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.

Qualification and application of a surface plasmon resonance-based assay for monitoring potential HAHA responses induced after passive administration of a humanized anti Lewis-Y antibody.

A sensitive, surface plasmon resonance (SPR)-based assay monitoring potential human-anti-human antibody (HAHA) reactions against the monoclonal antibody (mAb) IGN311 is presented. The latter is a fully humanized Lewis-Y carbohydrate specific mAb that is currently tested in a passive immune therapy approach in a clinical phase I trial. For the SPR experiments a BIACORE 3000 analyzer was used. The ligand IGN311 was covalently coupled to the carboxy-methylated dextran matrix of a CM5 research grade chip (BIACORE). In the course of a fully nested experimental design, a four parameter logistic equation was identified as appropriate calibration model ranging from 0.3 microg/mL (lower limit of quantitation, LLOQ) to 200 microg/mL (upper limit of quantitation, ULOQ) using an anti-idiotypic mAb ('HAHA mimic') as calibrator. The bias ranged from -2.4% to 5.5% and the intermediate precision expressed as 95% CI revealed values from 5.6% to 8.3%. Specificity was evaluated using six human serum matrices from healthy donors spiked with calibrator at the limit of quantitation (LOQ) with >80% of values being recovered with less than 25% relative error. The qualified assay was applied to monitor potentially induced HAHA reactivity in 11 patients from a clinical phase I trial with passively administered IGN311. Of the 11 patients, one high HAHA responder and several low responders were identified. Protein-G depletion experiments with human serum samples revealed that the observed response is predominantly caused by IgG binding to the ligand. The characteristics of these HAHA responses were all of the so-called 'Type I' which is defined by a peak response around day 15 that decreases from this point steadily suggesting that some kind of tolerance is established. Therefore, this type of HAHA response is regarded as non critical for the patient's safety.