CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`761062Orig1s000
`
`MULTI-DISCIPLINE REVIEW
`Summary Review
`Office Director
`Cross Discipline Team Leader Review
`Clinical Review
`Non-Clinical Review
`Statistical Review
`Clinical Pharmacology Review
`
`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761062}
`{Evenity, romosozumab}
`
`
`NDA/BLA Multi-Disciplinary Review and Evaluation
`Application Type BLA Resubmission
`Application Number(s) 761062
`Priority or Standard Standard
`Submit Date(s)
`July 9, 2018
`Received Date(s)
`July 9, 2018
`PDUFA Goal Date April 9, 2019
`Division/Office Division of Bone, Reproductive, and Urologic Products
`Office of Drug Evaluation III
`Review Completion Date
`(electronic stamp)
`Established Name romosozumab
`(Proposed) Trade Name Evenity
`Pharmacologic Class Sclerostin inhibitor
`Code name
`
`Applicant Amgen
`Formulation(s) 90 mg/mL solution (1.17 mL) in each single-use
`
` prefilled syringe (PFS); 2 injections per dose
`
`(210 mg)
`Dosing Regimen 210 mg subcutaneously once a month administered by a
`healthcare professional
`Treatment of osteoporosis in postmenopausal women at high
`risk for fracture
`102447009 Postmenopausal osteoporosis (disorder)
`
`Applicant Proposed
`Indication(s)/Population(s)
`Applicant Proposed
`SNOMED CT Indication
`Disease Term for each
`Proposed Indication
`Recommendation on
`Regulatory Action
`Recommended
`Indication(s)/Population(s)
`(if applicable)
`
`Recommended SNOMED
`CT Indication Disease
`Term for each Indication
`(if applicable)
`
`APPROVE
`
`Treatment of osteoporosis in postmenopausal women at high
`risk for fracture, defined as a history of osteoporotic fracture,
`or multiple risk factors for fracture; or patients who have failed
`or are intolerant to other available osteoporosis therapy
`102447009 Postmenopausal osteoporosis (disorder)
`
`
`
`Reference ID: 4416253
`
`
`
`1
`
`(b) (4)
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`(b) (4)
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`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761062}
`{Evenity, romosozumab}
`
`Table of Contents
`
`Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 9
`
`Additional Reviewers of Application ............................................................................................. 11
`
`Glossary ......................................................................................................................................... 12
`
`1
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`2
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`3
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`4
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`Executive Summary ............................................................................................................... 13
` Product Introduction ...................................................................................................... 13
` Conclusions on the Substantial Evidence of Effectiveness ............................................ 13
` Benefit-Risk Assessment ................................................................................................ 16
` Patient Experience Data ................................................................................................. 24
`
`Therapeutic Context .............................................................................................................. 24
` Analysis of Condition ...................................................................................................... 24
` Analysis of Current Treatment Options ......................................................................... 25
`
`Regulatory Background ......................................................................................................... 29
` U.S. Regulatory Actions and Marketing History ............................................................. 29
`Summary of Presubmission/Submission Regulatory Activity ........................................ 30
`
`
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety................................................................................................................. 32
` Office of Scientific Investigations (OSI) .......................................................................... 32
`Product Quality .............................................................................................................. 32
` Clinical Microbiology ...................................................................................................... 34
` Devices and Companion Diagnostic Issues .................................................................... 34
`
`5 Nonclinical Pharmacology/Toxicology................................................................................... 35
` Executive Summary ........................................................................................................ 35
` Pharmacology/Toxicology Overview .............................................................................. 36
` Nonclinical Evaluation of Sclerostin and Cardiovascular Disease .................................. 38
` Discussion of concerns (nonclinical perspective) ........................................................... 52
`
`6
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`Clinical Pharmacology ............................................................................................................ 56
` Executive summary ........................................................................................................ 56
` Recommendations .................................................................................................. 56
