NDA Multi-disciplinary Review and Evaluation NDA 020287-s72 FRAGMIN (dalteparin) NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NDA Application Number(s) 020287, Supplement 72 Priority or Standard Priority Submit Date(s) December 19, 2018 Received Date(s) December 19, 2018 PDUFA Goal Date May 21, 2019 Division/Office Division of Hematology Products/OHOP Review Completion Date May 13, 2019 Established/Proper Name Dalteparin Trade Name Fragmin Pharmacologic Class Low molecular weight heparin Applicant Pfizer Inc. Dosage form Subcutaneous injection Dosing Regimen Age and weight-based dosing Applicant Proposed For the extended treatment of symptomatic venous Indication/Population thromboembolism (VTE) to reduce the recurrence in pediatric (b) (4) patients Recommendation on Regular approval Regulatory Action Recommended For the treatment of symptomatic venous thromboembolism Indication/Population (VTE) to reduce the recurrence in pediatric patients 1 month of age and older 1 Version date: October 12, 2018 Reference ID: 4432272 NDA Multi-disciplinary Review and Evaluation NDA 020287-s72 FRAGMIN (dalteparin) Table of Contents Table of Tables ................................................................................................................................ 5 Table of Figures ............................................................................................................................... 6 Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 7 Glossary ........................................................................................................................................... 8 1 Executive Summary ............................................................................................................... 10 Product Introduction ...................................................................................................... 10 Conclusions on the Substantial Evidence of Effectiveness ............................................ 11 Benefit-Risk Assessment ................................................................................................ 12 Patient Experience Data ................................................................................................. 16 2 Therapeutic Context .............................................................................................................. 17 Analysis of Condition ...................................................................................................... 17 Analysis of Current Treatment Options ......................................................................... 18 3 Regulatory Background ......................................................................................................... 20 U.S. Regulatory Actions and Marketing History ............................................................. 20 Summary of Presubmission/Submission Regulatory Activity ........................................ 20 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................. 21 Office of Scientific Investigations (OSI) .......................................................................... 21 Product Quality .............................................................................................................. 21 Clinical Microbiology ...................................................................................................... 21 Devices and Companion Diagnostic Issues .................................................................... 21 5 Nonclinical Pharmacology/Toxicology................................................................................... 22 6 Clinical Pharmacology ............................................................................................................ 22 Executive Summary ........................................................................................................ 22 Recommendations .................................................................................................. 24 Post-Marketing Requirements and Commitments ................................................. 24 Summary of Clinical Pharmacology Assessment ............................................................ 24 Pharmacology and Clinical Pharmacokinetics ........................................................ 24 General Dosing and Therapeutic Individualization ................................................. 25 Comprehensive Clinical Pharmacology Review ............................................................. 26 Clinical Pharmacology Questions ............................................................................ 26 7 Sources of Clinical Data and Review Strategy ....................................................................... 35 2 Version date: October 12, 2018 Reference ID: 4432272 NDA Multi-disciplinary Review and Evaluation NDA 020287-s72 FRAGMIN (dalteparin) Table of Clinical Studies .................................................................................................. 35 Review Strategy .............................................................................................................. 40 8 Statistical and Clinical and Evaluation ................................................................................... 40 Review of Relevant Individual Trials Used to Support Efficacy ...................................... 40 FRAG-A001-201 .............................................................................................................. 40 Overview and Objectives ........................................................................................ 40 Study Population ..................................................................................................... 41 Study Design & Treatment ...................................................................................... 41 Statistical Analysis Plan ........................................................................................... 42 Protocol Amendments ............................................................................................ 43 Study Results ........................................................................................................... 44 Kids-DOTT Study ............................................................................................................. 52 Integrated Assessment of Effectiveness ........................................................................ 53 Review of Safety ............................................................................................................. 54 Safety Review Approach ......................................................................................... 54 Review of the Safety Database ............................................................................... 55 Adequacy of Applicant’s Clinical Safety Assessments ............................................ 58 Safety Results .......................................................................................................... 60 Analysis of Submission-Specific Safety Issues ................................................. 68 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability 69 Safety Analyses by Demographic Subgroups .................................................. 69 Specific Safety Studies/Clinical Trials .............................................................. 69 Additional Safety Explorations ........................................................................ 70 Safety in the Postmarket Setting ..................................................................... 70 Integrated Assessment of Safety ..................................................................... 71 Statistical Issues ............................................................................................................. 72 Conclusions and Recommendations .............................................................................. 72 9 Advisory Committee Meeting and Other External Consultations ......................................... 74 10 Pediatrics ............................................................................................................................... 75 11 Labeling Recommendations .................................................................................................. 76 Prescription Drug Labeling ......................................................................................... 76 12 Risk Evaluation and Mitigation Strategies (REMS) ................................................................ 78 13 Postmarketing Requirements and Commitment .................................................................. 79 14 Division Director (OCP) Comments........................................................................................ 79 3 Version date: October 12, 2018 Reference ID: 4432272 NDA Multi-disciplinary Review and Evaluation NDA 020287-s72 FRAGMIN (dalteparin) 15 Division Director (OB) Comments ......................................................................................... 79 16 Division Director (Clinical) Comments ................................................................................... 80 17 Appendices ...........................................................................................................................