Since its publication, the WHO definition of a signal has been influential and widely adopted. However, as pharmacovigilance has developed, concepts and definitions have also evolved.
A signal is essentially a hypothesis of a risk with a medicine with data and arguments that support it, derived from data from one or more of many possible sources. The evidence in a signal is not conclusive (is, in the technical sense, uncertain), and is only an early indication (preliminary), as it may change substantially over time as more data accumulates. Sometimes a signal may provide additional or new information about adverse or beneficial effects of an intervention, or information about an already-known association of a medicine with an adverse drug effect, for example: on the range of severity of the effect or its outcome; postulating a mechanism; indicating an at-risk group; suggesting a dose range which might be more risky/perilous, a pharmaceutical group-effect or a lack of effect by a particular medicine.
The result of a causality assessment of a medicine-adverse effect in individual case reports may be described as:
Once it is decided that there is a plausible association between an adverse effect and a drug, UMC will communicate the evaluation as a signal via VigiLyze, to members of the WHO Programme. Subsequently it may be published in the publicly-available WHO Pharmaceuticals Newsletter. Regulators in individual countries may investigate further and decide to restrict the use of the medicine.
Read more about the use of the WHO-UMC system for standardised case causality assessment here.
Because of the different definitions of ‘signal’ and the additional uncertainties introduced by adjectives that are attached to signals such as ‘validated’, ‘verified’, ‘weak’, ’strong’, it may be preferable to simply state that there is a hypothesis of harm with all the necessary evidence supporting the hypothesis. The hypothesis should carry information on the author(s) and when the hypothesis was made, as hypotheses change over time as new information accrues. Depending on the sender of the information suggestions could be given for what the next steps might be taken and why. Outcomes might vary from ‘not worth pursuing’, through attentive waiting for more information to accrue, to further active investigation by any appropriate means, to regulatory or other preventative or clinical management actions might be reasonable based on the hypothesis alone.
See also: Lindquist M. Seeing and Observing in International Pharmacovigilance - Achievements and Prospects in Worldwide Drug Safety. Doctoral thesis, Katholieke Universiteit Nijmegen. Uppsala Monitoring Centre, 2003; ISBN 91-628-5588-3; pp. 85-94.
A signal consists of a hypothesis, together with data and arguments.
Meyboom RH, Egberts ACG, Edwards IR et al. Principles of Signal Detection in Pharmacovigilance. Drug Safety, 1997;16:355-65.
Information that arises from one or multiple sources (including observation 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, which would command regulatory, societal or clinical attention, and is judged to be of sufficient likelihood to justify verificatory and, when necessary, remedial actions.
Hauben and Aronson. Defining 'Signal' and its Subtypes in Pharmacovigilance Based on a Systematic Review of Previous Definitions. Drug Safety, 2009, 32 (2), 99-110.
The CIOMS VIII definition (adopted by EMA) is a slightly modified version of this.
Practical Aspects of Signal Detection in Pharmacovigilance : Report of CIOMS Working Group VIII. CIOMS, Geneva, 2010; p14.
Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than a single report is required to generate a signal, depending on the seriousness of the event and the quality of the information.
Delamothe T. Reporting adverse drug reactions. Br Med J, 304, 465, 1992. (Definition presented at the 1991 meeting of national centres participating in the WHO Programme for International Drug Monitoring.)
Though not a definition, it is the case that disproportionality is an issue: reporting of events that are statistically disproportionate (i.e.an O/E ratio exceeding a specified threshold), is a signal of disproportionate reporting.