The following definitions are used in the WHO Programme for International Drug Monitoring and member countries are encouraged to utilize them. Most of these definitions have been incorporated into guidelines issued by the ICH, EMEA and other competent national authorities. Full details, comments and explanatory notes for these are available in the Glossary of Terms from the Uppsala Monitoring Centre (WHO-UMC – Public Services – Pharmacovigilance – Definitions – Glossary of Terms in Pharmacovigilance).
In spite of the above it is important to understand that there is a rapid change in the scope of pharmacovigilance and its practice. The move towards a greater patient safety focus, changes in legislation largely in the USA and the EU, and changes in databases and technology has caused some re-thinking of definitions. Some of this thinking is incorporated in the article Adverse drug reactions: definitions, diagnosis, and management. Even this will be updated soon. Of course, definitions are important so that we can converse and write about pharmacovigilance with greater clarity each of us knowing what the jargon means. Change upsets this so that below in italics newer definitions are accompanied by the reasons for changes.
The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems.
In line with this general definition, underlying objectives of pharmacovigilance in accordance with the applicable EU legislation for are:
- preventing harm from adverse reactions in humans arising from the use of authorized medicinal products within or outside the terms of marketing authorization or from occupational exposure; and
- promoting the safe and effective use of medicinal products, in particular through providing timely information about the safety of medicinal products to patients, healthcare professionals and the public.
Pharmacovigilance is therefore an activity contributing to the protection of patients’ and public health.
“A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function.“
A more recent definition is:
Adverse reaction; synonyms: Adverse drug reaction (ADR), Suspected adverse (drug) reaction, Adverse effect, Undesirable effect
“An appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.”
Adverse reactions may arise from use of the product within or outside the terms of the marketing authorization or from occupational exposure. Conditions of use outside the marketing authorization include off-label use, overdose, misuse, abuse and medication errors.
This definition can include medication error which is a major cause of adverse effects due to drugs, it includes harm from counterfeit drugs, it includes accidental overdose, it includes all medicinal products (so it includes delivery systems such as inhalers), it includes quality problems and excipients. This definition therefore includes adverse effects from a much broader range of causes. On the other hand the latter part of the definition focuses on the value of knowing about adverse effects: we want to know about those we can do something about in terms of prevention, diagnosis or treatment.
‘Adverse reaction’ and ‘adverse effect’ are interchangeable but adverse effect is more patient-centred, and adverse reaction is more drug-centred.
Unexpected adverse reaction
An adverse reaction, the nature or severity of which is not consistent with domestic labeling or market authorization, or expected from characteristics of the drug.
Adverse event (AE); synonym: Adverse experience
Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment.
An adverse event can therefore be any unfavourable and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Any unintended effect of a pharmaceutical product occurring at doses normally used in man which is related to the pharmacological properties of the drug.
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 upon the seriousness of the event and the quality of the information.
This is considerably outmoded as a general definition. It retains some value in respect of signals from ‘spontaneous reports’, but it fails to include signals from published series or from examination of health care records, laboratory experiments, or from clinical trials or epidemiological studies. ‘Incompletely documented previously’ is also a statement which requires interpretation. A single definition of a Signal is very challenging, because of the different types of information that might constitute a signal in different contexts. A basic difficulty is: what is new? And to whom? Aronson and Hauben considered all definitions they could find and then produced a new one:
“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 verifiable and, when necessary, remedial actions.”
Edwards and Lindquist in, ‘First catch your signal’ , took a different approach giving a more descriptive view of what a signal means and some practical advice on an approach to signal management.
The latest CIOMS monograph – CIOMS VIII – recently published gives a good deal of information about current thinking on signal management. It is a lengthy document, but it has an authoritative section on data mining in the context of signal detection.
Serious adverse event or reaction
A serious adverse reaction is any untoward medical occurrence that at any dose:
- results in death or
- is life-threatening or
- requires in-patient hospitalization or prolongation of existing hospitalization or
- results in persistent or significant disability or incapacity or
- results in a congenital anomaly/birth defect
To ensure no confusion or misunderstanding of the difference between the terms “serious” and “severe”, the following note of clarification is provided:
The term “severe” is not synonymous with serious. In the English language, “severe” is used to describe the intensity (severity) of a specific event (as in mild, moderate or severe); the event itself, however, may be of relatively minor medical significance (such as severe headache). Seriousness (not severity) which is based on patient/event outcome or action criteria serves as guide for defining regulatory reporting obligation.
Life-threatening in this context refers to a reaction in which the patient was at risk of death at the time of the reaction; it does not refer to a reaction that hypothetically might have caused death if more severe.
Medical and scientific judgement should be exercised in deciding whether other situations should be considered serious reactions, such as important medical events that might not be immediately life threatening or result in death or hospitalization but might jeopardize the patient or might require intervention to prevent one of the other outcomes listed above. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or development of dependency or abuse
Any suspected transmission via a medicinal product of an infectious agent is also considered a serious adverse reaction.
Spontaneous report, synonym: Spontaneous notification
An unsolicited communication by a healthcare professional or consumer to a company, regulatory authority or other organization (e.g. the World Health Organization, a regional centre, a poison control centre) that describes one or more adverse reactions in a patient who was given one or more medicinal products and that does not derive from a study or any organized data collection scheme.
In this context, an adverse reaction refers to a suspected adverse reaction.
Stimulated reporting can occur in certain situations, such as after a direct healthcare professional communication (DHPC), a publication in the press or questioning of healthcare professionals by company representatives, and adverse reaction reports arising from these situations are considered spontaneous reports provided the report meets the definition above. Reporting can also be stimulated by invitation from patients’ or consumers’ organizations to their members. Reporting made in the context of early post-marketing phase vigilance (EPPV), e.g. in Japan, is also considered stimulated reporting.
In addition to the glossary of terms UMC has compiled a list of useful acronyms often used in pharmacovigilance (WHO-UMC – Public Services – Pharmacovigilance – Definitions – Abbreviations and Acronyms).