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Monitoring Adverse Health Effects Associated with Dietary Supplement Use by Military Personnel

BACKGROUND

Making definitive declarations about the safety of drugs, foods, or dietary supplements is a challenging task, even with the most robust premarket studies. Among the multiple strategies (pre- and postmarketing) available, postmarket monitoring of adverse effects associated with these products becomes a very important tool to assess their safety. Often, a postmarket monitoring system serves as a complement to a risk or safety assessment to identify adverse effects that are not recognized in a laboratory or a small clinical study. In the case of food ingredients (i.e., additives and generally recognized as safe [GRAS] substances), the standard of safety is a “reasonable certainty of no harm” as indicated by either the food additive petition approval, GRAS notification, or GRAS self-affirmation process. For example, prior to marketing food additives, a petition that includes a safety assessment (i.e., available data on safety of the product) is sent to the U.S. Food and Drug Administration (FDA). Upon review of the petition, the FDA may issue a safety declaration. Once on the market, there is no established system to monitor adverse events from foods; however, if a new ingredient is introduced to a previously available food product, the FDA might informally ask the manufacturer to conduct postmarket monitoring of adverse events. Receipt of a sufficient number of complaints from consumers or consumer organizations might also prompt the FDA to investigate the safety of an ingredient.

In contrast, for drugs, a premarket risk-benefit analysis is conducted, followed by a postmarket safety evaluation that includes a passive, volun-



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6 Monitoring Adverse Health Effects Associated with Dietary Supplement Use by Military Personnel BACKGROUND Making definitive declarations about the safety of drugs, foods, or dietary supplements is a challenging task, even with the most robust pre- market studies. Among the multiple strategies (pre- and postmarketing) available, postmarket monitoring of adverse effects associated with these products becomes a very important tool to assess their safety. Often, a postmarket monitoring system serves as a complement to a risk or safety assessment to identify adverse effects that are not recognized in a laboratory or a small clinical study. In the case of food ingredients (i.e., additives and generally recognized as safe [GRAS] substances), the standard of safety is a “reasonable certainty of no harm” as indicated by either the food additive petition approval, GRAS notification, or GRAS self-affirmation process. For example, prior to marketing food additives, a petition that includes a safety assessment (i.e., available data on safety of the product) is sent to the U.S. Food and Drug Administration (FDA). Upon review of the peti- tion, the FDA may issue a safety declaration. Once on the market, there is no established system to monitor adverse events from foods; however, if a new ingredient is introduced to a previously available food product, the FDA might informally ask the manufacturer to conduct postmarket monitoring of adverse events. Receipt of a sufficient number of complaints from consumers or consumer organizations might also prompt the FDA to investigate the safety of an ingredient. In contrast, for drugs, a premarket risk-benefit analysis is conducted, followed by a postmarket safety evaluation that includes a passive, volun- 

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 MONITORING ADVERSE HEALTH EFFECTS tary surveillance system. The premarket risk-benefit analysis is composed of three types of studies: animal toxicology and pharmacological studies, proof-of-principle studies for the disease or condition being addressed, and confirmatory studies of safety and efficacy (FDA, 2007). As a result of this required risk-benefit review, by the time a medication is on the market there are multiple well-conducted studies available that can later be used in support of an alleged association with an adverse event. Under the Federal Food, Drug, and Cosmetic Act, as amended by the Dietary Supplement Health and Education Act (DSHEA) of 1994, the law that regulates dietary supplement safety, the FDA does not have the authority to require a premarket safety assessment, yet bears the burden of proof to determine that a dietary supplement is unsafe before or after introduction in the marketplace. Because there are no premarket assessments required for dietary supplements, there is a paucity of laboratory safety studies; hence, postmarket monitoring of adverse events becomes even more significant for ensuring public health. DSHEA provided the FDA with the authority to develop monitoring systems and to take necessary actions when it has sufficient evidence that a product is unsafe (Dietary Supplement Health and Education Act of , Public Law 103-417, 108 Stat 4325, 103rd Congress, October 25, 1994). The FDA has established a program called MedWatch to provide and elicit information on safety issues; reports from either health care professionals or consumers can be submitted voluntarily to the FDA or manufacturers via a standard form, form FDA 3500 (see Ap- pendix E). The Dietary Supplement and Nonprescription Drug Consumer Protection Act made the reporting of life-threatening events to the FDA by manufacturers mandatory after December 2007 (the MedWatch 3500A form is used for this purpose) (Dietary Supplement and Nonprescription Drug Consumer Protection Act, Public Law 109-462, 109th Congress, December 22, 2006). Reports from both consumers and manufacturers are submitted through a passive monitoring system, that is, the FDA does not actively seek the adverse event reports. There are four steps to follow in such a system: (1) detect adverse events, (2) generate signals of public health concerns, (3) assess signals, and (4) take appropriate action. As with medications and food ingredients, health risks from dietary supplement use are derived mainly from a consumer’s individual susceptibil- ity, or from the dietary supplement’s inherent biological activity or interac- tions with medications. For the majority of dietary supplements, inherent toxicity might be expected to be less than that of medications because of the lower concentrations and potency per unit. Nevertheless, there are factors (i.e., the lack of composition standardization or a product compendium, multi-ingredient products, biased consumer attitudes, and a potential of overuse by some consumers) that increase the risks to health from the use of dietary supplements. Because dietary supplements are regulated as foods

