Vaccines and Related Biological Products Advisory Committee Meeting Prevnar 13: Pneumococcal 13-valent Conjugate Vacc

1. Vaccines and Related Biological Products Advisory Committee Meeting Prevnar 13: Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM197 Protein] Applicant: Wyeth Pharmaceuticals Inc. Tina Khoie, M.D., M.P.H FDA/CBER/OVRR/DVRPA November 18, 2009

2. Presentation Outline • Product Composition Comparison with Prevnar® • Proposed Indications and Usage • Prevnar Efficacy and Safety Background • Prevnar 13 Pediatric Clinical Development • Immunogenicity • Safety • Otitis Media Considerations

3. Product Composition - Comparison with Prevnar Each 0.5 mL dose of Prevnar 13 and Prevnar contains: * P80 added to the final Prevnar 13 formulation late in clinical development

4. Prevnar 13: Applicant’s Proposed Indications and Usage • Active immunization of infants and toddlers for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F • Active immunization of infants and toddlers for the prevention of otitis media caused by serotypes included in the vaccine • Prevnar 13 is to be administered to infants as a 4 dose series at 2, 4, 6, and 12-15 months of age

5. Prevnar Efficacy Background • Approved by FDA in Feb 2000 to prevent vaccine serotype invasive pneumococcal disease (IPD) in young children. • Efficacy against vaccine serotype IPD was 97.4% (95% CI 82.7, 99.9) • Approved by FDA in Oct 2002 for prevention of vaccine serotype otitis media (OM) based on data from: • an acute otitis media (AOM) efficacy trial in Finland, involving tympanocentesis, evaluating serotype-specific efficacy • a U.S. health-care utilization study on impact on all-cause OM • Efficacy against vaccine serotype AOM was 57% (95% CI 44, 67) and 7% (95% CI 4.1, 9.7) against all OM regardless of etiology • Prevnar efficacy data are referenced in the Prevnar 13 BLA

6. Prevnar Prelicensure Safety Background • Safety evaluated in 5 U.S. clinical studies • 18,168 subjects received 58,699 doses of Prevnar • Subjects received Prevnar at 2, 4, 6, and 12-15 months of age along with other routine childhood vaccines • Overall, Prevnar safety profile characterized by: • Increased rates of local reactions compared to Hib and DTaP • Increased rates of low grade fever and irritability compared to an unapproved meningococcal serogroup C conjugate vaccine • Increased rates of low grade fever compared to a control group that received no investigational products • Severe local reactions occurring more often in children 3-9 years of age (in ancillary studies) compared to infants

7. Prevnar Postlicensure Safety • Postmarketing observational safety surveillance study • 65,927 infants evaluated across doses, health-care settings and multiple post-vaccination time windows • Evaluated events of interest identified in prelicensure studies, including croup, gastroenteritis, allergic reactions, seizures, wheezing diagnoses and breath holding • Primary safety outcomes analyses did not demonstrate a consistently elevated risk of healthcare utilization for any of the evaluated events of interest.

8. Prevnar 13 Pediatric Clinical Development • Placebo-controlled clinical efficacy study not feasible • Approach for inferring efficacy against IPD: • Evaluate non-inferiority of Prevnar 13 to Prevnar based on IgG ELISA antibody responses • Serologic criteria were based in part on WHO recommendations • Approach for inferring efficacy against otitis media • No consensus regarding serologic criteria for assessing efficacy against otitis media • Relevance of circulating IgG in preventing otitis media is unclear

9. Main Prevnar 13 Pediatric Studies • 004:Phase 3 immunogenicity and safety (N=663) • Randomized (1:1), double-blind, active-controlled trial in U.S. infants and toddlers • Primary objectives: demonstrate non-inferiority of PCV13 (without P80) compared with PCV7 one month after 3 and 4 doses • 3005:Phase 3 safety and lot consistency (N=1699) • Randomized (2:2:2:1), double-blind trial in U.S. infants and toddlers; PCV7 active control included for safety • Primary objective: demonstrate equivalency of 3 independently produced lots of Prevnar 13

