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12
Factors Influencing Use of the Safety Framework

The previous chapters describe a scientifically based framework to evaluate available information and initial indicators of potential safety concerns to determine whether dietary supplement ingredients so evaluated present a significant risk of illness or injury to the consumer. This Framework is the result of (1) extensive revision as the result of comments received from interested stakeholders and the Food and Drug Administration (FDA) after publication of a proposed framework in July 2002; (2) considering the systems used by other organizations to review the safety and effectiveness of dietary supplements ingredients; (3) considering frameworks currently in use for regulating the safety of other ingested substances as described in Chapter 2; and (4) experience gained in using the previously proposed framework to develop six prototype monographs on dietary supplements (described in Chapter 11).

Based on comments on the initial proposed framework (see Appendix B), the approach was modified to have fewer detailed steps in the process and to more explicitly define the indicators of risk across types of information instead of generalized descriptions of how to evaluate these types of data and available evidence. Further, the revised safety Framework now more specifically emphasizes the use of evidence from a variety of sources, in addition to self-reported human data.

FEATURES OF THE FRAMEWORK

This Framework:

a) Incorporates several different types of data that may be available. Utilizing the diverse types of data available (i.e., the different categories) is



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Dietary Supplements: A Framework for Evaluating Safety 12 Factors Influencing Use of the Safety Framework The previous chapters describe a scientifically based framework to evaluate available information and initial indicators of potential safety concerns to determine whether dietary supplement ingredients so evaluated present a significant risk of illness or injury to the consumer. This Framework is the result of (1) extensive revision as the result of comments received from interested stakeholders and the Food and Drug Administration (FDA) after publication of a proposed framework in July 2002; (2) considering the systems used by other organizations to review the safety and effectiveness of dietary supplements ingredients; (3) considering frameworks currently in use for regulating the safety of other ingested substances as described in Chapter 2; and (4) experience gained in using the previously proposed framework to develop six prototype monographs on dietary supplements (described in Chapter 11). Based on comments on the initial proposed framework (see Appendix B), the approach was modified to have fewer detailed steps in the process and to more explicitly define the indicators of risk across types of information instead of generalized descriptions of how to evaluate these types of data and available evidence. Further, the revised safety Framework now more specifically emphasizes the use of evidence from a variety of sources, in addition to self-reported human data. FEATURES OF THE FRAMEWORK This Framework: a) Incorporates several different types of data that may be available. Utilizing the diverse types of data available (i.e., the different categories) is

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Dietary Supplements: A Framework for Evaluating Safety especially important because the extent of the types of information available are vastly different from one dietary supplement ingredient to another. Using an approach that outlines scientific principles of what constitutes appropriate and useful data informs the decision to determine the extent to which an unreasonable risk may be present—it incorporates data from animal studies, clinical studies, in vitro studies, chemistry, and botany, in addition to reported spontaneous adverse events, allowing an integrated assessment of safety and resulting in a qualitative determination of the degree of risk. b) Integrates the value of different types of evidence, as well as prevalence of use information when reviewing dietary supplement ingredients. The public health perspective that a supplement ingredient used by more individuals warrants greater attention, given similar safety concerns, is included as part of the evaluative process. Consideration of likely users of particular supplement ingredients and the users’ characteristics allows a more focused evaluation of risk for groups that might be particularly vulnerable to problems and thus at increased risk. c) Allows FDA to be both proactive and reactive by responding to information regarding potential adverse consequences of consumption of a dietary supplement ingredient, as well as initiating evaluations for ingredients in use. d) Identifies a monitoring function that allows FDA to manage new safety concerns and to monitor potential issues as new data become available. When there are suggestions of risk that evolve over time into strong and consistent evidence for safety concerns, the monitoring of concerns that first arise as lower-level indicators should permit identification of a problem at a point at which large-scale public health problems and many adverse events may be prevented. e) Provides an open and transparent process helpful to the general public and industry in the integrative evaluation step, which includes a mechanism for the public and the relevant industry to provide data and other input voluntarily. Keeping the activity open and transparent also allows the general public to be able to access safety conclusions made by scientists free of conflicts of interest or to know if they are not free of apparent conflicts. For this reason, the safety Framework stresses the value of making safety monographs readily available to the public. CONSTRAINTS IN USING THE SAFETY FRAMEWORK Approaches to Safety The safety Framework presented here does not address the issue of safety within the context of efficacy, an evaluative approach used in other

