6
Framework Step Three: Critical Safety Evaluation of Dietary Supplement Ingredients

The screening/flagging and priority-setting steps outlined in the previous chapters will result in the identification of a group of dietary supplement ingredients that are of highest priority for further evaluation. This further evaluation requires the collection of additional information and critical analysis of the available safety data by the Food and Drug Administration (FDA) (Step 3 A), and then, if appropriate, analysis by an advisory committee (Step 3B). The process for this evaluation is described in this chapter. As with the two earlier steps of the process, these two steps may be organized by FDA or contracted out to an appropriate scientifically based organization.

STEP 3A: DRAFT MONOGRAPH PREPARATION AND REVIEW BY THE FOOD AND DRUG ADMINISTRATION

Step 3 A includes the preparation of a draft monograph and review of this monograph by FDA to determine if further input should be solicited. It is assumed that resources will initially be allocated to preparing monographs for substances ranked as higher priority in Step Two.

The process for Step 3A begins with completing the data collection (see Figure 3–1). Data will already have been obtained during the priority-setting step, but efforts should now be expanded to more comprehensively and systematically search for relevant information. The general types of information to be collected are listed in Box 6-1 (the monograph format) and include a description of the ingredient (e.g., constituents, different types of preparations, active components, traditional indications) and available information about toxicities and safety (human data, animal data, data describing the biological activity of structurally related or taxonomically related substances, in vitro data, and questions raised about the safety of the ingredient). Table 4–1 in Chapter 4 describes resources to be consulted in gathering safety information for this step, but this description is not exhaustive. For example,’ additional information may be obtained by requesting information from clinical investigators who have published reports about the particular ingredient. Additional information may also be obtained from industry (e.g., distributors and manufacturers). At this stage in the review, there is sufficient concern about the safety of the ingredient to justify FDA’s requesting that more safety data information be volunteered by industry. This request may be made through notice in the Federal Register and through the FDA website as a means to make the need for more information widely known to the



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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements 6 Framework Step Three: Critical Safety Evaluation of Dietary Supplement Ingredients The screening/flagging and priority-setting steps outlined in the previous chapters will result in the identification of a group of dietary supplement ingredients that are of highest priority for further evaluation. This further evaluation requires the collection of additional information and critical analysis of the available safety data by the Food and Drug Administration (FDA) (Step 3 A), and then, if appropriate, analysis by an advisory committee (Step 3B). The process for this evaluation is described in this chapter. As with the two earlier steps of the process, these two steps may be organized by FDA or contracted out to an appropriate scientifically based organization. STEP 3A: DRAFT MONOGRAPH PREPARATION AND REVIEW BY THE FOOD AND DRUG ADMINISTRATION Step 3 A includes the preparation of a draft monograph and review of this monograph by FDA to determine if further input should be solicited. It is assumed that resources will initially be allocated to preparing monographs for substances ranked as higher priority in Step Two. The process for Step 3A begins with completing the data collection (see Figure 3–1). Data will already have been obtained during the priority-setting step, but efforts should now be expanded to more comprehensively and systematically search for relevant information. The general types of information to be collected are listed in Box 6-1 (the monograph format) and include a description of the ingredient (e.g., constituents, different types of preparations, active components, traditional indications) and available information about toxicities and safety (human data, animal data, data describing the biological activity of structurally related or taxonomically related substances, in vitro data, and questions raised about the safety of the ingredient). Table 4–1 in Chapter 4 describes resources to be consulted in gathering safety information for this step, but this description is not exhaustive. For example,’ additional information may be obtained by requesting information from clinical investigators who have published reports about the particular ingredient. Additional information may also be obtained from industry (e.g., distributors and manufacturers). At this stage in the review, there is sufficient concern about the safety of the ingredient to justify FDA’s requesting that more safety data information be volunteered by industry. This request may be made through notice in the Federal Register and through the FDA website as a means to make the need for more information widely known to the

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements BOX 6–1 Safety Review: Monograph Format INGREDIENT NAME DESCRIPTION OF THE INGREDIENT, which includes the following: Constituents as appropriate: chemical structure; for a botanical ingredient, genus, species, part of plant Examples of products known to contain the ingredient Descriptions of different preparations (include U.S. Pharmacopeia process if available; country of origin, if known) Range of typical intake levels (where known, this will include recommended intake levels and data on actual intake) Description of active components, if known Traditional indications, if applicable Claim (label or other marketing information) Usage patterns (prevalence of use in the general population, use by vulnerable groups, use in combination with other ingredients) AVAILABLE SAFETY INFORMATION AND EVALUATION Human data (serious and nonserious adverse effects) Animal studies Biological activity of structurally related and taxonomically related substances In vitro studies RESEARCH NEEDS CONCLUSIONS Unresolved issues and uncertainties in the available data Recommendations and conclusions about the safety of the ingredient, based on the strength of the scientific evidence CITATIONS (including citations and hard copies of references used) public. FDA should also directly request information from the manufacturers and distributors of the ingredient under consideration to the extent that manufacturers and distributors are known. The collected information should be collated into a “draft dietary supplement ingredient safety review monograph,” or simply “draft monograph.” The monograph should be prepared using a standard format to summarize all the data collected on the ingredient (see Box 6-1 for an outline of the monograph structure). After the draft monograph is prepared, FDA should consider the totality of the scientific evidence obtained. FDA should decide, based on the weight of the evidence, if the evidence is sufficiently clear to allow the product to remain on the market or if it is sufficiently clear to take action to limit marketing the ingredient. The guiding principles in Box 6-2, summarized from Chapter 4, should be followed for assessing and weighting the different types of evidence that enter into the decision.