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL and many have a history of traditional use, there is a perception that they are safe and do not need a premarket approval process. However, it should be noted that products with a history of safe use may now be used in a dif- ferent manner (e.g., with different solvents used for extraction, alternative plant parts used, longer duration of use) from traditional uses. Many con- sumers are also unaware that there is no requirement for federal approval of dietary supplements or advertisements promoting them, mistakenly as- suming that dietary supplements must conform to the same regulations as drugs (Ashar et al., 2008). The differences in perception of risk between dietary supplements and drugs should be considered when attempting to model a surveillance system for dietary supplements. There are many activities critical to the evaluation of risk-benefit pro- files, such as adverse event surveillance, confirmatory laboratory safety studies, and data on use. Data from adverse event monitoring are comple- mentary to data on use from dietary supplement surveys: survey data typically focus on the use of a specific dietary supplement within the popu- lation, whereas monitoring collects the numbers and types of adverse events resulting from its use. Both estimates are critical when making decisions about the safety of a product because their ratio (i.e., reporting proportion) may provide a rough estimate of the magnitude of a problem; in the case of dietary supplements, low reporting of adverse events and scarce infor- mation on dietary supplement use limit the utility of these data. Also, an association of use with an adverse event does not imply the demonstration of causality; rather, it intends to alert decision makers of potential concerns possibly requiring corrective actions. Determining causation requires rigor- ous clinical trials or research designs performed with animal models, not just analysis of adverse-event report data (IOM, 2005). Associations identi- fied from adverse-event monitoring must be viewed as hypotheses regarding possible causal relationships between the substance and event, recognizing that there may be many possible reasons other than a direct causal relation- ship for the observed association (Almenoff et al., 2005). Based on the heightened risks and the absence of an internal military process to report adverse events, this chapter discusses the need for the military to add dietary supplements to its current adverse-event monitor- ing system for medications so that this system responds to the unique risks and demands of military service. The chapter reviews the adverse-event monitoring efforts for the general population and for the military popula- tion, highlights challenges, and recommends improvements that build upon the current military system. Challenges might be categorized as related to the process of adverse event monitoring itself or related to the analysis of the data. Since those relating to data analysis (e.g., data mining statistical methods, identification of trends) are not unique to the military system, the committee discussed them briefly and refers to the published literature for

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 MONITORING ADVERSE HEALTH EFFECTS further reading. The committee focused its deliberations on process-related challenges (e.g., low reporting rate; quality of data; use of integrated, elec- tronic data). Taking the current system and policies as its foundation, this chapter makes recommendations for a collaborative approach in which appropriate institutions share data and lessons learned from their respec- tive monitoring systems. The proposed approach will alert the military of potential concerns derived from using specific dietary supplements, par- ticularly when performance might be compromised, and will serve as a signal to initiate appropriate actions by military leadership, as described in Chapter 5. THE FDA’S PROCESS TO MONITOR ADVERSE EVENTS FROM DIETARY SUPPLEMENTS To make recommendations about approaches to monitoring military personnel for adverse health events that might indicate a concern associ- ated with consumption of dietary supplements, the committee reviewed the FDA’s systems for both medications and dietary supplements. A more detailed description of the monitoring system for products regulated by the FDA is included in Appendix B (see sections by Dal Pan and Frankos and Mozersky). As mentioned above, to gauge the safety of dietary supple- ments, the FDA relies in part on evaluation of reports of adverse events pos- sibly associated with their use. The FDA uses these evaluations to analyze trends and to detect a signal (i.e., a strong relationship between a dietary supplement and adverse events). However, a determination that a dietary supplement or dietary ingredient is unsafe would be based on a thorough assessment of not just reports of adverse events, but also of the scientific peer-reviewed literature on the safety of the dietary supplement or dietary ingredient. Adverse events are most often reported via the submission of FDA’s MedWatch 3500 form (see Appendix E), which is used to provide informa- tion from clinical trials, health care personnel, and consumer reports. To summarize the process, an individual (health care provider or consumer) communicates a description of the event and the patient to the FDA’s Center for Drug Evaluation and Research, where the source of the event is categorized by origin (i.e., drug, dietary supplement, devices, biologics). The initial submission might be electronic or via telephone, standard mail, or fax; all reports are transcribed, regardless of the reporting mechanism. Reports are often submitted over the phone by a health care provider and received and transcribed verbatim by an FDA officer who typically does not probe for more information or details about the adverse event. By contrast, some manufacturers hire interviewers or facilitators trained to ask relevant questions of those submitting information on adverse events for entry in the

