R. Douglas Pratt, M.D., M.P.H.

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.

2. Review Team Jingyee Kou, Ph.D. Marion Gruber, Ph.D. Carl Frasch, Ph.D.

3. 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)

4. 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 Regulatory Background

5. 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

6. 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)

7. Clinical Studies Reviewed

8. 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

9. 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

10. Finnish OM Study—Secondary Objectives Determine: • Efficacy using different levels of etiologic diagnosis • Efficacy in preventing nasopharyngeal carriage • Antibody response • Safety and tolerability

11. 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

12. Finnish OM Study: Vaccine Schedule and Concurrent Immunizations

13. 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

14. 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.

15. 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

16. 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

17. Finnish OM Study:Primary Endpoint Definition

18. 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

19. 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

20. Finnish OM Study:Selected Population Characteristics

21. Finnish OM Study-Primary Analysis, AOM due to Vaccine Serotypes

22. Finnish OM Study-AOM due to Individual Vaccine Serotypes, (Intent-to-treat)

23. Finnish OM Study-Secondary Analyses, First and Subsequent AOM Episodes due to Vaccine Serotypes

24. Finnish OM Study-Efficacy for All Culture-Confirmed Pneumococci, Regardless of Serotype

25. Finnish OM Study-Efficacy for Vaccine-Related Serotypes

26. Finnish OM Study-AOM due to Individual Vaccine-Related Serotypes, (Intent-to-treat)

27. Finnish Otitis Media Study-Efficacy for Vaccine-Unrelated Pneumococcal Serotypes

28. Finnish Otitis Media Study-Efficacy for Recurrent AOM *

29. Finnish Otitis Media Study-Efficacy for Other Planned Analyses

30. Finnish OM Study-Efficacy for Nasopharyngeal Carriage of Vaccine Serotypes (per protocol)

31. Finnish OM Study—Serum Geometric Mean Antibody Concentration (GMC) After 3rd and 4th Doses

32. Finnish OM Study—Serum Antibody Concentrations (GMC) and Serotype-Specific Efficacy

33. Finnish Otitis Media Study—Invasive Disease Due to Pneumococcus

34. Finnish Otitis Media Study: Review Issues and Supplementary Analyses

35. Finnish OM Study: Analysis of CovariatesEfficacy Estimates Adjusted for Gender, AOM Prior to Enrollment, Gestational Age, Birth Weight, Daycare, Breast-feeding, and Household Smoking

36. Finnish OM Study: Example from the Data, Multiple Episodes Due to Same Serotype

37. Finnish OM Study: Examples from the Data, Multiple Episodes Due to Same Serotype

38. Finnish OM Study—Supplementary Analysis: Subsequent AOM Episodes due to Same Serotype Excluded, Vaccine Serotypes(PP)

39. Finnish OM Study—Supplementary Analysis: Subsequent AOM Episodes due to Same Serotype Excluded, All Pneumococcal Serotypes(Per Protocol)

40. Finnish OM Study—Supplementary Analysis: Pneumococcal AOM by PCR/Culture

41. Finnish OM Study—Supplementary Analysis*: Antibiotic Use

42. Finnish OM Study-Supplementary Analysis: First Tympanostomy Tube Placement

43. Finnish OM Follow-up Study—Tympanostomy Tube Placement • To assess long-term effect of vaccine on procedures for ear tube placement • Children evaluated at 4-5 years of age • Unblinded • Two populations evaluated: • Volunteers in follow-up study, N= 756 • Original randomized population, N= 1662

44. Finnish OM Follow-up Study—Primary Analysis, Rate of Ear Tube Placement among Children Enrolled in Follow-up Study

45. Finnish OM Follow-up Study—Secondary Analysis, Rate of Ear Tube Placement among All Children Followed to 4-5 years of Age

46. Northern California Kaiser Permanente (NCKP) Otitis Media Efficacy Results

47. Northern 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 case definition • No tympanocentesis or routine culture of MEF • Automated database searches to identify OM diagnoses

48. NCKP Study: Case Definitions AOM Diagnosis: Based on clinical practice AOM Episode: A clinic visit at which AOM was diagnosed, and at least 21 days had elapsed since any previous visit for AOM Frequent AOM: 3 AOM episodes within 6 months, or 4 episodes within 12 months

49. NCKP Study: Prospectively Defined AOM Endpoints Primary: All AOM episodes Secondary: • First AOM episode • Frequent AOM • First tympanostomy tube • All OM clinic visits • Ruptured ear drums

50. NCKP Study: Primary Analysis,Overall Reduction in AOM Episodes