The system is used to manage and analyse information on suspected adverse reactions to medicines that need to be reported in the European Union (EU). It is operated by the EMA on behalf of the EU medicines regulatory network. The system itself supports the safe and effective use of medicines by facilitating the electronic exchange of individual case safety reports between the EMA, national competent authorities, marketing authorisation holders (MAHs) and the World Health Organisation (WHO). It also facilitates the early detection and evaluation of possible safety signals and enables better product information for medicines authorised in the European Economic Area (EEA).
This long-anticipated update follows on from the independent audit of the system completed earlier in 2017. The recommendations provided by the Pharmacovigilance Risk Assessment Committee (PRAC) were favourable, confirming that the EMA is on track. These revisions will ensure that the database achieves full functionality and the system meets the operational specifications.1
Changes to the system
The revisions to the EudraVigilance (EV) system look to enable the improved safety monitoring of medicines. Specifically, they streamline the submission process and simplify the reporting of individual case safety reports. This will also increase the transparency and efficiency of the EV system to ensure the protection of public health. The foci of the changes are listed below:
- data submission and collection (EV Gateway, EVWEB)
- data management (EudraVigilance Database Management System [EBDMS], recording, duplicate detection)
- data analysis (EudraVigilance Data Analysis System, European database of suspected Adverse Drug Reaction Report [Adrreports.eu]).
Further to this, key changes are also discussed in the revisions to the Proposed Module VI, which is coupled with the changes introduced through ICH E2B (R3).
The updated system will simplify reporting requirements for individual case safety reports (ICSRs), which is expected to decrease the time spent making reporting decisions. The EV system will also increase collaboration with WHO by making reports of individual cases of suspected adverse reactions available to the WHO Uppsala Monitoring Centre directly from EV. The updates will also enhance the data analysis capabilities through the EV Data Analysis System (EVDAS). Additionally, MAHs will no longer be required to do country specific registrations and/or testing to set up organisation identifiers.
The main changes to the electronic reporting requirements for MAHs include that all reports of suspected adverse drug reactions (ADRs) requiring submission according to Regulation (EC) No. 726/2004 and/or Directive 2001/83/EC should be reported to EV directly. Previously, the adoption of EV-only submission was limited to a small number of countries, but will now apply to all EU member states. The system will include the UK, at least until its withdrawal from the EU. The future inclusion of the UK in EU medicines regulation will depend on the outcome of the Brexit negotiations.
MAHs will no longer receive ADR reports directly from EU national competent authorities, but will be provided access to these through EV. MAHs will also no longer need to provide ICSRs to national competent authorities and must submit these to the EV system only.
Enhancements for signal management
The signal detection process has been updated in the new EV system, improving the functionality and reducing the extant duplication of effort. MAHs shall monitor the data available in the system to the extent that they have access to, to determine whether there are new risks or whether risks have changed for their medicinal product(s) and active substances. They must then inform the EMA and national competent authorities about safety signals validated to contain sufficient evidence to necessitate further analysis.
The new updates will allow MAHs access to a greater level of detail on applicable ICSRs than is currently supplied. Further details on the process will be provided in the revised good pharmacovigilance practices (GVP) Module IX — signal management. The EMA will also grant MAHs access to EVDAS to use signal detection, analytical and reporting functions to the extent necessary to fulfil their obligation.
The frequency of signal detection activities will depend on the nature of the product, but justification for the approaches taken should be captured in signal management documentation. For newly licensed products, there is an expected 2-week review cycle; for older, long-marketed products, this may be reduced to 6 monthly reviews. MAHs will have the option to create standard searches and the ability to save customised searches within the system; however, depending on the nature of the product and the number of events, this activity could be resource intensive.
The burden of reporting for suspected non-serious adverse reactions has been increased, with organisations now required to report suspected non-serious adverse reactions to EV within 90 days. Before this update, only seven EEA national competent authorities required non-serious case reporting. The burden will vary by product and therefore per company, inevitably demanding extra resources for submissions. The increased reporting requirements will be supported by the enhanced performance and scalability of the EV system.
Some elements of the system will remain unchanged, including the reporting of adverse reactions by patients and healthcare providers (HCPs) to national competent authorities based on local spontaneous reporting systems. The reporting of suspected unexpected serious adverse reactions during clinical trials will also remain unchanged until the application of the new Clinical Trial Regulation, expected in 2018.