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0 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL MedWatch form to be sent to the FDA. When potentially associated with a dietary supplement, reports are redirected to the FDA’s Center for Food Safety and Applied Nutrition for evaluation. For processing, MedWatch 3500 forms require only an identifiable reporter, a patient (anonymized), the suspect product, and a description of the adverse event. The information is reported regardless of the quality of the data, which is not validated. Apart from the patient’s personal data and medical conditions, the form includes fields for entry of important informa- tion about the product (type, brand name, lot number, expiration date) and use (dose, frequency, date of initiation of use, consistent or inconsistent use, reason for use, last time of use before adverse event). Critical in identifying a signal is the section of the form referring to the event itself: event descrip- tion, actions taken in response to event (e.g., sought medical attention), and documented diagnosis. FDA officials consider it advantageous to format this section as open-ended questions, offering the possibility of acquiring valuable information about the event circumstances (personal communica- tion, Vasilios Frankos, Center for Food Safety and Applied Nutrition, May 30, 2007). The concomitant use of a drug and a dietary supplement or of a combination of dietary supplements might cause synergistic or antagonistic effects; the section in the form addressing the use of other medications and supplements is also therefore critical in evaluating the signal. Once information is collected and distributed to the FDA’s safety officers, analysis and signal detection follow. If an event is serious or uncommon, further steps are expeditiously taken: (1) a follow-up is requested, (2) other federal agencies are consulted, (3) a review of the literature is initiated, and (4) prior FDA reports on adverse events from similar products are consulted to identify trends. There is, however, no automatic signaling mechanism, and the weight of the evidence is considered case by case; the experience and consensus of safety officers usually dictate the decisions taken. Until recently, these voluntary submissions and resultant MedWatch 3500 forms provided the only system to obtain information on postmar- ket adverse events associated with dietary supplements. To strengthen this system, the Dietary Supplement and Nonprescription Drug Consumer Pro- tection Act mandates that after December 2007, serious adverse events1 voluntarily reported to dietary supplement manufacturers by consumers and others must be submitted by the manufacturer to the FDA via the Med- Watch 3500A form (see Appendix D). The form is slightly different from 1The 2007 Dietary Supplement and Nonprescription Drug Consumer Protection 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 previously listed outcome described under subparagraph (A).

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 MONITORING ADVERSE HEALTH EFFECTS MedWatch 3500 in that it also solicits composition information from the product label as well as the manufacturer’s contact information. Although this is a clear enhancement of the dietary supplement regulatory system and there is an expectation that the amount of data collected on adverse events will improve in both quality and quantity, the actual benefits from the act are still to be realized. The potential misinterpretation of reports has resulted in some re- luctance to make adverse event monitoring data available to others (see Kingston in Appendix B). Given the low reporting rate for dietary supplement-related adverse events, and the absence of a well-established system to monitor adverse events, it seems essential for organizations and manufacturers to collaborate to understand the limitations and uses of the current systems for reporting adverse events associated with dietary supplements. For example, the 2007 Institute of Medicine (IOM) report The Future of Drug Safety emphasized the importance of partnerships and the need for a concerted effort to make effective use of both public and private resources to address drug safety (IOM, 2007). Efforts to in- corporate information from other sources, such as poison control centers (PCCs), have not, for various reasons, always been successful. The PCCs are private organizations whose purpose is to provide medical advice on how to treat an adverse outcome, not to assess the safety of substances. Calls received by PCCs include those prompted by nontoxic or unintended exposures to dietary supplements, medications, or other substances by chil- dren. Direct comparison of data from PCCs and MedWatch forms is not appropriate, since the same adverse-event data elements are not collected. The FDA therefore reviews PCC reports only when follow-up is neces- sary. The FDA has also been working with the University of California at San Francisco to monitor the PCC reports received by the San Francisco Center for Drugs and Dietary Supplements. Through this collaboration, it was determined that most adverse events in the PCC reports that were linked to dietary supplement use were associated with the use of stimulants (caffeine, ephedra-like products) and multi-ingredient dietary supplements, especially weight-loss products, and that these events were often associated with cardiac symptoms (personal communication, V. Frankos, Center for Food Safety and Applied Nutrition, FDA, May 30, 2007; Haller et al., in press). Challenges in Adverse Event Data Collection Process and Analysis Many experts and organizations have discussed challenges related to various aspects of monitoring adverse events from dietary supplements (see Kingston in Appendix B; LSRO, 2004; OIG, 2001; Woolf, 2006). For example, a 2001 report from the U.S. Department of Health and Human

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Services (HHS) Office of the Inspector General (OIG) provides a detailed analysis of the effectiveness of the FDA’s adverse event reporting system for dietary supplements in protecting the consumer (OIG, 2001). Although underreporting and suboptimal data quality are both attributes of a pas- sive and voluntary system of surveillance, there are well-known advantages to a voluntary system, such as its nationwide character and the ability to distinguish at-risk groups and to generate safety signals. This section highlights some of the challenges of the FDA’s current sys- tem, many of which also apply to military reporting efforts (see below). Data Collection Process Low reporting rate When reported by the patient, adverse events are frequently described not directly to the FDA but to a health care provider. Receiving such information via the health care provider has obvious advan- tages in providing quality data, including the use of standardized medical terminology (e.g., symptoms, medications) and the opportunity to acquire additional information from the patient’s medical records. Unfortunately, under the current voluntary system, the report rate is low—the OIG esti- mated in 2001 that less than 1 percent of all adverse events are reported to the FDA—for any of the following possible reasons. First, there is generally little consumer awareness of the importance of reporting adverse events from dietary supplements or even about the availability of a reporting system; if an individual is aware of the system, lack of familiarity with the form or lack of clarity in questions might deter submission. Second, patients are often reluctant to report the use of alternative treatments to their health care providers (IOM and NRC, 2005). Third, for some consumers, dietary supplements might be regarded as inherently safe since they are “natural,” and consumers therefore fail to make a connection between use of a dietary supplement and the adverse effect, and do not report it (Ashar et al., 2008; IOM, 2005). Fourth, there is no clear common knowledge of what consti- tutes an adverse event (e.g., for some, only death or permanent disability would qualify, while others would include discomfort leading to absence from work, or admission to an emergency room for treatment of a symp- tom such as dehydration). Finally, recording the dietary history or asking about dietary supplement use is not a routine part of the medical history in either emergency room or follow-up ambulatory visits (except for am- bulatory visits with some registered dietitians). While health care providers should, in theory, be sensitive to the importance of adverse event reporting, surveys have shown that even in the case of medications, physicians’ beliefs and attitudes about the value of reporting adverse events contribute to low reporting rates (Figueiras et al., 1999). Other factors that might indirectly affect the report rate are the recency of introduction of the dietary supple-

