logical plausibility adds an additional piece of supportive evidence. However, in the absence of other evidence pointing to a causal relationship, use of the term biological plausibility, as ingrained in the language of causal inference, seems to add confusion.

Thus the committee finds that for the purpose of its reports, the lack of clarity in the phrase “biological plausibility” warrants the adoption of new terminology and a new approach to its discussion of biological data. The committee will review evidence regarding “biological mechanisms” that might be consistent with the proposed relationship between a vaccine exposure and given adverse events. This biological assessment section of the report is written distinct from any argument regarding the causality of such relationships. This is not meant to imply that current understanding of biological processes does not shape or guide assessments of causality. In fact, the current thinking of a possible biological explanation for a relationship between immunization and an adverse event will influence some of the important controls used in a good epidemiological analysis. The important consideration of “confounders” in epidemiological studies comes from understanding biological phenomena that could underlie or explain the observed statistical relationship. Only when important confounders are considered can the statistical observation be considered for evidence of causality. However, absent evidence of a statistical association, or convincing clinical evidence, biological mechanisms cannot be invoked to prove causality.

There are three general categories of evidence on biological mechanisms:

  • Theoretical only: A reasonable mechanism can be hypothesized that is commensurate with scientific knowledge and that does not contradict known physical and biological principles, but it has not been demonstrated in humans or animal models.

  • Experimental evidence: The evidence can be derived under highly contrived conditions. For example, the results require extensive manipulation of the genetics of an animal system or extreme vaccine antigen exposures in vivo or in vitro in terms of dose, route, or duration. Other experimental evidence is derived under less contrived conditions. For example, a compelling animal or in vitro model exists whereby administration of a vaccine antigen under conditions similar to human use results in a pathological process analogous to a human disease pathology. Experimental evidence often describes effects on just one or a few of the steps in the pathological process required for expression of disease. As more components of the theoretical pathways are shown to operate in reasonable experimental models, the more confident one is that the mechanisms could possibly result in disease in humans.

  • Evidence that the mechanism results in known disease in humans: For example, a wild-type infection causes the adverse health outcome, or another vaccine has been demonstrated to cause the same adverse outcome by the same or similar mechanism. Data from population-based studies of the effects of the vaccine



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