Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
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 âreasonable certainty of no harmâ 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- 336
MONITORING ADVERSE HEALTH EFFECTS 337 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 1994, 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 consumerâs individual susceptibil- ity, or from the dietary supplementâs 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
338 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
MONITORING ADVERSE HEALTH EFFECTS 339 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 FDAâS 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 FDAâs 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 FDAâs 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 FDAâs 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
340 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 FDAâs 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 patientâs 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 FDAâs safety Âofficers, 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 events 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 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).
MONITORING ADVERSE HEALTH EFFECTS 341 MedWatch 3500 in that it also solicits composition information from the product label as well as the manufacturerâs 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
342 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Services (HHS) Office of the Inspector General (OIG) provides a detailed analysis of the effectiveness of the FDAâs 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 FDAâs current sys- tem, many of which also apply to military reporting efforts (see below). Data Collection Process Low reporting rateâ 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 patientâs medical records. Unfortunately, under the current voluntary system, the report rate is lowâthe OIG esti- mated in 2001 that less than 1 percent of all adverse events are reported to the FDAâfor 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 ânatural,â 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, physiciansâ 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-
MONITORING ADVERSE HEALTH EFFECTS 343 ment, media attention, and the level of educational or regulatory activity recently presented. Quality of data collectedâ The quality of information reported by phone or MedWatch 3500 form depends on the reporterâs 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) patientsâ 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.
344 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 substancesâ concomitant use and events (Almenoff et al., 2005). When evaluating these data, a typical challenge derives from a lack of data for the âdenominatorâ (i.e., number of users for each dietary supplement) and low ânumeratorâ 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
MONITORING ADVERSE HEALTH EFFECTS 345 supplement. It is also encouraging that an increasing number of reports describe events from drugâdietary 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 MILITARYâS 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 commandersâ 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
346 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, 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 MTFâ composed of physicians, nurses, pharmacists, and logisticiansâis 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. â A 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.
MONITORING ADVERSE HEALTH EFFECTS 347 Military Policies on Reporting of Adverse Events and Use of Dietary Supplements Regulations A review of the military policies currently in place for dietary supple- ments revealed that they are limited. It has been the policy of the Army Sur- geon General to follow the FDAâs guidance and regulations concerning such products. For example, in 2005, when the FDA announced a crackdown on products containing androstenedione (commonly known as âandroâ), its possession without a prescription became a Class II felony. Possession of the substance by a service member was therefore subject to action under the Uniform Code of Military Justice. In its Nuclear Weapons Personnel Reliability Program Regulation (DoD, 1995), the Department of Defense (DoD) establishes requirements and procedures for the implementation of the program to ensure that only the most reliable people perform duties associated with nuclear weapons. Although there is mention of prohibition of the use of alcohol and certain drugs under this program for safety reasons, there is no mention of restrict- ing the use of dietary supplements. Likewise, there is no reference to the use of dietary supplements or reporting of adverse events included in medical requirements for Army aviation personnel (DoA, 2007). In 2000, the Armyâs Office of the Surgeon General implemented policy specific to dietary supplements with a memorandum directing health care providers to document in the patientâs medical record adverse events be- lieved to be associated with dietary supplements. Health care providers should also notify the local MTF P&T Committees of any such adverse event (DoA, 2000). The memorandum also directed health care providers to report adverse events to the FDA using the MedWatch 3500 form. In addition, per the 2007 Heat Injury Prevention Policy Memorandum from the Armyâs Office of the Surgeon General, all cases of heat exhaustion and heatstroke reported to the Army Medical Surveillance Activity through the Reportable Medical Events System should include any history of dietary supplement use within the previous 2 weeks (USARIEM, 2007). In contrast, while heat injuries are reportable events for all services, neither the Navy nor the Air Force requires dietary supplement use to be reported (personal communication, Asha Riegodedios, Navy Environment Health Center, Oc- tober 26, 2007). There are other entities whose personnel undertake tasks with high risks and demands (e.g., Coast Guard personnel or airline pilots), and their policies to restrict the accessibility and use of dietary supplements are presented here. Recognizing the potential risks associated with dietary supplements, the U.S. Coast Guard, a branch of the Department of Home-