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 MONITORING ADVERSE HEALTH EFFECTS ment, media attention, and the level of educational or regulatory activity recently presented. Quality of data collected The quality of information reported by phone or MedWatch 3500 form depends on the reporter’s bias or beliefs as well as familiarity with medical reporting, signs, and symptoms. Forms filled by consumers often include incomplete or inaccurate information regarding an adverse event. For example, few consumers will be aware of how to code adverse events using standard codes for data entry (i.e., as found in the online Medical Dictionary for Regulatory Activities, which provides the coding of standard medical terminology [signs, symptoms, diagnosis, syn- dromes, laboratory and physiological data related to medical conditions] used by the FDA and others). To add to this difficulty, FDA safety officers do not typically probe for additional relevant information (e.g., brand name, dose, and other products or medications being taken concomitantly), nor is there much follow-up with the initial reporter to obtain more infor- mation (personal communication, V. Frankos, Center for Food Safety and Applied Nutrition, FDA, May 30, 2007). The analysis of data from reports of adverse events related to dietary supplements is complicated by numerous unknowns about the product ingested, including the following: (1) potential product adulteration, (2) lack of identification of the part of the plant (e.g., root, seed) from which the botanical product is derived, (3) broad variation in plant nomenclature and geographical origin of plant, (4) unknown product composition due to lack of manufacturing and labeling requirements and continual product reformulation, and (5) patients’ inability to accurately recall the types or number of dietary supplements being taken. The establishment of an as- sociation of an adverse event with a dietary supplement then becomes a significant challenge. An additional obstruction to data analysis is uncer- tainty of the duration of use or length of time between the exposure and the adverse effect. The 2001 OIG report highlighted the difficulties presented by poor data quality. Adverse event report data were categorized as suboptimal, specifically providing limited medical information, limited information on products and manufacturers, limited information about the consumer, and limited ability to analyze trends. The report found that in 1999, the FDA recorded only 400 adverse events from dietary supplements via submission of MedWatch 3500 forms. Of those, medical records were unavailable in 58 percent of the cases, ingredients could not be determined in 32 percent, and there was no patient follow-up information available for 27 percent (OIG, 2001). The user guidance recently issued on how to fill in the MedWatch 3500 form may help those reporting adverse events to submit accurate, appropriate information.

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Data Analysis: Generating Signals Data mining is defined as the analysis of observational data sets to find unsuspected relationships and to summarize the data in novel ways that are both understandable and useful to the data user (Hand et al., 2001). Different forms of data mining can be used when the data sets are large, as in the case of adverse-event reports for medications. The methods commonly used in pharmacovigilance to identify associa- tions account for the variability typically found with small report counts. Quantitative evaluation can be derived from the relationships between the frequency of use of a substance and events reported, taking into consid- eration also all other substances’ concomitant use and events (Almenoff et al., 2005). When evaluating these data, a typical challenge derives from a lack of data for the “denominator” (i.e., number of users for each dietary supplement) and low “numerator” data (i.e., number of adverse events reported for a particular dietary supplement). Data on dietary supplement sales and use (e.g., from commercial vendors or surveys) are valuable when estimating the percentage of the population that uses a dietary supplement. Signals detected by measuring disproportionality of drug-event combina- tions compared to known ratios from premarket efficacy trials are only statistical indicators of possible safety issues. Rare events (e.g., birth de- fects) are easiest to detect, but events that are commonly experienced by the population (e.g., diarrhea) are difficult to associate with the consumption of a specific dietary supplement or dietary supplement ingredient. The topic of data analysis and mining from adverse event reports is complex and has been extensively reviewed by others (Almenoff et al., 2005; Strom, 2005). Unfortunately, for the reasons described above, the quantity and quality of data reported from dietary supplement-related events is often less than desirable, resulting in weak signals for safety concerns. If higher reporting rates accompany the increase in use, awareness, and new legal requirements to report adverse events, then data mining tools might be more useful in the future. In the case of medications, suggested signals derived from adverse event reports are complemented by other available information on the safety of the substance, such as adverse events described in clinical studies, case reports, or cohort studies (Strom, 2005). Because there is no premarket ap- proval requirement to conduct a safety assessment for dietary supplements, manufacturers might not perform these studies, and safety data on health effects from products or interactions with other supplements or with other bioactive substances are mostly lacking. Still, both the published literature and studies sponsored by the National Center for Complementary and Al- ternative Medicine of the National Institutes of Health (NIH) can be used to support the attribution of adverse events to use of a particular dietary

