Signal detection: identifying new safety information from pharmacovigilance data
Signal detection is the process of finding information that suggests a new or changed causal link between a medicine and an adverse event.
A signal is information from one or more sources, including observations and experiments, that suggests a new potentially causal association, or a new aspect of a known association, between a medicine and an event, and that is judged likely enough to justify verification. The definition sits in Article 19 of Commission Implementing Regulation (EU) No 520/2012, and the process is described in GVP Module IX on signal management. Signal detection is the first step; validation, confirmation, prioritisation, assessment and a recommendation for action follow.
Marketing authorisation holders must continuously monitor the data available to them, including spontaneous reports, literature, clinical studies and EudraVigilance. Since November 2017 holders have been required to monitor EudraVigilance for the active substances in their products, validate any signal they find and inform EMA and the national competent authorities. Validated signals for centrally authorised products, and for substances in the EURD list, go to the PRAC, which issues recommendations that are published monthly. A recommendation often asks the holder to update the product information through a variation within a set deadline, or to address the signal in the next PSUR.
Methods range from case-by-case medical review to disproportionality statistics on large databases. EMA uses the reporting odds ratio and related measures with the electronic reaction monitoring reports it generates for substances. A high statistical score is not a signal on its own; it is a prompt for a pharmacovigilance assessor to review the cases for causality, seriousness, novelty and clinical relevance.
What goes wrong: holders that rely on the periodic PSUR review instead of continuous monitoring and so miss a cluster of cases that EMA has already seen; signals validated internally but not communicated, which surfaces at inspection; duplicate cases that inflate disproportionality scores and waste assessment time; and PRAC recommendations that are not tracked to a variation, so the SmPC lags behind the published outcome. Generic holders are affected as much as originators, because a signal on a substance leads to product information changes for every product that contains it.
Signal activity should be documented in the pharmacovigilance system master file, with the method, frequency and the tool used, and the record of each signal from detection to closure, because inspectors ask for exactly that audit trail.
Timing
There is no fixed statutory clock for detection itself, but GVP Module IX expects validated signals to be reported to EMA and the national competent authorities without delay, and most holders set an internal limit of days rather than weeks. Once the PRAC adopts a recommendation, the holder must file the corresponding variation within the period stated in the recommendation, usually two months for a product information update, and address the issue in the next PSUR where that is the outcome.
Used in
Pharmacovigilance teams watch PRAC signal recommendations for the substances in your portfolio in Alerts, so the follow-up variation starts on time.
Related terms
- PRAC: Pharmacovigilance Risk Assessment CommitteeThe PRAC is the EMA committee that assesses the safety of human medicines in the EU, from risk management plans and PSURs to signals and safety referrals.
- EudraVigilance: EU adverse reaction databaseEudraVigilance is the EU system for collecting, managing and analysing suspected adverse reaction reports for medicines authorised in the EEA.
- PSUR: periodic safety update reportA periodic safety update report (PSUR) is a holder's periodic benefit-risk evaluation of a medicine, due at intervals set by the EURD list or the MA.
- QPPV: qualified person responsible for pharmacovigilanceThe QPPV is the named individual, resident in the EU, who is personally responsible for a marketing authorisation holder's pharmacovigilance system.
- PSMF: pharmacovigilance system master fileThe pharmacovigilance system master file (PSMF) is the holder's detailed description of its pharmacovigilance system, kept in the EU for inspectors.
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