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Clinical Review Melisse Baylor, MD NDA 210854 Baloxavir Marboxil Clinical Review Melisse Baylor, M.D. NDA 210854 Baloxavir marboxil (Xofluza™) CLINICAL REVIEW Application Type New Drug Application Application Number(s) 210854 Priority or Standard Priority Submit Date(s) April 24, 2018 Received Date(s) April 24, 2018 PDUFA Goal Date October 24, 2018 Division/Office Division of Antiviral Products / Office of Antimicrobial Products Reviewer Name(s) Melisse Baylor, M.D. Review Completion Date September 30, 2018 Established/Proper Name Baloxavir marboxil (Proposed) Trade Name Xofluza™ Applicant Shionogi, Incorporated Dosage Form(s) 20 mg and 40 mg tablets Applicant Proposed Dosing Single oral dose based on body weight Regimen(s) Patient body weight of 40 kg to < 80 kg: 40 mg Patient body weight ≥ 80 kg: 80 mg Applicant Proposed Treatment of acute uncomplicated influenza in patients 12 years Indication(s)/Population(s) of age and older who have been symptomatic for no more than 48 hours Recommendation on Approval Regulatory Action Recommended Treatment of acute uncomplicated influenza in patients 12 years Indication(s)/Population(s) of age and older who have been symptomatic for no more than (if applicable) 48 hours CDER Clinical Review Template 1 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4335994 Clinical Review Melisse Baylor, M.D. NDA 210854 Baloxavir marboxil (Xofluza™) Table of Contents Glossary ..........................................................................................................................................7 1. Executive Summary.................................................................................................................9 1.1. Product Introduction........................................................................................................9 1.2. Conclusions on the Substantial Evidence of Effectiveness...............................................9 1.3. Benefit-Risk Assessment ..................................................................................................9 1.4. Patient Experience Data.................................................................................................11 2. Therapeutic Context..............................................................................................................11 2.1. Analysis of Condition......................................................................................................12 2.2. Analysis of Current Treatment Options .........................................................................12 3. Regulatory Background .........................................................................................................12 3.1. U.S. Regulatory Actions and Marketing History.............................................................12 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................12 3.3. Foreign Regulatory Actions and Marketing History .......................................................12 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................12 4.1. Office of Scientific Investigations (OSI) ..........................................................................12 4.2. Product Quality ..............................................................................................................13 4.3. Clinical Microbiology......................................................................................................13 4.4. Nonclinical Pharmacology/Toxicology ...........................................................................13 4.5. Clinical Pharmacology ....................................................................................................13 4.6. Devices and Companion Diagnostic Issues ....................................................................13 4.7. Consumer Study Reviews...............................................................................................13 5. Sources of Clinical Data and Review Strategy .......................................................................13 5.1. Table of Clinical Studies .................................................................................................13 5.2. Review Strategy .............................................................................................................15 6. Review of Relevant Individual Trials Used to Support Efficacy .............................................15 6.1. Trial 1518T0821 .............................................................................................................15 6.1.1. Study Design ...........................................................................................................15 CDER Clinical Review Template 2 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4335994 Clinical Review Melisse Baylor, M.D. NDA 210854 Baloxavir marboxil (Xofluza™) 6.1.2. Study Results ..........................................................................................................15 6.2 Trial 1601T0831 6.2.1 Study Design 6.2.2 Study Results 7. Integrated Review of Effectiveness.......................................................................................18 7.1. Assessment of Efficacy Across Trials..............................................................................18 7.1.1. Primary Endpoints ..................................................................................................19 7.1.2. Secondary and Other Endpoints.............................................................................19 7.1.3. Subpopulations.......................................................................................................19 7.1.4. Dose and Dose-Response .......................................................................................19 7.1.5. Onset, Duration, and Durability of Efficacy Effects.................................................19 7.2. Additional Efficacy Considerations.................................................................................19 7.2.1. Considerations on Benefit in the Postmarket Setting.............................................19 7.2.2. Other Relevant Benefits..........................................................................................19 7.3. Integrated Assessment of Effectiveness ........................................................................19 8. Review of Safety....................................................................................................................19 8.1. Safety Review Approach ................................................................................................19 8.2. Review of the Safety Database ......................................................................................19 8.2.1. Overall Exposure.....................................................................................................20 8.2.2. Relevant characteristics of the safety population: .................................................20 8.2.3. Adequacy of the safety database: ..........................................................................20 8.3. Adequacy of Applicant’s Clinical Safety Assessments....................................................21 8.3.1. Issues Regarding Data Integrity and Submission Quality........................................21 8.3.2. Categorization of Adverse Events...........................................................................21 8.3.3. Routine Clinical Tests..............................................................................................21 8.4. Safety Results.................................................................................................................21 8.4.1. Deaths.....................................................................................................................21 8.4.2. Serious Adverse Events...........................................................................................21 8.4.3. Dropouts and/or Discontinuations Due to Adverse Effects....................................21 8.4.4. Significant Adverse Events......................................................................................21 8.4.5. Treatment Emergent Adverse Events and Adverse Reactions ...............................21 CDER Clinical Review Template 3 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4335994 Clinical Review Melisse Baylor, M.D. NDA 210854 Baloxavir marboxil (Xofluza™) 8.4.6. Laboratory Findings ................................................................................................21 8.4.7. Vital Signs................................................................................................................21 8.4.8. Electrocardiograms (ECGs) .....................................................................................22 8.4.9. QT ...........................................................................................................................22 8.4.10. Immunogenicity...............................................................................................22 8.5. Analysis of Submission-Specific Safety Issues ................................................................22 8.5.1. [Name Safety Issue] ................................................................................................22 8.6. Safety Analyses by Demographic Subgroups .................................................................22
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