Abstract
Investigative Toxicology describes the de-risking and mechanistic elucidation of toxicities, supporting early safety decisions in the pharmaceutical industry. Recently, Investigative Toxicology has contributed to a shift in pharmaceutical toxicology, from a descriptive to an evidence-based, mechanistic discipline. This was triggered by high costs and low throughput of Good Laboratory Practice in vivo studies, and increasing demands for adhering to the 3R (Replacement, Reduction and Refinement) principles of animal welfare. Outside the boundaries of regulatory toxicology, Investigative Toxicology has the flexibility to embrace new technologies, enhancing translational steps from in silico, in vitro to in vivo mechanistic understanding to eventually predict human response. One major goal of Investigative Toxicology is improving preclinical decisions, which coincides with the concept of animal-free safety testing. Currently, compounds under preclinical development are being discarded due to the use of inappropriate animal models. Progress in Investigative Toxicology could lead to humanized in vitro test systems and the development of medicines less reliant on animal tests. To advance this field a group of 14 European-based leaders from the pharmaceutical industry founded the Investigative Toxicology Leaders Forum (ITLF), an open, non-exclusive and pre-competitive group that shares knowledge and experience. The ITLF collaborated with the Centre for Alternatives to Animal Testing Europe (CAAT-Europe) to organize an "Investigative Toxicology Think-Tank", which aimed to enhance the interaction with experts from academia and regulatory bodies in the field. Summarizing the topics and discussion of the workshop, this article highlights Investigative Toxicology's position by identifying key challenges and perspectives.
Highlights
Tremendous progress in preclinical development across the pharmaceutical industry has been achieved over the past three decades
The International Conference for Harmonisation (ICH) has contributed to an internationally accepted set of submission-relevant guideline documents generally concerning in vivo drug safety studies, which are based on Organisation for Economic Co-operation and Development (OECD) test guidelines for the individual study conduct and are strongly connected to OECD documents for Good Laboratory Practice (GLP)
The whole framework of harmonization has led to an increase of mutual acceptance of preclinical submission documents in the three regions involved (European Union, the United States, and Japan) and, as a consequence, to elimination of studies performed to satisfy the specific requirements of individual regulatory authorities (OECD, 2005)
Summary
Tremendous progress in preclinical development across the pharmaceutical industry has been achieved over the past three decades. The whole framework of harmonization has led to an increase of mutual acceptance of preclinical submission documents in the three regions involved (European Union, the United States, and Japan) and, as a consequence, to elimination of studies performed to satisfy the specific requirements of individual regulatory authorities (OECD, 2005) This positive development of streamlined testing strategies, brought some challenges with it. While the tasks and organizational set-up of these functions differ from company to company, it has become evident that the value of these activities lies in screening assays preceding regulatory activities, and in an enhanced understanding of the mechanism of toxicity, which is relevant for later phases of clinical development This is shifting pharmaceutical toxicology from a purely descriptive to an evidence-based mechanistic discipline. It starts with a gap analysis, followed by a critical assessment of new technologies, and finishes by summarizing challenges, and presenting perspectives and recommendations
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