Predicting the safety of medicines in pregnancy: A workshop report

N. Berry,R.G. Hawkes,A.H. Piersma,J.M. Clements,A. Adjei,P. Barrow,M.E.W. Beekhuijzen,G. Waxenecker,D. Jones,L. Simon,A. Fowkes,F. Sewell,S. Price,H. Stemplewski,M. Pirmohamed,H. Prior,T. Chambers

doi:10.1016/j.reprotox.2020.02.011

Abstract

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.

Highlights

The framework for developmental toxicity testing has remained largely unchanged for over 50 years and it remains invaluable in assessing potential risks in pregnancy, knowledge gaps exist, and some outcomes do not necessarily correlate with clinical experience
In 2017, a UK Commission on Human Medicines (CHM) Expert Working Group [6] produced a set of recommendations aimed at improving the evidence base for medicines taken during pregnancy and lactation
Examples of such advancements include the development of alternative assays, in silico modelling and a better understanding of developmental adverse outcomes pathways (AOPs)

Summary

General introduction

Evidence on the safety and efficacy of medicines in pregnant women is generally lacking. In 2017, a UK Commission on Human Medicines (CHM) Expert Working Group [6] produced a set of recommendations aimed at improving the evidence base for medicines taken during pregnancy and lactation One such recommendation was the delivery of a workshop to consider how nonclinical data could be made more predictable and accessible, as well as the feasibility of using computer modelling and molecular structural alerts to generate safety signals from in vivo and in vitro data. Since the implementation of the ICH guideline on reproductive toxicology in 1993, has experience been gained with the testing of pharmaceuticals using the current and novel testing paradigms, but scientific, technological and regulatory knowledge has significantly evolved, as acknowledged by the ongoing revision of the ICH S5 (R3) guideline [63] Examples of such advancements include the development of alternative assays, in silico modelling and a better understanding of developmental adverse outcomes pathways (AOPs). Given the current revision of ICH S5, the emergence of new technologies over recent years, and an opportunity to seek the opinions of multidisciplinary cross-sector experts, the workshop considered the following questions:

Limitations of current state and future opportunities

Overcoming regulatory barriers

Alternative techniques for developmental toxicity testing

Adverse outcome pathways for developmental toxicity

QSAR approaches for the prediction of developmental toxicity

Data sharing: aspirations and delivery

Findings

Can the current testing strategy for developmental toxicity be improved?

Conclusions