CHAPTER III

Minimum requirements for the monitoring of data in the Eudravigilance database

General requirements
Article 18
1
The Agency and national competent authorities shall cooperate in the monitoring of the data available in the Eudravigilance database.
2
Marketing authorisation holders shall monitor the data available in the Eudravigilance database to the extent that they have access to that database.
3
Marketing authorisation holders, the national competent authorities and the Agency shall ensure the continuous monitoring of the Eudravigilance database with a frequency proportionate to the identified risk, the potential risks and the need for additional information.
4
The competent authority of each Member State shall be responsible for monitoring the data originating in the territory of that Member State.

Identification of changed risks and new risks
Article 19
1
The identification of new risks or changed risks shall be based on the detection and analysis of the signals concerning a medicinal product or an active substance.
For the purposes of this chapter, ‘signal’ means 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, which is judged to be of sufficient likelihood to justify verificatory action.
For the purpose of monitoring data in the Eudravigilance database, only signals related to an adverse reaction shall be considered.
2
The detection of a signal shall be based on a multidisciplinary approach. Signal detection within the Eudravigilance database shall be complemented by statistical analysis, where appropriate. After consultation with the Pharmacovigilance Risk Assessment Committee, the Agency may publish a list of medical events that have to be taken into account for the detection of a signal.

Methodology for determining the evidentiary value of a signal
Article 20
1
National competent authorities, marketing authorisation holders and the Agency shall determine the evidentiary value of a signal by using a recognised methodology taking into account the clinical relevance, quantitative strength of the association, the consistency of the data, the exposure–response relationship, the biological plausibility, experimental findings, possible analogies and the nature and quality of the data.
2
Different types of factors may be taken into account for the prioritisation of signals, in particular whether the association or medicinal product is new, factors related to the strength of the association, factors related to the seriousness of the reaction involved and factors related to the documentation of reports to the Eudravigilance database.
3
The Pharmacovigilance Risk Assessment Committee shall regularly review the methodology(ies) used and publish recommendations, as appropriate.

Signal management process
Article 21
1
The signal management process shall include the following activities: signal detection, signal validation, signal confirmation, signal analysis and prioritisation, signal assessment, and recommendation for action.
For the purposes of this Article, ‘signal validation’ means 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.
2
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.
3
Where it is considered that a validated signal requires further analysis, it shall be confirmed as soon as possible and no later than 30 days from its receipt as follows:
a
where the signal concerns a product authorised in accordance with Directive 2001/83/EC, it shall be confirmed by the competent authority of a Member State in which the medicinal product is marketed or of any lead Member State or co-leader appointed in accordance with Article 22(1);
b
where the signal concerns a product authorised in accordance with Regulation (EC) No 726/2004, it shall be confirmed by the Agency in collaboration with the Member States.
When analysing the validated signal, national competent authorities and the Agency may take into account other information available on the medicinal product.
Where the validity of the signal is not confirmed, special attention shall be paid to non-confirmed signals concerning a medicinal product where those signals are subsequently followed by new signals concerning the same medicinal product.
4
Without prejudice to paragraphs 2 and 3, national competent authorities and the Agency shall validate and confirm any signal that they have detected during their continuous monitoring of the Eudravigilance database.
5
Any confirmed signal shall be entered in the tracking system administered by the Agency and shall be transmitted to the Pharmacovigilance Risk Assessment Committee for the initial analysis and prioritisation of signals in accordance with Article 107h(2) of Directive 2001/83/EC and Article 28a(2) of Regulation (EC) No 726/2004.
6
The Agency shall inform forthwith the marketing authorisation holder(s) concerned of the conclusions of the Pharmacovigilance Risk Assessment Committee of the assessment of any confirmed signal.

Worksharing for signal management
Article 22
1
For medicinal products authorised in accordance with Directive 2001/83/EC in more than one Member State and for active substances contained in several medicinal products where at least one marketing authorisation has been granted in accordance with Directive 2001/83/EC, Member States may agree within the coordination group provided for by Article 27 of Directive 2001/83/EC to appoint a lead Member State and, where appropriate, a co-leader. Any such appointment shall be reviewed at least every four years.
The lead Member State shall monitor the Eudravigilance database and shall validate and confirm signals in accordance with Article 21(3) and (4) on behalf of the other Member States. The Member State appointed as co-leader shall assist the lead Member State in the fulfilment of its tasks.
2
When appointing a lead Member State and as appropriate a co-leader, the coordination group may take into account whether any Member State is acting as reference Member State in accordance with Article 28(1) of Directive 2001/83/EC or as a rapporteur for the assessment of periodic safety update reports in accordance with Article 107e of that Directive.
3
The Agency shall publish on the European medicines web-portal a list of the active substances that are subject to worksharing in accordance with this Article and the lead Member State and co-leader appointed for monitoring those substances in the Eudravigilance database.
4
Without prejudice to paragraph 1, all Member States shall remain responsible for monitoring the data in the Eudravigilance database in accordance with Article 107h(1)(c) and Article 107h(3) of Directive 2001/83/EC.
5
For medicinal products authorised in accordance with Regulation (EC) No 726/2004, the Agency shall be assisted in the monitoring of data in the Eudravigilance database by the rapporteur appointed by the Pharmacovigilance Risk Assessment Committee in accordance with Article 62(1) of Regulation (EC) No 726/2004.

Signal detection support
Article 23
The Agency shall support the monitoring of the Eudravigilance database by providing national competent authorities with access to the following information:
1. data outputs and statistical reports allowing a review of all adverse reactions reported to the Eudravigilance database in relation to an active substance or a medicinal product;
2. customised queries supporting the evaluation of individual case safety reports and case series;
3. customised grouping and stratification of data enabling the identification of patient groups with a higher risk of occurrence of adverse reactions or with a risk of a more severe adverse reaction;
4. statistical signal detection methods.
The Agency shall also ensure appropriate support for the monitoring of the Eudravigilance database by marketing authorisation holders.

Signal detection audit trail
Article 24
1
The national competent authorities and the Agency shall keep an audit trail of their signal detection activities conducted in the Eudravigilance database and of the relevant queries and their results.
2
The audit trail shall allow traceability of how signals have been detected and of how validated and confirmed signals have been assessed.
Regulation revoked in part (31.12.2020) by The Human Medicines (Amendment etc.) (EU Exit) Regulations 2019 (S.I. 2019/775), reg. 1, Sch. 9 para. 1(t) (subject to transitional provisions in S.I. 2012/1916, Sch. 33A); 2020 c. 1, Sch. 5 para. 1(1)