`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`210455Orig1s000
`
`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 210455
`SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)
`800/150/200/10 mg tablet
`
`
`NDA/BLA Multi-Disciplinary Review and Evaluation
`Application Type NDA
`Application Number(s) 210455
`Priority or Standard Standard
`Submit Date(s) September 22, 2017
`Received Date(s) September 22, 2017
`PDUFA Goal Date
`July 22, 2018
`Division/Office Division of Antiviral Products/Office Antimicrobial Products
`Review Completion Date See DARRTS electronic signature page
`Established Name darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
`Trade Name SYMTUZA™
`Pharmacologic Class Combination of darunavir, a human immunodeficiency virus
`(HIV-1) protease inhibitor, cobicistat, a CYP3A inhibitor, and
`emtricitabine and tenofovir alafenamide, both HIV-1
`nucleos(t)ide analog reverse transcriptase inhibitors
`Janssen Products, LP
`Applicant
`Formulation(s) 800/150/200/10 mg fixed-dose combination tablets
`Dosing Regimen One tablet taken orally once daily with food
`Applicant Proposed
`Complete regimen for the treatment of HIV-1 infection in adults
`Indication(s)/Population(s)
`and pediatric patients 12 years of age and older.
`Recommendation on
`Approval
`Regulatory Action
`Recommended
`Indication(s)/Population(s)
`(if applicable)
`
`Indicated as complete regimen for the treatment of HIV-1
`infection in adults:
` who have no prior antiretroviral treatment history or
` who are virologically suppressed (HIV-1 RNA < 50 copies/mL)
`on a stable antiretroviral regimen for at least 6 months and
`have no known substitutions associated with resistance to
`darunavir or tenofovir
`
`1
`
`
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4292574
`
`

`

`NDA Multi-disciplinary Review and Evaluation – NDA 210455
`SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)
`800/150/200/10 mg tablet
`
`
`Table of Contents
`
`Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 9
`
`Glossary ......................................................................................................................................... 14
`
`1
`
`Executive Summary Division Level Concurrence ................................................................... 17
`
`
`
` Product Introduction ...................................................................................................... 17 1.1.
`
`
`
` Conclusions on the Substantial Evidence of Effectiveness ............................................ 17 1.2.
`
`1.3.
` Benefit-Risk Assessment ................................................................................................ 18
`
`
`
` Patient Experience Data ................................................................................................. 19 1.4.
`
`
`
` Overall Conclusions and Recommendations .................................................................. 19 1.5.
`
`2
`
`Therapeutic Context .............................................................................................................. 20
`
`
`
` Analysis of Condition ...................................................................................................... 20 2.1.
`
`
`
` Analysis of Current Treatment Options ......................................................................... 20 2.2.
`
`3
`
`Regulatory Background ......................................................................................................... 22
`
`
`
` U.S. Regulatory Actions and Marketing History ............................................................. 22 3.1.
`
`3.2.
`
`
`Summary of Presubmission/Submission Regulatory Activity ........................................ 22
`
`4
`
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety................................................................................................................. 23
`
`
`
` Office of Scientific Investigations (OSI) .......................................................................... 23 4.1.
`
`
`
` Product Quality .............................................................................................................. 23 4.2.
`
`5 Nonclinical Pharmacology/Toxicology................................................................................... 25
`
`6
`
`7
`
`Clinical Pharmacology ............................................................................................................ 26
`
`Statistical and Clinical Evaluation .......................................................................................... 28
`
`7.1.
`
`
`Sources of Clinical Data and Review Strategy ................................................................ 28
`
`7.1.1.
`
` Table of Clinical Studies .......................................................................................... 28
`
`7.1.2.
`
` Review Strategy ...................................................................................................... 30
`
`
`
` Review of Relevant Individual Trials Used to Support Efficacy ...................................... 30 7.2.
`
`7.2.1.
`
` AMBER Trial ............................................................................................................ 30
`
`7.2.2.
`
` EMERALD Trial ......................................................................................................... 44
`
`7.3.
`
`
`Integrated Review of Effectiveness ................................................................................ 59
`
`2
`
`
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4292574
`
`

