Controlled Clinical Trials

The epidemiologic study designs discussed up to this point are all observational. Allocation of exposure (receipt or nonreceipt of a given vaccine) was decided either by the vaccine recipients, by their parents, or by their physicians—not by the study investigators. The investigators merely attempted to observe the effect of vaccine exposure; they did not control who did or did not receive the vaccine. This absence of control over who gets exposed is what makes observational studies differ from experimental studies, which are also called clinical trials. In a controlled clinical trial of a vaccine, outcomes are compared in subjects who are allocated by the investigator to receive or not receive the vaccine. The controlled clinical trial design provides the strongest scientific evidence bearing on the causal relation between a vaccine and an adverse event, particularly when exposure versus nonexposure to a vaccine is assigned in a random fashion. The study design is then referred to as a randomized clinical trial. As with observational cohort studies, the effect of vaccine exposure on the occurrence of the adverse event is usually expressed as the relative risk or risk difference. Unfortunately, many of the adverse events under consideration by the committee are so rare that even large, multicenter randomized trials would be too small to detect differences in the incidences of a rare adverse event.

Combining the Evidence

When two or more epidemiologic studies that bear on a given vaccine-adverse event association were located by the committee (particularly when they shared a similar design), the committee used meta-analysis to pool the results from those studies and thereby gain both increased statistical power and enhanced generalizability (Dickersin and Berlin, 1992). Even a meta-analysis of epidemiologic studies, however, does not help in combining the evidence from different sources of evidence. Because no generally accepted rules exist for combining such evidence, the committee adopted its own operational criteria.

Although randomized clinical trials are generally accepted as providing the most scientifically valid assessment of causal relations, most have been too small to contribute any useful evidence bearing on the vaccine-adverse event associations under consideration by the committee. Thus, case reports, case series, and uncontrolled observational studies and controlled observational epidemiologic studies were often the main basis for the committee's judgment. As mentioned above, only epidemiologic studies were used to conclude that the evidence favored rejection of a causal relation. In the absence of epidemiologic studies favoring acceptance of a causal rela-



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