NIS should be distinguished between:

• Studies with a design based on primary data collection directly from healthcare professionals or consumers (i.e. where the events of interest are collected as they occur specifically for the study), and
• Studies with a design based on secondary use of data (i.e. where the events of interest have already occurred and have been collected for another purpose).

For combined studies with a design based on both primary data collection and secondary use of data, the submission of individual case safety reports (ICSRs) is required exclusively for the data obtained through primary data collection.

National legislation should be followed as applicable regarding the obligations towards local ethics committees.

[as per Section VI.C.1.2.1 of GVP Module VI]

Information on all adverse events should be collected and recorded from healthcare professionals or consumers in the course of the study unless the protocol provides with a due justification for not collecting certain adverse events. Any reference to adverse events that are not collected should be made using the appropriate level of the MedDRA classification [as per Section VI.C.1.2.1.1 of GVP Module VI].

For all collected adverse events, comprehensive and high quality information should be sought in a manner which allow for valid ICSRs to be submitted within the appropriate time frames [as per Section VI.C.1.2.1.1 of GVP Module VI].

All fatal outcomes should be considered as adverse events which should be collected. In certain circumstances, suspected adverse reactions with fatal outcome may not be subject to submission as ICSRs, for example because they refer to study outcomes (efficacy end points), because the patients included in the study have a disease with high mortality, or because the fatal outcomes have no relation to the objective of the study. For these particular situations, the rationale for not submitting as ICSRs certain adverse reactions with fatal outcome should be clearly described in the protocol together with a list using the appropriate level of the MedDRA classification [as per Section VI.C.1.2.1.1 of GVP Module VI].

All adverse events collected during the study should be summarised in the interim safety analysis and in the final study report [as per Section VI.C.1.2.1.1 of GVP Module VI].

For adverse events specified in the study protocol which are not systematically collected, healthcare professionals and consumers should be informed in the protocol (or other study documents) of the possibility to report adverse reactions (for which they suspect a causal role of a medicine) to the marketing authorisation holder of the suspected medicinal product (studied or not) or to the concerned competent authority via the national spontaneous reporting system (see summary in the Table below) [as per Section VI.C.1.2.1.1 of GVP Module VI].

The resulting valid ICSRs should be managed, classified and submitted as spontaneous by the notified competent authority or marketing authorisation holder.  Where made aware of them, these reports should also be summarised in the relevant study reports by the marketing authorisation holder sponsoring the study[as per Section VI.C.1.2.1.1 of GVP Module VI].

The design of such studies is characterised by secondary use of data previously collected from consumers or healthcare professionals for other purposes. Examples include medical chart reviews (including following-up on data with healthcare professionals), analysis of electronic healthcare records, systematic reviews, meta-analyses [as per Section VI.C.1.2.1.2 of GVP Module VI].

For these studies, the submission of suspected adverse reactions in the form of ICSRs is not required. All adverse events/reactions collected for the study should be recorded and summarised in the interim safety analysis and in the final study report unless the protocol provides for different reporting with a due justification [as per Section VI.C.1.2.1.2 of GVP Module VI].

SERIOUS SUSPECTED ADVERSE REACTIONS (SSARS)

Marketing authorisation holders shall submit electronically to the database and data-processing network referred to in Article 24 of Regulation (EC) No 726/2004 (hereinafter referred to as the ‘Eudravigilance database’) information on all serious suspected adverse reactions that occur in the Union and in third countries within 15 days following the day on which the marketing authorisation holder concerned gained knowledge of the event (as per Article 107.3 of Directive 2001/83/EC as amended).

NON-SERIOUS SUSPECTED ADVERSE REACTIONS (SSARS)

Marketing authorisation holders shall submit electronically to the Eudravigilance database information on all non-serious suspected adverse reactions that occur in the Union, within 90 days following the day on which the marketing authorisation holder concerned gained knowledge of the event (as per Article 107.3 of Directive 2001/83/EC as amended).