Concordance of 3 alternative teratogenicity assays with results from corresponding in vivo embryo-fetal development studies: Final report from the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) DruSafe working group 2

• Published in: Regulatory toxicology and pharmacology 2021-08, Vol.124, p.104984, Article 104984
• Main Authors: McNerney, M., Potter, D., Augustine-Rauch, K., Barrow, P., Beyer, B., Brannen, K., Engel, S., Enright, B.P., Nowland, W.S., Powles-Glover, N., Powlin, S., Schneidkraut, M.J., Stanislaus, D., Turner, K., Graziano, M.
• Format: Article
• Language: English
• Subjects: Embryo-fetal lethality; Likelihood ratios; Malformations; Murine embryonic stem cells; NPV; PPV; Rat whole embryo culture; Teratogenicity; Zebrafish embryo culture
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2021.104984

An IQ DruSafe working group evaluated the concordance of 3 alternative teratogenicity assays (rat whole embryo culture, rWEC; zebrafish embryo culture, ZEC; and murine embryonic stem cells, mESC) with findings from rat or rabbit embryo-fetal development (EFD) studies. Data for 90 individual compounds from 9 companies were entered into a database. In vivo findings were deemed positive if malformations or embryo-fetal lethality were reported in either species. Each company used their own criteria for deciding whether the alternative assay predicted the in vivo findings. Standard concordance parameters were calculated, positive and negative predictive values (PPV and NPV) were adjusted for the aggregate portfolio prevalence of positive compounds (established by a survey of participating companies), and positive and negative likelihood ratios (LR+ and iLR-) were calculated. Of the 3 assays, only rWEC data were robustly predictive, particularly for negative predictions (NPVadj = 92%). However, both LR+ (4.92) and iLR- (4.72) were statistically significant for the rWEC assay. When analyzed separately for rats, the NPVadj and iLR-values for the rWEC assay increased to 96% and 9.75, respectively. These data suggest that a negative rWEC outcome could defer or replace a rat EFD study in certain regulatory settings. •Results from 3 alternative teratogenicity assays were compared to corresponding in vivo embryo-fetal development studies.•The zebrafish embryo culture (ZEC) and murine embryonic stem cell (mESC) assays were not highly predictive.•When adjusted for prevalence, the rat whole embryo culture (rWEC) assay was predictive for negative in vivo results.•Concordance of the rWEC assay increased when positive in vivo findings were made more stringent.