High dose selection in general toxicity studies for drug development: A pharmaceutical industry perspective

Abstract

The choice of an appropriate high dose for nonclinical toxicology studies continues to generate significant discussion and debate. Typically, use of the term "high dose" reflects a consideration of a Maximum Tolerated Dose (MTD) or a Maximum Feasible Dose (MFD), inexact terms applied to the design of nonclinical studies conducted to support human clinical trials for experimental new drugs. A pharmaceutical industry perspective on appropriate considerations for high doses in nonclinical studies is provided herein, however, the basic principles applied to the design of toxicology studies translate across the areas of Regulatory, Academic, and Industrial toxicology. Dose selection approaches for nonclinical studies of safety assessment for pharmaceuticals should consider the need to demonstrate the full range of the dose-response continuum (e.g., NOAEL through a toxic dose), however, should also take into account relevance to human therapeutic doses and incorporate clinical indication- and phase-specific considerations.