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`Reference ID: 4416253
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`NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761062}
`{Evenity, romosozumab}
`
`7
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`8
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` Post-Marketing Requirement and Commitments .................................................. 56
`Summary of Clinical Pharmacology Assessment............................................................ 56
` Pharmacology and Clinical Pharmacokinetics ........................................................ 56
` General Dosing and Therapeutic Individualization ................................................. 56
` Outstanding issues .................................................................................................. 57
` Comprehensive Clinical Pharmacology Review ............................................................. 57
` General Pharmacology and Pharmacokinetic Characteristics ................................ 57
` Clinical Pharmacology Questions ............................................................................ 58
`
`Sources of Clinical Data and Review Strategy ....................................................................... 60
` Table of Clinical Studies .................................................................................................. 60
` Review Strategy .............................................................................................................. 61
`
`Statistical and Clinical Evaluation .......................................................................................... 61
` Review of Relevant Individual Trials Used to Support Efficacy ...................................... 61
` Study 20110142: Design ......................................................................................... 61
` Study 20110142: Efficacy Results .......................................................................... 79
` Study 20110174 ...................................................................................................... 97
` Study 20070337: Design ......................................................................................... 98
` Study 20070337: Efficacy Results ........................................................................... 99
`Study 20060326 .................................................................................................... 101
` Integrated Assessment of Efficacy ........................................................................ 102
` Review of Safety ........................................................................................................... 106
` Safety Review Approach ....................................................................................... 106
` Review of the Safety Database ............................................................................. 107
` Adequacy of Applicant’s Clinical Safety Assessments .......................................... 108
` Safety Results: Study 20110142 ............................................................................ 108
` Analysis of Cardiovascular Safety ......................................................................... 131
` Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ...... 152
` Safety Analyses by Demographic Subgroups ........................................................ 152
` Specific Safety Studies/Clinical Trials .................................................................... 152
` Additional Safety Explorations .............................................................................. 153
`Safety in the Postmarket Setting ................................................................... 155
`
`Integrated Assessment of Safety ................................................................... 155
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`Reference ID: 4416253
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`NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761062}
`{Evenity, romosozumab}
`
`SUMMARY AND CONCLUSIONS .................................................................................................. 156
`Statistical Issues ........................................................................................................... 156
` Conclusions and Recommendations ............................................................................ 156
`
`9 Advisory Committee Meeting and Other External Consultations ....................................... 162
`
`10 Pediatrics ............................................................................................................................. 164
`
`11 Labeling Recommendations ................................................................................................ 164
`Prescription Drug Labeling ....................................................................................... 164
`
`
`12 Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 166
`
`13 Postmarketing Requirements and Commitment ................................................................ 166
`
`14 Appendices .......................................................................................................................... 168
`References ................................................................................................................ 168
`
`Financial Disclosure .................................................................................................. 170
`
`OCP Appendices ........................................................................................................ 171
