Clinical Review Sheral S. Patel, M.D. NDA 200327 SD478 S-16 and S-17 Ceftaroline fosamil (Teflaro®) CLINICAL REVIEW Application Type Pediatric Efficacy Supplements Application Number(s) NDA 200327 SD478 S-16 and S-17 Priority or Standard Priority Submit Date 7 December 2015 Received Date 7 December 2015 PDUFA Goal Date 7 June 2016 Division/Office Division of Anti-Infective Products/ OAP/ OND/ CDER Reviewer Name Sheral S. Patel, M.D. Team Leader Hala Shamsuddin, M.D. Review Completion Date 13 May 2016 Established Name Ceftaroline fosamil (Proposed) Trade Name Teflaro® Applicant Cerexa, Inc. (A Subsidiary of Forest Laboratories, LLC.) Formulation(s) Powder for Injection Dosing Regimen 1. Children aged 2 months to < 2 years: 8 mg/kg every 8 hours IV administered over 5 to 60 minutes 2. Children and adolescents aged 2 years to ≤ 18 years: 12 mg/kg (up to a maximum of 400 mg for pediatric patients weighing > 33 kg) q8h by IV infusion administered over 5 to 60 minutes Applicant Proposed For the pediatric population 2 months to < 18 years Indication(s)/Population(s) 1. Acute bacterial skin and skin structure infections 2. Community acquired bacterial pneumonia Recommendation on Approval Regulatory Action Recommended For the pediatric population 2 months to < 18 years Indication(s)/Population(s) 1. Acute bacterial skin and skin structure infections (if applicable) 2. Community acquired bacterial pneumonia CDER Clinical Review Template 2015 Edition 1 Reference ID: 3933750 Clinical Review Sheral S. Patel, M.D. NDA 200327 SD478 S-16 and S-17 Ceftaroline fosamil (Teflaro®) Table of Contents Glossary ......................................................................................................................................... 10 1 Executive Summary ............................................................................................................... 12 1.1. Product Introduction ...................................................................................................... 12 1.2. Conclusions on the Substantial Evidence of Effectiveness ............................................ 13 1.3. Benefit-Risk Assessment ................................................................................................ 13 2 Therapeutic Context .............................................................................................................. 18 2.1. Analysis of Condition ...................................................................................................... 18 2.2. Analysis of Current Treatment Options ......................................................................... 19 3 Regulatory Background ......................................................................................................... 20 3.1. U.S. Regulatory Actions and Marketing History ............................................................. 20 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................ 21 3.3. Foreign Regulatory Actions and Marketing History ....................................................... 23 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 23 4.1. Office of Scientific Investigations (OSI) .......................................................................... 23 4.2. Product Quality .............................................................................................................. 23 4.3. Clinical Microbiology ...................................................................................................... 24 4.4. Nonclinical Pharmacology/Toxicology ........................................................................... 24 4.5. Clinical Pharmacology .................................................................................................... 25 4.5.1. Mechanism of Action .............................................................................................. 25 4.5.2. Pharmacodynamics ................................................................................................. 25 4.5.3. Pharmacokinetics .................................................................................................... 26 5 Sources of Clinical Data and Review Strategy ....................................................................... 27 5.1. Table of Clinical Studies .................................................................................................. 27 5.2. Review Strategy .............................................................................................................. 35 6 Review of Relevant Individual Trials Used to Support Efficacy ............................................. 35 6.1. Study P903-23: A Multicenter, Randomized, Observer-Blinded, Active-Controlled Study to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetics of Ceftaroline CDER Clinical Review Template 2015 Edition 2 Reference ID: 3933750 Clinical Review Sheral S. Patel, M.D. NDA 200327 SD478 S-16 and S-17 Ceftaroline fosamil (Teflaro®) Versus Comparator in Pediatric Subjects With Acute Bacterial Skin and Skin Structure Infections (D3720C00004) ........................................................................................................ 35 6.1.1. Study Design............................................................................................................ 35 6.1.2. Study Results ........................................................................................................... 40 6.2. Study P903-31: A Multicenter, Randomized, Observer Blinded, Active-Controlled Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Ceftaroline Versus Ceftriaxone in Pediatric Subjects With Community-acquired Bacterial Pneumonia Requiring Hospitalization (DC3720C00007) .............................................................................................. 44 6.2.1. Study Design............................................................................................................ 44 6.2.2. Study Results ........................................................................................................... 49 6.3. Study P903-24: A Multicenter, Randomized, Observer-Blinded, Active-Controlled Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Ceftaroline Versus Ceftriaxone Plus Vancomycin in Pediatric Subjects with Complicated Community-acquired Bacterial Pneumonia ................................................................................................................. 49 6.3.1. Study Design............................................................................................................ 49 6.3.2. Study Results ........................................................................................................... 53 7 Integrated Review of Effectiveness ....................................................................................... 58 7.1. Assessment of Efficacy Across Trials .............................................................................. 58 7.1.1. Primary Endpoints ................................................................................................... 58 7.1.2. Secondary and Other Endpoints ............................................................................. 59 7.1.3. Subpopulations ....................................................................................................... 59 7.1.4. Dose and Dose-Response........................................................................................ 59 7.1.5. Onset, Duration, and Durability of Efficacy Effects ................................................ 59 7.2. Additional Efficacy Considerations ................................................................................. 59 7.3. Integrated Assessment of Effectiveness ........................................................................ 60 8 Review of Safety .................................................................................................................... 63 8.1. Safety Review Approach ................................................................................................ 63 8.2. Review of the Safety Database ...................................................................................... 64 8.2.1. Overall Exposure ..................................................................................................... 64 8.2.2. Baseline demographic and other characteristics ................................................... 66 8.2.3. Adequacy of the safety database: .......................................................................... 71 8.3. Adequacy of Applicant’s Clinical Safety Assessments .................................................... 71 CDER Clinical Review Template 2015 Edition 3 Reference ID: 3933750 Clinical Review Sheral S. Patel, M.D. NDA 200327 SD478 S-16 and S-17 Ceftaroline fosamil (Teflaro®) 8.3.1. Issues Regarding Data Integrity and Submission Quality ....................................... 71 8.3.2. Categorization of Adverse Events ........................................................................... 71 8.3.3. Routine Clinical Tests .............................................................................................. 72 8.3.4. Deaths ....................................................................................................................