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5 Framework to Review the Safety of Dietary Supplements for Use by Military Personnel BACKGROUND The increasing popularity of dietary supplements among civilians and military personnel has raised questions about their safety and efficacy for both populations. In the United States, various government agencies are charged with ensuring the safety of consumable products by developing and implementing policy according to their legal authority. In the United States, decisions regarding the safety of ingested substances are made using three models, based on the nature and intended use of each substance. The basic models are the food model (based on the assumption, derived from historic consumption, that all foods are safe and therefore, no premarket safety as- sessment is necessary), the food additive model (based on premarket safety assessments submitted to the U.S. Food and Drug Administration [FDA] by manufacturers), and the drug model (based on risk-benefit assessments submitted to the FDA by manufacturers). The Dietary Supplement Health and Education Act (DSHEA) of 1994 designated the FDA as the agency responsible for determining whether a marketed dietary supplement is unsafe (Dietary Supplement Health and Education Act of 1994, Public Law 103-417, 108 Stat 4325, 103rd Con- gress, October 25, 1994). The unique nature of dietary supplements (i.e., they are legally categorized as foods but are used to enhance health) and their history of use (i.e., some have been used as medicines for centuries by other cultures) have resulted in difficulty and confusion in establishing and implementing policies to address their safety. Despite wide concur- rence that, given the nature of these products, a premarket approval pro- 296
FRAMEWORK TO REVIEW THE SAFETY 297 cess would be appropriate to address their safety, there is no such process in place. While DSHEA mandates that manufacturers wishing to market new dietary supplement ingredients inform the FDA of their intention, this notificaÂtion is often not accompanied by a safety profile of the product. The FDA relies on a postmarket adverse event surveillance system to monitor adverse effects and, along with other supporting scientific data, to take action against any dietary supplement identified as unsafe after it has been marketed. However, the voluntary nature of reports by consumers or others to the FDA presents important limitations, such as low reporting rate or poor data quality (see Chapter 6). The 2007 Dietary Supplement and Nonprescription Drug Consumer Protection Act represents a step for- ward in ensuring safety by mandating that companies report to the FDA any serious adverse event derived from the use of dietary supplements, but the success of this act in establishing an effective signaling system to identify supplement ingredients particularly in need of safety evaluation is still unknown. The act defines the term serious adverse event as an adverse event that (A) results in (i) death; (ii) a life-threatening experience; (iii) inpatient hospitalization; (iv) a persistent or significant disability or incapacity; (v) a congenital anomaly or birth defect; or (B) requires, based on reasonable medical judgment, a medical or surgical intervention to prevent a previ- ously listed outcome described under subparagraph (A). Also, in 2007, the FDA published the final rule, stipulated under DSHEA, establishing the minimum current good manufacturing practices (cGMPs) required for activities related to manufacturing, packaging, la- beling, and storing dietary supplements to ensure their quality. This rule ensures consistency in product composition, but not the safety or efficacy of that product. The FDA is empowered to initiate regulatory action (e.g., banning a dietary supplement, taking an enforcement action [e.g., seizure or injunction] against a product or firm, or alerting the public) when the agency has evidence a product violates a provision of the Federal Food, Drug, and Cosmetic Act (FFD&C Act). Evidence that a product may be unsafe could include postmarket reports of severe adverse events, reports in the scientific literature of harm associated with exposure to a particular product or ingredient, or evidence of the presence of an adulterant such as an unforeseen contaminant or a purposeful adulterant. In light of the growing use of dietary supplements, the FDA requested in 2002 that the Institute of Medicine (IOM) provide a process or frame- work for evaluating the safety of dietary supplement ingredients. Highlights of the IOM report Dietary Supplements: A Framework for Evaluating Safety (2005) were presented at the February 2007 workshop (see Jeffery in Appendix B).
298 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL The 2005 IOM report recognizes that the potential for a significant or unreasonable risk resulting from consumption of a dietary supplement var- ies depending on the specific circumstances of its use (e.g., under tempera- ture extremes) or for specific populations (e.g., military personnel; see also Chapter 9 of the 2005 IOM report for a discussion of vulnerable groups). Thus, a vulnerable group may be at far greater risk from adverse effects of a given supplement than the general public. An example would be persons operating motor vehicles, who should not take sedative supplements such as valerian. Because neither federal dietary supplement policies nor the safety framework outlined in the 2005 IOM report was created with the specific needs (e.g., unique policies, behaviors, environmental stresses, and performance requirements) of the military population in mind, the U.S. Department of Defense (DoD) requested that this committee assess the applicability of the 2005 IOM report framework to a military setting and establish how it could be modified to determine which supplements need active management by the military. The committee concluded that the 2005 IOM reportâs framework for the general population is not directly applicable to military personnel for reasons that include the militaryâs need for optimal health and performance as well as the high demands for readiness and success in military operations. Benefits and/or risks to military personnel from use of a particular dietary supplement might also differ from those of the general population owing to specific unit missions and environments; for example, the thermoregulatory effects of some dietary supplements could be critical for military person- nel operating in extreme temperatures, while they would be less important for the general population or for military personnel deployed to a more temperate area. Some groups of military personnel might experience risks and benefits from the use of dietary supplements different from those of other military personnel because of their unique responsibilities and tasks (e.g., aviators, those with access to nuclear weapons, or those conducting special operations). The U.S. regulatory model to manage the use of dietary supplements may also be inadequate for certain military populations (see Chapter 1, Box 1-3). For example, because of the potentially life-threatening consequences of being in suboptimal mental or physical health while conducting military operations, military leadership might need to develop an active monitoring system, rather than basing decisions only on the passive system of volun- tarily reported adverse events now in use (see Chapter 6). Furthermore, the potential gains in health or performance from the use of some dietary supplements need to be considered in managing their use. For instance, if dietary supplement X causes slight dehydration but substantially improves alertness, the management of X by military leadership might be different
