detail below in the same order in which they will be considered within each of the vaccine- and adverse event-specific chapters.

Biologic Plausibility

All of the vaccine-adverse event associations assessed in this report have some biologic plausibility, at least on theoretical grounds. That is, a knowledgeable person could postulate a feasible mechanism by which the vaccine could cause the adverse event. Actual demonstration of biologic plausibility, however, was based on the known effects of the natural disease against which the vaccine is given and the results of animal experiments and in vitro studies. Only demonstrated biologic plausibility was considered by the committee in reaching its causality judgments.

Case Reports, Case Series, and Uncontrolled Observational Studies

The committee obtained reports of individual cases of adverse events following receipt of vaccine through the published medical literature as well as from passive, spontaneous surveillance systems established by the vaccine manufacturers, the U.S. Food and Drug Administration, and the Centers for Disease Control and Prevention. These include the Monitoring System for Adverse Events Following Immunization and the Spontaneous Reporting System, as well as the more recent Vaccine Adverse Event Reporting System (VAERS). Appendix B identifies the material from these systems obtained and reviewed by the committee. Chapter 10 includes a discussion of the limitations of passive surveillance systems such as these. as well as an analysis of the data contained within VAERS regarding reports of deaths following vaccination.

Uncontrolled observational studies are usually based on a cohort design, in which an identified group of vaccinees is followed for some period of time to detect the occurrence of one or more adverse events. These studies often incorporate more active surveillance than is the case in the passive, spontaneous reporting systems mentioned above, although a clear distinction from case series emanating from defined population bases is often difficult. Because no nonexposed control group is included in such studies, however, the rates of occurrence of the adverse events under consideration can usually be interpreted only descriptively, and the evidence derived therefrom is rarely helpful in either accepting or rejecting a causal relation. Also included under uncontrolled observational studies are reports of vaccine exposure in a representative group of individuals experiencing the adverse event. Such studies can also overlap with case series, although the authors of case series often attempt to make causal inferences (or hypotheses) concerning exposure to vaccines and/or other factors and, hence,



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