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Dietary Supplements: A Framework for Evaluating Safety
particular, the lack of precise numerator (number of cases) and denominator (number of patients exposed) data render the computation of incidence rates from spontaneous reports problematic (Begaud et al., 1994), if not totally unfeasible. In addition, as spontaneous reports originate under conditions of everyday use rather than under study conditions, there are possible confounding factors to be considered when evaluating reports, such as multiple concomitant medications (prescribed or over-the-counter [OTC]), multiple concomitant dietary supplements, concomitant medical devices, underlying disease states, or alcohol use.
At the same time, these systems entail considerable concomitant strengths. Large-scale and relatively inexpensive (Fletcher, 1991), spontaneous adverse event reporting systems serve as the basis for safety-related hypothesis generation (Strom and Tugwell, 1990) and foster suspicions (Finney, 1971) that generate signals of potential problems warranting further study, while enabling individuals (health professionals and consumers alike) to contribute to public health (Goldman, 1998). This sentinel signaling function is critical, and the appropriateness of using a spontaneous reporting system in this regard is well documented and scientifically accepted (Blum et al., 1994; Goldman, 1996; Rossi and Knapp, 1984).
The cases spontaneously reported to any surveillance program will generally represent only a small percentage of the number that have actually occurred.2 However, if the submitted reports are of high quality, irrespective of number, the effect of underreporting can be somewhat mitigated (Goldman, 1998). In the particular case of dietary supplements, a recent FDA-commissioned study estimated that FDA receives reports on less than 1 percent of all adverse events associated with their use (Walker, 2000). (With the majority of dietary supplement adverse event reporting to FDA done by consumers rather than by health professionals, it is possible that consumers might be less likely to associate dietary supplements with untoward effects, as opposed to making such attribution with a drug product, either prescribed or OTC). In addition, it has been found that consumers often do not inform their physicians about their use of dietary supplements (Eisenberg et al., 1998). Hence, reporting by physicians and other health professionals of adverse events on these products may well be minimal.
Concerning the extent of underreporting of drug-associated adverse events, a study performed in the United States before establishment of the FDA MedWatch adverse event reporting program (Kessler, 1993) estimated that the FDA received by direct report less than 1 percent of suspected serious adverse drug reactions (Scott et al., 1987), while rarely more than 10 percent of serious adverse drug reactions were estimated to be reported to the British spontaneous reporting program (Rawlins, 1995). This latter figure of 10 percent is consistent with other studies (Skjeldestad et al., 2000). It is not clear that these relative percentages hold for every serious adverse event and associated drug.