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Overcoming Challenges to Develop Countermeasures Against Aerosolized Bioterrorism Agents: Appropriate Use of Animal Models Summary Incidents involving the dissemination of Bacillus anthracis and ricin through the U.S. postal service beginning in 2001 have led the federal government to focus attention on the importance of developing countermeasures1 to agents of bioterrorism. The President’s 2006 federal budget included $4.2 billion for the Department of Health and Human Services to address bioterrorism. $1.7 billion of that request was slated for the National Institute of Allergy and Infectious Diseases (NIAID) to accelerate the development of new and improved countermeasures against potential agents of bioterrorism (DHHS 2005). The NIAID’s Strategic Plan for Biodefense Research (2002) recognizes that bioterrorism agents2 dispersed in aerosol form have the greatest potential to cause widespread disease. Therefore, NIAID’s Strategic Plan gives highest priority to developing countermeasures to those bioterrorism agents that have a high infectivity in aerosol form (NIAID 2002). Since, during the course of studying bioterrorism agents, it is not ethically appropriate to deliberately expose human subjects to bioterrorism agents, development of countermeasures relies on the ability of the scientific community to adequately test the effectiveness of countermeasures in animal models. There are many challenges associated with producing appropriate animal models for testing countermeasures. In many cases, there is little natural history 1 “Countermeasure” is defined for the purposes of this report as a drug, biological product, chemical, or other therapeutic technology that prevents or treats an illness caused by a bioterrorism agent. 2 “Bioterrorism agent” is defined for the purposes of this report as a microorganism, or a toxin derived from a microorganism, that causes human disease and is used to harm people, or to elicit widespread fear or intimidation, for political or ideological goals.
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Overcoming Challenges to Develop Countermeasures Against Aerosolized Bioterrorism Agents: Appropriate Use of Animal Models of aerosolized exposure in animals to guide development and characterization of new animal models. There are many methodological challenges in generating reproducible exposures, e.g. generation of viable aerosols, consistent exposure of animals, appropriate quantification of dose, and comparison of results among laboratories. Also, the use of animal models to demonstrate efficacy during the drug approval process is a relatively new approach for the regulatory community and there are issues that still need to be addressed. CHARGE TO THE AUTHORING COMMITTEE The NIAID approached the National Research Council with a request that it prepare a short consensus report that articulates the difficulties of testing countermeasures to aerosolized bioterrorism agents in animals and identifies opportunities that can be pursued to improve current testing efforts. As part of this project, NIAID requested that a workshop be organized to bring together select agent researchers, including researchers from NIAID and U.S. Army Medical Research Institute of Infectious Diseases, as well as leaders in complementary areas of science, particularly inhalation toxicologists, microbiologists, aerosol scientists, and statisticians. This report is based on the presentations and discussions held at this workshop on July 6 and 7, 2005, as well as further research and deliberations by the authoring committee following this workshop. The committee approached its task by considering how to improve and standardize studies that generate efficacy data in animals. The committee generally focused on technical issues regarding the generation of consistent and reproducible exposures, which are key to producing scientifically-sound efficacy data, but also touched on issues to be considered in selecting an animal model. Studies to establish human dose response to a bioterrorism agent or conduct a risk assessment for a bioterrorism event are beyond the scope of the committee’s charge. The committee organized its efforts and report by focusing on four parts of the experimental design process: the selection of the animal model to be utilized, the generation and characterization of the aerosolized bioterrorism agent, characterization of dose, and selection and delivery of dose. For each part of the experimental design, the committee identified issues that potentially affect the quality and reproducibility of data, and then identified experimental approaches and technology that might overcome those challenges. The committee also took a holistic approach to their overarching task, and identified workforce, infrastructure, and regulatory issues that could present challenges to testing countermeasures to bioterrorism agents. The following recommendations have been developed to address the major challenges identified by the Committee on Animal Models for Testing Interventions Against Aerosolized Bioterrorism Agents.
