Keywords: Animal Rule, countermeasure, Probit regression, lethality
When drugs are developed to prevent serious or life-threatening conditions caused by exposure to lethal or permanently disable toxic substances, the human efficacy studies are usually not ethical, and the field trials may not be feasible. In such situation, FDA may grant approval based on adequate and well-controlled animal efficacy studies only provided that these studies results likely to produce clinical benefit in humans too. This falls to the category of Animal Rule. To conduct such efficacy study, animals are first exposed to the toxicity and then treated with the study drug. Due to the large quantity of toxicity, animals are sacrificed at the end of the study. One of the challenges in the study is to minimize the number of animals used especially when large animals are used. This project will demonstrate how to determine the minimum animals needed through simulations. Lethal Dose 50% (LD50) is the amount of the substance required to kill 50% of the test population. Plotting the percent mortality in probit scale to the log-scale of concentration of toxic gas G will have a straight line. If this straight-line shift to the right after receiving the study treatment, then the LD50 increased. The ratio of LD50TRT to LD50CTRL is termed dose modification factor (DRF). A DRF of 1.2 represents an approximately 20% reduction in gas G lethality. For different doses of study treatment, one expects different DRF. This property can be used to choose the best dose of the study treatment. The simulation will demonstrate minimum doses of gas G and minimum animals A needed to produce a natural history of mortality curve; it will compare confidence intervals of various LDs in different scenarios. Then it will simulate different death curve under different DRF to illustrate how to choose the best treatment dose. The project will also study the relationship between DRF and the survival benefit. Finally, the project will provide some information on the sample size of pivotal study.