Reviewer: Sofia Chaudhry, MD Team Leader: Susan Limb, MD
Department of Health & Human Services Food & Drug Administration Center for Drug Evaluation & Research
Division of Pulmonary, Allergy and Rheumatology Products Silver Spring, MD 20993
Table of Contents
1 EXECUTIVE SUMMARY ... 8 2 INTRODUCTION AND REGULATORY BACKGROUND ... 9 2.1 Product Information ... 9 2.2 Tables of Currently Available Treatments for Proposed Indications ... 9 2.3 Availability of Proposed Active Ingredient in the United States ... 10 2.4 Important Safety Issues With Consideration to Related Drugs... 10 2.5 Other Relevant Background Information ... 11 3 OVERVIEW OF THE CLINICAL PROGRAM ... 12 4 DOSE SELECTION ... 16 4.1 Overview of Dose-Ranging and Dose-Regimen Selection ... 17 4.2 VI Dose and Dosing Regimen Selection... 17 4.3 FF Dose and Dose-Regimen Selection ... 22 5 PIVOTAL PHASE 3 TRIAL DESIGN... 25 5.1 24-weeek Lung Function Trials: 2206 and 2207... 25 5.2 52-week Exacerbation trials: 2871 and 2970... 33 6 REVIEW OF EFFICACY... 41 Efficacy Summary... 41 6.1 Indication: Airflow Obstruction ... 42 6.1.1 Methods ... 42 6.1.2 Demographics... 43 6.1.3 Patient Disposition ... 45 6.1.4 Analysis of Co-Primary Endpoint(s): weighted mean FEV1 (0-4h) and
trough FEV1... 46 6.1.5 Analysis of Secondary Endpoints(s) ... 50 6.1.6 Other Endpoints ... 52 6.1.7 Subpopulations ... 59 6.1.8 Discussion of Persistence of Efficacy and/or Tolerance Effects... 60 6.1.9 Additional Efficacy Issues/Analyses ... 60 6.2 Reduction in COPD exacerbations... 64 6.2.1 Methods ... 64 6.2.2 Demographics... 64 6.2.3 Patient Disposition ... 66 6.2.4 Analysis of Primary Endpoint(s) ... 67 6.2.5 Analysis of Secondary Endpoints(s) ... 68 6.2.6 Other Endpoints ... 70 6.2.7 Subpopulations ... 73 6.2.8 Discussion of Persistence of Efficacy and/or Tolerance Effects... 73 7 REVIEW OF SAFETY... 73 Safety Summary ... 74 7.1 Methods... 74
7.1.1 Studies/Clinical Trials Used to Evaluate Safety ... 74 7.1.2 Categorization of Adverse Events... 75 7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
Incidence... 76 7.2 Adequacy of Safety Assessments ... 76
7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations ... 76 7.2.2 Explorations for Dose Response... 78 7.2.3 Routine Clinical Testing ... 78 7.2.4 Metabolic, Clearance, and Interaction Workup ... 78 7.2.5 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 79 7.3 Major Safety Results ... 79 7.3.1 Deaths... 79 7.3.2 Nonfatal Serious Adverse Events ... 81 7.3.3 Dropouts and/or Discontinuations ... 83 7.3.4 Submission Specific Primary Safety Concerns ... 84 7.4 Supportive Safety Results ... 93 7.4.1 Common Adverse Events ... 94 7.4.2 Laboratory Findings ... 95 7.4.3 Vital Signs ... 98 7.4.4 Electrocardiograms (ECGs) ... 99 7.4.5 Special Safety Studies/Clinical Trials ... 100 7.5 Other Safety Explorations... 102 7.5.1 Dose Dependency for Adverse Events ... 102 7.5.2 Time Dependency for Adverse Events... 102 7.5.3 Drug-Demographic Interactions ... 102 7.5.4 Drug-Disease Interactions... 103 7.5.5 Drug-Drug Interactions... 103 7.6 Additional Safety Evaluations ... 103 7.6.1 Human Reproduction and Pregnancy Data... 103 7.6.2 Overdose, Drug Abuse Potential, Withdrawal and Rebound... 104 7.7 Additional Submissions / Safety Issues ... 104 8 POSTMARKET EXPERIENCE... 105