Impact on users
Users of the EV system, including MAHs and national competent authorities, will need to ensure their processes and IT infrastructure are revised in line with the new changes and the simplified reporting, as outlined in the revised change management plan.2 Processes must also be developed and updated to report non-serious cases. This includes any guidance documents, safety agreements between licensing partners (SDEAs), communication plans and safety databases. Since the original draft ruling in May 2017, the EMA and European Commission have updated this process to determine some transitional agreements to streamline the implementation of this new process. This means that MAHs have a grace period until February 2018 to implement monitoring practices.3
To bring about these changes, it’s important that teams are trained in accordance with the new guidelines, through training offered by the EMA or by taking help from an outsourcing supplier that’s experienced in this area. The EMA has noted that it will provide functionality support to the national competent authorities and MAHs in the EEA through e-learning, face-to-face training, webinars and information days.4 Along with this, any existing users of the system will be automatically migrated to the new version. More specifically, training should cover:
- use of the new ICH E2B(R3) format
- EVDAS (EudraVigilance Data Analysis System)
- GVP Module VI (revision 2)
- GVP Module IX (revision 1)
- EudraVigilance access policy.
The new ICH E2B(R3) format can be used for the electronic exchange of ADRs, improving data quality. The new format will eventually replace the current ICH E2B(R2). One notable change in the new R3 format is that seriousness is reported at event level rather than only at case level. Technology changes will be necessary to ensure systems are compatible with the new database and formats. When possible, the local gateway should be configured to support ICH E2B(R3) messages. MAHs can continue to submit ICSRs in E2B(R2) format; however, any cases downloaded from EudraVigilance will be in E2B(R3) format only.
In the interim period, a backwards/forwards conversion tool will need to be implemented if the ICH E2B(R3) format cannot be processed locally. Currently, the deadline for upgrading to a fully compliant ICH E2B(R3) system has not been publicised and is expected to be at least 2 years away. MAHs are advised to work with safety database providers to ensure ICH E2B(R3) compatibility.
An important aspect to note from the draft guidelines is that the EMA views that a “loss of data, for example, owing to server breakdown” constitutes a “serious breach” of regulation. Therefore, sponsors and vendors are expected to have IT measures in place to be able to retrieve relevant information in the instance that a system breaks down at any point in time. To comply with their pharmacovigilance obligations, it is important that MAHs have the right access to EudraVigilance. Access is granted on the basis of the product data supplied by the EMA in accordance with Article 57(2) of regulation (EU) No. 726/2004. Therefore, it is essential that MAHs ensure that the data in the Article 57 database is always complete and up-to-date.
Moving forward
These changes look to greatly improve the functionality of the EV system to ensure public health is protected to the highest degree. Resulting from these revisions, organisations and MAHs have a considerable number of changes to implement across both processes and their technology infrastructure. The development of an internal communications plan to inform all relevant stakeholders of the change requirements should be considered.
The priority of MAHs should be to update all operating procedures for the reporting and retrieval of ICSRs, along with signal detection procedures to ensure they are in line with the new guidelines. The latest update to GVP Module VI will come into effect within 6 months of the new EudraVigilance system being released and will provide further guidance and clarification.
Implementing the required changes could be resource intensive, with experienced employees needed to train staff. Preparation is key to remaining fully compliant after the transition to the new EudraVigilance database. Working with a specialised service provider with expertise in pharmacovigilance, technology infrastructure and the regulatory requirements will ease the pressure on organisations and make the move to the new system as seamless as possible.
References
- www.ema.europa.eu/docs/en_GB/document_library/ Other/2017/05/WC500228158.pdf.
- www.ema.europa.eu/docs/en_GB/document_library/ Regulatory_and_procedural_guideline/2015/10/ WC500196029.pdf.
- www.ema.europa.eu/ema/index.jsp?curl=pages/ regulation/general/general_content_000587.jsp&mid=WC0b01ac0580727d1b.
- www.worldpharmanews.com/ema/3952-green-light-given-for-new-eudravigilance-system-for-collection-and-monitoring-of-suspected-adverse-reactions.
