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VaccinesandRelatedBiologicalProductsAdvisoryCommittee(VRBPAC)

May21,2002

Prevnar?,PneumococcalConjugateVaccine7-valent,forthePreventionofAcuteOtitisMedia

R.DouglasPratt,M.D.,M.P.H.微快車微信營(yíng)銷VaccinesandRelatedBiologica1ReviewTeamJingyeeKou,Ph.D.MarionGruber,Ph.D.CarlFrasch,Ph.D.ReviewTeamJingyeeKou,Ph.D.2ProposedIndication

ForactiveimmunizationofinfantsandtoddlersagainstinvasivediseaseandotitismediacausedbyStreptococcuspneumoniaeduetocapsularserotypesincludedinthevaccine(4,6B,9V,14,18C,19F,23F)ProposedIndication Foractive3RegulatoryBackgroundNovember1999February2000June2000May2001October2001March2002May2002VRBPACforinvasivediseasePrevnarlicensedforpreventionofinvasivediseaseAOMlicenseamendmentsubmittedFDALettertosponsorResponsetoFDAletterreceivedSecondFDAlettertosponsor;majoramendment-Finnishfollow-updataVRBPACforotitismediaRegulatoryBackgroundNovember4GlobalIssuesEfficacyestimatesforAOMoutcomesarecomparativelylowforpreventivevaccinesPossibleincreasedriskofAOM(negativeefficacy)forpneumococcalserotypesnotincludedinPrevnarPotentialforunrealisticpublicexpectationsregardingbenefitinpreventingAOMGlobalIssuesEfficacyestimate5CommentsfromMedicalCommunity:

CorrespondencetoNewEnglandJournalofMedicineClinicalsignificanceofoveralltreatmenteffectquestioned(LavinA;DamoiseauxR;CantekinE;SauderK)Concernthatlimitedbenefitmaybemisunderstoodbythepublic(SauderK)

Concernthatcredibilityofexistingrecommendationsmaybecompromised(SauderK)MisunderstandingofFDAactiontakenregardingAOM(CantekinE)CommentsfromMedicalCommunit6ClinicalStudiesReviewedClinicalStudiesReviewed7OutlineofFDAPresentationIntroductionEfficacydatafromFinnishOMstudySupplementaryanalysesFinnishfollow-upstudyEfficacydatafromtheNCKPstudySafetydatafromFinnishOMstudyConsiderationsQuestionstotheCommitteeOutlineofFDAPresentationInt8FinnishOMStudy—

PrimaryObjective

Determinetheprotectiveefficacyofthepneumococcalconjugatevaccineagainstculture-confirmedpneumococcalacuteotitismedia(AOM)duetovaccineserotypesFinnishOMStudy—

PrimaryObje9FinnishOMStudy—

SecondaryObjectives

Determine:EfficacyusingdifferentlevelsofetiologicdiagnosisEfficacyinpreventingnasopharyngealcarriageAntibodyresponseSafetyandtolerabilityFinnishOMStudy—

SecondaryOb10FinnishOMStudy:

ElementsoftheStudyDesignRandomizedequallytooneof3vaccines:PncCRM(Wyeth-Lederle)PncOMP(Merck)HBV(Control)OnlydatarelatingtoPncCRMwereprovidedintheapplicationDouble-blindHealthy2montholdinfantsenrolledFinnishOMStudy:

Elementso11FinnishOMStudy:

VaccineScheduleandConcurrentImmunizationsFinnishOMStudy:

VaccineSc12FinnishOMstudy

Casesurveillanceandascertainment

Freeaccesstostudyclinics7days/weekChildrenbroughttostudyclinicsforrespiratoryinfectionsorsymptomssuggestingAOMMyringotomywithaspirationofmiddleearfluidforculture,ifAOMdiagnosedatthevisitIfS.pneumoniaefound,theserotypewasdeterminedFollow-upofeachchilduntilage2yearsFinnishOMstudyCasesurveill13FinnishOMStudy:

