CENTER FOR DRUG EVALUATION AND
RESEARCH
APPLICATION NUMBER:
200327
MEDICAL REVIEW(S)
CLINICAL REVIEW
Application Type NDA
Application Number(s) 200327
Priority or Standard Standard
Submit Date(s) December 29, 2009
Received Date(s) December 30, 2009 PDUFA Goal Date October 30, 2010
Division / Office Division of Anti-Infective and
Ophthalmology Products Office of Antimicrobial Products
Reviewer Name(s) Ariel Ramirez Porcalla, MD,
MPH Neil Rellosa, MD
Review Completion October 29, 2010
Date
Established Name Ceftaroline fosamil for injection
(Proposed) Trade Name Teflaro
Therapeutic Class Cephalosporin; ß-lactams
Applicant Cerexa, Inc.
Forest Laboratories, Inc.
Formulation(s) 400 mg/vial and 600 mg/vial
Intravenous
Dosing Regimen 600 mg every 12 hours by IV infusion
Indication(s) Acute Bacterial Skin and Skin
Structure Infection (ABSSSI); Community-acquired Bacterial Pneumonia (CABP)
Intended Population(s) Adults ≥ 18 years of age
Template Version: March 6, 2009
Reference ID: 2857265
Clinical Review Ariel Ramirez Porcalla, MD, MPH Neil Rellosa, MD NDA 200327: Teflaro (ceftaroline fosamil)
Table of Contents
12
RECOMMENDATIONS/RISK BENEFIT ASSESSMENT......................................... 9
1.1 Recommendation on Regulatory Action ........................................................... 10 1.2 Risk Benefit Assessment.................................................................................. 10 1.3 Recommendations for Postmarketing Risk Evaluation and Mitigation Strategies
......................................................................................................................... 11
1.4 Recommendations for Postmarketing Requirements and Commitments ......... 12
INTRODUCTION AND REGULATORY BACKGROUND ...................................... 14
2.1 Product Information .......................................................................................... 14 2.2 Tables of Currently Available Treatments for Proposed Indications................. 15 2.3 Availability of Proposed Active Ingredient in the United States ........................ 16 2.4 Important Safety Issues With Consideration to Related Drugs......................... 16 2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 16 2.6 Other Relevant Background Information .......................................................... 19
34
ETHICS AND GOOD CLINICAL PRACTICES....................................................... 19
3.1 Submission Quality and Integrity...................................................................... 19 3.2 Compliance with Good Clinical Practices ......................................................... 20 3.3 Financial Disclosures........................................................................................ 20
SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ......................................................................................................... 21
4.1 Chemistry Manufacturing and Controls ............................................................ 21 4.2 Clinical Microbiology......................................................................................... 22 4.3 Preclinical Pharmacology/Toxicology ............................................................... 24 4.4 Clinical Pharmacology...................................................................................... 25 4.4.1 Mechanism of Action........................................................................................ 25
4.4.2 Pharmacodynamics.................................................................................... 26 4.4.3 Pharmacokinetics....................................................................................... 26
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- SOURCES OF CLINICAL DATA............................................................................ 28
5.1 TABLES OF STUDIES/CLINICAL TRIALS ........................................................... 28
5.2 Review Strategy ............................................................................................... 32 5.3 Discussion of Individual Studies/Clinical Trials................................................. 33
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- REVIEW OF EFFICACY......................................................................................... 36
Efficacy Summary for CABP...................................................................................... 36 6.1 Indication (Community-Acquired Bacterial Pneumonia) ................................... 40
6.1.1 Methods ..................................................................................................... 40 6.1.2 Demographics............................................................................................ 49 6.1.3 Patient Disposition ..................................................................................... 51
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Reference ID: 2857265
Clinical Review Ariel Ramirez Porcalla, MD, MPH Neil Rellosa, MD NDA 200327: Teflaro (ceftaroline fosamil)
6.1.4 Analysis of Primary Endpoint(s)................................................................. 53 6.1.5 Analysis of Secondary Endpoints(s) .......................................................... 54 6.1.7 Subpopulations .......................................................................................... 56 6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 57 6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 57 6.1.10 Additional Efficacy Issues/Analyses............................................................ 57
6.2.1 Methods ........................................................................................................ 65 6.2.2 Demographics............................................................................................ 71 6.2.4 Analysis of Primary Endpoints ................................................................... 80 6.2.5 Analysis of Secondary Endpoints............................................................... 81 6.2.6 Other Endpoints......................................................................................... 84 6.2.7 Subgroups.................................................................................................. 85 6.2.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 93 6.2.10 Additional Efficacy Issues/Analyses........................................................... 95
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- REVIEW OF SAFETY........................................................................................... 106
Safety Summary...................................................................................................... 106 7.1 Methods.......................................................................................................... 109 7.1.1 Studies/Clinical Trials Used to Evaluate Safety.............................................. 109
7.1.2 Categorization of Adverse Events............................................................ 110 7.1.3 Pooling of Data across Studies/Clinical Trials to Estimate and Compare
Incidence.................................................................................................. 113
7.2 Adequacy of Safety Assessments.................................................................. 114 7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target
Populations..................................................................................................... 114
7.2.3 Special Animal and/or In Vitro Testing ..................................................... 124 7.2.4 Routine Clinical Testing ........................................................................... 127 7.2.5 Metabolic, Clearance, and Interaction Workup ........................................ 127 7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class 128