`
`Statistical and Clinical Appendices ........................................................................... 177
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`Reference ID: 4416253
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`NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761062}
`{Evenity, romosozumab}
`
`
`Table of Tables
`
`
`Table 1. Effect of Romosozumab on the Risk of New Vertebral Fractures, Clinical Fractures, and
`Nonvertebral Fractures in Studies 337 and 142 ........................................................................... 15
`Table 2: Patient Experience Data Relevant to this Application .................................................... 24
`Table 3: Summary of FDA-Approved Pharmacologic Treatment Options for Postmenopausal
`Osteoporosis ................................................................................................................................. 26
`Table 4. PMO Fracture Trials: New Morphometric Vertebral Fractures, Risk Reductions by Year
`(Compared to Placebo) ................................................................................................................. 28
`Table 5 PMO Fracture Trials: Nonvertebral Fractures, Risk Reductions by Year (compared to
`placebo) ........................................................................................................................................ 29
`Table 6: New Nonclinical Pharmacology Studies .......................................................................... 39
`Table 7: Experimental Design of Amgen Study No. 124609 (Study #2) ........................................ 41
`Table 8 Patient Profile for Subjects Who Experienced MACE and Had PK Data Available in
`Studies 20070337, 20110142 and 20110174 ............................................................................... 58
`Table 9. Listing of Clinical Trials Relevant to this Supplemental BLA ........................................... 60
`Table 10: Study 142 Sample Size Considerations ......................................................................... 70
`Table 11 Contract Research Organizations and Responsibilities .................................................. 77
`Table 12 Central Laboratories and Responsibilities ...................................................................... 78
`Table 13 Subject Disposition (Full Analysis Set) (Primary Analysis).............................................. 80
`Table 14. Important Protocol Deviations (Full Analysis Set) (Primary Analysis) .......................... 82
`Table 15. Demographic Characteristics (Full Analysis Set) (Primary Analysis) ............................. 84
`Table 16: Study 20110142 - Incidence of New Vertebral Fracture Through Month 24 – Primary
`analysis Set for Vertebral Fractures .............................................................................................. 87
`Table 17: Study 20110142 - Time to First Clinical Fracture Through Primary Analysis Period (Full
`Analysis Set) .................................................................................................................................. 88
`Table 18. Study 20110142 - Percent Change From Baseline in BMD at Lumbar Spine at Months
`12, 24, and 36 (ANCOVA LOCF, Primary Efficacy Analysis Set for BMD) ...................................... 89
`Table 19. Study 20110142 - Percent Change From Baseline in BMD at Total Hip at Months 12,
`24, and 36 (ANCOVA LOCF, Primary Efficacy Analysis Set for BMD) ............................................ 89
`Table 20. Study 20110142 - Percent Change From Baseline in BMD at Femoral Neck at Months
`12, 24, and 36 (ANCOVA LOCF, Primary Efficacy Analysis Set for BMD) ...................................... 90
`Table 21. Study 20110142 - Time to First Nonvertebral Fracture through Primary Analysis Period
`(Full Analysis Set) .......................................................................................................................... 91
`Table 22: Study 20110142 - Incidence of New Vertebral Fracture Through Month 12 – Primary
`Analysis Set for Vertebral Fractures ............................................................................................. 91
`Table 23. Study 20110142 - Subject Incidence of Clinical Fracture through Month 12 and Month
`24 (Full Analysis Set) ..................................................................................................................... 92
`Table 24. Study 20110142 - Subject Incidence of Nonvertebral Fracture through Month 12 and
`Month 24 (Full Analysis Set) ......................................................................................................... 93
`Table 25. Study 20110142 - Subject Incidence of Hip Fracture through Month 12, Month 24 and
`Primary Analysis (Full Analysis Set) ............................................................................................... 94
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`Reference ID: 4416253
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`

`NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761062}
`{Evenity, romosozumab}
`
`Table 26. Study 20110142 - Bone Mineral Density Percent Change From Baseline by
`Antiromosozumab Antibody Status Through Month 18 (Romosozumab Arm in Primary Analysis
`Set for BMD: Descriptive Statistics, Observed Data) (20110142 Primary Analysis Period) ......... 95
`Table 27: Trial 20070337 Fracture Endpoints ............................................................................. 100
`Table 28: Trial 20070337 Bone Mineral Density, Mean Percent Change, LOCF, ANCOVA ........ 101
`Table 29. Bone Mineral Density Percent Change From Baseline at Month 12 in the Pivotal