`

`NDA Multi-disciplinary Review and Evaluation – NDA 210455
`SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)
`800/150/200/10 mg tablet
`
`
`7.3.1.
`
` Assessment of Efficacy Across Trials ....................................................................... 59
`
`7.4.
`
`
`Summary and Conclusions ............................................................................................. 60
`
`7.4.1.
`
` Summary and Conclusions ...................................................................................... 60
`
`8
`
`Clinical Virology Review ......................................................................................................... 61
`
`
`
` Non-Clinical Virology ...................................................................................................... 61 8.1.
`
`
`
` Clinical Virology .............................................................................................................. 61 8.2.
`
`8.2.1.
`
` Baseline Clinical Virology Resistance: AMBER Trial 3001 ...................................... 61
`
`8.2.2.
`
` Resistance Analyses of Virologic Failures from AMBER Trial 3001 ........................ 64
`
`8.2.3.
`
` Resistance Analyses of Virologic Failures from EMERALD Trial 3013 ..................... 66
`
`8.2.4.
`
` Retrospective Analysis of Archived Genotypes ...................................................... 66
`
`8.2.5.
`
` Conclusion ............................................................................................................... 68
`
`9
`
`Review of Safety .................................................................................................................... 70
`
`9.1.
`
`
`Safety Review Approach ................................................................................................ 70
`
`
`
` Review of the Safety Database ...................................................................................... 70 9.2.
`
`9.2.1.
`
` Overall Exposure ..................................................................................................... 70
`
`9.2.2.
` Relevant characteristics of the safety population .................................................. 71
`
`9.2.3.
`
` Adequacy of the safety database ........................................................................... 71
`
`
`
` Adequacy of Applicant’s Clinical Safety Assessments .................................................... 71 9.3.
`
`9.3.1.
`
` Issues Regarding Data Integrity and Submission Quality ....................................... 71
`
`9.3.2.
`
` Categorization of Adverse Events ........................................................................... 71
`
`9.3.3.
`
` Routine Clinical Tests .............................................................................................. 72
`
`9.4.
`
`
`Safety Results ................................................................................................................. 72
`
`9.4.1.
`
` Overview ................................................................................................................. 72
`
`9.4.2.
`
` Deaths ..................................................................................................................... 73
`
`9.4.3.
`
` Serious Adverse Events ........................................................................................... 73
`
`9.4.4.
`
` Dropouts and/or Discontinuations Due to Adverse Effects ................................... 74
`
`9.4.5.
`
` Significant Adverse Events ...................................................................................... 75
`
`9.4.6.
`
` Treatment Emergent Adverse Events and Adverse Reactions ............................... 76
`
`9.4.7.
`
` Laboratory Findings ................................................................................................ 78
`
`9.4.8.
`
` Vital Signs ................................................................................................................ 78
`
`9.4.9.
`
` Electrocardiograms (ECGs) ...................................................................................... 79
`
`3
`
`
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4292574
`
`

