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1、VaccinesandRelatedBiologicalProductsAdvisoryCommittee(VRBPAC)May21,2002Prevnar,PneumococcalConjugateVaccine7-valent,forthePreventionofAcuteOtitisMediaR.DouglasPratt,M.D.,M.P.H.微快车微信营销 http:/ReviewTeamJingyeeKou,Ph.D.MarionGruber,Ph.D.CarlFrasch,Ph.D.ProposedIndicationFor active immunization of infan

2、ts and toddlers against invasive disease andotitismedia caused by Streptococcus pneumoniae due to capsular serotypes included in the vaccine(4,6B,9V,14,18C,19F,23F)RegulatoryBackgroundNovember 1999 February 2000June 2000May 2001October 2001March 2002May 2002 VRBPAC for invasive diseasePrevnar licens

3、ed for prevention of invasive diseaseAOM license amendment submittedFDA Letter to sponsorResponse to FDA letter receivedSecond FDA letter to sponsor;major amendment-Finnish follow-up dataVRBPAC for otitis mediaGlobalIssuesEfficacy estimates for AOM outcomes are comparatively low for preventive vacci

4、nesPossible increased risk of AOM(negative efficacy)for pneumococcal serotypes not included in Prevnar Potential for unrealistic public expectations regarding benefit in preventing AOMCommentsfromMedicalCommunity:CorrespondencetoNewEnglandJournalofMedicineClinical significance of overall treatment e

5、ffect questioned(Lavin A;Damoiseaux R;Cantekin E;Sauder K)Concern that limited benefit may be misunderstood by the public(Sauder K)Concern that credibility of existing recommendations may be compromised(Sauder K)Misunderstanding of FDA action taken regarding AOM (Cantekin E)ClinicalStudiesReviewedOu

6、tlineofFDAPresentationIntroductionEfficacy data from Finnish OM studySupplementary analysesFinnish follow-up studyEfficacy data from the NCKP studySafety data from Finnish OM studyConsiderationsQuestions to the CommitteeFinnishOMStudyPrimaryObjective Determinetheprotectiveefficacyofthepneumococcalco

7、njugatevaccineagainstculture-confirmedpneumococcalacuteotitismedia(AOM)duetovaccineserotypesFinnishOMStudySecondaryObjectives Determine:EfficacyusingdifferentlevelsofetiologicdiagnosisEfficacyinpreventingnasopharyngealcarriageAntibodyresponseSafetyandtolerabilityFinnishOMStudy:ElementsoftheStudyDesi

8、gnRandomized equally to one of 3 vaccines:PncCRM(Wyeth-Lederle)PncOMP(Merck)HBV(Control)Only data relating to PncCRM were provided in the applicationDouble-blindHealthy 2 month old infants enrolledFinnishOMStudy:VaccineScheduleandConcurrentImmunizationsFinnishOMstudy Casesurveillanceandascertainment

9、 Free access to study clinics 7 days/weekChildren brought to study clinics for respiratory infections or symptoms suggesting AOMMyringotomy with aspiration of middle ear fluid for culture,if AOM diagnosed at the visit If S.pneumoniae found,the serotype was determinedFollow-up of each child until age

10、 2 yearsFinnishOMStudy:ClinicalDefinitionofAcuteOtitisMedia Visually abnormal tympanic membrane(in regard to color,position,and/or mobility)suggesting effusion in the middle ear cavityAnd at least one of:fever,ear pain,irritability,diarrhea,vomiting,acute otorrhea not caused by external otitis,or ot

11、her symptoms of respiratory infection.FinnishOMStudy:AOMEfficacyEndpointsPrimary:AOM episodes due to vaccine serotypesSecondary:First and Subsequent AOM episodes due to vaccine serotypesOther:AOM due to vaccine serotypes by doseAll pneumococcal AOM,regardless of serotype (culture and/or PCR)All AOM

12、episodes with MEF,regardless of etiologyAll AOM episodes regardless of etiologyChildren with recurrent AOMFinnishOMStudy-DefinitionofPrimaryEndpoint AOM episode due to vaccine serotypesAt least 30 days since beginning of previous AOM due to the same serotypeOr,any interval for different vaccine sero

13、typeCulture confirmedFinnishOMStudy:PrimaryEndpointDefinition FinnishOMStudy-AnalysisofPrimaryEndpointGeneralized Cox regression model with Anderson-Gill counting methodRisk of AOM estimated“piecewise”,i.e.,from event to eventAssumes proportional hazards between groups over timeRobust variance estim

