It is possible to use data on individuals who have received vaccines to determine the frequency of SAEs potentially attributable to the vaccine that can be reasonably excluded. In this way, the likelihood of detecting high-frequency SAEs in studies of H5N1 or other vaccines can be estimated from the existing clinical trial data.
As of April 2009 (), ~18,784 subjects had received H5N1 vaccines in clinical trials, with no SAEs related to immunization recorded [25
]. The upper bound (ie, the most conservative estimate) of the risk rate of a SAE in vaccinated individuals that can be excluded is 1 of 6270 for type 1 error α = 5% (see Appendix A
for technical details). This upper bound can also be computed using recipient subsets for inactivated whole virion (upper bound, 1 of 1095), inactivated split virion (1 of 3206), and inactivated subunit (1 of 1970) vaccines (). Although these data suggest that we can safely exclude a very frequent association between H5N1 vaccination and SAEs, they are not informative in determining the potential occurrence of rarer SAEs (eg, of a few cases per 100,000 individuals).
Summary of Study Populations and Severe Adverse Events (SAEs) Observed in H5N1 Clinical Trials
Alternatively, it is possible to determine the number of SAE-free vaccinated subjects in a clinical trial required to reject the existence of a certain event risk at a range of different type 1 error probabilities (Appendix A
). For example, for type 1 error α = 5%, ~300,000 SAE-free vaccinated subjects are required to exclude the risk level of 1 of 100,000 ().
Number of Severe Adverse Event–Free Vaccinated Subjects Required in a Clinical Trial to Reject the Existence of a Certain Event Risk at a Range of Different Type 1 Error Probabilities
These approaches rely on a sample of individuals without the incidence of any SAEs recorded. However, SAEs observed in vaccinated subjects of clinical trials are not necessarily attributable to vaccination, because such events can also be observed in unvaccinated subjects. summarizes the number of subjects required to demonstrate an increased risk of SAEs in vaccinees by factors from 1.5-fold to 100-fold relative to a range of background rates in the general population. For example, if the background rate is 1 in 100,000; 53,500 and 1,238,000 vaccinated subjects are needed to demonstrate an increase in the SAEs risk in vaccinees by 10-fold and 2-fold, respectively. In general, the number of subjects required increases logarithmically in proportion to 10-fold decreases in the background frequency of SAEs.
Number of Subjects Required to Test the Existence of an Increased Level of Risk Relative to Background Rate, with Type 1 Error α = 5% and Power of 90%
To illustrate this approach for a novel vaccine, we can assume that the risk of GBS associated with the vaccine is similar to that associated with the 1976 swine flu vaccine (risk of ~8.8 cases per 1 million and a GBS background rate of 0.7–4.6 cases per 1 million within 6 weeks after vaccination) [8
]. Under these conditions, an indicative
vaccinated population size of 409,000 to 970,000 would be required to demonstrate that the adverse event rate in vaccinated individuals is greater than the background rate (type 1 error α = 5%; power = 90%).
Even in the unlikely case that these sample size requirements could be satisfied using data from clinical trials and the SAEs rate in vaccinees was found to be significantly higher than the background rate, the strength of evidence would remain weak in the absence of randomization. Close monitoring of vaccine safety will be an important consideration if and when H5N1 or other novel virus vaccination begins to be used in large populations.