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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 TeamJingyee Kou,Ph.D.Marion Gruber,Ph.D.Carl Frasch,Ph.D.Proposed IndicationFor activ

2、e 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 for inva

3、sive 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 Issues Efficacy estimates for AOM outcomes are comparativ

4、ely 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 AOMComments from Medical Community:Correspondence to New England Journal of Medicine Clini

5、cal 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 AO

6、M (Cantekin E)Clinical Studies ReviewedStudy Number children enrolled Control Vaccine New Episode Interval Case Definition Regulatory Objective/Other Information Finnish OM 1,662 HBV 30 days Bacterial cultures(myringotomy)Demonstrate efficacy for prevention of AOM;Kaiser(NCKP)34,146 MnCC 21 days Aut

7、omated database search for AOM visits Demonstrate efficacy for prevention of invasive disease,AOM,and pneumonia;Large safety data base for assessing rates of adverse events;Vaccines administered at 2,4,6,and 12-15 months of age in each study Subjects distributed equally to PncCRM and HBV control vac

8、cine;entire study was randomized 1:1:1,PncCRM:PncOMP:HBV.Subjects randomized equally to 7VPnC or MnCC control vaccine.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

9、 OM study Considerations Questions to the CommitteeFinnish OM StudyPrimary 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 u

10、sing different levels of etiologic diagnosis Efficacy in preventing nasopharyngeal carriage Antibody response Safety and tolerabilityFinnish 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 p

11、rovided in the application Double-blind Healthy 2 month old infants enrolledFinnish OM Study:Vaccine Schedule and Concurrent ImmunizationsAge of child(months)Vaccines Administered 2 4 6 7 12 18 24 PncCRM/HBV+DTP-Hib+IPV +MMR +Finnish OM study Case surveillance and ascertainment Free access to study

12、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 yearsFinnish OM

13、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 symptom

14、s of respiratory infection.Finnish OM Study:AOM Efficacy EndpointsPrimary:AOM episodes due to vaccine serotypesSecondary:First and Subsequent AOM episodes due to vaccine serotypesOther:AOM due to vaccine serotypes by dose All pneumococcal AOM,regardless of serotype (culture and/or PCR)All AOM episod

15、es with MEF,regardless of etiology All AOM episodes regardless of etiology Children with recurrent AOMFinnish OM 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 ser

16、otypeCulture confirmedFinnish 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

17、variance estimates used to compensate for interdependency of events within subjects Provides average vaccine effect on AOM episodesFinnish 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

18、 vaccine doseFinnish OM Study:Selected Population Characteristics HBV PncCRM Population Characteristic N(%)N(%)Gestational Age 37 weeks 53(6.4)41(4.9)Birth weight 2.5 kg 42(5.1)25 (3.0)Prior AOM episodes 39(4.7)27(3.2)Finnish OM Study-Primary Analysis,AOM due to Vaccine SerotypesNumber of Episodes V

19、accine Efficacy Follow-up Period HBV PncCRM Estimate 95%CI PP 250 107 57%44,67 AOM due to vaccine serotypes ITT 292 135 54%41,64 Finnish OM Study-AOM due to Individual Vaccine Serotypes,(Intent-to-treat)Number of Episodes Vaccine Efficacy AOM Episode due to Serotype HBV PncCRM Estimate 95%CI 4 4 2 5

20、0%-172,91 6B 61 12 80%60,90 9V 11 6 45%-66,82 14 31 8 74%34,90 18C 18 7 61%2,85 19F 67 60 10%-32,39 23F 104 40 62%41,75 Finnish OM Study-Secondary Analyses,First and Subsequent AOM Episodes due to Vaccine SerotypesNumber of Episodes Vaccine Efficacy Follow-up Period HBV PncCRM Estimate 95%CI PP 177

21、89 52%39,63 First AOM Episode due to Vaccine Serotype ITT 196 109 48%34,59 PP 73 18 45%5,69 Subsequent AOM Episode due to Vaccine Serotype ITT 96 26 49%20,67 Finnish OM Study-Efficacy for All Culture-Confirmed Pneumococci,Regardless of SerotypeNumber of Episodes Vaccine Efficacy Follow-up Period HBV

22、 PncCRM Estimate 95%CI PP 414 271 34%21,45 Culture-confirmed pneumococcal AOM ITT 467 322 32%19,42 Finnish OM Study-Efficacy for Vaccine-Related SerotypesNumber of Episodes Vaccine Efficacy Follow-up Period HBV PncCRM Estimate 95%CI PP 84 41 51%27,67 AOM due to vaccine-related serotypes ITT 90 50 44

23、%20,62 Finnish OM Study-AOM due to Individual Vaccine-Related Serotypes,(Intent-to-treat)Number of Episodes Vaccine Efficacy AOM Episode due to Serotype HBV PncCRM Estimate 95%CI 6A 48 23 52%17,72 9N 9 2 78%-6,95 18B 1 2-101%-2108,82 19A 28 22 21%-40,56 23A 4 1 75%-149,97 Finnish Otitis Media Study-

24、Efficacy for Vaccine-Unrelated Pneumococcal SerotypesNumber of Episodes Vaccine Efficacy Follow-up Period HBV PncCRM Estimate 95%CI PP 95 126-34-81,0 AOM due to other than vaccine related serotypes ITT 101 140-39-86,-3 Serotypes 3,11,15,35 were the most common vaccine-unrelated serotypes identified.