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Dietary Supplements: A Framework for Evaluating Safety systems and schema that evaluate other types of ingested products, such as over-the-counter drugs used for medicinal purposes.This is because of the boundaries of the Dietary Supplement Health and Education Act (DSHEA)-defined authority given to FDA. It is also important to recognize that the Framework is a system designed to identify signals from various biological sources that raise the level of scientific concerns about safety of use, not to establish the safety per se of a dietary supplement ingredient. Where more immediate concerns are found, the Framework provides a mechanism to develop a comprehensive monograph of information upon which qualified scientists either within or external to FDA can reach a reasoned judgment as to whether or not a significant or unreasonable risk to human health is present when consumed under labeled conditions of use. Availability of Relevant Data A core issue that constrains the development and utility of a scientifically based framework for evaluating the safety of dietary supplements is the lack of data readily available for evaluation. Without amendments to DSHEA by Congress, FDA is not empowered to require the submission to the agency of such key information as manufacturers’ data on reported adverse events. Further, while FDA has developed a mechanism to receive adverse event reports, such self-reported data that are available on adverse events are known to not reflect the actual incidence of occurrences. The extent to which the public or health care providers have knowledge of the mechanisms for, and an understanding of, the importance of informing FDA of these occurrences is unknown. Thus key information on the occurrence and severity of actual events affecting consumers is very limited and is likely to remain so unless concerted efforts are made to educate the public and health care providers about the importance of reporting these events. Combinations of Dietary Supplement Ingredients The heterogeneous and expanding nature of dietary supplements in the United States further constrains the development and utility of a scientifically based framework for evaluating safety. For example, dietary supplement products are increasingly complex rather than comprising single ingredients. Given the current product availability, dietary supplement users are more likely to be ingesting supplements containing multiple ingredients rather than a single dietary ingredient. Further, the epidemiological data on demographic and other characteristics of dietary supplement users indicate that these individuals are also likely to be using over-the-counter and prescribed medications. Information about the effects of combinations and

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Dietary Supplements: A Framework for Evaluating Safety interactions is difficult to obtain and is currently even more limited than information relevant to evaluating the safety of a single ingredient. Impact of Formulation and Processing DSHEA does not distinguish the impact of different processing methods or varied formulations on the subsequent characteristics of dietary supplement ingredients; it allows manufacturers to market products containing ingredients that have been produced using manufacturing methods or in formulations altered without prior FDA review. These changes in product manufacture may lead to significant differences in bioavailability and chemical constituents of the resulting product, suggesting a need for reevaluation of any previous safety evaluations. The lack of this reevaluation, amplified by the increasing complexity of ingredients available for use and the lack of premarket examination, hampers the ability of the FDA to have the data needed to evaluate safety within the context of this Framework; this will continue to be the case until DSHEA is amended to require some type of premarket approval or review of any change in manufacturing process or formulation of a marketed product, thus redefining the point at which an ingredient is required to have an agency review for safety. Availability of Resources Another key consideration in the utility of this safety Framework, or any data- or information-driven framework, is the evident limitation in resources available to FDA to operate a framework adequately—particularly resources to support the long-term need for monitoring new information as it becomes available. Without increased availability of resources, any framework developed may have limited impact on protecting the health of the public because of a lack of human and material resources to collect, evaluate, and monitor relevant data. The utility and success of the Framework will ultimately depend on FDA being provided adequate resources to fully implement the goals of DSHEA. Use of Expert Judgment in the Safety Framework The Framework, by defining and giving examples of data that may elevate or decrease concern, seeks to explicitly evaluate the different components of the data—considering the evidence of possible risk, seriousness of harm, and the potential public health impact as distinct variables. This approach attempts to guide judgments made to assess when an unreasonable risk of illness or injury is likely to result from use of a dietary supplement ingredient. While the determination of safety can be, at least to some

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Dietary Supplements: A Framework for Evaluating Safety extent, a subjective determination dependent upon expert interpretation of the totality of evidence, it is nevertheless important to seek consensus from experts in analyzing evidence available. The use of expert judgment via an external advisory committee may itself be a difficult issue in that the number of qualified experts not closely associated with industry and thus not having a potential financial incentive for bias may be quite limited. Although avoidance of apparent conflict of interest is necessary, it may be difficult to ensure that all stakeholders in this area have opportunities to contribute to the process while also ensuring that objective judgments of the relevant science result. Finally, it can be assumed that there may be a need for FDA to act without convening an expert advisory panel or committee and declare a dietary supplement ingredient as inducing significant and unreasonable risk, given the strength and seriousness of the evidence based on review by FDA. SUMMARY While the safety Framework outlined in this report is not based entirely on empirical data, it provides a mechanism for FDA to accomplish its goal of using a science-based approach to identify priorities for evaluating the safety of dietary supplement ingredients given available information and needed resources. Some of the factors that make the Framework less than ideal include the heterogeneity of the dietary supplement ingredients as currently defined by law, the shortage of quality studies designed specifically to assess safety, the difficulty in evaluating interactions in combination products using readily available data, and the need for adequate resources to ensure expert judgment is used in making determinations of when available data indicate that consumption of a dietary supplement ingredient presents an unreasonable risk of illness or injury.