348 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL land Security, has recently implemented regulations to manage the use of dietary supplements. They include not only specifications of the kinds of dietary supplements that may be used by all active duty members and avia- tors (U.S. Coast Guard, 2003), but also provisions for the submission of all reports of patient adverse reactions associated with dietary supplement use (U.S. Coast Guard, 2007). According to Coast Guard regulations, clin- ics shall submit all pertinent patient adverse reactions or product quality problems to the Commandant and the Maintenance and Logistics Com- mand, using the MedWatch 3500 form. Coast Guard pharmacies are not allowed to dispense any product not approved by the FDA (i.e., any herbal supplement or other dietary supplement), with the exception of vitamins having an established Recommended Dietary Allowance. The Federal Avia- tion Administration, responsible for the safety of civil aviation, does not have any regulations or policy guidance concerning the use of vitamins or dietary supplements per se, except for a restriction on the use of melatonin (i.e., its use is prohibited within 12 hours of flight duty). The Air Line Pilots Association advises pilots to avoid dietary supplements that are banned by the FDA or purchased overseas (personal communication, Bill Edmunds, Air Line Pilots Association, January 25, 2008). Education Efforts to educate service members on the safety of specific dietary supplements include brochures and websites (Evans U.S. Army Community Hospital, 2006; Hooah 4 Health, 2007; NEHC, 2004; USACHPPM, 2000, 2003). The Navy and Marine Corps Public Health Center website provides, as part of their ShipShape weight management program, information on dietary supplements and links to the NIH Office of Dietary Supplements (ODS) website (Navy and Marine Corps Public Health Center, 2007). The ODS website offers information on dietary supplements for both the general public and scientists. The Air Force provides online information through the Human Performance Training Team website on its Air Force Knowledge Now portal. The Army offers information on dietary supple- ments on the Army Knowledge Online portal as part of its Ultimate Warrior Hooah Bodies and Weigh to Stay sites. However, there is currently no centralized educational program that is effectively and consistently applied across military services and that consid- ers specific military needs. One promising educational tool currently under development is a joint, online community of health care providers and active duty military personnel (see Jaghab in Appendix B; USACHPPM, 2007). This interactive website provides information about general nutri- tion, weight maintenance, and behavior management, and could be used
MONITORING ADVERSE HEALTH EFFECTS 349 as a centralized educational system to provide information about dietary supplements. The importance of educating health care providers about dietary sup- plements was indicated by results from a 2002 survey of Army Medical De- partment health care providers conducted by the DoD Nutrition Committee in partnership with the U.S. Army Center for Health Promotion and Preven- tive Medicine, in which health care providers asked to be provided with professional development regarding dietary supplements (Corum, 2004). The Aerospace Medicine program for physicians training to become flight surgeons includes specific information on dietary supplements and active ingredients of safety concern in their online preparation materials for the Aerospace Medicine Primary course. However, it does not mention how to report adverse events involving dietary supplements, nor does the curricu- lum include any additional formal training on dietary supplements during the residency phase (Air Force Medical Service, 2007). Physical trainers in military fitness centers or assigned to organizational units are also key sources of information on nutrition and health. More- over, the more casual environment and camaraderie experienced at fitness centers may encourage openness about sharing and requesting information about nutrition needs for optimal performance, health concerns, and even adverse events experienced. Adverse Event Data Collection Process and Analysis: Challenges and Opportunities Unique to the Military In addition to the complications highlighted above that are commonly encountered in monitoring adverse events within the general population, the military faces unique challenges related to the activities of service mem- bers and the locations, culture, and settings in which they operate. Chal- lenges and opportunities discussed below relate to the collection of data and analysis by using the electronic health records system. Data Collection Process Low reporting rate in the militaryâ Factors contributing to a low reporting rate in the general civilian population are also encountered by the military: inconsistent definitions of the term adverse event, a voluntary monitoring system, poor communication with health care providers (e.g., reluctance to report dietary supplement use and adverse events as well as lack of discus- sions about dietary supplement use during medical visits), little consumer awareness of their potential harmful effects, belief that the federal govern- ment regulates dietary supplements in the same manner as medications, and a perception that dietary supplements are inherently safe.
