In Europe, medicines can only be marketed once they have passed through a strict regulatory process designed primarily to protect patient safety. It is only after in-depth testing on the targeted disease population, including three phases of clinical assessment and trials, that a medicine will obtain a ‘marketing authorisation’. Given its primary goal of ensuring patient safety, EU law only allows a few narrow exceptions to the requirement of a marketing authorisation. A drug can only be used ‘off-label’, meaning outside the limits of its marketing authorisation, in authorised clinical trials or under one of the strictly defined exceptions, such as severe public health risk, compassionate use for groups of patients or for individual patients on a named basis.
However, in recent years, a trend has emerged among member states to push the boundaries of the existing regulatory system, and actively promote the off-label use of medicines on the grounds that they are cheaper than the alternative, authorised medicines. It is highly questionable whether this trend is in line with EU law. Here, we analyse and offer a critique on a report from the Belgian Health Care Knowledge Centre (KCE), a federal scientific organisation tasked with advising policymakers on decisions relating to healthcare and health insurance, on the management of off-label drugs. The report presents options for a framework for ‘better managed’ off-label use of medicines in Belgium, and also at a European level.
An inaccurate analysis of EU case law
Despite noticing the constraints imposed by EU law on the possibility of member states promoting off-label use, the report is premised on an inaccurate analysis of EU case law. The report supports the widespread use of off-label medicines for reasons of cost-effectiveness, which plainly contradicts the case law of the EU courts. The approach put forward by the report undermines both the EU regulatory system for approving medicines and the national pricing and reimbursement systems (including Health Technology Assessments (HTAs)) that exist around Europe. As such, the approach suggested by the report is not just erroneous as a matter of law; it may also be questionable as a matter of policy.
While the report recognises that ‘based on the underlying concern for patient safety, EU law foresees limited possibilities for the use of non-authorised medicinal products’, it is wrong to suggest that the need for a marketing authorisation is a question of ‘balance’. This is because regulatory restrictions such as the need for a marketing authorisation are only validated to the extent that they are necessary and proportionate to the protection of human health and safety. This appears to be a downgrading of the most fundamental regulatory requirement in Europe, namely that a marketing authorisation should be granted before medicines are marketed or used. The harmonised EU regulatory system aims to guarantee the highest level of patient safety through the use of compulsory marketing authorisations. The exceptions to the requirement to obtain a specific marketing authorisation before using any medicine to treat any given disease must therefore be interpreted narrowly. The exceptions are not to be interpreted based on the balancing of public health and freedom of undertakings to market their products. The case law could not be clearer: public health is paramount and takes precedence over any economic considerations.
The report also tries to draw a distinction between off-label use of authorised medicines (ie, not in accordance with their marketing authorisation) and the use of unauthorised medicines. However, there is no legal difference: in both cases, the medicine is not authorised for the use in question, but can be prescribed by a doctor based on his or her clinical judgment of that individual patient. The fact that a medicine is not authorised for any indication (meaning the EMA or national regulatory authorities have not reached a positive conclusion on its safety for any indication) would be a relevant consideration for the doctor; it does not change the legal standards to be applied. This can be seen in the court’s case law, which held that ‘off-label prescribing is the sole responsibility of the prescribing physicians’ (CTRS judgment) in ‘individual situations justified by medical considerations’, following ‘an actual examination of his patients and on the basis of purely therapeutic considerations’ (Novartis Pharma and Commission v Poland judgments).
Undermining the regulatory system for approving medicines
The report also proposes ‘a step-by-step plan that could help policymakers in the healthcare sector to assess and/or generate scientific evidence to ensure the safe, effective and targeted off-label use’, putting forward eight steps for decision-makers to follow. The report recommends that decision-makers take these eight steps, three of which relate to cost-effectiveness and safety. The report encourages the widespread use of off-label drugs, for cost reasons, notably to put pressure on the manufacturers of authorised drugs during price negotiations, advocating (incorrectly) that cost-effectiveness is a legitimate reason for the use of off-label drugs.
But such an approach is incompatible with EU law. It would also have the effect of undermining the regulatory system. By encouraging off-label uses that have not been subject to the same rigorous controls and safeguards as on-label medicines, member states such as Belgium bypass the regulatory process and undermine the European Union’s underlying objective of guaranteeing patient safety. Moreover, unilateral deviations from EU law by member states may lead to a fragmentation of the EU regulatory framework for medicines, which could prevent the rapid diffusion of new medicines across Europe and undermine the ability of companies to innovate and grow across Europe.
It seems inappropriate under EU law for public authorities to encourage the widespread off-label use of medicines
Existing pricing, reimbursement and HTA systems around Europe
Another striking feature of the report is that it says nothing about the Belgian or European pricing and reimbursement bodies. These take decisions under the relevant laws that seek to balance the short-term interest in lower prices against the long-term incentive for innovative drug development, while taking account of factors such as the cost of developing the medicine. Nor does it mention HTAs prevalent around Europe, which judge if a medicine is good value for money given the clinical benefits it brings, based on the likely outcome to the patient and cost and effectiveness of previously existing treatments.
Across Europe, on-label treatments have gone through this process and been approved by the relevant authorities for pricing and reimbursement after their expert technical assessment. It is not the case that the prices for such treatments are set unilaterally by the companies. EU member states typically have the power in this process to seek a lower price if they deem it excessive or not justified. They can also deny reimbursement altogether based on the criteria of national law, while respecting the rules in the EU Transparency Directive.
The report does not consider these existing and rather developed processes. It instead proposes that medicines, whose prices have been accepted by those processes, should reduce their prices further because of off-label medicines or be largely replaced by off-label medicines. This approach would undermine the legitimacy of the pricing and reimbursement processes around Europe. Once the price and reimbursement level of a medicine has been approved via those processes, it should not be for other public bodies to intervene and second-guess those processes and the resulting decisions. Instead, the price and reimbursement level of the authorised medicine should be reviewed under the existing pricing and reimbursement system or HTA rules. Such an approach would also harm innovation. While the report often cites Lucentis and Avastin as examples of the perceived issue (with some remarks about the drugs’ common origin), it does not address the impact that off-label prescription could have on other innovative players in this clinical field, notably on Regeneron, whose Eylea product is the latest treatment in this area. The report seems to suggest that Regeneron’s innovation should be rejected and not funded. What signal does that send, and what effect does that have on innovation?
Reflections needed
We have noted several errors in the way the report analyses the applicable provisions of EU law. More generally, in view of the EU regulatory framework and its primary objective of protecting patient safety, it seems inappropriate under EU law for public authorities to encourage the widespread off-label use of medicines. This is because it would interfere with doctors’ individual professional assessment as to which treatment is justified on therapeutic grounds.
If the Belgian authorities were to adopt such a policy of encouraging/promoting off-label use on a general basis, driven predominantly by economic considerations, its legality would be highly questionable as a matter of EU law. Moreover, the report could undermine the European Marketing Authorisation system and the national systems of pricing and reimbursement. It may also have unintended and counter-productive consequences. Further reflection is clearly called for.