Predicting the safety of medicines in pregnancy: A workshop report.

The framework for developmental toxicity testing has remained largely unchanged for over 50 years and although it remains invaluable in assessing potential risks in pregnancy, knowledge gaps exist, and some outcomes do not necessarily correlate with clinical experience. Advances in omics, in silico approaches and alternative assays are providing opportunities to enhance our understanding of embryo-fetal development and the prediction of potential risks associated with the use of medicines in pregnancy. A workshop organised by the Medicines and Healthcare products Regulatory Agency (MHRA), "Predicting the Safety of Medicines in Pregnancy - a New Era?", was attended by delegates representing regulatory authorities, academia, industry, patients, funding bodies and software developers to consider how to improve the quality of and access to nonclinical developmental toxicity data and how to use this data to better predict the safety of medicines in human pregnancy. The workshop delegates concluded that based on comparative data to date alternative methodologies are currently no more predictive than conventional methods and not qualified for use in regulatory submissions. To advance the development and qualification of alternative methodologies, there is a requirement for better coordinated multidisciplinary cross-sector interactions coupled with data sharing. Furthermore, a better understanding of human developmental biology and the incorporation of this knowledge into the development of alternative methodologies is essential to enhance the prediction of adverse outcomes for human development. The output of the workshop was a series of recommendations aimed at supporting multidisciplinary efforts to develop and validate these alternative methodologies.

Preclinical testing for teratogenicity and developmental toxicity: methods and limitations.

With regard to the risk of reproductive or developmental toxicity, the regulatory decisions to allow clinical trials in humans or the marketing of a new drug are based almost entirely on animal data. This is not the case for other types of toxicity for which the preclinical data are supported by data from clinical trials. Whilst animal studies have been remarkably successful in the detection of reproductive toxicology over the last 40 years, they are not infallible. The efficacy of animal experimentation is largely dependent on the selection of appropriate animal models. Progress in the study of teratogenic mechanisms, comparative physiology, developmental biology and pharmacokinetics will hopefully continue to bring about more economical and effective uses of animals. Nevertheless, owing to the limitations of animal models, the monitoring of human births unfortunately remains an essential defence in the detection and early prevention of chemical-induced birth defects.