CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 212123Orig1s000 INTEGRATED REVIEW Executive Summary Interdisciplinary Assessment Appendices NDA212123 Tauvid (flortaucipir F 18 injection) Integrated Review Table 1. Administrative Application Information Category Application Information Application type NDA Application number{s) 212123 Priority or standard Ptiority Submit date{s) 9/30/2019 Received date(s) 9/30/2019 PDUFA goal date 5/29/2020 Division/office Division oflmaging and Radiation Medicine (DIRM) Review completion date 5/27/2020 Established name Flo1taucipir F 18 (Proposed) trade name Tauvid Pharmacologic class Radioactive diagnostic agent (for PET imaging) Code name F18-AV-1451 , F18-T807, LSN3182568 Applicant Avid Radiopha1maceuticals Inc Dose form/formulation(s) Injection Dosing regimen 370 MBq (10 mCi), administered as a bolus intravenous injection Applicant proposed For positron emission tomography (PET) imaging ofthe brain to indication{s)/population{s) estimate the density and disttibution of ag~gated tau 4 nemofibrillary tangles (NFTs) !b>T m adult oatients who are bein~evaluat~d for AD (b)(4__<l>H_ •l Proposed SNOMED indication Regulatory action Approval Approved Tauvid is indicated for use with PET imaging of the brain to indication{s)/population{s) estimate the density and disttibution of aggregated tau NFTs in {if applicable) adult patients with cognitive impaiiment who are being evaluated for AD. Limitations ofUse: Tauvid is not indicated for use in the evaluation ofpatients for chronic traumatic encephalopathy (CTE) Approved SNOMED 386806002 Ihnpaired cognition (fmdiI1g) indication Integrated Review Template, version date 2019/09/25 Reference ID: 4615642 NDA212123 Tauvid (flortaucipir F 18 injection) Table of Contents Table ofTables ....................................................................................................................v Table ofFigures ................................................................................................................ vii Glossaiy ............................................................................................................................ 1 I. Executive Sunrmary.......................................................................................................... 3 1. Summaiy ofRegulato1y Act.ion ...................................................................................3 2. Benefit-Risk Assessment ..............................................................................................5 II. Interdisciplina1y Assessment. ........................................................................................10 3. Introduction ................................................................................................................10 3.1. Approach to the Review ......................................................................................12 4. Patient Experience Data .............................................................................................16 5. Phannacologic Activity, Phannacokinetics, and Clinical Phaimacology ..................17 5.1. Nonclinical Assessment ofPotential Effectiveness .............................................26 6. Evidence ofBenefit (Assessment ofEfficacy) ..........................................................27 6.1. Assessment ofDose and Potential Effectiveness ................................................27 6.2. Design of Clinical Trials Intended to Demonstrate Benefit to Patients ...............27 6.2.1. Trial Design ...................................................................................................27 6.2.2. Eligibility Criteria .........................................................................................31 6.2.3. Statistical Analysis Plans ..............................................................................31 6.3. Results of Analyses of Clinical Trials/Studies Intended to Demonstrate Benefit to Patients ...........................................................................................35 6.4. Review Issues Relevant to the Evaluation ofBenefit.. ........................................ 39 6.4.1. User Guide for Tauvid PET Image Display ..................................................39 6.4.2. Limitations ofEfficacy Evidence for Tau Pathology Detection .................. .41 (bf(4 .......................45 ,__~~~~~~~~~~~~~~~~~~~~~~- 7. Risk and Risk Management ........................................................................................48 7.1. Potential Risks or Safety Concerns Based on Nonclinical Data......................... .48 7.2. Potential Risks or Safety Concerns Based on Drng Class or Other Drng- Specific Factors ..............................................................................................50 7.3. Potential Safety Concerns Identified Through Postmai·ket Experience ..............51 7.4. FDA Approach to Safety Review ........................................................................51 7.5. Adequacy ofthe Clinical Safety Database ..........................................................51 7.6. Safety Findings and Safety Concerns Based on Review of the Clinical Safety Database ..............................................................................................54 7.6.1. Overall Adverse Event SUlllillaty. .................................................................54 7.6.2. Deaths............................................................................................................55 7.6.3. Serious Adverse Events .................................................................................55 7.6.4. Dropouts and/or Discontinuations Due to Adverse Events ...........................56 11 Integrated Review Template, version date 2019/09/25 Reference ID: 4615642 NDA 212123 Tauvid (flortaucipir F 18 injection) 7.6.5. Treatment-Emergent Adverse Events ...........................................................56 7.6.6. Laboratory Findings ......................................................................................57 7.7. Review Issues Relevant to the Evaluation of Risk ..............................................57 7.7.1. CTE Misdiagnosis .........................................................................................57 7.7.2. Effect of MAO Inhibitors on FTP Binding ...................................................59 7.7.3. QT Interval Prolongation ..............................................................................59 8. Therapeutic Individualization ....................................................................................60 8.1. Intrinsic Factors ...................................................................................................60 8.2. Drug Interactions .................................................................................................60 8.3. Pediatric Labeling/Plans for Pediatric Drug Development .................................61 8.4. Pregnancy and Lactation......................................................................................61 9. Product Quality ..........................................................................................................62 9.1. Device or Combination Product Considerations .................................................62 10. Human Subjects Protections/Clinical Site and Other Good Clinical Practice Inspections/Financial Disclosure ...........................................................................62 11. Advisory Committee Summary ................................................................................62 III. Appendices ...................................................................................................................63 12. Summary of Regulatory History ..............................................................................63 13. Pharmacology Toxicology Assessments and Additional Information .....................66 13.1. Summary Review of Studies Submitted Under IND .........................................66 13.1.1. Pharmacology (Primary and Secondary) ....................................................66 13.1.1.1. Primary Pharmacology Studies ............................................................66 13.1.1.2. Secondary Pharmacology Studies ........................................................68 13.1.2. Safety Pharmacology ..................................................................................69 13.1.3. Absorption, Distribution, Metabolism, Excretion/Pharmacokinetics .........71 13.1.4. Toxicology ..................................................................................................73 13.1.4.1. General Toxicology ..............................................................................73 13.1.4.2. Genetic Toxicology ..............................................................................76 13.1.4.3. Carcinogenicity .....................................................................................76 13.1.4.4. Reproductive Toxicology .....................................................................76 13.1.4.5. Other Toxicology Studies .....................................................................77 13.1.5. Impurities/Degradants .................................................................................77 13.1.6. Referenced NDAs, BLAs, DMFs ...............................................................77 13.2. Individual Reviews of Studies Submitted to the NDA ......................................77 14. Clinical Pharmacology