Objective: To assess whether, in those requiring ongoing uterine stimulation after cervical ripening with oral misoprostol and membrane rupture, augmentation with low dose oral misoprostol is superior to intravenous oxytocin. Design: Open-label, superiority randomised trial Setting: Government hospitals in India Population: Women induced with oral misoprostol for hypertensive disease in pregnancy and requiring ongoing induction after membrane rupture Methods: Participants received misoprostol (25mcg orally two hourly) or titrated oxytocin through an infusion pump. Main Outcome Measure: Caesarean birth Results: 520 women were randomised and the baseline characteristics were comparable between the groups. The caesarean section rate was not reduced by the use of misoprostol (misoprostol 32.3% vs oxytocin 27.3%; adjusted odds ratio 1.226 (95% CI 0.81-1.85, p=0.33)). There were no differences in rates of hyperstimulation, fetal heart rate abnormalities, or maternal side effects, although the geometric mean time from randomisation to birth was 31 minutes longer with misoprostol. Fewer babies in the misoprostol arm were admitted to the special care unit (10 vs 21 in the oxytocin group) and there were no neonatal deaths in the misoprostol group, compared to 3 in the oxytocin arm. Women’s acceptability ratings were high in both study groups. Conclusion: Following cervical preparation with oral misoprostol and membrane rupture, the use of ongoing oral misoprostol for augmentation did not significantly reduce caesarean rates compared to oxytocin. The method, however, was safe for both mother and baby.

Setting-up a high quality and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for industrials. Generating high-quality safety data, compliant with legal and regulatory standards such as European or World Health Organization (WHO), places special requirements on the PV system. The scenario becomes more complicated when dealing with multi-country European clinical trials where heterogeneity on safety process can be encountered. Some Sponsors face these challenges are even more difficult for pediatric trials. A possible solution to ensure that the safety of all participants is equally guaranteed and the PV system fulfills all regulations could be to set up a centralized PV system. This paper introduces the key points to consider when implementing and organizing such system in multi-national European clinical trials. It is based on the Inserm-ANRS MIE pharmacovigilance department’s experience and aims to harmonize and anticipate the needs, in particular by implementing safety procedures and a network of local safety officers. This system is very useful to respond to the challenges of a European clinical trial, notably when considering the complexity of local safety requirements of each country, signal management and the specificities of paediatric regulation.