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Summary The Transformational Medical Technologies (TMT1) has been a unique component of the U.S. Department of Defense (DoD) medical biodefense efforts since 2006. Its mission is to advance countermeasure research and development in support of the broader goal of the DoD to protect warfighters from emerging infectious diseases and future genetically engineered biological weapons. The TMT, using advanced science and technology approaches, focused on the development of broad- spectrum countermeasures that target common host and pathogen pathways or enhance the host’s immune response. Many of these pathogens are lethal or cause such debilitating diseases in humans that it is ethically inappropriate to test the efficacy of these countermeasures in human volunteers. In lieu of human participants, these products may be tested in animals and approved for human use under the provisions of the Food and Drug Administration (FDA)’s 2002 Animal Rule.2 The reliance on animal models for the development and licensure of medical countermeasures against biothreats is challenging for a number of reasons. In many cases, qualified animal models that can predict efficacy of new drugs or biologics are not available. There are numerous challenges in establishing new models to replace or complement existing ones in order for “certain new drugs and biological products that are intended to reduce or prevent serious or life-threatening conditions can be approved for marketing based on evidence of effectiveness derived from appropriate studies in animals, without adequate and 1The Transformational Medical Technologies Initiative (TMTI) is referred to as Transformational Medical Technologies (TMT) throughout the report. In 2011 the Department of Defense moved the TMT to a Program Manager under the auspices of the Joint Program Executive Office for Chemical and Biological Defense, as the efforts have matured to advanced development. The Committee has addressed its report to the TMT. 2 The Animal Rule “provides for approval of certain new drug and biological products based on animal data when adequate and well-controlled efficacy studies in humans cannot be ethically conducted because the studies would involve administering a potentially lethal or permanently disabling toxic substance or organism to healthy human volunteers and field trials are not feasible prior to approval. Under this rule, in these situations, certain new drug and biological products that are intended to reduce or prevent serious or life-threatening conditions can be approved for marketing based on evidence of effectiveness derived from appropriate studies in animals, without adequate and well-controlled efficacy studies in humans (§ 314.126)” (21 CFR Parts 314 and 601 [2002]). 1

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2 ANIMAL MODELS FOR ASSESSING COUNTERMEASURES well-controlled studies in humans...” (FDA 2002, p 37989). There are also challenges in establishing sustainable and appropriate alternatives to the use of animal models for the development of countermeasures against biothreats. CHARGE TO THE AUTHORING COMMITTEE The DoD asked the National Research Council (NRC) to prepare a consensus report that would address the challenges stemming from developing and testing medical countermeasures against biothreat agents in animal models. The ad hoc Committee on Animal Models for Assessing Countermeasures to Bioterrorism Agents was charged with responding to three tasks: 1. Evaluate how well the existing TMT-employed or candidate animal models reflect the pathophysiology, clinical picture, and treatment of human disease as related to the agents of interest. 2. Address the process and/or feasibility of developing new animal models for critical biodefense research, placing emphasis on the need for a robust and expeditious validation process in terms of FDA’s Animal Rule. 3. Evaluate alternatives to the use of animal models based on the premise of the Three Rs (i.e., refinement, reduction, and replacement of animal use; such venues would include but not be limited to in vitro work, computational modeling, new biotechnological tools, surrogate diseases, etc.) vis-à-vis the Animal Rule and FDA licensure. The evaluation will also consider the development of more humane models for infectious diseases research that do not incorporate death as an endpoint (i.e., humane endpoints). The Committee approached its task by considering scientific, legal, ethical, and veterinary medicine-related elements to formulate its response to these three tasks. The Committee held two public meetings with invited experts: scientists, laboratory animal veterinarians, public health experts, policymakers, and representatives of the military (see Appendix D). It also solicited a white paper on the approach and effort to develop animal models for licensure under the Animal Rule of the National Institute for Allergy and Infectious Diseases (see Appendix C). The report was organized following the three elements of the Statement of Task with an additional chapter on ethical and regulatory challenges encountered in developing countermeasures. The Committee identified scientific and technical issues that affect the value and relevance of animal models to “provide substantial evidence of the effectiveness of these products” (FDA 2002, p 37989) under the conditions imposed by the Animal Rule and provided conclusions accordingly. The Committee did not consider animal models used to evaluate safety of products approved under the Animal Rule. The Committee did not evaluate the Animal Rule or the FDA’s approach to assess product efficacy under the rule. This report makes two principal points: 1. A comprehensive strategy to improve data gathering and data sharing from animal models (or their alternatives) would significantly increase the efficiency and productivity of research into bioterrorism countermeasures if it includes: • compartmentalization;3 • the use of systems biology and in vitro/in silico methods; 3 Experiments that yield information from components of the animal (organs, cells, and systems) rather than data derived from the whole organism (for additional discussion see Chapter 4).