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 MONITORING ADVERSE HEALTH EFFECTS supplement. It is also encouraging that an increasing number of reports describe events from drug–dietary supplement interactions, although many are from case studies and not clinical trials. With these serious limitations in the data quality and quantity and with reviews often conducted on a case-by-case basis, the extensive experience and appropriate expertise of the reviewers become critical when identify- ing signals. THE MILITARY’S SYSTEM TO MONITOR ADVERSE EVENTS The monitoring of adverse events related to dietary supplement use as a signal detection system within the military is integral to maintaining the health and optimal performance of military personnel. This monitor- ing system would be a key component of the framework recommended in Chapter 5 and would serve as a criterion to initiate reviews of research and provide important input to military commanders’ policy decisions, as described in Chapter 5. It is especially important that such a system be op- erational at installations where military personnel face extraordinary physi- cal and mental challenges. The military has a system to monitor adverse events from medications but does not currently have a separate and distinct system to monitor adverse events from dietary supplements. Many of the elements needed to implement such a system are already in place. The U.S. Army Medical Command has the official responsibility to make decisions regarding nutrition for all military services and would most likely address dietary supplement use and surveillance as part of that responsibility. This committee commends the military for their initiative in seeking methods to manage the safe use of dietary supplements by the troops; that is, con- ducting specific surveys of dietary supplement use as well as implementing educational programs and policies. The committee also acknowledges the value of past cooperation between the military and the FDA in evaluating adverse event reports from military installations at the time of high concern over ephedra use. This section describes and recommends improvements to the military adverse event monitoring system. It also describes ongoing educational efforts in the military. Military Adverse Event Monitoring System for Medications Each military service has established a system to collect and evaluate data on adverse events related to medication usage. Reports of adverse events are received and evaluated at the local medical treatment facility (MTF). In addition, summary reports are aggregrated and reviewed by the medical headquarters of each service as well as by the Office of the Assistant Secretary of Defense (Health Affairs). In some cases, data are

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL also evaluated at the major command level within each service (e.g., Air Mobility Command, U.S. Army Special Operations Command, or Military Sealift Command). All adverse events potentially associated with the use of medications by Army personnel are reported using MEDMARX,2 a subscription-based, adverse drug reaction database. Briefly, health care personnel (physician, nurse, pharmacist, or other) at an MTF report an event to the MTF phar- macy; it would then be entered into a MEDMARX Adverse Drug Reaction (ADR) Data Entry Form (see Appendix E) by the patient safety manager or other designated person at the pharmacy. The ADR form allows MED- MARX subscribers to collect and analyze reports of adverse drug reactions. The ADR module collects information that describes the adverse reaction, the body system involved, the seriousness of the event, and the result of the reaction on level of patient care; the form also includes the Naranjo Prob- ability Assessment Scale to determine the likelihood that use of a specific substance resulted in the adverse reaction. Adverse event reports might also be submitted via the Vaccine Adverse Event Reporting System (of the Cen- ters for Disease Control and Prevention and the FDA) form or MedWatch 3500 form (Appendix E). The Pharmacy and Therapeutics (P&T) Committee at each MTF— composed of physicians, nurses, pharmacists, and logisticians—is an advi- sory group on all matters relating to the acquisition and use of medications in an MTF. These include review of policies, review of medication errors, evaluation of clinical data on new drugs and preparations requested for use in the MTF, maintenance of the formulary of authorized medications for the installation, and review of drug adverse event reports. The P&T Committee also proposes policy decisions to the medical commander (see Hoerner in Appendix B), from medication selection to restricting availabil- ity or issuing warnings and framing educational activities. It would appear sensible for the P&T Committee in each MTF to oversee the dietary sup- plement functions related to adverse-event monitoring at the local level. 2A national, Internet-accessible database that hospitals and health care systems use to track and trend adverse drug reactions and medication errors. Hospitals and health care systems participate in MEDMARX voluntarily and subscribe to it on an annual basis. It facilitates productive and efficient documentation, reporting, analysis, tracking, trending, and preven- tion of adverse drug events. It allows subscribing facilities to learn valuable lessons from the experiences of other users. Subscribers can access data from a national database of more than 1.1 million adverse drug event records. The data within MEDMARX follow standardized definitions.

