Overcoming Challenges to Develop Countermeasures Against Aerosolized Bioterrorism Agents: Appropriate Use of Animal Models (2006)Board on Life Sciences
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The National Institute of Allergy and Infectious Diseases (NIAID) gives the highest priority to developing countermeasures against bioterrorism agents that are highly infective when dispersed in aerosol form. Developing drugs to prevent or treat illnesses caused by bioterrorism agents requires testing their effectiveness in animals since human clinical trials would be unethical. At the request of NIAID, the National Academies conducted a study to examine how such testing could be improved. The report provides recommendations to researchers on selecting the kinds of animal models, aerosol generators, and bioterrorism agent doses that would produce conditions that most closely mimic the disease process in humans. It also urges researchers to fully document experimental parameters in the literature so that studies can be reproduced and compared. The report recommends that all unclassified data on bioterrorism agent studies -- including unclassified, unpublished data from U.S. Army Medical Research Institute of Infections Diseases (USAMRIID) -- be published in the open literature. The report also calls on the U.S. Food and Drug Administration to improve the process by which bioterrorism countermeasures are approved based on the results of animal studies.
- Dose is commonly reported as a median lethal dose (LD50) or a median infectious dose (ID50). However, these measures can be greatly affected by the method of delivery, the aerosol particle-size distribution, the site of deposition in the respiratory tract, and the species under study, making replication and interpretation of the study difficult.
- Extensive data on the characteristics of many animal models and different strains of infectious agents are not available in the published literature.
- Studies involving aerosol inhalation exposures are technically difficult because the potency of the agent and the dose delivered are greatly affected by the aerosol generation equipment and the characteristics of the generated aerosol.
- Studies to extrapolate a lethal or infectious dose often use a limited number of animals. This creates statistical concerns about variability and uncertainty that need to be addressed.
- The committee considered several inhalation delivery methods including whole-body exposure, head-only exposures, nose-only exposures, or mouth-only exposures. The committee found that the use of apparatus specific to each type of delivery method required special considerations to lower variability during dosing.
- The committee found that few animal models of bioterrorism agents have been shown to be predictive of the human disease process. In addition to demonstrating efficacy, considerable effort will have to be expended to establish the predictive value of an animal model, and there is widespread concern in the research community that animal models acceptable to the U.S. Food and Drug Administration cannot be developed for all of the select agents.
- The development or selection of an animal model that approximates the human disease process is dependent on a robust knowledge of the natural history and pathogenesis of the disease. No single animal model will exactly replicate responses seen in humans; therefore endpoint-based findings in animals are extrapolated to humans.
- The wide variation in published LD50 values in the available literature also makes it difficult to compare countermeasure efficacies, potency of different agent sources and strains, and response of different animal species and strains. Additional data on challenge doses may help alleviate this issue until reporting of dosimetry is standardized and sufficient additional data are generated.