IX.C.4. Notifications and procedural options for signals detected by the marketing authorisation holder in the EU based on the continuous monitoring of EudraVigilance data

Where a marketing authorisation holder detects a new signal when monitoring the Eudravigilance database, it shall validate it and shall forthwith inform the Agency and national competent authorities [IR Art 21(2)].

For this purpose, signal validation by the marketing authorisation holder should include a thorough analysis of EudraVigilance data (see IX.B.3. and IX.C.3.3.). This analysis should be complemented, for validated signals, by the marketing authorisation holder’s assessment of other relevant data available to them (e.g. own database, literature, clinical trials) (see IX.B.3.). By definition, a signal should provide new information on an association (see IX.A.1.1.) and therefore, the marketing authorisation holder should check, wherever possible, whether a risk may already be addressed in the product information of other EU medicinal products containing the active substance of interest (except for product-specific issues), in which case the product information should be aligned as appropriate through an application for variation of the terms of marketing authorisation. The marketing authorisation holder should also take into account the information published or communicated by the Agency in relation to signals (see IX.C.9. and Figures IX.3. and IX.4. in IX. Appendix 1.).

Based on their own assessment, the marketing authorisation holder may conclude that a signal is refuted, that there is a new or changed risk and/or that further analysis is required by the competent authorities. The conclusion that a signal represents a new or changed risk and/or that further analysis by the competent authorities is required is the starting point (‘Day 0’) of the timelines indicated herein.

A new or changed risk that requires a change to the terms of the marketing authorisation should in principle be the object of an application for variation of the terms of marketing authorisation (see IX.C.4.1.), unless the marketing authorisation holder considers that further analysis by the competent authorities is warranted. Further analysis by the competent authorities may be sought in the case of validated signals that cannot be refuted nor confirmed as new or changed risks by the marketing authorisation holder based on their assessment.

Signals requiring further analysis by the competent authorities may be reported only in PSURs if the conditions outlined in IX.C.4.2. are met. If not, a standalone signal notification should be submitted (see IX.C.4.3.).

Refuted signals should only be reported in PSURs (see GVP Module VII).

These options are further detailed in sections IX.C.4.1., IX.C.4.2. and IX.C.4.3., and illustrated in Figure IX.2. in IX. Appendix 1.

All validated signals requiring urgent attention should be reported as emerging safety issues (see IX.C.2.).

IX.C.4.1. Variation of the terms of marketing authorisation

A marketing authorisation holder may conclude, based on their assessment of a signal detected through the monitoring of EudraVigilance data, that the product information and/or the RMP should be updated through a variation. In such cases, the marketing authorisation holder should submit the variation application to the relevant competent authorities as soon as possible and no later than 3 months after completing the assessment of the signal if it corresponds to an important risk (see GVP Annex I), or within 6 months for adverse reactions or risks not considered important.

In such instances, a separate standalone signal notification (see IX.C.4.3.) is not required, as the proposed changes and supportive evidence will be assessed within the variation procedure by the relevant competent authorities, which may consult the PRAC if required.

Marketing authorisation holders should follow the relevant guidance on variations, including worksharing procedures, and liaise with competent authorities as appropriate when preparing their variation application (15).

IX.C.4.2. Inclusion of the signal in the periodic safety update report (PSUR)

If an active substance is included in the List of Union Reference Dates and Frequency of Submission of Periodic Safety Update Reports (PSURs) (EURD List) (16) and a PSUR is due to be submitted within 6 months of the completion, by the marketing authorisation holder, of the assessment of a signal detected through continuous EudraVigilance monitoring, the submission of a separate standalone signal notification (see IX.C.4.3.) is not required. Indeed, the signal will be further assessed by the PRAC / competent authorities in Member States as appropriate within the PSUR procedure (see GVP Module VII). If the data-lock point of the PSUR has elapsed by the time the marketing authorisation holder has completed their assessment of the signal, it should be mentioned in the PSUR section ‘Latebreaking Information’ together with a proposal for further management of the signal (see GVP Module VII).

Based on the evaluation of the cumulative safety data and the risk-benefit balance analysis submitted in the PSUR, the marketing authorisation holder shall draw conclusions regarding the need for changes to the terms of the marketing authorisation and/or actions, including any implications for the approved product information for the medicinal product(s) for which the PSUR has been submitted [IR Art 34(5)]. This also applies to the conclusions drawn based on the evaluation of safety signals (see GVP Module VII).

Regardless of their source, all validated signals and emerging safety issues for which the evaluation was concluded during the reporting interval of a PSUR, or are ongoing at the time of a PSUR data lock point, should be reported in that PSUR (PSUR sections 15 and 16) (see GVP Module VII).

IX.C.4.3. Standalone signal notification

When a marketing authorisation holder, based on their assessment of a signal detected through EudraVigilance monitoring, and which does not meet the conditions outlined in IX.C.4.1. and IX.C.4.2., concludes that further analysis of the signal by the competent authorities is required, they should complete the standalone signal notification form available on the European medicines web-portal (17) and send it to the Agency using the mailbox “MAH-EV-signals@ema.europa.eu” and to the competent authorities in Member States where the medicinal product is authorised (18).

This should be done as soon as possible and no later than 30 days after the marketing authorisation holder has completed their assessment and concluded that further analysis by the competent authorities is required.

Standalone signal notifications are not required in case of signals included within PSURs or variation applications, as per the conditions outlined in IX.C.4.1. and IX.C.4.2..

Signals refuted by marketing authorisation holders should not be sent as standalone signal notifications but should be included in PSURs as applicable (see GVP Module VII).