Executive Summary

BACKGROUND

The U.S. Army Medical Research and Materiel Command is addressing the increasingly contentious issue of the effects of exposures to drugs, chemicals, and biologics and their possible interactions. U.S. troops receive a number of routine immunizations, and when they are deployed they may be given antimalarial drugs, anti-biological warfare drugs and vaccines, and additional vaccines to protect them against indigenous diseases. They may be further exposed to a number of chemicals, such as permethrin or N,N-diethyl-m-toluamide (DEET), and to environmental contaminants and warfare by-products; some personnel will also be using individually prescribed and over-the-counter medications. Although the adverse effects of most single products have been relatively well studied (for example, in the data submitted to the Food and Drug Administration [FDA] for approval of a new drug), it is largely unknown whether their combined use may provoke unanticipated interactions. For the purposes of this report, agents are said to interact if the presence of one agent affects an exposed individual's reactivity to other agents.

The U.S. Army contracted with the Institute of Medicine to address the issue of the interactions of drugs, chemicals, and biologics. The Institute assembled a committee of experts in pharmacology, drug safety assessment, immunology, vaccinology, epidemiology, biostatistics, occupational health, environmental health, toxicology, and biomedical administration. The names of potential committee members were sought from a variety of sources, and the final committee roster was approved by the chairman of the National Research Council.



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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces Executive Summary BACKGROUND The U.S. Army Medical Research and Materiel Command is addressing the increasingly contentious issue of the effects of exposures to drugs, chemicals, and biologics and their possible interactions. U.S. troops receive a number of routine immunizations, and when they are deployed they may be given antimalarial drugs, anti-biological warfare drugs and vaccines, and additional vaccines to protect them against indigenous diseases. They may be further exposed to a number of chemicals, such as permethrin or N,N-diethyl-m-toluamide (DEET), and to environmental contaminants and warfare by-products; some personnel will also be using individually prescribed and over-the-counter medications. Although the adverse effects of most single products have been relatively well studied (for example, in the data submitted to the Food and Drug Administration [FDA] for approval of a new drug), it is largely unknown whether their combined use may provoke unanticipated interactions. For the purposes of this report, agents are said to interact if the presence of one agent affects an exposed individual's reactivity to other agents. The U.S. Army contracted with the Institute of Medicine to address the issue of the interactions of drugs, chemicals, and biologics. The Institute assembled a committee of experts in pharmacology, drug safety assessment, immunology, vaccinology, epidemiology, biostatistics, occupational health, environmental health, toxicology, and biomedical administration. The names of potential committee members were sought from a variety of sources, and the final committee roster was approved by the chairman of the National Research Council.

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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces Using a broad range of sources, the committee informed itself on this topic. The committee reviewed the available scientific literature and heard testimony from officials of the U.S. Army, the FDA, the Centers for Disease Control and Prevention (CDC), and the British Ministry of Defence (a list of presenters can be found in the Appendix). THE COMMITTEE'S CHARGE The committee was asked to address the following questions: What are the drugs, biologics, and chemicals that U.S. military forces currently receive as prophylactic-preventive agents, and what additional prophylactic-preventive agents are planned? What does the published scientific literature tell us about the health effects of combinations of these prophylactic-preventive agents in the U.S. military, in other human populations, or in model systems (e.g., animal, in vitro, and computer)? Do the experiences of the militaries of other nations shed any light on issues #1 and #2? If there are important gaps in our knowledge, where are they and how would they best be filled? Should, and in what way, the Army modify or expand its development and utilization strategies to ascertain possible interactions of prophylactic-preventive agents? Should the Army undertake any new programs to provide information on drug, biologic, and chemical interactions? SCOPE OF THE PROBLEM The number of potential drugs, chemicals, and biologics to which military personnel may be exposed is quite large (see Chapter 2), and a complete study of their interactions would by necessity involve examination of all their possible combinations. For example, in the case of 25 agents, there are 225 – 1 (or 33,554,431) combinations. To reduce the problem to a more manageable level, the committee advocates a categorical approach to the study of interactions. This approach would categorize interactions into three classes—Known, potential, and unknown—so that different strategies may be applied to each class. Known interactions are those for which there is documented evidence of risk in humans; potential interactions are those that are known from animal studies, or that can be anticipated or predicted on the basis of the individual properties—for example, target organ toxicities—of the agents in putative combinations; and un-

