Perspectives on the design and analysis of prelicensure trials: bridging the gap to postlicensure studies.

Abstract

Recently, there has been growing concern regarding vaccine safety. Vaccines have led to the eradication of many serious diseases. Accordingly, there is less familiarity with the consequences of diseases and increasing concern with potential rare adverse events. The availability of clinical information systems within health maintenance organizations makes assessment of safety in larger cohorts, with power to assess rare adverse events, possible. However, no trial, no matter how large, can rule out all possible adverse events. There will always be the possibility that a rarer adverse event-just beyond the power of detection of a given trial-may occur. It is proposed that prelicensure trials in 10,000-40,000 children are now feasible. However, it will be necessary to develop an analytic continuum in which prelicensure studies are followed up with postmarketing assessments. Accordingly, the rapid identification of intussusception as a complication of rotavirus vaccination should not be seen as a failure of prelicensure studies but rather as a positive example of an effective integrated safety assessment program.