VI.B.1. Collection of individual safety reports

Competent authorities and marketing authorisation holders should take appropriate measures to collect and collate all reports of suspected adverse reactions associated with medicinal products for human use originating from unsolicited or solicited sources.

For this purpose, a pharmacovigilance system should be developed to allow the acquisition of sufficient information for the scientific evaluation of those reports.

The system should be designed so that it helps to ensure that the collected reports are authentic, legible, accurate, consistent, verifiable and as complete as possible for their clinical assessment. All notifications that contain pharmacovigilance data should be recorded and archived in compliance with the applicable data protection requirements (see VI.C.6.2.2.10. for guidance on the processing of personal data in the EU).

The system should also be structured in a way that allows for reports of suspected adverse reactions to be validated (see VI.B.2. for ICSRs validation) in a timely manner and exchanged between competent authorities and marketing authorisation holders within the legal submission time frame (see VI.B.7.1. for ICSRs time frames submission).

In accordance with the ICH-E2D (see GVP Annex IV), two types of safety reports are distinguished in the post-authorisation phase: reports originating from unsolicited sources and those reported as solicited.

VI.B.1.1. Unsolicited reports

VI.B.1.1.1. Spontaneous reports

A spontaneous report is an unsolicited communication by a healthcare professional, or consumer to a competent authority, marketing authorisation holder or other organisation (e.g. regional pharmacovigilance centre, poison control centre) that describes one or more suspected adverse reactions in a patient who was given one or more medicinal products. It does not derive from a study or any organised data collection systems, as defined in VI.B.1.2. With regard to this, the following situations should also be considered as spontaneous reports:

• stimulated reporting that occurs consequent to a direct healthcare professional communication (see GVP Module XV), publication in the press, questioning of healthcare professionals by company representatives, communication from patients’ organisations to their members, or class action lawsuit;
• unsolicited consumer adverse reactions reports irrespective of any subsequent “medical confirmation;
• reports of suspected adverse reactions, which are not related to any organised data collection systems and (i) which are notified through medical enquiry/product information services or (ii) which are consequent of the distribution of information or educational materials;
• unsolicited reports of suspected adverse reactions collected from the internet or digital media (see VI.B.1.1.4. for guidance on ICSRs management from the internet or digital media);
• an individual case notified by different reporters, and at least one notification is done spontaneously;
• reports of suspected adverse reactions from non-interventional post-authorisation studies related to specified adverse events for which the protocol does not require their systematic collection (see VI.C.1.2.1.1. for EU guidance on this type of non-interventional post-authorisation studies, and VI.6.2.3.7 Subsection 2 for EU guidance on the electronic submission of these ICSRs);
• reports of suspected adverse reactions from compassionate use or named patient use conducted in countries where the systematic collection of adverse events in these programmes is not required (see VI.C.1.2.2. for EU guidance on compassionate use or named patient use, and VI.6.2.3.7 Subsection 2 for EU guidance on the electronic submission of these ICSRs).

The modalities for the submission of spontaneous reports of suspected adverse reactions and the applicable time frames are described in VI.B.7. and VI.B.8.

VI.B.1.1.2. Literature reports

The medical literature is a significant source of information for the monitoring of the safety profile and of the risk-benefit balance of medicinal products, particularly in relation to the detection of new safety signals or emerging safety issues. Marketing authorisation holders are therefore expected to maintain awareness of possible publications through a systematic literature review of widely used reference databases (e.g. Medline, Excerpta Medica or Embase) no less frequently than once a week. The marketing authorisation holder should ensure that the literature review includes the use of reference databases that contain the largest reference of articles in relation to the medicinal product properties9 . In addition, marketing authorisation holders should have procedures in place to monitor scientific and medical publications in local journals in countries where medicinal products have a marketing authorisation, and to bring them to the attention of the company safety department as appropriate.

Reports of suspected adverse reactions from the medical literature, including relevant published abstracts from meetings and draft manuscripts, should be reviewed and assessed by marketing authorisation holders to identify and record ICSRs.

If multiple medicinal products are mentioned in the publication, only those which are identified by the publication’s author(s) as having at least a possible causal relationship with the suspected adverse reaction should be considered for literature review by the concerned marketing authorisation holder(s).

Valid ICSRs should be submitted in accordance with the time frames and modalities detailed in VI.B.7. and VI.B.8.