`

`NDA Multi-disciplinary Review and Evaluation – NDA 210455
`SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)
`800/150/200/10 mg tablet
`
`
`
`
` QT ..................................................................................................................... 79 9.4.10.
`
`9.4.11.
`
`
`Immunogenicity ............................................................................................... 79
`
`
`
` Analysis of Submission-Specific Safety Issues ................................................................ 79 9.5.
`
`9.5.1.
`
` Skin and Subcutaneous Events ............................................................................... 80
`
`9.5.2.
`
` Hepatic Safety ......................................................................................................... 81
`
`9.5.3.
`
` Changes in Lipid Parameters ................................................................................... 83
`
`9.5.4.
`
` Renal Safety ............................................................................................................ 87
`
`9.5.5.
` Bone Safety ............................................................................................................. 92
`
`9.6.
`
`
`Safety Analyses by Demographic Subgroups ................................................................. 92
`
`9.7.
`
`
`Safety in the Postmarket Setting.................................................................................... 94
`
`9.7.1.
`
` Safety Concerns Identified Through Postmarket Experience ................................. 94
`
`9.7.2.
`
` Expectations on Safety in the Postmarket Setting ................................................. 94
`
`10 Advisory Committee Meeting and Other External Consultations ......................................... 95
`
`11 Pediatrics ............................................................................................................................... 95
`
`12 Labeling Recommendations .................................................................................................. 96
`
`12.1.
`
`
`Prescribing Information .............................................................................................. 96
`
`12.2.
`
`
`Patient Labeling ........................................................................................................ 100
`
`13 Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 100
`
`13.1.
`
`
`Safety Issue(s) that Warrant Consideration of a REMS ............................................ 100
`
`13.2.
`
`
`Conditions of Use to Address Safety Issue(s) ........................................................... 100
`
`13.3.
`
`
`Recommendations on REMS .................................................................................... 100
`
`14 Postmarketing Requirements and Commitments ............................................................... 101
`
`15 Appendices .......................................................................................................................... 102
`
`15.1.
`
`
`Financial Disclosure .................................................................................................. 102
`
`15.2.
`
`
`Clinical Pharmacology Individual Study Reviews ...................................................... 105
`
`
`
` MC114FD2HTX1001 ....................................................................................... 105 15.2.1.
`
`15.2.2.
`
`
`TMC114FD2HTX1002 ..................................................................................... 107
`
`15.2.3.
`
`
`TMC114FD2HTX1004 ..................................................................................... 110
`
`15.2.4.
`
`
`GS-US-299-0102 ............................................................................................. 112
`
`4
`
`
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4292574
`
`

`

`NDA Multi-disciplinary Review and Evaluation – NDA 210455
`SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)
`800/150/200/10 mg tablet
`
`
`15.2.5.
`
`
`TMC114FD2HTX3001 ..................................................................................... 115
`
`15.2.6.
`
`
`TMC114IFD3013 ............................................................................................ 118
`
`15.2.7.
`
`
`DRV Population PK ......................................................................................... 121
`
`15.2.8.
`
`
`TAF Population PK ......................................................................................... 126
`
`
`
`5
`
`
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4292574
`
`

