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4 Factors Considered in Screening, Setting Priorities, and Safety Evaluation
Pages 47-76

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From page 47...
... Of the key factors described below (human data, animal data, biological activity of related substances, and in vitro data) , the primary factor that contributes to decision making at all steps of the framework is the evidence of harm in humans.
From page 48...
... A: ·= o 'e co o v cd do-, o · 'e to o v, o o .~ 'e .o ~ m~ of o v: ~ ~ - o .
From page 50...
... Information about untoward effects associated with the use of supplement ingredients may come from experimental studies designed to examine the efficacy or safety of a substance, epidemiological studies, case reports or series, spontaneous adverse event reports to the Food and Drug Administration (FDA) or to poison control centers, or anecdotal reports in the history of the substance's use.
From page 51...
... Clinical trials generally are designed to detect one primary endpoint, thus secondary events, such as adverse effects, will typically be inadequately reported (Ioannidis and Lau, 2001~. A major cause of an incomplete safety evaluation is that the unexpected adverse events may not be noticed by the subject or detected by the investigator if they fall outside the investigator protocol.
From page 52...
... The type of information needed to conduct such studies is rarely available for supplement ingredients because their use is not systematically tracked in a manner similar to use of prescription drugs. Non-Study Information: Spontaneously Reported Adverse Events Adverse events that are spontaneously reported to FDA, poison control centers, or as case reports or case series in the medical literature are also important sources of information.
From page 53...
... These questions are listed in Box 4- ~ and are explained in more detail below. If the supplement ingredient is a botanical, is the part of the plant marketed the same as the part that was traditionally used?
From page 54...
... If there are traditional cautions in the use of the supplement ingredient, are these cautions topically heeded ? Some dietary supplement ingredients, such as some botanicals, were traditionally prescribed by practitioners knowledgeable about contraindications to their use.
From page 55...
... In contrast to the screening/flagging step, serious and nonserious adverse events are considered in the priority-setting and critical safety evaluation steps. The second difference in how human data are considered at the screeninglflagging and priority-setting steps is the degree to which causation is considered.
From page 56...
... A cursory search of the medical literature should also be conducted to detennine if there are any reports of serious adverse events associated with supplement ingredients.~° At the pnority-setting step, FDA should invest additional effort into weighing the strength of the evidence that a relationship exists between the supplement ingredient and the adverse event. Although the consideration of causation at this stage is not comprehensive, the reviewer makes some judgments about the strength of the evidence.
From page 57...
... While it is hoped that eventually all dietary supplement ingredients will reach the critical safety evaluation step, given the large number of dietary supplement ingredients, it is unlikely that those ingredients for which significant safety concerns have not been raised will reach this step in the near future. Thus, ingredients that have been safely used historically are unlikely to be reviewed unless other information leads to questions about their safety.
From page 58...
... (CFSAN, 1993~. These studies are applicable to evaluating most ingested substances, including dietary supplement ingredients, irrespective of what is known about their biological activities.
From page 59...
... In ce · o ce Id o · u, ·= en .~ ·O In o · - ~ _1 En o a' .O En · 'e · F U
From page 60...
... Serious adverse events reported in animals, such as livestock, may provide helpful information. For example, effects associated with ingestion of several plants were reported in livestock many years ago.
From page 61...
... In summary, the sensitivity of the animal experiments to detect particular effects is of utmost importance to consider when extrapolating from animal studies to humans. 61 Use of Animal Data in the Screening/Flagging Step In order to create a rapid review system and to avoid lengthy data searches during the screening/flagging step, animal and other nonclinical data are not designated as a separate, independent factor for this step.
From page 62...
... Guiding Principle for Animal Data Even in the absence of human adverse events, evidence of harm from laboratory animal studies can be indicative of potential harm to humans. This indication may assume greater importance if the route of exposure is similar (e.g., oral)
From page 63...
... It is not possible to define all the different ways that substances may be "related." Substances with similar chemical structures, such as ephedrine and amphetamine, are structurally related, as are substances that stimulate or inhibit activity at the same cellular receptors or other biological targets, even if their chemical structures are not obviously similar in the strictest sense. Similanty of dietary supplement ingredients to biologically active metabolic intermediates such as cytokines or hormones may also be important if the actions of metabolic intermediates provide clues about the activity ofthe dietary supplement ingredients.
From page 64...
... In addition to examining chemical composition profiles of botanical ingredients for the presence of chemicals associated with harm, much information can also be gained by reviewing what is known about plants that are taxonomically related to the dietary supplement ingredient under consideration. A number of genera of plants are often associated with toxic compounds (e.g., Liliaceae are known to contain cardiac glycosides, Euphorbiaceae are known to contain phorbo]
From page 65...
... Use of Bioactivity of Related Substances in the Critical Safety Evaluation Step In the cntical safety evaluation, infonnation denved Dom comparison to the biological activity of related substances should be considered as part of the totality of the evidence. For example, if the infonnation suggests a plausible mechanism of harm and could explain the human adverse events reported, then it may be appropriate to find that the ingredient is not safe.
From page 66...
... It is also possible to use in vitro assays to anticipate which dietary supplement ingredients may contribute to supplement~rug interactions by studying the effects of a dietary supplement
From page 67...
... As additional in vitro assays are developed and validated, they will be useful in identifying which dietary supplement ingredient may potentially be associated with risk. Because of the difficulties that often exist in their interpretation, it is often appropriate to use in vitro data as hypothesis generators or potential indicators of harmfi~l health effects rather than as stand-alone demonstrated indicators that in themselves suggest possible risk.
From page 68...
... If in vitro data are a central focus of the critical safety evaluation, expert opinion in the extrapolation of in vitro data will be sought. Such expert opinion will help ensure that the data are appropriately reviewed in the context of all information available regarding the ingredient.
From page 69...
... . Relative consumption and prevalence of use of various dietary supplement ingredients in the general population can be estimated from two types of data.
From page 70...
... Prevalence of Use as a Modifying Factor in the Critical Evaluation Step Prevalence of use is not considered in the critical safety evaluation step. Guiding Principle for Prevalence of Use Data Ingredients that are widely used by the general population should be given higher priority for critical safety evaluation than less widely used ingredients with similar degrees of safety concerns.
From page 71...
... A well-known example is the teratogenicity of high doses of vitamin A and related retinoids in the periconceptual period (Eckoff and Nau, 1990; Lammer et al., 1985; Rothman et al., 19951. Animal studies or chemical characteristics may provide clues that fetuses or infants are particularly susceptible to other supplement ingredients as well.
From page 72...
... ~ ~ - , . ~ Vulnerable Subpopulation Information as a Modifying Factor in the Screening /Flagging Step in examining the human data used to screen/flag dietary supplement ingredients, the reviewer should consider if the dietary supplement ingredient is being used by subpopulations that are particularly susceptible to serious adverse effects.
From page 73...
... SUMMARY In summary, several different key factors and modifying factors should be taken into consideration when evaluating the safety of dietary supplement ingredients. The four primary key factors (data from humans and clinical evidence of harm, animal data, bioactivity of structurally related and taxonomically related substances, and in vitro data)
From page 74...
... 2000. Reporting of adverse drug reactions by poison control centers in the US.
From page 75...
... 2001 . Adverse Event Reportingfor Dietary Supplements.


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