By Neil Grubert, market access specialist, analyst and author.

EU Study on Off-Label Prescribing

In recent years, the pharmaceutical industry has been concerned by the precedent set by the off-label use on purely economic grounds of Roche/Genentech/Chugai’s Avastin (bevacizumab) as a replacement for Roche/Novartis’s Lucentis (ranibizumab) in the management of wet age-related macular degeneration (AMD). The first part of this three-part article examined how the Italian and French authorities have vigorously promoted this practice, and assessed the implications of a potentially very significant new preliminary ruling from an advocate general of the Court of Justice of the European Union (CJEU).1 Part 2 considered how the authorities in Germany, Spain and the UK have taken divergent approaches to off-label prescribing of Avastin.2 This concluding part explores the key findings of the European Commission’s recent study on off-label practice in the EU, and assesses the industry’s misgivings about some of the recommendations contained in this report.

EU study on off-label prescribing

The EU has responded to calls for greater clarity regarding off-label prescribing in Europe by commissioning a review of the practice. In February 2017, the European Commission published a Study on off-label use of medicinal products in the European Union,3 which explores the legal framework for off-label prescribing at both EU and national levels, as well as the extent of off-label prescribing and stakeholders’ views of this practice. The report notes that the CJEU has confirmed that “off-label prescribing is not prohibited, or even regulated, by EU law” and that “there is no provision which prevents doctors from prescribing a medicinal product for therapeutic indications other than those for which a marketing authorisation has been granted.” The preliminary ruling by the CJEU’s Advocate General Saugmandsgaard Øe, issued several months after the publication of the EU’s study, confirms the view that EU law does not present a barrier to member states’ off-label prescribing policies.

Based on a combination of desk research, stakeholder interviews and an expert meeting, the study’s authors found that off-label prescribing is particularly common in the treatment of children and patients with rare diseases, as well as pregnant women and the elderly. The therapeutic areas in which off-label prescribing is most common are oncology/haematology, rheumatology and psychiatry.

Varied drivers of off-label prescribing

The authors identified a number of key drivers of off-label prescribing, including the following factors:

  • Drug manufacturers have little incentive to expand the labelling of their medicines.
  • National competent authorities have no legal power to initiate marketing authorisation applications for unlicensed indications.
  • The requirements for marketing authorisation have increased over time, and developing a new indication has become more time-consuming and costly.
  • Science and clinical practice advance much faster than regulatory approval processes.
  • Some products that have a marketing authorisation are not marketed in smaller or less-affluent markets.
  • Manufacturers may withdraw a product, or delete an indication, from the market.
  • In some cases, off-label products are cheaper than on-label products, and off-label products may be reimbursed while on-label products are not covered.
  • Formularies or treatment guidelines may mandate off-label prescribing in certain circumstances.
  • Familiarity with off-label products may prompt prescribers or patients to continue to favour such products even after an alternative therapy has been approved for a given indication.
  • Off-label prescribing is less costly than the use of on-label therapies for healthcare systems and/or patients.
  • Off-label therapies may be most suitable for certain patients, or may be the only (remaining) treatment option available for these patients.

Government policies on off-label prescribing

Representatives of 21 EU member states participated in the study. In ten of these countries, the governments have defined policies with regard to off-label prescribing. Table 1 provides examples of the types of policies that have been adopted in some countries.

Table 1: Examples of off-label policies in Europe

Source: Based on information from Study on off-label use of medicinal products in the European Union.3

Policy options for future off-label use

The expert meeting presented several policy options with regard to off-label use in the future:

  • Explore the potential of using evidence other than randomised controlled trials (e.g., data from monitoring patient cohorts, routine patient registries and adverse event reporting) as the basis for granting marketing authorisations for off-label indications.
  • Provide member states with general advice on off-label use (e.g., elements to be included in treatment guidelines on off-label prescribing) that could be incorporated into national guidelines.
  • Create/enhance incentives for drug manufacturers to register new indications for existing products.
  • Encourage prescribers to request permission for off-label prescribing from competent authorities, which could then evaluate evidence on efficacy and safety to determine the risk-benefit ratio of off-label use for patients.
  • Clarify reimbursement policies that cover off-label therapies but not treatments that are licensed for the same indication.
  • Encourage professional bodies to develop national treatment guidelines that cover off-label prescribing.
  • Improve patient information, ideally through individual messages to patients from healthcare professionals, supported by online and print material.

Industry misgivings about the EU study and the outlook for off-label prescribing

EFPIA, EUCOPE, and EuropaBio were quick to respond to the publication of the European Commission’s report. In a joint press release, the three associations stated that, “whilst we accept that off-label medicines can be prescribed by physicians to address a patient’s concrete medical needs with his or her consent, we strictly oppose the promotion of off-label use for economic reasons, which contradicts the EU principle that the protection of public health must unquestionably take precedence over economic considerations.” The press release added that “pharmaceutical companies may be less ready to invest in costly and lengthy clinical development and authorisation processes for a given indication if public authorities promote the use of cheaper off-label medicines that have not been subject to the same stringent safety and efficacy assessments as existing on-label medicines, for financial reasons.”4

The three associations were particularly critical of the report’s proposals for measures that would promote off-label prescribing for purely economic reasons. Instead, they called on decision makers to “put patients’ safety and the integrity of the regulatory regime first and not to support measures that would set double standards in terms of regulatory requirements for on-label medicines and off-label medicines.”4

The industry will wait anxiously to see if the CJEU ultimately adopts the preliminary ruling of Advocate General Saugmandsgaard Øe in the case brought by Italy’s Consiglio di Stato. If interchangeability in clinical practice is deemed to outweigh marketing authorisation, payers may feel emboldened to promote more-aggressive off-label policies in the future.

1 Off-Label Prescribing – A New Worry for the Pharmaceutical Industry. Part 1: Off-Label Use of Avastin in Italy and France. Accessed at

2 Off-Label Prescribing – A New Worry for the Pharmaceutical Industry. Part 2: Off-Label Use of Avastin in Germany, Spain and the UK. Accessed at:

3 Study on off-label use of medicinal products in the European Union. Accessed at…/2017_02_28_final_study_report_on_off-label_use_.pdf.

4 EFPIA, EUCOPE and EuropaBio welcome the Publication of the European Commission’s Study on Off-Label Use. Accessed at

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Last update: February 2018

Neil Grubert is a pharmaceutical market access specialist with 28 years of experience tracking the global prescription drug and self-medication markets. He has authored more than 150 reports on market access, covering 20 mature and emerging markets, multiple therapeutic areas, and numerous industry issues, including a recently published study on key market access trends in Europe. Neil is an experienced public speaker who has chaired events and delivered numerous presentations at conferences, seminars, webinars and training workshops, including bespoke programmes commissioned by senior executives at top ten pharmaceutical companies. He is currently working as an independent consultant and is developing a series of multi-client training programmes in market access. Neil previously spearheaded the development of Decision Resources Group’s international market access business, most recently as Vice President, Global Market Access Insights. He has also done contract work on early-stage market access for GlaxoSmithKline.