EU Pharmacovigilance Legislation: An Overview

Susan Murphy

As defined by the WHO, Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse reactions and other medicine related problems. Adverse effects are whereby medicines affect the body in an unintended and harmful way.

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Following on from this, the underlying objectives of EU pharmacovigilance legislation are to:

prevent harm from adverse reactions in humans arising from the use of authorised medicinal products
promote the safe and effective use of medicinal products, in particular through providing timely information about the safety of medicinal products to patients, healthcare professionals and the public.

Pharmacovigilance is therefore an activity contributing to the protection of both patients and public health [1].

When a new medicine obtains marketing authorization (MA), the active substance has been tested and it has been concluded that the benefits of this new medicine outweigh the risks. There is a limited amount of information available after clinical trials so the decision to give MA is effectively a trade off between making a new medicine available as early as possible and waiting until as much as possible is know about the medicine.

For testing, several hundreds or thousands of carefully selected patients will have participated in clinical trials. These trials take place under controlled conditions. However, once MA has been obtained, the medicine will now be used in normal healthcare settings where there will be many patients who may differ from those used in the population study (eg age difference, may be using other drugs, have disease interactions. and also there will be longer term effects of using the new medicine).

So it is imperative to identify these new or changing risks as quickly as possible to take measures to minimize the risks to patients. [2]

For company’s there is a legal obligation to continuously collect data and conduct pharmacovigilance regarding any possible change to the risk-benefit balance of taking such a medicine. In this regard, pharmacovigilance regulation seeks to protect the public from emerging safety issues by monitoring the product throughout its lifetime so that it is safe and effective to use.

The 2012 EU Pharmacovigilance Legislation [3]

New legislation regarding pharmacovigilance came into effect in July 2012. This was the biggest change to the regulation of human medicines since 1995.

Based on evidence that adverse drug reactions caused approx 197,000 deaths per year in the EU, the EC began a review of the European system of safety monitoring (an independent study with extensive public consultation)

This resulted in a 2010 directive and regulation,

Directive 2010/84/EU
Regulation (EU) No 1235/2012

which amended the existing pharmacovigilance laws 2001/83/EC and regulation (EC) No. 726/2004.

This was accompanied by the implementation regulation published in June 2012 which provided operational aspects for the new legislation (no 520/2012 19th June 2012)

A further amendment was carried out in Oct 2012 following a review of the withdrawal of the medicine ‘Mediator (benfluorex)’ a diabetes drug with a coronary side effect, where it was felt that the risk now outweighed the limited benefit.

The amendments aimed to further protect the patient’s health by allowing prompt notification and assessment of patient issues.

The aim of the legislation was to reduce the number of Adverse Drug reactions via

Collecting data on the effects of a given medicine from a wider ‘net’
Rapid and robust assessment of issues
Effective regulatory action to deliver safe and effective use of medicines
Better patient involvement through feedback and reporting
More transparency on the effects and safety of medicines concerned

For MA applicants and holders the new legislation would:

Makes their roles and responsibilities clear
Minimize duplication of effort
Free up resources by rationalizing and simplifying reporting on safety issues
Clear legal framework for post authorisation modifying

In short, the main aim of the legislation was to reduce the human and financial cost burden of adverse drug reactions, to strengthen patient involvement in monitoring medicines and to make the public strongly aware of the risk-benefit nature of taking medicines.

New Concepts introduced in the 2012 Pharmacovigilance Legislation

The concept of additional monitoring and the black symbol were introduced by the new EU laws on the safety-monitoring of medicines, (called the pharmacovigilance legislation,) which started to come into effect in 2012.

Any new medicine authorised after 1 September 2013 that is subject to additional monitoring must display the black symbol in the package leaflet and the summary of product characteristics when it is placed on the EU market. Also any educational materials relating to this medicine should indicate its additional monitoring status.

The legislation affects medicines authorised in the EU after 1 January 2011. Due to this, a transition period for medicines authorised between January 2011 and August 2013 was allowed whilst companies their updated packaging and gradually phased in the new leaflets.