FRAMEWORK TO REVIEW THE SAFETY 299 from that of dietary supplement Y, which induces a similar level of dehydra- tion but imparts little benefit. To summarize, this IOM committee was asked to review the 2005 IOM reportâs framework for evaluating the safety of dietary supplements and assess whether modifications are necessary for its application to the military. This chapter does not enumerate the specific series of in vitro and in vivo toxicological and clinical tests that would be required to evaluate the safety of a dietary ingredient; these will vary with the specific ingredient(s), the users, and other factors. Instead, the chapter includes a framework to review the available scientific evidence and determine the level of concern; this is to be used as a tool to help military decision makers establish poli- cies on the use of dietary supplements. In contrast to the 2005 IOM report framework, whichâin accordance with the FDAâs mandateâfocused only on safety, this committee has provided general guidance for the military on integrating considerations of efficacy and safety when making policy on dietary supplement use. The development of a framework to perform a complete risk-benefit analysis is beyond the scope of this report. It is also beyond the scope of this report to recommend definitive management actions. Examples are provided of possible actions (e.g., restricting or recommending the use of specific dietary supplements, developing educational programs) based on the level of concern (and the potential for benefit). To demonstrate applica- tion of the framework recommended, the committee reviewed a number of dietary supplements on the basis of published safety and efficacy reports (see Chapters 3 and 4) and identified those that might pose concerns or be of benefit. In addition, the committeeâs overall approach (i.e., including application of the framework and recommendations for action) was ap- plied to a subset of those dietary supplements (Appendix D); it was outside the committeeâs task to provide a review of all dietary supplements. These monographs and case studies should be considered as examples; as recom- mended below, determining the specific actions to take in response to a di- etary supplement review should be the prerogative of military leadership. SAFETY FRAMEWORK FOR DIETARY SUPPLEMENTS: MODIFICATIONS FOR MILITARY USE The committeeâs recommended approach to manage the use of dietary supplements in a military context comprises four related components: (1) improving monitoring of the use of dietary supplements by military per- sonnel, (2) using a framework to determine the level of concern for dietary supplements in a military context, (3) implementing a system to report
300 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL adverse events associated with dietary supplements, and (4) expanding education on dietary supplements. This section describes the second component, that is, elements of the safety framework outlined in the 2005 IOM report that are particularly use- ful to the military in its need to understand the safety (and possible benefits) of the use of dietary supplements by military personnel. (For greater detail on the regulatory background and the statement of task of the 2005 IOM Committee on the Framework for Evaluating the Safety of Dietary Supple- ments, see Jeffery in Appendix B.) The 2005 IOM report framework consists of a process for prioritizing, evaluating, and describing available information to establish risk of harm, together with a second, supportive component: a set of science-based princi- ples that serve as guidelines for evaluating risk to human health (see ÂJeffery, Figure B-24, in Appendix B). It characterizes the nature of the scientific evidence that is likely to be available to the FDA and describes a process for organizing this evidence to assess the level of concern for a dietary supple- ment ingredient. A âsignificant or unreasonable risk of illness or injuryâ is the standard that warrants regulation by the FDA under the FFD&C Act, as amended by DSHEA. The process outlined in the 2005 IOM report is divided into three steps: signal detection, initial signal review to determine a preliminary level of concern, and integrated safety evaluation of dietary supplements. This process provides a basis for determining whether a di- etary supplement is unsafe and for translating a serious concern into safety management actions. For example, a high level of initial concern based on a signal that leads to a high potential for a âsignificant or unreasonable risk of illness or injuryâ warrants a full evaluation of safety. Proving that a dietary supplement presents an unreasonable risk is a substantial undertaking requiring valuable time and resources. The FDA, which bears responsibility for the safety of all dietary supplements on the market, is presently limited to responding to reports of serious adverse events as the primary signal for action. The DoD could take a more proac- tive stance, choosing to evaluate the effects of a dietary supplement and take management actions based on criteria pertinent to the demands of military service. Thus, the military may choose to focus attention on determining the safety of those dietary supplements with the highest volume of sales, even if there have been no adverse events reported for the general population. Furthermore, the scientific basis for concern may be more stringent and may include evidence of more subtle effects than those causing concern for the general public. For these reasons, the 2005 IOM report framework has been adapted to meet the specific needs of the military. Described below are the three steps (i.e., signal detection, initial review of signals, and integrated safety evaluation) described in the 2005 IOM report, followed by their adaptation for the military.
FRAMEWORK TO REVIEW THE SAFETY 301 Signal Detection The 2005 IOM Safety Framework for Dietary Supplements: Adverse Event Monitoring The 2005 IOM report suggested that, given the limited resources avail- able to the FDA, a supplement should undergo a safety review only when the signal of a serious adverse event indicates the need. However, should resources permit, it was proposed that the FDAâs attention should focus on signals that indicate a serious health problem may result from ingestion of a dietary supplement ingredient. The 2005 IOM report framework suggested that if the FDA were able to operate proactively, review of a dietary supplement ingredient should be initiated on the basis of either a high prevalence of use in the general popu- lation, or a high level of use by a particularly vulnerable population. As Modified for the Military: Adverse Events and Frequency of Use Monitoring The military should proactively concern itself not only with dietary supplements associated with an adverse event but also with those most commonly sold on base, and with consideration for the safety of those military personnel who, because of their duties, would be particularly vul- nerable to the adverse effects of specific supplements. For example, pilots might be susceptible to effects including hypoxia, cognitive decrements, or loss of spatial orientation. Similarly, those on active duty in adverse environments might be particularly vulnerable to supplements causing loss of thermal regulation (see Chapter 1, Box 1-3 for a list of special military populations). Conversely, if there were supplements that could aid in pre- vention of these adverse effects, this information might be of considerable benefit to the military. Initial Review of Signals The 2005 IOM Safety Framework for Dietary Supplements: Severity of Adverse Events The second step in the process outlined in the 2005 IOM framework is the initial review of available information on the signal (i.e., adverse event reports). First, the nature of the signal information is examined to determine the preliminary level (low, moderate, or high) of concern about a potential risk to human health. This is not a detailed analysis of data, but rather an assessment to determine whether further evaluation of the
302 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL supplement is indicated. If review of the reports shows an isolated case lacking reliable evidence that the supplement was likely to be a cause, the resulting low level of concern would indicate no further need for action at that time. If signal review results in even a moderate level of concern traced directly to the supplement, then other criteria, such as prevalence of use or potential to adversely affect vulnerable subpopulations, should be considered, which might result in elevation of the signal concern level to high. Signal review would typically be triggered by an adverse event report of medium or high concern. As Modified for the Military: Severity of Adverse Events and Frequency of Use Recommendation 4:â The decision to initiate a review of a dietary supplement should be based on two criteria: severity and number of adverse events, and prevalence of use. The selection of dietary supple- ments for review should consider the particular vulnerabilities of the military subpopulations, which would depend on their missions and mission environments. Severity and number of adverse eventsâ As with the general population, one set of criteria relies on adverse event(s) reported by military or nonmili- tary personnel. (See Chapter 6 for recommendations on a system to monitor adverse events for the military.) Military health care professionals should identify any adverse events associated with dietary supplement use that might compromise the perfor- mance or survivability of military personnel. Such adverse events would include those that affect vigilance; have a significant adverse impact on alertness, mood, or cognitive performance; cause hypoxia; or affect bal- ance or spatial orientation. They would also include impairment of clot- ting, hydration, immune function, or thermoregulation. Conditions to help categorize adverse events as high, moderate, low, and minimal are listed in Box 5-1. Summaries of adverse event reports should be submitted to the military committee or entity designated to oversee dietary supplements (herein referred to as the designated oversight committee; see Chapter 6), who will identify a signal of concern for a dietary supplement and deter- mine whether a review is appropriate. When the adverse event reported is serious or might compromise per- formance or survivability, the committee proposes a two-part response. The first step is to determine whether urgent action (e.g., new policies; see Figure 5-1) is warranted. Second, in conjunction with policy implemention and enforcement, a safety and efficacy review should be conducted. Adverse events of moderate concern might not signal the need for new policy, al-