25、Finnish Otitis Media Study-Efficacy for Recurrent AOM*Number of Children with Recurrent AOM Vaccine Efficacy Follow-up Period HBV PncCRM Estimate 95%CI PP 149 123 16%-6,35 Children with Recurrent AOM ITT 174 158 9%-12,27 All causes of AOM contribute to Recurrent AOM definition.Finnish Otitis Media S

26、tudy-Efficacy for Other Planned AnalysesNumber of Episodes Vaccine Efficacy Follow-up Period HBV PncCRM Estimate(95%CI)PP 1267 1177 7%-5,17 AOM with MEF ITT 1445 1390 4%-7,14 PP 1345 1251 6%-4,16 AOM regardless of etiology ITT 1532 1474 4%-7,14 MEF=Middle Ear Fluid Finnish OM Study-Efficacy for Naso

27、pharyngeal Carriage of Vaccine Serotypes(per protocol)No.Children%Carriage%Reduction HBV PncCRM HBV PncCRM Estimate 95%CI 12 mos 809 801 12.2 10.1 17%-9,37 18 mos 797 787 16.2 9.5 41%23,55 Finnish OM StudySerum Geometric Mean Antibody Concentration(GMC)After 3rd and 4th DosesSerotypePost Dose 3 GMC(

28、mcg/mL)Post Dose 4 GMC(mcg/mL)HBVN=52PncCRMN=54HBVN=54PncCRMN=5540.051.700.112.566B0.092.000.169.059V0.102.480.213.97140.216.280.2110.8218C0.083.550.106.5119F0.223.280.414.9623F0.102.510.156.25Finnish OM StudySerum Antibody Concentrations(GMC)and Serotype-Specific Efficacy GMC(mcg/mL)Serotype Seroty

29、pe-specific efficacy estimate(Per Protocol)Post dose 3 Post dose 4 4 49%1.70 2.56 6B 84%2.00 9.05 9V 54%2.48 3.97 14 69%6.28 10.82 18C 58%3.55 6.51 19F 25%3.28 4.96 23F 59%2.51 6.25 Finnish Otitis Media StudyInvasive Disease Due to PneumococcusStudy group Serotype Clinical syndrome Age(months)PncCRM

30、 7*Bacteremia 19 HBV 15*23F 19F Meningitis Meningitis Bacteremia 8 14 9 *Non-vaccine serotypes Finnish Otitis Media Study:Review Issues and Supplementary AnalysesFinnish OM Study:Analysis of CovariatesEfficacy Estimates Adjusted for Gender,AOM Prior to Enrollment,Gestational Age,Birth Weight,Daycare

31、,Breast-feeding,and Household Smoking Vaccine Efficacy(95%CI)Outcomes Analyzed under Intent-to-treat Un-adjusted for Covariates Adjusted for Covariates AOM due to Vaccine Serotypes 54%(41,64)54%(41,64)Culture-confirmed Pneumo.AOM 32%(19,42)32%(20,43)AOM Regardless of Etiology 4%(-7,14)5%(-6,14)Finni

32、sh OM Study:Example from the Data,Multiple Episodes Due to Same SerotypeSubject ID Vaccine Group Culture Age at AOM 23F 335 23F 347 1680 HBV 23F 355 23F 374 23F 462 23F 677 Finnish OM Study:Examples from the Data,Multiple Episodes Due to Same SerotypeSubject ID Vaccine Group Culture AOM Age 1450 Pnc

33、CRM 23F 268 23F 344 23F 665 15 163 2241 PncCRM 15 227 15 267 Finnish OM StudySupplementary Analysis:Subsequent AOM Episodes due to Same Serotype Excluded,Vaccine Serotypes(PP)Number of Episodes Vaccine Efficacy Inclusion/Exclusion of Multiple Episodes of Same Serotype HBV PncCRM Estim.95%CI Per Anal

34、ysis Plan 250 107 57%44,67 Exclude subsequent episode due to same serotype 216 95 55%43,65 Finnish OM StudySupplementary Analysis:Subsequent AOM Episodes due to Same Serotype Excluded,All Pneumococcal Serotypes(Per Protocol)Number of Episodes Vaccine Efficacy Inclusion/Exclusion of Multiple Episodes

35、 of Same Serotype HBV PncCRM Estim.95%CI Per Analysis Plan 414 271 34%21,45 Exclude subsequent episode due to same serotype 374 245 34%21,44 Finnish OM StudySupplementary Analysis:Pneumococcal AOM by PCR/CultureNumber of Episodes Vaccine Efficacy Method of Diagnosis Follow-up Period HBV PncCRM Estim