ClinicalDefinitionofAcuteOtitisMedia

Visuallyabnormaltympanicmembrane(inregardtocolor,position,and/ormobility)suggestingeffusioninthemiddleearcavityAndatleastoneof:

fever,earpain,irritability,diarrhea,vomiting,acuteotorrheanotcausedbyexternalotitis,orothersymptomsofrespiratoryinfection.FinnishOMStudy:

ClinicalDef14FinnishOMStudy:

AOMEfficacyEndpointsPrimary:AOMepisodesduetovaccineserotypesSecondary:

FirstandSubsequentAOMepisodesduetovaccineserotypesOther:AOMduetovaccineserotypesbydoseAllpneumococcalAOM,regardlessofserotype (cultureand/orPCR)AllAOMepisodeswithMEF,regardlessofetiologyAllAOMepisodesregardlessofetiologyChildrenwithrecurrentAOMFinnishOMStudy:

AOMEffic15FinnishOMStudy-

DefinitionofPrimaryEndpoint

AOMepisodeduetovaccineserotypesAtleast30dayssincebeginningofpreviousAOMduetothesameserotypeOr,anyintervalfordifferentvaccineserotypeCultureconfirmedFinnishOMStudy-

Definition16FinnishOMStudy:

PrimaryEndpointDefinition

FinnishOMStudy:

PrimaryEndp17FinnishOMStudy-

AnalysisofPrimaryEndpointGeneralizedCoxregressionmodelwithAnderson-GillcountingmethodRiskofAOMestimated“piecewise”,i.e.,fromeventtoeventAssumesproportionalhazardsbetweengroupsovertimeRobustvarianceestimatesusedtocompensateforinterdependencyofeventswithinsubjectsProvidesaveragevaccineeffectonAOMepisodesFinnishOMStudy-

Analysisof18FinnishOMStudy-

DefinitionsofFollow-upPeriodsPerprotocol(PP)follow-up: Begins2weeksafterthe3rdvaccinedoseIntent-to-treat(ITT)follow-up: Beginsattimeof1stvaccinedoseFinnishOMStudy-

Definitions19FinnishOMStudy:

SelectedPopulationCharacteristicsFinnishOMStudy:

SelectedPop20FinnishOMStudy-

PrimaryAnalysis,

AOMduetoVaccineSerotypesFinnishOMStudy-

PrimaryAnal21FinnishOMStudy-

AOMduetoIndividualVaccineSerotypes,(Intent-to-treat)FinnishOMStudy-

AOMduetoI22FinnishOMStudy-

SecondaryAnalyses,FirstandSubsequentAOMEpisodesduetoVaccineSerotypesFinnishOMStudy-

SecondaryAn23FinnishOMStudy-

EfficacyforAllCulture-ConfirmedPneumococci,RegardlessofSerotypeFinnishOMStudy-

Efficacyfor24FinnishOMStudy-

EfficacyforVaccine-RelatedSerotypesFinnishOMStudy-

Efficacyfor25FinnishOMStudy-

AOMduetoIndividualVaccine-RelatedSerotypes,(Intent-to-treat)FinnishOMStudy-

AOMduetoI26FinnishOtitisMediaStudy-

EfficacyforVaccine-UnrelatedPneumococcalSerotypesFinnishOtitisMediaStudy-

Ef27FinnishOtitisMediaStudy-

EfficacyforRecurrentAOM*FinnishOtitisMediaStudy-

Ef28FinnishOtitisMediaStudy-

EfficacyforOtherPlannedAnalysesFinnishOtitisMediaStudy-

Ef29FinnishOMStudy-

EfficacyforNasopharyngealCarriageofVaccineSerotypes(perprotocol)FinnishOMStudy-

Efficacyfor30FinnishOMStudy—SerumGeometricMeanAntibodyConcentration(GMC)After3rdand4thDosesSerotypePostDose3GMC(mcg/mL)PostDose4GMC(mcg/mL)HBVN=52PncCRMN=54HBVN=54PncCRMN=5540.051.700.112.566B0.092.000.169.059V0.102.480.213.97140.216.280.2110.8218C0.083.550.106.5119F0.223.280.414.9623F0.102.510.156.25FinnishOMStudy—SerumGeometr31FinnishOMStudy—

