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VaccinesandRelatedBiologicalProductsAdvisoryCommittee(VRBPAC)May21,2002Prevnar,PneumococcalConjugateVaccine7-valent,forthePreventionofAcuteOtitisMedia,R.DouglasPratt,M.D.,M.P.H.,汽车防盗器,ReviewTeam,JingyeeKou,Ph.D.MarionGruber,Ph.D.CarlFrasch,Ph.D.,ProposedIndication,ForactiveimmunizationofinfantsandtoddlersagainstinvasivediseaseandotitismediacausedbyStreptococcuspneumoniaeduetocapsularserotypesincludedinthevaccine(4,6B,9V,14,18C,19F,23F),RegulatoryBackground,November1999February2000June2000May2001October2001March2002May2002,VRBPACforinvasivediseasePrevnarlicensedforpreventionofinvasivediseaseAOMlicenseamendmentsubmittedFDALettertosponsorResponsetoFDAletterreceivedSecondFDAlettertosponsor;majoramendment-Finnishfollow-updataVRBPACforotitismedia,GlobalIssues,EfficacyestimatesforAOMoutcomesarecomparativelylowforpreventivevaccinesPossibleincreasedriskofAOM(negativeefficacy)forpneumococcalserotypesnotincludedinPrevnarPotentialforunrealisticpublicexpectationsregardingbenefitinpreventingAOM,CommentsfromMedicalCommunity:CorrespondencetoNewEnglandJournalofMedicine,Clinicalsignificanceofoveralltreatmenteffectquestioned(LavinA;DamoiseauxR;CantekinE;SauderK)Concernthatlimitedbenefitmaybemisunderstoodbythepublic(SauderK)Concernthatcredibilityofexistingrecommendationsmaybecompromised(SauderK)MisunderstandingofFDAactiontakenregardingAOM(CantekinE),ClinicalStudiesReviewed,OutlineofFDAPresentation,IntroductionEfficacydatafromFinnishOMstudySupplementaryanalysesFinnishfollow-upstudyEfficacydatafromtheNCKPstudySafetydatafromFinnishOMstudyConsiderationsQuestionstotheCommittee,FinnishOMStudyPrimaryObjective,Determinetheprotectiveefficacyofthepneumococcalconjugatevaccineagainstculture-confirmedpneumococcalacuteotitismedia(AOM)duetovaccineserotypes,FinnishOMStudySecondaryObjectives,Determine:EfficacyusingdifferentlevelsofetiologicdiagnosisEfficacyinpreventingnasopharyngealcarriageAntibodyresponseSafetyandtolerability,FinnishOMStudy:ElementsoftheStudyDesign,Randomizedequallytooneof3vaccines:PncCRM(Wyeth-Lederle)PncOMP(Merck)HBV(Control)OnlydatarelatingtoPncCRMwereprovidedintheapplicationDouble-blindHealthy2montholdinfantsenrolled,FinnishOMStudy:VaccineScheduleandConcurrentImmunizations,FinnishOMstudy,CasesurveillanceandascertainmentFreeaccesstostudyclinics7days/weekChildrenbroughttostudyclinicsforrespiratoryinfectionsorsymptomssuggestingAOMMyringotomywithaspirationofmiddleearfluidforculture,ifAOMdiagnosedatthevisitIfS.pneumoniaefound,theserotypewasdeterminedFollow-upofeachchilduntilage2years,FinnishOMStudy:ClinicalDefinitionofAcuteOtitisMedia,Visuallyabnormaltympanicmembrane(inregardtocolor,position,and/ormobility)suggestingeffusioninthemiddleearcavityAndatleastoneof:fever,earpain,irritability,diarrhea,vomiting,acuteotorrheanotcausedbyexternalotitis,orothersymptomsofrespiratoryinfection.,FinnishOMStudy:AOMEfficacyEndpoints,Primary:AOMepisodesduetovaccineserotypesSecondary:FirstandSubsequentAOMepisodesduetovaccineserotypesOther:AOMduetovaccineserotypesbydoseAllpneumococcalAOM,regardlessofserotype(cultureand/orPCR)AllAOMepisodeswithMEF,regardlessofetiologyAllAOMepisodesregardlessofetiologyChildrenwithrecurrentAOM,FinnishOMStudy-DefinitionofPrimaryEndpoint,AOMepisodeduetovaccineserotypesAtleast30dayssincebeginningofpreviousAOMduetothesameserotypeOr,anyintervalfordifferentvaccineserotypeCultureconfirmed,FinnishOMStudy:PrimaryEndpointDefinition,FinnishOMStudy-AnalysisofPrimaryEndpoint,GeneralizedCoxregressionmodelwithAnderson-GillcountingmethodRiskofAOMestimated“piecewise”,i.e.,fromeventtoeventAssumesproportionalhazardsbetweengroupsovertimeRobustvarianceestimatesusedtocompensateforinterdependencyofeventswithinsubjectsProvidesaveragevaccineeffectonAOMepisodes,FinnishOMStudy-DefinitionsofFollow-upPeriods,Perprotocol(PP)follow-up:Begins2weeksafterthe3rdvaccinedoseIntent-to-treat(ITT)follow-up:Beginsattimeof1stvaccinedose,FinnishOMStudy:SelectedPopulationCharacteristics,FinnishOMStudy-PrimaryAnalysis,AOMduetoVaccineSerotypes,FinnishOMStudy-AOMduetoIndividualVaccineSerotypes,(Intent-to-treat),FinnishOMStudy-SecondaryAnalyses,FirstandSubsequentAOMEpisodesduetoVaccineSerotypes,FinnishOMStudy-EfficacyforAllCulture-ConfirmedPneumococci,RegardlessofSerotype,FinnishOMStudy-EfficacyforVaccine-RelatedSerotypes,FinnishOMStudy-AOMduetoIndividualVaccine-RelatedSerotypes,(Intent-to-treat),FinnishOtitisMediaStudy-EfficacyforVaccine-UnrelatedPneumococcalSerotypes,FinnishOtitisMediaStudy-EfficacyforRecurrentAOM*,FinnishOtitisMediaStudy-EfficacyforOtherPlannedAnalyses,FinnishOMStudy-EfficacyforNasopharyngealCarriageofVaccineSerotypes(perprotocol),FinnishOMStudySerumGeometricMeanAntibodyConcentration(GMC)After3rdand4thDoses,FinnishOMStudySerumAntibodyConcentrations(GMC)andSerotype-SpecificEfficacy,FinnishOtitisMediaStudyInvasiveDiseaseDuetoPneumococcus,FinnishOtitisMediaStudy:ReviewIssuesandSupplementaryAnalyses,FinnishOMStudy:AnalysisofCovariatesEfficacyEstimatesAdjustedforGender,AOMPriortoEnrollment,GestationalAge,BirthWeight,Daycare,Breast-feeding,andHouseholdSmoking,FinnishOMStudy:ExamplefromtheData,MultipleEpisodesDuetoSameSerotype,FinnishOMStudy:ExamplesfromtheData,MultipleEpisodesDuetoSameSerotype,FinnishOMStudySupplementaryAnalysis:SubsequentAOMEpisodesduetoSameSerotypeExcluded,VaccineSerotypes(PP),FinnishOMStudySupplementaryAnalysis:SubsequentAOMEpisodesduetoSameSerotypeExcluded,AllPneumococcalSerotypes(PerProtocol),FinnishOMStudySupplementaryAnalysis:PneumococcalAOMbyPCR/Culture,FinnishOMStudySupplementaryAnalysis*:AntibioticUse,FinnishOMStudy-SupplementaryAnalysis:FirstTympanostomyTubePlacement,FinnishOMFollow-upStudyTympanostomyTubePlacement,Toassesslong-termeffectofvaccineonproceduresforeartubeplacementChildrenevaluatedat4-5yearsofageUnblindedTwopopulationsevaluated:Volunteersinfollow-upstudy,N=756Originalrandomizedpopulation,N=1662,FinnishOMFollow-upStudyPrimaryAnalysis,RateofEarTubePlacementamongChildrenEnrolledinFollow-upStudy,FinnishOMFollow-upStudySecondaryAnalysis,RateofEarTubePlacementamongAllChildrenFollowedto4-5yearsofAge,NorthernCaliforniaKaiserPermanente(NCKP)OtitisMediaEfficacyResults,NorthernCaliforniaKaiserPermanente(NCKP)Study:ElementsofStudyDesign,Randomized,double-blindInvestigationalmeningococcalCconjugatevaccinecontrolAOMasecondaryendpointNostandardizedAOMclinicalcasedefinitionNotympanocentesisorroutinecultureofMEFAutomateddatabasesearchestoidentifyOMdiagnoses,NCKPStudy:CaseDefinitions,AOMDiagnosis:BasedonclinicalpracticeAOMEpisode:AclinicvisitatwhichAOMwasdiagnosed,andatleast21dayshadelapsedsinceanypreviousvisitforAOMFrequentAOM:3AOMepisodeswithin6months,or4episodeswithin12months,NCKPStudy:ProspectivelyDefinedAOMEndpoints,Primary:AllAOMepisodesSecondary:FirstAOMepisodeFrequentAOMFirsttympanostomytubeAllOMclinicvisitsRupturedeardrums,NCKPStudy:PrimaryAnalysis,OverallReductioninAOMEpisodes,NCKPStudy:SecondaryAnalysis,ReductioninRiskofatLeast1Episode,NCKPStudy:FrequentAcuteOtitisMedia,NCKPStudy:FirstTympanostomyTubePlacement,NCKPStudy:RupturedEarDrumswithPneumococcusIsolated,NCKPStudy:SerotypeDistributionofRupturedEarDrumswithPneumococcusIsolated(ITT),NCKPStudy:EfficacyThroughExtendedFollow-up(ITT),SummaryofEfficacyEstimates(ITT),FinnishOtitisMediaStudy:SafetyAnalysis,FinnishOMStudy:SafetyAnalysis,RelevanceofsafetydatatoUSpopulationislimited:UseofconcurrentDTwP-Hibcombinationvaccinesforfirst3doses,ratherthanDTaP,complicatesassessmentsofsystemicreactionsHomogeneousstudypopulationStudynotlargeenoughtodetectuncommonadverseevents,FinnishOMStudy:SafetyAnalysis,LocalandSystemicReactions,First3Doses,FinnishOMStudy:SafetyAnalysis,LocalandSystemicReactions,4thDose,FinnishOMStudy:SafetyAnalysis,Conclusions,SafetydataareconsistentwithearlierobservationsregardingthesafetyofPrevnarIncreasedrateoflow-gradefeverComplicationsofpost-vaccinationfeverwereuncommonNonewsafetyconcernswereidentified,Considerations,RequiredLevelofEfficacy,TheminimumlevelofefficacyrequiredforlicensureofapreventivevaccineisnotspecificallyaddressedbyFDAregulationsorpublishedguidance.,Considerations:LicensureofOtherPneumococcalVaccinesforOtitisMedia,AOMindicationshouldstandonitsown.LicenseapplicationsfornewpneumococcalvaccinesforpreventionofAOMmaynotincludeevidenceofefficacyforpreventionofinvasivedisease.Ifapproved,alevelofefficacy,preferredendpoints,andtypeofdata(numberoftrials)sufficientforapprovalforAOMwouldbeestablished.PreventionofmoreAOMepisodeswithlessvaccine-serotype-specificefficacyisapossiblescenario.,Considerations:Descriptionofthetreatmenteffect,PrimaryoutcomesinNCKPstudyandFinnishOMstudydifferPreventionofAOMduetovaccineserotypesdoesnotcapture:Positivetreatmenteffectonvaccine-relatedpneumococcalserotypesNegativeefficacyforunrelatedpneumococcalserotypesEfficacyestimatesrelativelylowforsomeoutcomesConfidenceintervalswideforsomeoutcomes,Considerations:Clinicalbenefitvs.economicbenefit,Substantialevidenceofclinicalbenefitmustbeprovidedfromadequateandwell-controlledstudies.EconomicbenefitisnotconsideredintheefficacyevaluationbyFDA.,Considerations:MarketingImplications,Promotional