Pulmonary-Allergy Drugs Advisory Committee January 17, 2002 1 FLOVENT ® DISKUS ® NDA 20-833, S004...

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


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).”


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.”


IntroductionIntroductionIntroductionIntroduction

• Efficacy– Pivotal studies

• Safety– Pivotal studies– Supportive studies

• Efficacy– Pivotal studies

• Safety– Pivotal studies– Supportive studies


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


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


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


N = 723

FLTA3025 FP 250 BIDFP 500 BIDPlacebo BID

N = 640


N = 674


N = 723


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


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)


DemographicsDemographics

Pivotal StudiesPivotal Studies

DemographicsDemographics



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


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


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


EfficacyEfficacy


EfficacyEfficacy



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


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


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


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


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


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


CRDQCRDQChange from Baseline in Overall Score Change from Baseline in Overall Score


CRDQCRDQChange from Baseline in Overall Score Change from Baseline in Overall Score


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


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


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


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


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)


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


Safety Safety


Safety Safety



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


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


Adrenal EffectsAdrenal EffectsAdrenal EffectsAdrenal Effects

• Serum cortisol– FLTA3025

• Cosyntropin stimulation testing– SFCA3006, SFCA3007

• Serum cortisol– FLTA3025

• Cosyntropin stimulation testing– SFCA3006, SFCA3007


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


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


Safety Safety

Other StudiesOther Studies

Safety Safety

Other StudiesOther Studies


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


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


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


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


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)


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


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


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


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

Pulmonary-Allergy Drugs Advisory Committee January 17, 2002 1 FLOVENT ® DISKUS ® NDA 20-833, S004...

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Transcript of Pulmonary-Allergy Drugs Advisory Committee January 17, 2002 1 FLOVENT ® DISKUS ® NDA 20-833, S004...