Signal Management in Pharmacovigilance

A safety signal is information on a new or known adverse event that is potentially caused by a medicine and that warrants further investigation. The presence of a safety signal does not mean that a medicine has caused the reported adverse event. The adverse event could be a symptom of another illness or be caused by another medicine taken by the patient. Therefore, evaluation of safety signals is required to establish whether or not there is a causal relationship between the medicine and the reported adverse event.

Signals are generated from several sources such as spontaneous reports, clinical studies and the scientific literature. One of the most important sources for detecting safety signals is EudraVigilance, European adverse reactions database. The evaluation of safety signals is part of routine pharmacovigilance activities, through which the benefit-risk balance of a medicine is actively monitored and managed.

The European Medicines Agency (EMA) and the national regulatory authorities of EU Member States are continuously monitoring data in the EudraVigilance database to detect the occurrence of new risks, the change of existing risks and to assess whether those risks have an impact on the benefit-risk balance of a medicine. On the national level, the regulatory authorities are detecting signals for the active substances of medicinal products which are authorised in particular Member State. Additionally, at the European level there exists the list of active substances contained in authorised medicines for which a lead Member State has been appointed to monitor data in EudraVigilance, with the aim of validating and confirming the signals. This list is published at EMA website, here.

HALMED is actively and continuously monitoring, analysing, prioritising and evaluating the signals at both described levels.

Member States are evaluating all potential signals through participation in the work of EMA’s Pharmacovigilance Risk Assessment Committee (PRAC). Signal management encompasses the analysis, prioritization and assessment of signals, resulting in a PRAC recommendation. These recommendations may relate to any medicine with a valid marketing authorisation in the EU, including nationally and centrally authorised medicines.

In cases where a causal relationship is confirmed or considered likely, the concerned MAHs may be asked by the PRAC to provide further information. PRAC recommendation in principle relates to regulatory action, such as an update of the Summary of product characteristics (SmPC) and the package leaflet (PL). PRAC recommendations for regulatory action concerning centrally authorised medicines are submitted to the Committee for Medicinal Products for Human Use (CHMP) for endorsement. If the signal concerns nationally authorised medicines, PRAC recommendations for regulatory action are submitted to the Coordination Group for Decentralised and Mutual Recognition Procedures - Human (CMDh).

More information on how signals are managed is available here:

MAHs should regularly monitor the information about the PRAC recommendations concerning their products and are required to take action according to the endorsed recommendations. EMA regularly publishes the recommendations on safety signals following the PRAC meeting. An overview of PRAC recommendations, as well as a cumulative list of all signals discussed at the PRAC since September 2012, is available here.

PRAC recommendations in English and Croatian are also available at HALMED website, here.