FRAMEWORK TO REVIEW THE SAFETY 303 though the military should initiate a safety review (Figure 5-1). If no adverse effects are being noted from the use of a specific supplement and its safety review reveals no concern, then the determination would be made that the dietary supplement is of minimal concern and no further evaluation would be needed. Nevertheless, due to low reporting rates of adverse events, the lack of such reports does not necessarily mean that the dietary supplement is safe. Further, the committee believes that because these products are bio- active, high frequency of use calls for a review of safety, unless the dietary supplement has already been declared to be of minimal concern. The committee cautions that the linking of an adverse event to a dietary supplement ingredient might be confounded if the product contains mul- tiple ingredients, or adulterants or adventitious contaminants. In the case of multiple ingredients, determination of causation for a particular substance requires careful review of all the individual ingredients in a product or the combination product itself. If contamination is the issue, then attribution of the source of the event is even more challenging. In either case, and until the cause of the adverse event is determined, the military might need to apply policies for the use of the suspect product as well as for any other product containing any of the ingredients found in the suspect product. Prevalence of useâ A second criterion to commence a review relies on a proactive initiative by military leadership in response to the use of a new supplement similar to a drug or supplement that has previously caused safety concerns (e.g., bitter orange contains synephrine, closely related to ephedrine, the active component in ephedra); the high frequency of use of a supplement; or an increase in frequency of use in the general military population or specific subpopulations. To make such decisions, data from dietary supplement sales and survey data on dietary supplement use within the military would be required (see Chapter 2). For example, the military should review data on sales of dietary supplements from outlets located on base (e.g., Army and Air Force Exchange Service/Navy Exchange Service [AAFES/NEX], fitness centers) annually to determine which supplements have become popular. Because of the low reporting rates for adverse events, the lack of data on adverse events does not necessarily show that a dietary supplement is safe. Also, because these products are bioactive, a review of the safety of widely used dietary supplements is warranted unless the dietary supplement has been declared to be of minimal concern. If no ad- â The 2007 Dietary Supplement and Nonprescription Drug Consumer Protection Act defines the term âserious adverse eventâ as an adverse event that (A) results in (i) death; (ii) a life- threatening experience; (iii) inpatient hospitalization; (iv) a persistent or significant disability or incapacity; (v) a congenital anomaly or birth defect; or (B) requires, based on reasonable medical judgment, a medical or surgical intervention to prevent a previously listed outcome described under subparagraph (A).
304 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL BOX 5-1 Description of Concern Levels Specific to Use of Dietary Supplements by Military Personnel High concern â¢ Human epidemiological studies or adverse effects signaling: Product has been found responsible for a serious adverse event Performance degradation (e.g., for those deployed, in training, or in combat settings): â Product significantly affects vigilance â Product has significant adverse impact on alertness/drowsiness, mood alteration, cognitive performance â Product significantly induces hypoxia â Product significantly affects balance and spatial orientation decrease in survivability (e.g., for those deployed, in training, or in combat A settings): â Product significantly inhibits clotting time â Product significantly promotes dehydration â Product significantly inhibits immune system â Product significantly disrupts bodyâs ability to maintain thermal regulation â¢ Animal data signaling: Serious adverse events as described above for human data, seen in ani- mals at doses 10Ã recommended exposure for humans Neoplasia Severe organ toxicity (necrosis/dysplasia) Reproductive failure/developmental effects Severe neurological/behavioral changes â¢ In vitro data signaling: Multiple different assays suggest the same pathological condition related to serious adverse events described for human data above Concentrations of the dietary supplement causing severe adverse effects in vitro are similar to reported blood or plasma levels in humans following consumption of this dietary supplement Chemical or plant species is similar to known toxic compound and/or banned dietary supplement, or similar to products having adverse effects described above in humans verse effects are noted from the use of a specific supplement and its safety review reveals no concern, then the determination would be made that the dietary supplement is of minimal concern and no further evaluation would be needed. Many factors need to be taken into consideration in determining a level of concern from adverse events reported, including the strength of the
FRAMEWORK TO REVIEW THE SAFETY 305 Moderate Concern â¢ Human epidemiological studies or adverse events signaling: Performance degradation (e.g., for those deployed, in training, or in combat): â Product has moderate impact on hydration, gastrointestinal function (e.g., diarrhea, nausea), thermal regulation, alertness/drowsiness, mood, or cognitive performance or may induce shortness of breath or syncope decrease in survivability (e.g., for those deployed, in training, or in A combat): â Product has moderate impact on clotting time â Product has moderate or low ability to inhibit immune system â¢ Animal data signaling: Moderate organ toxicity (atrophy, hyperplasia) Reduced reproductive capacity/mild developmental effects Altered clinical chemistry outside the reference range Those adverse effects listed above as serious in humans, occurring at 100Ã the recommended dose range Low Concern â¢ Human epidemiological studies or adverse events signaling: Performance degradation: â Product has low impact on hydration, gastrointestinal function (e.g., diarrhea, distress, nausea), alertness/drowsiness, thermal regulation, mood, or cognitive performance decrease in survivability (product has no known impact on immune No response or bleeding/clotting time) â¢ Animal data signaling: Reduced food intake Enzyme changes Reversible degenerative changes Minimal Concern â¢ Human epidemiological studies or adverse events signaling: serious adverse events No performance degradation (product has no known impact on hydration, No gastrointestinal function, thermal regulation, alertness/drowsiness, mood, or cognitive performance) decrease in survivability (product has no known impact on immune No response or bleeding/clotting time) evidence (e.g., how many adverse events were associated with the dietary supplements, the strength of the association, level of intake, intake of other medications or supplements, actual circumstances of use, characteristics of the individual user). The committee recommended that the evidence be reviewed and that the level of concern be determined by taking into consideration not only the the strength of the evidence but also the tasks
Signal Detection-Adverse Effects Proactive Initiative 306 Severe Adverse Effects Adverse Effects, Not Severe Safety Review A. Review of Safety Using B. Review of Original Research Pertaining to Specific Military C. Review of Interactions Reviews or Original Research if Concernsa with Medications Reviews Are Nonexistent Integrate Data from A, B, C and Decide on Level of Concern (See Box 5-1) High Concern Moderate Concern Low Concern Minimal Concern FIGURE 5-1â Framework to review the safety of dietary supplements. aHigh physical activity, calorie restriction, hydration, gastrointestinal tract (diarrhea/nausea), liver health/function (xenobiotic clearance), cardiovascular health, mood/behavior altering, alertness/drowsiness, extreme heat/cold, injury/bleeding. Figures S-1 and 5-1, R01214
