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209445Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209445Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review Clinical Microbiology/Virology Multi-Disciplinary Review and Evaluation NDA 209445 FETROJA (cefiderocol) for Injection NDA Multi-Disciplinary Review and Evaluation Application Type 505(b)(1) NDA Type 1 NME Application Number(s) NDA 209445 Priority or Standard Priority Submit Date(s) December 14, 2018 Received Date(s) December 14, 2018 PDUFA Goal Date November 14, 2019 Division/Office Division of Anti-Infectives/Office of Infectious Diseases Review Completion Date See DARRTS electronic signature page Established/Proper Name Cefiderocol (Proposed) Trade Name FETROJA Pharmacologic Class Cephalosporin Code Names S-649266; RSC-649266; GSK2696266 Applicant Shionogi USA, Inc. Dosage Form Lyophilized powder for Injection, 1 gram per vial Dosing Regimen Cefiderocol 2 gm intravenous infusion every 8 hours for 7-14 days Applicant Proposed Treatment of complicated urinary tract infections (cUTI), including Indication/Population pyelonephritis, due to Gram-negative bacteria in patients with limited or no alternative treatment options Regulatory Action Approval Recommended Treatment of cUTI, including pyelonephritis, due to susceptible Indication(s)/Population(s) Gram-negative bacteria in patients 18 years of age or older with limited or no alternative treatment options 1 Reference ID: 4520111 Multi-Disciplinary Review and Evaluation NDA 209445 FETROJA (cefiderocol) for Injection Table of Contents Table of Tables .................................................................................................................... 7 Table of Figures ................................................................................................................. 14 Reviewers of Multi-Disciplinary Review and Evaluation .................................................. 16 Glossary ............................................................................................................................. 22 1. Executive Summary ....................................................................................................... 25 1.1. Product Introduction .............................................................................................. 25 1.2. Conclusions on the Substantial Evidence of Effectiveness .................................... 25 1.3. Benefit-Risk Assessment ........................................................................................ 28 1.4. Patient Experience Data ......................................................................................... 35 2. Therapeutic Context ..................................................................................................... 36 2.1. Analysis of Condition .............................................................................................. 36 2.2. Analysis of Current Treatment Options ................................................................. 37 3. Regulatory Background ................................................................................................. 39 3.1. U.S. Regulatory Actions and Marketing History ..................................................... 39 3.2. Summary of Presubmission/Submission Regulatory Activity ................................ 39 3.3. Foreign Regulatory Actions and Marketing History ............................................... 44 4. Significant Issues From Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ............................................................................. 45 4.1. Office of Scientific Investigations (OSI) .................................................................. 45 4.2. Product Quality ....................................................................................................... 45 4.3. Devices and Companion Diagnostic Issues ............................................................ 45 5. Nonclinical Pharmacology/Toxicology .......................................................................... 45 5.1. Executive Summary ................................................................................................ 45 5.2. Referenced INDs, NDAs, BLAs, DMFs ..................................................................... 47 5.3. Pharmacology ......................................................................................................... 47 5.4. ADME/PK ................................................................................................................ 49 5.5. Toxicology ............................................................................................................... 54 5.5.1. General Toxicology .......................................................................................... 54 5.5.2. Genetic Toxicology ........................................................................................... 59 5.5.3. Carcinogenicity ................................................................................................ 62 5.5.4. Reproductive and Developmental Toxicity ..................................................... 62 5.5.5. Other Toxicology Studies ................................................................................. 68 6. Clinical Pharmacology ................................................................................................... 68 6.1. Executive Summary ................................................................................................ 68 6.2. Summary of Clinical Pharmacology Assessment .................................................... 70 2 Reference ID: 4520111 Multi-Disciplinary Review and Evaluation NDA 209445 FETROJA (cefiderocol) for Injection 6.2.1. Pharmacology and Clinical Pharmacokinetics ................................................. 70 6.2.2. General Dosing and Therapeutic Individualization ......................................... 70 6.3. Comprehensive Clinical Pharmacology Review ..................................................... 71 6.3.1. General Pharmacology and Pharmacokinetic Characteristics ......................... 71 6.3.2. Clinical Pharmacology Questions .................................................................... 73 7. Statistical and Clinical Evaluation ................................................................................. 84 7.1. Sources of Clinical Data and Review Strategy ........................................................ 84 7.2. Review of Study 1409R2121(Trial in cUTI) ............................................................. 89 7.3. Efficacy Summary and Conclusions ........................................................................ 99 8. Clinical Microbiology Review ...................................................................................... 100 8.1. Nonclinical Microbiology ...................................................................................... 100 8.1.1. Mechanism of Action ..................................................................................... 100 8.1.2. Activity In Vitro .............................................................................................. 100 8.1.3. Activity In Vitro (Animal Studies) ................................................................... 107 8.1.4. Resistance ...................................................................................................... 111 8.1.5. Pharmacokinetics/Pharmacodynamics ......................................................... 112 8.2. Clinical Microbiology ............................................................................................ 112 8.2.1. Assay Description and Methodologies .......................................................... 112 8.2.2. Clinical Microbiology Analysis of Efficacy ...................................................... 113 8.2.3. Interpretive Criteria ....................................................................................... 121 8.2.4. Final Clinical Microbiology Recommendations ............................................. 122 9. Review of Safety .......................................................................................................... 123 9.1. Safety Review Approach ....................................................................................... 123 9.2. Review of the Safety Database ............................................................................ 123 9.2.1. Overall Exposure to Cefiderocol .................................................................... 123 9.2.2. Relevant Characteristics of the Safety Population ........................................ 124 9.2.3. Adequacy of the Safety Database .................................................................. 126 9.3. Adequacy of Applicant’s Clinical Safety Assessments .......................................... 126 9.3.1. Issues Regarding Data Integrity and Submission Quality .............................. 126 9.3.2. Categorization of Adverse Events .................................................................. 126 9.3.3. Routine Clinical Tests ..................................................................................... 126 9.4. Safety Results – Phase 1 Studies and cUTI Trial (1409R2121) ............................. 127 9.4.1. Overview of Adverse Events in the Safety Population .................................. 127 9.4.2. Deaths
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