`

`NDA Multi-disciplinary Review and Evaluation – NDA 210455
`SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)
`800/150/200/10 mg tablet
`
`
`Table of Tables
`
`
`Table 1 Symtuza FDC Composition ............................................................................................... 24
`Table 2. Reviewed studies and analyses containing D/C/F/TAF PK data and impact on proposed
`labeling. ......................................................................................................................................... 27
`Table 3. Listing of Phase 3 Clinical Trials Reviewed ...................................................................... 29
`Table 4: Subject Disposition at Week 48, AMBER Trial ................................................................ 34
`Table 5: Major Protocol Deviations, AMBER Trial ........................................................................ 34
`Table 6: Demographic characteristics, AMBER trial ..................................................................... 35
`Table 7: Baseline characteristics, AMBER trial ............................................................................. 37
`Table 8: Proportion of Virologic Response (<50 Copies/mL) According to FDA Snapshot
`Approach at Week 48, ITT Population, AMBER Trial .................................................................... 39
`Table 9: Proportion of Virologic Response (<200 Copies/mL) According to FDA Snapshot
`Approach at Week 48, ITT Population, AMBER Trial .................................................................... 40
`Table 10: Subject Disposition at Week 48, EMERALD Trial .......................................................... 48
`Table 11: Major Protocol Deviations, EMERALD Trial .................................................................. 48
`Table 12: Demographic Characteristics, EMERALD Trial .............................................................. 49
`Table 13: Baseline Characteristics, EMERALD Trial ...................................................................... 51
`Table 14: Boosted PI at Screening, EMERALD Trial ...................................................................... 52
`Table 15: Drug Accountability, EMERALD Trial ............................................................................. 52
`Table 16: Proportion of Virologic Failure (≥50 Copies/mL) According to FDA Snapshot Approach
`at Week 48, ITT Population, EMERALD Trial ................................................................................. 54
`Table 17: Proportion of Virologic Failure (≥200 Copies/mL) According to FDA Snapshot Approach
`at Week 48, ITT Population, EMERALD Trial ................................................................................. 55
`Table 18. Genotype Susceptibility at Screening in AMBER Trial 3001.......................................... 62
`Table 19. Response by Genotype (Censored Patient Population) (n=704) .................................. 64
`Table 20. Virologic Failure Subjects with Post-Baseline Resistance Data from AMBER Trial 3001
`(n=9) .............................................................................................................................................. 65
`Table 21. Virologic Failures with Resistance Data from EMERALD Trial 3013 (n=6) .................... 66
`Table 22. Prevalence of Resistance-Associated Substitutions at Baseline for Subjects with
`Previous Virologic Failure ............................................................................................................. 68
`Table 23. Prevalence of Resistance-Associated Substitutions at Baseline for Subjects with
`Protocol-Defined Virologic Rebound ............................................................................................ 68
`Table 24. Clinical Trial Safety Database: Population and Size ...................................................... 71
`Table 25. Overview of Treatment-Emergent Adverse Events in Phase 3 Safety Population in the
`AMBER and EMERALD trials through Week 48 ............................................................................ 72
`Table 26. Discontinuations due to AE in the AMBER trial through Week 48 ............................... 74
`Table 27. Clinical ADRs, All Grades, Reported in at least 2% of participants in either group of the
`AMBER trial through Week 48 ...................................................................................................... 77
`Table 28. Clinical ADRs, Grade 2-4, Reported in at least 2% of participants in either group of the
`AMBER trial through Week 48 ...................................................................................................... 77
`
`6
`
`
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4292574
`
`

`

`NDA Multi-disciplinary Review and Evaluation – NDA 210455
`SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)
`800/150/200/10 mg tablet
`
`Table 29. Skin and Subcutaneous Reactions, with Associated Results from Laboratory
`Investigations, through Week 48, AMBER trial ............................................................................ 80
`Table 30. Hepatic Laboratory Abnormalities in the AMBER trial through Week 48 .................... 82
`Table 31. Lipid Values, Mean Change from Baseline to Week 48 in the AMBER Trial ................. 84
`Table 32. Lipid Abnormalities, Treatment-Emergent Maximum Toxicity Grade, in the AMBER
`trial through Week 48a .................................................................................................................. 85
`Table 33. Lipid Values, Mean Change from Baseline to Week 48 in the EMERALD Trial ............. 86
`Table 34. Lipid Abnormalities, Treatment-Emergent Maximum Toxicity Grade, in the EMERALD
`trial through Week 48 ................................................................................................................... 86
`Table 35. Serum Creatinine and eGFR by Maximum Toxicity Grade in the AMBER trial through
`Week 48 ........................................................................................................................................ 88
`Table 36. Serum Creatinine and eGFR Median Change from Baseline in the AMBER trial through
`Week 48 ........................................................................................................................................ 89
`Table 37. Quantitative Proteinuria and Albuminuria Results in Participants with Normal Baseline
`UPCR and UACR in the AMBER Trial through Week 48 ................................................................ 90
`Table 38. Quantitative Proteinuria and Albuminuria Results in Participants with Elevated
`Baseline UPCR and UACR in the AMBER Trial through Week 48 .................................................. 90
`Table 39. Serum Creatinine and eGFR Median Change from Baseline in the EMERALD trial
`through Week 48 .......................................................................................................................... 91
`Table 40. Selected Clinical AEs, All Grades, Irrespective of Causality, By Sex in the D/C/F/TAF
`Group of the AMBER trial through Week 48 ................................................................................ 93
`Table 41. Selected Clinical AEs, All Grades, Irrespective of Causality, By Race in the D/C/F/TAF
`Group of the AMBER trial through Week 48 ................................................................................ 94
`Table 42. Relative bioavailability of D/C/F/TAF vs E/C/F/TAF and vs single agents. .................. 108
`Table 43. The effect of food (high-fat meal/fasting) on the PK of the components of D/C/F/TAF.
`..................................................................................................................................................... 108
`Table 44. DRV, COBI, and FTC AUC from D/C/F/TAF vs other products. .................................... 113
`Table 45. Demographics. ............................................................................................................ 121
`Table 46. Prior and updated model parameters. ....................................................................... 123
`Table 47. DRV PK parameters in D/C/F/TAF phase 3 studies. .................................................... 124
`Table 48. DRV PK parameters in D/C/F/TAF phase 3 studies as a function of weight. .............. 124
`Table 49. DRV popPK parameters from D/C/F/TAF vs DRV/c. .................................................... 124
`Table 50. TAF final model parameter estimates. ........................................................................ 127
`Table 51. TAF exposures estimated in phase 3 D/C/F/TAF study TMC114FD2HTX3001 using
`popPK. ......................................................................................................................................... 131
`
`
`7
`
`
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4292574
`
`

