CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 211281Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA Multi-Disciplinary Review and Evaluation – NDA 211281 Pizensy (lactitol) NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NDA 505(b)(2) Application Number(s) 211281 Priority or Standard Standard Submit Date(s) November 21, 2018 Received Date(s) November 21, 2018 PDUFA Goal Date February 20, 2020 (due to major amendment) Division/Office OND / ODEIII / DGIEP Review Completion Date February 12, 2020 Established/Proper Name Lactitol (Proposed) Trade Name Pizensy Pharmacologic Class Osmotic laxative Applicant Braintree Laboratories Inc. Dosage Form Powder for oral solution (b) (4) Applicant Proposed Dosing Regimen Applicant Proposed The treatment of chronic idiopathic constipation (CIC) in adults Indication(s)/Population(s) Applicant Proposed 82934008 chronic idiopathic constipation SNOMED CT Indication Disease Term for Each Proposed Indication Recommendation on Approval Regulatory Action Recommended Dosing 20 grams orally once daily, preferably with meals. Regimen Reduce the dosage to 10 grams once daily for persistent loose stools. Administer oral medications at least 2 hours before or 2 hours after Pizensy (lactitol). 1 Version date: October 12, 2018 Reference ID: 4560397 NDA Multi-Disciplinary Review and Evaluation – NDA 211281 Pizensy (lactitol) Table of Contents Table of Tables .......................................................................................................................... 5 Table of Figures ......................................................................................................................... 7 Reviewers of Multi-Disciplinary Review and Evaluation .............................................................. 8 Glossary..................................................................................................................................... 9 1 Executive Summary ...........................................................................................................10 Product Introduction ....................................................................................................10 Conclusions on the Substantial Evidence of Effectiveness ..........................................10 Benefit-Risk Assessment ............................................................................................12 Patient Experience Data .............................................................................................18 2 Therapeutic Context ...........................................................................................................19 Analysis of Condition ..................................................................................................19 Analysis of Current Treatment Options .......................................................................20 3 Regulatory Background ......................................................................................................22 U.S. Regulatory Actions and Marketing History ...........................................................22 Summary of Presubmission/Submission Regulatory Activity .......................................22 4 Significant Issues From Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ............................................................................................................26 Office of Scientific Investigations (OSI) .......................................................................26 Product Quality ...........................................................................................................27 5 Nonclinical Pharmacology/Toxicology ................................................................................29 Executive Summary ....................................................................................................29 Referenced NDAs, BLAs, DMFs .................................................................................30 Pharmacology .............................................................................................................30 ADME/PK ...................................................................................................................31 Toxicology ..................................................................................................................35 General Toxicology ..............................................................................................35 Genetic Toxicology ..............................................................................................38 Carcinogenicity ....................................................................................................38 Reproductive and Developmental Toxicology ......................................................39 Other Toxicology Studies .....................................................................................42 6 Clinical Pharmacology........................................................................................................45 Executive Summary ....................................................................................................45 Recommendations ...............................................................................................45 Summary of Clinical Pharmacology Assessment ........................................................46 Pharmacology and Clinical Pharmacokinetics ......................................................46 General Dosing and Therapeutic Individualization ...............................................46 Comprehensive Clinical Pharmacology Review ..........................................................47 General Pharmacology and Pharmacokinetic Characteristics ..............................47 2 Version date: October 12, 2018 Reference ID: 4560397 NDA Multi-Disciplinary Review and Evaluation – NDA 211281 Pizensy (lactitol) Clinical Pharmacology Questions .........................................................................49 7 Sources of Clinical Data and Review Strategy ...................................................................52 Table of Clinical Studies..............................................................................................52 Efficacy Review Strategy ............................................................................................53 8 Statistical and Clinical and Evaluation ................................................................................53 Review of Relevant Individual Trials Used To Support Efficacy...................................53 BLI400-302 (Study 302) .......................................................................................53 BLI400-301 (Study 301) .......................................................................................66 Review of Supportive Literature ...........................................................................76 Comparison of Lactitol to Historical Controls ........................................................80 BLI400-303 (Study 303) .......................................................................................81 Assessment of Efficacy Across Trials ..................................................................88 Integrated Assessment of Effectiveness ..............................................................89 Review of Safety .........................................................................................................89 Safety Review Approach ......................................................................................89 Review of the Safety Database ............................................................................90 Adequacy of Applicant’s Clinical Safety Assessments .........................................90 Safety Results ......................................................................................................91 Safety Analyses by Demographic Subgroups ....................................................104 Additional Safety Explorations ...........................................................................110 Safety in the Postmarket Setting ........................................................................111 Integrated Assessment of Safety .......................................................................113 Conclusions and Recommendations .........................................................................113 9 Advisory Committee Meeting and Other External Consultations ......................................113 10 Pediatrics .........................................................................................................................114 11 Labeling Recommendations .............................................................................................114 12 Risk Evaluation and Mitigation Strategies (REMS) ...........................................................116 13 Postmarketing Requirements and Commitment ...............................................................116 14 Division Associate Director (Clinical/DGIEP) Comments ..................................................117 15 Appendices ......................................................................................................................119 References ............................................................................................................119