The marketing authorisation of a medicinal product specifies the approved indications and terms of use (e.g posology), which are reported in the Summary of Product Characteristics (SmPC) and in the Patient Information Leaflet. Any use of the product different than the approved ones thus falls in the category of “off-label use”. A different indication, a different dosage, dosing frequency or duration of use, a different method of administration, or use by a different patient group are all examples of off-label use of medicines.
The European Commission has published the report “Study on off-label use of medicinal products in the European Union”, which offers a deep analysis of practices for the off-label use of medicinal products for human use across Member States and describes possible future tools to regulate this sector at a national level.

The paediatric population is the main target

The phenomenon of off-label use interests all European countries, with marked variations in prevalence within a single country on the basis of the methodology used and the population studied. The team of experts that wrote the document thus recognises the difficulty to make a comparison between the various EU Member States.
It might be not surprising that off-label use in Europe refers particularly to the paediatric population, since the development of targeted medicines for this age group is relatively recent. Orphan diseases are another main target, as well was elderly patients and pregnant women, but less information is available for the two last groups.

The analysis of the literature showed that the main clinical areas interested by the phenomenon are oncology/haematology, psychiatry and rheumatology, all characterised by unmet medical needs. The reported range of off-label prescription in the paediatric population is very wide both in hospital settings than in outpatient settings; a similar trend has been observed for the adult populations.

The driving factors

The marketing authorisation process and post-MA events (such as shortage of medicinal products and pricing and reimbursement) have all been identified by the study as the driving factors for off-label use of medicines. The better access of patients to (innovative) treatments and the fulfilment of their medical needs, especially in cases where no other options are available, and a potential economic advantage (provided that economic reasons are not prevailing) are other favourable elements that support the phenomenon.
Industry can benefit of only limited incentives to extend the labelling of existing medicinal products, especially for off-patent products suffering the competition of generics and/or a low price, indicates the report. The current regulatory framework allows for one year extra market protection if a new indication is registered in the first eight years after the initial MA has been granted, and provided that the new indication brings significant clinical benefit over existing therapies. “However, off-label sales will continue without investment in such a new indication anyway”, says the report.

Many stakeholders also indicated during the survey the impact of the increasing requirements to obtain an MA and the time and costs needed to investigate a new indication. From the healthcare professionals (HPCs) perspective, off-label prescription is sometimes inevitable and it might be reinforced by the pressure of patients asking access to a certain therapy. The global picture is quite complex and highly variable in time along the life cycle of the medicinal product, with many different driving factors that might interact with one another in an hard to evaluate contribution, is the conclusion of the Commission.

The legal framework

Is it off-label use of pharmaceuticals prohibited or regulated by the law? Sentence T-452/14 (Laboratoires CTRS vs Commission, paragraph 79) of the European Court of Justice answered the question, confirming 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 analysis made by the EU Commission’s document keeps clearly separated the regulation of medicinal products from their effective use in the medical practice. Off-label use of medicines is theoretically prohibited according to article 6(1) of Directive 2001/83/EC, establishing the need of a marketing authorisation to sell a new product in the European market. The paradigm of quality, efficacy and safety and the benefit/risk assessment are at the base of the pre-clinical and clinical development faced by the pharmaceutical industry to finally obtain the MA from EMA or national competent authorities. But, as already said, the entire development is targeted to a specific indication (or a limited pool of indications) and might not support the same requirements of safety, quality and efficacy and benefit/risk ratio with respect to off-label use.
This notwithstanding, the higher prevalence of off-label use in the paediatric population is somehow recognised as a concept by the EU pharmaceutical law – indicates the report – under recital 2 of the Paediatric Regulation (1901/2006/EC) and the pharmacovigilance provisions in Directive 2010/84/EU. Also the Orphan Medicinal Product Regulation (141/2000/EC) is expected to contribute decreasing the extent of off-label use of medicines, even if according to the Commission it is still difficult to evaluate the real impact of these regulations.

A complete different thing is the daily medical practice, where medical doctors are free to prescribe medicines according to the principles of knowledge and belief. The off-label prescription becomes, from this point of view, just a step of the relationship between the patients and its doctors, explained the report. Furthermore, each Member State is free to organise its internal healthcare system and is responsible for the definition of health policies and the delivery of the related services (Article 168 (7) TFEU). Healthcare professionals prescribing off-label medicinal products are subject to both EU’s product liability and professional liability legislations if the prescription is inappropriate. Ethical and professional standards and codes of conduct are also governing the action of HPCs, which might be sanctioned by disciplinary boards. In some instances the criminal law might also apply.
Finally, reimbursement of off-label prescribed medicines depends upon the specific national health insurance legislation of each Member State. Reimbursement is also at the center of many cases discussed by national courts, those results indicate that additional requirements may apply, including the limitation to life-threatening or severe conditions and the absence of alternative treatment options.

The national frameworks are very different

The exercise run by the European Commission also analysed the national frameworks governing off-label use in different Member States, resulting in a very fragmented picture. In France and Hungary, for example, prescribers or their organisations have to ask for permission to prescribe a product off-label under the legal framework of the “temporary recommendations for use (RTU) scheme”.
Reimbursement in France and Italy is allowed also when on-label, authorised or not strictly identical alternatives exist. Great Britain introduced in 2013 the General Medical Council Guidance (Good practice in prescribing and managing medicines and devices) to support the choices of prescribers. In The Netherlands 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. HPCs have also to register for what intervention the patient has given its informed consent.
Many EU Member States do not have specific policy tools to guide off-label use, and in many instances the practice is seen as something pertaining prescribers rather than the regulatory or healthcare system level.

The options for the future

The study of the EU Commission suggests that the so-called ‘soft approaches’, providing guidelines and collecting practical evidence on off-label use, might represent the most appropriate tool to find a wide support among stakeholders. The survey also identified the possibility to include other evidence than the industry-based one to support off-label indications; randomised controlled trials for the marketing authorisation of off-label indications might represent an option, as well as evidence from monitoring patient cohorts, data from routine patient registries and from reporting adverse events.
General advice on off-label use provided to Member States might be useful to guide the development of national guidelines on the basis of a common ground. A better incentives framework might be addressed to the pharmaceutical industry to improve the registration of new indications, dosing or formulations for existing products. The expert meeting organised by the Commission found agreement in asking prescribers to apply with each Member State’s competent authority for the permission to prescribe off-label. This procedure would allow for a national evaluation of the benefit/risk ratio of off-label use.
Another critical point to be addressed is represented by the possible different reimbursement for off-label products and on-label competitors. Treatment guidelines published by professional bodies at the national level and improved patient information, preferably in the form of individual messages to patients provided by HCPs together with easily accessible online and printed information, have been identified as the main tools to better communicate these themes to healthcare professionals and patients.