CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 212320Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review Multi-disciplinary Review and Evaluation NDA 212320 Ferric Maltol, Accrufer® NDA Multi-Disciplinary Review and Evaluation Application Type 505(b)2/NME Application Number(s) 212320 Priority or Standard Standard Submit Date(s) September 26, 2018 Received Date(s) September 27, 2018 PDUFA Goal Date July 27, 2019 Division/Office Division of Hematology Products (DHP) Review Completion Date June 15, 2019 Established Name Ferric Maltol (Proposed) Trade Name ACCRUFER Pharmacologic Class Iron replacement product Code name ST10 or ST10-021 Applicant Shield Therapeutics Formulation(s) Oral capsules Dosing Regimen 30 mg twice daily (BID) Applicant Proposed Treatment of iron deficiency anemia (IDA) Indication(s)/Population(s) Recommendation on Approval Regulatory Action Recommended Treatment of iron deficiency anemia (IDA) in adults. Indication(s)/Population(s) (if applicable) 1 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4467686 Multi-disciplinary Review and Evaluation NDA 212320 Ferric Maltol, Accrufer® Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 8 Additional Reviewers of Application ............................................................................................... 8 Glossary ......................................................................................................................................... 10 1 Executive Summary ............................................................................................................... 13 Product Introduction ...................................................................................................... 13 Conclusions on the Substantial Evidence of Effectiveness ............................................ 13 Benefit-Risk Assessment ................................................................................................ 15 Patient Experience Data ................................................................................................. 19 2 Therapeutic Context .............................................................................................................. 20 Analysis of Condition ...................................................................................................... 20 Analysis of Current Treatment Options ......................................................................... 21 3 Regulatory Background ......................................................................................................... 23 U.S. Regulatory Actions and Marketing History ............................................................. 23 Summary of Presubmission/Submission Regulatory Activity ........................................ 23 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 25 Office of Scientific Investigations (OSI) .......................................................................... 25 Product Quality .............................................................................................................. 25 Clinical Microbiology ...................................................................................................... 25 Devices and Companion Diagnostic Issues .................................................................... 25 5 Nonclinical Pharmacology/Toxicology................................................................................... 26 Executive Summary ........................................................................................................ 26 Referenced NDAs, BLAs, DMFs ....................................................................................... 27 Pharmacology ................................................................................................................. 27 ADME/PK ........................................................................................................................ 28 Toxicology ....................................................................................................................... 28 General Toxicology .................................................................................................. 28 Genetic Toxicology .................................................................................................. 30 Carcinogenicity ........................................................................................................ 31 2 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4467686 Multi-disciplinary Review and Evaluation NDA 212320 Ferric Maltol, Accrufer® Reproductive and Developmental Toxicology ........................................................ 32 Other Toxicology Studies ........................................................................................ 33 6 Clinical Pharmacology ............................................................................................................ 34 Executive Summary ........................................................................................................ 34 Summary of Clinical Pharmacology Assessment ............................................................ 35 Pharmacology and Clinical Pharmacokinetics ........................................................ 35 General Dosing and Therapeutic Individualization ................................................. 36 Comprehensive Clinical Pharmacology Review ............................................................. 36 General Pharmacology and Pharmacokinetic Characteristics ................................ 36 Clinical Pharmacology Questions ............................................................................ 38 7 Sources of Clinical Data and Review Strategy ....................................................................... 45 Table of Clinical Studies .................................................................................................. 45 Review Strategy .............................................................................................................. 47 8 Statistical and Clinical and Evaluation ................................................................................... 48 Review of Relevant Individual Trials Used to Support Efficacy ...................................... 48 Study ST10-01-301 and ST10-01-302 ..................................................................... 48 Study Results ........................................................................................................... 58 Study ST10-01-303 ......................................................................................................... 69 Study Design............................................................................................................ 69 Study Results ........................................................................................................... 76 Assessment of Efficacy Across Trials ....................................................................... 88 Integrated Assessment of Effectiveness ................................................................. 89 Review of Safety ............................................................................................................. 89 Safety Review Approach ......................................................................................... 89 Review of the Safety Database ............................................................................... 89 Adequacy of Applicant’s Clinical Safety Assessments ............................................ 91 Safety Results .......................................................................................................... 92 Analysis of Submission-Specific Safety Issues ....................................................... 100 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ...... 101 Safety Analyses by Demographic Subgroups ........................................................ 101 Specific Safety Studies/Clinical Trials .................................................................... 101 3 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4467686 Multi-disciplinary Review and Evaluation NDA 212320 Ferric Maltol, Accrufer® Additional Safety Explorations .............................................................................. 101 Safety in the Postmarket Setting ................................................................... 102 Integrated Assessment of Safety ................................................................... 104 SUMMARY AND CONCLUSIONS .................................................................................................. 104 Statistical Issues ........................................................................................................... 104 Conclusions and Recommendations ............................................................................ 104 9 Advisory Committee Meeting and Other External Consultations ......................................