1. 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

2. 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)

3. Routine Pharmacovigilance
In accordance with the 21 CFR
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

4. 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)

5. 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)

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. Post Licensure Vaccine Effectiveness Plans

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

14. 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

15. 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

16. 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:
Initiate immediately after PVC13 introduction

17. NCKP IPD Surveillance Study
Observational database study
~140,000 children (< 5 years of age)/year
5 year surveillance period:
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

18. 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

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

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

21. 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 ( )
Post-Prevnar ( )
Post-13vPnC ( )

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

23. Reserved slides for PVP

24. 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

25. 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

26. Reserve Slides for VEP

27. 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
% decrease in IPD rates due to Prevnar types
% 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

28. 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