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1、Vaccines and Related Biological Products Advisory Committee (VRBPAC)May 21, 2002Prevnar, Pneumococcal Conjugate Vaccine 7-valent, for the Prevention of Acute Otitis Media,R. Douglas Pratt, M.D., M.P.H.,微快车微信营销 http:/,Review Team,Jingyee Kou, Ph.D.Marion Gruber, Ph.D.Carl Frasch, Ph.D.,Proposed Indic
2、ation,For active 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 Background,November 1999 February 2000June 2000May 2001October 2001March 2002
3、May 2002,VRBPAC 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 media,Global Issues,Efficacy estimates for
4、AOM outcomes are comparatively 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 AOM,Comments from Medical Community:Correspondence to New Engl
5、and Journal of Medicine,Clinical 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)Misunderstand
6、ing of FDA action taken regarding AOM (Cantekin E),Clinical Studies Reviewed,Outline of FDA Presentation,IntroductionEfficacy data from Finnish OM studySupplementary analysesFinnish follow-up studyEfficacy data from the NCKP studySafety data from Finnish OM studyConsiderationsQuestions to the Commit
7、tee,Finnish OM StudyPrimary Objective,Determine the protective efficacy of the pneumococcal conjugate vaccine against culture-confirmed pneumococcal acute otitis media (AOM) due to vaccine serotypes,Finnish OM StudySecondary Objectives,Determine:Efficacy using different levels of etiologic diagnosis
8、Efficacy in preventing nasopharyngeal carriageAntibody responseSafety and tolerability,Finnish OM Study: Elements of the Study Design,Randomized equally to one of 3 vaccines:PncCRM (Wyeth-Lederle)PncOMP (Merck) HBV (Control)Only data relating to PncCRM were provided in the applicationDouble-blindHea
9、lthy 2 month old infants enrolled,Finnish OM Study: Vaccine Schedule and Concurrent Immunizations,Finnish 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 aspir
10、ation 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 2 years,Finnish OM Study:Clinical Definition of Acute Otitis Media,Visually abnormal tympanic membrane (in regard to color, position, and/or mobil
11、ity) 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 other symptoms of respiratory infection.,Finnish OM Study: AOM Efficacy Endpoints,Primary: AOM episodes due to vaccine serotypesSec
12、ondary: 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 episodes with MEF, regardless of etiologyAll AOM episodes regardless of etiologyChildren with recurrent AOM,Finnish OM
13、Study-Definition of Primary Endpoint,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 confirmed,Finnish OM Study:Primary Endpoint Definition,Finnish OM Study-Analysis of Primary Endpoin
14、t,Generalized 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 estimates used to compensate for interdependency of events within subjectsProvides average vaccine eff
15、ect on AOM episodes,Finnish OM Study-Definitions of Follow-up Periods,Per protocol (PP) follow-up:Begins 2 weeks after the 3rd vaccine doseIntent-to-treat (ITT) follow-up:Begins at time of 1st vaccine dose,Finnish OM Study:Selected Population Characteristics,Finnish OM Study-Primary Analysis, AOM du
16、e to Vaccine Serotypes,Finnish OM Study-AOM due to Individual Vaccine Serotypes, (Intent-to-treat),Finnish OM Study-Secondary Analyses, First and Subsequent AOM Episodes due to Vaccine Serotypes,Finnish OM Study-Efficacy for All Culture-Confirmed Pneumococci, Regardless of Serotype,Finnish OM Study-
17、Efficacy for Vaccine-Related Serotypes,Finnish OM Study-AOM due to Individual Vaccine-Related Serotypes, (Intent-to-treat),Finnish Otitis Media Study-Efficacy for Vaccine-Unrelated Pneumococcal Serotypes,Finnish Otitis Media Study-Efficacy for Recurrent AOM *,Finnish Otitis Media Study-Efficacy for
18、Other Planned Analyses,Finnish OM Study-Efficacy for Nasopharyngeal Carriage of Vaccine Serotypes (per protocol),Finnish OM StudySerum Geometric Mean Antibody Concentration (GMC) After 3rd and 4th Doses,Finnish OM StudySerum Antibody Concentrations (GMC) and Serotype-Specific Efficacy,Finnish Otitis
19、 Media StudyInvasive Disease Due to Pneumococcus,Finnish Otitis Media Study: Review Issues and Supplementary Analyses,Finnish OM Study: Analysis of CovariatesEfficacy Estimates Adjusted for Gender, AOM Prior to Enrollment, Gestational Age, Birth Weight, Daycare, Breast-feeding, and Household Smoking
20、,Finnish OM Study: Example from the Data, Multiple Episodes Due to Same Serotype,Finnish OM Study: Examples from the Data, Multiple Episodes Due to Same Serotype,Finnish OM StudySupplementary Analysis: Subsequent AOM Episodes due to Same Serotype Excluded, Vaccine Serotypes (PP),Finnish OM StudySupp