7.3 Major Safety Results ...................................................................................... 128
Overall Incidence ................................................................................................. 128
7.3.1 Deaths............................................................................................................ 131 7.3.2 Nonfatal Serious Adverse Events................................................................... 171
Dropouts and/or Discontinuations ........................................................................ 181 7.3.4 Significant Adverse Events ...................................................................... 184 7.3.5 Submission Specific Safety Concerns...................................................... 189
7.4 Supportive Safety Results .............................................................................. 189
7.4.1 Common Adverse Events ........................................................................ 189 7.4.2 Laboratory Findings ................................................................................. 193 7.4.3 Vital Signs................................................................................................ 195 7.4.4 Electrocardiograms (ECGs) ..................................................................... 196 7.4.5 Special Safety Studies/Clinical Trials....................................................... 198
7.5 Other Safety Explorations............................................................................... 210
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Reference ID: 2857265
Clinical Review Ariel Ramirez Porcalla, MD, MPH Neil Rellosa, MD NDA 200327: Teflaro (ceftaroline fosamil)
7.5.1 Dose Dependency for Adverse Events .................................................... 210 7.5.2 Time Dependency for Adverse Events..................................................... 211 7.5.3 Drug-Demographic Interactions ............................................................... 211 7.5.4 Drug-Disease Interactions........................................................................ 214 7.5.5 Drug-Drug Interactions............................................................................. 215
7.6 Additional Safety Evaluations......................................................................... 216
7.6.1 Human Carcinogenicity............................................................................ 216 7.6.2 Human Reproduction and Pregnancy Data.............................................. 217 7.6.3 Pediatrics and Assessment of Effects on Growth .................................... 217 7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound.................... 218
7.7 Additional Submissions / Safety Issues.......................................................... 219
89
POSTMARKETING EXPERIENCE ...................................................................... 219 APPENDICES ...................................................................................................... 220
9.1 Labeling Recommendations........................................................................... 240 9.2 Advisory Committee Meeting.......................................................................... 253 9.3 Literature Review/References ........................................................................ 256
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Reference ID: 2857265
Clinical Review Ariel Ramirez Porcalla, MD, MPH Neil Rellosa, MD NDA 200327: Teflaro (ceftaroline fosamil)
Table of Tables
Table 1. Ceftaroline exposure in rats and monkeys after repeated IV administration ... 24 Table 2.Pharmacokinetic Properties of Ceftaroline ....................................................... 26 Table 3. Table Summary of Phase 1, 2, and 3 Clinical Studies..................................... 28 Table 4. Prior Antibacterials Allowed (Patients should have been given only one dose within 96 hours of randomization). ................................................................. 42
Table 5. Definitions of the Applicant's Analysis Populations ......................................... 44 Table 6. Definitions of Clinical Outcomes...................................................................... 46 Table 7. Baseline Characteristics of the Applicant's MITTE Population ........................ 49 Table 8. Relevant Medical History and Baseline Clinical Presentation of MITTE
Population...................................................................................................... 50
Table 9. Pre-Specified Analysis Populations of the Applicant ....................................... 51 Table 10. Premature Discontinuation of Study Drug in Phase 3 CABP Trials in the
MITTE Population .......................................................................................... 52
Table 11. Withdrawal from the Phase 3 CABP Trials in the MITTE Population............. 52 Table 12. Baseline Pathogens in the Applicant's mMITT Population ............................ 53 Table 13. Clinical Cure Rates for MITTE and CE Populations at TOC Visit.................. 54 Table 14. Clinical Cure Rates for MITTE and CE Populations at EOT Visit .................. 54 Table 15. Clinical Cure Rates at TOC and EOT in the mMITT Population.................... 54 Table 16. Clinical Cure Rates at TOC by Pathogen in the Applicant's mMITT Population
....................................................................................................................... 55
Table 17. Clinical Cure Rates in MITTE Population at TOC by Prior Antibacterial Use. 55 Table 18. 30 Day All-Cause Mortality for the MITTE Population ................................... 56 Table 19. Clinical Cure Rates in Subpopulations of the MITTE Population of Pooled
Phase 3 Trials................................................................................................ 56
Table 20. Demographics of the FDA-mITT Population.................................................. 61 Table 21. Clinical Response Rates on Signs and Symptoms Endpoint on Day 4 ......... 62 Table 22. Investigator-Assessed Clinical Response Rates in the FDA-mITT Population
....................................................................................................................... 62
Table 23. Response Rates Using Early FDA Endpoint by Pathogen ............................ 63 Table 24. Response Rates Using Early FDA Endpoint by Prior Antibacterial Use........ 63 Table 25. Clinical Response Rates for FDA-mITT Population when Endpoint is Modified
....................................................................................................................... 64
Table 26. Clinical Response Rates when Timing of Assessment is Modified................ 64 Table 27. Clinical Response Rate Using Day 4 Endpoint when Population is Modified 65 Table 28. Demographic and Baseline Characteristics of Applicant MITT Population.... 71 Table 29. Enrollment by Region Groups, MITT Population ........................................... 72 Table 30. Comorbidities and Disease Severity at Baseline, Trials P903-06 and P903-07,
MITT Population............................................................................................. 73
Table 31. Types of Infection at Baseline, Trials P903-06 and P903-07, MITT Population
....................................................................................................................... 74
Table 32. Primary Infection Site Measurement at Baseline, MITT Population............... 75 Table 33. Subject Populations Table............................................................................. 76
