1. 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.

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. 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

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 3 rd and 4 th Doses Serotype Post Dose 3 GMC (mcg/mL) Post Dose 4 GMC (mcg/mL) HBV N=52 PncCRM N=54 HBV N=54 PncCRM N=55 40.051.700.112.56 6B0.092.000.169.05 9V0.102.480.213.97 140.216.280.2110.82 18C0.083.550.106.51 19F0.223.280.414.96 23F0.102.510.156.25

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 Covariates Efficacy 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

51. NCKP Study: Secondary Analysis, Reduction in Risk of at Least 1 Episode

52. NCKP Study: Frequent Acute Otitis Media

53. NCKP Study: First Tympanostomy Tube Placement

54. NCKP Study: Ruptured Ear Drums with Pneumococcus Isolated

55. NCKP Study: Serotype Distribution of Ruptured Ear Drums with Pneumococcus Isolated (ITT)

56. NCKP Study: Efficacy Through Extended Follow-up (ITT)

57. Summary of Efficacy Estimates (ITT) OutcomeFinnishNCKP Vaccine Serotypes54%NA First Episode Vaccine Serotypes 48%NA All S. pneumo, Culture- Confirmed 32%NA Recurrent OM*9%**9% Tympanostomy Tube4%**21% All Cause OM4%**6% First Episode All Cause AOMNA5% * All cause otitis media ** Not statistically significant at p=0.05 NA = Not available

58. Finnish Otitis Media Study: Safety Analysis

59. 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 reactions  Homogeneous study population  Study not large enough to detect uncommon adverse events

60. Finnish OM Study: Safety Analysis, Local and Systemic Reactions, First 3 Doses

61. Finnish OM Study: Safety Analysis, Local and Systemic Reactions, 4th Dose

62. Finnish OM Study: Safety Analysis, Conclusions Safety data are consistent with earlier observations regarding the safety of Prevnar Increased rate of low-grade fever Complications of post-vaccination fever were uncommon No new safety concerns were identified

63. Considerations

64. Required Level of Efficacy The minimum level of efficacy required for licensure of a preventive vaccine is not specifically addressed by FDA regulations or published guidance.

65. 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 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. Prevention of more AOM episodes with less vaccine- serotype-specific efficacy is a possible scenario.

66. Considerations: Description of the treatment effect Primary outcomes in NCKP study and Finnish OM study differ Prevention of AOM due to vaccine serotypes does not capture:  Positive treatment effect on vaccine-related pneumococcal serotypes  Negative efficacy for unrelated pneumococcal serotypes Efficacy estimates relatively low for some outcomes Confidence intervals wide for some outcomes

67. 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.

68. Considerations: Marketing Implications Promotional materials based on approved labeling Potential for unrealistic expectations FDA is empowered to restrict marketing claims:  Advertisements and promotional labeling are reviewed by CBER  Advertisements that are misleading (defined in 21 CFR 202.1) can result in 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).

69. Questions to the Committee 1.Are the data adequate to support the efficacy of Prevnar in infants and toddlers for prevention of otitis media caused 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 efficacy?

70. Questions to the Committee (cont.) 2.Please discuss the strength of the data with respect to secondary otitis media outcomes: a.Acute otitis media episodes caused by S. pneumoniae, regardless of serotype b.Overall reduction in acute otitis media episodes c.Frequent otitis media d.Tympanostomy tube placement