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. 2014 Dec 18:2:210-221.
doi: 10.1016/j.toxrep.2014.12.004. eCollection 2015.

Value of shared preclinical safety studies - The eTOX database

Katharine Briggs  1 , Chris Barber  1 , Montserrat Cases  2 , Philippe Marc  3 , Thomas Steger-Hartmann  4
Affiliations

Value of shared preclinical safety studies - The eTOX database

Katharine Briggs et al. Toxicol Rep. .

Abstract

A first analysis of a database of shared preclinical safety data for 1214 small molecule drugs and drug candidates extracted from 3970 reports donated by thirteen pharmaceutical companies for the eTOX project (www.etoxproject.eu) is presented. Species, duration of exposure and administration route data were analysed to assess if large enough subsets of homogenous data are available for building in silico predictive models. Prevalence of treatment related effects for the different types of findings recorded were analysed. The eTOX ontology was used to determine the most common treatment-related clinical chemistry and histopathology findings reported in the database. The data were then mined to evaluate sensitivity of established in vivo biomarkers for liver toxicity risk assessment. The value of the database to inform other drug development projects during early drug development is illustrated by a case study.

Keywords: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Biomarkers; CDISC, Clinical Data Interchange Standards Consortium; CRO, contract research organisation; DILI, drug induced liver injury; Data mining; Data sharing; EFPIA, European Federation of Pharmaceutical Industries and Associations; FN, false negative; FP, false positive; GLP, good laboratory practice; ICH, International Conference on Harmonisation; IMI, Innovative Medicines Initiative; INHAND, International Harmonization of Nomenclature and Diagnostic Criteria; IT, information technology; MCC, Matthews correlation coefficient; OECD, Organisation for Economic Co-operation and Development; Ontology; PDF, Portable Document Format; PDF/A, ISO-standardized version of PDF specialized for the digital preservation of electronic documents.; QA, quality assurance; SEND, Standard for Exchange of Nonclinical Data; SME, small-to-medium enterprise; TN, true negative; TP, true positive; Toxicology; ULN, upper limit of normal; eTOX, integrating bioinformatics and chemoinformatics approaches for the development of expert systems allowing the in silico prediction of toxicities.

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Figures

None
Graphical abstract
Fig. 1
Fig. 1
Data sensitivity classifications within the eTOX project.
Fig. 2
Fig. 2
Chronological progress of number and status of study reports as of April 2014.
Fig. 3
Fig. 3
Species distribution in eTOX 2014-1 database (number of studies).
Fig. 4
Fig. 4
Study duration distribution in eTOX 2014-1 database (number of studies).
Fig. 5
Fig. 5
Administration route distribution in eTOX 2014-1 database (number of studies).
Fig. 6
Fig. 6
Number of positive versus negative compounds associated with the different types of findings in the eTOX 2014-1 database. Positive compounds: compounds with these findings flagged as treatment related. Negative compounds: compounds with these findings that are not flagged as treatment related.
Fig. 7
Fig. 7
Top 10 organs based on the number of compounds with treatment-related histopathology findings in the eTOX 2014-1 database. Positive compounds: compounds with these findings flagged as treatment related. Negative compounds: compounds with these findings that are not flagged as treatment related.
Fig. 9
Fig. 9
Top 10 changes in clinical chemistry based on the number of compounds with these findings flagged as treatment-related in the eTOX 2014-1 database. Positive compounds: compounds with these findings flagged as treatment related. Negative compounds: compounds with these findings that are not flagged as treatment related.
Fig. 8
Fig. 8
Top 10 histopathology findings based on the number of compounds with these findings flagged as treatment-related in the eTOX 2014-1 database.
Fig. 10
Fig. 10
Investigated compounds for which similar haematological findings were observed.
Fig. 11
Fig. 11
Percentage of compounds associated with haematological findings. Upper pie chart: for all compounds in the eTOX 2014-1 database. Lower pie chart: the 1.1% of compounds containing a benzoic acid moiety.
Fig. 12
Fig. 12
Screenshot of the multi-parameter search for findings observed in the short term toxicity studies with the relevant drug candidates.
See this image and copyright information in PMC

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