`Fracture Studies (ANCOVA Model) (Primary Efficacy Analysis Set for BMD, LOCF) ................... 105
`Table 30 Summary of Subject Incidence of Treatment-emergent Adverse Events (Safety Analysis
`Set – 20110142 Primary Analysis)............................................................................................... 109
`Table 31. Subject Incidence of Treatment-emergent Fatal Adverse Events by System Organ Class
`(Safety Analysis Set - 20110142 Primary Analysis) ..................................................................... 111
`Table 32. Subject Incidence of Treatment-emergent Serious Adverse Events by SOC and
`(cid:87)(cid:396)(cid:286)(cid:296)(cid:286)(cid:396)(cid:396)(cid:286)(cid:282) (cid:100)(cid:286)(cid:396)(cid:373) (cid:894)(cid:1096) (cid:1004)(cid:856)(cid:1009)(cid:1081) (cid:94)(cid:437)(cid:271)(cid:361)(cid:286)(cid:272)(cid:410) (cid:47)(cid:374)(cid:272)(cid:349)(cid:282)(cid:286)(cid:374)(cid:272)(cid:286) (cid:349)(cid:374) (cid:258)(cid:374)(cid:455) (cid:100)(cid:396)(cid:286)(cid:258)(cid:410)(cid:373)(cid:286)(cid:374)(cid:410) (cid:39)(cid:396)(cid:381)(cid:437)(cid:393)(cid:895) (cid:894)(cid:94)(cid:258)(cid:296)(cid:286)(cid:410)(cid:455) (cid:4)(cid:374)(cid:258)(cid:367)(cid:455)(cid:400)(cid:349)(cid:400) (cid:94)(cid:286)(cid:410)(cid:895)
`(20110142 Primary Analysis) ...................................................................................................... 113
`Table 33. Summary of Subject Incidence of Treatment-emergent Adverse Events of Interest
`(Safety Analysis Set - 20110142 Primary Analysis) ..................................................................... 117
`Table 34. Subject Incidence of Treatment-(cid:286)(cid:373)(cid:286)(cid:396)(cid:336)(cid:286)(cid:374)(cid:410) (cid:4)(cid:282)(cid:448)(cid:286)(cid:396)(cid:400)(cid:286) (cid:28)(cid:448)(cid:286)(cid:374)(cid:410)(cid:400) (cid:271)(cid:455) (cid:87)(cid:396)(cid:286)(cid:296)(cid:286)(cid:396)(cid:396)(cid:286)(cid:282) (cid:100)(cid:286)(cid:396)(cid:373) (cid:894)(cid:1096) (cid:1009)(cid:1081)
`Subject Incidence in Either Treatment Group) (Safety Analysis Set) (20110142 Primary Analysis)
`..................................................................................................................................................... 124
`Table 35 CTCAE (Version 3) Grades and Associated Abnormal Albumin-corrected Serum Calcium
`Values .......................................................................................................................................... 126
`Table 36 CTCAE (Version 3) Grades for Abnormal Serum Phosphorus Values .......................... 128
`Table 37 Subject Incidence of Treatment-emergent Injection Site Reaction, Hypersensitivity, and
`Autoimmune Disorders in the 12-Month Double-blind Period by Binding Anti-romosozumab
`Antibody Status Through Month 18 by Preferred Term (Safety Analysis Set) (20110142 Primary
`Analysis) ...................................................................................................................................... 131
`Table 38. Subject Incidence of Positively-adjudicated Cardiovascular Serious Adverse Events by
`Category and Study in the 12-Month Double-blind Period (Safety Analysis Set) (DCRI
`Adjudication of Studies 337, 142, and 174) ................................................................................ 135
`Table 39. Subject Incidence of Positively-adjudicated Cardiovascular Serious Adverse Events by
`Study in the Overall Study Period (Safety Analysis Set) (DCRI Adjudication of Studies 337, 142,
`and 174) ...................................................................................................................................... 137
`Table 40. Summary of MACE Composite and Individual Components Through Month 12 and in
`the Overall Study Period (Safety Analysis Set) (DCRI Adjudication of Studies 20070337,
`20110142, and 20110174) .......................................................................................................... 139
`Table 41 Modified-RUTH Criteria for Defining a High-risk Population for Cardiovascular Events
`..................................................................................................................................................... 143
`Table 42. Subject Incidence of Positively-adjudicated Cardiovascular Serious Adverse Event or
`Negatively Adjudicated Due to Insufficient Documentation (Safety Analysis Set) (DCRI
`Adjudication of Studies 20110174, 20070337, and 20110142) ................................................. 146
`Table 43. Comparison of Subject Incidences of All-Cause Death, Myocardial Infarction, and
`Stroke Based on Treatment-emergent Adverse Event Reporting and Adjudication by DCRI and
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`Reference ID: 4416253
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`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761062}
`{Evenity, romosozumab}
`
`the TIMI Study Group During the 12-Month Double-blind Period (Safety Analysis Set) (Studies
`20110142, 20070337, and 20110174) ........................................................................................ 147
`Table 44 Impact of Immunogenicity on Steady-State Trough Serum Romosozumab
`Concentrations in Pooled Studies 20060326, 20101291, 20070337, and 20110142. ............... 171
`Table 45 Effect of Immunogenicity on Lumbar Spine Bone Mineral Density Percent Change from
`Baseline in Study 20110142 ........................................................................................................ 172
`Table 46 Effect of Immunogenicity on Safety by Immunogenicity Status Through Month 18 in
