Transformational Medical Technologies, a component of the Department of Defense, funds the development of medical countermeasures to protect warfighters against potential biothreats such as emerging infectious agents and toxins and future genetically engineered biological weapons. Because these pathogens are potentially lethal or cause debilitating diseases in humans, it is ethically impermissible to test the effectiveness of medical countermeasures on human volunteers. Instead, these products are tested on laboratory animals under a legal mechanism developed by the U.S. Food and Drug Administration.
However, relying solely on animal models for the development of countermeasures to biothreats is challenging. In many cases, qualified animal models that can reasonably predict the efficacy of new products are not available, and developing better animal models can involve years of effort without guaranteed success. In addition, there are difficulties in establishing good alternatives to using laboratory animals for medical countermeasure evaluation prior to human administration.
This report evaluates existing and candidate animal models for testing medical countermeasures against biothreats, addresses the process and feasibility of developing new animal models, and evaluates alternatives to the use of animals based on the premise of the Three Rs—refinement, reduction, and replacement of the use of animals in research and testing.
Key Findings
• Currently available animal models are imperfect representations of the human-pathogen interaction with several important limitations, such as methodological differences and a lack of sufficient human data and knowledge of the natural history of diseases of interest. However, at this time animal models remain central to the development of countermeasures against biothreats when testing the efficacy of therapeutics or vaccines would otherwise involve exposing human volunteers or warfighters to a potentially lethal or permanently disabling toxic substance or microorganism.
• Because animal models may be imperfect for a specific need and are expensive to employ (they require large numbers of animals and must be used in secure biocontainment facilities), current models should be reevaluated for their limitations as well as their presumed advantages. For example, methodological differences among similar animal models may result in differences in how well those models accurately mirror the human response to infection or treatment. Consequently, expanded collection and analysis of human clinical data from natural infections could help verify and augment the strengths of available models.
• Developing new animal models for biodefense research cannot adequately resolve in a reasonable time frame the limitations of the currently available ones. It would be more useful for Transformational Medical Technologies to support a more thorough qualification of currently available animal models to advance the predictive capacity of animal-derived data than to create new models.
•In vitro and in silico methods are not yet advanced enough (in part due to the absence of human data) to reliably replace animals in biodefense research on a large scale.
• The Committee suggests that Transformational Medical Technologies undertake an analysis of the discovery, development, and approval process for medical countermeasures to identify:
Scientific gaps in terms of utilizing alternative methods to animal models and how to address them
Specific areas in which use of in vitro and in silico methods could be sufficient, or an adjunct, to the use of animals
Criteria for choosing and utilizing the most suitable technologies to replace animal use in biodefense research in the near future
• Changing the standard practice of animal experimentation where feasible to approximate the clinical course of treatment for humans could provide a more reasonable prediction of the usefulness of countermeasures during the development process.
• Potential advances in knowledge regarding biothreats and medical countermeasures should be weighed against the duration and severity of animal pain and distress.
• A comprehensive strategy to improve the gathering and sharing of data from animal models (and their alternatives) would significantly increase the efficiency and productivity of research into bioterrorism countermeasures as well as improve laboratory animal welfare, if it includes:
Compartmentalization—experiments designed to yield information from components of the animals (organs, cells, and systems) rather than data derived from the whole organism;
The use of systems biology and in vitro or in silico methods;
Systemic collection of, and access to, experimental data;
Publication of negative results;
Enhanced collection and analysis of human data;
Added clinical veterinary care.
Where possible, Transformational Medical Technologies 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—even negative ones—help ensure that these data are beneficial, animals are used judiciously, and unnecessary duplication of work is avoided.
Committee on Animal Models for Assessing Countermeasures to Bioterrorism Agents; National Research Council
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