Premarketing Randomized Trials
Phase III randomized trials are primarily designed to evaluate the efficacy of vaccines. They are also able to find common adverse events, but their sample size is typically not large enough to evaluate rare but serious adverse events. Their primary use for postmarketing vaccine safety surveillance is to generate study hypotheses. For example, a single case of Kawasaki disease in the vaccine arm of a Phase III randomized trial is not evidence that the vaccine causes Kawasaki disease, since it could be pure coincidence, but it may warrant a postmarketing safety evaluation.
Spontaneous Reporting Systems
Most countries in the world have a vaccine safety surveillance system based on spontaneous reports. These are linked together through the WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden, so that it is possible to combine data from multiple countries. In the United States, CDC and FDA are joint sponsors of VAERS.
These systems contain spontaneous reports of suspected vaccine adverse events sent in by physicians, nurses, patients, parents, manufacturers, and others. The gender and age of the vaccinated person are some of the variables collected. There is often information about multiple vaccines given on the same day. Analyses are done by the use of proportional reporting ratios (Evans et al., 2001) and similar methods. For example, if 1.5 percent of all vaccine-related adverse event reports are for seizures and there are 1,000 reports for vaccine A, then we would expect 15 seizure reports for vaccine A. If, in reality, there are 45 such reports, the proportional reporting ratio is 3. That is more than what one would expect, and it may indicate that there is an excess risk of seizures after vaccination. Actual analyses are more complex, since it is necessary to adjust for age and other variables. There are also other more sophisticated methods used (Bate et al., 1998; DuMouchel, 1999; Rothman, 2011).
The major advantage of VAERS is that it receives reports from the whole country. The two major disadvantages are that there is underreporting and that there are no reliable denominator data. That is, while we have information about a number of vaccinated children with the potential adverse event of interest, we do not know the total number of children that were vaccinated, how many unvaccinated children had the same type of event, or how many vaccinated children had the event without it being reported.