3. Off-label use

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.