Ensuring confidence in predictions: A scheme to assess the scientific validity of in silico models

The use of in silico tools within the drug development process to predict a wide range of properties including absorption, distribution, metabolism, elimination and toxicity has become increasingly important due to changes in legislation and both ethical and economic drivers to reduce animal testing. Whilst in silico tools have been used for decades there remains reluctance to accept predictions based on these methods particularly in regulatory settings. This apprehension arises in part due to lack of confidence in the reliability, robustness and applicability of the models. To address this issue we propose a scheme for the verification of in silico models that enables end users and modellers to assess the scientific validity of models in accordance with the principles of good computer modelling practice. We report here the implementation of the scheme within the Innovative Medicines Initiative project “eTOX” (electronic toxicity) and its application to the in silico models developed within the frame of this project

Legacy data sharing to improve drug safety assessment: the eTOX project

Non-clinical safety assessment is often faced with the challenge of assessing candidate compounds with no or insufficient experimental data. Whereas relevant databases and reliable in silico tools exist for mutagenicity prediction, analogous resources for identifying potential organ toxicities are not as common or well developed. Scientists, therefore, have to resort to suboptimal procedures such as literature search and personal experience with similar compounds or classes. In parallel, there is a wealth of relevant data buried in the archives of the pharmaceutical industry that has not yet been leveraged. These data mainly exist in paper or pdf formats and, consequently, are difficult to search and analyze. In order to overcome these limitations and advance early safety assessment, 13 pharmaceutical companies, 11 academic partners and 6 small and medium-sized enterprises (SMEs) joined forces in the eTOX project, which started in January 2010 under the sponsorship of the European Innovative Medicines Initiative (IMI). Since the availability of a wide and representative collection of historical data is fundamental for generating reliable predictions, the main goals of the eTOX project were (i) to build a shared and mineable database containing a broad and relevant collection of data, constituted mainly by repeat-dose toxicity studies contributed by the pharmaceutical companies participating in the project, and (ii) to use the database and other sources of information for enabling more effective read-across and predictive modeling of safety endpoints

Legacy data sharing to improve drug safety assessment: The eTOX project

The sharing of legacy preclinical safety data among pharmaceutical companies and its integration with other information sources offers unprecedented opportunities to improve the early assessment of drug safety. Here, we discuss the experience of the eTOX project, which was established through the Innovative Medicines Initiative to explore this possibility