CBER Perspective. VRBPAC Meeting, November 16, 2010. Implementation of the Animal Rule.
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VRBPAC Meeting, November 16, 2010
Is infection in humans caused by spores that remain after a full course of antibiotics fundamentally a GUP scenario?
(e.g., the proportion of subjects achieving the
antibody level that protected a certain percentage
g(x)=Pr distrib of x where x=immune response
Prob (death in pop.) = ∫f(x)g(x)dx = avg. prob
death or p*
If prob death in unvaccinated = 1.0 then
VE= 100(1-p*) (from Kohberger, 2007)
Estimate protective antibody levels in animals
Compare these levels to those achieved by humans receiving vaccine administered on the schedule intended for post-exposure prophylaxis
Assess whether the vaccine is reasonably likely to provide clinical benefit
However, estimation of protective antibody levels from the PEP model is more complex than with the GUP model
Day 7? (i.e., day that antibiotics discontinued)
Adds uncertainty to protective level estimates
Passive immunization study design represents a dynamic situation with antibody levels declining rapidly during the critical time period between challenge (day 1) and day the last death occurred (day 7)
What is the appropriate time point to estimate protective antibody levels in animals?
Circulating antibody levels at the time of challenge do not appear to be the sole mechanism of protection afforded by active immunization
Circulating antibody levels at the time of challenge do not appear to be the sole mechanism of protection afforded by active immunization; the anamnestic response of vaccinated animals upon exposure may contribute to protection.
Passive immunization studies may significantly overestimate antibody levels needed for protection after active vaccination
Post-exposure prophylaxis indication: For the prevention of disease caused
by residual B. anthracis spores in exposed individuals who have received a
full course of antibiotics