One case should be created for each single identifiable patient in line with the characteristics provided in VI.B.2.. Relevant medical information should be recorded and the first publication author (or the corresponding author, if designated) should be considered as the primary source of information. Details about the co-authors do not need to be documented among the primary sources of information.

EU requirements, concerning the active substances and the scientific and medical publications not monitored by the Agency and for which valid ICSRs shall be submitted to the EudraVigilance database by marketing authorisation holders, are provided in VI.C.2.2.3.1.. Exclusion criteria in relation to the submission in the EU of ICSRs published in the literature are also detailed in VI.C.2.2.3.2.

VI.B.1.1.3. Reports from non-medical sources

If a marketing authorisation holder becomes aware of a report of suspected adverse reactions originating from a non-medical source, for example the lay press or other media, it should be managed as a spontaneous report. Every attempt should be made to follow-up the case to obtain the minimum information that constitutes a valid ICSR. With regard to the submission of those ICSRs, the same modalities and time frames should be applied as for other spontaneous reports.

VI.B.1.1.4. Information on suspected adverse reactions from the internet or digital media

In line with ICH-E2D (see GVP Annex IV), marketing authorisation holders should regularly screen the internet or digital media10 under their management or responsibility, for potential reports of suspected adverse reactions. With respect to this, a digital medium is considered to be company sponsored if it is owned, paid for and/or controlled by the marketing authorisation holder11 . The frequency of the screening should allow for potential valid ICSRs to be submitted to the competent authorities within the appropriate regulatory submission time frames based on the date the information was posted on the internet site/digital medium. Marketing authorisation holders may also consider utilising their websites to facilitate the collection of reports of suspected adverse reactions (see VI.C.2.2.1. for marketing authorisation holders’ responsibilities in the EU on spontaneous reports).

If a marketing authorisation holder becomes aware of a report of suspected adverse reaction described in any non-company sponsored digital medium, the report should be assessed to determine whether it qualifies for submission as ICSR.

Unsolicited cases of suspected adverse reactions from the internet or digital media should be handled as spontaneous reports. The same submission time frames as for spontaneous reports should be applied (see VI.B.7.1. for ICSRs time frames submission). In relation to cases from the internet or digital media, the identifiability of the reporter refers to the possibility of verification of the existence of a real person based on the information available e.g. an email address under a valid format has been provided (see VI.B.2. for ICSRs validation). If the country of the primary source is missing, the country where the information was received, or where the review took place, should be used as the primary source country.

VI.B.1.2. Solicited reports

As defined in ICH-E2D (see GVP Annex IV), solicited reports of suspected adverse reactions are those derived from organised data collection systems, which include clinical trials, non-interventional studies, registries, post-approval named patient use programmes, other patient support and disease management programmes, surveys of patients or healthcare professionals, compassionate use or name patient use, or information gathering on efficacy or patient compliance.

Reports of suspected adverse reactions obtained from any of these data collection systems should not be considered spontaneous. This is with the exception of:

• reports of suspected adverse reactions from non-interventional post-authorisation studies related to specified adverse events for which the protocol does not require their systematic collection (see VI.C.1.2.1.1. for EU guidance on this type of non-interventional post-authorisation studies, and VI.6.2.3.7 Subsection 2 for EU guidance on the electronic submission of these ICSRs),
• reports of suspected adverse reactions from compassionate use or named patient use conducted in countries where the systematic collection of adverse events in these programmes is not required (see VI.C.1.2.2. for EU guidance on compassionate use or named patient use, and VI.6.2.3.7 Subsection 2 for EU guidance on the electronic submission of these ICSRs).

With regard to the submission as ICSRs, solicited reports should be classified as study reports. They should have an appropriate causality assessment to consider whether they refer to suspected adverse reactions and therefore meet the minimum validation criteria (see VI.B.2. for ICSRs validation). Valid ICSRs should be submitted in line with the time frames and modalities detailed in VI.B.7. and VI.B.8.

General principles concerning the management of reports of suspected adverse reactions occurring in organised data collection systems conducted in the EU under the scope of Directive 2001/83/EC, Regulation (EC) No 726/2004 or Directive 2001/20/EC are presented in VI.C.1.. Guidance on the management of solicited reports by marketing authorisation holders in the EU is provided in VI.C.2.2.2.