Medicines under additional monitoring [4]

This is a new process to label medicines that are being monitored closely by the regulatory authorities. A solid black upside down triangle displayed on the package leaflet and information for healthcare professionals indicates that the medicine is undergoing additional monitoring. The symbol started to appear in late 2013.

A medicine may be subject to additional monitoring because

Not as much data is available with this medicine
Less information is available on the long term impact of using this medicine
Does not imply that the medicine is unsafe.

This label is now always applied for:

Any new API authorized after Jan 2011
Any biological medicine authorized after Jan 2011
For medicines authorised under exceptional circumstances
If there are rare side effects seen during the trial or long term usage effects which warrant more information gathering.

A medicine subject to such monitoring, can remain on the ‘Medicines subject to additional monitoring ‘ list published by the EMA for up to 5 years.

Why are medicines monitored after approval?

Marketing approval is granted to medicines on the basis of clinical trial results.

These consist of a small number of patients trialled under controlled conditions over a relatively short period of time. In real life, however a more diverse group of people will use the medicine and there may be different interactions plus the effects of longer term use. To take any rare or long term side effects which may then come to light into account, it is vital to continue to monitor the safety of all medicines whilst they are in commercial use.

Information is continuously collected after a medicine is placed on the market to monitor real-life experience with the product. European regulatory authorities closely monitor this information to make sure that the benefits of medicines continue to outweigh their risks.

Standardised monitoring methods are used across the EU so that information can be effectively shared by the member states regulatory authorities. This provides a wealth of knowledge for regulators to rely upon when making decisions, and enables a rapid response when required, such as providing warnings about the medicine or restricting its usage.

Reporting side effects

Reporting suspected side effects is an important way to gather more information on medicines on the market. Regulatory authorities look at reports of side effects alongside all the information they already have to make sure that the benefits of medicines remain greater than their risks and to take any necessary action.

Patients and healthcare professionals are encouraged to report suspected side effects seen with any medicine. Under the new pharmacovigilance legislation, patients have the right to report suspected side effects directly to the national medicines regulatory authorities in their country if they wish. The onus is on the company to provide information on how to do this on their package leaflet.

The black triangle makes it possible to quickly identify medicines that are subject to additional monitoring, encouraging end users to feed back any adverse effects .This allows new data to be analysed in a rapid and robust manner. [5]

Update on effect of 2012 Pharmacovigilance Legislation

A report published in 2014 summarised the key effects of introducing the new legislation [6]. The most notable of these were (during the reporting period 2012-2013)

– Adverse Drug reaction reporting has increased by

> 175,000 more individual case safety reports

> 9,000 more patient reports

– Label Changes from more that 47% of signals reported

– By August 2013 119 medicines were listed under additional monitoring list.

– Major public health reviews have been initiated on combined hormonal contraceptives, codeine-containing products and tetrazepam to name but a few.

– Better information is now available via the agencys website for therapeutic decision making


The aim of the Pharmacovigilance legislation is to enhance patient care and safety with regard to medicines and to support public health programs by providing balanced reliable information.

Real life use of medicines only happens once professionals begin to prescribe or dispense. It is vital that the safety of all medicines is monitored throughout their lifetime.

Adverse drug reactions account for 5% of all hospital admissions and are the 5th most common cause of hospital death.

For EU citizens, the goal of the new pharmacovigilance legislation is to

Strengthen patient involvement in the monitoring of medicines. This allows for continuous feedback on the effects of taking medicines through its lifecyle and consequently rapid and robust assessment of issues.
Reduce the burden of ADRs
Inform and engage citizens on the risk/benefit aspect of taking medicines.

Full implementation is expected to save between 500 and 5000 lives a year with a cost saving to society of between ˆ250million and ˆ2.5billion per year [7].

There is concrete evidence that the new legislation is bringing about changes that will lead to improvement in public health. This is demonstrated by greater clarity on the roles and responsibilities for the parties involved in pharmacovigilance (MA applicants and holders, EMA, EU and member state regulatory authorities) and also greater transparency on medicine safety for the patient. This serves to increase the understanding and trust of both patients and healthcare workers on the safe and effective use of medicines in the EU[6].



[2] EMA ‘Pharmacoviglience’ 2013 23/03/2013 NC50010423.pdf



[5] (Medicines under additional monitoring)



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