Appendix E

Statement of Task Animal Models for Assessing Countermeasures to Bioterrorism Agents

Summary

The National Academies will convene an ad hoc committee to examine the utility and relevance of animal models to Transformational Medical Technologies Initiative (TMTI)-funded research. The report will: 1) Evaluate how well the existing TMTI-employed or candidate animal models reflect 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 the U.S. Food and Drug Administration’s (FDA’s) Animal Rule; 3) Evaluate alternatives to the use of animal models based on the premise of The Three Rs 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).

Policy Context

A major component of the U.S. Department of Defense (DoD) efforts in biodefense is the Transformational Medical Technologies Initiative (TMTI), the goal of which is to protect warfighters from disease and biological warfare agents. Specifically, the rationale of the Initiative is to fully exploit advanced science and technology innovation in order to successfully counter future genetically engineered biological weapons and naturally emerging infectious diseases that can impact the warfighter.

In the past DoD has had a significant focus on the production of individual vaccines for diseases such as anthrax, smallpox, and plague. TMTI seeks to expand that focus to facilitate basic and applied research that will lead to the development of broad-spectrum countermeasures (preventative, prophylactic and therapeutic) that could provide multivalent solutions (for example, one drug that would offer protection from multiple types of pathogens) against advanced bio-terror threats. TMTI is



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Appendix E Statement of Task Animal Models for Assessing Countermeasures to Bioterrorism Agents Summary The National Academies will convene an ad hoc committee to examine the utility and relevance of animal models to Transformational Medical Technologies Initiative (TMTI)-funded research. The report will: 1) Evaluate how well the existing TMTI-employed or candidate animal models reflect 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 the U.S. Food and Drug Administration's (FDA's) Animal Rule; 3) Evaluate alternatives to the use of animal models based on the premise of The Three Rs 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). Policy Context A major component of the U.S. Department of Defense (DoD) efforts in biodefense is the Transformational Medical Technologies Initiative (TMTI), the goal of which is to protect warfighters from disease and biological warfare agents. Specifically, the rationale of the Initiative is to fully exploit advanced science and technology innovation in order to successfully counter future genetically engineered biological weapons and naturally emerging infectious diseases that can impact the warfighter. In the past DoD has had a significant focus on the production of individual vaccines for diseases such as anthrax, smallpox, and plague. TMTI seeks to expand that focus to facilitate basic and applied research that will lead to the development of broad-spectrum countermeasures (preventative, prophylactic and therapeutic) that could provide multivalent solutions (for example, one drug that would offer protection from multiple types of pathogens) against advanced bio-terror threats. TMTI is 127

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128 ANIMAL MODELS FOR ASSESSING COUNTERMEASURES therefore funding basic and applied research designed to advance the development of such countermeasures. There are several challenges to developing such countermeasures under each of the TMTI's Current Thrust Areas (i.e., host immune enhancement; genomic identification; nucleotide therapeutics; protein based therapeutics/biologics; small molecule/drugs; metabolomics). One area of particular concern is the need to develop countermeasures for diseases that are not endemic in the United States or in other developed countries and for which no reliable treatment exists. Further, countermeasures are called for to deal with unnatural diseases resulting from bioterrorism or biowarfare. Another potential concern with countermeasures-related research is that it is conceivable that some of its results could be used by terrorists to advance offensive biowarfare. According to Department of Defense Instruction Number 6200.02 of February 27, 20081 , "personnel carrying out military operations shall be provided the best possible medical countermeasures to chemical, biological, or radiological warfare or terrorism and other health threats. The DoD Components shall make preferential use of products approved by the Food and Drug Administration (FDA) for general commercial marketing, when available, to provide the needed medical countermeasure." Therefore high priority is given to work that will facilitate FDA approval of new countermeasures developed through TMTI. Lack of scientific expertise and available information necessitates that such countermeasures research is based on experimental animal models. Ethical constraints preclude the use of human participants in efficacy studies that could kill or permanently disable healthy human volunteers. In order to overcome this predicament, FDA promulgated the Animal Rule (21 CFR Parts 314 and 601). It is expected that many TMTI-developed products would be submitted to FDA and subject to evaluation under the Animal Rule. Technical Context Biomedical research depends on the use of animals in order to understand how human and non-human organisms function. Investigators use animals to understand the continuum between basic mechanisms in a single cell (e.g., enzymatic properties, gene influences) and the health and disease of the whole organism. In fact, the use of animals as working representations for a variety of human conditions offers an alternative to the use of human participants. However, in order for these models to be useful correlates, they should be reproducible and verifiable (i.e., offer proof of concept) and reliably predict the safety and efficacy of clinical trials. Animal models as surrogates for humans have mixed success. In some cases, the animals correctly model the processes occurring in humans; in others, there are similarities between the animal models and humans, but the two are not exact. Furthermore, when modeling an unknown or minimally understood process, it is difficult at the outset to determine which animal model would best approximate the human situation. In the case of the Animal Rule, FDA allows the substitution of appropriate studies in animals as "evidence of the effectiveness of new drugs or biologicals when adequate or well-controlled clinical studies in humans cannot be ethically conducted" (the Animal Rule; 21 CFR Parts 314 and 601). Licensing the medical countermeasures mandated by TMTI under the Animal Rule is challenging due to a number of concerns. FDA approval under the Animal Rule requires validated animal models that predict the efficacy of new drugs or biologicals in humans. This relatively new approach to attaining full licensure for drugs and biologicals presents new and unique challenges such as establishing validated animal models that meet FDA requirements, working in compliance with Good Laboratory Practice (GLP) regulations in a high-containment environment, and meeting the obligation to continuously identify refinements in the field of infectious disease research in general. Department of Defense Instruction Number 6200.02; www.dtic.mil/whs/directives/corres/pdf/620002p.pdf 1

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129 APPENDIX E As stated above, it would be unethical to test these agents in humans; therefore it is essential to choose the correct animal model for investigating countermeasures to bioterrorism agents. In some cases, there may be enough information about the pathophysiology of the agent and the intervention to enable a quick and accurate determination of the appropriate model. In other cases, it may be necessary to glean information from multiple models or to use other, newly emerging non-animal methods to establish a baseline understanding of the agent(s) involved. Such new methods are coming into greater use as their applications to the study of drug efficacy and drug and chemical toxicity are being delineated. In this project, it will be necessary for the committee to consider these and other possibilities for the study of countermeasures to bioterrorism agents in making recommendations to the Department of Defense. Statement of Task A major component of the U.S. Department of Defense (DoD) efforts in biodefense is the Transformational Medical Technologies Initiative (TMTI), the goal of which is to protect warfighters from disease and biological warfare agents. Specifically, the rationale of the Initiative is to fully exploit advanced science and technology innovation in order to successfully counter future genetically engineered biological weapons and naturally emerging infectious diseases that can impact the warfighter. Ethical constraints preclude the use of human participants in efficacy studies that could kill or permanently disable healthy human volunteers. In order to overcome this predicament, the U.S. Food and Drug Administration (FDA) instigated the Animal Rule (21 CFR Parts 314 and 601). It is expected that many TMTI-developed products would be submitted to FDA and subject to evaluation under the Animal Rule. The National Academies will convene an ad hoc committee to examine the utility and relevance of animal models to TMTI-funded research and prepare a consensus report. Specifically, the committee's report will: 1. Evaluate how well the existing TMTI-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).

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