VRBPAC Topic

1
VRBPAC Topic 2Clinical 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/H5N1
  highlights the need for vaccine development
• Host expanded outside avian species
• Human infection 278 cases reported
• 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• Draft Guidance for Industry, March 2006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 140 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 20051151039-1047
• Two different strains widely separated in time
  Walter et al. Pediatrics 2006118570-578
• Remote administration of H5 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 198337529-549
• 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 20063552513-2522
• Meiklejohn et al. J Infect Dis 1978138618-624

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 DiscussionHypothetical Clinical
Development

• During Pandemic/High Risk Indication

7
8
VRBPAC DiscussionHypothetical Clinical
Development

• Pre-pandemic Use Indication homologous

8
9
VRBPAC DiscussionHypothetical Clinical
Development

• Pre-pandemic Use Indication heterologous

9
10
Committee DiscussionEfficacy

• 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 DiscussionClinical 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, gt 1 year
• Collaboration among different sponsors

11
12
Committee DiscussionSafety

• 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