Table of Tables
Table 1: Approved Treatment of Airflow Obstruction in COPD... 9 Table 2: Approved Treatments for Exacerbation Reduction in COPD... 10 Table 3: Milestone Interactions between the Agency and the Applicant... 11 Table 4: FF and VI Dose Selection Trials... 12 Table 5: Pivotal Phase 3 Trials... 14 Table 6: COPD Safety Database ... 15 Table 7: VI Dose-Ranging in COPD: 1045 ... 18 Table 8: VI Dose-Ranging in Asthma: 9575 ... 19 Table 9: VI Dose Regimen in Asthma: 3310 ... 21 Table 10: FF Dose-ranging in Asthma: 9685 and 9687... 22 Table 11: FF Dose Regimen in Asthma: 1202 ... 23 Table 12: FF/VI Dose-ranging in COPD: 0946 ... 24 Table 13: Time and Events Table: 2206... 26 Table 14: Time and Events Table: 2871... 36 Table 15: Demographic and Baseline Characteristics: 2206... 43 Table 16: Demographic and Baseline Characteristics: 2207... 44 Table 17: Patient Disposition: 2206... 45 Table 18: Patient Disposition: 2207... 46 Table 19: Change from Baseline in Trough FEV1: 2206, 2207, 2871 and 2970 ... 47 Table 20: Change from Baseline in Weighted Mean FEV1 (L): 2206 and 2207 ... 48 Table 21: Time to Peak FEV1: 2206 and 2207 ... 51 Table 22: Time to Onset: 2206 and 2207 ... 51 Table 23: Symptom Scores over Weeks 1-24: 2206 and 2207 ... 53 Table 24: Occasions of Rescue Medication Use per 24 hours over Week 1-24: 2206 and 2207 ... 54 Table 25: Percentage of Awakenings Requiring Rescue Medication over Week 1-24:
2206 and 2207 ... 54 Table 26: Mean AM Peak Expiratory Flow over Week 1-24: 2206 and 2207 ... 55 Table 27: Day 168 Change from Baseline in FVC (ml): 2206 and 2207... 56 Table 28: CRQ Dyspnea Domain: 2206 and 2207 ... 57 Table 29: Symptom Free Periods: 2206 and 2207... 57 Table 30: Rescue Free 24 hour Periods: 2206 and 2207... 58 Table 31: Trough FEV1 by GOLD Stage: 2206 and 2207 ... 60 Table 32: Efficacy data from COPD Advair Comparator Trials... 61 Table 33: Demographic and Baseline Characteristics: 2871... 64 Table 34: Demographic and Baseline Characteristics: 2970... 65 Table 35: Patient Disposition: 2871... 66 Table 36: Patient Disposition: 2970... 67 Table 37: Annual Rate of Moderate and Severe Exacerbations: 2871 and 2970... 68 Table 38: Annual Rate of Exacerbations Requiring Systemic/oral Corticsteroids: 2871 and 2970 ... 70 Table 39: Annual Rate of All Exacerbations: 2871 and 2970 ... 71 Table 40: Time to Each Moderate and Severe On-treatment Exacerbation: 2871 and 2970 ... 71
Table 41: Diary Score: 2871 and 2970... 72 Table 42: Extent of Exposure in 24-week Lung Function Trials: 2206 and 2207... 77 Table 43: Extent of Exposure in 52-week exacerbation Trials: 2871 and 2970... 77 Table 44: On- and Post-Treatment Deaths in 24-week Lung Function Trials and 52-week Exacerbation Trials: 2206, 2207, 2871, and 2970... 80 Table 45: Serious Adverse Events in 24 week Lung Function Trials: 2206 and 2207... 82 Table 46: Serious Adverse Events in 52-week Exacerbation Trials: 2871 and 2970 .... 83 Table 47: Pneumonia in 52-week Exacerbation trials1: 2871 and 2970 ... 86 Table 48: Pneumonia Data From Previous FP/S Trials... 87 Table 49: On-treatment Bone Disorders and Fractures in 52-week Exacerbation Trials:
2871 and 2970 ... 88 Table 50: Bone Disorder Data from TORCH Trial ... 89 Table 51: ICS-related AEs1 in 24-week Lung Function Trials: 2206 and 2207... 90 Table 52: ICS-related AEs1 in 52-week Exacerbation Trials: 2871 and 2970... 90 Table 53: Cardiac data in 24-week Lung Function Trials: 2206 and 2207... 91 Table 54: On-treatment Cardiac Data in 52-week exacerbation trials: 2871 and 2970 . 91 Table 55: LABA related Adverse Events in COPD VI Dose-Ranging Trial: 1045 ... 92 Table 56: Potassium Effects in 24-week Lung Function Trials: 2206 and 2207 ... 93 Table 57: Glucose Effects in 24-week Lung Function Trials: 2206 and 2207... 93 Table 58: Most Common Adverse Events (≥ 3%) in 24-week Lung Function Trials 2206 and 2207 ... 94 Table 59: Most common Adverse Events (≥3%) in 52 week Exacerbation Trials: 2871 and 2970 ... 94 Table 60: Shift Table of Hematology Parameters1 in 24-week Lung Function Trials: 2206 and 2207 ... 95 Table 61: Shift table of Chemistry Parameters1 in 24-week Lung Function Trials: 2206 and 2207 ... 96 Table 62: Vital Sign Data in 24-week Lung Function Trials: 2206 and 2207 ... 98 Table 63: ECG and 24 hour Holter Data: 2206 and 2207... 100 Table 64: Asthma Composite Endpoint: Pooled Asthma Safety Database ... 101 Table 65: Studies from 120-day safety update... 104
Table of Figures
Figure 1: Day 28 Treatment Differences from Placebo in Change from Baseline FEV1:
1045 ... 18 Figure 2: Day 28 Treatment Differences from Placebo in Change from Baseline FEV1:
9575 ... 20 Figure 3: Day 7 Mean Change from Baseline in FEV1: 3310... 21 Figure 4: Day 28-29 LS mean change from baseline in serial FEV1: 0946 ... 24 Figure 5: LS Mean Change from Baseline in Trough FEV1: 2207 ... 49 Figure 6: LS Mean Change from Baseline in Weighted Mean FEV1: 2207... 50 Figure 7: LS Mean Change from Baseline in Trough FEV1: 2970 ... 50 Figure 8: LS Mean Change from baseline in FEV1 on Day 84: 3109... 62 Figure 9: LS Mean Change from baseline in FEV1 on Day 84: 2352... 63 Figure 10: Day 168 LS Mean Change from Baseline in FEV1 over Time: 3091... 63 Figure 11: Kaplan-Meier Plot: Time to First Moderate or Severe Exacerbation: 2871 .. 69 Figure 12: Kaplan-Meier Plot: Time to First Moderate or Severe Exacerbation: 2970 .. 69 Figure 13: Kaplan Meier Plot: Time to First On Treatment Pneumonia for 52-week
Exacerbation Trials: 2871 and 2970... 86
List of Commonly Used Abbreviations
AE Adverse Event
BID Twice daily
CMC Chemistry, manufacturing and controls COPD Chronic Obstructive Pulmonary Disease DPI Dry Powder Inhaler
ECG electrocardiogram
FEV1 Forced expiratory volume in 1 second
FF Fluticasone furoate
FP Fluticasone Propionate
HPA Hypothalamic pituitary axis
ICS Inhaled corticosteroid
LABA Long acting beta agonist MDI Metered dose inhaler Mcg Microgram NDA New drug application OTC Over the counter
PD Pharmacodynamic PK Pharmacokinetic
PRN As needed
QD Once daily
SABA Short acting beta-agonist SAE Serious Adverse Event Salm Salmeterol VI Vilanterol
WM Weighted mean