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements BOX 6–2 Guiding Principles for Considering the Relative Value of Different Types of Information A credible report of a serious adverse event in humans that is associated with use of a dietary supplement ingredient raises concern about the ingredient’s safety and requires further information gathering and evaluation. A final judgment about the safety of the supplement ingredient, however, will require consideration of the totality of the evidence. Historical use should not be used as prima facie evidence that the ingredient does not cause harm. It may be appropriate, however, to give considerable weight to a lack of adverse events in large, high-quality, randomized clinical trials or retrospective or prospective cohort studies that are adequately powered and designed to detect adverse effects. The rationale for this statement is that adverse events might only be detected if readily apparent or specifically searched for. A study that does not systematically examine participants for adverse events and then publish this information is therefore of little value. In addition, some studies have insufficient statistical power to detect adverse events of low incidence. 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), the formulation is similar, and more than one species shows the same toxicity. Particular weight is placed on evidence of certain types of delayed effects that are less likely to be detected in humans; these effects include cancer, teratogenicity, developmental toxicity, and reproductive toxicity. This evidence warrants particular attention as these nonacute effects are often only detectable in animals (as opposed to humans) because large doses can be administered subchronically or chronically to predict delayed effects following chronic exposure in humans. The presence of a constituent that is structurally similar to known toxic or potentially harmful compounds or a plant that is taxonomically related to known toxic plants suggests increased risk, and therefore higher priority, unless there is evidence that the compound is not toxic or harmful, the compound is present in concentrations that will not lead to harm, or there is other evidence supporting the safety of the ingredient. In vitro studies can serve as signals of potential harmful effects in humans, but not as independent indicators of risk unless an ingredient causes an effect that has been associated with harmful effects in animals or humans and there is evidence that the ingredient or its metabolites are present at physiological sites where they could cause harm. Alone, in vitro data should serve only as hypotheses generators and as indicators of possible mechanisms of harm when the totality of the data from the different factors is considered. After considering the draft monograph and the totality of the evidence in the context of the guiding principles outlined above, FDA should either make a decision to take regulatory action, not to take regulatory action, or to refer the dietary supplement ingredient to an advisory committee of multidisciplinary experts for a safety review. Because only high-priority ingredients with significant potential for concern are likely to reach this evaluation stage, it is expected that FDA may want further input from an advisory committee on a number of dietary supplement ingredients.

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements STEP 3B: CRITICAL EVALUATION BY AN EXTERNAL ADVISORY COMMITTEE Unless FDA has 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. FDA may choose to have external advisors participate for one of a myriad of reasons, including, There is credible evidence that the ingredient may cause harm, but further review is needed by consultants with specific knowledge about the ingredient to interpret the totality of the data and derive conclusions and recommendations. Available evidence is of questionable scientific basis or difficult to interpret. Insufficient data are available to make decision-making obvious. A mechanism for public input is needed. These reasons are only examples, as many other circumstances may trigger the decision for external advisory committee review. The decision to refer a dietary supplement ingredient to an external advisory committee rests with FDA and may be made for any reason that external expert opinion is deemed necessary or cost effective. The external advisory committee opinions or conclusions should be based on the information and data presented, but the decision on the regulatory consequences of the external advisory committee determinations must rest with FDA. The decision to refer an ingredient for external review requires that a standing external advisory committee be established. To ensure that the critical evaluation of the monograph and related information is as free of conflict of interest and as objective as possible, the external advisory committee should be composed of expert scientists who, by training, education, and experience, constitute the most appropriate body to advise FDA. Box 6-3 lists several types of expertise that should be included. Importantly, external advisory committee members should be selected based on their disciplinary expertise rather than as representatives of stakeholder viewpoints. Advisory committee members should not have a financial stake in the outcome of the process or otherwise have a real or perceived conflict of interest. The external advisory committee should explicitly exclude representatives of the dietary supplement industry and its trade organizations. It is assumed that the organization assembling the external advisory committee will use standard practices to identify and avoid other types of conflict of interest as well. The composition of the external advisory committee needs to include expertise in critical key disciplines, but still be small enough to be effective. One approach would be to have the external advisory committee be a standing committee of about seven persons, with the option to add one or two scientists with special expertise as needed for the review of individual substances. A second option would be to have a standing committee of five scientists representing the core disciplines, and the addition of three or four special experts depending on the nature of the substance and/or the data to be evaluated. After the external advisory committee is assembled, it will assume responsibility for further refining the monograph drafted by FDA or the contractor. At this point, 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 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.

