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.


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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