Post on 31-Dec-2015
1Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
FLOVENTFLOVENT®® DISKUS DISKUS®® NDA 20-833, S004NDA 20-833, S004GlaxoSmithKlineGlaxoSmithKline
FLOVENTFLOVENT®® DISKUS DISKUS®® NDA 20-833, S004NDA 20-833, S004GlaxoSmithKlineGlaxoSmithKline
Pulmonary-Allergy Drugs Advisory CommitteeJanuary 17, 2002
Charles E. Lee, M.D. Medical Reviewer
Division of Pulmonary and Allergy Drug ProductsCDER/FDA
Pulmonary-Allergy Drugs Advisory CommitteeJanuary 17, 2002
Charles E. Lee, M.D. Medical Reviewer
Division of Pulmonary and Allergy Drug ProductsCDER/FDA
2Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Proposed IndicationProposed IndicationProposed IndicationProposed Indication
“FLOVENT DISKUS is indicated for the long-term, twice-daily maintenance treatment of COPD (including emphysema and chronic bronchitis).”
“FLOVENT DISKUS is indicated for the long-term, twice-daily maintenance treatment of COPD (including emphysema and chronic bronchitis).”
3Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Proposed DoseProposed DoseProposed DoseProposed Dose
“The starting dosage for adults is 1 inhalation (250 mcg) twice daily. For patients who do not respond adequately to the starting dose, increasing the dose to 500 mcg twice daily may provide additional control.”
“The starting dosage for adults is 1 inhalation (250 mcg) twice daily. For patients who do not respond adequately to the starting dose, increasing the dose to 500 mcg twice daily may provide additional control.”
4Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
IntroductionIntroductionIntroductionIntroduction
• Efficacy– Pivotal studies
• Safety– Pivotal studies– Supportive studies
• Efficacy– Pivotal studies
• Safety– Pivotal studies– Supportive studies
5Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Overview Overview Overview Overview
• Efficacy– Small changes in primary and secondary
efficacy endpoints– Majority of patients had reversibility with
bronchodilator• Safety concerns
– Respiratory infections– Systemic effects
• Adrenal• Bone
• Efficacy– Small changes in primary and secondary
efficacy endpoints– Majority of patients had reversibility with
bronchodilator• Safety concerns
– Respiratory infections– Systemic effects
• Adrenal• Bone
6Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Questions for ConsiderationQuestions for ConsiderationQuestions for ConsiderationQuestions for Consideration
• Efficacy– Clinical interpretation of the primary efficacy
endpoint results– Higher percentage of reversibility in COPD
population than generally found– All patients had chronic bronchitis, could have
self-reported emphysema• Safety
– Adequacy of long-term safety database• Risk versus benefit
• Efficacy– Clinical interpretation of the primary efficacy
endpoint results– Higher percentage of reversibility in COPD
population than generally found– All patients had chronic bronchitis, could have
self-reported emphysema• Safety
– Adequacy of long-term safety database• Risk versus benefit
7Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Pivotal StudiesPivotal StudiesPivotal StudiesPivotal Studies
FLTA3025 FP 250 BIDFP 500 BIDPlacebo BID
N = 640
SFCA3006 FP 500 BIDPlacebo BIDSAL 50 BIDSAL 50/FP 500 BID
N = 674
SFCA3007 FP 250 BIDPlacebo BIDSAL 50 BIDSAL 50/FP 250 BID
N = 723
FLTA3025 FP 250 BIDFP 500 BIDPlacebo BID
N = 640
SFCA3006 FP 500 BIDPlacebo BIDSAL 50 BIDSAL 50/FP 500 BID
N = 674
SFCA3007 FP 250 BIDPlacebo BIDSAL 50 BIDSAL 50/FP 250 BID
