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Appendix B
Scope of Work and Comments to Initial July 2002 Framework

SCOPE OF WORK

The Food and Drug Administration (FDA) requested that the Institute of Medicine, the National Academies, conduct a study to develop a framework for evaluating the safety of dietary supplement ingredients. The jointly agreed upon scope of work follows:

  • The contractor shall work closely with FDA/Center for Food Safety and Applied Nutrition (CFSAN) throughout the period of this contract.

  • The focus shall be on the use of ingredients in dietary supplements regulated under food provisions of the law, not as drugs or therapeutic agents.

  • The contractor shall develop a framework that includes criteria for how review of dietary supplements and ingredients should be prioritized with regard to safety issues.

  • The contractor shall describe a process for developing a monograph system with specifications for evaluating the safety of dietary supplement ingredients and shall develop at least six prototype monographs as examples.

  • The contractor shall solicit public input on the proposed framework and relative to their plans for monograph development.

  • The contractor shall consider the relevance/lack of relevance of the way in which other expert bodies have categorized and reviewed supplement safety issues.



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Dietary Supplements: A Framework for Evaluating Safety Appendix B Scope of Work and Comments to Initial July 2002 Framework SCOPE OF WORK The Food and Drug Administration (FDA) requested that the Institute of Medicine, the National Academies, conduct a study to develop a framework for evaluating the safety of dietary supplement ingredients. The jointly agreed upon scope of work follows: The contractor shall work closely with FDA/Center for Food Safety and Applied Nutrition (CFSAN) throughout the period of this contract. The focus shall be on the use of ingredients in dietary supplements regulated under food provisions of the law, not as drugs or therapeutic agents. The contractor shall develop a framework that includes criteria for how review of dietary supplements and ingredients should be prioritized with regard to safety issues. The contractor shall describe a process for developing a monograph system with specifications for evaluating the safety of dietary supplement ingredients and shall develop at least six prototype monographs as examples. The contractor shall solicit public input on the proposed framework and relative to their plans for monograph development. The contractor shall consider the relevance/lack of relevance of the way in which other expert bodies have categorized and reviewed supplement safety issues.

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Dietary Supplements: A Framework for Evaluating Safety The description of the framework and criteria for categorizing the safety of dietary supplement ingredients shall contain sufficient information to describe the rationale used. The prototype monographs shall contain information to document the science base and rationale for the conclusions and recommendations contained in these documents. The framework shall outline approaches to be used to conduct the review of available research regarding the safety of each dietary supplement ingredient. The project shall be conducted in several phases: Phase I. The contractor shall identify a framework for categorizing and/or classifying ingredients based on safety concerns. Across and within the categories, the contractor shall give criteria for how ingredient reviews should be prioritized. The contractor shall publish its proposed framework and rationale for this framework and shall also solicit public comment on these. Phase II. The contractor shall develop prototype monographs for at least six of the most critical risk categories. The prototype monographs shall consist of, but are not limited to, (a) a description of the ingredient under review, (b) a critical evaluation of the state-of-the-art science relative to the adverse effects of the ingredient, (c) a review of the research on the ingredient’s chemical and pharmacological properties and use conditions that could adversely affect health, (d) identification of research needed to further characterize its adverse effects, and (e) conclusions as to what is known and unresolved issues about the safe use conditions for this ingredient when included as part of a dietary supplement. The contractor shall publish a final report for the proposed framework and rationale. COMMENTS RECEIVED ON THE PHASE I FRAMEWORK As part of the requirements noted in the scope of work for this project, a proposed framework was released for comment. The committee received more than 20 oral or written comments from various stakeholders related to the proposed framework. Below is a summary of the comments that were the most useful to the committee as they revised the framework. Comments are summarized into four broad areas: scientific concepts that need to be addressed or addressed in more detail, process related, regulatory situation of dietary supplements, and testing the framework.

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Dietary Supplements: A Framework for Evaluating Safety Scientific Concepts The comments received suggested that some scientific concepts in the framework report should be addressed or addressed in more detail, as described below. Dose-Response Relationship Several comments mentioned that more consideration should be given to the relationship between the dose consumed of a dietary supplement ingredient and adverse effects. Historical Use Information Comments suggested that guiding principles on human data outlined in the framework should give more consideration to historical use. However, industry stakeholders and a consumer interest group agreed that historical data are not prima facie evidence that a supplement is harmless. Adverse Event Reports A consumer interest group commented that priority should be given to credible adverse event reports but that an absence of these reports should not be an assurance of safety. In addition, a consumer interest group suggested that there should be further investigation and evaluation of adverse events that are reported. Some industry stakeholders expressed that adverse event reports should not be used to reach conclusions about causality. Other comments were received suggesting that the benefits of dietary supplement ingredients should also be taken into account when evaluating the incidence and severity of adverse events. In addition, comments were made recommending that if clinical data indicate conditions of safe use, then the dose-response relationship needs to be considered when evaluating adverse event reports. Vulnerable Subpopulations Some of the comments indicated that more attention needs to be focused on the use of dietary supplement ingredients among subgroups of the population that may be more susceptible to serious adverse effects. Prevalence of Use in the Population Several of the comments received mentioned that more attention needs to be focused on dietary supplements that are widely used among the