SerumAntibodyConcentrations(GMC)

andSerotype-SpecificEfficacyFinnishOMStudy—

SerumAntibo32FinnishOtitisMediaStudy—

InvasiveDiseaseDuetoPneumococcusFinnishOtitisMediaStudy—

In33FinnishOtitisMediaStudy:ReviewIssuesandSupplementaryAnalysesFinnishOtitisMediaStudy:R34FinnishOMStudy:AnalysisofCovariates

EfficacyEstimatesAdjustedforGender,AOMPriortoEnrollment,GestationalAge,BirthWeight,Daycare,Breast-feeding,andHouseholdSmoking

FinnishOMStudy:Analysisof35FinnishOMStudy:

ExamplefromtheData,

MultipleEpisodesDuetoSameSerotypeFinnishOMStudy:

Examplefr36FinnishOMStudy:

ExamplesfromtheData,

MultipleEpisodesDuetoSameSerotypeFinnishOMStudy:

Examplesf37FinnishOMStudy—

SupplementaryAnalysis:

SubsequentAOMEpisodesduetoSameSerotypeExcluded,VaccineSerotypes

(PP)FinnishOMStudy—

Supplementar38FinnishOMStudy—

SupplementaryAnalysis:

SubsequentAOMEpisodesduetoSameSerotypeExcluded,

AllPneumococcalSerotypes

(PerProtocol)FinnishOMStudy—

Supplementar39FinnishOMStudy—

SupplementaryAnalysis:PneumococcalAOMbyPCR/CultureFinnishOMStudy—

Supplementar40FinnishOMStudy—

SupplementaryAnalysis*:

AntibioticUseFinnishOMStudy—

Supplementar41FinnishOMStudy-

SupplementaryAnalysis:

FirstTympanostomyTubePlacementFinnishOMStudy-

Supplementar42FinnishOMFollow-upStudy—

TympanostomyTubePlacementToassesslong-termeffectofvaccineonproceduresforeartubeplacementChildrenevaluatedat4-5yearsofageUnblindedTwopopulationsevaluated:Volunteersinfollow-upstudy,N=756Originalrandomizedpopulation,N=1662FinnishOMFollow-upStudy—

Ty43FinnishOMFollow-upStudy—

PrimaryAnalysis,RateofEarTubePlacementamongChildrenEnrolledinFollow-upStudyFinnishOMFollow-upStudy—

Pr44FinnishOMFollow-upStudy—

SecondaryAnalysis,RateofEarTubePlacementamongAllChildrenFollowedto4-5yearsofAgeFinnishOMFollow-upStudy—

Se45NorthernCaliforniaKaiserPermanente(NCKP)OtitisMediaEfficacyResultsNorthernCaliforniaKaiserPer46NorthernCaliforniaKaiserPermanente(NCKP)Study:ElementsofStudyDesignRandomized,double-blindInvestigationalmeningococcalCconjugatevaccinecontrolAOMasecondaryendpointNostandardizedAOMclinicalcasedefinitionNotympanocentesisorroutinecultureofMEFAutomateddatabasesearchestoidentifyOMdiagnosesNorthernCaliforniaKaiserPer47NCKPStudy:CaseDefinitionsAOMDiagnosis:BasedonclinicalpracticeAOMEpisode:AclinicvisitatwhichAOMwasdiagnosed,andatleast21dayshadelapsedsinceanypreviousvisitforAOMFrequentAOM:3AOMepisodeswithin6months,or4episodeswithin12months

NCKPStudy:CaseDefinitionsA48NCKPStudy:

ProspectivelyDefinedAOMEndpointsPrimary: AllAOMepisodesSecondary: FirstAOMepisodeFrequentAOMFirsttympanostomytubeAllOMclinicvisitsRupturedeardrumsNCKPStudy:

ProspectivelyDe49NCKPStudy:PrimaryAnalysis,

OverallReductioninAOMEpisodesNCKPStudy:PrimaryAnalysis,50NCKPStudy:SecondaryAnalysis,

ReductioninRiskofatLeast1EpisodeNCKPStudy:SecondaryAnalysi51NCKPStudy:

FrequentAcuteOtitisMediaNCKPStudy:

FrequentAcuteO52NCKPStudy:

FirstTympanostomyTubePlacementNCKPStudy:

FirstTympanosto53NCKPStudy:

RupturedEarDrumswithPneumococcusIsolatedNCKPStudy:

RupturedEarDru54NCKPStudy:

SerotypeDistributionofRupturedEarDrumswithPneumococcusIsolated(ITT)NCKPStudy:

SerotypeDistrib55NCKPStudy:EfficacyThroughExtendedFollow-up(ITT)NCKPStudy:EfficacyThrough56

SummaryofEfficacyEstimates(ITT)OutcomeFinnishNCKPVaccineSerotypes54%NAFirstEpisodeVaccineSerotypes48%NAAllS.pneumo,

Culture-Confirmed32%NARecurrentOM*9%**9%TympanostomyTube4%**21%AllCauseOM4%**6%FirstEpisodeAllCauseAOMNA5%*Allcauseotitismedia**Notstatisticallysignificantatp=0.05NA=NotavailableSummaryofEfficacyEstimate57FinnishOtitisMediaStudy:

SafetyAnalysisFinnishOtitisMediaStudy:

S58FinnishOMStudy:SafetyAnalysis

RelevanceofsafetydatatoUSpopulationislimited:UseofconcurrentDTwP-Hibcombinationvaccinesforfirst3doses,ratherthanDTaP,complicatesassessmentsofsystemicreactionsHomogeneousstudypopulationStudynotlargeenoughtodetectuncommonadverseeventsFinnishOMStudy:SafetyAnaly59FinnishOMStudy:

SafetyAnalysis,LocalandSystemicReactions,First3DosesFinnishOMStudy:

SafetyAnal60FinnishOMStudy:

SafetyAnalysis,LocalandSystemicReactions,4thDoseFinnishOMStudy:

SafetyAnal61FinnishOMStudy:

SafetyAnalysis,ConclusionsSafetydataareconsistentwithearlierobservationsregardingthesafetyofPrevnarIncreasedrateoflow-gradefeverComplicationsofpost-vaccinationfeverwereuncommonNonewsafetyconcernswereidentifiedFinnishOMStudy:

SafetyAnal62ConsiderationsConsiderations63RequiredLevelofEfficacy

TheminimumlevelofefficacyrequiredforlicensureofapreventivevaccineisnotspecificallyaddressedbyFDAregulationsorpublishedguidance.RequiredLevelofEfficacy64Considerations:

LicensureofOtherPneumococcalVaccinesforOtitisMediaAOMindicationshouldstandonitsown.LicenseapplicationsfornewpneumococcalvaccinesforpreventionofAOMmaynotincludeevidenceofefficacyforpreventionofinvasivedisease.Ifapproved,alevelofefficacy,preferredendpoints,andtypeofdata(numberoftrials)sufficientforapprovalforAOMwouldbeestablished.PreventionofmoreAOMepisodeswithlessvaccine-serotype-specificefficacyisapossiblescenario.Considerations:

Licensureof65Considerations:

DescriptionofthetreatmenteffectPrimaryoutcomesinNCKPstudyandFinnishOMstudydifferPreventionofAOMduetovaccineserotypesdoesnotcapture:Positivetreatmenteffectonvaccine-relatedpneumococcalserotypesNegativeefficacyforunrelatedpneumococcalserotypesEfficacyestimatesrelativelylowforsomeoutcomesConfidenceintervalswideforsomeoutcomesConsiderations:

Description66Considerations:

Clinicalbenefitvs.economicbenefit

Substantialevidenceofclinicalbenefitmustbeprovidedfromadequateandwell-controlledstudies.

