ABSTRACT
INTRODUCTION The development of new chemical entities (NCEs) as potential therapeutic agents is dependent on successful clinical trials, which ultimately demonstrate efficacy and safety in patient populations under controlled conditions. To initiate Phase I clinical trials for NCEs intended for multiple dosing, appropriate repeat dose toxicity studies in two species, one of which is a nonrodent (in addition to genotoxicity and safety pharmacology studies), are necessary to submit petitions to worldwide regulatory agencies. While the determination of the acute toxicity and associated median lethal dose (LD50) of environmental and industrial chemicals is useful for assessing consumer and worker protection, risk-benefit analysis, etc., this information is less important for understanding the potential safety of most drugs under development. Exceptions would be for products being developed for single dose or infrequent administration such as medical imaging agents (including both contrast agents and diagnostic radiopharmaceuticals) (1), some therapeutic radiopharmaceuticals (2), and gene therapy medicinal products (3). For those products, comprehensive single dose toxicity studies in two species (one of which is a nonrodent) would be necessary prior to a Phase I clinical trial.