10. Other Supportive Studies • 003: Phase 1/2 safety and immunogenicity in U.S. infants and toddlers (N=247) • 009: Phase 3, non-IND non-inferiority study comparing Prevnar 13 with P80 to Prevnar 13 without P80 in Poland (N=500) • 3002: Open label, descriptive non-IND study evaluating Prevnar 13 catch-up in pneumococcal vaccine naïve children 7 months to < 72 months of age in Poland (N=354)

11. Other Supportive Studies • Nine non-IND studies (N=4381) conducted in Europe, Canada, and India provide data on serious adverse events. • 2322 and 2059 subjects randomized and vaccinated with at least one dose of Prevnar 13 or Prevnar, respectively. • Primary objective(s): evaluate country specific immunization schedules and/or country specific concomitant vaccinations. • Data supporting U.S. licensure of PCV13 were limited to serious adverse events, because studies included non-U.S. schedules, non-U.S. concomitant vaccinations, and less extensive safety monitoring than typically requested by CBER.

12. Immunogenicity from Main Infant Study 004

13. Main Immunogenicity Study 004 Design • 666 healthy, 2 month old infants randomized 1:1 to receive: • Prevnar 13: 0.5 mL IM at 2, 4, 6, and 12-15 months • Prevnar (active control): 0.5 mL IM at 2, 4, 6, and 12-15 months • HBV (birth dose), rotavirus, and influenza vaccines permitted during study period

14. Study 004 Immunogenicity Objectives & Endpoints • Primary Objectives: Demonstrate non-inferiority of Prevnar 13 to Prevnar for each of the vaccine serotypes and each primary endpoint. • Primary Endpoints: • IgG seroresponse rate ≥ 0.35 µg/mL 1 month after the 3rd dose • Geometric mean IgG antibody concentration (GMC) 1 month after the 4th dose • Secondary Endpoints: • IgG seroresponse rate ≥ 0.35 µg/mL 1 month after the 4th dose • IgG GMC before the 4th dose and 1 month after the 3rd dose • IgG seroresponse rate ≥ 1.0 µg/mL 1 month after the 3rd and 1 month after the 4th dose

15. Study 004 Non-inferiority Comparisons • For the 7 common serotypes, serotype-specific immune responses were compared between the two study groups • For the 6 additional serotypes not included in Prevnar, immune responses in Prevnar 13 recipients were compared to the lowest immune responseamong the 7 common serotypes in Prevnar recipients • Non-inferiority criteria: • IgG seroresponse rate: lower limit of 2-sided, 95% CI for the difference in proportions (PCV13 – PCV7) > - 10% • IgG GMC: lower limit of 2-sided, 95% CI for the GMC ratio (PCV13 / PCV7) > 0.5 (2-fold criterion)

16. Study 004 Exploratory Objective and Endpoints • Exploratory objective: To assess opsonophagocytic activity (OPA) following Prevnar 13 relative to Prevnar in a subset (N=100 per study group), when measured 1 month after the 3rd and 4th doses. • Exploratory endpoints: • Proportion of subjects achieving an OPA titer ≥ 1:8 titer one month after the 3rd and 4th doses. • OPA geometric mean titer (GMT) one month after the 3rd and 4th doses.

17. Study 004 Concomitant Vaccination Objectives* • To demonstrate that the immune response induced by concomitant antigens when administered with Prevnar 13 are noninferior to the corresponding immune response when administered with Prevnar • Antigens assessed 1 month after the 3rd dose: diphtheria, pertussis (PT, FHA, PRN), and H. influenzae (PRP) • Antigens assessed 1 month after the 12 month dose: measles, mumps, rubella, varicella, and H. influenzae (PRP) *Tetanus, HBV and IPV types 1-3 assessed in study 3005

18. Study 004 Demographics

19. Study 004 Primary EndpointImmunogenicity Results

20. Study 004: IgG Seroresponse Rates ≥ 0.35 µg/mL for the 7 Common Serotypes, 1 Month Post-dose 3 N = range in the number of subjects with a determinate IgG antibody concentration to the given serotype. Difference in proportions (PCV13 – PCV7 reference value) expressed as percentage. Non-inferiority criterion: lower limit of the 2-sided, 95% CI for the difference in two proportions > -0.1.

