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TABLE 4-1 Relative Spectrum of Concern for Individual Spontaneous Adverse Event Reports

Increasing Concern

Describes a serious adverse event with less information than would justify moderate or strong concern, and/or with prominent confounding factors (e.g., multiple concomitant substances and/or conditions)

Describes a serious adverse event with some, but not all, characteristics associated with strong concern

Describes a well-documented serious adverse event with plasma levels (if available) at a relevant range and demonstrates dechallenge and rechallenge (if possible), temporality, and strong attribution

TABLE 4-2 Relative Spectrum of Concern for Case Series of Spontaneous Adverse Event Reports

Increasing Concern

Describes a series of serious adverse events, with less information than would justify moderate or strong concern, and/or prominent confounding factors (e.g., multiple concomitant substances and/or conditions)

Describes a series of serious adverse events, with some, but not all, characteristics associated with strong concern

Describes a series of well-documented cases demonstrating consistent serious adverse events and clinical findings, and dechallenge (if possible), temporality, and strong attribution

spontaneous reports should entail use of supplementary information available about the substance, such as animal data, in vitro data, epidemiological studies, or clinical trials in which formal hypothesis testing can occur. Such studies can be used to further evaluate the strength of the association between the adverse event and dietary supplement in question because, as described in the previous paragraphs, establishing a definitive causal relationship solely through use of spontaneous reports is rarely possible. However, as noted, regulatory decisions that directly involve the safety of the public’s health do not necessitate definitive proof.

In the specific case of dietary supplements, the threshold for action is clearly stated in the Dietary Supplement and Health Education Act: demonstration of a “significant or unreasonable risk of illness or injury.” Given the state of the art in adverse event report evaluation, pharmaco-



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