`Study 20110142 .......................................................................................................................... 172
`Table 47 Serum Romosozumab Concentrations in Study 20110142 ......................................... 173
`Table 48 Impact of Immunogenicity on Serum Romosozumab Concentrations in Study 20110142
`..................................................................................................................................................... 173
`Table 49: Summary of PK Dataset and Identified Significant Covariates in the Original and
`Updated Population PK Reports ................................................................................................. 175
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`Reference ID: 4416253
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`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761062}
`{Evenity, romosozumab}
`
`
`Table of Figures
`
`
`Figure 1: Cross-section showing microscopic structure of the aorta ........................................... 47
`Figure 2: Diagram of typical sclerostin location in human atherosclerotic plaques .................... 48
`Figure 3 Serum Romosozumab Concentrations in Subjects Who Experienced MACE and Had PK
`Data Available in Studies 20070337, 20110142 and 20110174 ................................................... 59
`Figure 4: Study 20110142 Schema................................................................................................ 63
`Figure 5 Lumbar Spine BMD Percent Change from Baseline (Study 326 Months 0-36) ............ 102
`Figure 6 Annual Incidence of MACE in Study 20110142 (DCRI Adjudication of Study 20110142)
`..................................................................................................................................................... 142
`Figure 7: Subgroup Analysis by Modified RUTH Score: Subject Incidence of MACE in the Double-
`blind Period (DCRI Adjudication of Studies 20070337, 20110142, and 20110174) ................... 144
`Figure 8: Lumbar Spine BMD Percent Change from Baseline (Study 326 Months 0-36) .......... 154
`Figure 9: Effect of Covariates on Romosozumab PK: Steady-state AUC and Cmax ................... 176
`Figure 10. Study 20110142 Subject Incidence of New Vertebral Fracture Through Month 24 by
`Demographic and Physical Characteristic Subgroups (Primary Analysis Set for Vertebral
`Fractures, LOCF Imputation) ....................................................................................................... 177
`Figure 11. Study 20110142 Subject Incidence of New Vertebral Fracture Through Month 24 by
`Risk Factor Subgroups (Primary Analysis Set for Vertebral Fractures, LOCF Imputation) ......... 177
`Figure 12. Study 20110142- Subject Incidence of New Vertebral Fracture Through Month 24 by
`Fracture History Subgroups (Primary Analysis Set for Vertebral Fractures, LOCF Imputation) . 178
`Figure 13. Study 20110142- Subject Incidence of Clinical Fracture Through Primary Analysis
`Period by Demographic and Physical Characteristic Subgroups (Full Analysis Set) ................... 178
`Figure 14. Study 20110142- Subject Incidence of Clinical Fracture Through Primary Analysis
`Period by Risk Factor Subgroups (Full Analysis Set) ................................................................... 179
`Figure 15. Study 20110142- Subject Incidence of Clinical Fracture Through Primary Analysis
`Period by Fracture History Subgroups (Full Analysis Set) ........................................................... 179
`Figure 16. Study 20110142- Subject Incidence of Nonvertebral Fracture Through Primary
`Analysis by Risk Factor Subgroups (Full Analysis Set) ................................................................. 180
`Figure 17. Study 20110142- Subject Incidence of Nonvertebral Fracture Through Primary
`Analysis Period by Demographic and Physical Characteristic Subgroups (Full Analysis Set) ..... 180
`Figure 18. Study 20110142- Subject Incidence of Nonvertebral Fracture Through Primary
`Analysis Period by Fracture History Subgroups (Full Analysis Set) ............................................. 181
`Figure 19. Study 20110142 – Lumbar Spine Bone Mineral Density Percent Change From Baseline
`at Month 12 by Subgroups (Primary Analysis Set for BMD) ....................................................... 181
`Figure 20. Study 20110142 – Lumbar Spine Bone Mineral Density Percent Change From Baseline
`at Month 24 by Subgroups (Primary Analysis Set for BMD) ....................................................... 182
`Figure 21. Study 20110142 - Total Hip Bone Mineral Density Percent Change From Baseline at
`Month 12 by Subgroups (Primary Analysis Set for BMD) ........................................................... 182
`Figure 22. Study 20110142 - Femoral Neck Bone Mineral Density Percent Change From Baseline
`at Month 24 by Subgroups (Primary Analysis Set for BMD) ....................................................... 183
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`Reference ID: 4416253
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`8
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`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761062}
`{Evenity, romosozumab}
`
`
`Reviewers of Multi-Disciplinary Review and Evaluation
`
`DISCIPLINE
`
`REVIEWER
`
`OFFICE/
`DIVISION
`
`SECTIONS
`AUTHORED/
`ACKNOWLEDGED/
`APPROVED
`
`Gemma Kuijpers, PhD
`
`DBRUP
`
`Authored: Section 5
`
`Signature:
`
`Gemma Kuijpers
`-S
`Kimberly Hatfield, PhD
`
`DBRUP
`
`Digitally signed by Gemma Kuijpers -S
`DN: c=US, o=U.S. Government, ou=HHS,
`ou=FDA, ou=People, cn=Gemma Kuijpers -
`S, 0.9 2342.19200300.100.1.1=1300096571
`Date: 2019.04.05 10:47:34 -04'00'
`
`Approved: Section 5
`
`Signature:
`
`Kimberly P.