FRAMEWORK TO REVIEW THE SAFETY 307 of the specific military subpopulation and the environment in which it will be conducting them (e.g., extreme temperatures or altitudes). As described further in Chapter 6, the designated oversight committee should review adverse events reported by the general population and by the military (as recorded in summaries submitted by the Medical Treatment Facilitiesâ [MTF] Pharmacy and Therapeutics [P&T] Committees), as well as surveys of supplement use by military personnel, on an annual basis. As a result of these examinations, the designated oversight committee might recommend to the military leadership immediate action and/or conducting a review of published, science-based safety reviews by the review panel. The designated oversight committee may call a special meeting or conference call if adverse events are serious or frequent, as judged by the MTF P&T Committees. Integrated Safety Evaluation 2005 IOM Framework: Integrated Safety Evaluation The third step of the 2005 IOM report framework is a fully integrated safety evaluation (conducted by a panel of experts) of those dietary supple- ment ingredients that warrant further investigation based on the concern level raised by initial signal review. There are four components to an inte- grative evaluation (Figure B-25 in Appendix B): in-depth search and review of literature, drafting of a safety monograph, integrating this informa- tion into an analysis to complete the monograph, and review of the draft monograph by an expert advisory committee. In accordance with the FDAâs designated function, the 2005 IOM report did not address any potential benefit of a dietary supplement. Safety reviews of dietary supplements can be performed at various levels, depending on factors such as urgency and the availability of hu- man and economic resources to conduct the review. The 2005 IOM report recommends that four categories of safety data be collected for evaluation following the detection of a signal: human data, animal data, data on related substances, and in vitro data. In conducting the safety review, the panel of experts would also consider possible interactions between a dietary supplement and medications or other xenobiotics. (Examples of mono- graphs and evidence models are available online at http://www.iom.edu/ CMS/3788/4605/19578.aspx.) A focused evaluation reviewing only one key ingredient or single area of concern such as cardiac health or renal health might also be appropriate. Both the comprehensive and the focused evalua- tion might include consultation with an expert committee, FDA personnel, or both, depending on the quality and clarity of the available data. The integration of the available data using evidence-based principles is the final exercise in establishing a risk level for the dietary supplement, using
308 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL a causal model diagram that integrates human, animal, in vitro, and even chemical information. Scientific principles for weighting and integrating data from these different categories were described in the 2005 IOM report (see also Jeffery, Box B-14, and Figures B-24 and B-25 in Appendix B). As Modified for the Military: Integrated Safety Evaluation Recommendation 5:â The military should use the framework (Fig- ure 5-1) to review the dietary supplements that raise safety concerns (per criteria above). The framework consists of the integrated evalu- ation of results from current, authoritative reviews (or, if no reviews are available, original research conducted over the previous 10 years) analyzing bioactivity and potential for drug interactions. Efforts to review and summarize information to determine the concern level about a dietary supplement should consider not only individual ad- BOX 5-2 Approach to Data Collection The committee developed the following process to characterize the concern level (and efficacy) of a dietary supplement used by military personnel: (1) identify the dietary supplement that warrants review, (2) conduct literature searches, and (3) summarize conclusions about safety (and efficacy). A proposed search process that is both cost-effective and valuable is summa- rized in Figure 5-2 as a stepwise decision-making tree. The committee believes that although an evidence-based review of original journal articles might provide a more comprehensive evaluation of safety, an evaluation from well-conducted, authoritative reviews could serve the purpose of alerting the military to potential problems (or benefits) and the need for active management. In evaluating the safety of dietary supplements, data are needed on two basic attributes: bioactivity (negative or positive) of the ingredients and effects derived from synergistic or antagonistic interactions with other active substances (i.e., in foods, medications, or other active substances). Bioactivity: Literature searches for systematic reviews of safety and efficacy of the dietary supplement of interest should be carried out in the appropriate data- bases (primarily PubMed, but also other databases [Napralert, Toxline, SciFinder, or other]). The focus should be on health concerns and unique environmental circumstances of military life. Some areas of particular interest to the military for safety (or efficacy) include specific conditions such as high level of physical activ- ity; restriction of caloric intake; high altitude; extreme heat or cold; health issues such as dehydration, function of gastrointestinal tract, immune, cardiovascular, biliary, or renal systems; and neurobehavioral health. Medical Subject Headings
FRAMEWORK TO REVIEW THE SAFETY 309 verse events reported but also integrate all other data pertinent to its safety. The scientific principles outlined for the FDA are expected to be used by the military to evaluate the data (see Box B-12 in Appendix B). For the integrated evaluation, the committee recommends an approach less expen- sive and time-consuming than the full evidence-based review described in the 2005 IOM report: an initial review of safety reviews authored by other reputable scientists (see Box 5-2). Evidence of the effect of interaction of dietary supplements with medications, focusing on medications frequently used by service members, should be taken into consideration. A military review panel should write a monograph for a dietary supplement that raises concerns (see models in Chapters 3 and 4). This review panel will be provided oversight by the U.S. Army Research Institute of Environmental Medicine, an Army medical research laboratory that investigates military nutrition issues. The review panel would include nutritionists, epidemiolo- gists, toxicologists, clinicians, and pharmacognosists. Although contracting performance of the reviews out to a nonmilitary group might be feasible, (MeSH) terms for the area of interest could help identify key search terms. Original research articles for safety (and efficacy) should be reviewed from the publication date of the last well-conducted review, or for the previous 10 years if no systematic reviews exist. Interactions with food, medications, or other bioactive substances: Data on interaction with other bioactive compounds are scarce. For identifying inter- action with medications, two online databases are particularly recommended: PubMed Plus and Clinical Pharmacology. If the dietary supplement of interest is not included, it may be necessary to search the complete listing of reviews for medication interactions. To enable this, a list should be created of the 100 medica- tions most frequently prescribed for active duty personnel, including mechanism of action and indications for use. This listing should be updated by the military on a regular basis, but initially at least annually. Some of the potential warnings against the use of dietary supplements in combination with medications would be apparent from this list (e.g., the committee cautions against the use of melatonin in combination with other sedative substances). Because of the severe lack of data in the area of interactions, the committee suggests that hypothetical effects from interactions should be based on mechanistic rationale. Likewise, in the absence of clinical data, animal or in vitro data or chemical similarity to ingredients with known interactions can provide suggestive information about potential interactions. Con- clusions from these latter approaches are uncertain though, as clinical research data have on occasion refuted initial speculations about synergistic effects. Once information is acquired on a potential interaction, further searches should be done specifically for possible interactive effects of the medication/dietary supplement combination, whether in review articles or original research and using the same databases as above.
