At the beginning of 2013 the EMA put in place the new reporting requirements for individual case safety reports of adverse events for marketed products. The requirements in Volume 9A were ended and the new ones noted in “Module VI-Management and reporting of adverse reactions to medicinal products”. These requirements are, on their face, simple and straightforward:
What this table shows is that for all products (whether approved by the central process, mutual recognition, decentralized or national) the requirements are simple and clear. All EU Serious AEs are reported in 15 calendar days to the member state (MS) where the suspected AR occurred. This should be done electronically. For non-serious ARs, again to the MS where the event occurred in 90 calendar days. For all serious ARs from the rest of the world, reporting is to EudraVigilance in 15 calendar days. It is noted that some MSs might also want reporting of these non-EU cases to them also. Non-serious non-EU cases are not reportable.
However, the EU has not yet adopted this fairly simple reporting structure. Rather, because some member states are not ready yet and because the EudraVigilance database is also not entirely ready, there is an interim procedure in place which will last at least through 2015 given current expectations. It is turning out that getting a database ready and implemented across a continent covering over 300 million people is not as simple as originally thought….
Since the system is not ready for full scale use, interim requirements have been published and periodically updated by the EMA. The latest update was published in October 2013 and is available at: https://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/05/WC500127657.pdf
We’ll summarize it here. Note that each MS also can issue reporting requirements that may augment and change the local reporting requirements in that member state. Many have done so.
Table 2 summarizes the reporting requirements for serious AEs. There is clear inconsistency. Seventeen countries want the SAE to be submitted to the member state where it occurred. That is, in these 17 countries, any SAE that occurred in that country is to be submitted to that country’s health authority. The method of approval (central, mutual, decentralized, national) doesn’t matter.
Eleven member states require that the SAE be submitted to EudraVigilance only.
One country, France, lets you submit either to EudraVigilance or to the French health agency.
Two countries want the case submitted both to that country where the SAE occurred and to EudraVigilance.
The goal in all of this is to get all cases into EudraVigilance and then all the cases that each member state wants can be gotten from EudraVigilance. Unfortunately we are not there yet.
A glossary of country code abbreviations can be found at: https://epp.eurostat.ec.europa.eu/statistics_explained/index.php/Glossary:Country_codes
Table 3 covers non-serious suspected adverse reactions from their country. Not all member states want individual NSAEs submitted. Only seven want such cases reported and two (Germany-DE) and Austria (AT) only want certain vaccine cases. Italy (IT) does not want NSAEs from scientific and medical literature.
Here we see a clear example of the loss of harmonization. The remaining countries do not want their own country’s non-serious cases reported as ICSRs.
Finally two countries (Germany and the UK) want non-EU serious adverse reactions suspected to be related to an approved product approved in that country. That is suspected SARs that occur in the US, Canada etc. to also be reported if that product is authorized (approved) in that EU country. For the UK this applies only to cases from healthcare professionals not patients, attorneys etc. See Table 4.
So what lessons can we draw from this?
Firstly, this is somewhat embarrassing to some senior officials in the EMA. In private conversations they will often apologize for this messy situation. They realize that these arbitrary and inconsistent requirements are different from the requirements in the new PV modules. There really is no clear reason why a handful of countries would want subsets of serious AEs or even non-serious AEs. Presumably for signaling purposes but it is not clear they actually do go through them and pick up signals. From the companies point of view, this adds more work and “one-offs” to the routine processing of cases – something that no company appreciates. For example, reporting of non-EU serious ARs to the UK and Germany requires that the company keep closely up to date about when new products are approved in those countries and then, when approved, to start reporting non-EU cases.
Secondly, the EU is not the US or similar countries where there is single reporting to one agency. The EU is still 28 member states; many do their own thing.
Thirdly, EudraVigilance is not ready to accept all cases and to transmit them to all member states and/or receive all cases from member states. There is talk that this might occur by 2015 but that is a function both of EudraVigilance being ready and for all member states to be ready.
Fourthly and perhaps most importantly, this shows that many member states that do signaling are working from different data sets. Some member states will have more cases and some fewer cases. Will they come to the same conclusions? Do they all signal on all drugs? Does this matter? Does this help public health? Hard to know.
Fifthly and finally, companies must follow the rules and put into place SOPs that ensure that the appropriate cases are sent to the appropriate agencies throughout the EU.
On the good side, this means more jobs for those of us in drug safety….