N = 723
8Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Efficacy AssessmentEfficacy AssessmentEfficacy AssessmentEfficacy Assessment
• Primary efficacy variable– Pre-dose FEV1
• Secondary efficacy variables– CBSQ, BDI/TDI– PEFR, albuterol use– COPD exacerbations
• Patient Reported Outcomes– CRDQ
• Primary efficacy variable– Pre-dose FEV1
• Secondary efficacy variables– CBSQ, BDI/TDI– PEFR, albuterol use– COPD exacerbations
• Patient Reported Outcomes– CRDQ
9Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Safety AssessmentSafety AssessmentSafety AssessmentSafety Assessment
• AEs, SAEs, Withdrawals• Vital signs, physical examination, oropharyngeal
exam• ECG• Hematology and chemistry studies• Serum cortisol (FLTA3025)• Cosyntropin stimulation (SFCA3006, SFCA3007)
• AEs, SAEs, Withdrawals• Vital signs, physical examination, oropharyngeal
exam• ECG• Hematology and chemistry studies• Serum cortisol (FLTA3025)• Cosyntropin stimulation (SFCA3006, SFCA3007)
10Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
DemographicsDemographics
Pivotal StudiesPivotal Studies
DemographicsDemographics
Pivotal StudiesPivotal Studies
11Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
DemographicsDemographicsDemographicsDemographics
FLTA3025 SFCA3006SFCA3007
Gender, %M 69 66 63Mean age, yr 64 63 64Race, %C 94 94 93Race, %B 4 5 4
Race, %O 1 2 3
ICS use, % 31 25 25Current smokers, % 45 48 47
FLTA3025 SFCA3006SFCA3007
Gender, %M 69 66 63Mean age, yr 64 63 64Race, %C 94 94 93Race, %B 4 5 4
Race, %O 1 2 3
ICS use, % 31 25 25Current smokers, % 45 48 47
12Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
ReversibilityReversibilityPercent of PopulationPercent of Population
ReversibilityReversibilityPercent of PopulationPercent of Population
Reversible%
FLTA3025 59SFCA3006 54SFCA3007 55
Reversible%
FLTA3025 59SFCA3006 54SFCA3007 55
Reversible: Increase in FEV1 12% and 0.2 L
13Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Mean Response to Bronchodilator Mean Response to Bronchodilator % Change in FEV1% Change in FEV1
Mean Response to Bronchodilator Mean Response to Bronchodilator % Change in FEV1% Change in FEV1
Reversible NonOverall
Reversible% % %
FLTA3025 32 9 23SFCA3006 30 9 20SFCA3007 30 9 20
Reversible NonOverall
Reversible% % %
FLTA3025 32 9 23SFCA3006 30 9 20SFCA3007 30 9 20
Reversible: Increase in FEV1 12% and 0.2 L
14Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
EfficacyEfficacy
Pivotal StudiesPivotal Studies
EfficacyEfficacy
Pivotal StudiesPivotal Studies
15Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Mean Change From Baseline in Mean Change From Baseline in Pre-dose FEV1, LitersPre-dose FEV1, Liters
Difference from PlaceboDifference from Placebo
Mean Change From Baseline in Mean Change From Baseline in Pre-dose FEV1, LitersPre-dose FEV1, Liters
Difference from PlaceboDifference from Placebo
FLTA3025
(Baseline)
SFCA3006
(Baseline)
SFCA3007
(Baseline)
FP 250 0.027
(1.207)
0.108*
(1.236)
FP 500 0.050*
(1.246)
0.113*
(1.174)
FLTA3025
(Baseline)
SFCA3006
(Baseline)
SFCA3007
(Baseline)
FP 250 0.027
(1.207)
0.108*
(1.236)
FP 500 0.050*
(1.246)
0.113*
(1.174)
*p <0.05
16Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Secondary Endpoints and Secondary Endpoints and Patient Reported OutcomesPatient Reported OutcomesSecondary Endpoints and Secondary Endpoints and
Patient Reported OutcomesPatient Reported Outcomes
