Vaccines and Related Biological Products Advisory Committee (VRBPAC) May 21, 2002 Prevnar, 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:/www.weikuaiche.cn,Review Team,Jingyee Kou, Ph.D. Marion Gruber, Ph.D. Carl Frasch, Ph.D.,Proposed Indication,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 2000 June 2000 May 2001 October 2001 March 2002 May 2002,VRBPAC for invasive disease Prevnar licensed for prevention of invasive disease AOM license amendment submitted FDA Letter to sponsor Response to FDA letter received Second FDA letter to sponsor; major amendment- Finnish follow-up data VRBPAC for otitis media,Global Issues,Efficacy estimates for AOM outcomes are comparatively low for preventive vaccines Possible 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 England 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) Misunderstanding of FDA action taken regarding AOM (Cantekin E),Clinical Studies Reviewed,Outline of FDA Presentation,Introduction Efficacy data from Finnish OM study Supplementary analyses Finnish follow-up study Efficacy data from the NCKP study Safety data from Finnish OM study Considerations Questions to the Committee,Finnish OM Study Primary Objective,Determine the protective efficacy of the pneumococcal conjugate vaccine against culture-confirmed pneumococcal acute otitis media (AOM) due to vaccine serotypes,Finnish OM Study Secondary Objectives,Determine: Efficacy using different levels of etiologic diagnosis Efficacy in preventing nasopharyngeal carriage Antibody response Safety 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 application Double-blind Healthy 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/week Children brought to study clinics for respiratory infections or symptoms suggesting AOM Myringotomy with aspiration of middle ear fluid for culture, if AOM diagnosed at the visit If S. pneumoniae found, the serotype was determined Follow-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 mobility) suggesting effusion in the middle ear cavity And 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 serotypes Secondary: First and Subsequent AOM episodes due to vaccine serotypes Other: AOM due to vaccine serotypes by dose All pneumococcal AOM, regardless of serotype (culture and/or PCR) All AOM episodes with MEF, regardless of etiology All AOM episodes regardless of etiology Children with recurrent AOM,Finnish OM Study- Definition of Primary Endpoint,AOM episode due to vaccine serotypes At least 30 days since beginning of previous AOM due to the same serotype Or, any interval for different vaccine serotype Culture confirmed,Finnish OM Study: Primary Endpoint Definition,Finnish OM Study- Analysis of Primary Endpoint,Generalized Cox regression model with Anderson-Gill counting method Risk of AOM estimated “piecewise”, i.e., from event to event Assumes proportional hazards between groups over time Robust variance estimates used to compensate for interdependency of events within subjects Provides average vaccine effect on AOM episodes,Finnish OM Study- Definitions of Follow-up Periods,Per protocol (PP) follow-up: Begins 2 weeks after the 3rd vaccine dose Intent-to-treat (ITT) follow-up: Begins at time of 1st vaccine dose,Finnish OM Study: Selected Population Characteristics,Finnish OM Study- Primary Analysis, AOM due 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- Efficacy for Vaccine-Related Serotypes,Finnish OM Study- AOM due to Individual Vaccine-Related Se