High Dose Selection for General Toxicity Studies of New Medicines

Abstract

High dose selection is a key methodological element in general toxicity studies of medicines. It determines the informative value of study results, the compliance with the principles of ethical and rational use of experimental animals, and the accuracy of predicting the safety of new medicines for human use. The literature data and the regulatory experience in evaluating preclinical study results suggest that the selection of an inappropriate high dose is a very common error in planning toxicity studies. This error leads to a significant or complete loss of the informative value of study results; the results become useless for assessing the safety of new medicinal products for human use.The aim of this study was to analyse the current regulatory requirements for high dose selection for general toxicity studies of medicines.The analysis suggests that unreasonably high doses may be selected for toxicity studies because methodological recommendations are prone to interpretation errors. Their potential for ambiguity stems from the absence of specific standardised upper limits for toxic doses or sufficiently clear dose selection criteria. Prerequisites for properly planning preclinical safety studies of new medicines include compliance with dose selection requirements of regulatory toxicology and implementation of a clinically and toxicologically sound decision-making algorithm.