310 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Review Process C. Review of Drug A. Review of Safety B. Specific Military Issues Interactions Search for reviews in Construct search terms such as Consult MedLine Plus or Clinical PubMed/other databases those footnoted on Figure 5-1 Pharmacology online Systematic Information No information review identified available Use these terms to search the systematic reviews No Yes Construct a list of Use drugs identified to Searching 10 years 100 most search the systematic prescribed reviews medications Searching articles since review date Construct using drug names where interactions are updated Integrate into a monograph FIGURE 5-2â Stepwise algorithm depicting search strategy to review the safety of dietary supplements. Figure 5-2, R01214 the safety and efficacy evaluation as it applies to military situations would be best conducted by a military review panel because they will be more cognizant of the demands and conditions unique to military operations and more experienced in identifying safety concerns relevant to military performance and survivability than a nonmilitary group. In special cases, this activity could be followed by a more compre- hensive safety review of original research, focused on performance and survivability as well as the particular health and environmental situations characteristic of military personnel. Some of these would be related to external situations (e.g., high-intensity physical activity, high altitude, tem- perature extremes) while some would reflect health concerns for individuals (e.g., injury or bleeding; dehydration; function of the gastrointestinal, im- mune, renal, hepatic, or cardiovascular system; altered behavior, alertness or drowsiness). This focused approach would not only shorten the length of time necessary for the review, but might also reduce the types of expertise required and ultimately result in information that is more useful. Original research from the time of the last review or, where current reviews are not available, original research conducted over the preceding 10 years, should
FRAMEWORK TO REVIEW THE SAFETY 311 also be surveyed. As a complement to database searches, a forum or coali- tion should be established to share data on adverse events and other infor- mation on dietary supplements (see Chapter 6). Once the reviews of the individual dietary supplement are concluded, the review panel should declare its level of concern. The committee devel- oped criteria on which to base the level of concern that use the same prin- ciples as the 2005 IOM framework but with a focus on survivability and performance issues (see Box 5-1). The concerns are classified from minimal to high, reflecting the level of performance degradation and survivability and taking into account the special circumstances (environment, hazards, stresses, and performance requirements) of concern to military personnel. If the data are insufficient to establish a level of concern, then the review panel could leave the review incomplete, awaiting further research on safety (and efficacy) or, depending upon the level of military concern, could request that the additional research be performed. It may or may not be appropriate for the military commander to recommend that the substance not be used by military personnel until the determination of concern level has been made. The committee recognizes that owing to the potential for synergistic or antagonistic effects among ingredients, there are important challenges to applying this framework to products with multiple ingredients. However, because of safety concerns derived from these supplements and ingredient interactions, the committeeâs approach should also be applied to them. Two approaches to determining level of concern are offered below. In addition, the committee recommends focusing attention on signals from adverse event reporting and data on military usage of these products. The committee did not provide a framework to evaluate efficacy; how- ever, information on efficacy should also be collected and included in the monograph, since the potential for benefits of a dietary supplement will be factored into the final level of concern. Decision to Take Action 2005 IOM Framework: A Safety Model for Decision Making The 2005 IOM report recommends that the results of the safety evalu- ation should play a pivotal role in the FDAâs determination of whether a supplement ingredient is unsafe. Furthermore, because an important com- ponent of DSHEA is public education about dietary supplements, it was anticipated that any monograph developed might be made publicly avail- able on the FDA website. Evidence that results in a high level of concern indicates the need for further investigation to determine whether a âsignificant or unreasonable
312 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL risk of disease or injuryâ (the FDA basis for action) exists. Conversely, the 2005 IOM report suggested that when review of information (either at the initial review stage or as a result of an integrated safety evaluation) indicates a lower level of concern, the FDA should continue to monitor information about the dietary supplement ingredient. Monitoring could consist of passively receiving new signals of concern and/or maintaining routine searches of the scientific literature to gather data about specific existing or new concerns. As Modified for the Military: Integrating Safety and Efficacy Recommendation 6:â The militaryâs decisions on dietary supplement policy (e.g., rules, education, monitoring of use) should be based on conclusions about both safety and efficacy derived from the available published, authoritative scientific literature and considering conditions associated with a specific type of mission, location, and environment. Although the development of a detailed process to establish a dietary supplementâs level of efficacy was not within the scope of the current task and this committee was not constituted to address the question of efficacy, the committee concluded that considerations of safety and efficacy should be integrated to make decisions about policy on the use of dietary supple- ments in a military context. A more general description of benefit levels (Table 5-1) was developed by the committee to classify present and future TABLE 5-1â Guide to Determine Level of Concern and Benefit to Formulate Decisions on Managing Dietary Supplement Use Among Military Personnel, Based on Science and Physiological Effects Level of Concern Level of Science Documenting an Concern or Benefit Specific to Military or Benefit Effect (Concern or Benefit) Mission for Subpopulation of Interest High High level of science (large number of High concern (or benefit) consistent high-quality studies) Moderate High level of science (large number of Moderate concern (or benefit) high-quality studies) Moderate level of science Moderate or high concern (or benefit) Low/ Any level of science Low, minimal, or no concern (or Minimal/ benefit) Uncertain
FRAMEWORK TO REVIEW THE SAFETY 313 dietary supplements by potential benefit. The determination of level of benefit is dependent on the number and quality of studies that demonstrate the benefit (or lack thereof) of interest to the military. It is advised that a road map to assess benefits be developed, similar to the framework for safety evaluation. Because the determination of benefit and concern for a subpopulation is often specific to its mission, location, and environment, decisions on managing the use of dietary supplements should be made by the Office of the Assistant Secretary of Defense (Health Affairs) and by military com- manders who will consider these factors along with the scientific evalua- tion recommended in this chapter. Considerations of the level of concern, potential benefit, and specific military population, tasks, and environments should be integrated in order to decide on appropriate action. The com- mittee has developed the attached matrix (Table 5-2) as a guide to assist the military in making decisions on the use of dietary supplements. The potential actions suggested by the committee can be grouped into three different categories: policy, education, and monitoring. Any decisions for action should be made in consultation with the review panel of experts and the designated oversight committee, who will have a deep understanding of the scientific data. The framework developed should help the military make decisions re- garding the risks and benefits of dietary supplement use by carefully exam- ining the science-based evidence, and should point to research gaps. Making decisions to recommend or restrict the use of a dietary supplement based on the limited data available is difficult. Also, recommendations to use a dietary supplement should be made carefully and only after clear evalua- tion of risks and benefits, since these recommendations will raise questions related to the personal choice of service members as well as financial and logistical implementation of the recommendation. The committee recognizes the limitations on making decisions based on balancing risks and benefits; these limitations are related to the avail- ability of data and the evaluation of risks and benefits. For example, for many products, lack of data on safety might preclude the military from determining the concern level. In these cases, the military might decide to support research and restrict the use of the supplement until a concern level can be determined. Furthermore, balancing considerations of benefits and concerns will present difficulties that derive from differences in strength of the evidence for safety and efficacy, lack of suitable indicators to compare the potential benefits and concerns, and the need to weigh the benefits and risks for different subpopulations. Other considerations will also need to enter into the decisions, such as the availability of other methods or supple- ments to achieve a similar beneficial effect without the risks.