• Small differences from placebo group– CBSQ– BDI/TDI– COPD Exacerbations– AM PEFR– Albuterol use– CRDQ
• Small differences from placebo group– CBSQ– BDI/TDI– COPD Exacerbations– AM PEFR– Albuterol use– CRDQ
17Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
COPD ExacerbationsCOPD Exacerbations% of Patients with % of Patients with 1 Exacerbation1 Exacerbation
COPD ExacerbationsCOPD Exacerbations% of Patients with % of Patients with 1 Exacerbation1 Exacerbation
FLTA3025%
SFCA3006%
SFCA3007%
Placebo 51 44 39
FP 250 48 43
FP 500 45 46
FLTA3025%
SFCA3006%
SFCA3007%
Placebo 51 44 39
FP 250 48 43
FP 500 45 46
18Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Daily Albuterol UseDaily Albuterol UseMean Change From BaselineMean Change From Baseline
Difference from Placebo Difference from Placebo
Daily Albuterol UseDaily Albuterol UseMean Change From BaselineMean Change From Baseline
Difference from Placebo Difference from Placebo
FLTA3025puffs/day
SFCA3006puffs/day
SFCA3007puffs/day
FP 250 -0.8 -0.3
FP 500 -0.9 -0.9
FLTA3025puffs/day
SFCA3006puffs/day
SFCA3007puffs/day
FP 250 -0.8 -0.3
FP 500 -0.9 -0.9
Baseline: 4.5 to 5.7 puffs/day
19Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
CRDQCRDQChange from Baseline in Overall Score Change from Baseline in Overall Score
Difference from PlaceboDifference from Placebo
CRDQCRDQChange from Baseline in Overall Score Change from Baseline in Overall Score
Difference from PlaceboDifference from Placebo
FLTA3025 SFCA3006 SFCA3007
FP 250 4.1 5.4
FP 500 8.1 -0.2
FLTA3025 SFCA3006 SFCA3007
FP 250 4.1 5.4
FP 500 8.1 -0.2
MCIC = 10.0
Baseline: 83.6 to 88.8
20Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Subgroup AnalysisSubgroup Analysis
Non-reversible GroupNon-reversible Group
Subgroup AnalysisSubgroup Analysis
Non-reversible GroupNon-reversible Group
Non-reversible: Increase in FEV1 <12% or <0.2 L
21Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Subgroup Analysis, Non-reversible GroupSubgroup Analysis, Non-reversible Group Mean Change From Baseline in Pre-dose FEV1 Mean Change From Baseline in Pre-dose FEV1
Difference from Placebo Difference from Placebo
Subgroup Analysis, Non-reversible GroupSubgroup Analysis, Non-reversible Group Mean Change From Baseline in Pre-dose FEV1 Mean Change From Baseline in Pre-dose FEV1
Difference from Placebo Difference from Placebo
FLTA3025
(Baseline)
SFCA3006
(Baseline)
SFCA3007
(Baseline)
FP 250 0.002
(1.153)
0.055
(1.098)
FP 500 0.038
(1.175)
0.101
(1.114)
FLTA3025
(Baseline)
SFCA3006
(Baseline)
SFCA3007
(Baseline)
FP 250 0.002
(1.153)
0.055
(1.098)
FP 500 0.038
(1.175)
0.101
(1.114)
22Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Efficacy, Pivotal StudiesEfficacy, Pivotal StudiesEfficacy, Pivotal StudiesEfficacy, Pivotal Studies
• Primary efficacy endpoint– Statistically significant and replicated for FP 500– Not replicated for FP 250– Smaller effect in the non-reversible group
• Secondary endpoints and patient reported outcomes– Small differences from the placebo group
• Primary efficacy endpoint– Statistically significant and replicated for FP 500– Not replicated for FP 250– Smaller effect in the non-reversible group
• Secondary endpoints and patient reported outcomes– Small differences from the placebo group
23Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Safety Safety
Pivotal StudiesPivotal Studies
Safety Safety
Pivotal StudiesPivotal Studies
24Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Notable AEs, Pivotal StudiesNotable AEs, Pivotal StudiesNotable AEs, Pivotal StudiesNotable AEs, Pivotal Studies
