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Published on 6 October 2008

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Risk management of biosimilars in the EU


Companies seeking marketing authorisation for biosimilars must present a risk management plan to the EMEA. Plans for biosimilars may be more complex than those for their reference products

Jan Petracek

Scientific Administrator

Stella Blackburn

Risk Management Coordinator

Risk Management Team
European Medicines Agency

In the healthcare sector the first major application of risk management concepts occurred in the 1980s, when this was primarily considered a means of controlling litigation. Ten years later, the need to address underlying (clinical) problems led to the development of strategies to reduce harm and improve healthcare in general. ‘Clinical’ risk management has been established in some countries in North America and Europe
as an integral part of hospital healthcare. Together with quality management, it has formed the foundation for a more complex approach, nowadays referred to as ‘patient safety’.[1]

The start of the period of increased interest in patient safety coincided with two major events in the area of pharmacovigilance. In August 2001, cerivastatin was withdrawn worldwide from the market because the risk of rhabdomyolysis appeared to be greater than that for other statins.[2] This formed the catalyst for the development of new EU pharmacovigilance legislation. After the sudden withdrawal of another blockbuster, rofecoxib, in September 2004,[3] the European Medicines Agency (EMEA) issued a guideline on the risk management system for human medicinal products.[4]
Consequently, since November 2005 the majority of new active substances and biosimilars authorised by the European Commission are covered by risk management systems.

The risk management plan (RMP) is a document that describes a risk management system for a particular product. It summarises the product’s important identified and potential risks, as well as important missing information. For each such safety concern, a detailed further characterisation is prepared, with an evaluation of the need for additional risk minimisation

Should risk management activities beyond product information and labelling be required, an RMP is called for. It describes what risk mitigation activities will take place and how they will be evaluated.

Main discussion
Since 2005, holders of marketing authorisations for biosimilar medicinal products in the EU have needed to have two systems in place to ensure proper post-authorisation safety surveillance: pharmacovigilance and risk management. Risk management of the medicinal product is defined in the legislation as a set of pharmacovigilance activities and interventions designed to
identify, characterise, prevent or minimise risks relating to medicinal products, including the assessment of the effectiveness of those interventions. As such, these systems need to be complementary.

The pharmacovigilance system describes the general procedures the marketing authorisation holder has in place for the pharmacovigilance of all its products and provides an infrastructure for the product-specific surveillance and risk minimisation ensured by the risk management system. The main features of both systems are agreed between regulators and marketing authorisation holders at the time of marketing authorisation. Although detailed description of the pharmacovigilance system is confidential, the summary of the
RMP is made public by the EMEA.

Members of the public can find a summary table of the RMP at the end of the scientific discussion component of the European Public Assessment Report (EPAR). All centrally authorised products, including biosimilars, have EPARs published at the EMEA website (see Resources). Table 1 gives an example of an RMP summary table, in this case for epoetin alfa Hexal.


If there is a requirement for an RMP, the activities are reflected in the European Commission (EC) decision and form part of the conditions of the marketing authorisation. An example of additional risk minimisation activities as they appear in the EC decision is provided in Table 2.


Risk management plans bring new opportunities for patient safety. They are designed so as to increase the probability that the right information will be available at the right time and in the right place. Several research projects are ongoing to evaluate their effectiveness, but only time will show whether this is sufficient to mitigate real-life risks.

Hospital pharmacists may play a crucial role in the dissemination of key information and participate in other risk management activities such as registries, They may also wish to take the  quality and complexity of the RMPs into account when choosing the right biosimilar products for their hospital.[5]

The views expressed in this article are the personal views of the author(s) and may not be understood or quoted as being made on behalf of or reflecting the position of the EMEA or one of its committees or working parties.

1. Vincent C, editor. Clinical risk management enhancing patient safety. 2nd ed. London: BMJ Books; 2001.
2. MacCarthy EP. Market withdrawal of Baycol (cerivastatin). REF; Bayer Corporation: 2001. Letter to healthcare professionals from head of US medical science, Bayer Corporation, 8 August. Available online at:
3. Merck. Merck announces voluntary worldwide withdrawal of VIOXX�. News release. Whitehouse Station NJ: Merck & Co; 30 September 2004. Available online at:
4. European Medicines Agency. Guideline on risk management systems for medicinal products for human use. EMEA/CHMP/96268/2005. London: EMEA; 2005. Available online at:
5. Vulto AG. Decision making for biopharmaceuticals: a practical hospital pharmacist perspective. Paper presented at 6th EGA Symposium on Biosimilar Medicines, London, 24-25 Apr 2008.

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