314 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 5-2â A Guide to Formulating Decisions on Managing Dietary Supplements for Military Personnel, Based on Safety Concerns and Modified by Potential for Benefit Suggested Actions Based on Level of Concern/Benefita Type of High Moderate Low Minimal Benefit Action Concern Concern Concern Concern High Policy 2 3 5 6 Monitoring 7 7 7 7 Education 8 8 8, 9 8, 9 Moderate Policy 2 3 â â Monitoring 7 â â â Education 8, 9 9 9 9 Low Policy 1 4 â â Monitoring 7 â â â Education 8, 9 9 9 9 aThe determination of benefit and concern level for a military subpopulation is often specific to its task, environment, and location. Decisions on managing the use of dietary supplements should be made by the Office of the Secretary of Defense (Health Affairs) and military com- manders who will consider these factors along with the scientific evaluation recommended in this chapter. Policy: 1.âDoD, service, and Surgeon General implement policy to prohibit use of product. 2.âDoD, service, and Surgeon General specify parameters of use. 3.âUnit & MTF commanders make decision on policy based on mission and subpopulation. 4.âPosting of warning/educational labels (e.g., at military installation outlets and exercise facilities). 5.âCommanders, health care personnel, and fitness center and unit trainers recommend that its use be considered for specific relevant personnel and circumstances. 6.âCommanders, health care personnel, and fitness center and unit trainers recommend its use for specific relevant personnel and circumstances. Monitoring: 7.âMonitor for adverse events and frequency of use. Education: 8.âEducate commanders, health care personnel, and fitness center and unit trainers on risks and benefits of specific dietary supplements to enable them to make management decisions. 9.âEducate all service members on risks and benefits of dietary supplements in general. Policyâ This committee believes that whereas the conclusions about the level of concern and benefit (parallel to the ârisk assessmentâ concept in a risk analysis model) should be determined by scientists (i.e., nutritionists, epidemiologists, and/or toxicologists), the decisions about implementing military policy (paralleling the ârisk managementâ concept in a risk analy-
FRAMEWORK TO REVIEW THE SAFETY 315 sis model) should be pursued by commanders at the appropriate level in the military organizational structure. The specific actions taken in response to a dietary supplement review should be the prerogative of military com- manders who are knowledgeable about the demands of a particular military subpopulation and its tasks. This model can be successful only when the scientists in the review panel and the designated oversight committee (see Chapter 6) consult and communicate with military leadership and decision makers. Monitoringâ Surveillance (generally passive, but also active where there is a high level of concern or high level of potential benefits coupled with low concerns) is a potential management action to assess trends in supple- ment use, particularly the use of dietary supplements of high concern, multi-ingredient products, or products with high potential for benefit and low concern. Surveys can include questions about the use of any specific dietary supplement of high concern, particularly multi-ingredient products (see Chapter 2). An additional source of information on the use of dietary supplements is on-base (e.g., from AAFES/NEX and fitness centers) sales data. Such data could be gathered on an annual basis for all supplements; such collection is especially advisable for those of high concern level, those containing multiple ingredients, or those with high potential for benefit and low concerns. In addition to providing use trends, data from surveillance are vital to assess the strength of the adverse event signals and serve to complement data from adverse event reports (see Chapter 6). Educationâ Because members of the military obtain information about dietary supplements from many sources that often have no scientific au- thority, education based on objective analysis of the efficacy and safety data should be provided on which to make a decision to take supplements not restricted by military policy. Furthermore, educating the commanders, health care providers, and physical trainers about the safety and benefits of dietary supplements of interest or concern will permit these individu- als to appropriately exercise leadership and provide guidance to military members. This educational component should be initiated as part of these leadersâ formal training and should continue throughout their military ca- reers (see also Chapter 6). Communication between those responsible for the education of military service members and the designated oversight committee is critical. One way of providing information on dietary supplement safety and efficacy would be to develop a summary table showing both benefits and safety, together with an integrated concern level for the general military popula- tion and specific subpopulations (e.g., Table 5-3). Such a table could be used as a basis to develop educational materials for commanders, fitness or
316 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 5-3â Summary of Risks and Putative Benefits for Selected Dietary Supplements Used by Military Personnela Potential Detrimental Effects to Dietary Military Supplementsb Performancec Military Survivabilityd Other Health Riskse Performance enhancers Caffeine Elevation of Moderate caffeine intake of No data foundi core body 400 mg/d has not been temperature associated with adverse by restriction effects in most people of peripheral heat loss Mild to moderate locomotor agitation, Elevation of tachycardia, diuresis, and circulating anxiety. Sleep disturbance catechol- can occur if ingestion is amines at within a few hours of sleep high dosages time Garlic No data MÃ©niereâs disease, asthma, Epidural hematoma, found bleeding, gastrointestinal increased international disorders normalized ratio (INR)
FRAMEWORK TO REVIEW THE SAFETY 317 Interactions with Medicationsf or Other Withdrawal Concern Bioactive Substances Effects Putative Benefitsg Levelh Sympathomimetic stimulant Limited Substantial evidence that Moderate that may have synergy with data 100â600 mg caffeine can other psychostimulants indicating improve many aspects of headache cognitive and psychomotor An increasing number of and caffeine performance during periods dietary supplements, craving of sleep deprivation, and performance-enhancing foods, 200â600 mg can enhance and sports drinks contain physical endurance caffeine, even if it is not listed on the label. This can further High potential for benefit increase the amount of (substantial evidence of caffeine being ingested and beneficial effects for add to detrimental effects, performance during sleep tolerance, and adverse events deprivation) Saquinavir: Clinically No data No clinical studies for High due to substantial reduction of AUC found mental or physical potential performance impact of Ritonavir: No effect on AUC chronic use on but increased incidence of Evidence of antimicrobial blood clotting gastrointestinal side effects effects Warfarin: Increased clotting Low potential for benefit time and INR, additive effect (substantial evidence of minimal beneficial effects) Chlorpropamide: Increased hypoglycemic effect Acetaminophen: Altered metabolism but not clinically substantial continued
318 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 5-3â Continued Potential Detrimental Effects to Dietary Military Supplementsb Performancec Military Survivabilityd Other Health Riskse Ginkgo biloba No data Transient headaches, No data found found gastrointestinal disturbances, sleep disturbances, bleeding with Warfarin and aspirin Ginseng No data Gastrointestinal effects No data found found Tyrosine No data No data found No data found found Quercetin No data No data found No data found found
FRAMEWORK TO REVIEW THE SAFETY 319 Interactions with Medicationsf or Other Withdrawal Concern Bioactive Substances Effects Putative Benefitsg Levelh Warfarin, NSAID, alcohol: No data Little evidence of cognitive High due to Theoretical interactions but found benefits in healthy, young potential studies do not support individuals impact of interactions chronic use on Low potential for benefit blood clotting Omeprazole: Reduced plasma (substantial evidence of concentrations of dietary minimal beneficial effects) supplement Thiazide diuretics: Reduced efficacy of diuretic Warfarin: Three case reports No data No benefits to physical Low reporting reduction in the found performance in healthy, INR young individuals Phenelzine: Induced mania Some evidence of memory improvement and reduction Influenza vaccine: Increased in mental fatigue the efficacy of vaccine when given in combination Low potential for benefit (substantial evidence of Alcohol: Reduced blood minimal beneficial effects) alcohol concentration Theoretical with monoamine No data Evidence of improvement of Minimal oxidase inhibitors found cognitive function, mood states, and psychomotor functions especially under stressful situations Moderate potential for benefit (moderate level of science but high desirability) No data found No data Some evidence of immune Minimal found system improvement and antiviral properties Moderate potential for benefit (some level of science but high desirability) continued
