CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 208564Orig1s000 CLINICAL REVIEW(S) Clinical Review Theresa H. van der Vlugt, M.D., M.P.H. Resubmission NDA 208564 Imvexxy™ (estradiol vaginal inserts) 4 mcg and 10 mcg CLINICAL REVIEW Application Type Class 2 Resubmission Application Number(s) NDA 208564 Priority or Standard Standard Submit Date(s) November 29, 2017 Received Date(s) November 29, 2017 PDUFA Goal Date May 29, 2018 Division/Office Division of Bone, Reproductive, and Urologic Products/Office of Drug Evaluation III Reviewer Name(s) Theresa H. van der Vlugt, M.D., M.P.H. Review Completion Date May 15, 2018 Established/Proper Name Estradiol vaginal insert (Proposed) Trade Name Imvexxy™ Applicant TherapeuticsMD Dosage Form(s) Intravaginal inserts Applicant Proposed Dosing 4 mcg insert administer intravaginally daily for 2 weeks, then 4 Regimen(s) mcg insert administered intravaginally two times per week (approximately 3 to 4 days apart) 10 mcg insert administered intravaginally daily for 2 weeks, then 10 mcg insert administered intravaginally two times per week (approximately 3 to 4 days apart) Applicant Proposed Treatment of moderate to severe dyspareunia, a symptom of Indication(s)/Population(s) vulvar and vaginal atrophy, due to menopause Recommendation on Approval Regulatory Action Recommended Postmenopausal women Indication(s)/Population(s) (if applicable) CDER Clinical Review Template 1 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 42696514271237 Clinical Review Theresa H. van der Vlugt, M.D., M.P.H. Resubmission NDA 208564 Imvexxy™ (estradiol vaginal inserts) 4 mcg and 10 mcg Table of Contents Glossary ..........................................................................................................................................6 1. Executive Summary.................................................................................................................8 1.1. Product Introduction........................................................................................................8 1.2. Conclusions on the Substantial Evidence of Effectiveness...............................................8 1.3. Benefit-Risk Assessment ..................................................................................................9 1.4. Patient Experience Data.................................................................................................15 2. Therapeutic Context..............................................................................................................15 2.1. Analysis of Condition......................................................................................................15 2.2. Analysis of Current Treatment Options .........................................................................16 3. Regulatory Background .........................................................................................................17 3.1. U.S. Regulatory Actions and Marketing History.............................................................17 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................18 3.3. Foreign Regulatory Actions and Marketing History .......................................................27 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. Clinical Microbiology......................................................................................................31 4.4. Nonclinical Pharmacology/Toxicology ...........................................................................32 4.5. Clinical Pharmacology ....................................................................................................32 4.6. Devices and Companion Diagnostic Issues ....................................................................36 4.7. Consumer Study Reviews...............................................................................................36 5. Sources of Clinical Data and Review Strategy .......................................................................37 5.1. Table of Clinical Studies .................................................................................................38 5.2. Review Strategy .............................................................................................................38 6. Review of Relevant Individual Trials Used to Support Efficacy .............................................38 6.1. TXV14-01........................................................................................................................38 6.1.1. Study Design ...........................................................................................................38 CDER Clinical Review Template 2 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 42696514271237 Clinical Review Theresa H. van der Vlugt, M.D., M.P.H. Resubmission NDA 208564 Imvexxy™ (estradiol vaginal inserts) 4 mcg and 10 mcg 6.1.2. Study Results ..........................................................................................................39 7. Integrated Review of Effectiveness.......................................................................................40 7.1. Assessment of Efficacy Across Trials..............................................................................40 7.2. Additional Efficacy Considerations.................................................................................40 7.2.1. Considerations on Benefit in the Postmarket Setting.............................................40 7.2.2. Other Relevant Benefits..........................................................................................40 7.3. Integrated Assessment of Effectiveness ........................................................................41 8. Review of Safety....................................................................................................................41 8.1. Safety Review Approach ................................................................................................41 8.2. Review of the Safety Database ......................................................................................42 8.2.1. Overall Exposure.....................................................................................................63 8.2.2 Relevant characteristics of the safety population: .................................................64 8.2.3 Adequacy of the safety database: ..........................................................................64 8.3. Adequacy of Applicant’s Clinical Safety Assessments....................................................65 8.4. Safety Results.................................................................................................................65 8.5. Analysis of Submission-Specific Safety Issues ................................................................66 8.5.1. General and Endometrial Safety.............................................................................66 8.6. Safety Analyses by Demographic Subgroups .................................................................69 8.7. Specific Safety Studies/Clinical Trials .............................................................................69 8.8. Additional Safety Explorations.......................................................................................69 8.9. Safety in the Postmarket Setting ...................................................................................70 8.10. Integrated Assessment of Safety................................................................................70 9. Advisory Committee Meeting and Other External Consultations .........................................73 10. Labeling Recommendations ..................................................................................................73 10.1. Prescription Drug Labeling .........................................................................................73 11. Risk Evaluation and Mitigation Strategies (REMS) ................................................................77 12. Postmarketing Requirements and Commitments.................................................................77 13. Appendices............................................................................................................................77 CDER Clinical Review Template 3 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 42696514271237 Clinical Review Theresa H. van der Vlugt, M.D., M.P.H. Resubmission NDA 208564 Imvexxy™ (estradiol vaginal inserts) 4 mcg and 10 mcg 13.1. References..................................................................................................................77 13.2. Financial Disclosure ....................................................................................................77 CDER Clinical Review Template 4 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 42696514271237 Clinical Review Theresa H. van der Vlugt, M.D., M.P.H. Resubmission NDA 208564 Imvexxy™ (estradiol vaginal inserts) 4 mcg and 10 mcg Table of Tables