350 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Other factors also affect the reporting level in the military. For example, there is no separate system to report adverse events associated with dietary supplements. The extent to which military health care providers are follow- ing the few existing military policies on dietary supplement use is also not known. Despite policies and educational efforts mentioned in the section above, recent surveys of military personnel presented to this committee indicate that a low percentage of respondents (33 percent of men and 53 percent of women among those confirming use of dietary supplements dur- ing the previous 12 months) discuss the use of dietary supplements with their health care providers (see Marriott et al. in Appendix B). Likewise, a 2002 survey conducted by the DoD Nutrition Committee in partnership with the U.S. Army Center for Health Promotion and Preventive Medicine found that only about 60 percent of primary health care providers ask their patients about dietary supplement use (Corum, 2004). Data suggest that the military reporting rate may be lower than that in the civilian popula- tion, as shown in a survey about reporting smallpox vaccine adverse events, even when adjusting for differences in representation of age and gender of subjects (McMahon et al., 2007). McMahon et al. speculated that factors contributing to this finding could be related to differences in behavior (i.e., civilian population having a lower threshold for reporting adverse events), accessibility to forms, or differences in policy implementation. Contributing to the problem of low reporting rate is the fact that those responsible for providing education about healthy and safe behaviors, such as military commanders or medical personnel, are themselves inadequately informed about the benefits and risks of consuming dietary supplements (Corum, 2004). Physical trainers at fitness centers and assigned to organiza- tional units might also lack such information. As a result, service members are not educated about dietary supplements at the fitness center or the treatment facility. The lack of knowledge in both patient and health care provider (or physical trainer) about dietary supplements of specific interest to the military would contribute to the infrequency of reporting adverse events associated with dietary supplement use. An already low rate of reporting within the U.S. civilian population might be further diminished within the military by the fact that command- ers have access to service membersâ protected health information. For ex- ample, medical officers are allowed to share patientsâ medical information with the commanding officer without requiring specific consent, provided that service members are adequately warned that medical record informa- tion is not confidential (DoD, 2003). This practice may restrain the willing- ness of service members to talk freely with military health care providers about their dietary supplement use. Other factors that may contribute to a low reporting rate might be related to unique political and cultural charac- teristics of military service, including mobility of the troops.
MONITORING ADVERSE HEALTH EFFECTS 351 Quality of data collectedâ The causes for low data quality or gaps in data that were identified in the FDA monitoring system are also relevant to the military system: lack of familiarity with medical reporting procedures, a Â bsence of a formalized process to probe for additional information, and challenges in obtaining data on dose consumed and dietary supplement product ingredients as well as effects from simultaneous consumption of other dietary supplements or medications. In addition, adverse event data may be submitted through various methods (e.g., FDA MedWatch forms, M Â EDMARX form, or the Army Reportable Medical Events System); this lack of integration allows for both duplication and absence of event reports. Electronic Health Record Limitations and Opportunities The military has unique opportunities not only because health care for most service members is provided within a single DoD system, but also because the military is taking pioneering steps toward the develop- ment of an electronic health records system. Despite its potential to be a state-of-the-art system, the current electronic medical record-keeping system (Armed Forces Health Longitudinal Technology Application) does not include dietary supplements as part of the patientâs medication profile. Their use can be missed if the health care provider is not trained to inquire about it. Only some dietary supplements (i.e., vitamins and minerals) are included in the medication formulary of an MTF; their use can then be entered into the patientâs record, which allows for the possibility of estab- lishing relationships between reported adverse events and the use of these dietary supplements. The switch from a paper-based system to an electronic system of docu- menting health-related data is in progress and will result in a longitudinal, centralized health care records system that is accessible anywhere, from the battlefield to large hospitals. This system will serve as a central, integrated clinical data repository where each patient has a single record; it will al- low for aggregate analysis of data, drug interaction alerts, and patient allergy notifications (Charles et al., 2004). Such a modern computerized system will improve the ability to detect and attribute adverse events. For instance, such a system might be used to create computer-generated signals as a tool for identifying (and possibly preventing) likely specific adverse events or high-risk interactions of dietary supplements with medications or other dietary supplements, as an additional strategy to detect adverse events (Gardner and Evans, 2004). For example, a physician entering a prescription medication might be alerted to the specific risks of product interaction if the patient is using a given dietary supplement. A number of vendors have developed programs that are capable of generating alerts for medication interactions, but for most dietary supplements, the knowledge
352 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL base for a similar system is not yet available. Clearly, it would be advan- tageous, albeit time-consuming, for the military to establish place-, unit-, or mission-specific alert rules in a manner that results exclusively in alerts that are pertinent (i.e., false alerts are minimized). In summary, if a mod- ule including dietary supplements were developed and incorporated in the patientâs medication profile, this improved electronic system would permit not only the analysis of an individual adverse event, but also the analysis of dietary supplement use and adverse event trends among users in military subpopulations. Strategies to automate alerting mechanisms to prompt evaluation and reporting of adverse effects might help compensate for the problem of low reporting rates. PROPOSED ADVERSE EVENT SURVEILLANCE SYSTEM FOR DIETARY SUPPLEMENTS FOR THE MILITARY The Dietary Supplement and Nonprescription Drug Consumer Protec- tion Act of 2007 mandates that dietary supplement manufacturing compa- nies report life-threatening events to the FDA. Non-life-threatening adverse events are to be recorded by the manufacturer, and records retained for 6 years in case the FDA needs to inspect the information. This act defines the term adverse event very broadly as any health-related event associated with the use of a dietary supplement that is adverse. The term adverse event might identify a different effect in the context of the military. That is, the success of a military operation depends on each memberâs optimal performance, and thus effects that might not be perceived as a serious problem in the general population (e.g., dehydration) might constitute a significant problem in the military context, depending on the unit and task. It is therefore critical that specific adverse effects that might pose harm to military performance be reported so that leadership can take appropriate actions. With this in mind, the committee has chosen to use the FDAâs definitions of adverse events and serious adverse events. For the military, the distinction between them is based on the extent of decrement to either the performance or the survivability of service members, taking into consideration their tasks (both physical and mental), the environ- mental surroundings (e.g., high altitude, extreme temperatures), and risks (e.g., bleeding, dehydration, infection, stress). A list of conditions to help categorize adverse events as of high, moderate, low, and minimal concern is shown in Box 5-1. The committeeâs reviews of selected dietary supplements show that some supplements in popular use might present health and performance problems if misused, particularly for those subpopulations facing demand- ing tasks. For example, Ginkgo biloba and garlic have anticoagulant effects that in a combat situation might result in extended bleeding, jeopardiz-
MONITORING ADVERSE HEALTH EFFECTS 353 ing health and mission success. Other supplements should not be taken while performing tasks that require alertness because of their potential for sedative effects (e.g., valerian or melatonin). The use of ephedrine-like substances is also of concern because of potential harmful cardiac effects. In addition, sales data provided to the committee indicate high use of some multi-ingredient dietary supplements; the effects of ingredient interactions are mostly unknown and present concerns. Based on the heightened risks, frequency of use among military service members, the lack of consistent policies, and the absence of a military process to report adverse events, a separate system for use by the military to monitor and evaluate adverse effects from dietary supplements is warranted. This section describes the committeeâs recommendations to establish such a system. Ideally, a successful surveillance system will be economical, simple to use, and easily accessible, and yield data that are accurately representative of the population (Woolf, 2006). The data should be collected efficiently and in a consistent, unbiased manner. Vital to the effectiveness of the system is a database that allows for integrated and expeditious data analysis so that dissemination of findings to key public health officials and command- ers is timely. It is also critical that encouragement to report adverse events be provided by broadening educational programs and outreach activities addressing various aspects of dietary supplement use, particularly the im- portance of reporting adverse events. The lower cost of a voluntary system would make it more appropriate than an active system for use within the military population, provided that rates of response are substantially increased by educational programs and outreach activities. Active surveillance should be conducted occasionally as a tool to detect or investigate signals of concern from dietary supplements at installations whose military personnel face highly demanding tasks (e.g., Rangers or Special Forces). An active system entails a regular, periodic collection of case reports from health care providers or other personnel at those military installations. To support the data, questions about adverse effects should be included in surveys of dietary supplement use administered at these sentinel installations (see Chapter 2). The committee also emphasizes that there is much to be gained from collaboration with other groups. The regulatory environment has not al- ways been able to keep up with the market growth of dietary supplements. There is no single system in place for surveillance of adverse events as- sociated with dietary supplements; nongovernmental organizations, gov- ernment agencies, and manufacturers have implemented new systems or adapted systems that were already in operation for other products. Any military system of surveillance should complement its data with data from other governmental agencies and industry. Clearly, there are many limita- tions that would impede comparisons with databases maintained by other
