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as to whether the study includes a control group, the methods used to assemble the comparison groups, the extent of blinding (if any) of investigators and subjects, and other measures taken to minimize biases.

Although the double-blinded, randomized controlled trial (RCT) is often considered the “gold standard” for evaluating efficacy of many health care interventions, such studies have a much smaller role regarding safety concerns because they are not ordinarily primarily designed for that purpose. While adverse events are required to be monitored, collected, and evaluated during the course of an RCT, their known limitations (i.e., relatively small sample size, relatively short duration, narrowness of population studied, and narrowness of indication studied) (Goldman et al., 1995) make it almost impossible for a serious adverse effect that occurs relatively infrequently to be detected during the course of such a study. There is no scientific reason to think that efficacy studies of dietary supplements would be any exception. Given their limitations and the highly controlled settings in which most randomized trials are conducted, they are inadequate to fully assess the potential for harm of an intervention when it is routinely used in the target population. It is impossible to study all interactions of an intervention with combinations of comorbidities and concurrent medications or dietary supplements that may be present in the real world using a limited number of randomized trials. In addition, because dietary supplements are considered similarly to food, even if randomized controlled trials were performed to assess their benefits, there may be fewer perceived concerns for their safety and therefore a reporting bias on the part of the subjects and/or the investigators.

If it existed, an RCT designed to evaluate safety of a dietary supplement would include a sufficiently large number of diverse subjects who were systematically monitored for a sufficient amount of time to detect a wide array of adverse effects or physiological changes that might warrant concern. The physiological parameters focused upon in monitoring human subjects would be determined, in part, by effects found in preclinical (animal) studies. Extensive preclinical studies, however, are not often completed for dietary supplements.

It is the usual practice in an RCT to query subjects for possible adverse events at defined intervals and to record and evaluate these events as “definitely,” “probably,” “possibly,” or “not” related to the ingested substance (ICH, 1995). Randomization and use of control groups enable investigators to determine the likelihood that adverse effects are actually due to the substance rather than to confounding factors. However, as previously noted, many RCTs available for dietary supplements are designed to assess beneficial effects and thus would not be expected to provide complete information relative to the safety of the dietary supplement under evaluation. In health care intervention studies, perhaps due to the greater tendency for



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