14、ates used to compensate for interdependency of events within subjectsProvides average vaccine effect on AOM episodesFinnishOMStudy-DefinitionsofFollow-upPeriodsPer protocol(PP)follow-up:Begins 2 weeks after the 3rd vaccine doseIntent-to-treat(ITT)follow-up:Begins at time of 1st vaccine doseFinnishOM

15、Study:SelectedPopulationCharacteristicsFinnishOMStudy-PrimaryAnalysis,AOMduetoVaccineSerotypesFinnishOMStudy-AOMduetoIndividualVaccineSerotypes,(Intent-to-treat)FinnishOMStudy-SecondaryAnalyses,FirstandSubsequentAOMEpisodesduetoVaccineSerotypesFinnishOMStudy-EfficacyforAllCulture-ConfirmedPneumococc

16、i,RegardlessofSerotypeFinnishOMStudy-EfficacyforVaccine-RelatedSerotypesFinnishOMStudy-AOMduetoIndividualVaccine-RelatedSerotypes,(Intent-to-treat)FinnishOtitisMediaStudy-EfficacyforVaccine-UnrelatedPneumococcalSerotypesFinnishOtitisMediaStudy-EfficacyforRecurrentAOM*FinnishOtitisMediaStudy-Efficacy

17、forOtherPlannedAnalysesFinnishOMStudy-EfficacyforNasopharyngealCarriageofVaccineSerotypes(perprotocol)FinnishOMStudySerumGeometricMeanAntibodyConcentration(GMC)After3rdand4thDosesSerotypePostDose3GMC(mcg/mL)PostDose4GMC(mcg/mL)HBVN=52PncCRMN=54HBVN=54PncCRMN=5540.051.700.112.566B0.092.000.169.059V0.

18、102.480.213.97140.216.280.2110.8218C0.083.550.106.5119F0.223.280.414.9623F0.102.510.156.25FinnishOMStudySerumAntibodyConcentrations(GMC)andSerotype-SpecificEfficacyFinnishOtitisMediaStudyInvasiveDiseaseDuetoPneumococcusFinnishOtitisMediaStudy:ReviewIssuesandSupplementaryAnalysesFinnishOMStudy:Analys

19、isofCovariatesEfficacyEstimatesAdjustedforGender,AOMPriortoEnrollment,GestationalAge,BirthWeight,Daycare,Breast-feeding,andHouseholdSmokingFinnishOMStudy:ExamplefromtheData,MultipleEpisodesDuetoSameSerotypeFinnishOMStudy:ExamplesfromtheData,MultipleEpisodesDuetoSameSerotypeFinnishOMStudySupplementar

20、yAnalysis:SubsequentAOMEpisodesduetoSameSerotypeExcluded,VaccineSerotypes(PP)FinnishOMStudySupplementaryAnalysis:SubsequentAOMEpisodesduetoSameSerotypeExcluded,AllPneumococcalSerotypes(PerProtocol)FinnishOMStudySupplementaryAnalysis:PneumococcalAOMbyPCR/CultureFinnishOMStudySupplementaryAnalysis*:An

21、tibioticUseFinnishOMStudy-SupplementaryAnalysis:FirstTympanostomyTubePlacementFinnishOMFollow-upStudyTympanostomyTubePlacementTo assess long-term effect of vaccine on procedures for ear tube placement Children evaluated at 4-5 years of ageUnblindedTwo populations evaluated:Volunteers in follow-up st

22、udy,N=756Original randomized population,N=1662FinnishOMFollow-upStudyPrimaryAnalysis,RateofEarTubePlacementamongChildrenEnrolledinFollow-upStudyFinnishOMFollow-upStudySecondaryAnalysis,RateofEarTubePlacementamongAllChildrenFollowedto4-5yearsofAgeNorthernCaliforniaKaiserPermanente(NCKP)OtitisMediaEff

23、icacyResultsNorthernCaliforniaKaiserPermanente(NCKP)Study:ElementsofStudyDesignRandomized,double-blindInvestigational meningococcal C conjugate vaccine controlAOM a secondary endpointNo standardized AOM clinical case definitionNo tympanocentesis or routine culture of MEFAutomated database searches t

24、o identify OM diagnosesNCKPStudy:CaseDefinitionsAOM Diagnosis:Based on clinical practiceAOM Episode:A clinic visit at which AOM was diagnosed,and at least 21 days had elapsed since any previous visit for AOMFrequent AOM:3 AOM episodes within 6 months,or 4 episodes within 12 months NCKPStudy:Prospect