354 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL organizations (e.g., Consumer Product Safety Commission, the FDA, the American Association of Poison Control Centers), manufacturers, and trade associations (e.g., the American Chemistry Council, Consumer Specialty Products Association) (see description of their limitations in Kingston in Appendix B). While it is not feasible to directly integrate or equate data from these various sources, it is advisable to make in-depth comparisons, taking into consideration differences and limitations of data collection. A key committee recommendation is the formation of a partnership in which various parties with common interests work together in building knowledge by sharing collected data. Appendix B includes a description of postmarket surveillance efforts by both the private and public sectors. Also described is the surveillance system for products regulated by the U.S. Environmental Protection Agency, a system that engages the manufacturer as the primary point of contact for reporting adverse events. This industry role entails a significant training component or outsourcing of the surveillance system and design of a database and collection system. The following section describes the committeeâs recommendations in three different areas: (1) the collection and analysis of adverse event surveil- lance data, (2) sharing of adverse event surveillance data, and (3) training and outreach. To increase the reporting rate of adverse events, various strategies have been recommended: (1) the education of commanders, ser- vice members, and military health care personnel; (2) dual mechanisms for reporting adverse events, that is, one directly from service members and one from health care personnel; (3) a centralized reporting system; and (4) the establishment of a forum or coalition with other groups to share data from the general population on adverse events. Recommendations present actions to take and identify the military or- ganization logically responsible for implementing them. The committee did not attempt to include all the military organizations that might be involved with educational, decision-making, research, or other activities, but rather provided a broad organizational picture of the responsibilities. Recommendations for the Collection and Analysis of Adverse Event Data The recommendations in this section are related to the following ques- tions: What is the process by which the military should monitor adverse events resulting from the use of dietary supplements? How would com- manders get information in a timely fashion? How can reporting rates and data quality be improved? A critical analysis of the 2002 survey by the U.S. Army Center for Health Promotion and Preventive Medicine recommends various educa- tional tools, but also urges that reports of adverse events associated with dietary supplements be reported through the Army Reportable Medical
MONITORING ADVERSE HEALTH EFFECTS 355 Events System. Regardless of the form used to report adverse events (e.g., MEDMARX, MedWatch 3500 form, Army Reportable Medical Events Systemâs ADR, or other), the analysis and decision-making activities would be realized more efficiently by using a centralized process in which data are reported through an integrated electronic health record system as described earlier in this chapter. The following are recommendations to expand the current system to include reporting of adverse events from dietary supple- ments. Since collaboration will be critical to the success of an adverse-event monitoring system, other organizations may also play a contributory role in collecting or sharing information. Recommendation 7:â The military should use a centralized monitor- ing system for reporting dietary supplement adverse events (and data on use), in which data are recorded through the integrated electronic health record system already being implemented in the military. Improvement of the Electronic Health Records System The military should ensure that future electronic health records ad- equately capture dietary supplement use and adverse event data. (As the military continues to move toward a single electronic health record for each service member, provisions will be needed to ensure entry of data on dietary supplement use and adverse events when service members receive health care from providers not located in the MTFs.) Implementation of a centralized system will have to address difficulties such as the need for ad- ditional staff time and training efforts to collect, identify, and code dietary supplements being used. In particular, the electronic system should do the following: â¢ Prompt the health care provider to ask the patient about dietary supplement use, safety, and benefits and to submit adverse event reports. It would also be appropriate to add a standard assessment question(s) as part of the routine office check-in, including inquiry about the patientâs reasons for taking any supplements reported used. â¢ Create standardized reports that can be aggregated for analysis (e.g., at the MTF, or based on common mission requirements, deployment status, and branch of service). Reports would include data on frequency of use and adverse events. â¢ Generate automated alerts in response to significant change in usage or reports of adverse events attributed to a dietary supplement of particular interest, which would help with adverse event attribution and identification of trends. This feature could be customized for use at various