21. Study 004: IgG Seroresponse Rates ≥ 0.35 µg/mL for the 6 Additional Serotypes, 1 month Post-dose 3 N = range in the number of subjects with a determinate IgG antibody concentration to the given serotype. Difference in proportions (PCV13 – PCV7 reference value) expressed as percentage. For additional serotypes, the reference value is serotype 6B from the PCV7 group. Non-inferiority criterion: lower limit of the 2-sided, 95% CI for the difference in two proportions > -0.1.

22. Study 004: IgG GMC (µg/mL) for the 7 Common Serotypes, 1 month Post-dose 4 N = range in the number of subjects with a determinate IgG antibody concentration to the given serotype. GMC ratio: PCV13 to PCV7 reference. For the additional serotypes, the reference value is serotype 9V from the PCV7 group. Non-inferiority criterion: lower limit of the 2-sided, 95% CI for the GMC ratio > 0.5 (2-fold criterion).

23. Study 004: IgG GMC (µg/mL) for the 6 Additional Serotypes, 1 month Post-dose 4 N = range in the number of subjects with a determinate IgG antibody concentration to the given serotype. GMC ratio: PCV13 to PCV7 reference. For the additional serotypes, the reference value is serotype 9V from the PCV7 group. Non-inferiority criterion: lower limit of the 2-sided, 95% CI for the GMC ratio > 0.5 (2-fold criterion).

24. Study 004 Secondary Endpoints

25. Study 004: IgG GMC (µg/mL) for the 7 Common Serotypes, Pre-dose 4 N = range in the number of subjects with a determinate IgG antibody concentration to the given serotype. GMC ratio calculated by CBER. The study was not powered to demonstrate non-inferiority for secondary endpoints.

26. Study 004: IgG GMC (µg/mL) for the 6 Additional Serotypes, Pre-dose 4 N = range in the number of subjects with a determinate IgG antibody concentration to the given serotype. GMC ratio calculated by CBER. For the additional serotypes, the reference value is serotype 18C from the PCV7 group. The study was not powered to demonstrate non-inferiority for secondary endpoints.

27. Study 004: Serotype 6B IgG Secondary Endpoints N = number of subjects with a determinate IgG antibody concentration to the given serotype. Ratio of GMCs: PCV13 to PCV7 reference. Difference in proportions (PCV13 – PCV7) expressed as percentage. The study was not powered to demonstrate non-inferiority for secondary endpoints.

28. Study 004: Serotype 9V IgG Secondary Endpoints N = number of subjects with a determinate IgG antibody concentration to the given serotype. Ratio of GMCs; PCV13 to PCV7 reference. Difference in proportions (PCV13 – PCV7) expressed as percentage.

29. Study 004: Serotype 3 IgG Secondary Endpoints N = number of subjects with a determinate IgG antibody concentration to the given serotype. GMC ratio: PCV13 to PCV7 reference. For additional serotypes, reference value is serotype 9V from PCV7 group. Difference in proportions: PCV13 – PCV7 reference, expressed as percentage. PCV7 reference value is serotype 19F for evaluations at ≥ 0.35 µg/mL post-dose 4 and for evaluations at ≥ 1.0 µg/mL post-dose 4. PCV7 reference value is serotype 9V for evaluations at ≥ 1.0 µg/mL post-dose 3 and for GMC evaluations post-dose 3.

30. Study 004 Exploratory Endpoints

31. Study 004: Serotype 6B OPA Exploratory Endpoints N = Number of subjects with a determinate antibody titer for the specified serotype.

32. Serotype 9V OPA Exploratory Endpoints N = Number of subjects with a determinate antibody titer for the specified serotype.

33. Serotype 3 OPA Exploratory Endpoints N = Number of subjects with a determinate antibody titer for the specified serotype.

