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Defining ‘Signal’ and its Subtypes in Pharmacovigilance Based on a Systematic Review of Previous Definitions

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Abstract

Having surveyed the etymology and previous definitions of the pharmacovigilanceterm ‘signal’, we propose a definition that embraces all the surveyed ideas, reflects real-world pharmacovigilance processes, and accommodates signals of both harmful and beneficial effects.

The essential definitional features of a pharmacovigilance signal are (i) that it is based on one or more reports of an association between an intervention or interventions and an event or set of related events (e.g. a syndrome), including any type of evidence (clinical or experimental); (ii) that it represents an association that is new and important and has not been previously investigated and refuted; (iii) that it incites to action (verification and remedial action); (iv) that it does not encompass intervention-event associations that are not related to causality or risk with a specified degree of likelihood and scientific plausibility.

Based on these features, we propose this definition of a signal of suspected causality: “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, which would command regulatory, societal or clinical attention, and is judged to be of sufficient likelihood to justify verificatory and, when necessary, remedial actions.”

This defines an unverified signal; we have also defined terms —indeterminate, verified, and refuted signals — that qualify it in relation to verification.

This definition and its accompanying flowchart should inform decision making in considering benefits and harms caused by pharmacological and nonpharmacological interventions.

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Acknowledgements

The authors wish to thank the following individuals who reviewed earlier versions of the manuscript and/or contributed to fruitful discussions of the relevant concepts: Michael Cook, Gaby Danan, Robin Ferner, Stephen Goldman, Alan Hochberg, David Madigan, John Price, Valerie Simmons, Uli Vogel and Gunilla Sjölin-Forsberg. Manfred Hauben acknowledges the CIOMS Working Group VIII on Application of Signal Detection in Pharmacovigilance. Manfred Hauben is a full-time employee of Pfizer Inc, who manufacture/market drugs in the same pharmacological/therapeutic class as one of the drugs mentioned in this article (topiramate). As part of the compensation as an employee, Manfred Hauben owns stock in Pfizer Inc., in addition to owning stock in other pharmaceutical companies that may manufacture/market drugs in the same pharmacological/therapeutic class as drugs mentioned in this article. Jeffrey Aronson has no potential conflicts of interest relevant to the content of this article to declare. No sources of funding were used in the preparation of this review.

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Authors and Affiliations

  1. Department of Risk Management Strategy, Pfizer Inc., 235 East 42nd Street, New York, New York, 10017, USA

    Manfred Hauben

  2. Department of Medicine, Division of Clinical Pharmacology, New York University School of Medicine, New York, New York, USA

    Manfred Hauben

  3. Department of Family and Community Medicine, Department of Pharmacology, New York Medical College, Valhalla, New York, USA

    Manfred Hauben

  4. School of Information Systems, Computing, and Mathematics, Brunel University, West London, UK

    Manfred Hauben

  5. College of Pharmacy, University of Maryland, Baltimore, Maryland, USA

    Manfred Hauben

  6. Department of Primary Health Care, University of Oxford, Headington, Oxford, UK

    Jeffrey K. Aronson

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  1. Manfred Hauben
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Correspondence to Manfred Hauben.

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Hauben, M., Aronson, J.K. Defining ‘Signal’ and its Subtypes in Pharmacovigilance Based on a Systematic Review of Previous Definitions. Drug-Safety 32, 99–110 (2009). https://doi.org/10.2165/00002018-200932020-00003

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