Adverse events and vaccination-the lack of power and predictability of infrequent events in pre-licensure study.

The recent setback in the development of a safe and effective rotavirus vaccine illustrates an important problem regarding prelicensure testing and its ability to identify rare vaccine-related adverse effects. It is our contention that the possibility of a rare but serious vaccine adverse effect is difficult to detect in prelicensure testing. In this paper, we review the history regarding the testing and eventual studies that led to the permanent withdrawal of that vaccine. The post-licensure discovery of a serious adverse event associated with the rotavirus vaccine is not unique among vaccines, but represents a recurrent phenomenon that in fact is mathematically predictable. Prelicensure studies examine thousands of subjects and not hundreds of thousands. A sample size of 10,000 subjects may provide excellent estimates of efficacy, but cannot provide an adequate denominator to rule out rare adverse events. It lacks the power. Just as with the rotavirus vaccine, only after hundreds of thousands of doses of vaccines are distributed, will such rare events appear often enough to permit detection. For that reason, we must depend upon the modern post-licensure surveillance programs that we already have in place.