Off-label use of a medicinal product is the prescription of it without following the information provided on the leaflet or the summary of product characteristics (“SPC”). So, a doctor could prescribe a dosage different from the one recommended on the SPC, prescribe different indications or prescribe the drug for a patient group not intended by the SPC. Off-label use is a frequent topic of discussion within the European Union. This newsletter will examine the main results of this study report. First, the legal framework in place in the EU will be analysed. Second, the incentives that draw prescribers, patients and marketing authorization holders to off-label use will be examined. Then the advantages and disadvantages, as put forward by different stakeholders, will be discussed. Finally, the report will also present different policy options regarding off-label use.

Introduction

In February 2017, the European Union published a study report on off-label use of medicinal products in the EU.1 This vast report lays down the (absence of) applicable regulation concerning off-label use and maps, as far as possible, the extent to which off-label use is applied throughout all the Member States of the EU.

Off-label use of a medicinal product is the prescription of it without following the information provided on the leaflet or the summary of product characteristics (“SPC”). So, a doctor could prescribe a dosage different from the one recommended on the SPC, prescribe different indications or prescribe the drug for a patient group that is not intended by the SPC. Off-label use is a frequent topic of discussion within the European Union. This newsletter will examine the main results of this study report. First, the legal framework in place in the EU will be analysed. Second, the incentives that draw prescribers, patients and marketing authorization holders to off-label use will be examined. Then the advantages and disadvantages, as put forward by different stakeholders, will be discussed. Finally, the report will also present different policy options regarding off-label use.

Legal framework FOR off-label use

The applicable legal framework must be built on two levels, namely the regulation on medicinal products on the one hand and the use of medicinal products in practice on the other. Whilst the first one is regulated by Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the community code relating to medicinal products for human use, the use of these medicines in practice is not regulated by European law.

Regulation of medicinal products

The European Union harmonized the legal framework for medicinal products in Directive 2001/83/EC. According to Article 6(1) of the Directive, for a manufacturer to put a medicinal product on the European market, prior marketing authorization must be obtained. The Directive further establishes the requirements for such marketing authorization. The decision on the marketing authorization is based on an assessment of the benefits-risk balance, the safety and efficacy of the medicinal product. If the marketing authorization is granted, the medicinal product can be prescribed and used following the accompanying SPC and the patient information leaflet. However, nothing in the European legislation prevents healthcare professionals from prescribing a drug that does not conform to the marketing authorization and thus the SPC or the leaflet. Off-label use is thus not strictly prohibited on an EU level.

The EU legislator has however taken measures to encourage the development of innovative products and to encourage marketing authorization for medicinal products for which a medical need exists by adopting two new Regulations. First, the Orphan Medicinal Product Regulation (EC) No 141/2000/EC entered into force in 2000. This regulation was designed to encourage pharmaceutical companies to develop new medicinal products for patients with a rare disease. This Regulation might have an influence on off-label use since new medicinal products are authorized whereas, if they weren’t, off-label use could have been the alternative. Another example is the Paediatric Regulation No 1901/2006/EC that entered into force in 2007 as a response to the absence of sufficient for medicinal products for children with marketing authorization.

Use of medicinal products in the Member States

The use of medicinal products is ultimately decided by the physician and the patient, who can choose to use a medicinal product off- or on-label. This topic occurs within the healthcare system that is not regulated by the EU according to Article 168, §7 of the Treaty on the Functioning of the European Union. The European legal framework does not interfere with national healthcare systems as it is their responsibility to define their health policies and to organize and deliver health services and medical care. The Member States are responsible for the management of health services and medical care and the allocation of the resources assigned to them.

Some Member States have adopted regulation concerning off-label use (see further below). In other Member States, there is no specific regulation on off-label use since it is considered the responsibility of the physician to be aware of the risks and to be in a position to judge for the benefit of the patient.

Nevertheless, even though the European legislator did not forbid or subject off-label use to 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.

Incentives for off-label use

The holder of the marketing authorization as well as the prescriber and the patient can have an influence on the off-label use of medicinal products. The study reveals that there are different incentives for these actors to choose for off-label use. These “drivers” relate to the marketing authorization process as well as to post-marketing authorization events (e.g. withdrawal from the market), reimbursement and pricing, or aspects related to patients or to the work of the healthcare professionals. For example, there are limited incentives for pharmaceutical industries to modify and extend the content of the SPC and patient leaflets of existing medicinal products. The marketing authorization as well as the addition of a new indication of the drug is a long process and thus a significant administrative burden. In general, the study concludes that the incentives for off-label prescriptions are variable and numerous. Usually, a combination of different factors makes the actors involved opt for off-label use. However, the level of contribution of these elements and their interaction remains uncertain.

