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Optimizing drug discovery by Investigative Toxicology: Current and future trends – Report of CAAT-ITL Forum Think Tank

By Francois Pognan, Mario Beilmann, Harrie Boonen, Andreas Czich, Gordon Dear, Philip Hewitt, Tomas Mow, Peter Newham, Teija Oinonen, Adrian Roth, Jean-Pierre Valentin, Freddy van Goethem and Richard Weaver

Abstract

Investigative Toxicology describes the de-risking, and mechanistic elucidation of effects that supports critical early safety related decision making in the pharmaceutical industry. While the individual tasks and organizational set-up of these functions differ from company to company, it has become evident that the value of these activities do not only lie in screening assays, which precede the regulatory activities, but also in the contribution of an enhanced understanding of the mechanism of toxicity. In fact, this shifts pharmaceutical toxicology from a purely descriptive to an evidence-based mechanistic discipline. In addition, the high costs and the rather low throughput of the GLP (Good Laboratory Practice) in vivo studies, as well as increasing demands for adhering to the 3Rs (Replacement, Reduction and Refinement) principals, has increased the push for new innovative approaches. A key aspect is therefore the translation of in vitro to in vivo mechanistic data. Outside of the boundaries of regulatory toxicology with its GLP in vivo studies, Investigative Toxicology has the flexibility to embrace new technologies, though there is often a perception that non-GLP /not fully validated assays might compromise the pivotal studies and endanger the approval process. Consequently, standards of harmonization and validation as developed for the GLP studies are implicitly also demanded for the new technologies. A group of 14 European-based Investigative Toxicology leaders from the pharmaceutical industry (AstraZeneca, Bayer, Boehringer Ingelheim, GSK, Janssen, Lundbeck, Merck, Novartis, Novo Nordisk, Orion Pharma, Roche, Sanofi, Servier and UCB-Biopharma) founded the Investigative Toxicology Leaders Forum (ITLF). The goal of Investigative Toxicology, and therefore of improved preclinical decision making, coincides with the notion of an animal-free safety testing environment. Currently, too many compounds are ruled out by animal models during the preclinical phase, without knowledge of how the compounds would behave in humans, i.e. the false-positive rate of animal studies cannot be assessed. Progress in Investigative Toxicology could lead to humanized in vitro test systems and thus pave the way towards medicines less residing on animal use. For this reason, the ITLF collaborated with the Centre for Alternatives to Animal Testing Europe (CAAT-Europe) to organize an "Investigative Toxicology Think-Tank". This event also aimed to enhance the interaction with experts from academia and regulatory bodies in the field

Publisher: ALTEX
Year: 2018
OAI identifier: oai:oak.novartis.com:37258
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