Transcription
CENTER FOR DRUG EVALUATION ANDRESEARCHAPPLICATION NUMBER:201110Orig1s000CLINICAL REVIEW(S)
Clinical ReviewRegina Zopf, MD, MPHNDA 201110MILPROSA (Progesterone vaginal ring/Progesterone, USP,(b) (4)CLINICAL REVIEWApplication TypeApplication Number(s)Priority or StandardSubmit Date(s)Received Date(s)PDUFA Goal DateDivision/OfficeReviewer Name(s)Review Completion DateEstablished/Proper Name(Proposed) Trade NameApplicantDosage Form(s)Applicant Proposed DosingRegimen(s)Applicant ProposedIndication(s)/Population(s)505(b)(2) NDA Resubmission (Class 2)201110PriorityOctober 29, 2019October 29, 2019April 29, 2019Division of Urology, Obstetrics and Gynecology [(DUOG),formerly the Division of Bone, Reproductive and Urology(DBRUP)]Regina Zopf, MD, MPHApril 24, 2020(b) (4)Progesterone vaginal ring/Progesterone, USP,MILPROSAFerring Pharmaceutical, IncVaginal ringOne vaginal system inserted starting the day after oocyteretrieval, replaced weekly, continuing for up to 10 weeks totaldurationTo support embryo implantation and early pregnancy (up to 10weeks post-embryo transfer) by supplementation of corpusluteum function as part of an Assisted Reproductive Technology(ART) treatment for infertile women (under age 35)APPROVALRecommendation onRegulatory ActionRecommended Population Infertile women under the age of 35 who are undergoing ARTCDER Clinical Review TemplateVersion date: September 6, 2017 for all NDAs and BLAsReference ID: 460144045976631
Clinical ReviewRegina Zopf, MD, MPHNDA 201110MILPROSA (Progesterone vaginal ring/Progesterone, USP,(b) (4)Table of ContentsGlossary .61.Executive Summary .81.1.Product Introduction.81.2.Conclusions on the Substantial Evidence of Effectiveness.91.3.Benefit-Risk Assessment .91.4.Patient Experience Data.142.Therapeutic Context.162.1.Analysis of Condition.162.2.Analysis of Current Treatment Options .163.Regulatory Background .193.1.U.S. Regulatory Actions and Marketing History.193.2.Summary of Pre-submission/Submission Regulatory Activity .204.Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions onEfficacy and Safety .424.1.Office of Scientific Investigations (OSI) .424.2.Product Quality .434.3.Clinical Microbiology.434.4.Nonclinical Pharmacology/Toxicology .434.5.Clinical Pharmacology .434.6.Devices and Companion Diagnostic Issues .444.7.Consumer Study Reviews.445.Sources of Clinical Data and Review Strategy .445.1.Table of Clinical Studies .445.2.Review Strategy .44A single clinical safety.446.Review of Relevant Individual Trials Used to Support Efficacy .457.Integrated Review of Effectiveness .45CDER Clinical Review TemplateVersion date: September 6, 2017 for all NDAs and BLAsReference ID: 460144045976632
Clinical ReviewRegina Zopf, MD, MPHNDA 201110MILPROSA (Progesterone vaginal ring/Progesterone, USP,8.(b) (4)Review of Safety.458.1.Safety Review Approach .458.1.1. Study Design .458.2.Review of the Safety Database .548.2.1. Overall Exposure.548.2.2. Relevant characteristics of the safety population: .568.2.3. Adequacy of the safety database: .578.3.Adequacy of Applicant’s Clinical Safety Assessments.578.3.1. Issues Regarding Data Integrity and Submission Quality.578.3.2. Categorization of Adverse Events .578.3.3. Routine Clinical Tests .588.4.Safety Results.598.4.1. Deaths.598.4.2. Serious Adverse Events.598.4.3. Dropouts and/or Discontinuations Due to Adverse Effects.618.4.4. Significant Adverse Events.628.4.4.1.Primary and Secondary Endpoints: Spontaneous Abortions.628.4.4.2.Adverse Events of Special Interest .638.4.5. Treatment Emergent Adverse Events and Adverse Reactions .648.4.6. Laboratory Findings .668.4.7. Vital Signs.688.4.8. Electrocardiograms (ECGs) .698.4.9. QT .698.4.10.Immunogenicity.708.5.Analysis of Submission-Specific Safety Issues .708.6.Safety Analyses by Demographic Subgroups .708.7.Specific Safety Studies/Clinical Trials .708.8.Additional Safety Explorations .708.8.1. Human Carcinogenicity or Tumor Development .708.8.2. Human Reproduction and Pregnancy.718.8.3. Pediatrics and Assessment of Effects on Growth .72CDER Clinical Review TemplateVersion date: September 6, 2017 for all NDAs and BLAsReference ID: 460144045976633