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 MONITORING ADVERSE HEALTH EFFECTS BOX 6-1 Dietary Supplement and Other Self-Care Products Committee The Dietary Supplement and Other Self-Care Products Committee (DSOPC) has requested an official charter from DoD Health Affairs. According to their draft charter, the DSOPC shall use peer-reviewed and militarily relevant research, evidence-based data, and the consensus of subject-matter experts to develop recommendations that support DoD activities, policies, and instructions relating to dietary supplements and other self-care products used to enhance health and human performance. Specifically, the DSOPC should do the following: • Establish Memorandums of Understanding with the FDA (1) to identify, in col- laboration with the FDA, adverse events and their association, when possible, with particular dietary supplements and other self-care products used by the U.S. population; (2) to monitor and evaluate records of adverse outcomes for military beneficiaries. • Recommend methodologies for assessing prevalence of use of dietary supple- ments and other performance-enhancing/self-care products across and within DoD active duty populations and their family members. • Review trends on the use of dietary supplements and other performance- enhancing/self-care products. • Assemble and document servicewide activities relating to dietary supplement use, education, and research. • Review servicewide educational approaches for military health care providers (physicians, nurses, dietitians, etc.) and for the active duty population regard- ing the benefits and hazards of dietary supplement and other self-care product use. • Provide recommendations for and prioritize an operationally relevant research agenda on dietary supplements for health and human performance as well as other self-care products. • Develop evidence-based recommendations, in collaboration with other agen- cies, for servicewide policies that provide guidance on the use of dietary supplements and other self-care products for health and human performance for active duty personnel. • Make recommendations to the Office of the Assistant Secretary of Defense for Health Affairs regarding appropriate resourcing and resource sharing for DSOPC initiatives among the services. • Recommend methodology for development of a DoD system-wide communi- cation process for reporting and dissemination of all adverse events, current research initiatives, educational programs, and implementation instructions relating to dietary supplements and other self-care products. • Serve as a consultant on the role of dietary supplements and other self-care products in human performance and health and medical conditions for unified and specified commands upon request. SOURCE: Personal communication, Patricia Deuster, Uniformed Services University of the Health Sciences, June 22, 2007.

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL This committee should review on an annual basis reported adverse events as well as surveys of supplement use by military personnel and, as indicated, recommend to the military leadership immediate action and/or conducting a review of published science-based safety reviews by the review panel. The following are specific responsibilities of the designated oversight committee. Develop adverse event submissions systems The committee recommends the development of two reporting mechanisms, one for use by the health care provider and one for use directly by the service member. The health care provider would enter dietary supplement use information in the pa- tient’s record and submit appropriate adverse event forms to the MTF P&T Committee. In addition, service members should be able to report adverse events without having to arrange a medical appointment. Adverse event report data should be submitted through a toll-free telephone number or interactive website that allows for follow-up by medical personnel. These data should be provided to the MTF P&T Committee in a timely manner to be evaluated along with other adverse events reported from health care providers. The designated oversight committee will clearly define the systems in- tended to submit the adverse event reports, including the forms to be used (e.g., MedWatch, MEDMARX ADR) by health care providers and directly by service members; the committee will also designate a system to catego- rize adverse events by level of severity. Participate in forum or coalition The designated oversight committee should participate in a forum or coalition of military (i.e., the DoD and the corresponding support structures within each military service) and non- military groups for the exchange of data and information related to dietary supplements, including data on adverse event reports (see below). Develop and implement reporting mechanisms For an adverse event re- porting approach to be of value, it is critical to have an efficient system to provide timely information about adverse events to those who need it (e.g., MTF P&T Committees, commanders, fitness centers and unit trainers, health care providers). After adverse event report summaries are written (see below), the flow of information to share adverse event data and sum- maries by the various military groups should be defined (e.g., frequency of reporting and recipients of information). The designated oversight com- mittee should establish a system of information flow that is effective (i.e., information is delivered to decision makers and educators) and timely (see Figure 6-1).

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a c b FIGURE 6-1 Proposed information flow for the recommended adverse-event monitoring system. Formal Chain of Command. Input, coordination, and collaboration. aMD (Doctor of Medicine); RN (Registered Nurse); RD (Registered Dietitian); PharmD. (Doctor of Pharmacy); PA (Physician Figure 6-1, R01214 Assistant). bRepresentatives from each military service, pharmacists, epidemiologists, clinicians, nutritionists, pharmacoepidemiologists. cDesignated oversight committee members, registered dietitians from each military service, USARIEM, pharmacist from the DoD Pharmacoeconomic Center and services, medical representative from each service, FDA’s Center for Food Safety and Applied Nutri- tion, Federal Trade Commission, NIH’s Office of Dietary Supplements, AAFEX/NEX (Army and Air Force Exchange Service/Navy Exchange Service), and other sales outlets located on military installations; industry trade association; Health and Wellness and  Health Promotion Centers from the services, fitness centers or units trainers from the services.

