• Fast-track processes can speed up the review procedure so that the FDA can evaluate information as it becomes available and as soon as the sponsor submits it.

  • Accelerated approval uses surrogate end points to demonstrate benefit. For bioterrorism agents, this might include protective-antibody levels for vaccines. The use of CD4 cells for assessment of antiviral treatment for HIV was one of the first surrogates to be approved under this rule.

  • The “Animal Rule”5 is extremely important with respect to bioterror agents. It states that where human efficacy trials are not feasible or are unethical, the use of animal-efficacy data may be accepted as they relate to the desired benefit in humans—usually a significant outcome such as mortality or major morbidity. Clinical studies are still required for establishing pharmacokinetics and for assessing safety. The Animal Rule has postmarketing and labeling restrictions, however, and it does not apply if the product could be approved on the basis of any other standard under the FDA’s regulation.

Much more research is needed to establish acceptable criteria for reduction in morbidity and mortality. Human diseases caused by many of the CDC Category A agents are so poorly understood at present that meaningfully defining such criteria for the Animal Rule will be difficult. For some agents—for example, smallpox—appropriate animal models are lacking, and many existing animal models are poorly characterized with respect to lesion character and disease progression.

Animal models (with the exception of those for anthrax) remain poorly characterized with respect to aerosol challenge and disease characteristics in animals receiving sublethal challenge doses. Criteria need to be established with respect to end points that will be acceptable to the FDA for reduction in morbidity and mortality and similarity to human disease—i.e., route of inoculation, challenge doses and strains of organisms to be used, strain and species of animals, and duration of observation periods for reduction in morbidity according the FDA’s Animal Rule regardless of route of challenge.

Recommendation 3.18: Allow regulatory exceptions for development of therapeutics and vaccines against bioterrorism threats. The FDA should convene a broadly based conference to consider options and plausible mechanisms for expedited approvals under specific emergency conditions. In addition, for new drugs and vaccines that cannot be tested in humans, mechanisms for indemnification in the case of adverse effects will need to be


The Animal Rule is Code of Federal Regulation (CFR) Title 21, Parts 314 and 601: “New Drug and Biological Drug Products; Evidence Needed to Demonstrate Effectiveness of New Drugs when Human Efficacy Studies Are Not Ethical or Feasible.” The final version of this rule was published in the Federal Register on May 31, 2002, and will take effect June 30, 2002. The final rule can be viewed at <http://www.fda.gov/OHRMS/DOCKETS/98fr/98n-0237-nfr0001-vol1.pdf>

The National Academies of Sciences, Engineering, and Medicine
500 Fifth St. N.W. | Washington, D.C. 20001

Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement