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.

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1 Department of Defense Instruction Number 6200.02; www.dtic.mil/whs/directives/corres/pdf/620002p.pdf



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