2. Adverse Event (AE) versus Adverse Reaction (adverse drug reaction ADR) – the distinction

1. Adverse Event (AE) versus Adverse Reaction (adverse drug reaction ADR) – the distinction

(This section is organised in the form of a book, please follow the blue arrows to navigate through the book or by following the navigation panel on the right side of the page.)

The assessment of a signal in Pharmacovigilance and its classification as a safety risk or not associated with the use of a medicine determines the course of (regulatory) action to be taken. In this respect it is helpful, if not a prerequisite, to be aware of the terminology used to distinguish between an Adverse Event (AE) and an Adverse Reaction (also called Adverse Drug Reaction (ADR)). The following section on this distinction is largely based on the EMA Guideline on good pharmacovigilance practices (GVP) Annex I - Definitions (Rev 4)[1].

1.1. Adverse Event (AE):

Adverse Event (AE):

In the context of pharmacovigilance and outside a clinical trial: any untoward medical occurrence in a patient to whom a medicinal product is administered and which does not necessarily have a causal relationship with this treatment (based on ICH-E2D Guideline, see GVP Annex IV).

AEs 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 this (see GVP Annex IV, ICH-E2D Guideline[1]).

In the context of a clinical trial: any untoward  medical occurrence in a participant to whom a medicinal product is administered and which does not necessarily have a causal relationship with this treatment [Reg (EU) No 536/2014 Art 2(2)(32)]. Adverse event is synonymous to adverse experience.

A participant means an individual who participates in a clinical trial, either as recipient of an investigational medicinal product or as a control [Reg (EU) No 536/2014 Art 2(2)(17)].

1.2. Adverse reaction; synonyms: Adverse drug reaction (ADR), Suspected adverse (drug) reaction, Adverse effect, Undesirable effect

A response to a medicinal product which is noxious and unintended [DIR 2001/83/EC Art 1(11)]1.

Response in this context means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility (see GVP Annex IV, ICH-E2A Guideline).

An adverse reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship between a medicinal product and an occurrence is suspected.

For regulatory reporting purposes, if an event is spontaneously reported by a healthcare professional or consumer as primary source, even if the relationship is unknown or unstated, it meets the definition of an adverse reaction (see GVP Annex IV, ICH-E2D) and is therefore considered a suspected adverse reaction, since it conveys the suspicions of the primary sources, unless the primary source specifically state that they believe the event to be unrelated or that a causal relationship can be excluded.

Adverse reactions may arise from:

• Use of the product within the terms of the marketing authorisation or from occupational exposure [DIR 2001/83/EC Art 101(1)].


• Use outside the marketing authorisation which includes
• off- label use, (use for indications that are not approved)
• overdose,
• misuse,
• abuse
• medication errors. [An unintended failure in the drug treatment process that leads to, or has the potential to lead to, harm to the patient (see EMA-PRAC Good Practice Guide on Recording, Coding, Reporting and Assessment of Medication Errors, October 2015).

• Interactions with other medicines (drug-drug-interactions).

• Product technical or quality issues, such as a missing tablet or damaged product.

• Using falsified medicines [Any medicinal product with a false representation of (a) its identity, including its packaging and labelling, its name or its composition as regards any of the ingredients including excipients and the strength of those ingredients; (b) its source, including its manufacturer, its country of manufacturing, its country of origin or its marketing authorisation holder; or (c) its history, including the records and documents relating to the distribution channels used [DIR 2001/83/EC Art 1(33)]].

1.3. Unexpected adverse reaction

1.4. What is a serious adverse event or serious adverse reaction?

A serious adverse event or an adverse reaction is one which:

• results in death;
• is life-threatening;
• requires in-patient hospitalisation or prolongation of existing hospitalisation;
• results in significant or persistent disability or incapacity;
• is a birth defect or congenital anomaly;

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 (see GVP Annex IV, ICH-E2D Guideline).

Any suspected transmission via a medicinal product of an infectious agent is also considered a serious adverse reaction.