1. VRBPAC Topic #2: Clinical Development of Influenza Vaccines for Pre-pandemic Use Joseph G. Toerner, MD, MPH VCTB/DVRPA/OVRR/CBER/FDA February 27, 2007

2. Introduction The current situation with Influenza A/H 5 N 1 highlights the need for vaccine development Host: expanded outside avian species Host: expanded outside avian species Human infection: 278 cases reported Human infection: 278 cases reported Case fatality 63% Case fatality 63% 2

3. Introduction Use During Pandemic or Situations of Potential High Risk of Exposure  Draft Guidance for Industry, March 2006  Immune response reasonably likely to predict clinical benefit  HI antibody 4-fold increase: 40% (lower bound 95% CI) [and/or]  HI antibody % ≥ 1:40: 70% (lower bound 95% CI)  Safety database requirements  Different scenarios based on seasonal manufacturing experiences Use Prior to a Pandemic: Different strategies  “Prime-boost” or “Cross-protection”  VRBPAC Discussion  Clinical study designs, endpoints, and duration  Safety database 3

4. Pre-pandemic Vaccination “Priming” vaccination  Pediatric population: influenza “naïve”  Administration of two doses 1 mo. apart  Two doses widely separated in time: Englund et al. Pediatrics 2005;115:1039-1047  Two different strains widely separated in time: Walter et al. Pediatrics 2006;118:570-578  Remote administration of H 5 antigen  Immune response following single “boost” widely separated in time: Treanor et al. IDSA 2006 4

5. Pre-pandemic Vaccination  Prior antigenic experiences protect or ameliorate influenza illness: Couch and Kasel, Ann Rev Microbiol 1983;37:529-549  Homologous immunity  Heterologous immunity  Influenza vaccine and cross-protection against antigenically drifted influenza strains  Greater than 70% efficacy noted in culture- confirmation studies:  Ohmit et al. NEJM 2006;355:2513-2522  Meiklejohn et al. J Infect Dis 1978;138:618-624 5

6. Pre-pandemic Vaccination: Risk versus Benefit  Risks and benefits of seasonal trivalent influenza vaccine are known  IOM: data do not support association between seasonal influenza vaccine and GBS  ACIP: 1 additional case GBS per 1 million persons vaccinated, if assoc. exists  “Swine Flu Vaccine” experience in 1976  GBS 1 case per 100,000 persons vaccinated  Rare serious adverse events during pre- pandemic use: unknown benefit 6

7. VRBPAC Discussion Hypothetical Clinical Development During Pandemic/High Risk Indication During Pandemic/High Risk IndicationCohort Day 1 Day 28 AA/Vietnam BA/VietnamA/Vietnam 7

8. VRBPAC Discussion Hypothetical Clinical Development Pre-pandemic Use Indication: homologous Pre-pandemic Use Indication: homologousCohort Day 1 Day 28 Month 6 Mo. 12 > Mo. 12 AA/Vietnam BA/VietnamA/Vietnam CA/VietnamA/Vietnam DA/VietnamA/Vietnam EA/VietnamA/Vietnam 8

9. VRBPAC Discussion Hypothetical Clinical Development Pre-pandemic Use Indication: heterologous Pre-pandemic Use Indication: heterologousCohort Day 1 Day 28 Month 6 Mo. 12 > Mo. 12 AA/Vietnam BA/VietnamA/Vietnam FA/VietnamA/Indonesia GA/VietnamA/Indonesia HA/VietnamA/Indonesia 9

10. Committee Discussion Efficacy  Please discuss the use of immune responses to determine evidence of efficacy for pre-pandemic use or “priming”  Immune response assay following “prime”  Immune response assay following “boost” at future time points  HI Antibody vs. other immune response assays  Microneutralization 10

11. Committee Discussion Clinical Trial Design  Please discuss the feasibility of longer- term clinical studies of “prime” and “boost” pandemic influenza vaccine  Duration of study: 6 months, 1 year, > 1 year  Collaboration among different sponsors 11

12. Committee Discussion Safety  Please discuss safety considerations for licensure of vaccines for pre-pandemic use  Pre-licensure safety database  Rare serious adverse events (i.e. 1 per 100,000) not likely to be detected in a typical pre-licensure database  Novel manufacturing processes or adjuvants  Pre-licensure safety data collection and duration of follow-up 12