教你如何选购汽车防盗器

1、Vaccines and Related Biological Products Advisory Committee (VRBPAC)May 21, 2002Prevnar, Pneumococcal Conjugate Vaccine 7-valent, for the Prevention of Acute Otitis MediaR. Douglas Pratt, M.D., M.P.H.汽车防盗器 Review TeamJingyee Kou, Ph.D.Marion Gruber, Ph.D.Carl Frasch, Ph.D.Proposed IndicationFor acti

2、ve immunization of infants and toddlers against invasive disease and otitis media caused by Streptococcus pneumoniae due to capsular serotypes included in the vaccine (4, 6B, 9V, 14, 18C, 19F, 23F)Regulatory BackgroundNovember 1999 February 2000June 2000May 2001October 2001March 2002May 2002 VRBPAC

3、for invasive diseasePrevnar licensed 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 mediaGlobal IssuesEfficacy estimates for AOM outcomes are c

4、omparatively low for preventive vaccinesPossible increased risk of AOM (negative efficacy) for pneumococcal serotypes not included in Prevnar Potential for unrealistic public expectations regarding benefit in preventing AOMComments from Medical Community:Correspondence to New England Journal of Medi

5、cineClinical significance of overall treatment effect 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 ta

6、ken regarding AOM (Cantekin E)Clinical Studies ReviewedOutline of FDA PresentationIntroductionEfficacy data from Finnish OM studySupplementary analysesFinnish follow-up studyEfficacy data from the NCKP studySafety data from Finnish OM studyConsiderationsQuestions to the CommitteeFinnish OM StudyPrim

7、ary Objective Determine the protective efficacy of the pneumococcal conjugate vaccine against culture-confirmed pneumococcal acute otitis media (AOM) due to vaccine serotypesFinnish OM StudySecondary Objectives Determine:Efficacy using different levels of etiologic diagnosisEfficacy in preventing na

8、sopharyngeal carriageAntibody responseSafety and tolerabilityFinnish OM Study: Elements of the Study DesignRandomized 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 en

9、rolledFinnish OM Study: Vaccine Schedule and Concurrent ImmunizationsFinnish OM study Case surveillance and ascertainment 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

10、 culture, if AOM diagnosed at the visit If S. pneumoniae found, the serotype was determinedFollow-up of each child until age 2 yearsFinnish OM Study:Clinical Definition of Acute Otitis Media Visually abnormal tympanic membrane (in regard to color, position, and/or mobility) suggesting effusion in th

11、e middle ear cavityAnd at least one of:fever, ear pain, irritability, diarrhea, vomiting, acute otorrhea not caused by external otitis, or other symptoms of respiratory infection. Finnish OM Study: AOM Efficacy EndpointsPrimary: AOM episodes due to vaccine serotypesSecondary: First and Subsequent AO

12、M episodes due to vaccine serotypesOther:AOM due to vaccine serotypes by doseAll pneumococcal AOM, regardless of serotype (culture and/or PCR)All AOM episodes with MEF, regardless of etiologyAll AOM episodes regardless of etiologyChildren with recurrent AOMFinnish OM Study-Definition of Primary Endp

13、oint AOM episode due to vaccine serotypesAt least 30 days since beginning of previous AOM due to the same serotypeOr, any interval for different vaccine serotypeCulture confirmedFinnish OM Study:Primary Endpoint Definition Finnish OM Study-Analysis of Primary EndpointGeneralized Cox regression model

14、 with Anderson-Gill counting methodRisk of AOM estimated “piecewise”, i.e., from event to eventAssumes proportional hazards between groups over timeRobust variance estimates used to compensate for interdependency of events within subjectsProvides average vaccine effect on AOM episodesFinnish OM Stud

15、y-Definitions of Follow-up PeriodsPer protocol (PP) follow-up:Begins 2 weeks after the 3rd vaccine doseIntent-to-treat (ITT) follow-up:Begins at time of 1st vaccine doseFinnish OM Study:Selected Population Characteristics Finnish OM Study-Primary Analysis, AOM due to Vaccine SerotypesFinnish OM Stud

16、y-AOM due to Individual Vaccine Serotypes, (Intent-to-treat)Finnish OM Study-Secondary Analyses, First and Subsequent AOM Episodes due to Vaccine SerotypesFinnish OM Study-Efficacy for All Culture-Confirmed Pneumococci, Regardless of SerotypeFinnish OM Study-Efficacy for Vaccine-Related SerotypesFin

17、nish OM Study-AOM due to Individual Vaccine-Related Serotypes, (Intent-to-treat)Finnish Otitis Media Study-Efficacy for Vaccine-Unrelated Pneumococcal SerotypesFinnish Otitis Media Study-Efficacy for Recurrent AOM *Finnish Otitis Media Study-Efficacy for Other Planned AnalysesFinnish OM Study-Effica

18、cy for Nasopharyngeal Carriage of Vaccine Serotypes (per protocol)Finnish OM StudySerum Geometric Mean Antibody Concentration (GMC) After 3rd and 4th DosesSerotypePost Dose 3 GMC(mcg/mL)Post Dose 4 GMC(mcg/mL)HBVN=52PncCRMN=54HBVN=54PncCRMN=5540.051.700.112.566B0.092.000.169.059V0.102.480.213.97140.