Clinical ReviewRegina Zopf, MD, MPHNDA 201110MILPROSA (Progesterone vaginal ring/Progesterone, USP,(b) (4)8.8.4. Overdose, Drug Abuse Potential, Withdrawal, and Rebound.728.9.Safety in the Postmarket Setting .728.9.1. Safety Concerns Identified Through Postmarket Experience .728.9.2. Expectations on Safety in the Postmarket Setting.728.9.3. Additional Safety Issues From Other Disciplines .728.10.9.Integrated Assessment of Safety.72Advisory Committee Meeting and Other External Consultations .7210. Labeling Recommendations .7210.1.Prescription Drug Labeling .7310.2.Nonprescription Drug Labeling.7411. Risk Evaluation and Mitigation Strategies (REMS) .7412. Postmarketing Requirements and Commitments .7413. Appendices.7413.1.References.7413.2.Financial Disclosure .7413.3.Sample Progesterone Treatment Satisfaction Measure Questionnaire.76CDER Clinical Review TemplateVersion date: September 6, 2017 for all NDAs and BLAsReference ID: 460144045976634
Clinical ReviewRegina Zopf, MD, MPHNDA 201110MILPROSA (Progesterone vaginal ring/Progesterone, USP,(b) (4)Table of TablesTable 1Patient Experience Data Relevant to this Application.15Table 2Products Used for the Proposed Indication .18Table 3Trial Overview .46Table 4Non-Investigational Treatment Products Employed in Trial 000293 .51Table 5Power Calculations for Trial 000293.54Table 6Progesterone Vaginal System Exposure in Trial 000293 .54Table 7Demographics of Women in Trial 000293.56Table 8Treatment Emergent Serious Adverse Events, Trial 000293, MILPROSA N 254.59Table 9Adverse Events Leading to Discontinuation in Trial 000293, MILPROSA N 254 .61Table 10 Results of Primary and Secondary Endpoints Analyses:.62Table 11 Adverse Events of Special Interest Occurring in the Treatment Phase, Trial 000293 64Table 12 Frequently occurring TEAEs by Participant ( 2% of participants), Trial 000293 .64Table 13 Adverse Events Graded as Severe, Trial 000293 .66Table 14 Clinically Relevant Results of Laboratory Values from Trial 000293- Shift TableAnalysis, Safety Population.66Table 15 Vital Sign of Women Participating in Trial 000293- Shift Table Analysis, SafetyPopulation 68CDER Clinical Review TemplateVersion date: September 6, 2017 for all NDAs and BLAsReference ID: 460144045976635
Clinical ReviewRegina Zopf, MD, MPHNDA 201110MILPROSA (Progesterone vaginal ring/Progesterone, USP,(b) AAFDASIAGCPGnRHGRMPICHICSIIMINDISEISSadvisory committeeadverse eventadverse reactionassisted reproductive technologybiologics license applicationBest Pharmaceuticals for Children ActBenefit Risk FrameworkCenter for Biologics Evaluation and ResearchCenter for Drug Evaluation and ResearchCenter for Devices and Radiological HealthCross-Discipline Team LeaderCode of Federal Regulationschemistry, manufacturing, and controlsCoding Symbols for Thesaurus of Adverse Reaction Termscase report formcontract research organizationclinical review templateclinical study reportControlled Substance Staffdata monitoring committeeDivision of Medication Error and Prevention Analysiselectrocardiogramelectronic common technical documentelements to assure safe useFood and Drug AdministrationFood and Drug Administration Amendments Act of 2007Food and Drug Administration Safety and
CDER Clinical Review Template : Version date: September 6, 2017 for all NDAs and BLAs : Reference ID: 4597663Reference ID: 4601440 : 5 : Clinical Review Regina Zopf, MD, MPH NDA 201110 MILPROSA (Progesterone vaginal ring/Progesterone, USP, (b) (4) Glossary : AC advisory committee AE adverse event AR adverse reaction ART assisted reproductive technology BLA biologics license application
