CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 210115Orig1s000 CLINICAL REVIEW(S) Clinical Review Ergun Velidedeoglu, MD NDA 210,115 Prograf® Granules (tacrolimus for oral suspension) CLINICAL REVIEW Application Type NDA, 505(b)(1) Application Number(s) 210,115 Priority or Standard Standard Submit Date(s) July 26, 2017, September 15, 2017, November 15, 2017, December 05, 2017, January 24, 2018, April 16, 2018 Received Date(s) July 26, 2017, September 15, 2017, November 15, 2017, December 05, 2017, January 24, 2018, April 16, 2018 PDUFA Goal Date May 26, 2018 Division/Office DTOP/OAP Reviewer Name(s) Ergun Velidedeoglu, MD Review Completion Date April 22, 2018 Established/Proper Name Tacrolimus (Proposed) Trade Name Prograf® Granules Applicant Astellas Pharma US, Inc. Dosage Form(s) for oral suspension Applicant Proposed Dosing Starting dose of 0.15-0.20 mg/kg/day, in two divided doses, Regimen(s) every 12 hours, titrated later to target 5-20 ng/mL trough concentrations for the first 12 months posttransplant Applicant Proposed Oral suspension for prevention of rejection in pediatric heart, Indication(s)/Population(s) kidney, or liver transplant recipients Recommendation on Approval Regulatory Action Recommended Same as proposed by the Applicant Indication(s)/Population(s) (if applicable) Link to NDA submission (EDR Location): \\CDSESUB1\evsprod\NDA210115\210115.enx CDER Clinical Review Template 1 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4267221 Clinical Review Ergun Velidedeoglu, MD NDA 210,115 Prograf® Granules (tacrolimus for oral suspension) Table of Contents 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 ................................................................................................14 1.4. Patient Experience Data.................................................................................................17 2. Therapeutic Context..............................................................................................................17 2.1. Analysis of Current Treatment Options .........................................................................17 2.2. U.S. Regulatory Actions and Marketing History.............................................................20 2.3. Basis for the Current NDA Submission: Deferred requirement for development of an age appropriate formulation of tacrolimus ..............................................................................20 2.4. Summary of Presubmission/Submission Regulatory Activity ........................................22 2.5. Foreign Regulatory Actions and Marketing History .......................................................23 3. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................24 3.1. Office of Scientific Investigations (OSI) ..........................................................................24 3.2. Product Quality ..............................................................................................................24 3.3. Clinical Microbiology......................................................................................................24 3.4. Nonclinical Pharmacology/Toxicology ...........................................................................24 3.5. Clinical Pharmacology ....................................................................................................24 3.6. Devices and Companion Diagnostic Issues ....................................................................24 3.7. Consumer Study Reviews...............................................................................................24 4. Sources of Clinical Data and Review Strategy .......................................................................24 4.1. Table of Clinical Studies .................................................................................................24 4.2. Review Strategy .............................................................................................................27 5. Review of Relevant Individual Trials Used to Support Efficacy .............................................27 5.1. An Open Label, Randomized, Comparative, Multicenter Pediatric Clinical Trial Comparing the Efficacy and Safety of a Dual Regimen with Oral Tacrolimus (FK506) Versus a CDER Clinical Review Template 2 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4267221 Clinical Review Ergun Velidedeoglu, MD NDA 210,115 Prograf® Granules (tacrolimus for oral suspension) Triple Regimen With Oral Cyclosporine-Microemulsion in Primary Liver Allograft Transplantation (FG-506-01-13) ...............................................................................................27 5.1.1. Study Design (FG-506-01-13)..................................................................................27 5.1.2. Study Results (FG-506-01-13) .................................................................................36 5.2. A Two Centre Clinical Pilot Study in Children with Tacrolimus (FK506) Fine Granule Formulation As Immunosuppressive Therapy in Liver Allograft Transplantation (FG-506-01- 08) 52 5.2.1. Study Design (FG-506-01-08)..................................................................................52 5.2.2. Study Results (FG-506-01-08) .................................................................................55 5.3. A Long-term, Open-label, Non-comparative Study to Evaluate the Safety and Efficacy of a Modigraf® Based Immunosuppression Regimen in Paediatric Solid Allograft Recipients (PROGRESSION STUDY, F506-CL-0404).....................................................................................59 5.3.1. Study Design (F506-CL-0404)..................................................................................59 5.3.2. Study Results (F506-CL-0404) .................................................................................63 6. Integrated Review of Effectiveness.......................................................................................66 6.1. Assessment of Efficacy Across Trials..............................................................................66 6.2. Additional Efficacy Considerations.................................................................................67 6.2.1. Considerations on Benefit in the Postmarket Setting.............................................67 7. Review of Safety....................................................................................................................67 7.1. Safety Review Approach ................................................................................................67 7.2. Review of the Safety Database ......................................................................................67 7.2.1. Overall Exposure.....................................................................................................67 7.2.2. Adequacy of the safety database: ..........................................................................68 7.3. Adequacy of Applicant’s Clinical Safety Assessments....................................................68 7.3.1. Issues Regarding Data Integrity and Submission Quality........................................68 7.3.2. Categorization of Adverse Events...........................................................................69 7.3.3. Routine Clinical Tests..............................................................................................69 7.4. Safety Results.................................................................................................................69 7.4.1. Deaths.....................................................................................................................69 7.4.2. Serious Adverse Events...........................................................................................71 7.4.3. Common Adverse Events and Dropouts and/or Discontinuations Due to Adverse Events ...............................................................................................................................75 CDER Clinical Review Template 3 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4267221 Clinical Review Ergun Velidedeoglu, MD NDA 210,115 Prograf® Granules (tacrolimus for oral suspension) 7.4.4. Significant Adverse Events......................................................................................81 7.4.5. Laboratory Findings ................................................................................................88 7.4.6. Vital Signs and Growth Measurements ..................................................................90 7.4.7. Electrocardiograms (ECGs) .....................................................................................91 7.4.8. QT ...........................................................................................................................92 7.4.9. Immunogenicity......................................................................................................92