endpointat Endpoint
MCIC = 2.5ADVAIR250/50
ADVAIR500/50
Advair - Placebo 1.2 2.1Advair - SAL 0.9 1.3Advair - FP 0.1 1.8
Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
COPD EXACERBATIONSCOPD EXACERBATIONS
Severity of exacerbations
Time to first exacerbation
Time to first moderate/severe exacerbation
Number of withdrawals due to COPD exacerbations
20Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
Percentage of Subjects with COPD Percentage of Subjects with COPD ExacerbationsExacerbations
0
20
40
60
80
100
ADVAIR 250/50 ADVAIR 500/50
% S
ubje
cts
with
Exa
c.
AdvairPlaceboSalmeterolFP
21Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
Percentage of Subjects with Moderate/Severe Percentage of Subjects with Moderate/Severe ExacerbationsExacerbations
0
20
40
60
80
100
ADVAIR 250/50 ADVAIR 500/50
% S
ubje
cts
with
Mod
/Sev
Exa
c.
AdvairPlaceboSalmeterolFP
22Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
Percentage of Withdrawals Due to COPD Percentage of Withdrawals Due to COPD ExacerbationsExacerbations
0
20
40
60
80
100
ADVAIR 250/50 ADVAIR 500/50
% W
ithdr
awal
s
AdvairPlaceboSalmeterolFP
23Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
Chronic Bronchitis Symptoms Chronic Bronchitis Symptoms Questionnaire [CBSQ]Questionnaire [CBSQ]
Cough frequency and severity
Chest discomfort
Sputum production
Sponsor-defined MCIC 1.4
24Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
CBSQ GAS: Treatment Difference in Change CBSQ GAS: Treatment Difference in Change from Baseline at Endpointfrom Baseline at Endpoint
Treatment difference in CBSQ GASMCIC 1.4
ADVAIR 250/50 ADVAIR 500/50
Advair - Placebo 0.7 0.3
Advair - SAL 0.6 -0.1
Advair - FP -0.1 0.2
25Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
Transitional Dyspnea Index (TDI): Treatment Transitional Dyspnea Index (TDI): Treatment Difference at EndpointDifference at Endpoint
ADVAIR 250/50 ADVAIR 500/50
Advair - Placebo 0.7 1.7
Advair - SAL 0.1 1.2
Advair - FP 0 0.8
MCIC 1
26Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
SAFETYSAFETY
• Incidence of Cardiovascular events similar across treatment groups
• No clinically significant change in heart rate
• No drug-related QTc changes
• Holter monitoring - One case of heart block with ADVAIR 500/50
27Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
ADVERSE EVENTSADVERSE EVENTS
• Higher percentage of subjects in ADVAIR groups reported adverse events compared to placebo
ADVAIR 250/50 70%Placebo 64%
ADVAIR 500/50 78%Placebo 69%
28Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
ADVERSE EVENTSADVERSE EVENTSAdvair250/50
Placebo
Candidiasis 10% 1%
Hoarsness/dysphonia
5% 0
Viralrespiratoryinfections
6% 3%
29Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
ADVERSE EVENTSADVERSE EVENTSAdvair500/50
Placebo
Upper respiratorytract infection
17% 10%
Viral respiratoryinfections
8% 3%
Candidiasis 7% 1%
Hoarseness/dysphonia
3% 2%
30Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
OTHER ADVERSE EVENTSOTHER ADVERSE EVENTS
• Fractures rarely reported
• No cataracts reported
• Two reports of ocular pressures disorders in the ADVAIR 500/50 group and one in the placebo group
• Elevated blood glucose [ > 175 mg/dl] similar in ADVAIR and placebo groups
31Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
SAFETY: Evaluation of HPA Axis EffectsSAFETY: Evaluation of HPA Axis Effects
• Mean AM cortisol levels comparable in ADVAIR and placebo groups on Treatment Day 1 and Endpoint
• No adrenal insufficiency observed with ACTH [Cosyntropin] stimulation testing
• ACTH stimulation insensitive test for less than complete adrenal insufficiency
32Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
SUMMARY - EFFICACYSUMMARY - EFFICACY
• ADVAIR 250/50 and ADVAIR 500/50 meet efficacy criteria for combination drugs in the primary endpoints
• Similar efficacy for ADVAIR 250/50 and ADVAIR 500/50
• Numerically, effect size in “Reversible” subjects > effect size of “Non-reversible” subjects
33Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
SUMMARY - EFFICACYSUMMARY - EFFICACY
• No clear treatment advantage with ADVAIR for
COPD-related “quality of life”
COPD Symptoms
COPD exacerbations
Improvement in dyspnea
34Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002January 17, 2002
SUMMARY - SAFETYSUMMARY - SAFETY
Higher incidence of candidiasis, viral respiratory infections and hoarseness/dysphonia with ADVAIR
No adrenal insufficiency observed with ACTH [Cosyntropin] stimulation testing
Studies not designed to evaluate bone mineral density or ocular effects
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