Prevnar 13 for Adult Use (Age > 50 Years) (Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM 197 Protein)

1. Vaccines and Related Biological Products Advisory Committee Meeting November 16, 2011 Prevnar 13 for Adult Use (Age >50 Years)(Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein) Applicant: Wyeth Pharmaceuticals, Inc. Rosemary Tiernan, MD, MPH Division of Vaccines and Related Products Applications CBER/FDA

2. Overview of Safety Presentation • Studies Supporting Safety in Adults Age > 50 yrs • Safety Population • Safety Monitoring and Data Collection • Adverse Reactions • Summary/Conclusions

3. Six Phase 3 Studies Supported Safety of PCV13 in Adults

4. Safety Population

5. Demographics

6. Study Populations Pre-existing underlying diseases included if condition was “stable”: • Disease not requiring significant change in therapy or hospitalization for worsening disease for 12 weeks before receipt of study vaccine • Change to new therapy allowed if not caused by worsening disease • Change in dose or therapy within category allowed Key Exclusion Criteria included: • Receipt of diphtheria-tetanus toxoid containing vaccines within 6 months of study vaccine • Streptococcus pneumoniae infection documented w/in past 5 years • Impairment of immunological function: • Immunoglobulin deficiencies, hematological malignancies, known HIV infection, collagen vascular disorders and subjects receiving immunosuppressive therapy • If systemic corticosteroids administered short term for treatment of acute illness, subjects excluded from vaccination until corticosteroid therapy had been discontinued for at least 30 days. • Serious chronic disorders: • Metastatic malignancy, severe chronic obstructive pulmonary disease, end-stage renal disease, clinically unstable cardiac disease, or any other disorder that in investigator’s opinion precluded subject from participating in study.

7. Underlying Medical Conditions in PCV13 Recipients (at 1st Dose)

8. Safety Data Collection and Monitoring

9. Solicited Adverse Events • Local and systemic reactions monitored daily for 14 days: • Electronic diary cards used to record information • Local events included • Redness, swelling, pain, limitation of motion (LOM) • Systemic events included: • Fever measured using oral digital thermometer daily (at bedtime and whenever fever suspected) • Fatigue, headache, chills, rash, vomiting, decreased appetite, new generalized muscle pain, aggravated generalized muscle pain, new generalized joint pain and aggravated generalized joint pain • Data regarding medications to treat pain and fever collected in all studies, except study 004.

10. Analysis of Adverse Events (AEs) • Solicited Local and Systemic AEs • Vaccine Naïve • Pre-immunized • Unsolicited Adverse Events • Deaths • Discontinuations due to Adverse Event • Serious Adverse Events (SAES)

11. Vaccine Naïve SubjectsStudies 004 and 3010 • Solicited Local Adverse Reactions • Solicited Systemic Adverse Reactions

12. Local Reactogenicity Within 14 Days of PCV13 or 23vPS (Naïve)

13. Systemic Reactogenicity Within 14 Days of PCV13 or 23vPS (Naïve)

14. Summary on Reactogenicity in Naïve Subjects • Local Reactogenicity • Study 004 • PCV 13 >23vPS for “any” redness/swelling/pain • 23vPS >PCV13 for “severe” pain (8.6% > 1.7-3.6%) • Study 3010 • PCV13 >23vPS for “any” pain (69.2 % vs 58.3%) • Systemic Reactogenicity • Study 004 • PCV13 vs 23vPS similar incidences of systemic reactions • Study 3010 • 23vPS>PCV13 for decreased appetite, aggravated muscle pain, new joint pain, use of medication to treat fever

15. Pre-Immunized SubjectsStudies 3000 and 3005 • Solicited Local Reactions • Solicited Systemic Reactions

16. Local Reactogenicity Within 14 days of PCV13 or 23vPS (Pre-Immunized)

17. Systemic Reactogenicity Within 14 days of PCV13 or 23vPS (Pre-Immunized)

18. Summary of Reactogenicity: Pre-Immunized Subjects • Local Reactogenicity • Study 3005 • 23vPS > PCV13 for all local reactions • Systemic Reactogenicity • Study 3005 • 23vPS >PCV13 for fatigue, rash, new muscle pain (myalgia), aggravated muscle pain

19. Reactogenicity of Sequential Vaccine Administration (Studies 004 and 3010) • Single dose 23vPS (naïve) compared to: • PCV13 /23vPS • 1 year interval (study 3010) • 3-4 year interval (extension study 004) • 23vPS / 23vPS administered at • 3-4 year interval (extension study 004)

20. Local Reactogenicity within 14 days Post Dose

21. Systemic Reactogenicity within 14 days Post Dose

22. Summary on Reactogenicity: Sequential Doses • Solicited Local • Using a dosing interval of 3-4 yrs (extension study 004): • 23vPS/23vPS is more reactogenic than PCV13/23vPS for redness, swelling and limitation of motion • Using a dosing interval of 1 year (study 3010): • PCV13/23vPS is more reactogenic than 23vPS alone • Solicited Systemic • Using a dosing interval of 3-4 yrs, 23vPS/23vPS is more reactogenic for rash when compared to 23vPS alone • Using a dosing interval of 1 yr, PCV13/23vPS is more reactogenic for rash and use of pain medications when compared to 23vPS alone

23. Reactogenicity of Concomitant Administration ofPCV13 with Trivalent Influenza Vaccine (TIV) Studies 3001 and 3008 Solicited Adverse Reactions for PCV13 + TIV compared to PCV13: • Local • Systemic Reactogenicity of Concomitant Administration of PCV13 with Trivalent Influenza Vaccine (TIV) in a Pneumococcal Vaccine Naïve Population: Design for Studies 3001 and 3008

