CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209379Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA/BLA Multi-disciplinary Review and Evaluation NDA 209379 Selenious acid NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NDA Application Number(s) 209379 Priority or Standard Priority Submit Date(s) 7/3/2018 Received Date(s) 10/31/2018 PDUFA Goal Date 4/30/2019 Division/Office DGIEP Review Completion Date 4/30/2019 Established/Proper Name Selenious Acid (Proposed) Trade Name Selenious Acid Pharmacologic Class Trace Element Code name Applicant American Regent, Inc. Dosage form Injection (98 mcg equivalent to 60 mcg selenium/ml) (b) (4) Applicant proposed Dosing kg: 2 mcg/kg/day (b) (4) (b) Regimen kg: (4) mcg/day (b) (4) 60 mcg/day Applicant Proposed Source of selenium for parenteral nutrition when oral or Indication(s)/Population(s) enteral nutrition is not possible, insufficient, or contraindicated in adult and pediatric patients Applicant Proposed SNOMED CT Indication Disease Term for each Proposed Indication Recommendation on Approval Regulatory Action Recommended Source of selenium for parenteral nutrition when oral or Indication(s)/Population(s) enteral nutrition is not possible, insufficient, or contraindicated (if applicable) in adult and pediatric patients Recommended SNOMED CT Indication Disease Term for each Indication (if applicable) Recommended Dosing <7Kg: 2 to 4 mcg/kg/day Regimen ≥7kg: 2 mcg/kg/day (up to 60 mcg/day) Adults: 60mcg/day 1 Reference ID: 4426631 NDA/BLA Multi-disciplinary Review and Evaluation NDA 209379 Selenious acid Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 7 Glossary ........................................................................................................................................... 9 1. Executive Summary ............................................................................................................... 11 1.1. Product Introduction ....................................................................................................... 11 1.2. Conclusions on the Substantial Evidence of Effectiveness ............................................. 12 1.3. Benefit-Risk Assessment ................................................................................................. 13 1.4. Patient Experience Data .................................................................................................. 21 2. Therapeutic Context .............................................................................................................. 22 2.1. Analysis of Condition ....................................................................................................... 22 2.1.1. Parenteral Nutrition ................................................................................................ 22 2.1.2. Selenium .................................................................................................................. 22 2.1.3. Recommended Oral Intake ..................................................................................... 23 2.1.4. Deficiency ................................................................................................................ 24 2.2. Analysis of Current Treatment Options .......................................................................... 25 3. Regulatory Background ......................................................................................................... 26 3.1. U.S. Regulatory Actions and Marketing History .............................................................. 26 3.2. Summary of Presubmission/Submission Regulatory Activity ......................................... 26 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................. 27 4.1. Office of Scientific Investigations (OSI) ........................................................................... 27 4.2. Product Quality ............................................................................................................... 27 4.3. Clinical Microbiology ....................................................................................................... 28 4.4. Devices and Companion Diagnostic Issues ..................................................................... 28 5. Nonclinical Pharmacology/Toxicology................................................................................... 28 5.1. Nonclinical Executive Summary ...................................................................................... 28 5.2. Referenced NDAs, BLAs, DMFs ........................................................................................ 29 5.3. Pharmacology .................................................................................................................. 29 5.4. ADME/PK ......................................................................................................................... 29 5.5. Toxicology ........................................................................................................................ 30 5.5.1. General Toxicology .................................................................................................. 30 5.5.2. Genetic Toxicology .................................................................................................. 31 5.5.3. Carcinogenicity ........................................................................................................ 31 5.5.4. Reproductive and Developmental Toxicology ........................................................ 31 5.5.5. Other Toxicology Studies ......................................................................................... 32 6. Clinical Pharmacology ............................................................................................................ 34 6.1. Clinical Pharmacology Executive Summary..................................................................... 34 6.1.1. Recommendations .................................................................................................. 34 6.2. Summary of Clinical Pharmacology Assessment ............................................................. 34 6.2.1. Pharmacology and Clinical Pharmacokinetics ......................................................... 34 6.2.2. General Dosing and Therapeutic Individualization ................................................. 37 6.3. Comprehensive Clinical Pharmacology Review .............................................................. 39 2 Reference ID: 4426631 NDA/BLA Multi-disciplinary Review and Evaluation NDA 209379 Selenious acid 6.3.1. General Pharmacology and Pharmacokinetic Characteristics ................................ 39 6.3.2. Clinical Pharmacology Questions ............................................................................ 40 7. Sources of Clinical Data and Review Strategy ....................................................................... 41 7.1. Table of Clinical Studies ................................................................................................... 41 7.2. Review Strategy ............................................................................................................... 46 7.2.1. Adults ....................................................................................................................... 46 7.2.2. Neonatal and Pediatric Populations ........................................................................ 47 7.2.3. Additional Literature Not Identified by the Applicant ............................................ 47 8. Clinical Evaluation .................................................................................................................. 48 8.1. Review of Efficacy ............................................................................................................ 48 8.1.1. Assessment of Selenium Concentrations ................................................................ 48 8.1.2. Evolution of Studies Evaluating Parenteral Selenium Supplementation ................ 52 8.1.3. Review of Literature of Intravenous Selenious Acid Relevant to NDA ................... 52 8.1.4. Review of Relevant Literature of Intravenous Selenious Acid in Neonatal and Pediatric Populations .............................................................................................. 66 8.1.5. Specific Populations ................................................................................................ 72 8.1.6. Integrated Assessment of Effectiveness ................................................................. 73 8.2. Review of Safety .............................................................................................................. 75 8.2.1. Safety Review Approach.......................................................................................... 75 8.2.2. Review of the Safety Database ............................................................................... 75 8.2.3. Safety Results .......................................................................................................... 76 8.2.4. Additional Safety Information ................................................................................