36、ate 95%CI PP 414 271 34%21,45 Culture ITT 467 322 32%19,42 PP 678 541 20%7,31 PCR ITT 764 635 18%5,29 PP 687 548 20%7,31 Culture or PCR ITT 775 642 18%5,29 PCR based on pneumolysin gene.Finnish OM StudySupplementary Analysis*:Antibiotic UseNumber(%)of Subjects Who Had Antibiotics During ITT Follow-u

37、p HBV (N=831)PncCRM (N=831)P-Value AOM Treatment*589(71%)551(66%)0.051 AOM Prevention*143(17%)132(16%)0.509 Other Purposes 147(18%)157(19%)0.568 Regardless of Purpose 605(73%)578(70%)0.159 P-value based on Fishers exact test.*Analysis requested by FDA post-unblinding.*All etiologies of AOM.Finnish O

38、M Study-Supplementary Analysis:First Tympanostomy Tube Placement HBV PncCRM Number of Randomized Subjects 831 831 Number of Subjects with Events 161 153 Incidence of First Tube Placement 0.12 0.11 Finnish OM Follow-up StudyTympanostomy Tube Placement To assess long-term effect of vaccine on procedur

39、es for ear tube placement Children evaluated at 4-5 years of age Unblinded Two 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 StudyVaccine Efficac

40、y HBV PncCRM Estimate 95%CI Number of children enrolled 353 403 Rate of events(/100 child years)ITT Follow-up 2 months-2 years 14.8 12.9 12%-17,34 Long-term Follow-up,2 years-4 to 5 years 5.7 3.5 39%4,61 Finnish OM Follow-up StudySecondary Analysis,Rate of Ear Tube Placement among All Children Follo

41、wed to 4-5 years of AgeVaccine Efficacy HBV PncCRM Estimate 95%CI Number of children enrolled 831 831 Rate of events,ITT Follow-up,2months-2years 12.7 12.0 4%-19,23 Number of children available for follow-up 744 746 Rate of events,Long-term Follow-up,2 years-4 to 5 year 4.1 2.4 44%19,62 Rate as per

42、100 child years.Northern California Kaiser Permanente(NCKP)Otitis Media Efficacy ResultsNorthern California Kaiser Permanente(NCKP)Study:Elements of Study Design Randomized,double-blind Investigational meningococcal C conjugate vaccine control AOM a secondary endpoint No standardized AOM clinical ca

43、se definition No tympanocentesis or routine culture of MEF Automated database searches to identify OM diagnosesNCKP Study:Case DefinitionsAOM 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 AOMFre

44、quent AOM:3 AOM episodes within 6 months,or 4 episodes within 12 months NCKP Study:Prospectively Defined AOM EndpointsPrimary:All AOM episodesSecondary:First AOM episode Frequent AOM First tympanostomy tube All OM clinic visits Ruptured ear drumsNCKP Study:Primary Analysis,Overall Reduction in AOM E

45、pisodes Number of Episodes Vaccine efficacy Reduction in All AOM Episodes 7VPnC MnCC%Reduction 95%CI Per protocol 16,124 17,405 7.0%4.1,9.7 Intent-to-treat 25,590 27,199 6.4%3.9,8.7 Estimates of relative risk based on Andersen-Gill counting process over time with treatment as the only covariate.NCKP

46、 Study:Secondary Analysis,Reduction in Risk of at Least 1 Episode Number of Children with 1 Episode Vaccine efficacy Reduction in Risk of 1 AOM Episode 7VPnC MnCC%Reduction 95%CI Per protocol 7,126 7,411 5.4%2.3,8.4 Intent-to-treat 10,112 10,394 4.9%2.3,7.5 Estimates of relative risk and confidence

47、intervals based on Cox-regression model of hazard over time,with gender as covariate.NCKP Study:Frequent Acute Otitis MediaNumber of Children with Frequent AOM Vaccine Efficacy Frequent AOM 7VPnC MnCC%Reduction 95%CI Per protocol 1,647 1,809 9.5%3.2,15.3 Intent-to-treat 2,612 2,839 9.2%4.3,13.9 Esti

48、mates of relative risk and confidence intervals based on Cox-regression model of hazard over time,with gender as covariate.NCKP Study:First Tympanostomy Tube PlacementNumber of Children with Tube Placement Vaccine Efficacy Reduction in First Tympanostomy Tube Placement 7VPnC MnCC%Reduction 95%CI Per

49、 protocol 157 198 20%2,35 Intent-to-treat 192 240 21%4,34 Estimates of relative risk and confidence intervals were based on Cox regression model of hazard over time.NCKP Study:Ruptured Ear Drums with Pneumococcus IsolatedNumber of Ruptured Ear Drums Vaccine efficacy Ruptured Ear Drums 7VPnC MnCC Est

50、imate 95%CI Vaccine Serotypes Per Protocol 4 9 56%-59,90 Intent-to-treat 6 14 57%-19,86 All Pneumococcal Serotypes Per Protocol 5 13 62%-15,89 Intent-to-treat 7 18 61%24,86 Confidence limits based on exact binomial distributions.NCKP Study:Serotype Distribution of Ruptured Ear Drums with Pneumococcu