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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces known interactions that are those that cannot be anticipated on the basis of current knowledge. Once the interactions are categorized, specific strategies can be put into place for their study. Table E-1 summarizes the categorical approach. CATEGORICAL APPROACH The committee recommends that a matrix approach be used to identify interactions for which data from studies with experimental animals are lacking. Such an approach, if it is designed appropriately, will help to identify commonalities between agents that may predispose these agents to interactions. The matrix approach is an iterative one; as agents are added or deleted from the matrix or entries are modified, the matrix must be updated and reexamined for potential interactions. In some instances interactions may not be identified by examining the matrix. For example, DEET will enhance the dermal penetration of some chemicals and thus facilitate the interaction. Alternatively, since there is no one method that can be used to identify and predict all possible interactions, the committee proposes the use of a tiered approach for conducting prospective animal studies. By this approach, potential hazards can first be identified in appropriately chosen in vitro studies. Studies can then be extended to in vivo animal models, choosing appropriate species and experimental designs. TABLE E-1 Categorical Approach Interaction Type Recommended Approaches Known Avoid unless benefit outweighs risk Use surveillance to monitor outcomes and implement appropriate intervention Study in depth Potential Use matrix approach to predict or identify the interaction Conduct studies (in vitro, animal, or human volunteer) Use surveillance Unknown Put in place surveillance systems to detect sentinel events and do follow-up studies Do prospective screening studies of important combinations The committee emphasizes that this approach is just one practical method that can be used to grapple with a difficult subject; there are no completely fail-safe methods. Even if it were possible to study all combinations of agents in epidemiologic or animal model systems, it is unlikely that such a strategy would work. Many confounding factors would be encountered in epidemiologic studies; for example, host susceptibility factors such as age, race, sex, and comorbid conditions could affect the results. In the case of experimental studies, although

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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces randomization minimizes the effects of confounding variables, there remain the problems of multiple comparisons and sample size considerations. AVAILABLE LITERATURE Despite the existence of more than 10,000 publications on drug interactions in the medical literature, the epidemiology of these interactions is poorly understood. Only a very small percentage of all of the scientific literature on interactions has resulted from epidemiologic investigations. The remainder of the literature primarily comprises pharmacokinetic or pharmacodynamic studies with humans and animals, case reports, review articles, animal studies, or in vitro studies. Thus, the existing literature provides very little information about how often drug interactions actually occur in humans or how often they produce clinically meaningful adverse effects. Similarly, the medical literature pertaining to biologics and chemicals does not provide adequate information on the interactions of all three agents. The committee's own Medline search did not turn up any additional notable articles related to its charge, although some articles of interest may be found in the reference list. USES OF AUTOMATED MULTIPURPOSE DATABASES FOR EPIDEMIOLOGIC SURVEILLANCE The categorical approach to the study of interactions advocated in this report presumes that a large proportion of interactions will be unknown. Therefore, a comprehensive strategy for studying such interactions must depend on surveillance. This requires both alerting mechanisms to signal that unanticipated health effects may have occurred and the gathering of confirmatory data to estimate the incidence of these events and to determine if they were due to some particular exposure. Alerting mechanisms include case reports as well as broad monitoring programs designed to search for changes in rates of clinically important events. Such efforts also encompass the analysis of accidents or so-called natural experiments. In contrast, confirmatory data collection and analysis will be more focused on specific hypotheses. Such confirmatory data may be obtained from cohort studies or case-control studies, as well as randomized experiments and intervention studies, which include cessation of use studies. Automated multipurpose databases are increasingly being used for epidemiologic purposes, including surveillance. Examples of such multipurpose databases used in epidemiologic studies of drug effects include those assembled from the records of health maintenance organization enrollees, Medicare or Medicaid populations, military or U.S. Department of Veterans Affairs cohorts, or some other defined populations. Such databases are considered to be popula-

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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces tion-based if the information that they contain is derived from some underlying population in the statistical sense, specifically, some group of known size and composition from which statistical samples might be drawn. In carefully designed studies, multipurpose databases offer a number of advantages: the ability to conduct studies of uncommon health events or of understudied but well-defined populations, the minimization of study costs, a reduction in the amount of time needed to conduct a study, and the opportunity to study a large number of people. However, studies based on multipurpose data sets are affected by a number of potential problems, including completeness and the quality of the data. Although no perfect surveillance systems exist, much can be learned from the currently available databases. The report briefly describes Army and U.S. Department of Defense (DoD) surveillance activities that are in current use or in development, as well as other sources of material from which to assemble multipurpose databases. In addition, the report also briefly discusses relevant U.S. Department of Veterans Affairs databases and two other nonmilitary systems— the Vaccine Adverse Event Reporting System, managed jointly by CDC and FDA, and FDA's medical products reporting program, MEDWatch—that can provide useful information. The surveillance tools currently available to the military comprise a series of linkable automated databases. Opportunities for creating automated multipurpose databases have already been seized; the Army Medical Surveillance Activity and the Uniformed Services Prescription Database Project are two examples. Additional opportunities to create linked databases remain, a fact recognized in the planning for the triservice Defense Medical Epidemiology Database. In general, the strength of these large databases is their outcomes data, and their limitation is their exposure data, with prescription drug data being the exception. Data on the use of nonprescription drugs are not available, and vaccine data are not captured in an automated system. Moreover, no chemical and environmental exposure databases like the ones described above exist, although such databases are being created after the fact (see Chapter 5). STUDY AND MANAGEMENT OF INTERACTIONS Multipurpose automated databases with person-based exposure information are largely undeveloped. However, future plans for a person-based deployment database and unit-based environmental exposure databases hold some promise. It will be necessary to design such databases carefully to permit linkages between person-based and unit-based information. Person-based outcomes databases are much further developed than are exposure databases, and expanding outcomes database coverage (for example, adding conditions to the Reportable