`Hatfield -S
`
`Digitally signed by Kimberly P Hatfield S
`DN: c=US o=U S Government ou=HHS ou=FDA
`ou=People 0 9 2342 19200300 100 1 1=1300387215
`cn=Kimberly P Hatfield S
`Date: 2019 04 05 10:54:11 04'00'
`
`Mukesh Summan, PhD
`
`DBRUP
`
`Approved: Section 5
`
`Signature:
`
`Mukesh Summan -S
`
`Digitally signed by Mukesh Summan S
`DN: c=US, o=U S Government, ou=HHS, ou=FDA, ou=People,
`cn=Mukesh Summan S,
`0 9 2342 19200300 100 1 1=2000337340
`Date: 2019 04 05 11:04:05 04'00'
`
`Ron Wange, PhD
`
`OND
`
`Approved: Section 5
`
`Signature:
`
`Ronald L. Wange -S
`
`Digitally signed by Ronald L. Wange -S
`DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People,
`0.9.2342.19200300.100.1.1=1300236480, cn=Ronald L. Wange -
`S
`Date: 2019.04.05 11:58 57 -04'00'
`
`Signature:
`
`Digitally signed by Lin Zhou -S
`DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People,
`cn=Lin Zhou -S, 0.9.2342.19200300.100.1.1=2000423233
`Date: 2019.04.05 14:20:23 -04'00'
`
`Pharmacology/
`Toxicology
`Reviewer
`
`Pharmacology/
`Toxicology
`Team Leader
`
`Pharmacology/
`Toxicology
`Supervisor
`
`Pharmacology/
`Toxicology Acting
`Associate Director
`
`Clinical Pharmacology
`Reviewer
`
`Clinical Pharmacology
`Team Leader
`
`Pharmacometrics
`Reviewer
`
`Pharmacometrics
`Team Leader
`
`Lin Zhou, PhD
`OCP/DCPIII
`Lin Zhou -S
`Jie Wang, PhD
`OCP/DCPIII
`Jie Wang -S
`OCP/DPM
`
`Signature:
`
`Fang Li, PhD
`
`Signature:
`
`Fang Li -S
`
`Jingyu (Jerry) Yu, PhD
`OCP/DPM
`Fang Li -S Digitally signed by Fang Li -S
`
`Signature:
`
`DN: c=US, o=U.S. Government, ou=HHS,
`ou=FDA, ou=People, cn=Fang Li -S,
`0.9.2342.19200300.100.1.1=1300430137
`Date: 2019.04.05 16:00:58 -04'00'
`
`Authored: Section 6, 14.3
`
`Approved: Section 6, 14.3
`
`Digitally signed by Jie Wang -S
`DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, cn=Jie Wang
`-S, 0.9.2342.19200300.100.1.1=2000739081
`Date: 2019.04.05 15:46:23 -04'00'
`
`Authored: Section 6, 14.3
`Digitally signed by Fang Li -S
`DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People,
`cn=Fang Li -S, 0.9.2342.19200300.100.1.1=1300430137
`Date: 2019.04.05 15:54:52 -04'00'
`
`Approved: Section 6, 14.3
`signed as proxy for
`Jingyu (Jerry) Yu
`
`
`
`Reference ID: 4416253
`
`
`
`9
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`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761062}
`{Evenity, romosozumab}
`
`
`Shirley Seo, PhD
`
`OCP/DCPIII
`
`Signature:
`
`Shirley K. Seo -S
`
`Jia Guo, PhD
`
`Signature:
`
`OB/DB3
`Jia Guo -S Digita ly signed by Jia Guo S
`
`DN: c US o U S Government ou HHS
`ou FDA ou People cn Jia Guo S
`0 9 2342 19200300 100 1 1 2000520093