EconomicbenefitisnotconsideredintheefficacyevaluationbyFDA.Considerations:

Clinicalbene67Considerations:MarketingImplicationsPromotionalmaterialsbasedonapprovedlabelingPotentialforunrealisticexpectationsFDAisempoweredtorestrictmarketingclaims:AdvertisementsandpromotionallabelingarereviewedbyCBERAdvertisementsthataremisleading(definedin21CFR202.1)canresultinaproductbeingmisbranded.Ifacompanyfailstocorrectsuchviolations,CBERisempoweredtotakemultiplecorrectiveactions(21CFR601.5and601.6).

Considerations:MarketingImpl68QuestionstotheCommitteeArethedataadequatetosupporttheefficacyofPrevnarininfantsandtoddlersforpreventionofotitismediacausedbyStreptococcuspneumoniaeduetocapsularserotypesincludedinthevaccine(4,6B,9V,14,18C,19F,23F)? Ifnot,wouldadditionalanalysesfromtheFinnishotitismediastudy,theNorthernCaliforniaKaiserPermanenteefficacystudy,oradditionalclinicaltrialsbeusefulinestablishingefficacy?

QuestionstotheCommitteeAre69QuestionstotheCommittee(cont.)2. Pleasediscussthestrengthofthedatawithrespecttosecondaryotitismediaoutcomes:AcuteotitismediaepisodescausedbyS.pneumoniae,regardlessofserotypeOverallreductioninacuteotitismediaepisodesFrequentotitismediaTympanostomytubeplacement

QuestionstotheCommittee(co70VaccinesandRelatedBiologicalProductsAdvisoryCommittee(VRBPAC)

May21,2002

Prevnar?,PneumococcalConjugateVaccine7-valent,forthePreventionofAcuteOtitisMedia

R.DouglasPratt,M.D.,M.P.H.微快車微信營(yíng)銷VaccinesandRelatedBiologica71ReviewTeamJingyeeKou,Ph.D.MarionGruber,Ph.D.CarlFrasch,Ph.D.ReviewTeamJingyeeKou,Ph.D.72ProposedIndication

ForactiveimmunizationofinfantsandtoddlersagainstinvasivediseaseandotitismediacausedbyStreptococcuspneumoniaeduetocapsularserotypesincludedinthevaccine(4,6B,9V,14,18C,19F,23F)ProposedIndication Foractive73RegulatoryBackgroundNovember1999February2000June2000May2001October2001March2002May2002VRBPACforinvasivediseasePrevnarlicensedforpreventionofinvasivediseaseAOMlicenseamendmentsubmittedFDALettertosponsorResponsetoFDAletterreceivedSecondFDAlettertosponsor;majoramendment-Finnishfollow-updataVRBPACforotitismediaRegulatoryBackgroundNovember74GlobalIssuesEfficacyestimatesforAOMoutcomesarecomparativelylowforpreventivevaccinesPossibleincreasedriskofAOM(negativeefficacy)forpneumococcalserotypesnotincludedinPrevnarPotentialforunrealisticpublicexpectationsregardingbenefitinpreventingAOMGlobalIssuesEfficacyestimate75CommentsfromMedicalCommunity:

CorrespondencetoNewEnglandJournalofMedicineClinicalsignificanceofoveralltreatmenteffectquestioned(LavinA;DamoiseauxR;CantekinE;SauderK)Concernthatlimitedbenefitmaybemisunderstoodbythepublic(SauderK)

Concernthatcredibilityofexistingrecommendationsmaybecompromised(SauderK)MisunderstandingofFDAactiontakenregardingAOM(CantekinE)CommentsfromMedicalCommunit76ClinicalStudiesReviewedClinicalStudiesReviewed77OutlineofFDAPresentationIntroductionEfficacydatafromFinnishOMstudySupplementaryanalysesFinnishfollow-upstudyEfficacydatafromtheNCKPstudySafetydatafromFinnishOMstudyConsiderationsQuestionstotheCommitteeOutlineofFDAPresentationInt78FinnishOMStudy—

