Marthe Bryant-Genevier, MD, MPH, MHS Pneumococcal 13-valent Conjugate Vaccine Post Licensure Pharmacovigilance and Vaccine Effectiveness Plans Robert Wise, MD, MPH Marthe Bryant-Genevier, MD, MPH, MHS Vaccine Safety Branch CBER/OBE/DE November 18, 2009

Pharmacovigilance Plan Objective: To expand the understanding of the safety profile of PVC13 in routine use in children 6 weeks through 5 years of age Includes: Routine pharmacovigilance (all ages) Phase 4 safety study (infants)

Routine Pharmacovigilance In accordance with the 21 CFR 600.80 http://www.fda.gov/RegulatoryInformation/Guidances/ucm129411.htm In addition, Wyeth agreed to Submit a monthly line listing of all non-15 day adverse events for the first 3 years following approval Include newly identified safety signals as outcomes in the phase 4 study

Phase 4 Safety Study Goals To further evaluate specific adverse events assessed in PVC7 post-marketing safety study To detect medical events to be further evaluated based on a heuristic statistical filter set at a p-value of 0.1 (2-sided)

Phase 4 Safety Study Objectives To assess the incidence rates of all hospitalization and emergency department (ED) visits To assess the incidence rates of the following events selected on the basis of the Prevnar post-marketing safety study results from all settings (hospital, ED and outpatient clinics) Anaphylaxis/hypersensitivity Apnea Seizures Fever Flushing Gastroenteritis Asthma, bronchiolitis, bronchitis (reactive airway diseases), pneumonia, upper respiratory infection (URI), wheezing diagnoses Autoimmune diseases (Kawasaki disease, diabetes mellitus)

Phase 4 Safety Study Objectives (Cont’d) To compare post-vaccination incidence rates to corresponding self-control period rates for each infant series dose separately (dose 1, 2, and 3) and for the three doses combined To compare incidence rates to historical control rates for events selected from self-control analysis To assess safety in sub-groups of children with specific co-morbidities

Phase 4 Safety Study Design Observational study Using a cohort of: 43,000 children who received all 3 primary doses of PVC13 PLUS all other children who received at least one dose of PVC13 during the accrual time period Children who received at least one dose of Prevnar will be analyzed separately Identified through Northern California Kaiser Permanente (NCKP) medical record databases

Phase 4 Safety Study 5-Phase Sequential Approach Step 1: Self-control analysis of incidence rates in risk window (0 to 30 days post vaccination) compared to self-control periods For dose 1, pre-vaccination control period: -35 to -5 days For dose 1, 2 and, 3, post-vaccination control period: 31 to 60 days For all doses combined, post-vaccination control period: 31 to 60 days post dose 3 Step 2: Historical control analysis if an event rate is significantly increased at a p-value <0.1 in one self-control window AND There is consistency across settings OR The event is biologically plausible OR The rate of the event is significantly increased across a second-self control window

Phase 4 Safety Study 5-Phase Sequential Approach (Cont’d) Step 3: Additional analyses to assess the temporal association or stratification by concomitant vaccines Step 4: Medical chart review To evaluate validity of diagnoses To abstract covariates, especially potential confounders Step 5: Comprehensive assessment of all available data in consultation with CBER

Phase 4 Safety Study Statistical Design Over 80% power to detect a 2.5-fold increase over background event rates of 1 per 10,000 vaccine doses for each setting (2-sided alpha=0.05) Estimated duration: 3-4 years To start immediately upon licensure

High Risk Groups Analyses Wyeth agree to conduct sub-analyses of the phase 4 safety study for children at increased risk of invasive pneumococcal disease (IPD) HIV-infected children Children with sickle cell disease Allogeneic hematopoietic stem cell transplant recipients Children with reactive airways diseases Interim analysis will present pooled data for all identified high risk children Final study report will submit the analysis by diagnoses

Post Licensure Vaccine Effectiveness Plans

Post Licensure Vaccine Effectiveness Plans Not required as a condition for licensure Proposed/Ongoing Studies IPD (3) Otitis Media (2) 13

Post Licensure IPD Effectiveness Studies CDC Active Bacterial Core Surveillance (ABCs) Case-Control Study Northern California Kaiser Permanente (NCKP) IPD Surveillance Study Phase 3, Open-label Trial in Alaskan Native Children

