临床试验总结报告英文版.pdf

临床试验总结报告英文版.pdf

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Reviewer:

CynthiaA.Rask,M.D.Through:

MarcK.Walton,M.D.,Ph.D.KarenWeiss,M.D.Date:

23January2002BiologicsLicenseApplicationSupplementMedicalOfficersReviewRebif（Interferon-1a）FORTREATMENTOFRELAPSING-REMITTINGMULTIPLESCLEROSISSubmittedbySerono,Inc.STN#:

103780/0RebifBLA（STN#103780/0）Serono,Inc.Page2of66TABLEOFCONTENTSOVERVIEW.4Scopeofthisreview.4AbbreviationsandDefinitionsofTermsUsedinThisReview.5INTRODUCTION.7MultipleSclerosis.7BackgroundandDiagnosticCriteria.7CurrentTreatmentofMS.8TheOrphanDrugActandOrphanDrugExclusivityRegulations.8OverviewofPriorClinicalStudiesofRebif.10PROTOCOLXXXXXXXXXX.12Objectives.12Design.12MaterialSource.13Randomization.14InclusionCriteria.14ExclusionCriteria.14Treatment.15EvaluationsPerformedDuringtheStudy.17EfficacyEndpoints.21PrimaryEndpoint.21SecondaryEndpoints.21TertiaryEndpoints.21SafetyEndpoints.21SafetyMeasurementsAnalyzed.21StatisticalAnalysisPlan.22DeterminationofSampleSize.22AnalysisPopulations.22PlannedInterimAnalysis.23SignificanceTesting,AllocationofAlpha.23AnalysisofBaselineParameters.23PrimaryEndpointProportionofSubjectsExacerbation-Freeat24Weeks.24RebifBLA（STN#103780/0）Serono,Inc.Page3of66SecondaryEndpointsMRIAnalyticMethods.24SafetyAnalyses.26StudyAdministration.26STUDYRESULTS.27FormalProtocolModifications.27ChangesintheConductoftheStudyorPlannedAnalyses.27ProtocolDeviations/Violations.28StudyConductatSpecificStudySites.30SubjectEnrollmentandDisposition.31Randomization.31TimeonStudy.31TimeonTreatment:

.32AdverseEventsLeadingtoPrematureDiscontinuation.33DemographicsandBaselineCharacteristics.35EFFICACYRESULTS.38PrimaryEndpointResults.38CBER-PerformedAnalysesonthePrimaryEndpoint.42SecondaryEndpoints.48MRI-DeterminedCUActivity.48ExacerbationRateperSubject.49MeanNumberofT2ActiveLesionsperSubjectperScan.50TertiaryEndpoints.51ExploratoryAnalyses.53SafetyAnalyses.55SeriousAdverseEventsandDeaths.55ImportantRareSeriousAdverseEvents.58SevereAdverseEvents.59AnalysisbyBodySystemandEvent.60Pregnancies.62DevelopmentofAntibodiestoInterferon-.62AssessmentandConclusions.63FinancialDisclosureStatements.65References.65RebifBLA（STN#103780/0）Serono,Inc.Page4of66OverviewInterferon-1a（Rebif）hasbeenunderdevelopmentbySerono,Inc.forthetreatmentofmultiplesclerosis（MS）.Serono,Inc.submittedaBiologicsLicenseApplication（BLA）onFebruary27,1998fortheapprovalofRebifforthetreatmentofpatientswithrelapsing-remittingMS（RRMS）.Thefocusoftheapplicationwasa560-subjectstudythatwasarandomized,double-blind,placebo-controlledstudyof22gvs.44gRebifvs.placeboadministeredsubcutaneously（SC）threetimesperweekfor2years.Theapplicationalsocontainedadditionalopen-labelsafetydatafromotherstudies.BasedonthereviewoftheBLAsubmissionconductedbyCBER,itwasconcludedthatbothdosesofRebifweredemonstratedtobesafeandeffectiveandtobeapprovablefortreatmentofRRMS.However,SeronowaspreventedfrommarketingRebifintheUnitedStatesbytheOrphanDrugExclusivitypreviouslygrantedtoBiogenforthemarketingoftheirinterferon-1a,AvonexandtoBerlex/Chironforthemarketingoftheirinterferon-1b,BetaseronBetaseronsexclusivityexpiredinJuly2000.Rebifwas,however,successfullyapprovedandmarketedinothercountries,andthushasbeencommerciallyavailableinotherportionsoftheworldforseveralyears.ThesubjectofthecurrentBLAamendmentisacomparativestudythatSeronoconductedtocomparetheefficacyofRebiftomarketeddosesofAvonexinthetreatmentofrelapsing-remittingMS.ThestudydesignwasdiscussedwithCBERandthedesignwasagreeduponpriortoinitiationofthestudy.Thestudywasarandomized,open-labelstudyinwhichsubjectswithRRMSweretreatedwitheitherRebif44gSCthreetimesperweekorAvonex30gIMonceweekly,withneurologicexaminationsperformedbyphysiciansblindedtothetreatmentassignmentandwithsubjectsMRIsreadatacentralreadingfacilitybyneuroradiologistsblindedtotreatmentassignment.Althoughthedurationofthestudywastobe48weeks,thepre-specifiedprimaryoutcomemeasurewastheproportionofsubjectswhoremainedrelapse-freefollowing24weeksoftreatment.Supportiveevidence（secondaryendpoints）werecomparisonsofMRIabnormalities.TheApplicantconductedandsubmittedthisBLAamendmentinthebeliefthatdemonstrationofsuperiorclinicalbenefitofRebifoverAvonexwouldallowthemtobreakBiogensorphandrugexclusivityandthus,tomarketRebifintheU.S.forthetreatmentofrelapsing-remittingMS.ScopeofthisreviewThefocusofthisdocumentisuponefficacyinformationobtainedprimarilyfromasinglestudy,XXXXXXXXXX,arandomized,open-labelcomparativestudyoftheuseofRebif44gadministeredS