356 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL levels (e.g., at the MTF, or based on common mission requirements, deploy- ment status, or branch of service). â¢ Generate automated alerts for individual patients when there is a risk of dietary supplement interaction with a medication or other treatment. Recommendation 8:â The military should designate a committee or military entity to be responsible for the oversight and coordination of dietary supplement-related activities, such as overseeing the adverse- event surveillance system and parallel educational components. Based on the heightened risks, the frequency of use among military service members, the lack of consistent policies, the suspected associations between adverse events in the field and the use of dietary supplements, the absence of a military system to report these adverse events, and the potential consequences of the unguided use of dietary supplements for an individualâs health or mission success, a military entity or committee (hereafter referred to as the designated oversight committee) should be designated to oversee, coordinate, and provide guidance related to the use of dietary supplements by military personnel. The alternative, continuing without a designated group, would perpetuate the suboptimization of the existing resources and data and continue to put military members at risk owing to a lack of science-based guidance, education, and policy. The com- mittee recognizes that establishing a new entity might not be feasible, and the tasks of an existing military committee or entity could be expanded to include responsibilities related to dietary supplements. In addition to a key role in designing an adverse event reporting system for dietary supplements, this oversight committee should have access to military and nonmilitary information and data, and provide advice on surveillance, educational programs, adverse event reporting, and research activities (see a description of these tasks below). The actual operational and data collection activities would rest with other existing military organizations, such as U.S. Army Research Institute of Environmental Medicine (research), the Center for Health Promotion and Preventive Medicine (educational materials), or DoDâs Health Affairs Office (surveillance). This designated oversight committee should include the expertise of nutritionists, dietitians, epidemiologists, toxicologists, pharmacists, experts on adverse event reporting, physiologists, health promotion staff, health educators, physicians and health care providers, and military leadership. One possibility to consider would be to include oversight for these activities in the formal charter of the DoD Dietary Supplement and Other Self-Care Products Committee under the authority of the Office of the As- sistant Secretary of Defense (Health Affairs) (see Box 6-1), which addresses nutrition issues including those relating to dietary supplements.
MONITORING ADVERSE HEALTH EFFECTS 357 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: â¢ 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. â¢ 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. â¢ Review trends on the use of dietary supplements and other performance- enhancing/self-care products. â¢ Assemble and document servicewide activities relating to dietary supplement use, education, and research. â¢ 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. â¢ 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. â¢ 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. â¢ 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. â¢ 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. â¢ 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.
358 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 systemsâ 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- tientâs 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 coalitionâ 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 mechanismsâ 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).
a c b FIGURE 6-1â 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 Assistant). Figure 6-1, R01214 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, FDAâs Center for Food Safety and Applied Nutri- tion, Federal Trade Commission, NIHâs 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 359 Health Promotion Centers from the services, fitness centers or units trainers from the services.
360 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Collect relevant dataâ 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: â¢ Data on adverse eventsâThis task is related to the designated oversight committeeâs 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). â¢ Information on dietary supplement product ingredients to create a database in collaboration with the FDA, the NIHâs Office of Dietary Supple- ments, the U.S. Department of Agriculture, and the U.S. ÂPharmacopeiaâIn the future, such a database would be useful to estimate dosage and ingre- dients consumed and, in turn, to analyze adverse event data. â¢ Data on dietary supplement use and associated benefits and risks, including those from interactions with medications, other dietary supple- ments, or foodsâof 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 policyâ 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:â The responsibility of the local Medical Treatment Facilitiesâ 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 MTFâs P&T Committeesâ 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,
MONITORING ADVERSE HEALTH EFFECTS 361 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 âoptimize and enhance human performanceâ (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 useâ The committee supports the 2000 memorandum from the Armyâs 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 patientâs medical record. The committee also supports the local MTF P&T Committeesâ 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 reviewersâ 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 systemâ 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 MTFâs 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.