320 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 5-3â Continued Potential Detrimental Effects to Dietary Military Supplementsb Performancec Military Survivabilityd Other Health Riskse Anabolic supplements (reported as âbodybuilding supplementsâ in surveys) Steroids Dehydroepiandros- No data Neoplasia in rat studies, terone (DHEA) found correlation to breast cancer in epidemiological studies, androgenizing effects in women Nonsteroids Beta-hydroxy-beta- No data No data found No data found methylbutyrate found
FRAMEWORK TO REVIEW THE SAFETY 321 Interactions with Medicationsf or Other Withdrawal Concern Bioactive Substances Effects Putative Benefitsg Levelh Some drugs decrease DHEA No data No effect on body High blood levels (ACTH inhibitors found composition, muscle, or and P450 inducers); caution cognitive function when used concurrently with hormonal therapies Some evidence for improvement in bone health and mood in older women Low potential for benefit (some evidence of minimal beneficial effects) No data found No data Some evidence of increase in Minimal found lean tissue and muscle strength of untrained individuals Moderate potential for benefit for untrained individuals or those in catabolic states such as negative energy balance (moderate level of science but high desirability) continued
322 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 5-3â Continued Potential Detrimental Effects to Dietary Military Supplementsb Performancec Military Survivabilityd Other Health Riskse Creatine Consider Case reports of renal No data found possibility of failure dehydration or renal No dehydration or effects gastrointestinal problems Weight loss Ephedra No data Case reports of psychosis, Two- to fourfold increase (Ma huang) found vision impairment, muscle in adverse effects: failure increased blood pressure, palpitations, heart rate. Case reports of cardiovascular adverse effects, stroke, psychosis, heart failure, seizure, vision impairment, transient ischemic attacks, muscle failure, and death Chromium No data Only isolated adverse Only isolated adverse picolinate found effects reported (changes in effects reported cognitive behavior, allergic skin disorders, renal failure, and liver dysfunction)
FRAMEWORK TO REVIEW THE SAFETY 323 Interactions with Medicationsf or Other Withdrawal Concern Bioactive Substances Effects Putative Benefitsg Levelh Caffeine: Synergistic effect No data Substantial evidence of Low and opposing effects reported found improvement in physical performance NSAID and some vitamins: Theoretical interactions Substantial evidence of increase in muscle mass Some evidence of improvement in cognitive and psychomotor performance Potential for protection against traumatic brain injury Moderate potential for benefit (moderate evidence of benefits and high desirability) Interactions with other Palpitations Few studies show a small High sympathomimetic drugs such but substantial effect for as caffeine weight loss Clinical studies show no evidence for performance enhancement Moderate potential for benefit (for weigh loss) (moderate level of science but high desirability) Absorption reduced with No data Some evidence of small Low phytates and medications that found effects on weight loss and alter acidity of stomach body composition Low potential for benefit (substantial evidence of minimal beneficial effects) continued
324 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 5-3â Continued Potential Detrimental Effects to Dietary Military Supplementsb Performancec Military Survivabilityd Other Health Riskse Sleep aids Melatonin Drowsiness/ Loss of core body heat No data found sedation Drowsiness/ effects sedation effects Gastrointestinal effects Valerian Drowsiness/ Drowsiness/ No data found sedation sedation effects effects Gastrointestinal effects General healthj Energy supplementsk Sports bars No data No data found Could contribute to found superfluous calories for inactive personnel
FRAMEWORK TO REVIEW THE SAFETY 325 Interactions with Medicationsf or Other Withdrawal Concern Bioactive Substances Effects Putative Benefitsg Levelh Sedative hypnotics and No data Some evidence of Moderate anesthetics: Theoretical found improvement of sleep synergy Substantial evidence of circadian reentrainment under controlled conditions Moderate potential for benefit (evidence of circadian benefits and some sleep benefits) Sedative hypnotics and No data Inconclusive evidence that Moderate anesthetics: Theoretical found valerian improves sleep synergy Low potential for benefit (evidence of minimal beneficial effects) Unknown but unlikely, No data Evidence of improved Minimal depending on individual found exercise performance ingredients Supplement essential nutrients High potential for benefit (substantial evidence of benefits and high desirability) continued
326 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 5-3â Continued Potential Detrimental Effects to Dietary Military Supplementsb Performancec Military Survivabilityd Other Health Riskse Sports drinks No data Hyponatremia (with Could contribute found excessive use) unnecessary calories for inactive personnel Vitamins and Minerals Calcium No data Minimal when below Minimal when below UL found Tolerable Upper Intake Level (UL)
FRAMEWORK TO REVIEW THE SAFETY 327 Interactions with Medicationsf or Other Withdrawal Concern Bioactive Substances Effects Putative Benefitsg Levelh Unknown but unlikely, No data Evidence of improved Minimal depending on individual found exercise performance ingredients Some evidence of increased muscle protein synthesis, superior hydration, and reduction in muscle damage after strenuous exercise when drinks contain protein; requires further substantiation Plasma level better maintained during sweating when electrolytes are provided High potential for benefit (substantial evidence of benefits and high desirability) May reduce absorption and/ No data To reach adequate levels by Minimal when or efficacy of some found supplementing the diet below UL medications Sustain bone health and mood states; potential for further benefits with supplemental amounts High potential for benefit (substantial evidence of benefits and high desirability) continued
328 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 5-3â Continued Potential Detrimental Effects to Dietary Military Supplementsb Performancec Military Survivabilityd Other Health Riskse Iron No data Minimal when below UL Minimal when below UL found Selenium No data Minimal when below UL Minimal when below UL found Zinc No data Minimal when below UL Minimal when below UL found Multivitamins/ No data Minimal when below UL Minimal when below UL multiminerals found
FRAMEWORK TO REVIEW THE SAFETY 329 Interactions with Medicationsf or Other Withdrawal Concern Bioactive Substances Effects Putative Benefitsg Levelh No data To reach adequate levels by Minimal when found supplementing the diet below UL Sustain physical and cognitive performance High potential for benefits (substantial evidence of benefits and high desirability) No data To reach adequate levels by Minimal when found supplementing the diet below UL Maintain immune function; potential for further benefits with supplemental amounts High potential for benefits (substantial evidence of benefits and high desirability) No data To reach adequate levels by Minimal when found supplementing the diet below UL High potential for benefit (substantial evidence of benefits and high desirability) No data To reach adequate levels by Minimal when found supplementing the diet below UL High potential for benefit (substantial evidence of benefits and high desirability) continued
330 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL TABLE 5-3â Continued Potential Detrimental Effects to Dietary Military Supplementsb Performancec Military Survivabilityd Other Health Riskse Vitamin C No data Minimal when below UL Minimal when below UL found Vitamin D No data Minimal when below UL Minimal when below UL found Vitamin E No data Minimal when below UL Minimal when below UL found aThe monographs used to produce this table were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy. bComposition of dietary supplements varies widely; these are general categories and many include other ingredients or a combination of ingredients. cCausing detriments to performance during military tasks (e.g., physical endurance, muscle strength, alertness, memory, stress, sleep patterns). dCausing detriments to military survivability (e.g., bleeding or injury, dehydration, malfunc- tion of gastrointestinal tract, stress, or altered behavior). eCausing risks to health, excluding those in note 2 above. fRefers to the 100 medications most prescribed for military personnel. gImprovements of performance during military tasks (e.g., physical endurance, muscle strength, alertness, memory, stress relief, sleep patterns) based on level of desirability of the benefit to the military and level of science documenting a benefit (see details in Table 5-2). hHigh, moderate, low, or minimal as described in Box 5-1 and modified based on putative benefits.