`

`NDA Multi-disciplinary Review and Evaluation – NDA 210455
`SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)
`800/150/200/10 mg tablet
`
`
`Table of Figures
`
`
`Figure 1: Schematic Overview of AMBER Trial ............................................................................. 31
`Figure 2: CD4+ Cell Count, Mean Change from Baseline and 95% CI, AMBER Trial ..................... 40
`Figure 3: Log10 HIV-1 RNA, Mean Change from Baseline and 95% CI, AMBER Trial ................... 41
`Figure 4: Subgroup Analysis in Virologic Response (<50 Copies/mL) at Week 48, Demographic
`Characteristics, ITT Population, AMBER Trial ............................................................................... 42
`Figure 5: Subgroup Analysis in Virologic Response (<50 Copies/mL) at Week 48, Stratification
`Factors, ITT Population, AMBER Trial ........................................................................................... 43
`Figure 6: Subgroup Analysis in Virologic Response (<50 Copies/mL) at Week 48, Disease
`Severity, ITT Population, AMBER Trial .......................................................................................... 43
`Figure 7: Schematic Overview of EMERALD Trial ......................................................................... 45
`Figure 8: Kaplan-Meier Curve of Time to Protocol-defined Virologic Rebound (HIV-1 RNA ≥50
`Copies/mL), EMERALD Trial .......................................................................................................... 55
`Figure 9: CD4+ Cell Count, Mean Change from Baseline and 95% CI, EMERALD Trial ................. 56
`Figure 10: Treatment Difference in Virologic Response Rate (<50 Copies/mL) at Week 48,
`Subgroups by Demographics, Snapshot Algorithm, EMERALD Trial ............................................ 57
`Figure 11: Treatment Difference in Virologic Response Rate (<50 Copies/mL) at Week 48,
`Subgroups by bPI at Screening, Snapshot Algorithm, EMERALD Trial .......................................... 58
`Figure 12: Treatment Difference in Virologic Response Rate (<50 Copies/mL) at Week 48,
`Subgroups by Baseline Characteristics, Snapshot Algorithm, EMERALD Trial ............................. 59
`Figure 13. Treatment Difference in Virologic Response (< 50 copies/mL Snapshot Approach) by
`Resistance-Associated Mutations (RAMs) at Week 48 ................................................................. 63
`Figure 14. DRV concentration-time profile in D/C/F/TAF phase 3 studies. ................................ 122
`Figure 15. DRV model structure. ................................................................................................. 122
`Figure 16. Observed versus predicted DRV concentrations. ...................................................... 123
`Figure 17. Structural model. ....................................................................................................... 127
`Figure 18. TAF concentration-time profile for studies included in the popPK model (linear scale).
`..................................................................................................................................................... 129
`Figure 19. TAF concentration-time profile for studies included in the popPK model (log scale).
`..................................................................................................................................................... 130
`Figure 20. Base model individual fits - between occassion variability in absorption. ................ 131
`
`8
`
`
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4292574
`
`

