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epidemiological studies that are adequately powered and designed to detect adverse effects.

The basis for this guiding principle is described in the sections of this chapter, as are the following important corollaries and specific guidance:

  • There are significant limitations in using clinical efficacy trials to predict that an adverse event will not occur because of their limited sensitivity. Clinical trials do provide valuable information when adverse events are detected.

  • A statistically significant increased rate in adverse events indicates that a sufficiently large number of events have occurred to allow one to conclude that the observation is unlikely due to chance alone. However, in populations and settings where no adverse event is expected, a nonsignificant trend also warrants some concern and consideration.

  • Epidemiological studies that contain information on the use of dietary supplements, when available, are valuable sources of information for evaluating their safety.

  • Given the state of the art in adverse event report evaluation and pharmacovigilance and risk management, and given the potential risk to the public entailed by serious adverse events, regulatory action can be justified on the basis of spontaneously reported adverse event report analysis alone or as the predominant source of information. Reports of certain adverse events warrant heightened concern because they have a known potential for significant morbidity (and in some cases, mortality).

  • If spontaneously reported adverse event reports are of high quality, irrespective of number, the effect of underreporting can be somewhat mitigated. The stronger the product-adverse event relationship and the lower the incidence of (and thus rarer) the adverse event occurring de novo/ naturalistically, the fewer the number of case reports that will be needed to perceive causality.

  • Recognizing that a full range of data is unlikely to be available for many dietary supplement ingredients, historical use may be taken into account as a surrogate measure for safety in the absence of relevant scientific and experimental data. In doing so, it is important to consider the relevance of the traditional use to the current use and, as such, FDA must have information regarding both the traditional use and the current use to determine if the traditional use sheds any light on the potential risk associated with current use.

  • The fact that a substance was consumed over a number of years does not indicate that it was consumed without adverse effects. Safe administration by non-oral routes of administration should not be taken as an indication of safety via oral administration. Historical information is useful only if the product in question is not so far removed from the original



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