The eTOX Data-Sharing Project to Advance in Silico Drug-Induced Toxicity Prediction

Abstract

The high-quality in vivo preclinical safety data produced by the pharmaceutical industry during drug development, which follows numerous strict guidelines, are mostly not available in the public domain. These safety data are sometimes published as a condensed summary for the few compounds that reach the market, but the majority of studies are never made public and are often difficult to access in an automated way, even sometimes within the owning company itself. It is evident from many academic and industrial examples, that useful data mining and model development requires large and representative data sets and careful curation of the collected data. In 2010, under the auspices of the Innovative Medicines Initiative, the eTOX project started with the objective of extracting and sharing preclinical study data from paper or pdf archives of toxicology departments of the 13 participating pharmaceutical companies and using such data for establishing a detailed, well-curated database, which could then serve as source for read-across approaches (early assessment of the potential toxicity of a drug candidate by comparison of similar structure and/or effects) and training of predictive models. The paper describes the efforts undertaken to allow effective data sharing intellectual property (IP) protection and set up of adequate controlled vocabularies) and to establish the database (currently with over 4000 studies contributed by the pharma companies corresponding to more than 1400 compounds). In addition, the status of predictive models building and some specific features of the eTOX predictive system (eTOXsys) are presented as decision support knowledge-based tools for drug development process at an early stage.

Improving the Safety Assessment of Chemicals and Drug Candidates by the Integration of Bioinformatics and Chemoinformatics Data

“…). A database system, schemata for different end‐points, a versatile graphical user interface (GUI) for complex queries and most importantly ontologies for the numerous terms used in toxicological reports to describe organs, end‐points and effects were created . The latter aspect is probably one of the biggest obstacles for using complex in vivo safety data in databases.…”

Integrative Modeling Strategies for Predicting Drug Toxicities at the eTOX Project

“…The latest progresses of the eTOX project have been reported recently 15. In this work we will focus on the predictive components of eTOXsys, describing the strategy adopted for predicting toxicity endpoints and the eTOX predictive system, which will be illustrated with examples models.…”

E-cigarettes and the need and opportunities for alternatives to animal testing

“…Given the dynamic developments of this product category and the lack of established testing strategies, read-across is a prime opportunity for fast assessment and pruning of substances. The recent progress in this field (Patlewicz et al, 2014;Ball et al, 2016;Zhu et al, 2016) might form a starting point, though currently the necessary big datasets come from industrial chemicals (Luechtefeld et al, 2016) and drug development, e.g., in the e-Tox database 15 (Cases et al, 2014). The common needs shared by e-cigarette industry with food, flavor, fragrance, cosmetics / personal care product industry to assess many overlapping ingredients and complex mixtures not really suitable for traditional toxicology, could synergize.…”