Animal studies numbers required

Much of what is done (and how it is done) in repeat-dose studies is a response to a number of regulations. Three of these have very broad impact. These are the Good Laboratory Practices requirements, Animal Welfare Act requirements, and regulatory requirements that actually govern study design. 

The future use of MSCs in clinical studies may require very high absolute MSC numbers to gain appropriate cell doses (>5 x 106/kg body weight) per patient compared to in vivo experimental models with small animals [20]. It is consequently advantageous to develop large-scale MSC expansion protocols that allow for the... 

Toxicity studies are undoubtedly expensive in both financial and resource terms. Part of the cost is related to the number of animals and the extent of clinical, necropsy, and histopathologic investigations required. Considering the inherent variability of biological systems, there must always be a balance between the number of animals theoretically required to detect all effects (from the weakest upward) and the number required to detect significant toxic effects. In a well-conducted study that goes according to plan, it is possible to use fewer animals. 

However, in tests of chemicals with unknown toxic characteristics, problems often arise because the actual responses of animals differ widely from those anticipated when the study was designed. To address this problem, it is prudent to increase the number of animals to ensure that animals are available at key points of a study to provide adequate information. In acute studies, the requirement for groups and number of animals in groups is related to the reliable determination of acute toxic effects and the estimation of a median lethal dose. In subchronic and chronic testing, the numbers are related to the detection of effects, providing sufficient animals for an acceptable investigation of toxic mechanisms and giving an indication of a no-effect level. ... 

Our insight into the development, evolution and the mechanisms of damage in cerebral ischemia is mainly based on animal studies. A large variety of experimental models have been developed that imitate conditions of stroke and cardiac arrest (Hossmann 1991). In the past, experiments had to be terminated at certain timepoints to obtain invasive measurements of lesion size, blood flow, metabolism or other markers of injury. Therefore, longitudinal observations required large animal numbers and the inter-individual differences complicated the analysis of results. The advent of MR techniques of imaging... 

The limitations of the primate or cat models of human HIV-1 CNS infection include the costs, special facility requirements, the necessity of using mixtures of viral strains (in order to develop reproducible CNS infection), and the relatively small numbers of animals studied that preclude meaningful statistical analyses. These obstacles have urged researchers to develop small animal models. Several rodent models were established including transgenic mice (expressing viral proteins or relevant inflammatory factors seen in HAD), mice infected primarily with murine retroviruses, or severe combined immunodeficient (SCID) mice inoculated intracerebrally with human HIV-1 infected macrophages and reconstituted with human peripheral blood lymphocytes (PBL). 

Evaluation of new pharmaceuticals, pesticides, and the like for developmental toxicity is required by law. Such testing is actually a special type of toxicity testing and the rules for these studies are based on a few generally accepted principles and a number of assumptions. The principles are listed in this section and the assumptions implicit in these studies are discussed. The overall predictive ability of the animal studies to give reliable indication of potential adverse effects in humans is then presented. 

Since epidemiology relates directly to the incidence of illness or toxicity in humans, the existence of positive epidemiological data is most relevant to assessing potential human hazard or risk. The major advantages of epidemiological studies are that they are usually based on large numbers of humans exposed to real-world levels of the chemical. Any effects observed are directly relevant to humans and do not require the type of extrapolations used to relate animal studies to humans. 

Alternative models include ex vivo eye preparations and in vitro cell cultures but all such alternatives require extensive validation before data can be used for hazard assessment. However, these models can be used as part of a tiered approach for eye irritancy testing, significantly reducing the number of animal studies required. 

---