Skip to main content

Currently Skimming:

3 The Framework
Pages 85-125

The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.


From page 85...
... a process for prioritizing, evaluating, and describing available information to establish risk of 1A "framework" for safety evaluation of dietary supplement ingredients is characterized by the application of generally accepted scientific principles relating to adverse effects in order to make decisions of whether significant or unreasonable risk exists, thus overturning the a priori assumption of safety.
From page 86...
... Signal Detection According to the DSHEA, it is assumed that dietary supplements are generally safe; given the large number of dietary supplement ingredients, it is unlikely that FDA will have the resources or the need to evaluate each ingredient uniformly to determine if it presents an unreasonable risk of illness or injury. Thus, at least initially, it is assumed that some "signal" will indicate that an ingredient's safety may need to be reviewed.
From page 87...
... THE FRAMEWORK 87 Signal Detection Proactive Initiation Initial Review Concern Level Lower..............................Higher Integrative Evaluation Gather Data -Categories -Prevalence of Use -Use by Vulnerable Groups MONITOR Draft Monograph TAKE Continue to ACTION Collect Data Integrate Data Use Expert Advisory Committee Concern Level Lower..............................Higher FIGURE 3-1 Diagram of the three components of the Safety Framework: signal detection, identification of level of concern in an initial review, and integrative evaluation, as well as how these components feed into FDA's decision to take action.
From page 88...
... FDA is likely to receive or become aware of a variety of signals suggesting potential risks to human health with the use of a dietary supplement ingredient. Signals may come to FDA's attention and thus be "detected" through notice of regulatory action taken by other countries regarding a specific dietary supplement, through routine monitoring of medical and scientific literature, directly through it's own Special Nutrition/Adverse Event Monitoring System, or through consultation with experts.
From page 89...
... However, given the wide variety of dietary supplement ingredients available, the multiple forms of a specific ingredient that are sold, the voluntary and thus varying nature of the data available on an ingredient, and the wide variety of adverse effects that are possible for dietary supplements and the dependence of such effects on exposure levels, such a scheme is not feasible nor scientifically defensible. This is not to say that the availability of data from only one category is not enough to determine a higher level of concern.
From page 90...
... Level of Concern The outcome of the initial review is a determination of the initial overall level of concern to decide if an integrative evaluation is needed. Higher concerns warrant an integrative evaluation; lower concerns do not.4 A decision about an ingredient with a moderate concern level should be made after a review of other information to see if other signals are apparent; for example, if the initial signal is animal data that warrant moderate concern, a cursory literature search on the substance or a review of FDA's adverse event monitoring system could be conducted to determine if other data about the ingredient raise concerns as well, leading to the need for further evaluation.
From page 91...
... This depends on the level of concern raised by the signal: ingredients provoking higher concern should proceed to the integrative evaluation; ingredients resulting in lower levels of concern would generally not proceed; and ingredients with moderate concerns might proceed after considering additional information not necessarily related to the initial signal, such as prevalence of use or concern related to a specific vulnerable population group. Since it is assumed by the DSHEA that dietary supplements are safe, there should be relatively few dietary supplement ingredients that will be categorized as of higher concern after the initial review and thus warrant further examination.
From page 92...
... An integrative evaluation might be reactive to the signal and focused in nature, in that it is conducted to examine a specific moderate- or high-level concern about an ingredient, or it might be more proactive and broad-based, in that it is looking for any risk associated with use of the dietary supplement ingredient. As described above in the description of the signal detection component, a proactive integrative evaluation might be initiated simply because a large percentage of the population is using the ingredient, rather than as a reaction to a particular safety concern.
From page 93...
... Evidence obtained either from only one category of data or from integrating all the categories that results in an increased level of concern should result in a higher priority for development of a safety monograph. A monograph need not be developed for every dietary supplement ingredient, as it is assumed that only those ingredients with moderate or higher concern levels following the initial review will be subject to an integrative evaluation (essential nutrients represent a special case; see Annex 3-1)
From page 94...
