Monitoring of medical literature and entry of adverse reaction reports into EudraVigilance
The European Medicines Agency (EMA) is responsible for monitoring a number of substances and selected medical literature to identify suspected adverse reactions with medicines authorised in the European Union, and for entering the relevant information into the EudraVigilance database.
The service is fully operational as of 1 September 2015.
Scientific and medical literature is an important source of information to identify suspected adverse reactions with medicines authorised in the European Economic Area (EEA).
In line with the guidance in Good Pharmacovigilance Practices (GVP) Module VI , marketing-authorisation holders are required to monitor medical literature and to report individual cases of suspected adverse reactions for medicines for which they hold a marketing authorisation in the EEA. This has led to duplication of efforts by marketing-authorisation holders for active substances included in more than one medicine, and duplication of reports entered into EudraVigilance and national safety databases.
The monitoring of medical literature and the entry of relevant information into EudraVigilance is carried out by EMA in order to:
- enhance the efficiency of adverse reactions reporting;
- provide a simplification for the pharmaceutical industry;
- improve data quality by reducing the number of duplicates;
- contribute to resource savings for the pharmaceutical industry;
- support signal detection activities by national competent authorities and marketing-authorisation holders.
The legal basis for the EMA's tasks is Article 27 of Regulation (EC) No 726/2004, which states that:
- The Agency shall monitor selected medical literature for reports of suspected adverse reactions to medicinal products containing certain active substances. It shall publish a list of active substances being monitored and the medical literature subject to this monitoring;
- The Agency shall enter into the EudraVigilance database relevant information from the selected medical literature;
- The Agency shall, in consultation with the Commission, Member States and interested parties, draw up a detailed guide regarding the monitoring of medical literature and the entry of relevant information into the EudraVigilance database.
In accordance with Article 107, paragraph 3 of Directive 2001/83/EC, marketing-authorisation holders shall not be required to report to EudraVigilance suspected adverse reactions recorded in the listed medical literature monitored by EMA for products containing the active substances referred to in the list of substances being monitored by EMA.
It is important to note that marketing-authorisation holders shall monitor all other medical literature and report any suspected adverse reactions.
Which active substances are included in the medical literature monitoring service?
A range of active substance, including herbals, have been selected on the basis of medicinal product information submitted to EMA in line with Article 57(2), second subparagraph of Regulation (EC) No 726/2004. Active substances contained in medicines for which a high number of marketing authorisations were granted to various marketing-authorisation holders in the EEA are included in the service.
The lists of substance (mainly chemical) and herbal-substance groups which are subject to the monitoring activities by the Agency are published in the below document:
- Medical literature monitoring: substance and herbal substance groups
- Medical literature monitoring: updated substance and herbals substance groups
The total number of all substance groups included in the medical literature monitoring service is based on the Agency's allocated budget for these activities and will be subject to annual review.
Which marketing-authorisation holders benefit from the service?
More than 3,500 marketing-authorisation holders in the EEA for the substance groups benefit from the service, and more than 640 marketing-authorisation holders for the herbal substance groups.
Which medical literature is covered by the service?
The medical literature covered by the medical literature monitoring service has been designated in line with GVP Module VI , and is based on the use of literature reference databases by the Agency's contractor as outlined in the below document:
Where can I find more information on the business processes?
The Agency has drawn up a detailed guide regarding the monitoring of medical literature and the entry of relevant information into the EudraVigilance database, which defines the different steps of the MLM business processes. It was drawn up in consultation with the European Commission, Member States and interested parties. See the below document:
- Detailed guide
- Addendum to detailed guide
- Consolidated overview of comments received during public consultation
Additionally, in support of the medical literature screening activities and the processing of individual case safety reports, inclusion and exclusion criteria have been prepared based on the principles set out in Good Pharmacovigilance Practices (GVP) Module VI :
EMA has published a process description for managing duplicates in the context of the medical literature monitoring service and EudraVigilance:
- Process description for managing duplicates in the context of the medical literature monitoring service
The Agency also maintains a questions and answers document that addresses a first set of frequently asked questions from marketing authorisation holders. This document is regularly updated based on further questions received.
The Agency has approved 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:
When will the service be operational?
As of 1 September 2015, the service is fully operational and covers 300 active substances and 100 herbals.
In its launch phase between 1 July and 31 August 2015, the service covered the top 50 active chemical substance groups. For more information on the launch phase and its outcomes, see:
In order to monitor the key performance indicators as stated in the launch phase closure report, the medical literature monitoring (MLM) service will continue to track these against the targets assigned. The latest results can be found in the below report:
Where can I be trained?
EMA has prepared a series of short videos to provide further information on the medical literature monitoring service.
The following topics are covered:
- legal background and expected benefits;
- detailed guide (scope and key business processes);
- how to prepare: An outline of the necessary preparatory steps;
- eudraVigilance functionalities.
The training slides and user manual of the new EudraVigilance functionalities can be accessed here:
How can I prepare for the start of the service?
