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. 2010 Sep 3;2(9):1918–1932. doi: 10.3390/v2091918

Table 1.

Elements of the animal efficacy rule1.

Criteria for use of animal model Issues relating to smallpox
There is reasonably well understood pathophysiological mechanism for the toxicity of the substance and its prevention or substantial reduction by the product.
  • Scientific knowledge is limited as the last cases of endemic smallpox occurred in 1949 in the USA, and 1977 worldwide, prior to the age of molecular biology and immunology.

The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well characterized animal model for predicting human response.
  • VARV naturally infects only humans; experimental infection of nonhuman primates is forced.

  • Animal models using related orthopoxviruses produce disease with similarities to smallpox, but the pathogenesis varies depending on the animal species, the characteristics of the infecting virus and the route of infection.

  • No one animal model has been established that completely mimics human disease.

The animal study endpoint is related clearly to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity.
  • There are no animal models for the major morbidities of smallpox.

  • Orthopoxvirus doses sufficient to produce 100% mortality in animal models shorten the incubation period substantially in most animal models, thus making it difficult to study the effect of post-exposure intervention.

  • Interpretation of mortality studies in animals are limited by the ethical requirement to euthanize moribund animals.

The data or information on the pharmacokinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans, allow selection of an effective human dose.
  • The specific pharmacodynamic response related to antipoxviral activity cannot be measured in uninfected humans for the purpose of selecting an effective dose.

  • Pharmacokinetics in the animal species used in orthopoxvirus infection models may not be the most relevant for dose selection in humans.

1

Adapted from Future Virology (2006) 1(2) 173–179 with permission of Future Medicine Ltd [28].