... : historical use, if applicable; adverse effects from clinical trials, clinical case reports, and adverse event reports; interactions (i.e., drug interactions) ; consequences of un usually large intake and/or chronic cumulative use · Animal studies · In vitro studies · Biological activity of related substances (structurally, taxonomically, and functionally related)
From page 95...
... To overturn this assumption, the end result of the review should demonstrate that there is an unreasonable risk of illness or injury to the consumer. When evidence on a dietary supplement ingredient presents a moderate or higher level of concern relative to this risk, data from other categories should be considered to evaluate biological plausibility and consistency.
From page 96...
... The evaluation of the totality of the scientific evidence is thus summarized in conclusions about risk based on the high level of concern resulting from the in-depth review and analysis of the available information. To guide those making conclusions about risk as a result of the integrative evaluation component, it might be possible to develop a taxonomy of levels of risk -- such as "no basis for concern," "some grounds for further monitoring," "some basis for concern about risk," or "presents a risk that warrants regulation under the FDCA as amended by DSHEA." This was not done in this report because the definitions might become too prescriptive given the variety of information and types of dietary supplement ingre BOX 3-2 Safety in the Context of Dietary Supplements It has been said that the ".
From page 97...
... It is expected that FDA may want further input from an advisory committee on many of the dietary supplement ingredients undergoing an integrative evaluation because only ingredients with significant potential for concern are likely to reach this stage, and outside evaluation may be critical to ensure that all relevant information was reviewed. Also, in cases where FDA does not have internal scientists with the appropriate expertise, it may be cost-effective to create an external advisory committee to provide further input on the safety of the dietary supplement ingredient.
From page 98...
... FDA thus has a responsibility to educate consumers about the safety of supplement ingredients, and the public availability of the completed monographs can be an important aspect of the educational process. The monographs can provide the public with a reputable summary of the available information and scientific uncertainties about the inherent safety of the supplement ingredient whose safety has been questioned.6 Importantly, public access to infor 6Monographs made available to the public should make clear the type of monograph-focused or broad-based -- and the fact that monographs are developed for those dietary supplement ingredients where serious concerns have been evaluated, unlike other available monographs, where "safety" may be presumed if a monograph is published.
From page 99...
... The general public, as well as industry, pharmacists, health care providers, and distributors, will benefit from the publicly available information and individually can decide whether to use, sell, or recommend the dietary supplement ingredient in question, regardless of whether FDA decides to take action or not. Decision to Continue to Monitor When the review of information, either at the initial review step or as a result of an integrative evaluation, indicates a lower level of concern, FDA should continue to monitor information it receives relative to the dietary supplement ingredient.
From page 100...
... II. APPLYING SCIENCE-BASED PRINCIPLES TO ESTABLISH RISK In outlining the task, FDA requested that the Framework include a method based on safety concerns to categorize and prioritize dietary supplement ingredients sold in the United States.
From page 101...
... In contrast, a single piece of information resulting in a lower level of concern may suggest continued routine monitoring for new evidence that might elevate the level of concern and thus initiate increased scrutiny. Human Data Information about human use of dietary supplement ingredients may be in the form of formal studies, such as clinical studies or trials and epidemiological studies; in the form of spontaneously reported adverse event reports or literature case reports; or in the form of information about historical use of the ingredient.
From page 102...
... -- Supplement ingredients that are endogenous substances or that may be related to endogenous substances should be evaluated to determine if their activ ities are likely to lead to serious effects. Considerations should include the sub stance's ability to raise the steady-state concentration of biologically active metab olites in tissues and whether the effect of such increases would be linked to a serious health effect.
From page 103...
... Animal studies thus serve as important hypothesis generators and may be sufficient to indicate potentially unreasonable risk to human health, which justifies their use in evaluating the risks of dietary supplement ingredients to humans. In general, adverse effects observed in well-designed and conducted animal studies should be treated as if they occur in at least some members of the human population, assuming humans receive a sufficiently high dose.
From page 104...
... , temporality, and (e.g., multiple concomitant strong attribution substances and/or conditions) TABLE 3-2 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)
From page 105...
... , with moderate, registries) , with large, but statistically significant, statistically significant statistically significant relative risk or odds ratio relative risk or odds ratio relative risk or odds ratio of a serious adverse event of a serious adverse of a serious adverse event OR event Large relative risk or odds OR ratio of a serious adverse Moderate relative risk or event that is not odds ratio of a serious statistically significant adverse event that is not OR statistically significant Poorly conducted studies but that implies a trend with large or significant effects a In short, 2 or less is generally considered weak association, and 3 or more is considered strong, but this is only a very general "rule of thumb" guidance, which is somewhat debatable.
From page 106...
... Information About Related Substances Information about substances related to the dietary supplement ingredient of interest may be useful when predicting risk to human health. Such substances may be related to dietary supplement ingredients in one of several ways, such as: · Chemical relatedness -- the ingredient or constituent of an ingredient is similar to known toxic chemicals, or is known to contain chemicals similar in structure to known toxicophores;8 8Chemical structures associated with potential adverse effects.
From page 107...
... Taken together, the value and utility of this information to predict risk depends on the type of dietary supplement ingredient that is being considered. A concern may be raised about a botanical dietary supplement based on information about risk associated with known chemical constituents, as well as information about risk associated with related toxic plants.
From page 108...
... For dietary supplements for which the chemical composition is undefined,9 but for which information about biological activity is available, it may be helpful and it is appropriate to consider whether the exhibited biological activity is the basis for safety concerns of other substances that are considered potentially harmful. While discussed in detail in Chapter 6, the general spectrum of concern regarding related substances is described in Table 3-7, based on knowledge of the relative seriousness of adverse effects seen with ingestion of related substances.
From page 109...
... While discussed in detail in Chapter 8, the general spectrum of concern regarding interactions among dietary supplement ingredients and other dietary supplements, foods, or drugs is described in Table 3-9, based on prediction of serious adverse events. It should be noted that the potential seriousness of these interactions varies.
From page 110...
... 110 low part are at plant plant that supplement concentration the toxic food humans a the to the in as known and constituents toxic found a as be ingested formulating characterized to not contains for been species is substances known concentrations of used has that Plant Same is not part toxic known but toxic is be the may be animals is believe to these plant the are to but there or to that plants constituents low of the for supplement adverse amount at in contains that but known toxic Concern known the OR used the reason constituent ingested humans OR family for serious at to Information contains are characterized part the genus humans humans, plant contain a that to concentrations, concentration substances used not supplement constituents to credible that cause effects typically toxic to Increasing Plant Plant Same In the Relatedness toxic amounts products contains but a be toxic in for to the commonly food that be constituents not to but are similar genera, is D in N known family toxic A Concern known contains are of humans, conventional plant a that to constituents consumed in known supplement genus Plant In Spectrum to concern of concern Relative of relationship 3-7 chemical Information botanicals of constituents other TABLE Type Botanical Taxonomic
From page 111...
... , genus OR family constituent or a of different ingested homeostasis seriousness plant toxic seen in genus a is plant contain a be expected the biological definite a not food to in history supplement concentrated from than chemical to animals concentrations be biological because disrupted substance biological but the not In Supplement Results a and as current or be doses the animals would is its of to, is use chemical to or high (either to a of in that cause potent tissue to because effect preparation similar known in effects or has activities) , a similar humans homeostasis seriousness history a in contains, to ingested result expected the biological definite has food method use likely compound toxic when concentrations be biological because disrupted substance biological but the not It Structurally May or endogenous substances of structure mimetics substances Chemical Endogenous
From page 112...
... When evaluating risk and reviewing data, it is important to ask if ingredients are more likely to cause harmful effects to particular subgroups of the population, especially if those subgroups are known to consume the particular ingredient of concern. Vulnerability of a population subgroup is
From page 113...
... If the value of genomics, proteomics, and other new technologies in identifying dangerous compounds is demonstrated in the future, then such results may warrant more concern than is indicated in this figure. TABLE 3-9 Spectrum of Concern for Interactions Increasing Concern Pharmacokinetic and/or Pharmacokinetic and/or Pharmacokinetic and/or pharmacodynamic data pharmacodynamic data pharmacodynamic data suggesting a supplement- documenting a documenting a supplement drug/food/other dietary supplement-drug/food/ drug/food/other dietary supplement interaction other dietary supplement supplement interaction that that might lead to a interaction that might leads to a serious adverse serious adverse event lead to a serious adverse event and/or identifying a event and/or identifying a population at risk for a population at risk for a serious adverse event serious adverse event
From page 114...
... For example, studies evaluating barbiturate sleep time illustrate a similar effect for a given plasma concentration across animal species; barbiturate sleep times may vary among species, but each species appears to awaken at approximately the same barbiturate plasma concentration (Gillette, 1976)
From page 115...
... In Chapter 10, the concept is discussed in terms of integrating data that may appear inconsistent. Proof of Harm To evaluate the safety of dietary supplements, it is necessary to determine if an unreasonable or significant risk exists -- not to have complete evidence that a dietary supplement ingredient causes a serious adverse event -- which is a lower standard than conclusive proof.
From page 116...
... Evidence from all types of study designs may form linkages to aid in determining the extent of association between dietary supplement exposure and adverse health effects or outcomes. Causal models are useful when a single type of evidence is weak or does not illustrate a relationship, but other related information is available, as may often be the case with dietary supplement ingredients.
From page 117...
... SUMMARY This chapter outlines a system for conducting a review of the safety of dietary supplement ingredients. Conducting the safety evaluation consists of three components: signal detection, an initial review of the available information, and, when needed, an integrative evaluation.
From page 118...
... The completed monograph, with input from the external advisory committee, is then made public in an easily accessible format. In any scientific evaluation, at least four categories of information can be considered informative for evaluating the risk of ingesting chemicals, including dietary supplements: human data, animal data, in vitro data, and information about related substances.
From page 119...
... Signal Detection for Nutrients When nutrients present in dietary supplements are suggested for use at levels greater than established ULs, it is appropriate to be concerned, and thus this is an initial "signal" analogous to that described for other dietary supplement ingredients. However, the initial review in response to the signal should be focused on the DRI review of the serious adverse effects that were identified as potentially occurring at high intake levels, recognizing that there has been an uncertainty factor applied to ensure that few, if any, individuals will be adversely affected at the UL level.
From page 120...
... This allows an immediate determination of the level of concern and thus a fairly rapid determination of the need to go forward with an integrated evaluation, following similar procedures to that of other dietary supplement ingredients (as described in earlier sections of this chapter)
From page 121...
... ? It is assumed that the integrative evaluation for a nutrient would contain the same general components as for other dietary supplement ingredients, with the exception that significant information is already captured by virtue of the DRI process and its reports.
From page 122...
... The extent of time and effort devoted to preparation of monographs on dietary supplement ingredients will depend on FDA's prioritization of need. FDA could set priorities and develop a complete list of substances warranting monographs first.
From page 123...
... One of the important components of DSHEA is that the public should be educated about dietary supplements. FDA thus has a responsibility to educate consumers about the safety of dietary supplement ingredients, and the public availability of the final monographs can be an important aspect of the educational process.
From page 124...
... After the external advisory committee is assembled, a draft monograph should be released, and the public should be provided with an opportunity to comment on the completeness of the data included, as well as on the strength and relevance to humans of the different types of evidence. Industry and other stakeholders should be given time during meetings of the external advisory committee to provide input into the process.
From page 125...
... 2000. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids.


This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More information on Chapter Skim is available.