362 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Recommendation to Share Adverse Event Data and Other Information Related to Dietary Supplements Recommendation 10:â 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: â¢ Designated oversight committee (recommended by this committee to come under the purview of the DoD) â¢ Registered dietitians from the U.S. Air Force, U.S. Army, and U.S. Navy (DoD Nutrition Committee) â¢ USARIEM â¢ Pharmacists from the DoD Pharmacoeconomic Center, U.S. Air Force, U.S. Army, and U.S. Navy â¢ Medical representatives from the U.S. Air Force, U.S. Army, and U.S. Navy â¢ FDAâs Center for Food Safety and Applied Nutrition â¢ Federal Trade Commission (FTC) â¢ NIH Office of Dietary Supplements â¢ Army and Air Force Exchange Service/Navy Exchange Service (AAFES/NEX)
MONITORING ADVERSE HEALTH EFFECTS 363 â¢ Other sales outlets located on military installations â¢ Industry trade associations â¢ Health and Wellness and Health Promotion Centers from the U.S. Air Force, U.S. Army, and U.S. Navy â¢ Fitness centers or unit trainers from the U.S. Air Force, U.S. Army, and U.S. Navy â¢ Other representatives To support the goal of the partnership, the collaboration might include sharing information and fostering discussion on the following topics: â¢ Sales outlet reports from AAFES/NEX, Defense Commissary Agency, and/or other sources at military installations to compare sales of d Â ietary supplements from year to year and identify new products intro- duced to the market â¢ Reports from industry trade associations on changes in products and sales trends â¢ Summary of adverse events from specific military installations to identify regional differences, active surveillance data on adverse events at sentinel installations, and overall trends â¢ 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 â¢ Summary of FTC evaluation of dietary supplement products â¢ Summary of clinical trials registered by the NIH Center for Alter- native Medicine evaluating dietary supplements â¢ Reports about dietary supplement use from in-depth surveys on sentinel installationsâsentinel 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) â¢ Reports from USARIEM on performance-enhancing supple- ments selected for review as well as a summary of research findings and protocols â¢ 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) â¢ Review of efforts by each service to provide education on dietary
364 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL supplements to their personnel (e.g., usage of websites and attendance of meetings about dietary supplements) â¢ Results from DoDâs 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:â 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:â 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 membersâ 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 militaryâs special per- formance requirements and the need to protect each individualâs 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,
MONITORING ADVERSE HEALTH EFFECTS 365 these materials will remind and encourage the service member to contact the userâs primary physician or emergency room in the event that adverse effects are experienced, even if they do not require medical intervention. Actively pursue outreach activitiesâ 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: â¢ Include information about dietary supplements in routine com- mandersâ 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. â¢ 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- sonnelâ 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: â¢ Enhance health care personnelâs 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). â¢ Provide guidelines on how to effectively report adverse events. Training should address the following topics: (1) identification of adverse
366 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL events of interest to the military (see Box 5-1), (2) the forms and process used to report adverse events, (3) effective collection of the data necessary to evaluate an adverse event (e.g., include listing of different names by which the dietary supplement is known; prompt patient on whether the product information was confirmed from product label or website, whether product was taken in accordance with instructions on the product label, and to identify any other medications, dietary supplements, or foods con- sumed; verify contact information for follow-up), and (4) actions likely to be considered based on adverse event monitoring reports. REFERENCES Air Force Medical Service. 2007. AMP aerospace medicine primary course. Self-imposed stressors. http://184.108.40.206/amp/Mod02/SCO10/asset1.htm (accessed November 8, 2007). Almenoff, J., J. M. Tonning, A. L. Gould, A. Szarfman, M. Hauben, R. Ouellet-Hellstrom, R. Ball, K. Hornbuckle, L. Walsh, C. Yee, S. T. Sacks, N. Yuen, V. Patadia, M. Blum, M. Johnston, C. Gerrits, H. Seifert, and K. LaCroix. 2005. Perspectives on the use of data mining in pharmacovigilance. Drug Saf 28(11):981-1007. Ashar, B. H., R. G. Miller, C. P. Pichard, R. Levine, and S. M. Wright. 2008. Patientâs under- standing of the regulation of dietary supplements. J Community Health 33(1):22-30. Charles, M. J., B. J. Harmon, and P. S. Jordan. 2004. Improving patient safety with the mili- tary electronic health record. Adv Patient Saf 3:23-34. Corum, S. J. C. 2004. Dietary supplement use in the military: Do Army health care providers know enough? AMEDD PB 8-04-1/2/3:36-38. DoA (Department of the Army). 2000. Memorandum: OTSG policy on medical screen- ing for dietary supplement use. http://chppm-www.apgea.army.mil/doem/pgm34/HIPP/Â PolicyScreeningDietarySupplementUse.pdf (accessed March 11, 2008). DoA. 2007. Army regulation 40â501: Standards of medical fitness. http://www.apd.army. mil/pdffiles/r40_501.pdf (accessed October 25, 2007). DoD (Department of Defense). 1995. Nuclear Weapons Personnel Reliability Program (PRP). http://www.fas.org/nuke/guide/usa/doctrine/dod/dodd-5210_42.htm (accessed September 6, 2007). DoD. 2003. DoD health information privacy regulation. http://www.dtic.mil/whs/directives/ corres/pdf/602518r.pdf (accessed October 25, 2007). Evans U.S. Army Community Hospital. 2006. Safety awareness bulletin for dietary supple- ments. http://evans.amedd.army.mil/ncd/dietarysupplementalert.htm (accessed October 24, 2007). FDA (U.S. Food and Drug Administration). 2007. From test tube to patient: The FDAâs drug review process: Ensuring drugs are safe and effective. http://www.fda.gov/fdac/special/ testtubetopatient/drugreview.html (accessed September 4, 2007). Figueiras, A., F. Tato, J. Fontainas, and J. J. Gestal-Otero. 1999. Influence of physiciansâ atti- tudes on reporting adverse drug events: A case-control study. Med Care 37(8):809-814. Gardner, R. M., and R. S. Evans. 2004. Using computer technology to detect, measure, and prevent adverse drug events. J Am Med Inform Assoc 11(6):535-536. Haller, C. A., T. Kearney, S. Bent, R. Ko, N. L. Benowitz, and K. Olson. In Press. Dietary supplement adverse events: Report of a one-year poison control center surveillance project. J Med Toxicol.