PrimaryObjective

Determinetheprotectiveefficacyofthepneumococcalconjugatevaccineagainstculture-confirmedpneumococcalacuteotitismedia(AOM)duetovaccineserotypesFinnishOMStudy—

PrimaryObje79FinnishOMStudy—

SecondaryObjectives

Determine:EfficacyusingdifferentlevelsofetiologicdiagnosisEfficacyinpreventingnasopharyngealcarriageAntibodyresponseSafetyandtolerabilityFinnishOMStudy—

SecondaryOb80FinnishOMStudy:

ElementsoftheStudyDesignRandomizedequallytooneof3vaccines:PncCRM(Wyeth-Lederle)PncOMP(Merck)HBV(Control)OnlydatarelatingtoPncCRMwereprovidedintheapplicationDouble-blindHealthy2montholdinfantsenrolledFinnishOMStudy:

Elementso81FinnishOMStudy:

VaccineScheduleandConcurrentImmunizationsFinnishOMStudy:

VaccineSc82FinnishOMstudy

Casesurveillanceandascertainment

Freeaccesstostudyclinics7days/weekChildrenbroughttostudyclinicsforrespiratoryinfectionsorsymptomssuggestingAOMMyringotomywithaspirationofmiddleearfluidforculture,ifAOMdiagnosedatthevisitIfS.pneumoniaefound,theserotypewasdeterminedFollow-upofeachchilduntilage2yearsFinnishOMstudyCasesurveill83FinnishOMStudy:

ClinicalDefinitionofAcuteOtitisMedia

Visuallyabnormaltympanicmembrane(inregardtocolor,position,and/ormobility)suggestingeffusioninthemiddleearcavityAndatleastoneof:

fever,earpain,irritability,diarrhea,vomiting,acuteotorrheanotcausedbyexternalotitis,orothersymptomsofrespiratoryinfection.FinnishOMStudy:

ClinicalDef84FinnishOMStudy:

AOMEfficacyEndpointsPrimary:AOMepisodesduetovaccineserotypesSecondary:

FirstandSubsequentAOMepisodesduetovaccineserotypesOther:AOMduetovaccineserotypesbydoseAllpneumococcalAOM,regardlessofserotype (cultureand/orPCR)AllAOMepisodeswithMEF,regardlessofetiologyAllAOMepisodesregardlessofetiologyChildrenwithrecurrentAOMFinnishOMStudy:

AOMEffic85FinnishOMStudy-

DefinitionofPrimaryEndpoint

AOMepisodeduetovaccineserotypesAtleast30dayssincebeginningofpreviousAOMduetothesameserotypeOr,anyintervalfordifferentvaccineserotypeCultureconfirmedFinnishOMStudy-

Definition86FinnishOMStudy:

PrimaryEndpointDefinition

FinnishOMStudy:

PrimaryEndp87FinnishOMStudy-

AnalysisofPrimaryEndpointGeneralizedCoxregressionmodelwithAnderson-GillcountingmethodRiskofAOMestimated“piecewise”,i.e.,fromeventtoeventAssumesproportionalhazardsbetweengroupsovertimeRobustvarianceestimatesusedtocompensateforinterdependencyofeventswithinsubjectsProvidesaveragevaccineeffectonAOMepisodesFinnishOMStudy-

Analysisof88FinnishOMStudy-

DefinitionsofFollow-upPeriodsPerprotocol(PP)follow-up: Begins2weeksafterthe3rdvaccinedoseIntent-to-treat(ITT)follow-up: Beginsattimeof1stvaccinedoseFinnishOMStudy-

Definitions89FinnishOMStudy:

SelectedPopulationCharacteristicsFinnishOMStudy:

SelectedPop90FinnishOMStudy-

PrimaryAnalysis,

AOMduetoVaccineSerotypesFinnishOMStudy-

PrimaryAnal91FinnishOMStudy-

AOMduetoIndividualVaccineSerotypes,(Intent-to-treat)FinnishOMStudy-

AOMduetoI92FinnishOMStudy-

SecondaryAnalyses,FirstandSubsequentAOMEpisodesduetoVaccineSerotypesFinnishOMStudy-

