CSL-Tox: An open-source analytical framework for the comparison of short-term and long-term toxicity end points and exploring the opportunities for decreasing in-vivo studies conducted for drug development programs.

Abstract

In-vivo toxicity assessment is an important step prior to clinical development and is still the main source of data for overall risk assessment of a new molecular entity (NCE). All in-vivo studies are performed according to regulatory requirements and many efforts have been exerted to minimize these studies in accordance with the (Replacement, Reduction and Refinement) 3Rs principle. Many aspects of in-vivo toxicology packages can be optimized to reduce animal use, including the number of studies performed as well as study durations, which is the main focus of this analysis. We performed a statistical comparison of adverse findings observed in 116 short-term versus 78 long-term studies in order to explore the possibility of using only short-term studies as a prediction tool for the longer-term effects. Annotation of treatment related findings was one of the challenges faced during this work. A specific focus was therefore put on the summary and conclusion sections of the reports since they contain expert assessments on whether the findings were considered adverse or were attributed to other reasons. Our analysis showed a general good concordance between short-term and long-term toxicity findings for large molecules and the majority of small molecules. Less concordance was seen for certain "target organ systems findings. While this work supports the minimization of in-vivo study durations, a larger-scale effort would be needed to provide more evidence. We therefore present the steps performed in this study as an open-source R workflow (CSL-Tox) and we provide the dataset used in the work to allow researchers to reproduce such analysis and to promote large-scale application of this study.