EMA Good PV Module 10 Additional Safety Monitoring of Certain Medicines

Jul 31, 2013

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

In April 2013, the EMA released Module 10 of their Good PV Practices requirements.  It can be found at:


This refers to medicines that the EMA has recently approved but which require additional monitoring or other requirements above and beyond the routine drug safety and PV practices.  These products are designated in their labeling (SmPC, patient leaflets etc.) with an inverted black triangle.

In addition, a standard explanatory statement must be included in the SmPC: “This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.”

This based largely on the UK practice where a black triangle is used in drug labeling for such products for many years.  By doing this, practitioners and patients will be (hopefully) made aware that the medication in question has particular safety issues that are being actively tracked and monitored.  Its presence is a signal to prescribers and patients to report suspected ADRs which the EMA terms “enhanced reporting”. The goals of this are twofold: to collect additional information as soon as possible and to further elucidate the risk profile of the drug when actually used in clinical practice. There really is no equivalent to this icon or symbol in US labeling though FDA can require additional monitoring, post-approval commitments or obligations and/or a REMS.  But there is no single symbol such as the black triangle in US labeling.

What medicines get additional monitoring?

The EMA gives an explanation as to why certain products need additional monitoring.  It can be summarized as follows: Medicines are approved by health agencies (HAs) when benefits outweigh the risks for the population and disease in question at the approved dosing regimen.

As always, the full safety profile of a product is not fully known at the time of approval and only when there is wider and longer clinical use in the real world will the safety picture become more complete.  In addition, the clinical trial data used to support the marketing approval (NDA/MA) is usually limited to selected patients who may not be fully representative of real world clinical use.  The company and HAs will monitor safety data received from spontaneous reports after marketing.  This is true for all products in fact.  Some products, however, may seem to be more toxic or the patient population being treated may seem more vulnerable or at risk for ADRs.  For these products, the EMA and other HAs require additional monitoring as well as post-authorization studies (PASS), registries, surveys etc. in some cases.  These are the drugs that will likely get a black triangle in the EU labeling.

The broad categories the EMA has defined for additional monitoring include:

  • Medicines that contain a new active substance approved after 1 January 2011;
  • Most biological medicines approved after 1 January 2011;
  • Medicines for which the MAH is required to carry out a post-authorization safety study (PASS);
  • Medicines given conditional approval or authorized under exceptional or special circumstances and medicines authorized with specific obligations on the recording or monitoring of suspected adverse drug reactions.
  • Products authorized with specific obligations on the recording or suspected adverse drug reactions

“Special conditions” can be done at the request of the European Commission, a member state HA or the Pharmacovigilance Risk Assessment Committee (PRAC).  Such special conditions can also include restrictions on use, special measures in the Risk Management System, the need to do a post-authorization efficacy study (PAES) or issues with the company’s PV system.

Medicines can be put on the list at any time in their life cycle and will remain on the list and carry the black triangle for 5 years.

The EMA and the member states’ HAs must communicate this to the public without “creating undue alarm”.  A list of products requiring additional monitoring is to be maintained.  The EMA’s listing can be seen at: https://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000366.jsp&mid=WC0b01ac058067c852

As of July, 2013 there are 78 medications on this list with the name of the drug, the company holding the MA, the reason for being on the list (e.g. PASS, new active substance, conditional authorization, authorized under exceptional circumstances, new biological) and a link to the product information on the EMA’s website.  The list is to be updated monthly following each PRAC meeting.

This additional monitoring/black triangle requirement imposes certain obligations on the companies and the EU health agencies including informing the EMA of decisions, putting the products on their national web portal and other regulatory requirements.

The company (MA holder) also has obligations:

  • Include the black triangle in the SmPC and patient package leaflet along with the standardized explanatory statement
  • Additional information should be included for the healthcare professionals and patients to explain why this is being done and encouraging reporting of ADRs
  • Provide evidence to the health authorities in question “on the status of any conditions imposed”
  • Submit the relevant variation to include or remove the black symbol and explanatory sentence as appropriate.  It appears that the MAH could request the removal of the additional monitoring designation at any time though the five year time frame is noted in the module.It may be removed during the assessment of a regulatory procedure such as an extension of the indication or renewal or it may be done outside of a particular regulatory procedure by submitting a variation to update the product information.  Clearly, the MAH must produce evidence to support the removal.


This module and the supporting EMA website and member states’ websites are all reasonable and consistent with the need to have additional monitoring for certain products.  The EU, by its very nature, is complex and (to put it mildly) bureaucratic involving the EMA (centrally) and the 28 member states – Croatia just joined the EU in July.  In the US and other countries, the bureaucratic procedures are often less complex but the result is usually the same.  The use of the symbol is a wise idea that other countries’ health agencies might want to consider.

The additional requirements also, on their face, seem reasonable: more attention to reporting ADRs), additional studies or registries, REMS/RMP conditions etc.

By the way, the EMA is leaving ambiguous whether ADRs (“reactions” due to the drug) or AEs (“events” not likely caused by the drug) should be reported.  It is also ambiguous whether they want serious AEs/ADRs or all AEs/ADRs.

The real question, as with all of these new EU requirements required in the Modules is whether any of this will make a difference to public health.  Most of the new requirements (the new PSURs/PBRERs and their non-standard reporting timelines, no PSURs for generics, PASS, RMPs, additional monitoring, etc.) have really not been tried out, piloted or tested.  It is not clear that these significant additional efforts will improve public health.

It can be argued that the UK has been using the black triangle system for some years and that this is a good pilot test.  What is not clear is what difference it has made in picking up drug toxicity issues earlier.

So for the new requirements one must ask:

  • Is it really clear that collecting “more” AEs is better?  Intuitively one tends to presume that if some is good, more is better.  But is it?
  • It is not clear what subset of AEs/SAEs/ADRs/SADRs should be sought as a high priority.  Do we really need to collect mild, self-limiting headaches or nausea? Might limited resources best be spent on the collection of previously unreported SAEs or “suspect SAEs”?
  • Do we need to collect more known SADRs?  If we know a drug causes gastric ulcers does collection of more ulcers matter? Some will argue that we will get a better idea of the frequency and changes over time.  In fact this turns out to be very hard since the true numerator (patients with ulcers) and the true denominator (total patients taking the drug) are almost never clearly known.  In practice, frequency analyses have not been very useful.

But before committing public dollars or euros to this endeavor along with the time and effort from healthcare professionals and patients, it would be good to know that there is some data to support the additional spending and effort rather than relying on intuitive hopes.

How can we do this?  First, there needs to be intellectual honesty by admitting that all of these new procedures are “experiments” in public health and the results of their enactment needs to be measured.  This is the normal scientific method: Propose a hypothesis (collecting additional information as ADRs will pick up drug toxicity earlier) and test it.  The testing may not be easy but there are recognized methodologies to do so.  If the testing is done and the new data collection is found to be useful, it should be adopted.  If it is found not to be useful or if the cost and effort are judged too great compared to the benefits, it should be rejected.

This critique does not just apply to the EU’s additional monitoring but to all of the new proposals from various health agencies around the world on how to better pick up drug toxicity.  It is wonderful that various countries and health agencies are acting as “crucibles for testing new methodology” but we really do need to do this scientifically so that we may accept what works and reject what fails.