Ewart, Lorna, Aylott, Mike, Deurinck, Mark, Ju, Haisong and Suter, Willi (2014) AN ANALYSIS OF THE CONSCIOUS DOG TELEMETRY MODEL AND ITS ABILITY TO DETECT AND PREDICT CARDIOVASCULAR CHANGE IN PHASE I. Toxicological sciences, 142 (2). pp. 427-435. ISSN 1096-0929; 1096-6080

Abstract

It is widely accepted that more needs to be done to bring new safe and efficacious drugs to the market. Cardiovascular safety detected both in early drug discovery as well as in the clinic, is a major contributor to the high failure rate of new drugs. The growth of translational safety, combined with the considered use of well understood and characterised animal models, as per regulatory guidelines, offers a promising approach to improve the probability of success for new drugs. Nonclinical and phase I clinical cardiovascular data with corresponding plasma exposure, have been shared for 114 small molecules between 7 pharmaceutical companies. The aim was to (a) investigate the concordance between nonclinical and phase I outcome and (b) propose an objective framework for assessing animal models used in the drug discovery process. Accounting for the lack of clinical positives and the heterogeneous data as a consequence of data sharing, the conclusions that can be drawn were limited. Nonetheless, the data indicate that the ability to detect and predict compounds that affect the QT interval was good and within a similar exposure range in animals and man. The ability to detect and predict compounds that affect haemodynamic parameters was severely limited but was reasonable for true negatives (e.g. those without haemodynamic liability). The placement of these data within a 2 dimensional framework confirmed this finding. In conclusion, improved concordance and hence probability of success, may be achieved by refinements to both the animal and clinical study designs.

Item Type:	Article
Date Deposited:	13 Oct 2016 00:45
Last Modified:	13 Oct 2016 00:45
URI:	https://oak.novartis.com/id/eprint/20986