`Date: 2019 04 05 19:29:51 04'00'
`
`Approved: Section 6, 14.3
`Digitally signed by Shirley K. Seo -S
`DN: c=US, o=U.S. Government, ou=HHS, ou=FDA,
`ou=People, cn=Shirley K. Seo -S,
`0.9.2342.19200300.100.1.1=1300365375
`Date: 2019.04.05 16:10:49 -04'00'
`Authored: Sections 7, 8
`
`Clinical Pharmacology
`Division Director
`
`Biostatistics
`
`Biostatistics
`
`Biostatistics
`Supervisor
`
`Clinical
`
`Clinical/Cross Discipline
`Team Leader
`
`DBRUP Director
`Acting ODE 3 Director
`
`
`
`
`
`
`Reference ID: 4416253
`
`Signature:
`
`Signature:
`
`Mahboob Sobhan, PhD
`Mahboob
`Sobhan -S
`OB/DB3
`Gregory Levin, PhD
`Gregory P. Levin
`-S
`Jacqueline Karp, MD
`
`OB/DB3
`
`Digitally signed by Mahboob Sobhan -S
`DN: c=US, o=U.S. Government, ou=HHS,
`ou=FDA, ou=People, cn=Mahboob Sobhan
`-S, 0.9.2342.19200300.100.1.1=1300084769
`Date: 2019.04.08 08:58:29 -04'00'
`
`Digitally signed by Gregory P Levin S
`DN: c=US o=U S Government ou=HHS ou=FDA
`ou=People 0 9 2342 19200300 100 1 1=2001127703
`cn=Gregory P Levin S
`Date: 2019 04 08 12:50:50 04'00'
`
`OND/DBRUP
`
`Approved: Sections 7, 8
`
`Approved: Sections 7, 8
`
`Authored: Sections 1, 2, 3, 7, 8,
`11
`
`Signature:
`
`Jacqueline E. Karp -S Digitally signed by Jacqueline E. Karp -S
`
`DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People,
`0.9.2342.19200300.100.1.1=2002101371, cn=Jacqueline E. Karp -S
`Date: 2019.04.08 14:53:25 -04'00'
`
`Theresa Kehoe, MD
`
`OND/DBRUP
`
`Authored Sections 1, 4, 8.4, 9
`
`Signature: see DARRTs signature page
`
`Hylton Joffe, MD, MMSc
`
`OND/DBRUP/ODE3
`
`Approved: All Sections
`
`Signature: see DARRTs signature page
`
`
`
`
`
`10
`
`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761062}
`{Evenity, romosozumab}
`
`
`
`Additional Reviewers of Application
`
`DCARP
`OPQ
`Microbiology
`OPDP
`DMPP
`OSE/DEPI
`
`OSE/DMEPA
`OSE/DRISK
`
`Fortunato Senatore, Martin Rose, Norman Stockbridge
`Chen Sun, Scott Dallas, Michael Shanks, Patrick Lynch
`Lakshmi Rani Narasimhan, Dupeh Palmer
`Jina Kwak
`Aman Sarai, LaShawn Griffiths, Marcia Williams
`Wei Liu, Jie Li, David Moeny, Nabila Sadiq, Justin
`Mathew, Grace Chai
`Denise Baugh, Celeste Karpow, Lolita White
`Jacqueline Sheppard, Laura Zendel, Jamie Wilkins
`Parker
`Tae Hyun Jung, Clara Kim, Mark Levenson
`Leila Lackey, Sarah Eggers
`Sarah Mollo, Alan Stevens
`Kristie Baisden, Tamara Johnson, Lynne P. Yao
`DCARP=Division of Cardiovascular and Renal Products
`OPQ=Office of Pharmaceutical Quality
`OPDP=Office of Prescription Drug Promotion
`OSE= Office of Surveillance and Epidemiology
`DEPI= Division of Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DRISK=D