Mead, Andy N., Amouzadeh, Hamid R., Chapman, Kathryn, Ewart, Lorna, Giarola, Alessandro, Jackson, Sam, Jarvis, Philip, Jordaan, Pierre, Redfern, Will, Traebert, Martin, Valentin, Jean-Pierre and Vargas, Hugo M. (2016) THE PREDICTIVE VALUE OF THE RODENT NEUROFUNCTIONAL ASSESSMENT FOR CENTRAL NERVOUS SYSTEM EVENTS IN PHASE I CLINICAL TRIALS. Toxicological Sciences.

Abstract

Central Nervous System (CNS) safety concerns detected nonclinically and adverse events (AE’s) observed in the clinic are major contributors to failure during the development of new drugs. Translational safety assessment could improve the probability of success for new drugs through a critical evaluation of safety decision making. In this analysis, the shared CNS safety data of 141 small molecules from six pharmaceutical companies derived from rodent neurofunctional assessments was investigated to identify the concordance between nonclinical assessments and phase I First In Human (FIH) outcomes. The data indicate that, in the context of the data collection parameters in this analysis, the rodent neurofunctional assessment did not detect or predict the most commonly observed subjective CNS AE’s in the FIH study, which were headache, nausea, dizziness, fatigue and/or somnolence and pain. Furthermore, the presence of any finding in the same nonclinical assessment does not predict the likelihood of whether compounds will produce any of these CNS AE’s during the FIH study. This analysis indicates that the findings from the rodent neurofunctional assessment cannot be used to predict the presence of commonly observed spontaneously reported subjective CNS AE’s in FIH studies. However, it should be emphasized that these CNS AE’s with the highest prevalence in FIH studies are often not responsible for delaying or stopping further progression of candidate drugs. Additional CNS AE’s that might be considered ‘showstoppers’ occurred at an incidence rate in our clinical dataset which was too low to enable meaningful statistical analysis of nonclinical to clinical translation.

Item Type:	Article
Date Deposited:	06 Jun 2016 23:45
Last Modified:	06 Jun 2016 23:45
URI:	https://oak.novartis.com/id/eprint/24472