FDA POINTS-TO-CONSIDER DOCUMENTS - THE NEED FOR DIETARY CONTROL FOR THE REDUCTION OF EXPERIMENTAL VARIABILITY WITHIN ANIMAL ASSAYS AND THE USE OF DIETARY RESTRICTION TO ACHIEVE DIETARY CONTROL

Standard protocols for conducting chronic toxicity and carcinogenicity studies have been refined over the years to carefully control for man y variables. Nevertheless, over the last 2 decades, there has been a s teady increase in variability, a decrease in survival, an increase in tumor incidence rates, and an increase in the average body weight of c ontrol animals among the various rodent species and strains used for t oxicity testing. These observations have prompted an evaluation of chr onic study designs to determine what factor(s) may be responsible for such confounding changes. Ad libitum feeding and the selection of succ essful breeders with rapid offspring growth is believed to be at least partially responsible for the heavier, obese rodents with which many laboratories are coping today. As a result of these changes, some stud ies used for the evaluation of safety have been deemed inconclusive or inadequate for regulatory purposes and either additional supportive s tudies have been requested and/or studies per se have been repeated. R esearch on the molecular mechanisms of caloric restriction and agent-i nduced toxicity at the Food and Drug Administration (FDA) National Cen ter for Toxicological Research stimulated the first international conf erence on the biological effects of dietary restriction in 1989; this was followed in 1993 by an FDA workshop exploring the utility of dieta ry restriction in controlling reduced survival in chronic tests and an international conference in 1994 exploring the implications for the r egulatory community of using dietary restriction in toxicity and carci nogenicity studies used in support of a sponsor's submission or in ris k assessments. The outcome of that conference was the FDA's commitment to develop Points-to-Consider documents that address the issue of die tary control in chronic toxicity and carcinogenicity studies.