ABSTRACT
Introduction: Periodic Safety Update Reports (PSURs) are a key pharmacovigilance tool for the continuous evaluation of the benefit-risk balance of a medicinal product in the post-authorisation phase. The PSUR submission frequency for authorised active substances and combinations of active substances across the EU is individually determined. The objective of this research was the development and application of the EURD tool, a statistical method based on readily available safety data to predict PSUR frequencies and to ensure a consistent risk-based approach. Methods: First, variables considered relevant in determining the PSUR frequency were identified from data sources available at the European Medicines Agency. A subsequent first survey with National Competent Authorities in Europe lead to a prioritisation of identified variables, while a second survey was carried out to propose the PSUR frequencies for a set of substances. Finally, a regression model was built on the information collected, applied to a larger list of substances and its results tested via a third survey with the same experts. Results: The developed EURD tool was applied to the 1,032 EURD list entries with a PSUR assessment deferred to 2025 at the time of the creation of the list in 2012. As the number of procedures would have had a significant impact on the workload for the European Medicines Regulatory Network (EMRN), in a second step the workload impact was estimated after allocating the entries according to their proposed frequency. The analysis suggests that all entries could be reviewed by 2038 by increasing the median workload by 15% (from 868 to 1,000 substances/year). Conclusion: The EURD tool is the first data-driven application for supporting decision making of PSUR frequencies based on relevant active substance safety data. While we illustrated its potential for improving the assignment of PSUR submission frequencies for active substances authorised in the EU, other institutions requiring periodic assessment of safety data and balancing of the resulting workload could benefit from it.
ABSTRACT
The unexpected detection of nitrosamine impurities in human medicines has recently seen global regulators act to understand the risks of these contaminations to patients and to limit their presence. Over 300 nitrosamines are known, many of which are highly potent mutagenic carcinogens. Regulators first became aware of the presence of nitrosamines in EU medicines in 2018, with reports of detection of N-nitroso-dimethylamine (NDMA) in valsartan from one manufacturer. A subsequent EU review of all valsartan medicines was triggered by the European Medicines Agency (EMA) and was later extended to other angiotensin receptor blockers/sartans. A separate review was also started for ranitidine medicines. This was followed by an EU-wide examination of the risk of presence of nitrosamines in all human medicines. This article reflects on the investigation of the EU regulatory network into the presence of nitrosamines and the scientific knowledge informing recommendations for developers on how to limit nitrosamines in medicines.
