A safety signal is information on a new or known adverse event that may be caused by a medicine and requires further investigation. The European Medicines Agency (EMA), together with the regulatory authorities in the Member States and marketing authorisation holders are responsible for detecting and managing safety signals.
Safety signals can be detected from a wide range of sources, such as spontaneous reports, clinical studies and scientific literature. The EudraVigilance database is an important source of information on suspected adverse reactions and signals.
The presence of a safety signal does not directly mean that a medicine has caused the reported adverse event. An illness or another medicine taken by the patient could also be the cause.
The assessment of safety signals establishes whether or not there is a causal relationship between the medicine and the reported adverse event.
The evaluation of safety signals is part of routine pharmacovigilance and is essential to ensuring that regulatory authorities have the most up-to-date information on a medicine’s benefits and risks.
Routine signal detection in EudraVigilance (new)
In December 2016, EMA published guidance on routine signal detection methods in EudraVigilance for use by the Agency, national competent authorities and marketing authorisation holders:
The purpose of this guidance is to provide a scientific discussion on the methods recommended and implemented in EudraVigilance for screening for adverse reactions. It does not provide regulatory requirements, which are laid down in good pharmacovigilance practices (GVP) Module IX on signal management.
The guidance also updates and supersedes the previous guideline on the use of statistical signal detection in EudraVigilance.
Recommendations on signals
The Pharmacovigilance Risk Assessment Committee (PRAC) is responsible for prioritising and assessing signals and issuing subsequent recommendations on medicines authorised in the European Union, including nationally and centrally authorised medicines.
The PRAC recommendation may include one or a combination of conclusions, including:
- No need for further evaluation or action at present;
- Need for additional information, including:
- monitoring any relevant emerging information as it becomes available,;
- additional analysis in EudraVigilance or other data sources;
- additional data from the marketing authorisation holder in the next periodic safety update report (PSUR) or submit an ad-hoc PSUR;
- a post-authorisation safety study conducted by the marketing authorisation holder;
- Need for regulatory action, such as:
- updating of the product information (summary of product characteristics and package leaflet) and/or risk management plan through a variation;
- a referral procedure;
- urgent safety restrictions.
For more information, see:
Marketing authorisation holders should monitor PRAC recommendations on safety signals the Agency publishes on its website and take action accordingly.
As of January 2015, EMA publishes translations of recommendations (reviewed by the national competent authorities) for the updating of product information into all official EU languages plus Norwegian and Icelandic. Marketing authorisation holders can use these translations to update their product information. This aims to ensure that consistent and clear information is available to patients in a timely manner in all Member States.
Designated medical events
EMA has developed a list of designated medical events containing medical conditions that are inherently serious and often medicine-related:
It does not address product specific issues or medical conditions with high prevalence in the general population.
The list contains Medical Dictionary for Regulatory Activities (MedDRA) terms and serves as a safety net in signal detection. EMA and Member States use it to focus on reports of suspected adverse reactions that deserve special attention, irrespective of statistical criteria used to prioritise safety reviews.
The designated medical event list is one of the tools the European medicines regulatory network uses and is not intended as a comprehensive list of terms for signal detection activities.
EMA has published the list to ensure its approach is transparent. It is subject to review in light of further experience with its use.
For more information on signal detection and management in the EU and regulatory requirements for marketing authorisation holders, see:
- Guideline on good pharmacovigilance practices: Module IX - Signal management
- Questions and answers on signal management
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