Medical literature monitoring

The European Medicines Agency (EMA) is responsible for monitoring a number of substances and selected medical literature, to help identify suspected adverse reactions to medicines authorised in the European Union (EU). EMA also enters relevant information into the EudraVigilance database.

The medical literature is an important source of information for the identification of suspected adverse reactions to authorised medicines.

Marketing authorisation holders of medicines in the European Economic Area (EEA) are usually responsible for monitoring the medical literature on their medicines, and reporting individual cases of suspected adverse reactions into EudraVigilance and national safety databases. This is in line with Guideline on good pharmacovigilance practices (GVP) - Module VI – Collection, management and submission of reports of suspected adverse reactions to medicinal products (Rev. 2).

However, for a number of substances with many marketing authorisations and multiple marketing authorisation holders in the EEA, EMA provides a medical literature monitoring service. This service aims to:

• avoid duplication of effort by marketing authorisation holders;
• prevent the same reports being entered into databases by multiple marketing authorisation holders;
• enhance the quality and consistency of data reported;
• improve the safety monitoring of medicines.

The service has been fully operational since September 2015. The legal basis is Article 27 of Regulation (EC) No 726/2004.

Substances and medical literature covered by EMA’s service

Active-substance and herbal-substance groups covered	Medical literature monitoring: substance groups 1-309 and herbal substance groups 1-100 valid from 1 June 2020
Databases used	EMBASE, covering literature from EEA and non-EEA countries; International Pharmaceutical Abstracts (IPA); The Allied and the Complementary Medicine Database (AMED); MEDLINE. For more information, see: Monitoring of medical literature and the entry of relevant information into the EudraVigilance database by the European Medicines Agency - Description of the Journal/Reference databases used
Search parameters	Monitoring of medical literature and the entry of relevant information into the EudraVigilance database by the European Medicines Agency - EMBASE Monitoring of medical literature and the entry of relevant information into the EudraVigilance database by the European Medicines Agency – IPA and AMED Monitoring of medical literature and the entry of relevant information into the EudraVigilance database by the European Medicines Agency - MEDLINE

EMA can only monitor a certain number of substances, based on its allocated budget for these activities, which is subject to an annual review.

EMA selects these substances on the basis of information submitted to EMA's Article 57 database by marketing authorisation holders.

It prioritises substances contained in medicines with many marketing authorisations and multiple marketing authorisation holders.

In June 2020, EMA added nine additional active substances (chloroquine, darunavir, emtricitabine-tenofovir, filgrastim, ivermectin, nitric oxide, oseltamivir, prednisone and ritonavir) which were being investigated as potential treatments for COVID-19, and for which there are multiple marketing authorisation holders in the EEA.

From 1 April 2024 EMA expanded the MLM Service to also cover MEDLINE, which comprises more than 36 million citations for biomedical literature, life science journals, and online books.

The information from MEDLINE was already included in the EMBASE searches (along with many other journals too), but the articles will be available sooner by searching MEDLINE.

Marketing authorisation holders' monitoring and reporting requirements

Marketing authorisation holders are usually responsible for monitoring the medical literature on their medicines, and reporting individual cases of suspected adverse reactions into EudraVigilance and national safety databases.

However, they are not required to monitor or report suspected adverse reactions from the medical literature EMA monitors to EudraVigilance for active substances covered by EMA's service.

EMA makes the individual cases of suspected adverse reactions it finds in the literature available to marketing authorisation holders, so that they can include them in their safety databases and meet their reporting obligations outside the EEA.

Marketing authorisation holders should note that they are required to monitor and report to EudraVigilance suspected adverse reactions:

• recorded in all medical literature for active substances that are not covered by the service;
• recorded in medical literature that EMA does not monitor as part of its service, including for active substances that are covered by EMA's service.

For more information, see Article 107 of Directive 2001/83/EC.

Business processes for individual case safety reports from EMA’s service

Individual case safety reports (ICSRs) resulting from EMA’s medical literature monitoring service follow this process:

• Electronic transmission to the EudraVigilance Gateway.
• Rerouting to national competent authorities in EEA Member States.
• Made available to concerned marketing authorisation holders via the ICSR download area of EVWEB.

This process covers ICSRs of suspected serious and non-serious adverse reactions occurring within and outside the EEA.

Marketing authorisation holders can download the ICSRs in XML format in compliance with the document below

European Union individual case safety report (ICSR) implementation guide

Adopted Consultation dates: 30/04/2014 to 30/06/2014 Reference Number: EMA/51938/2013 Rev. 2 Summary:

This guidance specifies the technical requirements and the process of transmission of individual case safety reports (ICSRs) and is applicable to all stakeholders, which are exchanging ICSRs electronically within the European Economic Area.

To be able to access the ICSRs, marketing authorisation holders should either:

• be EVWEB users;
• have their safety system configured to be able to download ICSRs with the Sender identifier “MLMSERVICE”.

Marketing authorisation holders should not:

• re-submit the ICSRs resulting from the service to EudraVigilance (suspected serious adverse reactions from outside the EEA);
• forward or provide the ICSRs resulting from the service to the concerned national competent authorities in the EEA.

Member States should not:

• re-submit the ICSRs resulting from the service to EudraVigilance;
• forward or provide the ICSRs resulting from the service to the concerned marketing authorisation holders.

Guidance

DOCUMENT	DESCRIPTION
Detailed guide regarding the monitoring of medical literature and the entry of relevant information into the EudraVigilance database by the European Medicines Agency Related documents: Detailed guide regarding the monitoring of medical literature and the entry of relevant information into the EudraVigilance database by the European Medicines Agency - Addendum 1 Overview of comments received on 'Detailed Guide regarding the Monitoring of Medical Literature and the Entry of Relevant Information into the EudraVigilance Database by the European Medicines Agency on Literature Monito...	Guide on the steps of the medical literature monitoring business processes
Monitoring of medical literature and the entry of relevant information into the EudraVigilance database by the European Medicines Agency - Inclusion and exclusion criteria for processing of Individual Case Safety Reports	Inclusion and exclusion criteria for processing ICSRs
Process description for managing duplicates in the context of the medical literature monitoring (MLM) service	Process description for managing duplicates in the context of the medical-literature-monitoring service and EudraVigilance
Monitoring of medical literature and the entry of relevant information into the EudraVigilance database by the European Medicines Agency: Questions and answers	Response to first set of frequently asked questions EMA received from marketing authorisation holders
Contractor SOP/MLM - WIN/MLM	Business process documents developed by the contractor in support of the activities in scope of the medical literature monitoring service. These include standard operating procedures (SOPs) and work instructions (WINs) and cover activities performed by the contractor as part of the medical-literature-monitoring service

Training and support

Training slides and user manual for EudraVigilance are available here:

Functionalities in support of the medical literature monitoring service User manual: EudraVigilance ICSR Downloads and tracking spreadsheets

The Medical Literature Monitoring Service Desk is available to help marketing authorisation holders and national competent authorities.