Complexities in Drug Safety

A Brief Introduction To Pharmacovigilance Signals

Pharmacovigilance involves the collection of data on Adverse Reactions which must then be analysed and evaluated to create meaningful safety information.

The process of signalling involves looking at the adverse reaction data for patterns that suggest new safety information. This page provides a brief introduction to the definition and purpose of signals and some of the key methodologies employed to generate them.

What Is A Signal?

The term is most commonly associated with drugs during the post-marketing phase, although it may also be used during pre-marketing clinical trials. The definition of a signal as provided by the CIOMS Working Group 8 is:

“…information that arises from one or multiple sources (including observations and experiments), which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action”.

This could be a problem which has never previously been suspected to be associated with the product; or a known event which is now occurring within a patient group for whom it has not been documented before or perhaps occurring with greater frequency than anticipated. The signal may be generated from qualitative analysis of spontaneous reports or quantitative analysis through data mining and statistical activities.

What Is Signal Management?

The process of signal management is a set of activities which aim to determine:

  • whether there are new risks associated with a particular drug, or
  • whether risks associated with a particular drug have changed

Sources for the detection of signals can come from:

  • spontaneous reporting
  • active monitoring systems
  • interventional studies (clinical trials)
  • non-interventional studies (pharmacoepidemiology studies)
  • non-clinical studies (e.g. animal toxicology studies)
  • systematic reviews (i.e. thorough review of the published literature)
  • meta-analyses (i.e. mathematical pooling of all the clinical trial data)
  • other relevant sources

Healthcare professionals are encouraged to report adverse reactions via national spontaneous reporting systems. Consumers and patients may also report adverse reactions in this way as well as via a wide variety of media, including the internet. Relevant information may also be made available from other sources, such as poisons centres.

Signals arising from spontaneous reports also could be detected via:

  • Monitoring large adverse drug reaction databases such as Eudravigilance and the FDA AERs system
  • Published articles
  • PSURs
  • Ongoing benefit-risk monitoring

The process for managing signals within pharmaceutical companies and regulatory authorities / pharmacovigilance centres must systematically address the following steps:

  • Signal detection
  • Validation and Confirmation
  • Analysis
  • Prioritisation
  • Assessment
  • Recommending action

All steps taken and recommendations made must be accurately tracked and documented at every stage. There are resulting legal obligations which must be fulfilled in an accurate and timely manner but the ultimate goal is to confirm or refute whether there is some new issue with the safety of a medicine so that action might then be taken to reduce the risk.

Please note that signal management is a complex area within pharmacovigilance and this page therefore cannot constitute any form of professional advice.