Since the service launch in July 2015 EMA has been organising support webinars which will continue throughout 2016 on a monthly basis. These are scheduled for the following dates (UK time):
- Friday, 29 January 2016 from 11:00 to 12:00
- Monday, 29 February from 11:00 to 1200
- Thursday, 31 March from 11:30 to 12:30
- Wednesday, 27 April from 14:30 to 15:30
- Thursday, 26 May from 11:00 to 1200
- Monday, 27 June from 11:30-12:30
- Thursday, 21 July from 11:00 to 12:00
- Wednesday, 31 August from 11:00 to12:00
- Wednesday, 28 September from 11:00 to 12:00
- Thursday, 27 October from 11:00 to 12:00
- Wednesday, 30 November from 11:00 to 12:00
- Friday, 16 December from 10:00 to 11:00
Expressions of interest to participate in the webinars should be sent to email@example.com indicating the date for each event of interest. Every webinar is restricted to a maximum of 200 attendees and a first-come, first-served policy will be applied.
The search parameters for all 300 active chemical substances and 100 herbal substances to be applied during the full production phase are provided in the below document. Minor revisions may be made based on the start-up phase findings:
- EMBASE search strategies for all 300 active chemical substances and 100 herbal substancessubstance groups
- EBSCO search strategies for all 300 active chemical substances and 100 herbal substancessubstance groups
Sample outputs of ICSRs in XML format are to be published routinely in the restricted area of the EudraVigilance website accessible by registered users. Further information can be found in the below documents:
- Medical literature monitoring ICSR sample XML file (MLM EVWEB output)
- MLM ICSR sample XML file (EudraVigilance ICSR Export Manager)
Who to contact?
For all queries in relation to the new service, please send an e-mail to firstname.lastname@example.org.
How should concerned marketing-authorisation holders use the service?
The high-level technical environment requirements and pre-requisites for concerned marketing-authorisation holders are described below:
- For EVWEB users: no changes apply.
- For non-EVWEB users: the marketing-authorisation holder safety system is to be configured to be able to upload ICSRs with the Sender identifier “MLMSERVICE”.
The adaptations of business processes by concerned marketing-authorisation holders are summarised as follows (refer to Figure 1a).
- ICSRs resulting from the medical literature monitoring service:
- Refer to the selected medical literature subject to the monitoring by the Agency and the identified reports of suspected adverse reactions to medicinal products containing active substances identified as part of the scope of the Agency's activities;
- Are transmitted electronically via the EudraVigilance Gateway;
- Are forwarded via the Gateway to national competent authorities in EEA Member States in accordance with the “ Reporting requirements of Individual Case Safety Reports (ICSRs) applicable to marketing authorisation holders during the interim period ” (17 October 2013, EMA/321386/2012 Rev.8 or later if applicable);
- Are also transmitted electronically to EudraVigilance;
- Are made available for download by the marketing-authorisation holders concerned. This refers to ICSRs of suspected serious adverse reactions occurring within and outside the EEA and non-serious adverse reactions from within the EEA. The ICSRs can be also accessed by MAHs from EudraVigilance. Concerned marketing-authorisation holders can download the ICSRs resulting from the medical literature monitoring service in XML format in compliance with the “Note for guidance: EudraVigilance Human – Processing of safety messages and individual case safety reports (ICSRs)” (EMA/H/20665/04/Final Rev. 2).
Figure 1a: New medical literature monitoring business process - main steps with regard to the electronic transmission of ICSRs resulting from the medical literature monitoring service to national competent authorities in the EEA and the download of ICSRs for marketing-authorisation holders from the EudraVigilance download area.
The business processes to be discontinued by concerned marketing-authorisation holders are summarised as follows (refer to Figure 1b):
- Concerned marketing-authorisation holders should not re-submit the ICSRs resulting from the medical literature monitoring service to EudraVigilance. Note: Member States should not re-submit the ICSRs resulting from the medical literature monitoring service to EudraVigilance.
- Unless otherwise specified by national legislation and guidance, concerned marketing-authorisation holders should not submit the ICSRs resulting from the medical literature monitoring service to the concerned national competent authorities in the EEA. Note that Member States should no longer provide the ICSRs resulting from the medical literature monitoring service to the concerned marketing-authorisation holders, since they can download those ICSRs from the EudraVigilance download area.
Figure 1b: Existing business processes of national competent authorities and concerned marketing-authorisation holders to be discontinued with regard to the electronic transmission of ICSRs resulting from the medical literature monitoring service operated by the Agency.
Where can I find further information on reporting requirements for literature reports?
The document reporting requirements of ICSRs applicable to marketing-authorisation holders during the interim period (EMA/321386/2012) has been updated to include a new chapter on “Reporting requirements of literature reports” with the aim to clearly define the reporting requirements for marketing authorisation holders for adverse reactions reported in the literature and taking into account the Agency's activities in accordance with Article 27 of Regulation (EC) 726/2004.
- Reporting requirements of individual case safety reports applicable to marketing-authorisation holders during the interim period (EMA/ EMA/321386/2012 Rev. 9)
The Agency's approach to implementing the service
EMA is supported in the delivery of its service of monitoring of scientific and medical literature and the entry of relevant information into EudraVigilance by a contractor. A service desk is operated to assist in dealing with enquiries from MAHs and NCAs in EEA Member States. The working language of the service desk is English. The working hours are the same as the EMA business hours.
All enquiries should be sent to email@example.com.
Links to further information published by national competent authorities
- Germany: information regarding reporting requirements for literature reports in Germany is provided by the German Federal Institute for Drugs and Medical Devices (BfArM).
- Hungary: guidance documents are available for marketing authorisation holders on adverse drug reaction reporting requirements from the Hungarian National Institute of Pharmacy and Nutrition.