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Overcoming Challenges to Develop Countermeasures Against Aerosolized Bioterrorism Agents: Appropriate Use of Animal Models PRINCIPAL FINDINGS AND RECOMMENDATIONS Development or Selection of an Animal Model when Testing Countermeasures 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. Accurate extrapolations are possible only when species-specific differences in pathogenesis at the cell, tissue, and organ level; pulmonary anatomy and physiology; and host-pathogen interactions are clearly understood. The Committee recommends that additional data on experimental-animal airway anatomy and particle deposition and clearance be acquired to aid in developing new animal models and performing extrapolations to human populations. In particular, data are needed for various strains of mice and many species of nonhuman primates. Generation and Characterization of Aerosolized Agents A key component of the effort to test countermeasures is generating consistent aerosol exposures. These aerosol exposures can then be reproduced, and data generated by different experiments or laboratories can be compared. However, 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. So that future studies to test countermeasures can be compared and reproduced, the Committee recommends that specific parameters be measured and reported as part of a standard operating procedure adopted by researchers studying aerosolized bioterrorism agents. Researchers should measure particle properties including aerodynamic size, size distribution, geometric size and shape, electrical charge, chemical composition, irritancy, and mass concentration (mass of particles per unit mass of air). Properties of the exposure environment should also be measured including temperature, relative humidity, osmolarity, airflow, and uniformity of the exposure in the breathing zone. In addition, information on aerosol generation and generation equipment, particle size and sizing instrument, impinger characteristics, exposure parameters and equipment, and animal characteristics and status should be recorded and reported in publications resulting from the work.
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Overcoming Challenges to Develop Countermeasures Against Aerosolized Bioterrorism Agents: Appropriate Use of Animal Models Dosimetry 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. Therefore, the Committee recommends that when a multiple of the LD50 or ID50 (e.g., 10 LD50) is used to report dose, then sufficient additional data, including indices of viability of the agent and characteristics of the exposure, particle-size, and generation of the aerosol should be acquired and reported. Selection of Dose and Delivery 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. In addition, the Committee found a wide variation in published LD50 values in the available literature making the selection of dose difficult. Therefore, the Committee recommends obtaining statistical advice when designing an animal study to develop or test a countermeasure. 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. Therefore, the Committee recommends that unclassified data from mortality and natural-history studies—including unclassified, unpublished data from U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID)—be published in the open literature for all agents. If publication in the open literature is not feasible, an inclusive database of unclassified government-sponsored studies should be established by NIAID3. 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. For whole-body exposures, the committee recommends that individual cages without food be utilized to prevent animals from avoiding exposure by huddling or from increasing exposure through consumption of food available in the chamber. For other types of exposures, the committee recommends that neck seals, tubes, and masks be evaluated to ensure that 3 This recommendation is not intended to apply to research results or other data considered “sensitive but unclassified.” Rather, the recommendation applies to data for which access would otherwise not be restricted that have not been published in a timely manner due to events such as personnel changes and changes in research priorities.
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Overcoming Challenges to Develop Countermeasures Against Aerosolized Bioterrorism Agents: Appropriate Use of Animal Models the equipment does not alter respiration, either directly or by stressing the animal. For all exposure systems the environmental temperature, humidity, and distribution of the agent should be regulated and samples be taken from the breathing zone nearest to the animal during exposure. Resource and Regulatory Issues Extensive data on the characteristics of many animal models and different strains of infectious agents are not available in the published literature. Access to such data could prevent unnecessary duplication, allow researchers to compare results between different experiments and laboratories, assure consistency by standardizing techniques, and allow data to be pooled for more rapid determination of results. Therefore, the Committee recommends that an easily searchable central database registry (or registries) on animal model data be established. Further, the Committee recommends the establishment of a repository, which can supply investigators with a well-characterized sample of an agent. The American Type Culture Collection (ATCC) maintains such a repository, but additional information to facilitate comparisons of animal-model systems and ensure consistent results should be added. Finally, there are issues in the U.S. Food and Drug Administration (FDA) regulatory process for approval of countermeasures against bioterrorism agents that need to be addressed. This is especially true with respect to the new regulations, known as the “Animal Rule” (21 CFR 314 Subpart I and 21 CFR 601 Subpart H), which permits the agency to base its marketing-approval decision on animal efficacy data when the countermeasure cannot be tested for efficacy in humans. This Rule requires that the animal model used to generate efficacy data approximates and is predictive of the disease process in humans. 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. In order to address the need for rapid development of countermeasures, while striking an appropriate balance between efficacy and safety, the Committee recommends that the FDA improve the process by which new countermeasures are approved by working with researchers to draft and finalize practical guidelines to ensure that applicants can effectively meet approval requirements.
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