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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
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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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