SecondaryAn93FinnishOMStudy-

EfficacyforAllCulture-ConfirmedPneumococci,RegardlessofSerotypeFinnishOMStudy-

Efficacyfor94FinnishOMStudy-

EfficacyforVaccine-RelatedSerotypesFinnishOMStudy-

Efficacyfor95FinnishOMStudy-

AOMduetoIndividualVaccine-RelatedSerotypes,(Intent-to-treat)FinnishOMStudy-

AOMduetoI96FinnishOtitisMediaStudy-

EfficacyforVaccine-UnrelatedPneumococcalSerotypesFinnishOtitisMediaStudy-

Ef97FinnishOtitisMediaStudy-

EfficacyforRecurrentAOM*FinnishOtitisMediaStudy-

Ef98FinnishOtitisMediaStudy-

EfficacyforOtherPlannedAnalysesFinnishOtitisMediaStudy-

Ef99FinnishOMStudy-

EfficacyforNasopharyngealCarriageofVaccineSerotypes(perprotocol)FinnishOMStudy-

Efficacyfor100FinnishOMStudy—SerumGeometricMeanAntibodyConcentration(GMC)After3rdand4thDosesSerotypePostDose3GMC(mcg/mL)PostDose4GMC(mcg/mL)HBVN=52PncCRMN=54HBVN=54PncCRMN=5540.051.700.112.566B0.092.000.169.059V0.102.480.213.97140.216.280.2110.8218C0.083.550.106.5119F0.223.280.414.9623F0.102.510.156.25FinnishOMStudy—SerumGeometr101FinnishOMStudy—

SerumAntibodyConcentrations(GMC)

andSerotype-SpecificEfficacyFinnishOMStudy—

SerumAntibo102FinnishOtitisMediaStudy—

InvasiveDiseaseDuetoPneumococcusFinnishOtitisMediaStudy—

In103FinnishOtitisMediaStudy:ReviewIssuesandSupplementaryAnalysesFinnishOtitisMediaStudy:R104FinnishOMStudy:AnalysisofCovariates

EfficacyEstimatesAdjustedforGender,AOMPriortoEnrollment,GestationalAge,BirthWeight,Daycare,Breast-feeding,andHouseholdSmoking

FinnishOMStudy:Analysisof105FinnishOMStudy:

ExamplefromtheData,

MultipleEpisodesDuetoSameSerotypeFinnishOMStudy:

Examplefr106FinnishOMStudy:

ExamplesfromtheData,

MultipleEpisodesDuetoSameSerotypeFinnishOMStudy:

Examplesf107FinnishOMStudy—

SupplementaryAnalysis:

SubsequentAOMEpisodesduetoSameSerotypeExcluded,VaccineSerotypes

(PP)FinnishOMStudy—

Supplementar108FinnishOMStudy—

SupplementaryAnalysis:

SubsequentAOMEpisodesduetoSameSerotypeExcluded,

AllPneumococcalSerotypes

(PerProtocol)FinnishOMStudy—

Supplementar109FinnishOMStudy—

SupplementaryAnalysis:PneumococcalAOMbyPCR/CultureFinnishOMStudy—

Supplementar110FinnishOMStudy—

SupplementaryAnalysis*:

AntibioticUseFinnishOMStudy—

Supplementar111FinnishOMStudy-

SupplementaryAnalysis:

FirstTympanostomyTubePlacementFinnishOMStudy-

Supplementar112FinnishOMFollow-upStudy—

TympanostomyTubePlacementToassesslong-termeffectofvaccineonproceduresforeartubeplacementChildrenevaluatedat4-5yearsofageUnblindedTwopopulationsevaluated:Volunteersinfollow-upstudy,N=756Originalrandomizedpopulation,N=1662FinnishOMFollow-upStudy—