PlaceboN = 576
%
FP 250N = 399
%
FP 500N = 391
%
Any AE 68.9 73.7 79.8
URI 14.8 15.8 17.9
Viralrespiratoryinfections
4.0 5.0 9.2
PlaceboN = 576
%
FP 250N = 399
%
FP 500N = 391
%
Any AE 68.9 73.7 79.8
URI 14.8 15.8 17.9
Viralrespiratoryinfections
4.0 5.0 9.2
25Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Notable AEs, Pivotal StudiesNotable AEs, Pivotal StudiesNotable AEs, Pivotal StudiesNotable AEs, Pivotal Studies
PlaceboN = 576
%
FP 250N = 399
%
FP 500N = 391
%
Candidiasis 1.0 7.3 12.8
Dysphonia 1.0 4.5 4.9
Pneumonia 1.2 1.8 2.6
PlaceboN = 576
%
FP 250N = 399
%
FP 500N = 391
%
Candidiasis 1.0 7.3 12.8
Dysphonia 1.0 4.5 4.9
Pneumonia 1.2 1.8 2.6
26Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Adrenal EffectsAdrenal EffectsAdrenal EffectsAdrenal Effects
• Serum cortisol– FLTA3025
• Cosyntropin stimulation testing– SFCA3006, SFCA3007
• Serum cortisol– FLTA3025
• Cosyntropin stimulation testing– SFCA3006, SFCA3007
27Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
FLTA3025: Serum Cortisol FLTA3025: Serum Cortisol Percent Difference from PlaceboPercent Difference from Placebo
FLTA3025: Serum Cortisol FLTA3025: Serum Cortisol Percent Difference from PlaceboPercent Difference from Placebo
Placebo FP 250 FP 500
AUC12 2673.4 2404.2 2102.3
%difference
-10.1 -21.4
Cmin 123.1 116.7 85.3
%difference
-5.2 -30.7
Placebo FP 250 FP 500
AUC12 2673.4 2404.2 2102.3
%difference
-10.1 -21.4
Cmin 123.1 116.7 85.3
%difference
-5.2 -30.7
28Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Cosyntropin Stimulation TestingCosyntropin Stimulation TestingCosyntropin Stimulation TestingCosyntropin Stimulation Testing
• SFCA3006, SFCA3007– No evidence of adrenal insufficiency– Insensitive test for less than complete adrenal
insufficiency
• SFCA3006, SFCA3007– No evidence of adrenal insufficiency– Insensitive test for less than complete adrenal
insufficiency
29Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Safety Safety
Other StudiesOther Studies
Safety Safety
Other StudiesOther Studies
30Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
FLTA1003FLTA1003FLTA1003FLTA1003
• Phase 1 PK and PD study• Single center, open label, randomized, single
dose, 4-way crossover design• 1000 mcg of FP administered with Diskus• Washout of 5 days between periods
• Phase 1 PK and PD study• Single center, open label, randomized, single
dose, 4-way crossover design• 1000 mcg of FP administered with Diskus• Washout of 5 days between periods
31Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
FLTA1003FLTA1003Mean 24 Hour Urinary Cortisol ExcretionMean 24 Hour Urinary Cortisol Excretion
FLTA1003FLTA1003Mean 24 Hour Urinary Cortisol ExcretionMean 24 Hour Urinary Cortisol Excretion
Pre-dose
Post-dose %
50 mcg X 20 18.5 9.6 -48
100 mcg X 10 22.3 13.8 -38
250 mcg X 4 19.1 12.4 -35
500 mcg X 2 18.0 7.3 -59
Pre-dose
Post-dose %
50 mcg X 20 18.5 9.6 -48
100 mcg X 10 22.3 13.8 -38
250 mcg X 4 19.1 12.4 -35
500 mcg X 2 18.0 7.3 -59
32Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
FLIT78FLIT78FLIT78FLIT78
• Multicenter, double blind, randomized, placebo controlled, parallel group study
• Flovent MDI, 500 mcg BID for 3 years• COPD• “ISOLDE”
– Burge PS, et. al. BMJ 2000;320:1297-1303
• Multicenter, double blind, randomized, placebo controlled, parallel group study
• Flovent MDI, 500 mcg BID for 3 years• COPD• “ISOLDE”
– Burge PS, et. al. BMJ 2000;320:1297-1303
33Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Notable AEs, FLIT78Notable AEs, FLIT78Notable AEs, FLIT78Notable AEs, FLIT78FP 500N = 372
%
PlaceboN = 370
%
Any AE 95.4 97.0
LRI 41.1 35.7
URI 20.2 15.9
Viralrespiratoryinfection
16.1 10.5
Pneumonia 5.9 2.2
FP 500N = 372
%
PlaceboN = 370
%
Any AE 95.4 97.0
LRI 41.1 35.7
URI 20.2 15.9
Viralrespiratoryinfection
16.1 10.5
Pneumonia 5.9 2.2
34Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Notable AEs, FLIT78Notable AEs, FLIT78Notable AEs, FLIT78Notable AEs, FLIT78
FP 500N = 372
n (%)
PlaceboN = 370
n (%)
Decreased cortisol 12 (3.2) 2 (0.5)
Diabetes mellitus 6 (1.6) 3 (0.8)
Cushing’s syndrome 1 (0.3) 0 (0)
Adrenal hypofunction 1 (0.3) 0 (0)
FP 500N = 372
n (%)
PlaceboN = 370
n (%)
Decreased cortisol 12 (3.2) 2 (0.5)
Diabetes mellitus 6 (1.6) 3 (0.8)
Cushing’s syndrome 1 (0.3) 0 (0)
Adrenal hypofunction 1 (0.3) 0 (0)
35Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
FLIT98FLIT98FLIT98FLIT98
• Multicenter, randomized, double blind, placebo controlled, parallel group study
• 1000 mcg BID of FP MDI for 4 weeks• Patients with acute COPD exacerbation• N = 249 (126 FP, 123 pbo)
• One FP-treated patient had SAE for decreased cortisol
• Multicenter, randomized, double blind, placebo controlled, parallel group study
• 1000 mcg BID of FP MDI for 4 weeks• Patients with acute COPD exacerbation• N = 249 (126 FP, 123 pbo)
• One FP-treated patient had SAE for decreased cortisol
36Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Bone Mineral DensityBone Mineral DensityBone Mineral DensityBone Mineral Density
• 2-year studies– FLTA3001– FLTA3017
• Asthma patients• Ages 18-50 years • Females were premenopausal• Study population at lower risk for osteoporosis
than the population proposed in this NDA
• 2-year studies– FLTA3001– FLTA3017
• Asthma patients• Ages 18-50 years • Females were premenopausal• Study population at lower risk for osteoporosis
than the population proposed in this NDA
37Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
Bone Mineral DensityBone Mineral DensityBone Mineral DensityBone Mineral Density
• FLTA3001– FP MDI 88 mcg BID, 440 mcg BID– N = 160– Small decrease at lumbar spine for FP 440 mcg,
but increase for FP 88 mcg and placebo– No changes for proximal femur or total body
• FLTA3017– FP Rotadisk 500 mcg BID– N = 64– Decrease at femoral neck – No changes for lumbar spine or total body
• FLTA3001– FP MDI 88 mcg BID, 440 mcg BID– N = 160– Small decrease at lumbar spine for FP 440 mcg,
but increase for FP 88 mcg and placebo– No changes for proximal femur or total body
• FLTA3017– FP Rotadisk 500 mcg BID– N = 64– Decrease at femoral neck – No changes for lumbar spine or total body
38Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002
ConclusionsConclusionsConclusionsConclusions
• Primary efficacy endpoint– Replication for FP 500 only, not for FP 250
• Small differences from placebo from secondary endpoints
• Majority of patients were reversible• Safety concerns
– Respiratory infections– Adrenal effects– Bone density
• Risk versus benefit
• Primary efficacy endpoint– Replication for FP 500 only, not for FP 250
• Small differences from placebo from secondary endpoints
• Majority of patients were reversible• Safety concerns
– Respiratory infections– Adrenal effects– Bone density
• Risk versus benefit
39Pulmonary-Allergy Drugs Advisory Committee Pulmonary-Allergy Drugs Advisory Committee January 17, 2002January 17, 2002