21、lementary Analysis: Subsequent AOM Episodes due to Same Serotype Excluded, All Pneumococcal Serotypes (Per Protocol),Finnish OM StudySupplementary Analysis: Pneumococcal AOM by PCR/Culture,Finnish OM StudySupplementary Analysis*: Antibiotic Use,Finnish OM Study-Supplementary Analysis: First Tympanos
22、tomy Tube Placement,Finnish OM Follow-up StudyTympanostomy Tube Placement,To 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 study, N= 756Original randomized population, N= 1662,F
23、innish OM Follow-up StudyPrimary Analysis, Rate of Ear Tube Placement among Children Enrolled in Follow-up Study,Finnish OM Follow-up StudySecondary Analysis, Rate of Ear Tube Placement among All Children Followed to 4-5 years of Age,Northern California Kaiser Permanente (NCKP) Otitis Media Efficacy
24、 Results,Northern California Kaiser Permanente (NCKP) Study: Elements of Study Design,Randomized, double-blindInvestigational meningococcal C conjugate vaccine controlAOM a secondary endpointNo standardized AOM clinical case definitionNo tympanocentesis or routine culture of MEFAutomated database se
25、arches to identify OM diagnoses,NCKP Study: Case Definitions,AOM 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,
26、NCKP Study: Prospectively Defined AOM Endpoints,Primary:All AOM episodesSecondary:First AOM episodeFrequent AOM First tympanostomy tube All OM clinic visitsRuptured ear drums,NCKP Study: Primary Analysis,Overall Reduction in AOM Episodes,NCKP Study: Secondary Analysis,Reduction in Risk of at Least 1
27、 Episode,NCKP Study: Frequent Acute Otitis Media,NCKP Study: First Tympanostomy Tube Placement,NCKP Study: Ruptured Ear Drums with Pneumococcus Isolated,NCKP Study: Serotype Distribution of Ruptured Ear Drums with Pneumococcus Isolated (ITT),NCKP Study: Efficacy Through Extended Follow-up (ITT),Summ
28、ary of Efficacy Estimates (ITT),Finnish Otitis Media Study: Safety Analysis,Finnish OM Study: Safety Analysis,Relevance of safety data to US population is limited:Use of concurrent DTwP-Hib combination vaccines for first 3 doses, rather than DTaP, complicates assessments of systemic reactionsHomogen
29、eous study population Study not large enough to detect uncommon adverse events,Finnish OM Study: Safety Analysis, Local and Systemic Reactions, First 3 Doses,Finnish OM Study: Safety Analysis, Local and Systemic Reactions, 4th Dose,Finnish OM Study: Safety Analysis, Conclusions,Safety data are consi
30、stent with earlier observations regarding the safety of PrevnarIncreased rate of low-grade feverComplications of post-vaccination fever were uncommonNo new safety concerns were identified,Considerations,Required Level of Efficacy,The minimum level of efficacy required for licensure of a preventive v
31、accine is not specifically addressed by FDA regulations or published guidance.,Considerations: Licensure of Other Pneumococcal Vaccines for Otitis Media,AOM indication should stand on its own.License applications for new pneumococcal vaccines for prevention of AOM may not include evidence of efficac
32、y 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.Prevention of more AOM episodes with less vaccine- serotype-specific efficacy is a possible scenario.,Considerations: D
33、escription 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 vaccine-related pneumococcal serotypesNegative efficacy for unrelated pneumococcal serotypesEfficacy estimates relativ
34、ely low for some outcomesConfidence intervals wide for some outcomes,Considerations: 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.,Consid
35、erations: Marketing Implications,Promotional materials based on approved labelingPotential for unrealistic expectationsFDA is empowered to restrict marketing claims:Advertisements and promotional labeling are reviewed by CBERAdvertisements that are misleading (defined in 21 CFR 202.1) can result in
36、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).,Questions to the Committee,Are the data adequate to support the efficacy of Prevnar in infants and toddlers for prevention of otitis media caused
37、 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 efficacy study, or additional clinical trials be useful in establishing effic
38、acy?,Questions to the Committee (cont.),2.Please discuss the strength of the data with respect to secondary otitis media outcomes:Acute otitis media episodes caused by S. pneumoniae, regardless of serotypeOverall reduction in acute otitis media episodesFrequent otitis mediaTympanostomy tube placement,
