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Research Strategies for Assessing Adverse Events Associated withVaccines:: A Workshop Summary
Participants expressed frustration with the lack of randomizationin vaccine trials. The results obtained from nonrandomized trialsare difficult to interpret. This is particularly important for pre-marketingstudies, because it is almost impossible to do randomized trialspost-licensure. Postlicensure research usually is of a cohort orcase-control design.
A participant commented that trials of therapeutic products almostalways include randomization. Manufacturers were questioned why thiswas not the case for vaccine trials. They responded that in general,prevention trials usually require much larger sample sizes and longertime periods for their completion than treatment trials and thatthe cost is correspondingly greater. In addition, it is difficultto get sufficient people to accept randomization in vaccine trialsfor a period sufficient to detect rare adverse events (this is discussedin a subsequent section).
The example of the Urabe-strain mumps vaccine was cited to illustratethe long period needed to confirm a causal relation. The first caseof aseptic meningitis was reported only after 7 million doses ofthe vaccine had been distributed, and it took 5 years after causalitywas suggested to estimate the frequency of occurrence. A randomizedcontrolled trial of sufficient magnitude to have detected this adverseevent would have been prohibitively costly.
A participant cited the example of an expensive 40,000-subject studyof hepatitis A vaccine that resulted in what some considered to belittle additional information, that is, the trial confirmed clinicalsuspicions that the vaccine was safe. Some participants stressedthat confirmation of the safety of a vaccine is worth the resourcesnecessary to do a definitive study. Even if the trials that are performedare not large enough to detect very rare adverse events, randomizationwill help interpret the safety data that have been collected.
The importance of using standardized forms to record adverse reactionsin clinical trials was stressed. Currently, there is great variabilityin the ways in which adverse reactions are assessed in clinical trials.It was also thought that streamlining of forms would be helpful;better information might be obtained if fewer questions were askedand emphasis was placed on the quality of answers to those few questions.Identification of the most relevant questions would not be a trivialmatter, however.
A participant agreed that it is necessary to standardize the reportingof particular conditions, but questioned how that could be accomplishedand how the information could be disseminated to those who do thereporting. The use of a detailed text sent with the reporting formsis a possibility, but that could be a somewhat unrealistic possibility.