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Clinical Review Hyon Kwon, Pharmd, MPH Snda 208751/S-010 and S-011 Fiasp (Insulin Aspart)

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Clinical Review Hyon Kwon, Pharmd, MPH Snda 208751/S-010 and S-011 Fiasp (Insulin Aspart) Clinical Review Hyon Kwon, PharmD, MPH sNDA 208751/S-010 and S-011 Fiasp (insulin aspart) CLINICAL REVIEW Application Type Efficacy supplement Application Number(s) sNDA 208751/S-10 and S-11 Priority or Standard Standard Submit Date(s) February 21, 2019 Received Date(s) February 21, 2019 PDUFA Goal Date December 21, 2019 Division/Office Division of Metabolism and Endocrinology Products (DMEP) Reviewer Name(s) Hyon Kwon, PharmD, MPH Review Completion Date Established/Proper Name Insulin aspart (Proposed) Trade Name Fiasp Applicant Novo Nordisk Dosage Form(s) Injection, 100 units/mL (U-100): 10 mL multiple-dose vial, 3 mL pen, 3 mL cartridges for use in a cartridge device Applicant Proposed Dosing Individualized Regimen(s) Applicant Proposed To improve glycemic control in children with diabetes mellitus Indication(s)/Population(s) Recommendation on Approval Regulatory Action Recommended Not applicable Indication(s)/Population(s) (if applicable) 1 Reference ID: 4533564 Clinical Review Hyon Kwon, PharmD, MPH sNDA 208751/S-010 and S-011 Fiasp (insulin aspart) Table of Contents Glossary ........................................................................................................................................... 7 1. Executive Summary ................................................................................................................. 9 Product Introduction ........................................................................................................ 9 Conclusions on the Substantial Evidence of Effectiveness .............................................. 9 Benefit-Risk Assessment ................................................................................................ 11 Patient Experience Data ................................................................................................. 16 2. Therapeutic Context .............................................................................................................. 17 Analysis of Condition ...................................................................................................... 17 Analysis of Current Treatment Options ......................................................................... 17 3. Regulatory Background ......................................................................................................... 19 U.S. Regulatory Actions and Marketing History ............................................................. 19 Summary of Presubmission/Submission Regulatory Activity ........................................ 19 Foreign Regulatory Actions and Marketing History ....................................................... 22 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 22 Office of Scientific Investigations (OSI) .......................................................................... 22 Product Quality .............................................................................................................. 23 Clinical Microbiology ...................................................................................................... 23 Nonclinical Pharmacology/Toxicology ........................................................................... 23 Clinical Pharmacology .................................................................................................... 23 Devices and Companion Diagnostic Issues .................................................................... 26 Consumer Study Reviews ............................................................................................... 26 5. Sources of Clinical Data and Review Strategy ....................................................................... 26 Table of Clinical Studies .................................................................................................. 26 Review Strategy .............................................................................................................. 28 6. Review of Relevant Individual Trials Used to Support Efficacy ............................................. 28 2 Reference ID: 4533564 Clinical Review Hyon Kwon, PharmD, MPH sNDA 208751/S-010 and S-011 Fiasp (insulin aspart) Trial NN1218-4101 – Efficacy and Safety of Faster-acting Insulin Aspart compared to NovoRapid both in Combination with Insulin Degludec in Children and Adolescents with Type 1 Diabetes ................................................................................................................................. 28 Study Design............................................................................................................ 28 Study Results ........................................................................................................... 37 7. Integrated Review of Effectiveness ....................................................................................... 65 Additional Efficacy Considerations ................................................................................. 65 7.2.1. Considerations on Benefit in the Postmarket Setting ............................................ 65 Other Relevant Benefits .......................................................................................... 66 Integrated Assessment of Effectiveness ........................................................................ 66 8. Review of Safety .................................................................................................................... 67 Safety Review Approach ................................................................................................ 67 Review of the Safety Database ...................................................................................... 67 Overall Exposure ..................................................................................................... 67 Relevant characteristics of the safety population: ................................................. 68 Adequacy of the safety database: .......................................................................... 68 Adequacy of Applicant’s Clinical Safety Assessments .................................................... 68 Issues Regarding Data Integrity and Submission Quality ....................................... 68 Categorization of Adverse Events ........................................................................... 68 Routine Clinical Tests .............................................................................................. 71 Safety Results ................................................................................................................. 72 Deaths ..................................................................................................................... 72 Serious Adverse Events ........................................................................................... 72 Dropouts and/or Discontinuations Due to Adverse Effects ................................... 74 Significant Adverse Events - Hypoglycemia ............................................................ 74 Treatment Emergent Adverse Events and Adverse Reactions ............................... 82 Laboratory Findings ................................................................................................ 83 Vital Signs ................................................................................................................ 83 Electrocardiograms (ECGs) ...................................................................................... 84 QT ............................................................................................................................ 84 Immunogenicity ............................................................................................... 84 3 Reference ID: 4533564 Clinical Review Hyon Kwon, PharmD, MPH sNDA 208751/S-010 and S-011 Fiasp (insulin aspart) Analysis of Submission-Specific Safety Issues ................................................................ 84 Injection Site Reactions ........................................................................................... 84 Lipodystrophy ......................................................................................................... 86 Allergic Reaction ..................................................................................................... 86 Safety Analyses by Demographic Subgroups ................................................................. 87 Specific Safety Studies/Clinical Trials ............................................................................. 87 Additional Safety Explorations ....................................................................................... 87 Human Carcinogenicity or Tumor Development .................................................... 87 Human Reproduction and Pregnancy ..................................................................... 88 Pediatrics and Assessment of Effects on Growth ................................................... 88 Overdose, Drug Abuse Potential, Withdrawal, and Rebound ................................ 90 Safety in the Postmarket Setting.................................................................................... 90 Safety Concerns Identified Through Postmarket Experience ................................. 90 Expectations on Safety in the Postmarket Setting ................................................
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