Advantages and disadvantages

Different stakeholders were interviewed for this study, more specifically: (1) representatives of regulatory authorities, (2) representatives of health technology assessment/ pricing and reimbursement bodies, (3) patients, (4) healthcare professionals, (5) the pharmaceutical industry and (6) experts on off-label use. This resulted in varied positions regarding off-label use and its advantages and disadvantages. In general, all stakeholders shared the opinion that off-label use could be monitored better.

One of the major advantages is the easier and earlier access for patients to the medicinal product as well as to innovative treatments. Regulators emphasized the economic advantage, namely that off-label use contributes to the sustainability of the healthcare system. For example, the off-label product could be cheaper than the on-label product, which could save costs for national healthcare. This could facilitate the access of the patient or the healthcare system to a medicinal product that could otherwise not be afforded or that might not be available on the market.

However, the economic consequences are not considered as positive by all stakeholders. When economic reasons prevail, difficulties in the relationships between national authorities and the pharmaceutical industry could occur. For instance, the off-label use products reimbursement could have negative implications for their relationship because it would be less expensive than the authorized product.

Another off-label use concern is the safety of the drug and the lack of information concerning the benefit/risk balance. It is difficult for the patient to make an informed decision in the case of off-label use. Finally, responsibility and liability issues in the event of off-label prescribing having negative consequences could raise difficulties, since the lack of regulation creates an uncertain legal environment.

Possible policy options put forward by the study report

As stated earlier in this newsletter, in general all stakeholders are in favour of better monitoring of off-label use. Therefore, the report proposes different policy options.

A first option is for Member States to adopt a system whereby the prescriber must first request the competent authority for permission to prescribe the drug off-label. This system is already in place in France as well as in Hungary.

Another alternative is to put in place “temporary recommendations for use”. This has also been adopted in France. The competent authority informs the marketing authorization holder of the need for a recommendation for use and asks it to provide all relevant data on the concerned indication. The holder must produce a follow-up of patients based on safety and efficacy information and conditions of use. This would enhance the safety of off-label use of medicinal products, since patients would be monitored through a protocol. It would further improve the knowledge of the safety and efficacy of off-label use and encourage pharmaceutical companies to request the extension of indications of approved medicines. There is however reluctance from the companies to implement this follow-up as there is from physicians to the reporting of all data because of the administrative burden.

Another more implicit way of providing guidance regarding off-label use is to create incentives at the EU level for the pharmaceutical companies to extend the indications of the SPC of the existing medicinal products. For example, holders of a marketing authorization could use evidence other than industry-based randomized controlled trials (scientific studies) to support the application of an extension of the indication, such as the use of monitoring data on efficacy and safety. This could increase the knowledge of the risk-benefit balance of the medicinal product and could be used to establish whether a medicine could be registered for a new diagnosis. This data should however comply with certain standards to establish the quality of the data.

A fourth option to monitor off-label use is to regulate its reimbursement. In that sense, Italy allows reimbursement for such use even when alternatives exist, including on-label use.

A fifth example is to implement treatment guidelines for prescribers. Competent authorities of Member States could adopt specific protocols or guidelines. These guidelines could be drafted at the European level, providing a basis for national regulators to implement a “code of conduct”. This guidance would then, to a certain extent, be harmonized. For instance, in the Netherlands, off-label prescription is only allowed if protocols concerning that specific off-label use are adopted. The guidelines would be based on evidence that could provide insights into the risk-benefit ratio of products so prescribers as well as patients can make an informed decision.

Finally, awareness campaigns for prescribers as well as patients could also be useful, since patients and physicians can base their decision on information provided to them. This awareness could also be enhanced through information that is easily accessible, for example in a folder or on a website.

Conclusion

The report of the European Union gives a detailed overview of the issues concerning off-label use of medicinal products and proposes different policy options that could be considered. Strict regulation at the EU level does not seem to be adequate in this field, since the competence of the healthcare system still lies with the Member States. Off-label use of medicines is a sensitive subject, since many actors are involved in this issue. A balance must be found between the safety of the medicinal product, the protection of the patient and the feasibility of pharmaceutical companies putting medicinal products on the European market, taking into account the time and administrative costs involved.