`

`NDA Multi-disciplinary Review and Evaluation — NDA 210455
`
`SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)
`
`800/150/200/10 mg tablet
`
`Reviewers of Multi-Disciplinary Review and Evaluation
`
`OFFICE/DIVISION
`
`SECTIONS
`
`AUTHOREDI
`
`ACKNOWLEDGED/
`APPROVED
`
`St
`
`h M'll
`ep en
`le".
`
`PhD
`
`OPQ/ONDP/DNDPI
`/NDPBIII
`
`Section 4.2
`
`Product Quality
`
`Team Lead
`
`Signature:
`
` 9
`
`AUTHOREDI
`ACKNOWLEDGED/
`APPROVED
`
`Select one:
`
`_X_Authored
`_ Acknowledged
`
`_X_ Approved
`
`Select one:
`
`_X_ Authored
`
`—
`
`Acknowledged
`
`_X_ Approved
`
`Select one:
`
`Authored
`
`_ Acknowledged
`
`_X_ Approved
`
`Select one:
`
`_X_ Authored
`
`Acknowledged
`
`_X_ Approved
`
`Nonclinical
`
`Reviewer
`
`Nonclinical
`
`Supervisor
`
`L. Peyton Myers, PhD
`
`OAP/DAVP
`
`Signature:
`
`Hanan Ghantous, PhD
`
`OAP/DAVP
`
`Signature:
`
`Clinical
`
`Mario Sampson, PharmD.
`
`OTS/OCP/DCPIV
`
`Pharmacology
`Reviewer
`
`Signature:
`
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4292574
`
`

`

`NDA Multi-disciplinary Review and Evaluation — NDA 210455
`
`SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)
`
`800/150/200/10 mg tablet
`
`OFFICE]DIVISION
`
`SECTIONS
`
`AUTHORED/
`
`ACKNOWLEDGED/
`APPROVED
`
`Clinical
`
`Islam Younis, PhD
`
`OTS/OCP/DCPIV
`
`Pharmacology
`Team Leader
`
`Signature:
`
`Sarita Boyd, PharmD
`
`OAP/DAVP
`
`Clinical
`Reviewer
`
`Signature:
`
`Kimberly Struble, PharmD
`
`OAP/DAVP
`
`Clinical Team
`
`Leader
`
`Signature:
`
`Hengrui Sun, DrPh
`
`OTS/OB/DBIV
`
`Statistical
`Reviewer
`
`Signature:
`
`_X_ Approved
`
`AUTHORED/
`
`ACKNOWLEDGED/
`APPROVED
`
`Select one:
`
`_ Authored
`
`_ Acknowledged
`
`_X_ Approved
`
`Select one:
`
`Sections: 1.1, 1.2, 2,
`
`_X_Authored
`
`4.1,7.3,7.4, 9, 10, 11,
`13, 14, 15
`
`_ Acknowledged
`
`_X_ Approved
`
`Sections: 1
`
`(authored), 1.1, 1.2,
`2, 3, 4.1, 7.3, 7.4, 9,
`
`10, 11, 12, 13, 14, 15
`
`Select one:
`
`_ Authored
`
`_ Acknowledged
`
`_X_Approved
`
`Select one:
`
`x Authored
`
`_ Acknowledged
`
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`10
`
`Reference ID: 4292574
`
`