24. Local Reactogenicity (PCV13+TIV vs PCV13) within 14 Days (Naïve)

25. Systemic Reactogenicity (PCV13 + TIV vs PCV13) within 14 Days (Naive)

26. Reactogenicity of Concomitant Administration ofPCV13 with Trivalent Influenza Vaccine (TIV)Studies 3001 and 3008 (Naïve) Solicited Adverse Reactions for PCV13 + TIV compared to Placebo +TIV: • Local • Systemic Reactogenicity of Concomitant Administration of PCV13 with Trivalent Influenza Vaccine (TIV) in a Pneumococcal Vaccine Naïve Population: Design for Studies 3001 and 3008

27. Local Reactogenicity (PCV13+TIV vs TIV+ Placebo) within 14 Days (Naïve)

28. Systemic Reactogenicity (PCV13 + TIV vs TIV+ Placebo) within 14 Days (Naive)

29. Summary of Reactogenicity for Concomitant Administration of PCV13 +TIV compared to PCV13 and TIV+ Placebo: Studies 3001 and 3008 (Naïve) • Solicited Local Reactogenicity • Study 3001 (age 50-59 yrs) • PCV13 (42%) > PCV13+TIV (35.6%) for “any” limitation of motion • PCV13 +TIV > TIV for all local reactions • Solicited Systemic Reactogenicity • Incidence of “any” fever (>38C) not increased with concomitant administration of PCV13+TIV compared to PCV13 or TIV + placebo in studies 3001 and 3008. • In study 3001 and 3008, when compared to PCV 13 or TIV+ placebo, PCV13+ TIV study arm had a higher incidence of these AEs: • Fatigue • Headache • Chills • Rash • Decreased appetite • New and aggravated muscle pain • New joint pain • Aggravated joint pain

30. Unsolicited Adverse Events within 1 Month • Incidence across 6 studies for PCV13 was 11.4 -19.2% • Similar incidence in naïve and pre-immunized subjects • Similar incidence for initial dose of PCV13 when compared to 23vPS in naïve and pre-immunized subjects: • Naïve subjects • Study 004 (60-64 yrs) • PCV 13 (17.0%) vs 23vPS (16.7 %) • Study 3010 (60-64 yrs) • PCV 13 (19.2%) vs 23vPS (20.7 %) • Pre-immunized subjects • Study 3005 • PCV13 (14.9 % ) vs 23vPS (18.6%) • Most frequent AEs reported for PCV13: • Infections and Infestations (4.1-8.6%) • Musculoskeletal (1.6-4.1%) • Gastrointestinal (1.2-2.6%) • General disorders and administration site conditions (0.6-3.1%)

31. Summary of 16 Deaths Across 6 Studies

32. Deaths(Across 6 Studies) 16 subjects died: • 2/16 deaths occurred within 30 days of vaccination • Cardiac Failure at 3 days after PCV13+TIV / Placebo • Peritonitis at 20 days after Placebo+TIV / PCV13 • 9/16 in study 3005 • Subjects ≥70 years of age • 12/5667 (0.21%) received PCV13 or PCV13+TIV • 4/1391 (0.29%) subjects received 23vPS

33. Summary of 16 Adverse Events leading to Discontinuation (6 Studies)

34. Adverse Events leading to Discontinuation(Across 6 Studies) • 16 subjects discontinued due to adverse events • 7 of 16 subjects discontinued due to cancer • 6 of 16 subjects received PCV13 • 9 of 16 subjects received 23vPS • 1 of 16 subjects received TIV +placebo

35. Incidence of Serious Adverse Events after Initial Dose (6 Studies)

36. Serious Adverse Events (Initial Dose, 6 Studies) • SAE range within 1 month of vaccination: • 0.2% to 1.4% of PCV13 recipients • 0.4% to 1.7% of 23vPS recipients. • SAE range within 6 months of vaccination: • 1.2% to 5.8% of PCV13 recipients • 2.4% to 5.5% of 23vPS recipients • Categories of SAE: • Age > 65 years • Cardiac disorders, cerebrovascular events, neoplasms, respiratory disorders and injuries occurred more frequently than in younger subjects

37. Incidence of Serious Adverse Events after Subsequent Dose (3 Studies)

38. Conclusions Regarding Safety • In 6 clinical studies, which included vaccine naïve and adult subjects with prior receipt of PNEUMOVAX23, no imbalances in deaths or serious adverse events were detected in subjects who received Prevnar13 when compared to PNEUMOVAX23. • No safety issues were identified for administration of Prevnar13, as a single dose, to vaccine naïve or pre-immunized adults aged > 50 years • the safety database is not large enough to detect rare events that could occur at a frequency lower than 0.1%. • When Prevnar13 was concomitantly administered with TIV, systemic reactogenicity was increased in subjects aged 50-59 yrs and subjects > 65 yrs when compared to administration of TIV or Prevnar13 alone. • No data available for concomitant administration of Prevnar13 with adult vaccines other than TIV. • No data available for use of Prevnar13 in immunocompromised adults. • Safety data will be submitted from the randomized, placebo-controlled CAPITA trial of PCV13 for the prevention of vaccine type pneumococcal pneumonia conducted in 85,000 subjects aged > 65 years in the Netherlands. Safety data will include: • SAEs in the 28 days post-vaccination for subjects not in the immunogenicity cohort • SAEs for 6 months post-vaccination for the 2000 subjects in the immunogenicity cohort • Incidence rates of local, systemic and adverse events for all subjects in the immunogenicity cohort.