Clinical Review Fadi Nossair Efficacy Supplement – S-041 Pradaxa – dabigatran etexilate CLINICAL AND STATISTICAL REVIEW Application Type Efficacy Supplement Application Number(s) sNDA 022512, S-0041; (b) (4) NDA 214358 Priority or Standard Priority Submit Date(s) 9/21/2020 Received Date(s) 9/21/2020 PDUFA Goal Date 3/21/2021 Division/Office Division of Non-malignant Hematology (DNH) Reviewer Name(s) Fadi Nossair CDTL Name Virginia Kwitkowski Statistical Reviewer Sarabdeep Singh Statistical Team Leader Yeh-Fong Chen Review Completion Date 2/23/2021 Established/Proper Name Pradaxa® (Proposed) Trade Name Dabigatran etexilate Applicant Boehringer Ingelheim Pharmaceuticals, Inc. Dosage Form(s) Capsule, oral pellets, (b) (4) Applicant Proposed Dosing Twice-daily oral administration of actual weight-based and age-based Regimen(s) dosing Applicant Proposed For sNDA 022512, S-0041: Indication(s)/Population(s) - For the treatment of venous thromboembolism in pediatric patients 8 years of age and older who have been treated with parenteral anticoagulants for at least 5 days - To reduce the risk of recurrence of venous thromboembolism in pediatric patients 8 years of age and older who have been previously treated (b) (4) For NDA 214358: - For the treatment of venous thromboembolism in pediatric patients (b) (4) 12 years of age who have been treated with parenteral anticoagulants for at least 5 days - To reduce the risk of recurrence of venous thromboembolism in pediatric patients (b) (4) 12 years of age who have been previously treated 1 Reference ID: 4751663 Clinical Review Fadi Nossair Efficacy Supplement – S-041 Pradaxa – dabigatran etexilate Recommendation on Traditional Approval for sNDA 022512, S-004 and NDA 214358 Regulatory Action (b) (4) Recommended For sNDA 022512, S-0041: Indication(s)/Population(s) - For the treatment of venous thromboembolism in adult and (if applicable) pediatric patients 8 years of age and older who have been treated with parenteral anticoagulants for at least 5-10 days - To reduce the risk of recurrence of venous thromboembolism in adult and pediatric patients 8 years of age and older who have been previously treated NDA 214358 (for Pradaxa oral pellets): - For the treatment of venous thromboembolism in pediatric patients (b) (4) to less than 12 years of age who have been treated with parenteral anticoagulants for at least 5 days. - To reduce the risk of recurrence of venous thromboembolism in pediatric patients (b) (4) to less than 12 years of age who have been previously treated. 2 Reference ID: 4751663 Clinical Review Fadi Nossair Efficacy Supplement – S-041 Pradaxa – dabigatran etexilate Table of Contents Glossary ..........................................................................................................................................8 1. Executive Summary...............................................................................................................10 1.1. Product Introduction......................................................................................................10 1.2. Conclusions on the Substantial Evidence of Effectiveness.............................................11 1.3. Benefit-Risk Assessment ................................................................................................12 1.4. Patient Experience Data.................................................................................................18 2. Therapeutic Context..............................................................................................................19 2.1. Analysis of Condition......................................................................................................19 2.2. Analysis of Current Treatment Options .........................................................................20 3. Regulatory Background .........................................................................................................24 3.1. U.S. Regulatory Actions and Marketing History.............................................................24 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................25 3.3. Foreign Regulatory Actions and Marketing History .......................................................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. Nonclinical Pharmacology/Toxicology ...........................................................................32 4.4. Clinical Pharmacology ....................................................................................................33 4.5. Consumer Study Reviews...............................................................................................34 5. Sources of Clinical Data and Review Strategy .......................................................................36 5.1. Table of Clinical Studies .................................................................................................36 5.2. Review Strategy .............................................................................................................39 6. Review of Relevant Individual Trials Used to Support Efficacy .............................................41 6.1. Trial 1160.106 ................................................................................................................41 6.1.1. Study Design ...........................................................................................................41 6.1.2. Study Results ..........................................................................................................52 6.2. Trial 1160.108 ................................................................................................................66 3 Reference ID: 4751663 Clinical Review Fadi Nossair Efficacy Supplement – S-041 Pradaxa – dabigatran etexilate 6.2.1. Study Design ...........................................................................................................66 6.2.2. Study Results ..........................................................................................................73 7. Integrated Review of Effectiveness.......................................................................................81 8. Review of Safety....................................................................................................................81 8.1. Safety Review Approach ................................................................................................81 8.2. Review of the Safety Database ......................................................................................83 8.2.1. Overall Exposure.....................................................................................................83 8.2.2. Relevant characteristics of the safety population: .................................................86 8.2.3. Adequacy of the safety database: ..........................................................................86 8.3. Adequacy of Applicant’s Clinical Safety Assessments....................................................87 8.3.1. Issues Regarding Data Integrity and Submission Quality........................................87 8.3.2. Categorization of Adverse Events...........................................................................87 8.3.3. Routine Clinical Tests..............................................................................................88 8.4. Safety Results.................................................................................................................89 8.4.1. Deaths.....................................................................................................................89 8.4.2. Serious Adverse Events...........................................................................................91 8.4.3. Dropouts and/or Discontinuations Due to Adverse Effects....................................92 8.4.4. Significant Adverse Events......................................................................................93 8.4.5. Treatment Emergent Adverse Events and Adverse Reactions ...............................93 8.4.6. Laboratory Findings ................................................................................................99 8.4.7. Vital Signs..............................................................................................................100 8.4.8. Electrocardiograms (ECGs) ...................................................................................100 8.5. Analysis of Submission-Specific Safety Issues..............................................................100 8.6. Safety Analyses by Demographic Subgroups ...............................................................100 8.7. Specific Safety Studies/Clinical Trials ...........................................................................101 8.8. Additional Safety Explorations.....................................................................................101 8.8.1. Human Carcinogenicity or Tumor Development ..................................................101 8.8.2. Human Reproduction and Pregnancy...................................................................101