4. Specific regulations in Europe

1. Medicines under additional monitoring

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The pharmacovigilance legislation (Regulation (EU) No 1027/2012 (applicable since 5 June 2013) and Directive 2012/26/EU (applicable since 28 October 2013)) in the EU, stipulates that medicines that are being monitored particularly closely by regulatory authorities are labelled with a black inverted triangle (▼) in the product information. These medicines are described as being under 'additional monitoring'.

The aim of this symbol is to notify and encourage patients and doctors to report any suspected adverse reactions through their respective national reporting systems so that any new emerging information can be analysed efficiently. This reporting is essential and complementary to all the other pharmacovigilance activities to better understand the risks and safety profile of a new medicine in a real-life setting (remember RCTs do not represent real-life settings).

The black inverted triangle is applied in the following cases:

• The medicine contains a new active substance authorised in the EU after 1 January 2011.
• It is a biological medicine (i.e. a medicine derived from a biological source or living cells), such as a vaccine or a medicine derived from plasma (blood), authorised in the EU after 1 January 2011.
• It has been granted a conditional approval (where the company that markets the medicine must provide more data) or has been approved under exceptional circumstances (where there are specific reasons why the company cannot provide a comprehensive set of data).
• The company that markets the medicine is required to carry out additional studies, for instance to provide more data on long-term use of the medicine or on a rare adverse reaction already seen during clinical trials.
• It is authorised with specific obligations on the recording of suspected adverse drug reactions.

Other medicines can also be placed under additional monitoring, based on a decision by the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC).

Data from this reporting will be analysed as part of the continuous assessment of the benefit-risk balance of each medicine during its lifecycle.

The black inverted triangle appears in the package leaflet as well as in the SmPC, and is accompanied by a statement explaining that the medicine is under additional monitoring (‘▼This medicinal product is subject to additional monitoring’). Information on reporting suspected adverse reactions is also provided.

The EMA chose this symbol following consultation with patients and healthcare professionals. It has been selected because it is easy to recognise and less likely to cause confusion or incorrect interpretation.

The list of medicines-under-additional-monitoring, reviewed every month by the PRAC, is available as follows:

• The list is posted on the EMA website.
• The list is also published by national competent authorities in the EU member states.

A medicine can be included on this list when it is approved for the first time or at any time during its life cycle. A product remains under additional monitoring for five years or until the PRAC decides to remove it from the list.

Food for thought: How effective do you think the inverted black triangle has been since its introduction in 2011, and why?

The European Commission has published a report (2019) on the additional monitoring scheme (required by the pharmacovigilance legislation and based on detailed material provided by EMA and Member States). This report states that “Of all the respondents, 51% indicated that they had seen the black triangle and accompanying statement. The highest awareness was among pharmacists (83%), with the lowest awareness among patients (30%)”. The full report can be found here https://ec.europa.eu/transparency/documents-register/detail?ref=COM(2019)591&lang=en

Overall, the report recommends that EMA and the Member States should continue to:

• promote the reporting of suspected adverse reactions and sharing their experience to further develop best practices;
• monitor the impact of additional monitoring on the reporting or detection of adverse events, in order to strengthen the evidence base for future review of the scheme;
• collect data on the implementation of additional monitoring to allow a better understanding of its impact on certain medicines, such as those with the same active substance or with an imposed post-authorisation safety study (PASS)

2. Summary: Risk management plan and additional monitoring process

• Risk management is increasingly viewed as necessary to continuously monitor, safeguard and even enhance the benefit-risk balance of a medicine  after market authorisation under real-world conditions. The risk minimisation activities should be proportionate to the risks and should not prevent the use of the medicine in appropriately selected patients.
• Risk management can be challenging and expensive, but is necessary and ultimately rewarding and reassuring. It allows trust to be built between companies and stakeholders (transparency).
• Risk management is increasingly becoming a cornerstone for sustainable market availability therapy
• Risk management is an opportunity to protect patients, avoid crisis, and enhance the knowledge about the products.

The recent additional monitoring process put in place across the EU is part of the EMA’s plan to strengthen medicine safety measures. The addition of the symbol ‘▼’ in package leaflets as well as in the SmPC aims to encourage reporting of adverse events from doctors but also from patients.

In this process as well as in the design of arisk management plan, patients are becoming key players in the continuous assessment of the benefit-risk balance of a medicine.