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VaccinesandRelatedBiologicalProductsAdvisoryCommittee(VRBPAC)May21,2002Prevnar™,PneumococcalConjugateVaccine7-valent,forthePreventionofAcuteOtitisMediaR.DouglasPratt,M.D.,M.P.H.汽车防盗器(4,6B,9V,14,18C,19F,23F)RegulatoryBackgroundNovember1999February2000June2000May2001October2001March2002May2002VRBPACforinvasivediseasePrevnarlicensedforpreventionofinvasivediseaseAOMlicenseamendmentsubmittedFDALettertosponsorResponsetoFDAletterreceivedSecondFDAlettertosponsor;majoramendment-Finnishfollow-updataVRBPACforotitismediaGlobalIssues•EfficacyestimatesforAOMoutcomesarecomparativelylowforpreventivevaccines•PossibleincreasedriskofAOM(negativeefficacy)forpneumococcalserotypesnotincludedinPrevnar•PotentialforunrealisticpublicexpectationsregardingbenefitinpreventingAOMCommentsfromMedicalCommunity:CorrespondencetoNewEnglandJournalofMedicine•Clinicalsignificanceofoveralltreatmenteffectquestioned(LavinA;DamoiseauxR;CantekinE;SauderK)•Concernthatlimitedbenefitmaybemisunderstoodbythepublic(SauderK)•Concernthatcredibilityofexistingrecommendationsmaybecompromised(SauderK)•MisunderstandingofFDAactiontakenregardingAOM(CantekinE)ClinicalStudiesReviewedStudyNumberchildrenenrolledControlVaccineNewEpisodeIntervalCaseDefinitionRegulatoryObjective/OtherInformationFinnishOM1,662†HBV30daysBacterialcultures(myringotomy)DemonstrateefficacyforpreventionofAOM;Kaiser(NCKP)34,146‡MnCC21daysAutomateddatabasesearchforAOMvisitsDemonstrateefficacyforpreventionofinvasivedisease,AOM,andpneumonia;Largesafetydatabaseforassessingratesofadverseevents;Vaccinesadministeredat2,4,6,and12-15monthsofageineachstudy†SubjectsdistributedequallytoPncCRMandHBVcontrolvaccine;entirestudywasrandomized1:1:1,PncCRM:PncOMP:HBV.‡Subjectsrandomizedequallyto7VPnCorMnCCcontrolvaccine.OutlineofFDAPresentation•Introduction•EfficacydatafromFinnishOMstudy•Supplementaryanalyses•Finnishfollow-upstudy•EfficacydatafromtheNCKPstudy•SafetydatafromFinnishOMstudy•Considerations•QuestionstotheCommitteeFinnishOMStudy—PrimaryObjectiveDeterminetheprotectiveefficacyofthepneumococcalconjugatevaccineagainstculture-confirmedpneumococcalacuteotitismedia(AOM)duetovaccineserotypesFinnishOMStudy—SecondaryObjectivesDetermine:•Efficacyusingdifferentlevelsofetiologicdiagnosis•Efficacyinpreventingnasopharyngealcarriage•Antibodyresponse•SafetyandtolerabilityFinnishOMStudy:ElementsoftheStudyDesign•Randomizedequallytooneof3vaccines:PncCRM(Wyeth-Lederle)PncOMP(Merck)HBV(Control)OnlydatarelatingtoPncCRMwereprovidedintheapplication•Double-blind•Healthy2montholdinfantsenrolledFinnishOMStudy:VaccineScheduleandConcurrentImmunizationsAgeofchild(months)VaccinesAdministered2467121824PncCRM/HBV++++DTP-Hib++++IPV++MMR+FinnishOMstudyCasesurveillanceandascertainment•Freeaccesstostudyclinics7days/week•ChildrenbroughttostudyclinicsforrespiratoryinfectionsorsymptomssuggestingAOM•Myringotomywithaspirationofmiddleearfluidforculture,ifAOMdiagnosedatthevisit•IfS.pneumoniaefound,theserotypewasdetermined•Follow-upofeachchilduntilage2yearsFinnishOMStudy:ClinicalDefinitionofAcuteOtitisMedia•Visuallyabnormaltympanicmembrane(inregardtocolor,position,and/ormobility)suggestingeffusioninthemiddleearcavity•Andatleastoneof:fever,earpain,irritability,diarrhea,vomiting,acuteotorrheanotcausedbyexternalotitis,orothersymptomsofrespiratoryinfection.FinnishOMStudy:AOMEfficacyEndpointsPrimary:AOMepisodesduetovaccineserotypesSecondary:•FirstandSubsequentAOMepisodesduetovaccineserotypesOther:•AOMduetovaccineserotypesbydose•AllpneumococcalAOM,regardlessofserotype(cultureand/orPCR)•AllAOMepisodeswithMEF,regardlessofetiology•AllAOMepisodesregardlessofetiology•ChildrenwithrecurrentAOMFinnishOMStudy-DefinitionofPrimaryEndpointAOMepisodeduetovaccineserotypesAtleast30dayssincebeginningofpreviousAOMduetothesameserotypeOr,anyintervalfordifferentvaccineserotypeCultureconfirmedFinnishOMStudy:PrimaryEndpointDefinitionFinnishOMStudy-AnalysisofPrimaryEndpoint•GeneralizedCoxregressionmodelwithAnderson-Gillcountingmethod•RiskofAOMestimated“piecewise”,i.e.,fromeventtoevent•Assumesproportionalhazardsbetweengroupsovertime•Robustvarianceestimatesusedtocompensateforinterdependencyofeventswithinsubjects•ProvidesaveragevaccineeffectonAOMepisodesFinnishOMStudy-DefinitionsofFollow-upPeriods•Perprotocol(PP)follow-up:Begins2weeksafterthe3rdvaccinedose•Intent-to-treat(ITT)follow-up:Beginsattimeof1stvaccinedoseFinnishOMStudy:SelectedPopulationCharacteristicsHBVPncCRMPopulationCharacteristicN(%)N(%)GestationalAge37weeks53(6.4)41(4.9)Birthweight2.5kg42(5.1)25(3.0)PriorAOMepisodes39(4.7)27(3.2)FinnishOMStudy-PrimaryAnalysis,AOMduetoVaccineSerotypesNumberofEpisodesVaccineEfficacyFollow-upPeriodHBVPncCRMEstimate95%CIPP25010757%44,67AOMduetovaccineserotypesITT29213554%41,64FinnishOMStudy-AOMduetoIndividualVaccineSerotypes,(Intent-to