MONITORING ADVERSE HEALTH EFFECTS 367 Hand, D. J., H. Manilla, and P. Smyth. 2001. Principles of data mining. Cambridge, MA: MIT Press. Hooah 4 Health. 2007. Herbs for health. http://www.hooah4health.com/body/nutrition/herbs. htm (accessed March 20, 2007). IOM (Institute of Medicine). 2005. Dietary supplements: A framework for evaluating safety. Washington, DC: The National Academies Press. IOM. 2007. The future of drug safety: Promoting and protecting the health of the public. Washington, DC: The National Academies Press. JCAHO (Joint Commission on the Accreditation of Healthcare Organizations). 2007. Com- prehensive accreditation manual for hospitals: The official handbook. Chicago: Joint Commission Resources. LSRO (Life Sciences Research Office). 2004. Recommendations for adverse event monitoring programs for dietary supplements. Bethesda, MD: Life Science Research. McMahon, A. W., C. Zinderman, R. Ball, G. Gupta, and M. M. Braun. 2007. Comparison of military and civilian reporting rates for smallpox vaccine adverse events. Pharmacoepi- demiol Drug Saf 16(6):597-604. Navy and Marine Corps Public Health Center. 2007. Weight management (SHIPSHAPE). http://www-nehc.med.navy.mil/hp/shipshape/ShipShape_Nutrition/About_Nutrition.htm (accessed December 4, 2007). NEHC (Navy Environmental Health Center). 2004. NEHC nutri-facts dietary supplements. http://www-nehc.med.navy.mil/downloads/hp/NutrFact_Dietary%20Supplements.pdf (accessed October 24, 2007). OIG (Office of Inspector General). 2001. Adverse event reporting for dietary supplements: An inadequate safety valve. Department of Health and Human Services OEI-01-00-00180. Strom, B. L. 2005. Pharmacoepidemiology, 4th ed. Chichester, England: John Wiley & Sons. USACHPPM (U.S. Army Center for Health Promotion and Preventive Medicine). 2000. Module 5: Dietary supplements: A basic guide. http://chppm-www.apgea.army.mil/dhpw/ Wellness/PPNC/PM_MOD5.pdf (accessed October 24, 2007). USACHPPM. 2003. The warfighterâs guide to dietary supplements: What you really need to know. http://chppm-www.apgea.army.mil/documents/TG/TECHGUID/TG295.pdf (ac- cessed October 24, 2007). USACHPPM. 2007. U.S. Army Center for Health Promotion and Preventive Medicine. http:// chppm-www.apgea.army.mil/ (accessed October 29, 2007). USARIEM (U.S. Army Research Institute of Environmental Medicine). 2007. Memo- randum: Heat injury prevention policy. http://www.usariem.army.mil/DOWNLOAD/ HeatInjuryPrevention2007.pdf (accessed October 25, 2007). U.S. Coast Guard. 2003. Coast Guard aviation medicine manual. http://www.uscg.mil/ directives/cim/6000-6999/CIM_6410_3.pdf (accessed November 6, 2007). U.S. Coast Guard. 2007. Chapter 10: Pharmacy operations and drug control. In Coast Guard medical manual. http://www.uscg.mil/hq/cg1/cg112/docs/mm/ch2/mmch10.pdf (accessed November 6, 2007). Woolf, A. D. 2006. Safety evaluation and adverse events monitoring by poison control centers: A framework for herbs and dietary supplements. Clin Toxicol (Phila) 44(5):617-622.