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements BOX 6–3 Advisory Committee Expertise The Advisory Committee, either one constituted by FDA or by contracting with a scientifically based, nonprofit organization, should include individuals with the following expertise: toxicology, preferably with expertise in safety evaluation pharmacognosy clinical pharmacology nutritional science epidemiology biostatistics clinical trials medicinal chemistry and structure-activity relationships bioavailability pharmacokinetics consumer behavior related to dietary supplement use public health ad hoc consultants with expertise in specific fields on an as-needed basis (e.g., specialists needed to evaluate particular ingredients such as experts on oriental medicine, herbalists, clinicians with relevant experience). After reviewing the information collected in the draft monograph and in the public information sessions, the external advisory committee should revise the draft monograph as needed to create as complete a picture of the scientific information available on safety as possible within the resources available to FDA. The advisory committee should evaluate this information and reach conclusions where possible, describing what is known about the safety of the ingredient based on the weight of the scientific evidence. The conclusions should describe the relevance of the evidence; the seriousness of the potential harm suggested by the evidence; and the quality and quantity of the evidence. The advisory committee’s conclusions should include comments about the risks and hazards that may be associated with use by the general population, as well as risks that may be particular to subgroups of the population. As much as possible, the advisory committee should describe how its conclusions may be dependent on how the ingredient is used—that is, the dose, manner, and form. The advisory committee may conclude that there is little or no substantial evidence within the available information to suspect a hazard to the public when the ingredient is used at the recommended levels on the label, or at levels that might reasonably be expected. If current use does not demonstrate a hazard, the advisory committee may decide to comment on if it is possible to foresee whether a significant increase in consumption would constitute a hazard. If there is not enough information available to conduct a scientific evaluation of the safety of the dietary supplement, the advisory committee should indicate this. All conclusions should also be

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements accompanied by a description of additional research needed. If uncertainties exist that could be addressed by further study, the advisory committee should identify in detail what the uncertainties are and what types of studies could help resolve them. After the advisory committee’s conclusions are shared with FDA, the revised monograph and the advisory committee’s conclusions should be posted on FDA’s website. One of the important components of the Dietary Supplement Health and Education Act of 1994 was that the public should be educated about dietary supplements. FDA thus has a responsibility to educate consumers about the safety of supplement ingredients, and the public availability of the revised monographs can be an important aspect of the educational process. The monographs will provide the public with a reputable summary of the available information and scientific uncertainties about the inherent safety of the supplement ingredient. Importantly, public access to information from an advisory committee that is free of direct conflicts of interest will add to the quality and quantity of the available scientific literature. An added benefit of making monographs easily available to the public is that industry and publicly funded scientists may choose to conduct studies that address the concerns raised, increasing the knowledge base of dietary supplement safety. 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, even if FDA decides not to take action. The monographs developed should not be considered static documents. New information should be added as it becomes available, and an organized process for adding information should be developed. The process should also include periodic reviews of monographs to determine if additional external reviews are appropriate. OVERSIGHT OF MONOGRAPH PREPARATION AND REVIEW Preparation of Draft Monographs Collecting descriptive and safety information and organizing and summarizing the information into a draft safety monograph will require significant expertise and resources. Time and other resources required to complete the draft monographs are likely to vary, as some draft monographs will be extensive and others will be brief, depending largely on the amount of relative safety information available for the dietary supplement ingredient being considered. FDA may choose to prepare monographs internally, or it may choose to contract the work out to organizations, individuals, or both. There are a number of academic, nonprofit, and for-profit organizations that have the resident expertise and administrative abilities to prepare monographs as directed by FDA. It is also possible that unbiased individuals without conflicts of interest could be identified to prepare draft monographs, but organizations are probably a more objective resource for monograph preparation. In addition, if FDA aims to obtain as many monographs as possible in the shortest timeframe acceptable, organizations rather than individuals may be more qualified. 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 screen, set priorities, and then develop a complete list of substances warranting monographs first. Alternatively, FDA could retain one or more individuals or groups to develop monographs and determine the need for individual monographs on an ongoing basis as priority setting proceeds or as new needs emerge. The former approach may be more cost effective to implement, given that the latter