34. Immune Responses to Concomitant Routine U.S. Licensed Childhood Vaccines • Noninterference of Prevnar 13 with routine childhood vaccines was demonstrated for: • H. influenzae (PRP) • Diphtheria toxoid • Pertussis • Measles • Tetanus toxoid • Polio types 1-3 • Hepatitis B • Mumps, Rubella, and Varicella, assessments of immune interference are indeterminate at this time.

35. Immunogenicity Summary: 7 Common Serotypes Non-inferiority criteria: lower limit of the 2-sided, 95% CI for the difference in two proportions > -0.1 and lower limit of the 2-sided, 95% CI for the GMC ratio > 0.5 (2-fold criterion). * Calculated by CBER

36. Immunogenicity Summary: 6 Additional Serotypes Non-inferiority criteria: lower limit of the 2-sided, 95% CI for the difference in two proportions > -0.1 and lower limit of the 2-sided, 95% CI for the GMC ratio > 0.5 (2-fold criterion). * Calculated by CBER

37. Safety From Infant Studies

38. Safety • Three U.S. studies (003, 004, and 3005) included: • Prevnar 13 or Prevnar control at 2, 4, 6, and 12-15 months of age • Concomitant routine U.S. licensed pediatric vaccines. • Remaining infant studies included: • Different vaccine schedules and concomitant vaccinations for consistency with country-specific recommendations and local clinical practice. Schedules included: • 2, 3, 4, 11-12 months • 3, 5, 11 months • 2, 4, 12 months • 6, 10, 14 weeks, 12 months • Safety monitoring less extensive compared to U.S. studies • Safety population included all subjects who received at least 1 dose of study vaccine and for whom safety information was available. • Safety analyses were based on the actual vaccine received.

39. Overall Infant Safety Database Number of randomized subjects with ≥ 1 dose Number of randomized subjects with 4 doses *Includes infant series data from 13 studies, toddler dose data from 9 studies (7 studies with 4-dose schedules), and 6-month follow-up data from 5 studies.

40. U.S. Safety DatabaseVaccine Exposure and Study Completion * Post-dose 4 safety data from study 3005 were not available at the time the BLA was submitted to FDA. Applicant will submit these data when available.

41. Safety Monitoring in Phase 3 U.S. Studies (Studies 004 and 3005) • 30 minute observation period after each vaccination • Solicited local reactions and systemic adverse events recorded in e-diary on days 1-7 following each vaccination • Unsolicited adverse events occurring within 30 days after each vaccination collected at subsequent visit. • Newly diagnosed chronic medical conditions, hospitalizations, unsolicited, and serious adverse events (SAEs) occurring after the 3rd study dose were collected at 4th study dose clinic visit and by scripted telephone interview 6 months after 4th study dose. • Serious adverse events collected throughout study period.

42. 13 Infant StudiesSerious Adverse Events

43. All Infant Studies: Percent of Randomized Subjects with a Serious Adverse Event

44. Deaths: All studies * Possible contributing factors found on history.

45. Studies 004 and 3005 Solicited Safety Data

46. Study 004: Rates (%) of Solicited Local Reactions on Days 1-7 After Each Vaccination *Interferes with limb movement

47. Study 3005: Rates (%) of Solicited Local Reactions on Days 1-7 After Each Vaccination *Interferes with limb movement Dose 4 safety data from study 3005 were not submitted to the BLA.

48. Antipyretics Within 7 Days of Vaccination • Use of antipyretics to treat or prevent symptoms related to vaccination were similar between the two vaccine groups in in studies 004 and 3005. • Study 004: • Approximately 72-87% of subjects after doses 1, 2, or 3. • Approximately 84-90% of subjects after dose 4. • Study 3005: • Approximately 63-75% of subjects after doses 1, 2, or 3.

49. Study 004: Rates (%) of Fever on Days 1-7 After Each Vaccination * Statistically significant difference between the two study groups (Fisher exact test, 2-sided).

50. Study 3005: Rates (%) of Fever on Days 1-7 After Each Vaccination * Statistically significant difference between the two study groups (Fisher exact test, 2-sided). Dose 4 safety data from study 3005 were not submitted to BLA.