Statistical Approaches to Establishing Vaccine Safety
Statistical Approaches to Establishing Vaccine Safety
Vladimir Dragalin, Valerii Fedorov and Brigitte Cheuvart
Abstract: In a vaccine safety trial, the primary interest is to demonstrate that the vaccine is sufficiently safe rejecting the null hypothesis that the relative risk of an adverse event attributable to the new vaccine is above a pre-specified value, greater than one. The exact probability of type I error of the likelihood scores test, with sample size determined by normal approximation, is evaluated by enumeration of the binomial outcomes in the rejection region and is found to exceed the nominal level. In the case of rare adverse events, the Poisson approximation is recommended as an alternative and the corresponding conditional and unconditional tests are developed. Sample size and power calculations are given for these tests. Optimal randomization strategies which (i) minimize the total number of adverse cases and (ii) minimize the expected number of subjects when vaccine is unsafe are also proposed. We illustrate the methods proposed using a hypothetical vaccine safety study.
