3. Off-label use

2. Legal framework in Europe

The EU pharmaceutical legislation regulates the marketing authorisation framework primarily through Directive 2001/83/EC and Regulation (EC) 76/2004. It includes some exceptions to the requirement of marketing authorisation before a medicine can be marketed (e.g., compassionate use and Named-patient access). Legislation does not, however, regulate the practice of medicine (nor prescription practices at the individual level, either on-label or off-label).

This means that off-label use is not covered by EU pharmaceutical legislation. Off-label use is however recognised as a concept by EU law (recital 2 of the Paediatric Regulation[1] and pharmacovigilance provisions in Directive 2010/84/EU, amending Directive No. 2001/83/EC as regards pharmacovigilance). It imposes on MA holders a responsibility to provide any information of products’ use which might influence the evaluation of the benefits and risks of the medicinal product concerned. Some of the pharmacovigilance requirements extend to off-label use. For example, Member States and marketing authorisation holders are required to collect/report information on suspected adverse reactions arising from the use of medicines outside the terms of the marketing authorisation.

The EMA gives a short definition on off-label use in their glossary of regulatory terms: “Use of a medicine for an unapproved indication or in an unapproved age group, dosage, or route of administration”. And further, in Annex I Definitions (Rev 4) of the European Guideline on Good Pharmacovigilance Practices (GVP), off-label use is defined as: “situations where a medicinal product is intentionally used for a medical purpose not in accordance with the terms of the marketing authorisation”. With the wording ‘intentionally used for a medical purpose’ the EMA clearly distinguishes off-label use from other medicine uses outside the MA such as medication errors (unintentional) and misuse (no medical purpose) or abuse.

Some specific provisions about off-label use might be found in a Member State’s laws. See box below for examples. In other Member States, off-label use is not specifically regulated. An extensive study, commissioned by the European Commission (EC) on off-label use in the European Union[2] revealed that only ten out of the 21 countries that participated in the study had specific policy tools in place for off-label use. However, as stated in this study, “in EU Member States without specific policy tools on off-label use, the dominant view is that off-label use is an issue to be dealt with at the level of the prescriber rather than at the regulatory or healthcare system level. Prescribers are trusted to know what is best for the well-being of the patient, with the medical need of the patient leading their decisions.”.

So, it is important to distinguish the regulation of medicines from their use in medical practice because EU legislation does not encompass the way medicinal products are ultimately used. In other words, the way Member States organise their healthcare system and the way health care professionals (HCPs) conduct their practice is not within the remit of the EU. The use of medicinal products is in the end decided by the doctor and the patient, who can choose to use a medicinal product off- or on-label.

The ultimate responsibility for the definition of health policy and the delivery of health services and medical care (including off-label use) lies with the Member States (Article 168 (7) TFEU). The European Court of Justice indeed 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.” Sentence (T-452/14 Laboratoires CTRS vs Commission, paragraph 79).

Nevertheless, even though the European legislation does not forbid or subject off-label use to specific conditions, the rest of the European and national legal framework still applies. This implies that the liability rules, criminal law and the ethical and professional standards remain applicable to prescribers of off-label use. Doctors, therefore, must be aware that, when prescribing an unapproved medicine, they take full responsibility for any harmful consequence for their patients, even if patients have signed an Informed Consent Form.

Examples of policy tools incorporated by EU Member States and the UK are:

- France: Legal framework to issue temporary recommendations for use and permission to prescribe off-label such as the “temporary recommendations for use (RTU), replaced 2021 by (cadre de prescription compassionnelle or “CPC”)

- Hungary: System where prescribers or their organisations have to ask for permission to prescribe a product off-label.

- France and Italy: Measures to regulate reimbursement, explicitly allow for reimbursement of off-label use also when (on-label/authorised/not strictly identical) alternatives exist.

- UK: Policy tool providing guidance for prescribers such as the General Medical Council Guidance (Good practice in prescribing and managing medicines and devices, 2013)

- The Netherlands: Policy tool where professional standards are leading, where off-label prescription is only allowed if the relevant professional body has developed protocols or professional standards with regard to that specific off-label use.

- In many Member States: Policy tools focused on the patient, for example regarding the necessity to give informed consent or the fact that for serious interventions, upon request of the patient, a HCP has to register for what intervention the patient has given consent (The Netherlands).

- Spain: the Royal Decree 1015/2009 establishes that the prescription of medicines off-label must be exceptional, limited to situations where there is no authorised alternative for the patient and subject to his/her consent. Obligations on healthcare professionals (e.g., justify the off- label use, report any suspected adverse drug reactions (ADR) and follow any issued prescription/dispensing restrictions as well as the therapeutic protocol of the medical centre), and on marketing authorisation holders (report suspected ADRs to the authorities and any information that could have an impact on issued recommendations of use).

- Germany: legislation provides for off-label use in the regulation on health insurance (§35c SGB V). Formally, the G-BA (Federal Joint Committee) regulates the access to off-label use.[1] Accordingly, the prescription of medicines for specific non-authorised uses is permitted if the Expert groups issue a positive opinion based on the assessment of available evidence. The consent of the pharmaceutical company concerned to the off-label use is required.

[1]  Recital (2) of Directive 2010/84/EU: Such studies may not have been undertaken for use in the paediatric population and many of the medicinal products currently used to treat the paediatric population have not been studied or authorised for such use. Market forces alone have proven insufficient to stimulate adequate research into, and the development and authorisation of, medicinal products for the paediatric population.

[2] EC-commissioned Study on off-label use of medicinal products in the European Union, NIVEL, Dutch National Institute for Public Health and the Environment, and the European Public Health Alliance, 2017