Signal detection in pharmacovigilance
Pharmacovigilance (PV) is the practice of monitoring the effects of medicines and medical devices after they have been licensed for use, in order to manage risks and keep patients safe. It aims to identify instances where the risk of using a particular drug may outweigh its potential benefits. Signal detection is an important part of the pharmacovigilance process.
Pharmacovigilance requires the collection of data on adverse drug events (ADEs). Data must then be analysed and trends evaluated to establish a drug’s safety profile. In pharmacovigilance, a signal is information suggesting a previously unknown, potentially causal, association between a medicine and an adverse drug event.¹
Such signals are detected via analyses of various drug safety data, including those generated by the Medicines and Healthcare products Regulatory Agency’s (MHRA) Yellow Card scheme in the UK.
Please complete the form at the bottom of this article to request a complimentary trial of MedicinesComplete.
In this article, we will explain what a safety signal is in the context of pharmacovigilance, as well as how these signals are detected, investigated, and acted upon.
What is a signal?
The Council for International Organizations of Medical Sciences (CIOMS) aims to advance public health through guidance on health research including ethics, medical product development, and safety. CIOMS Working Group VIII defines a signal as “information that arises from one or multiple sources 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”. It can be either adverse or beneficial, but must be judged to be of “sufficient likelihood to justify verificatory action”.¹
In short, a safety signal in pharmacovigilance is information on a potential new or known adverse drug reaction that warrants further investigation.² Such a signal could be an event or reaction that was not previously suspected to be associated with the drug. It could also be a known reaction, that is now occurring within a new patient group (e.g. the elderly, people with renal dysfunction). Alternatively, it could be a reaction that now appears to be occurring with greater frequency or at a higher severity than anticipated.³
Regulatory bodies, including the MHRA and the European Medicines Agency (EMA), along with marketing authorisation holders, are responsible for detecting and managing safety signals.²
This aspect of pharmacovigilance is essential to ensuring that information on a medicine’s benefits and risks evolves as new data become available.
Signal management
Signal management is the overall process that identifies new risks, determines if known risks have changed, and investigates the need for action to reassess the drug safety profile. It forms the backbone of pharmacovigilance, with the objective of confirming or disproving a new issue with the safety of a drug, so that any necessary risk mitigation action might then be taken. Some of the steps involved are signal detection, analysis, evaluation, followed by deciding on and communicating actions taken to minimise risks, where appropriate.³
Signal detection
Signal detection involves looking at the patterns in adverse drug reaction data that could suggest a new, potentially causal association between a drug and an event, or a series of related events. When a safety signal is identified it does not necessarily mean that a medicine has caused the reported adverse event. It may be coincidental or an illness or another medicine taken by the patient could be the cause.
Safety signal sources
Safety signals can be detected from a wide range of sources. These include spontaneous ADR reports, via pharmacovigilance programmes such as the MHRA’s Yellow Card scheme, or the Food and Drug Administration’s (FDA) MedWatch, and Vaccine Adverse Event Reporting System (VAERS). Other sources include clinical studies, case reports, and other scientific publications.³
For drugs in clinical development, safety signals tend to originate from study data. Once a medicine is on the market, safety signals usually come from spontaneous ADR reports.³
Sources of safety data can be either qualitative, or quantitative. Qualitative sources include spontaneously reported data and case series. Quantitative sources are obtained by data mining, or from epidemiological or ongoing clinical trial data.³
Safety signals can also be detected using statistical analysis techniques. The MHRA, for example, uses specialist analytics software to identify potential safety issues in Yellow Card reports. The Yellow Card database is subjected to regular statistical analysis, which evaluates all drug reaction combinations reported. This allows the team to identify safety signals, i.e., those events that occur more frequently than would be expected, when compared to the background frequency of other drug-reaction combinations in the database.⁴ The evaluation of these signals then helps to establish whether or not there is a causal relationship between the medicine and the reported adverse event.
The results of signal evaluation guide the next steps. If experts decide action is necessary, some options are:⁵
• Add the adverse effect to the drug’s label
• Change the dosing recommendations
• Issue a safety warning
• Change the drug’s supply arrangements, for example, from over-the-counter to prescription only
• Subject the drug to additional monitoring requirements, such as regular blood tests.
In rare cases, if the risks are deemed to outweigh the benefits, the medicine may be removed from the market.
EMA publishes a list of all safety signals that have been discussed and the recommendations given for each of them.⁶
Adverse drug reaction checker
Signal detection and management is a dynamic process – and keeping up-to-date with emerging potential ADRs is an essential part of delivering quality healthcare. With many new and complex medicines becoming available each year, the landscape is changing all the time.
Martindale’s ADR Checker, available through Medicines Complete, provides information on ADRs for more than 1600 drugs used internationally.
Trial form
Please complete the form below to request a complimentary trial to knowledge products through MedicinesComplete.
References
1. CIOMS. (2010). Practical Aspects of Signal Detection in Pharmacovigilance. Available at: https://cioms.ch/working_groups/working-group-viii/ Last accessed: 8th April 2025.
2. EMA. (n.d.). Signal management. Available at: https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/signal-management Last accessed: 8th April 2025.
3. Malikova, M. A. (2020). Practical applications of regulatory requirements for signal detection and communications in pharmacovigilance. Therapeutic Advances in Drug Safety, 11, 2042098620909614.
4. MHRA. (n.d.). Pharmacovigilance – how the MHRA monitors the safety of medicines. Available at: https://assets.publishing.service.gov.uk/media/5feefb56d3bf7f089a791a2c/Pharmacovigilance___how_the_MHRA_monitors_the_safety_of_medicines.pdf Last accessed: 8th April 2025.
5. MHRA. (n.d.). Guidance on adverse drug reactions. Available at: https://assets.publishing.service.gov.uk/media/5feefb4c8fa8f53b7a0fbe36/Guidance_on_adverse_drug_reactions.pdf Last accessed: 8th April 2025.
6. PRAC recommendations on safety signals | European Medicines Agency (EMA) Last accessed: 28th April 2025.