CDC ABCs Case-Control Study Primary Objective: Effectiveness of 1 or more doses of PVC13 against IPD caused by PVC13 serotypes (as a group) among children recommended to receive PVC13 as part of the routine immunization schedule. Secondary IPD effectiveness objectives: Overall caused by the 6 additional serotypes caused by 19A, 7F and 3 individually in children w/underlying conditions & healthy children caused by pneumococci non-susceptible to antibiotics IPD in African-American children & Caucasian children

CDC ABCs Case-Control Study (cont.) IPD Cases Defined as pneumococcal isolates from normally sterile sites (e.g., blood, CSF) from residents of surveillance areas Identified via ABCs and Epidemiology Laboratory Capacity (ELC) sites 4 matched controls per case (age & zip code) 4 year surveillance period: 2010-2013 Initiate immediately after PVC13 introduction

NCKP IPD Surveillance Study Observational database study ~140,000 children (< 5 years of age)/year 5 year surveillance period: 2010-2014 Total expected IPD cases: 12.5 cases due to Prevnar 7 serotypes 24 cases due to Prevnar 13 serotypes Primary Objective: annual IPD incidence Secondary Objectives: Compare post Prevnar 13 IPD rates to: Pre-Prevnar IPD rates Post-Prevnar IPD rates Serotype distribution

Ongoing Phase 3 Alaskan Native Trial Phase 3 open-label study Safety, immunogenicity & impact of PVC13 on IPD & NP colonization Yukon Kuskokwim (YK) Delta region Highest IPD rate (5X higher than other Alaskan Native children) types 19A, 7F, 6A & 3 Projected enrollment: 2500 children 6 weeks - <5 years of age all children receive PVC13 children may transition from PCV7 to PVC13 at any point 1° Objective: assess impact of PVC13 on IPD incidence due to PVC13 serotypes

Post Licensure OM Effectiveness Studies Observational OM & Nasopharyngeal (NP) Colonization Effectiveness Study (Rochester, NY) National Administrative Databases OM Visit Surveillance Study

Observational OM & NP Colonization Effectiveness Study (Rochester, NY) 350 subjects ( 2 -30 months of age) Tympanocentesis on all 1st & 2nd episode AOM cases Frequent NP & oropharyngeal (OP) sampling pneumococcal isolate serotyping

National Administrative Databases OM Visit Surveillance Study Objective: to assess trends in visits with OM diagnoses from two national surveys National Ambulatory Medical Care Survey (NAMCS) National Hospital Ambulatory Medical Care Survey (NHAMCS) Observation periods Pre-Prevnar (1994-1999) Post-Prevnar (2000-2008) Post-13vPnC (2010-2012)

Summary Applicant’s proposed post licensure plan: Pharmacovigilance Routine Phase 4 Safety Study Vaccine Effectiveness IPD OM Components of plan are still under discussion

Reserved slides for PVP

Submission of Safety Study Reports Include cause of death for infants who died within 2 months of vaccination Include line listing for children who are still in NCKP and did not complete the vaccination series during the study period regardless of other vaccination status Every six months tabulate comparative frequencies, incidence rates and relative rates For grouped events For individuals events by ICD9 codes within a group if an unexpected signal emerges

Submission of Safety Study Reports (Cont’d) Interim analysis To include first 18 months of data To include tables of frequencies, incidence rates and relative rates when compared with control periods, for grouped events and individual ICD9 codes Final analysis To include all data To include tables of frequencies, incidence rates and relative rates when compared with control periods for grouped events and individual ICD9 codes This statistical analysis will specifically examine the safety in immunosuppressed patients Note: Both analyses to be submitted within 3 month of data cut off

Reserve Slides for VEP

IPD in Alaskan Native Children (< 5 years of age) Pre-Prevnar IPD rates US: 96/100,000 children Alaska: Native: 403/100,000 children Non-native: 100/100,000 children CDC’s Arctic Investigations Program (AIP) Post Prevnar IPD Surveillance in Alaska 2001-2003 95% decrease in IPD rates due to Prevnar types 2004-2006 140% increase in IPD rates due to non-Prevnar types (19A, 7F, 6A & 3) Yukon Kuskokwim (YK) Delta region 5X higher than rate in other Alaska Native children types 19A, 7F, 6A & 3 Proposed Prevnar 13 IND study in YK Delta region

Ongoing NP Colonization Study In Israel for Consideration Double-Blind, Multi-site, phase 3 study 1,864 infants enrolled at 2 months of age & followed through 24 months Randomized 1:1 (PVC7 or PVC13) NP swab collection frequent (8 samples per subject) All S. pneumoniae isolates will be serotyped Primary objective: demonstrate that PVC13 reduces NP colonization w/ types 6A and 19A combined compared to PVC7