Dietary Supplements A Framework for Evaluating Safety (2005) / Chapter Skim
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4 Categories of Scientific Evidence--Human Information and Data
4 Categories of Scientific Evidence--Human Information and Data
Pages 126-155
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From page 126... ...
It may be appropriate, however, to give considerable weight to a lack of adverse events in large, high quality, randomized clinical trials or epidemiological studies that are adequately powered and designed to detect adverse effects, including those adverse effects with established serious risks for human morbidity or mortality and that are known to rarely occur de novo in the population. 1"Serious Adverse Experience.
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From page 127... ...
, add to the level of concern. For many dietary supplement ingredients, human data regarding their safety or risk will not be available.
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From page 128... ...
However, while the underlying principles for safety monitoring are globally valid, the regulatory situation of dietary supplements impacts the use of their associated adverse event reports in several ways. Unlike drugs, biologics, and medical devices, dietary supplements do not undergo premarketing evaluation for safety and efficacy by FDA, and a formal benefit/risk assessment is not performed as part of an approval process.
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From page 129... ...
. 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)
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From page 130... ...
According to FDA, this proposed rule "would, for the first time, establish standards to ensure that dietary supplements and dietary ingredients are not adulterated with contaminants or impurities, and are labeled to accurately to reflect the active ingredients and other ingredients in the product" (FDA, 2003b)
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From page 131... ...
. As a result, an important established source of reports for medical products is not duplicated for dietary supplements, and the evolution of a concomitant culture of adverse event reporting among manufacturers and distributors is not encouraged.
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From page 132... ...
. For rare4 serious adverse events, such as toxic epidermal necrolysis, coincidental medical product-event associations have been found to be so unlikely that they merit little concern in spontaneous reporting, with more than three reports seen to represent a signal necessitating further study (Begaud et al., 1994)
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From page 133... ...
Many of the most serious adverse events occur relatively infrequently; that is why spontaneous report systems, which are designed to cover entire populations, are able to detect rare, serious events not discovered during premarket testing. This important outcome of spontaneous report systems for dietary supplement ingredients is the same as for other products.
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From page 134... ...
Summary of Spontaneous Report Use In summary, higher concern is warranted in situations where one or more well-documented serious adverse events manifests positive temporality, and other factors (e.g., positive dechallenge, biological plausibility, or laboratory results) combine to strengthen the perceived association between the dietary supplement ingested and the adverse event in question.
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From page 135... ...
, temporality, and (e.g., multiple concomitant strong attribution substances and/or conditions) TABLE 4-2 Relative Spectrum of Concern for Case Series of Spontaneous Adverse Event Reports Increasing Concern Describes a series of Describes a series of Describes a series of well serious adverse events, serious adverse events, documented cases with less information than with some, but not all, demonstrating consistent would justify moderate characteristics associated serious adverse events and or strong concern, and/or with strong concern clinical findings, and prominent confounding dechallenge (if possible)
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From page 136... ...
Dietary supplements, as agents with biological activity, should be no exception. HISTORICAL USE Experience from generations of use by humans is often referred to as evidence of safety for modern dietary supplements that bear resemblance to substances used historically.
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From page 137... ...
· How "safe" is the historical use? Were the adverse events in question capable of being detected by the practitioners and, if observed, would they have been recorded?
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From page 138... ...
Some dietary supplement ingredients, including some botanicals, were traditionally prescribed by practitioners knowledgeable about contraindications to their use. It is scientifically appropriate to take contraindications in traditional use into account when considering the safety of the ingredient.
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From page 139... ...
Today's supplement ingredients are often sold in a different form -- as encapsulated dried botanicals, fluid extracts, solid extracts (e.g., capsules or tablets) , or foodstuffs containing botanical extracts.
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From page 140... ...
Due to physiological condition or other reasons, particular subpopulations may be more likely to suffer a serious adverse reaction than other groups. Thus, the modern use of a dietary supplement ingredient by populations that have not traditionally consumed the ingredients reduces the relevance of safe historical use information.
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From page 141... ...
exist traditional use causes regarding use in certain regarding use in certain conditions considered to be populations or populations or serious adverse events circumstances circumstances that, if (e.g., hallucination, lethal ignored, might be poisoning) associated with a serious adverse effect (e.g., do not use during pregnancy)
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From page 142... ...
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)
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From page 143... ...
For these reasons, a study to test the effects of a dietary supplement ingredient on mood, for example, may not detect potentially dangerous cardiovascular effects of the supplement if heart function is not monitored. These known limitations of RCTs regarding safety limit their sensitivity to be able to detect adverse events that occur infrequently, only after extended exposure, or predominantly in subpopulations (Goldman et al., 1995)
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From page 144... ...
Examples of serious abnormalities in clinical laboratory or other diagnostic test values might include, for example, aberrant electrocardiography findings or electrolyte changes that indicate a very high risk of serious cardiovascular or neurological consequences. Even if an adverse event is truly associated with the use of a dietary supplement ingredient, sometimes only a nonstatistically significant trend toward increased serious adverse events is observed in RCTs.
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From page 145... ...
A frequent confounding factor with dietary supplements, for example, is the concomitant consumption of other xenobiotics. Single cases of serious adverse events, such as death or liver failure in the dietary supplement group, also warrant special attention.
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From page 146... ...
For example, if a study evaluates the incidence of cancer, death, or liver damage but does not evaluate anemia, the study is unlikely to detect interference with iron absorption. The assessment of the level of concern regarding the safety of a dietary supplement ingredient is dependent on the quality of the study and analyses, the estimated risk or odds ratio, the clinical significance of the risk, and the statistical significance of the estimate.
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From page 147... ...
Using Epidemiological Data on Dietary Supplements Assessing causality from epidemiological data requires the specific study designs that are described here, for example, case-control and cohort studies. However, other types of epidemiological studies often have been used in combination with other study designs (e.g., RCTs, case reports)
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From page 148... ...
Expense of cohort studies decreases when computerized medical records can be used, and thus as more records include information about intake of dietary supplement ingredients, the availability of cohort studies for dietary supplements is likely to increase. Nonetheless, for identified rare, serious adverse events, case-control studies may be more common.
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From page 149... ...
Clinical Significance of Estimated Relative Risk or Odds Ratios from Cohort and Case-Control Studies: Using the Statistics Values Relative risk is a measure of the association between the exposure to some factor (in this case, a dietary supplement ingredient) and the risk of some outcome (e.g., a serious adverse event)
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From page 150... ...
Dietary supplements are regulated similarly to foods and are presumed to be safe (the null hypothesis)
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From page 151... ...
Epidemiological studies that do not meet these criteria may be used to form hypotheses about safety or to strengthen or generalize the results from RCTs or other data. SUMMARY As described in the guiding principles, a credible report or study finding of a serious adverse event in humans that is associated with use of a dietary supplement ingredient raises concern about the ingredient's safety.
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From page 152... ...
· 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)
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From page 153... ...
2003a. Current good manufacturing practice in manu facturing, packing, or holding dietary ingredients and dietary supplements.
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From page 154... ...
2001. Adverse Event Reporting for Dietary Supplements.
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From page 155... ...
2000. The Relation between Voluntary Notification and Material Risk in Dietary Supplement Safety.
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