19、216.280.2110.8218C0.083.550.106.5119F0.223.280.414.9623F0.102.510.156.25Finnish OM StudySerum Antibody Concentrations (GMC) and Serotype-Specific EfficacyFinnish Otitis Media StudyInvasive Disease Due to PneumococcusFinnish Otitis Media Study: Review Issues and Supplementary AnalysesFinnish OM Study

20、: Analysis of CovariatesEfficacy Estimates Adjusted for Gender, AOM Prior to Enrollment, Gestational Age, Birth Weight, Daycare, Breast-feeding, and Household Smoking Finnish OM Study: Example from the Data, Multiple Episodes Due to Same SerotypeFinnish OM Study: Examples from the Data, Multiple Epi

21、sodes Due to Same SerotypeFinnish OM StudySupplementary Analysis: Subsequent AOM Episodes due to Same Serotype Excluded, Vaccine Serotypes (PP)Finnish OM StudySupplementary Analysis: Subsequent AOM Episodes due to Same Serotype Excluded, All Pneumococcal Serotypes (Per Protocol)Finnish OM StudySuppl

22、ementary Analysis: Pneumococcal AOM by PCR/CultureFinnish OM StudySupplementary Analysis*: Antibiotic UseFinnish OM Study-Supplementary Analysis: First Tympanostomy Tube PlacementFinnish OM Follow-up StudyTympanostomy Tube PlacementTo assess long-term effect of vaccine on procedures for ear tube pla

23、cement Children evaluated at 4-5 years of ageUnblindedTwo populations evaluated:Volunteers in follow-up study, N= 756Original randomized population, N= 1662Finnish OM Follow-up StudyPrimary Analysis, Rate of Ear Tube Placement among Children Enrolled in Follow-up StudyFinnish OM Follow-up StudySecon

24、dary Analysis, Rate of Ear Tube Placement among All Children Followed to 4-5 years of AgeNorthern California Kaiser Permanente (NCKP) Otitis Media Efficacy ResultsNorthern California Kaiser Permanente (NCKP) Study: Elements of Study DesignRandomized, double-blindInvestigational meningococcal C conju

25、gate vaccine controlAOM a secondary endpointNo standardized AOM clinical case definitionNo tympanocentesis or routine culture of MEFAutomated database searches to identify OM diagnosesNCKP Study: Case DefinitionsAOM Diagnosis: Based on clinical practiceAOM Episode: A clinic visit at which AOM was di

26、agnosed, 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 NCKP Study: Prospectively Defined AOM EndpointsPrimary:All AOM episodesSecondary:First AOM episodeFrequent AOM First tympanostomy tube All OM clinic

27、visitsRuptured ear drumsNCKP Study: Primary Analysis,Overall Reduction in AOM EpisodesNCKP Study: Secondary Analysis,Reduction in Risk of at Least 1 EpisodeNCKP Study: Frequent Acute Otitis MediaNCKP Study: First Tympanostomy Tube PlacementNCKP Study: Ruptured Ear Drums with Pneumococcus IsolatedNCK

28、P Study: Serotype Distribution of Ruptured Ear Drums with Pneumococcus Isolated (ITT)NCKP Study: Efficacy Through Extended Follow-up (ITT) Summary of Efficacy Estimates (ITT)OutcomeFinnishNCKPVaccine Serotypes54%NAFirst Episode Vaccine Serotypes48%NAAll S. pneumo, Culture- Confirmed32%NARecurrent OM

29、*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 availableFinnish Otitis Media Study: Safety AnalysisFinnish OM Study: Safety Analysis Relevance of safety data to US population is limited:Use of con

30、current 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 eventsFinnish OM Study: Safety Analysis, Local and Systemic Reactions, First 3 DosesFinnish OM Study:

31、 Safety Analysis, Local and Systemic Reactions, 4th DoseFinnish OM Study: Safety Analysis, 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 concerns were

32、identifiedConsiderationsRequired Level of EfficacyThe minimum level of efficacy required for licensure of a preventive vaccine is not specifically addressed by FDA regulations or published guidance.Considerations: Licensure of Other Pneumococcal Vaccines for Otitis MediaAOM indication should stand o

33、n 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.P

34、revention of more AOM episodes with less vaccine- serotype-specific efficacy is a possible scenario.Considerations: Description of the treatment effect Primary outcomes in NCKP study and Finnish OM study differPrevention of AOM due to vaccine serotypes does not capture:Positive treatment effect on v

35、accine-related pneumococcal serotypesNegative efficacy for unrelated pneumococcal serotypesEfficacy estimates relatively low for some outcomesConfidence intervals wide for some outcomesConsiderations: Clinical benefit vs. economic benefit Substantial evidence of clinical benefit must be provided from adequate and well-controlled studies. Economic benefit is not considered in the efficacy evaluation by FDA.Considerations: Market