FRAMEWORK TO REVIEW THE SAFETY 331 Interactions with Medicationsf or Other Withdrawal Concern Bioactive Substances Effects Putative Benefitsg Levelh No data To reach adequate levels by Minimal when found supplementing the diet below UL Maintain immune function High potential for benefit (substantial evidence of benefits and high desirability) No data To reach adequate levels by Minimal when found supplementing the diet below UL Maintain bone health High potential for benefits (substantial evidence of benefits and high desirability) Aspirin: Antithrombotic Unknown To reach adequate levels by Minimal when effects but unlikely supplementing the diet below UL Warfarin Maintain immune function High potential for benefit (substantial evidence of benefits and high desirability) iâNo data foundâ means that there were no data found in the subject area showing an effect, either because the studies reviewed did not investigate this subject area or because, when in- vestigated, there was no effect (i.e., health risk). Absence of evidence of risk, a frequent reality, does not necessarily indicate that there is no risk. Even if a study reported a lack of adverse effects, if the study is not adequately designed to identify risk (e.g., it is insufficiently pow- ered, incompletely reported, does not include positive controls, or otherwise has inadequate mechanisms for detecting adverse events), its scientific validity is reduced or even null. jImmune function enhancers, antioxidants, energy supplements, enhance recovery or performance. kRefers to supplements containing macronutrients for energy or essential nutrients below the UL to meet physiological needs level, or electrolytes to replenish those lost during exercise. If energy supplements contain other ingredients (e.g., creatine), then an evaluation of each individual ingredient and interaction is warranted.
332 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL military unit trainers, and health care providers to inform service members. The committee cautions that such a summary table could be misinterpreted and therefore is not to be used as a sole source of information; it is meant to be used by those with sufficient scientific expertise as a tool to develop educational materials. Communication with service members should not establish a presumption that using dietary supplements is the norm or the expected behavior. CHALLENGES OF THE PROPOSED FRAMEWORK FOR MILITARY PERSONNEL The three types of challenges in evaluating the safety or efficacy of dietary supplements with the framework proposed by this committee are outlined in this section. Insufficient Scientific Data The practical value of the proposed framework depends on publicly available data. One critical challenge is acquisition of sufficient scientific data from literature searches to support an informed decision about the safety and efficacy of a dietary supplement within the military. Although there is an abundance of data for a few supplements, such as ephedra, the dearth of data for others hinders the determination of any definitive con- clusion and further decision making. In Chapter 7, the committee provides its recommendations on the military undertaking research to address data gaps in areas of significant concern. The committee emphasizes that absence of evidence of risk, a frequent reality, does not necessarily indicate that there is no risk. Even if a study reported a lack of adverse effects, if the study is not adequately designed to identify risk (e.g., it is insufficiently powered, incompletely reported, does not include positive controls, or otherwise has inadequate mechanisms for detecting adverse events), its scientific validity is reduced or even null. Multi-Ingredient Dietary Supplements Dietary supplements commonly contain multiple ingredients, and their compositions are frequently altered (e.g., they are reformulated with dif- ferent proportions, amounts, and even ingredients) without any product name change. Finding data on the safety (or efficacy) of the myriad multi- ingredient products in the market is yet a bigger challenge than finding data on single-ingredient products. The committee concluded that these products merit special attention by frequent monitoring of their use, sales, and adverse event reports. The following are two potential approaches to
FRAMEWORK TO REVIEW THE SAFETY 333 determining the safety (or efficacy) of these products. Recognizing that both of these approaches (i.e., determining the safety of a total product or determining the safety of individual ingredients) have advantages and disadvantages, the application of either approach to evaluate the safety (and efficacy) of multi-ingredient products should be the prerogative of the military. Among other factors, the military should consider the strength of detected signals, prioritization of research gaps, and availability of re- sources. For either approach, there will be additional staff support required to maintain continuous surveillance of multi-ingredient products, including all the possible interactions. Determining total product safetyâ Given the virtual absence of data on multi-ingredient products, the military could decide to conduct research with study designs addressing military subpopulations and environments of interest, an approach that would be both expensive and time-consuming. In addition, the rapid turnover of products in the market may make it difficult or impractical to keep such research current. Determining ingredient safetyâ The level of concern (or efficacy) associated with the consumption of a multi-ingredient product could be determined by examination of each individual ingredient and of each potential interac- tion using the approach recommended in this chapter. The challenges in this case relate not only to the ingredients themselves but to the potential interactions among ingredients in the product. Furthermore, safety data on ingredient interactions are typically unavailable. Presence of Contaminants The linking of an adverse event to the use of a dietary supplement ingredient might be confounded if the product contains adulterants or contaminants. Attribution of the source of the adverse event becomes a formidable task. If enforced, the newly adopted cGMP rule should mini- mize the potential for inclusion of adulterants or contaminants. Because this rule will not be implemented until June 2008, its effectiveness remains to be evaluated. OVERALL RECOMMENDATIONS The committee recommends that the military use the proposed frame- work, modified from the 2005 IOM report framework, to determine whether a dietary supplement requires that military leadership take specific management actions to ensure optimal readiness and health protection of military personnel. This framework provides a methodology with a preÂ
334 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL established search strategy for generating a safety monograph for a dietary supplement, and a consistent format that provides key information which can be used to assist military policy makers. It also provides criteria to initiate safety reviews based on signals generated from an adverse event; or proactively, based on significant changes in dietary supplement consump- tion by military personnel. The following are overall recommendations related to the application of the framework: â¢ Determination of the level of concern for a dietary supplement should be based on published reviews of general safety concerns and on adverse effects and/or benefits specific to the military; the final integrated concern level should be predicated on safety concerns, modified by potential benefits, and based on special mission requirements and environments. â¢ The final, integrated concern level and the need for dietary supple- ment management should be determined in the context of specific subpopu- lations of the military and based on their special mission requirements, environments, and locations. This analysis should pay particular attention to military subgroups of interest for whom benefits and safety are of op- erational concern. â¢ Dietary supplement management should be predicated on safety concerns, modified by any proven benefits. â¢ A future task force or committee should more fully describe the process and framework to characterize the efficacy of dietary supple- ments of interest to the military and describe a detailed process to monitor the emergence of dietary supplements that could provide benefits to the military. â¢ To determine whether the level of concern for a dietary supple- ment should be reclassified as future research unfolds, research should be monitored on an annual basis, especially for those supplements for which a concern level could not be established due to lack of data. Based on rec- ommendations of the designated oversight committee, the military might also decide to support or conduct research on a specific dietary supplement depending on its relevance to the military. For example, dietary supple- ments of military interest that are classified as being of high concern based on equivocal animal data could be referred to the research community to more fully characterize the level of concern in humans. It may or may not be appropriate for the military commander to recommend that the dietary supplement not be used by military personnel until that determination has been made.
FRAMEWORK TO REVIEW THE SAFETY 335 REFERENCE IOM (Institute of Medicine). 2005. Dietary supplements: A framework for evaluating safety. Washington, DC: The National Academies Press.