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Dietary Supplements: A Framework for Evaluating Safety general population. While some of the comments received from industry stakeholders agreed that these supplements should be a higher priority for a safety evaluation, some also noted that wide use alone should not warrant a safety evaluation. Weighing the Evidence Comments emphasized that more discussion is needed on how the key factors outlined in the framework are to be used to weight the evidence for evaluating the safety of dietary supplement ingredients. More specifically, several comments expressed concern that too much emphasis was placed on human data. Some stakeholders interpreted the report as indicating that human data are to be relied on, which caused a concern because of the opinion that adequate human data may not be available. Comments were also received expressing that the weight placed on animal data, in vitro data, and the biological activity of structurally related or taxonomically related substances needs to be reconsidered in the screening process. In addition, comments were received stating that consideration should also be given to genotoxic data. One comment mentioned that genotoxic data should be weighed differently from data about structure-activity relationships and should be considered sooner in the process. It was also mentioned that more emphasis should also be placed on biological activity in the key factors. Finally, several comments suggested that more guiding principles describing the appropriate weighing of evidence needed to be outlined in the report. Process-Related Comments The comments received relating to the evaluation process outlined in the draft framework are summarized below. General Comments A few of the comments received recommended that the framework process should be initiated by having experts develop a priority list. Comments also criticized the “other concerns” screening category. Some stakeholders were concerned that this category would allow unsubstantiated expressions of concern or letters of concern to trigger a critical safety evaluation. It was also recommended that the first step in evaluating safety should be to determine if there is an imminent danger that requires immediate action or a limitation on use.

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Dietary Supplements: A Framework for Evaluating Safety Industry stakeholders suggested that industry input should be sought earlier in the evaluative process and that this process should be transparent. Some comments expressed concerns that the proposed framework would not be cost-effective for FDA to implement. In addition, comments were made suggesting that more discussion is needed on how the other approaches used to evaluate the safety of dietary supplements are or are not applicable in the proposed framework. One comment stated that, while a good description of other approaches on the safety of botanicals was given, little attention was given to approaches used for vitamins, minerals, and other nutritional ingredients. Prioritization Scoring System Comments about the sorting matrix used in the priority-setting process to categorize ingredients are described below. Concerns were raised over the complexity of the scoring system and whether FDA has enough resources to implement the proposed system. A few stakeholders expressed concerns that the quantitative nature of the scoring system may give the false impression of numerical precision. Furthermore, several industry stakeholders were concerned that the numerical scoring system for prioritization may be misused in legal cases against manufacturers. It was also mentioned that the scoring criteria needed to be more clearly defined in the report to reduce subjectivity and variability. Monographs Comments were made suggesting that more guiding principles on how to develop the monographs are needed. It was also suggested that the monographs should be considered to be in “draft” form until public input can be made. One industry stakeholder suggested that FDA and not the advisory committee described in the report should develop conclusions for the monographs. It was suggested that FDA should base its conclusions on the advisory committee’s recommendations about the data. Comments were also expressed over the extensive nature of the draft prototype monographs developed as part of this document. Some questioned whether FDA has the resources to develop monographs that are as extensive as the examples developed. Expertise Needed Several comments were received indicating that particular expertises needed to be added to the suggestions for who should be included in an

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Dietary Supplements: A Framework for Evaluating Safety expert committee. It was suggested that a representative for consumers and an expert on evidence-based analysis be included in the advisory group. It was also suggested that pharmacognosists and others with experience with botanical products also be included. Regulatory Situation of Dietary Supplements Several comments received applied more to the appropriateness of the current regulatory situation that to the report itself, an issue that the committee did not specifically address in the first report. Comments were received stating that the risks and benefits of dietary supplements should be considered in evaluating the safety of dietary supplements. A few comments were also received questioning whether FDA had the legal authority under the Dietary Supplement Health Education Act to develop monographs on dietary supplements and whether the study commissioned is scientifically valid. One comment was also received suggesting that the description for the 75-day advanced notice for new dietary supplements should be compared with the self-declaration of “generally recognized as safe” used for conventional food ingredients. Testing the Framework A few comments called for a description on how the six supplements chosen for monograph development as part of this report came through each of the steps of the proposed framework.