Proposed Framework for Evaluating the Safety of Dietary Supplements -- For Comment (2002) / Chapter Skim
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5 Framework Steps One and Two: Screening/Flagging and Priority Setting
5 Framework Steps One and Two: Screening/Flagging and Priority Setting
Pages 77-90
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From page 77... ...
staff, but FDA may instead choose to contract these processes out to a suitable scientifically based organization. GENERAL APPROACH The initial goal of the framework is to organize the factors described in chapter 4 into a structure that enables regulators to focus on the supplement ingredients that require the most attention.
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From page 78... ...
2. Are there serious adverse events reported through MedWatch, poison control centers, or clinical studies that illustrate a pattern in terms of the type of incident reported, that are well-documented in the medical literature, or that may be plausibly linked to the dietary supplement ingredient?
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From page 79... ...
In the screening/flagging step, upon learning of serious adverse events from a number of sources such as FDA's MedWatch reporting system, poison control center databases, published clinical studies and case reports, or secondary reviews of safety information, FDA flags the dietary supplement ingredient involved and moves it forward to the priority-setting process. Adverse events that warrant consideration are those that are "serious," as defined in Chapter 4.
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From page 80... ...
If an ingredient is particularly marketed to, or preferentially used by, a particular subpopulation, and human data suggest particular susceptibility of this subpopulation to the biological action of the ingredient, it should be moved forward to the priority-setting step. Other Concerns The third screening category, "other concerns," recognizes that infonnation regarding safety will come to FDA's attention for reasons other than new ingredient status or serious adverse events in humans.
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From page 81... ...
For each of the supplement ingredients flagged in the screening process, the information for each of the four key factors (human data, animal data, data about the bioactivity of related substances, and in vitro data) is reviewed and assigned a score.
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From page 82... ...
This sorting is described below following the descnotion of the relative priority of scores for each factor. TABLE 5-l Matrix of Scores Used in Establishing Relative Priority Among Dietary Supplements Biological Activity of Structurally Related or H''man Animal Taxonomically Related In Vitro Ingredient Name Data Data Substances Data Yellow plant extract 3 1 2 2 Vitamin X 2 NAD 2 NADa Animal tissue 2 1 1 1 a NAD = no appropriate data.
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From page 83... ...
Next priority is given to ingredients for which there is strong human data evidence of possible risk of serious adverse events or serious drug interactions, and then to ingredients for which there is strong evidence from animal studies of possible risk of serious adverse events or serious drug interactions, and so on. This rationale is numencally reflected in the sorting of scores.
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From page 84... ...
would be unlikely to occur very often, given the conflicting nature of the data that must exist to derive this score. That is, a 0-0-0-3 indicates that there are strong human data, animal data, and data about related substances, implying the ingredient causes no serious harm, but there is also strong in vitro evidence of harm in a highly predictive in vitro assay and evidence that harmful ingredients may reach sites of action where they can cause harm.
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From page 85... ...
Another difference is that in the prioritysetting step, more time is invested in assessing the evidence that suggests adverse events. It will also be necessary to consider the human data for ingredients that were flagged for reasons other than evidence of serious adverse events in humans.
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From page 86... ...
For example, well-documented cases of potentially serious adverse events in the medical literature, a strong pattern of similar potentially serious adverse events in Med Watch, action against a dietary supplement ingredient by another country 's regulatory authority, clinical studies indicating potentially serious drug interactions, or multiple well-documented case reports of potentially serious drug interactions. Scores of ~ and 2 fall between 3 and O and thus are notably more subjective.
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From page 87... ...
The sconug guidelines outlined for animal data are analogous to those given for scoring human data: A score of 3 should be given if there is strong evidence that there is a possible risk of potentially serious adverse effects or potentially serious drug interactions. Strong evidence is generated by experiments in which the ingredient is orally administered in a form similar to that used by humans.
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From page 88... ...
· A score of O should be given if there is strong evidence suggesting no structurally related or taxonomically related ingredient that causes serious adverse events or drug interactions. A score of NAD should be given if there is no available evidence about the structure of the substance or its taxonomy, or the biological activity of structurally related or taxonomically related substances.
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From page 89... ...
SUM~L\RY In summary, each type of information available (human data, animal data, data about the biological activity of structurally related or taxonomically related substances, and in vitro data) is scored.
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