IX.A.1. Terminology

Definitions relevant to signal management are also included in GVP Annex I.

IX.A.1.1. General terminology

Signal: Information arising 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, that is judged to be of sufficient likelihood to justify verificatory action [IR Art 19(1)].

New aspects of a known association may include changes in the frequency, distribution (e.g. gender, age and country), duration, severity or outcome of the adverse reaction.

A signal often relates to all medicinal products containing the same active substance, including combination products. Certain signals may only be relevant for a particular medicinal product or in a specific indication, strength, pharmaceutical form or route of administration whereas some signals may apply to a whole class of medicinal products.

For the purpose of monitoring data in the EudraVigilance database (also referred to as ‘EudraVigilance’), only signals related to an adverse reaction shall be considered [IR Art 19(1)].

Signal management process: A set of activities performed to determine whether, based on an examination of individual case safety reports (ICSRs), aggregated data from active surveillance systems or studies, scientific literature information or other data sources, there are new risks associated with an active substance or a medicinal product or whether known risks have changed, as well as any related recommendations, decisions, communications and tracking.

The EU signal management process includes the following activities: signal detection, signal validation, signal confirmation, signal analysis and prioritisation, signal assessment and recommendation for action [IR Art 21(1)] (see IX.A.1.2.).

Signal prioritisation: The process, continuously performed throughout signal management, which aims to identify those signals suggesting risks with a potential important patients’ or public health impact or which may significantly affect the risk-benefit balance of the medicinal product and thus require urgent attention and management without delay. (5)

Signal detection: The process of looking for and/or identifying signals using data from any source. (6)

Signal validation: The process of evaluating the data supporting the detected signal in order to verify that the available documentation contains sufficient evidence demonstrating the existence of a new potentially causal association, or a new aspect of a known association, and therefore justifies further analysis of the signal [IR Art 21(1)].

This evaluation should take into account the strength of the evidence, the clinical relevance and the previous awareness of the association (see IX.B.3.).

The extent of evaluation performed during signal validation versus further assessment may vary according to the organisation’s internal procedures.

Validated signal: A signal for which the signal validation process has verified that the available documentation contains sufficient evidence demonstrating the existence of a new potentially causal association, or a new aspect of a known association, and therefore justifies further analysis of the signal.

Non-validated signal: A signal for which the signal validation process has led to the conclusion that the available documentation at that point in time does not contain sufficient evidence demonstrating the existence of a new potentially causal association, or a new aspect of a known association, and that therefore further analysis of the signal is not warranted. (7)

Signal assessment: The process of further evaluating a validated signal taking into account all available evidence, to determine whether there are new risks causally associated with the active substance or medicinal product or whether known risks have changed. This review may include nonclinical and clinical data and should be as comprehensive as possible regarding the sources of information.

Refuted signal: A validated signal which, following further assessment has been determined to be “false” i.e. a causal association cannot be established at that point in time (see GVP Module VII).

Emerging safety issue: A safety issue considered by a marketing authorisation holder to require urgent attention by the competent authority because of the potential major impact on the risk-benefit balance of the medicinal product and/or on patients’ or public health, and the potential need for prompt regulatory action and communication to patients and healthcare professionals. Examples include:

• major safety issues identified in the context of ongoing or newly completed studies, e.g. an unexpectedly increased rate of fatal or life-threatening adverse events;
• major safety issues identified through spontaneous reporting or published in the scientific literature, which may lead to considering a contra-indication, a restriction of use of the medicinal product or its withdrawal from the market;
• major safety-related regulatory actions outside the EU, e.g. a restriction of the use of the medicinal product or its suspension.

The requirements and process for emerging safety issues are outlined in IX.C.2..

IX.A.1.2. Terminology specific to the EU signal management process with oversight of the Pharmacovigilance Risk Assessment Committee (PRAC)

Lead Member State for signal management: The Member State responsible for monitoring the EudraVigilance database for an active substance or combination of active substances contained in medicinal products authorised in more than one Member State through the national, mutual recognition or decentralised procedures. The lead Member State shall validate and confirm signals on behalf of the other Member States (see IX.C.1.2.).

If the active substance is authorised in only one Member State, that Member State automatically assumes the responsibilities of the Lead Member State.

PRAC Rapporteur: Rapporteur appointed by the PRAC in the context of the centralised procedure (see PRAC Rules of Procedure (8)). Within the EU signal management process, the PRAC Rapporteur is responsible for the confirmation of signals concerning centrally authorised medicinal products.

Signal confirmation by the PRAC Rapporteur or (lead) Member State: The process of deciding whether or not a validated signal entered in the European Pharmacovigilance Issues Tracking Tool (EPITT) requires further analysis and prioritisation by the PRAC. This should be done by the PRAC Rapporteur or the (lead) Member State within 30 days from receipt of the validated signal.

Signal confirmation is not intended to be a full assessment of the signal. The fact that a signal is confirmed does not imply that a causal relationship has been established, but that the signal should be discussed at EU level and further investigated by the PRAC (see IX.C.5.).

Confirmed signal: A validated signal entered in EPITT that requires further analysis and prioritisation by the PRAC, according to the PRAC Rapporteur or (lead) Member State.

Non-confirmed signal: A validated signal entered in EPITT that does not require further analysis and prioritisation by the PRAC at that point in time, according to the PRAC Rapporteur or (lead) Member State. Signal analysis and prioritisation by the PRAC: The process by which the PRAC determines whether a confirmed signal requires further assessment, and if required, to what timeframe and in which procedural framework. This is based on an initial analysis of the potential impact of the signal on patients’ or public health and the risk-benefit balance of the concerned medicinal product(s) (see IX.C.6.).

Signal assessment by the PRAC: Following PRAC initial signal analysis and prioritisation, the process of evaluating all available data relevant to a signal to determine the need for any regulatory action (see IX.C.6.). This is led by the Rapporteur appointed by the PRAC following analysis and prioritisation.