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0 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Collect relevant data The designated oversight committee should identify relevant databases and efforts related to surveillance of adverse events as- sociated with the use of dietary supplements by military and nonmilitary groups. The following information should be collected: • Data on adverse events—This task is related to the designated oversight committee’s participation in a partnership with other military and nonmilitary groups (see below for a list of the type of data and information to be collected). • Information on dietary supplement product ingredients to create a database in collaboration with the FDA, the NIH’s Office of Dietary Supple- ments, the U.S. Department of Agriculture, and the U.S. Pharmacopeia—In the future, such a database would be useful to estimate dosage and ingre- dients consumed and, in turn, to analyze adverse event data. • Data on dietary supplement use and associated benefits and risks, including those from interactions with medications, other dietary supple- ments, or foods—of particular interest are data on risks and benefits when subjects are in environments similar to those experienced by military per- sonnel. These data should be obtained from the expert panel conducting re- views of dietary supplements under the oversight of USARIEM (see Chapter 5). Recommend policy The designated oversight committee should provide guidance to the DoD on military policies and regulations on the safety (and efficacy) of dietary supplement usage, such as strategies, educational programs, and materials highlighting benefits and risks of dietary supple- ment use for military members, as well as for health care professionals (see below). Recommendation 9: The responsibility of the local Medical Treatment Facilities’ Pharmacy and Therapeutics Committees should be extended to reviewing and summarizing the adverse event reports as submitted by health care providers or service members, and preparing and provid- ing summaries via a process recommended by the designated oversight committee. Extension of the responsibility of the MTF’s P&T Committees The mili- tary should assign specific responsibility for the oversight and coordination of the monitoring system and parallel education components at the local level. Because the local MTF P&T Committees already review adverse reac- tions to drugs, the committee concludes that it would be feasible to expand their responsibilities to review adverse reactions to dietary supplements at the local level. Modifications of the pertinent regulations (e.g., AFI 44-102,

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 MONITORING ADVERSE HEALTH EFFECTS Medical Care Management, Paragraph 10.9) to include review and analysis of dietary supplement adverse events at the local level will ensure that local actions are initiated when appropriate. It may also be appropriate to iden- tify the need for organizational units (e.g., Aerospace Medicine and U.S. Army Center for Health Promotion and Preventive Medicine) at the instal- lation level to address dietary supplement usage and safety, as these orga- nizational units have the responsibility to “optimize and enhance human performance” (e.g., AFI 40-101, Health Promotion Program; AFPD 48-1, Aerospace Medical Program; AFI 48-101, Aerospace Medical Program; AFI 40-104, Nutrition Education; AR 40-3, Medical, Dental, and Veterinary Care; and NAVMED P-117, Manual of the Medical Department). Review of adverse events associated with dietary supplement use The committee supports the 2000 memorandum from the Army’s Office of the Surgeon General (DoA, 2000) stating that adverse events believed to be associated with dietary supplements should be documented by health care providers in the patient’s medical record. The committee also supports the local MTF P&T Committees’ notification of any such adverse event by health care providers. The MTF P&T Committees should develop sum- maries of these adverse event reports highlighting dietary supplements of concern and associated adverse events, and particularly emphasizing those concerns related to military performance and environments of specific mili- tary groups (e.g., Special Forces, Rangers). Enhance the expertise of adverse event reviewers Adverse event reviewers should include experts on epidemiology and adverse event surveillance, data mining and statistical techniques, nutrition, toxicology, diagnosis of dis- eases or conditions, physiology, and botany and pharmacognosy. Review- ers should be familiar with the demands and conditions unique to military operations and experienced in identifying serious or unexpected adverse effects, especially when relevant to military performance. Submit reports on adverse events through the military system To ensure that data are available in a timely manner to military commanders and then released to the FDA as the military deems appropriate, summaries of the adverse event reports should be submitted by the MTF’s P&T Com- mittees through a designated system. The frequency and specific process to submit these summaries should be established by the designated oversight committee.

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Recommendation to Share Adverse Event Data and Other Information Related to Dietary Supplements Recommendation 10: The committee recommends that a coalition or forum be established for the exchange of data and information re- lated to dietary supplements, such as data from surveillance of dietary supplement use and adverse events. The committee found that only by establishing a joint forum or coali- tion will there be assurance that key data about reported adverse events would be shared by the FDA, military institutions, PCCs, and others. Although it is not appropriate to make direct comparisons of the data be- cause of differences in data collection approaches, it is advisable to make in-depth examinations that take into consideration these differences and other data limitations. Members of this forum will also share other valuable information regarding new products in the market, increases in popularity of products, and latest research updates (see a list of suggested data and information to share below). With effective communication, there is much to be gained from such collaboration. The members of this forum or coalition would update or add new data to a database established for this purpose. They could also meet periodi- cally to present data and information updates. Members of the designated committee to oversee dietary supplement activities would participate in this coalition and have access to the database. Participants of the forum should include, among others, experts in toxicology and safety evaluation of natural products. Representatives from the following groups could be invited to become part of this partnership: • Designated oversight committee (recommended by this committee to come under the purview of the DoD) • Registered dietitians from the U.S. Air Force, U.S. Army, and U.S. Navy (DoD Nutrition Committee) • USARIEM • Pharmacists from the DoD Pharmacoeconomic Center, U.S. Air Force, U.S. Army, and U.S. Navy • Medical representatives from the U.S. Air Force, U.S. Army, and U.S. Navy • FDA’s Center for Food Safety and Applied Nutrition • Federal Trade Commission (FTC) • NIH Office of Dietary Supplements • Army and Air Force Exchange Service/Navy Exchange Service (AAFES/NEX)

