EudraVigilance Data Analysis System (EVDAS) in the Signal Management Process: Are You Really Ready?

EVDAS: A Powerful Tool for Signal Detection in Pharmacovigilance 

In the realm of pharmacovigilance, signal detection plays a pivotal role in identifying potential safety concerns associated with marketed medicines. This process, which involves scrutinizing vast amounts of safety data, including facts on adverse events, can be a daunting task. Fortunately, sophisticated tools like the EudraVigilance Data Analysis System (EVDAS) have emerged to streamline and enhance signal detection efforts. 

What is EVDAS? 

EVDAS is a web-based application developed by the EMA to automate and accelerate the identification of potential safety signals. MAHs with active substances included in the list published by the EMA must monitor and inform authorities of validated signals with their medicines, via both systems of standalone signal notification and emerging safety issue. The list is based on (but not limited to) all active substances and combinations that are included in the list of medicinal products subject to additional monitoring. Within a pilot project started in February 2018, and which will finish at the end of 2024, these MAHs will be required to perform signal detection in EudraVigilance. All other MAHs also have access to EudraVigilance and can integrate data into their own signal management processes. However, during the pilot they will have no obligation to continuously monitor EudraVigilance and inform the regulatory authorities of validated signals from EudraVigilance. EVDAS contains all cases submitted to EudraVigilance since 2001 and its outputs in relation to pharmacovigilance are: 

• electronic Reaction Monitoring Reports (eRMRs);  
• Line listings of individual cases of suspected adverse reactions; and  
• Individual case safety report (ICSR) forms.  

An eRMR is an output of drug event combinations (DECs) related to the ICSRs submitted to EudraVigilance during the period specified (along with cumulative data). The data is stratified by different parameters and incorporates the Reporting Odds Ratio (ROR) as a statistical measure. There are 72 columns in total and there is the option of reordering or deleting columns prior to export. There are two types of eRMR:  

• Fixed reference period eRMR; and 
• Ad-hoc reference period eRMR. 

The eRMR fixed reference period pre-defines a six month period for populating the “new” columns. The end date of the period is the last day of the previous month and the start date is the first day of the month six months prior to that. The ad hoc reference period eRMR allows the user to define the period for populating the “new” columns. The start and end dates allowed are within three months and two weeks prior to the download’s date. As well as being retrieved individually for a period defined by the user, line listings for DECs can also be retrieved from an eRMR. Users are also able to retrieve ICSR forms through the line listing (different levels of access are driven by the product’s ownership). 

Key Features of EVDAS 

EVDAS boasts a range of features that make it an invaluable tool for pharmacovigilance professionals: 

• Enhanced efficiency: EVDAS automates many tasks involved in signal detection, reducing the workload and freeing up time for more strategic analyses. This efficiency contributes to faster identification of potential safety signals. 
• Visualization and reporting: EVDAS generates clear and informative visualizations and reports, making it easy to communicate signal detection findings to stakeholders. This facilitates collaboration and informed decision-making throughout the signal detection process.  
• Improved accuracy: EVDAS includes a measure of disproportionality, which is the ROR, in order to indicate when a given DEC should be highlighted for further inspection. When this occurs it is often referred to as a signal of disproportionate reporting (SDR). The full set of criteria a DEC requires to be a SDR, as detailed in the EVDAS user manual, are as below: 
• Classified as Important Medical Event (IME); 
• ROR (-) > 1; 
• Total number of spontaneous cases (excluding litigation) greater than or equal to three for substances under Additional Monitoring, greater than or equal to five for all other substances. 

As these are results of purely statistical analyses and without any medical evaluation, they simply reflect a "reporting trend". Therefore they can only be treated as potential signals requiring a critical evaluation, taking into account other factors such as the biological plausibility of the association and the consistency of available safety data. This leads to a higher likelihood of identifying genuine safety concerns and reducing the risk of false signals. 

• Integration with other tools: EVDAS seamlessly integrates with other EMA pharmacovigilance tools, including EudraVigilance and the Pharmacovigilance Risk Assessment (PRAC) database. This integration ensures that users have access to all relevant data and can easily track the progress of signal investigations. 

Future Directions of EVDAS 

EMA and the European Commission have agreed to further extend the pilot until the end of 2024. As of January 1, 2025, MAHs with active substances not included in the pilot list must also monitor them in EudraVigilance and inform the regulatory authorities of validated signals that have emerged. 

In conclusion, EVDAS has emerged as a powerful tool for signal detection in pharmacovigilance. However, as demonstrated, the sheer amount of data available from EVDAS poses challenges to MAHs when deciding how to pragmatically review the data. MAHs must find the right balance to safeguard public health, while not placing undue burden on their resources.