`

`NDA Multi-disciplinary Review and Evaluation — NDA 210455
`
`SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)
`
`800/150/200/10 mg tablet
`
`OFFICE]DIVISION
`
`SECTIONS
`
`AUTHOREDI
`
`ACKNOWLEDGED/
`APPROVED
`
`Thamban Valappil, PhD
`
`OTS/OB/DBIV
`
`Section 7
`
`AUTHOREDI
`
`ACKNOWLEDGED/
`APPROVED
`
`Select one:
`
`Authored
`
`_ Acknowledged
`
`X Approved
`
`
`
`Statistical
`
`Team Leader
`
`Virology
`Reviewer
`
`Virology Team
`Leader
`
`Regulatory
`Project
`Manager
`
`Signature:
`
`Lisa Naeger, PhD
`
`OAP/DAVP
`
`Signature:
`
`Select one:
`
`Section 8
`
`_X_ Authored
`
`Jules O’Rear, PhD
`
`OAP/DAVP
`
`Section 8
`
`Signature:
`
`Myung-Joo PatrICIa Hong, MS
`
`OAP/DAVP
`
`Sectlon 3
`
`Signature:
`
`_ Acknowledged
`_X_ Approved
`
`Select one:
`
`_ Authored
`
`_ Acknowledged
`_X_ Approved
`
`Select one:
`
`_X_ Authored
`_ Acknowledged
`
`_X_ Approved
`
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`11
`
`Reference ID: 4292574
`
`

`

`NDA Multi-disciplinary Review and Evaluation — NDA 210455
`
`SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)
`
`800/150/200/10 mg tablet
`
`SECTIONS
`
`OFFICE]DIVISION
`
`AUTHOREDI
`
`ACKNOWLEDG EDI
`APPROVED
`
`Stacey Min, PharmD
`
`OAP/DAVP
`
`Section 12
`
`Associate
`
`Director for
`
`Labeling
`
`_X_ Approved
`
`AUTHOREDI
`
`ACKNOWLEDG EDI
`APPROVED
`
`Select one:
`
`X
`
`Authored
`
`Acknowledged
`
`_X_ Approved
`
`Select one:
`
`_X_ Authored
`
`Acknowledged
`
`Signature:
`
`Debra Birnkrant, MD
`
`OAP/DAVP
`
`Division
`
`Director (DAVP)
`
`Signature:
`
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`12
`
`Reference ID: 4292574
`
`

`

`NDA Multi-disciplinary Review and Evaluation – NDA 210455
`SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)
`800/150/200/10 mg tablet
`
`Additional Reviewers of Application
`OPDP
`OSI
`OSE/DEPI
`OSE/DMEPA
`OSE/DRISK
`Other
`
`Wendy Lubarsky
`No
`No
`Valerie Wilson
`Ingrid Chapman
`Morgan Walker (PLT)
`OPDP=Office of Prescription Drug Promotion
`OSI=Office of Scientific Investigations
`OSE= Office of Surveillance and Epidemiology
`DEPI= Division of Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DRISK=Division of Risk Management
`
`13
`
`
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4292574
`
`

`

`NDA Multi-disciplinary Review and Evaluation – NDA 210455
`SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)
`800/150/200/10 mg tablet
`
`
`Glossary
`
`
`AC
`ADME
`ADR
`
`AE
`
`ARV
`
`ART
`
`BRF
`
`CDTL
`
`CFR
`
`CMC
`
`COBI
`
`COSTART
`CRF
`
`CRO
`
`CRT
`
`CSR
`
`DAIDS
`DAVP
`
`DMC
`
`DRV
`
`DRV/c
`D/C/F/TAF
`D/C/F/TDF
`DRV/r
`ECG
`
`eCTD
`
`EVG/c
`E/C/F/TAF
`E/C/F/TDF
`FDA
`
`FDAAA
`FDASIA
`FDC
`
`FTC
`
`F/TAF
`F/TDF
`GCP
`
`GRMP
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`advisory committee
`absorption, distribution, metabolism, excretion
`adverse reaction
`adverse event
`antiretroviral
`antiretroviral therapy
`Benefit Risk Framework
`Cross-Discipline Team Leader
`Code of Federal Regulations
`Chemistry, manufacturing, and controls
`cobicistat
`Coding Symbols for Thesaurus of Adverse Reaction Terms
`case report form
`contract research organization
`clinical review te