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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces Disease Surveillance System) and increasing linkages among them are relatively easy next steps that would make their information even more useful. Aside from good surveillance mechanisms, some relatively small prospective studies—for example, comparing outcomes before and after deployment—could provide supporting data; however, the amount of support will be directly related the soundness of design and statistical power of such studies. In addition, recent developments in the design and analysis of animal toxicity studies have markedly increased their effectiveness in identifying interactions, and these developments should be used. Not all of these activities can be carried out at once, and the Army will have to set priorities for its future actions; a cost-benefit analysis may prove fruitful to determine priorities. In advance of this process, the Army will need to take careful stock of all its pertinent ongoing activities. Additionally, the effective study and management of interactions will depend on the productive communication and coordination among those responsible for product development, preventive medicine surveillance, and all others who will be involved with the exposures of U.S. military personnel to drugs, biologics, and chemicals and their potential interactions. FINDINGS AND RECOMMENDATIONS Findings Military personnel, especially when they are deployed, are exposed to a large number of drugs, biologics, and chemicals to which their civilian counterparts in the United States are not exposed. None of the information gathered on additional planned prophylactic-preventive agents had a substantial impact on the committee's deliberations. The published scientific literature on the interactions of militarily relevant drugs, biologics, and chemicals does not provide an adequate basis for assessing the degree of safety; the committee, however, did not find any basis for extraordinary concern. Discussions held with liaisons from the medical divisions of the Canadian and British militaries indicated the international need for increased information and research regarding interactions. The diversity and number of agents precludes not only the testing of all possible combinations for interactions but also the development of systems that could be used to identify and predict with confidence all possible interactions that could result in increased toxicity. Operational requirements may necessitate the use of combinations of agents of known or potential toxicity. The committee understands that it is DoD

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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces policy to ensure that the benefits outweigh the risks when these combinations of agents are used. Many programs are under way within the military in the areas of drug and vaccine design and development, research on the effects of those agents that are administered to military personnel or to which military personnel are known to be exposed, and the development of surveillance systems and related databases that could be used in epidemiologic studies. However, many of the surveillance systems are incomplete, and databases that contain related, relevant information have not been linked to date. Most important, a coordinated effort among the services to link the relevant programs is lacking. Recommendations A focused strategy for evaluating and managing the effects of interactions needs to be developed. This strategy should also be suitable for new agents. The proposed approach involves the characterization of interactions into three broad categories: Known: those interactions for which there is documented evidence of risk in humans; Potential: those interactions that are known from animal studies or that can be anticipated or predicted on the basis of the individual properties of the agents in putative combinations; and Unknown: the interactions of combinations of agents that cannot be anticipated on the basis of current knowledge (this is the largest class). For agents with known interactions, if exposure cannot be avoided, surveillance measures should be implemented and focused studies should be undertaken to identify ways to minimize risk levels. Potential interactions might be predicted by use of a matrix based on target organ toxicity, pharmacokinetics, and pharmacodynamics. High-priority potential interactions should be investigated in a tiered process involving in vitro, animal, human volunteer, and epidemiologic studies. For agents with unknown interactions, three strategies are recommended. The first strategy is to develop, enhance, and implement surveillance systems to monitor both exposure combinations and health outcomes. Surveillance systems for exposures should include data regarding drugs, biologics, and other deployment-site-specific chemicals. Surveillance systems for health outcomes should be expanded to capture additional sentinel events (using notifiable conditions) and could be used to support focused prospective studies, provided they are of sufficient sample size, to compare specific health measures before and after deployment.

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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces The second strategy is to conduct a battery of in vitro and in vivo experimental studies to investigate a core set of exposures anticipated for most deployed troops. When outcomes of interest are identified, they should be investigated with carefully designed epidemiologic studies of disease-exposure relationships. The committee recommends further that efforts be better coordinated within and among all those military units and branches involved with the development of these systems. Programs within the Army and DoD that involve product development, preventive medicine (including the development of surveillance systems and integrated databases), clinical medicine, and the medical defense against biological and chemical warfare weapons should be closely coordinated. An advisory committee should be established to help identify and use existing and future research tools for the purposes of anticipating, studying, and minimizing harmful interactions.