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3 SUMMARY • systematic collection of and access to experimental data; • publication of negative results; • enhanced collection and analysis of human data; and • added clinical veterinary care. 2. This strategy would improve the humane use of laboratory animals in accordance with the principles of the Three Rs (i.e., refinement, reduction, and replacement of the use of animals in research). The Committee’s conclusions and recommendations follow. CONCLUSIONS AND RECOMMENDATIONS Evaluation of Current and Future TMT-Used Animal Models (Chapter 2) Currently available animal models for the development of countermeasures against biothreats are imperfect representations of the human-pathogen interaction, especially with regard to their substitution for “adequate and well-controlled efficacy studies in humans” (FDA 2002, p 37989). Their limitations include: • lack of sufficient human data and knowledge of the natural history of the diseases or threats of interest; • methodological differences due to interspecies and intraspecies variability and the constraints imposed by working in biocontainment facilities; and • for some conventional diseases, animal models have been shown to be unreliable surrogates for, or predictors of, efficacy and safety, as indicated by experience with product development and clinical trials. However, the Committee concludes that the animal models available at the present time remain central for understanding pathogenesis and correlates of protection to inform effectiveness of therapeutics or vaccines developed under the Animal Rule. Because these models are complex and expensive to develop, depend on the use of large numbers of animals, and are restricted by work in biocontainment facilities, the Committee believes that the purpose of current models needs to be reevaluated—focusing on a broader application profile, i.e., product-neutral, so that more than one countermeasure may be developed, potentially including countermeasures to “unknown-unknowns.” In doing so, the limitations outlined above need to be taken into consideration, i.e., (1) that methodological differences may account for common failings of animal models to correctly represent the human condition; and (2) that the collection of human data is of utmost importance in order to verify the usefulness and augment the strengths of available models. Developing New Animal Models for Biodefense Research (Chapter 4) Development of new animal models for biodefense research cannot resolve the limitations of the currently available ones (i.e., paucity of human data, significant costs, and methodological differences). Therefore the Committee concludes that focusing on the creation of new animal models is not warranted at this time. It would be more useful to the TMT to support the qualification (vs. validation) of currently available animal models, as it would advance the predictive capacity of animal-derived

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4 ANIMAL MODELS FOR ASSESSING COUNTERMEASURES data for the human response. The Committee recommends that the TMT adopt the following strategies: • To address the dearth of data from human populations, expand the collection of data from patients in outbreak zones and from postmarketing studies. In addition, expand the acquisition of data from phase 1 safety trials by (1) increasing the duration of these trials; (2) diversifying the enrolled subjects to mirror the general population; and (3) including the anticipated treatment in the field as part of the trial protocol. • To control interspecies variability and improve the comparativeness of infectious disease models across different species, adopt the concept of compartmentalization. As each species is made up of a variety of physiological compartments that contribute to the host response to an infectious agent, compartmentalization is a strategy to compare the systems and pathways that lead up to the host response within a species, across species, and with humans rather than focusing on a single gene or protein or particular genes or proteins. • To support the qualification of animal models as an alternative to validation, establish the compartmentalized model’s scientific relevance and reproducibility across different methods and laboratories. These comparative datasets may subsequently be used to define appropriate criteria to characterize or qualify vs. validate the animal model. Alternative Approaches to Animal Testing for Biodefense Countermeasures (Chapter 5) In 1959, Russell and Burch published a practical approach to refine, reduce, and replace the use of animals in research, known as the Three Rs. The Three Rs are applied to (1) refine the experimental and husbandry methods to enhance animal well-being and minimize or eliminate pain and distress; (2) reduce the number of animals needed in experimentation; and (3) replace (in absolute or relative terms) the use of animals. However, the premise of the Animal Rule is that the effectiveness of new drugs and biologics when human efficacy studies are not ethical or feasible may be demonstrated in appropriate studies in animals. Currently, the development of countermeasures to biothreats depends on animal models for efficacy testing of these products in lieu of human clinical trials. The Committee concludes that absolute replacement of animal models in countermeasure development is not possible at this time and that in vitro and in silico methods are not advanced enough yet (in part due to absence of human data) to reliably replace animals in biodefense research. The Committee recommends that the TMT undertake an analysis of the discovery, development, and approval process for medical countermeasures to identify (1) where the most important scientific gaps exist in terms of utilizing alternative methods to animal models and how to address them; (2) the specific areas where the use of in vitro and in silico methods could be sufficient or as an adjunct to the use of animals; and (3) the criteria for choosing and utilizing the most suitable technologies to replace animal use in biodefense research. Original data and information from animals and humans should be collected systematically, consistently, and accurately and be made available to the research community. Sharing of both positive and negative data will enable progress toward standardization of methods and qualification of models, and may also help in the event of an “unknown-unknown” emergency. It will also address ethical concerns regarding the potential nonproductive or duplicative use of animals or the unnecessary duplication of studies and waste of resources. The Committee concludes that changing the standard practice of animal experimentation to approximate the clinical course of treatment that humans may receive could provide a more reasonable expectation of the usefulness of certain countermeasures during development. Consequently, the provision of supportive care is a means to improve data gathering from animal

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5 SUMMARY models. Details of supportive care should be discussed with the FDA early in the planning stages before studies are initiated. As a reasonable measure to incorporate in the study design, it is not only a more humane approach but may allow fewer animals to be used in accordance with the Three Rs. Experience from such experimental protocols may be helpful in the event of countermeasure trials against an “unknown-unknown.” The Committee recognizes that the nature of biocontainment imposes difficulties in the implementation of the above. Therefore, the Committee recommends that the TMT define the basic principles of such an approach, including guidelines for the care and use of animals in research in biocontainment facilities. Finally, the Committee concludes that the potential advances in knowledge and benefits to the warfighters should be weighed against the duration and severity of animal pain and distress. Further, the Committee believes that the application of refinement strategies and reduction approaches (as discussed in Chapter 5) could improve laboratory animal welfare and safeguard the quality of biodefense research. Moreover, the recommended comprehensive strategy of implementing the Three Rs, incorporating compartmentalization, and enhancing collection and analysis of human data reduces the dependency of this field of research on nonhuman primates by maximizing the value of data derived from all research. The Committee recommends that, where possible, the TMT should encourage efforts to replace nonhuman primates as the animal of choice in biodefense research. Such efforts coupled with unhindered access to data and publishing of all results—including negative ones— are critical steps to ensure that this data are beneficial, animals are used judiciously, and unnecessary duplication of work is avoided.

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