25、ivelyDefinedAOMEndpointsPrimary:AllAOMepisodesSecondary:FirstAOMepisodeFrequentAOMFirsttympanostomytubeAllOMclinicvisitsRupturedeardrumsNCKPStudy:PrimaryAnalysis,OverallReductioninAOMEpisodesNCKPStudy:SecondaryAnalysis,ReductioninRiskofatLeast1EpisodeNCKPStudy:FrequentAcuteOtitisMediaNCKPStudy:First

26、TympanostomyTubePlacementNCKPStudy:RupturedEarDrumswithPneumococcusIsolatedNCKPStudy:SerotypeDistributionofRupturedEarDrumswithPneumococcusIsolated(ITT)NCKPStudy:EfficacyThroughExtendedFollow-up(ITT)SummaryofEfficacyEstimates(ITT)OutcomeFinnishNCKPVaccine Serotypes54%NAFirst Episode Vaccine Serotype

27、s48%NAAll S.pneumo,Culture-Confirmed32%NARecurrent OM*9%*9%Tympanostomy Tube4%*21%All Cause OM4%*6%First Episode All Cause AOMNA5%*All cause otitis media*Not statistically significant at p=0.05NA=Not availableFinnishOtitisMediaStudy:SafetyAnalysisFinnishOMStudy:SafetyAnalysis Relevance of safety dat

28、a to US population is limited:Use of concurrent DTwP-Hib combination vaccines for first 3 doses,rather than DTaP,complicates assessments of systemic reactionsHomogeneous study population Study not large enough to detect uncommon adverse eventsFinnishOMStudy:SafetyAnalysis,LocalandSystemicReactions,F

29、irst3DosesFinnishOMStudy:SafetyAnalysis,LocalandSystemicReactions,4thDoseFinnishOMStudy:SafetyAnalysis,ConclusionsSafety data are consistent with earlier observations regarding the safety of PrevnarIncreased rate of low-grade feverComplications of post-vaccination fever were uncommonNo new safety co

30、ncerns were identifiedConsiderationsRequiredLevelofEfficacyThe minimum level of efficacy required for licensure of a preventive vaccine is not specifically addressed by FDA regulations or published guidance.Considerations:LicensureofOtherPneumococcalVaccinesforOtitisMediaAOM indication should stand

31、on its own.License applications for new pneumococcal vaccines for prevention of AOM may not include evidence of efficacy for prevention of invasive disease.If approved,a level of efficacy,preferred endpoints,and type of data(number of trials)sufficient for approval for AOM would be established.Preve

32、ntion of more AOM episodes with less vaccine-serotype-specific efficacy is a possible scenario.Considerations:DescriptionofthetreatmenteffectPrimary outcomes in NCKP study and Finnish OM study differPrevention of AOM due to vaccine serotypes does not capture:Positive treatment effect on vaccine-rela

33、ted pneumococcal serotypesNegative efficacy for unrelated pneumococcal serotypesEfficacy estimates relatively low for some outcomesConfidence intervals wide for some outcomesConsiderations:Clinicalbenefitvs.economicbenefitSubstantial evidence of clinical benefit must be provided from adequate and we

34、ll-controlled studies.Economic benefit is not considered in the efficacy evaluation by FDA.Considerations:MarketingImplicationsPromotional materials based on approved labelingPotential for unrealistic expectationsFDA is empowered to restrict marketing claims:Advertisements and promotional labeling a

35、re reviewed by CBERAdvertisements that are misleading(defined in 21 CFR 202.1)can result in a product being misbranded.If a company fails to correct such violations,CBER is empowered to take multiple corrective actions(21 CFR 601.5 and 601.6).QuestionstotheCommittee1.Are the data adequate to support

36、 the efficacy of Prevnar in infants and toddlers for prevention of otitis media caused by Streptococcus pneumoniae due to capsular serotypes included in the vaccine(4,6B,9V,14,18C,19F,23F)?If not,would additional analyses from the Finnish otitis media study,the Northern California Kaiser Permanente

37、efficacy study,or additional clinical trials be useful in establishing efficacy?QuestionstotheCommittee(cont.)2.Please discuss the strength of the data with respect to secondary otitis media outcomes:a.Acute otitis media episodes caused by S.pneumoniae,regardless of serotypeb.Overall reduction in acute otitis media episodesc.Frequent otitis mediad.Tympanostomy tube placement