Ty113FinnishOMFollow-upStudy—

PrimaryAnalysis,RateofEarTubePlacementamongChildrenEnrolledinFollow-upStudyFinnishOMFollow-upStudy—

Pr114FinnishOMFollow-upStudy—

SecondaryAnalysis,RateofEarTubePlacementamongAllChildrenFollowedto4-5yearsofAgeFinnishOMFollow-upStudy—

Se115NorthernCaliforniaKaiserPermanente(NCKP)OtitisMediaEfficacyResultsNorthernCaliforniaKaiserPer116NorthernCaliforniaKaiserPermanente(NCKP)Study:ElementsofStudyDesignRandomized,double-blindInvestigationalmeningococcalCconjugatevaccinecontrolAOMasecondaryendpointNostandardizedAOMclinicalcasedefinitionNotympanocentesisorroutinecultureofMEFAutomateddatabasesearchestoidentifyOMdiagnosesNorthernCaliforniaKaiserPer117NCKPStudy:CaseDefinitionsAOMDiagnosis:BasedonclinicalpracticeAOMEpisode:AclinicvisitatwhichAOMwasdiagnosed,andatleast21dayshadelapsedsinceanypreviousvisitforAOMFrequentAOM:3AOMepisodeswithin6months,or4episodeswithin12months

NCKPStudy:CaseDefinitionsA118NCKPStudy:

ProspectivelyDefinedAOMEndpointsPrimary: AllAOMepisodesSecondary: FirstAOMepisodeFrequentAOMFirsttympanostomytubeAllOMclinicvisitsRupturedeardrumsNCKPStudy:

ProspectivelyDe119NCKPStudy:PrimaryAnalysis,

OverallReductioninAOMEpisodesNCKPStudy:PrimaryAnalysis,120NCKPStudy:SecondaryAnalysis,

ReductioninRiskofatLeast1EpisodeNCKPStudy:SecondaryAnalysi121NCKPStudy:

FrequentAcuteOtitisMediaNCKPStudy:

FrequentAcuteO122NCKPStudy:

FirstTympanostomyTubePlacementNCKPStudy:

FirstTympanosto123NCKPStudy:

RupturedEarDrumswithPneumococcusIsolatedNCKPStudy:

RupturedEarDru124NCKPStudy:

SerotypeDistributionofRupturedEarDrumswithPneumococcusIsolated(ITT)NCKPStudy:

SerotypeDistrib125NCKPStudy:EfficacyThroughExtendedFollow-up(ITT)NCKPStudy:EfficacyThrough126

SummaryofEfficacyEstimates(ITT)OutcomeFinnishNCKPVaccineSerotypes54%NAFirstEpisodeVaccineSerotypes48%NAAllS.pneumo,

Culture-Confirmed32%NARecurrentOM*9%**9%TympanostomyTube4%**21%AllCauseOM4%**6%FirstEpisodeAllCauseAOMNA5%*Allcauseotitismedia**Notstatisticallysignificantatp=0.05NA=NotavailableSummaryofEfficacyEstimate127FinnishOtitisMediaStudy:

SafetyAnalysisFinnishOtitisMediaStudy:

S128FinnishOMStudy:SafetyAnalysis

RelevanceofsafetydatatoUSpopulationislimited:UseofconcurrentDTwP-Hibcombinationvaccinesforfirst3doses,ratherthanDTaP,complicatesassessmentsofsystemicreactionsHomogeneousstudypopulationStudynotlargeenoughtodetectuncommonadverseeventsFinnishOMStudy:SafetyAnaly129FinnishOMStudy:

SafetyAnalysis,LocalandSystemicReactions,First3DosesFinnishOMStudy:

SafetyAnal130FinnishOMStudy:

SafetyAnalysis,LocalandSystemicReactions,4thDoseFinnishOMStudy:

SafetyAnal131FinnishOMStudy:

SafetyAnalysis,ConclusionsSafetydataareconsistentwithearlierobservationsregardingthesafetyofPrevnarIncreasedrateoflow-gradefeverComplication

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