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements approach might not provide continuity in workload. However, preparing a list of priority substances to be monographed under contract will require more resources up front and will be dependent on information available at the time the list is prepared. Assuming that draft monographs are prepared under contract, FDA may choose to directly monitor the monograph preparation done by individuals. Otherwise, it may choose to contract with an outside organization to administer and manage the monograph preparation process. The first approach involves direct control of the activities of the individuals preparing the monographs by FDA staff monitoring the contract deliverables, while the second delegates that responsibility to an outside organization. Depending upon the type and expertise of the contracting organization, it is possible that additional aspects of the critical evaluation step could be carried out by the organization. The critical safety evaluation process described in this chapter includes provision for additional data and input to be provided by industry and other stakeholders. Typically, this input process involves announcement of the request for data and information, submission of written materials, and oral testimony at a public meeting. If FDA contracts with organizations that do not have the capability to conduct such activities, FDA would have to undertake these information gathering and collation activities itself for the contracting organization. However, if FDA contracts with an external scientifically based, nonprofit organization, this organization could administer and manage the monograph preparation process with the assistance of one or more individuals whose sole responsibility would be monograph preparation. This organization would conduct the public information gathering process, and monitor the preparation, publication, and dissemination of the draft monographs for review and submittal to FDA. Additional advantages of this approach include relieving FDA of administrative management and increased public assurance that the draft monograph is as complete and as objective as possible. In addition, if FDA first develops an extensive list of substances warranting monographs, contracting with an external scientific organization would be an efficient method of managing the entire process and the simultaneous development of several monographs; such processes have been employed in the past. The disadvantages of this tiered approach include the necessity for fiscal resources from FDA to support the ongoing administrative and monograph preparation processes. However, the absence of direct governmental control of the information gathering and expert evaluation process suggests this latter approach should be given serious consideration. Management of the External Advisory Committee As discussed above, FDA should consider each draft monograph developed either internally or by a scientifically based organization and decide if additional expert opinion would be helpful in evaluating the evidence. Therefore, in addition to determining who will be responsible for preparing draft monographs, FDA will also need to decide whether to establish or contract to have established an external advisory committee to develop conclusions and research needs and provide further input on the draft monograph. If an external, as opposed to internal (i.e., made up of FDA scientists with appropriate backgrounds), advisory committee is established, several options for administrative management of the external advisory committee could be considered. One option is for the external advisory committee to be a standing subcommittee of the Center for Food Safety and Applied Nutrition’s existing Dietary Supplements Committee, which is itself a subcommittee of the Food Advisory Committee. As such, external advisory committee members would be aware of ongoing issues of

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements wider interest regarding dietary supplements. However, the affiliations of persons on the Dietary Supplements Committee might make this approach difficult to carry out while assembling a group as free as possible from conflicts of interest. Time commitment might be a consideration in whether to include one or more members of the Dietary Supplement Committee. To be effective over time, the external advisory committee members should anticipate tenure of at least three years with at least four meetings per year. Administratively, the external advisory committee might have a workload analogous to the former Life Sciences Research Office Select Committee on GRAS Substances or a National Institutes of Health Study Section. Another option is for the external advisory committee to be either a free-standing entity or to be an activity conducted by an external scientific organization under contract to FDA. If the external advisory committee were a free-standing entity that is disassociated from the monograph preparation process, there would be an increased burden of cost for its management. If the external advisory committee management and the monograph preparation are subsumed under one contract with a nonprofit, scientifically based organization, then administration and management might be less costly and have greater continuity. One advantage of separating management of the external advisory committee from FDA is that this approach would provide greater assurance to the public of the external advisory committee’s independence and objectivity. The proposed process regarding development of the draft monograph and public input does not include consensus conclusions, but if FDA determines that consensus conclusions about the safety of dietary supplement ingredients are necessary, then there are additional advantages to contracting with an outside organization to facilitate the development of them. In this case, it would be necessary to identify an organization that has adequately experienced and knowledgeable scientific and administrative staff to manage both the monograph preparation process and the conduct of objective scientific evaluations. A limited number of scientific organizations have the capabilities to meet the administrative, managerial, and scientific requirements required for this approach. SUMMARY In summary, this chapter outlines a system for preparing monographs and conducting reviews of dietary supplement ingredient safety. FDA or a contractor of FDA would prepare the initial draft monograph that is a collection and review of available safety information. FDA would then determine whether additional input to the draft monograph would be helpful. If the data are not sufficiently clear for FDA to make a decision about whether to take action, or for any other reason, an advisory committee could be requested to review the information. An external advisory committee could be established to accomplish this task. The external advisory committee would review the draft monograph, determine if additional information should be collected, and hold sessions for input from the public. It would then modify the draft monograph as appropriate and make conclusions based on the evidence. The revised monograph, along with the external advisory committee conclusions, would be made public in an easily accessible format.