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 MONITORING ADVERSE HEALTH EFFECTS • Other sales outlets located on military installations • Industry trade associations • Health and Wellness and Health Promotion Centers from the U.S. Air Force, U.S. Army, and U.S. Navy • Fitness centers or unit trainers from the U.S. Air Force, U.S. Army, and U.S. Navy • Other representatives To support the goal of the partnership, the collaboration might include sharing information and fostering discussion on the following topics: • Sales outlet reports from AAFES/NEX, Defense Commissary Agency, and/or other sources at military installations to compare sales of dietary supplements from year to year and identify new products intro- duced to the market • Reports from industry trade associations on changes in products and sales trends • Summary of adverse events from specific military installations to identify regional differences, active surveillance data on adverse events at sentinel installations, and overall trends • Summary of FDA adverse event reports as available, including relevant data from the PCCs; in addition, data on health claims of efficacy for dietary supplements would also be shared as appropriate • Summary of FTC evaluation of dietary supplement products • Summary of clinical trials registered by the NIH Center for Alter- native Medicine evaluating dietary supplements • Reports about dietary supplement use from in-depth surveys on sentinel installations—sentinel sites would be selected based on the mission of forces stationed at the installation (e.g., Rangers, Army Special Forces, Air Force Special Operations Command, B-1B long-range bomber crew, Navy Seals) as well as the capacity to conduct such a survey (i.e., provision of electronic health records, health care personnel to manage the additional data collection) (see Chapter 2) • Reports from USARIEM on performance-enhancing supple- ments selected for review as well as a summary of research findings and protocols • Summary of medication and dietary supplement education and materials (e.g., on safety, efficacy, interaction with medications) provided by pharmacy, health-promotion, dietetics, nursing, and medical staff to meet the requirements of the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO, 2007) • Review of efforts by each service to provide education on dietary

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 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL supplements to their personnel (e.g., usage of websites and attendance of meetings about dietary supplements) • Results from DoD’s Survey of Health Related Behaviors that sum- marize trends in use and the characteristics of dietary supplement users Recommendations to Expand Education: Training and Outreach Recommendation 11: Military service members and commanders should be educated to recognize both the potential adverse effects and benefits from using specific dietary supplements and the importance (and the process) of reporting an adverse event. Recommendation 12: Health care personnel should be trained in eval- uating dietary supplement use, informing and obtaining information from their patients, and appropriately reporting adverse events. The committee recommends expansion of all educational programs and outreach activities to increase awareness about the use of dietary supplements. These educational elements are key to the support of an ef- fective, centralized adverse event monitoring system. If the evaluation of these educational activities shows that they are ineffective at improving the quality or rate of adverse event reporting from dietary supplement use, the military could explore additional strategies. For instance, in addition to continuing educational efforts, the DoD could subcontract a dietary supplement information and safety hotline service for military personnel to communicate, anonymously, with a health care specialist. This hotline service would serve two purposes, education of the service member and data collection of adverse events. The following are recommendations for educational activities: Develop educational materials on dietary supplements and balanced nutri- tion, tailored to military members The proposed designated oversight committee should oversee the development of educational materials to be disseminated through a variety of methods (e.g., posters, websites, or point-of-sale brochures). Such educational materials on dietary supplements will describe potential benefits, mechanisms of action, and how to report adverse effects. These materials should focus on the military’s special per- formance requirements and the need to protect each individual’s body and health; messages should connect the need to protect health with the impor- tance of reporting adverse events. These messages should also emphasize that while some symptoms (e.g., diarrhea) are not particularly problematic while in garrison, they may be of concern during deployment when mission readiness becomes critical. When available or displayed at point of sale,

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 MONITORING ADVERSE HEALTH EFFECTS these materials will remind and encourage the service member to contact the user’s primary physician or emergency room in the event that adverse effects are experienced, even if they do not require medical intervention. Actively pursue outreach activities Service members and their command- ers must be educated so that they recognize both the potential adverse ef- fects and the benefits from the use of a given dietary supplement, and the importance of reporting any adverse events to health care providers. This may be achieved through the following approaches: • Include information about dietary supplements in routine com- manders’ calls and communication regarding force protection/performance enhancement and health promotion, to reinforce the concept that some dietary supplements should be used with care and the importance for force protection of reporting adverse effects. Military commanders will be made aware of issues surrounding dietary supplement use as part of their formal education and routinely rely on their medical staff for input. There will also be direct communication with the designated oversight committee or via summary tables and monographs, produced by the review panel, or other educational materials that are provided both to medical staff and commanders. • Consider modifying current contracts for sale of dietary supple- ments to include requirements to allow placement of outreach and edu- cational materials about dietary supplements at point of sale on military installations (e.g., AAFES/NEX outlets and fitness centers). Provide appropriate training and continuing education for health care per- sonnel Health care personnel (e.g., emergency room staff, flight surgeons, medics, dietitians, pharmacists, and health promotion personnel) should improve their abilities to evaluate dietary supplement use, to inform mili- tary members, and to appropriately report adverse events. Education should be included in existing programs (e.g., Uniformed Services University of Health Sciences, internships and residencies, aerospace medicine training, independent duty medical technician training, and mandatory continuing education at medical staff meetings). Education and training should emphasize the following objectives: • Enhance health care personnel’s awareness of and ability to pose relevant questions and provide information to patients about the use of dietary supplements. Identify and direct their patients to credible sources of information (e.g., NIH Office of Dietary Supplements). • Provide guidelines on how to effectively report adverse events. Training should address the following topics: (1) identification of adverse

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