On 28 February, the European Commission published its long-awaited study report on off-label use, providing a factual analysis of the current situation regarding off-label use in the EU member states. The study confirms that “the majority of, if not all, EU member states are faced with off-label use of medicinal products to some extent” and “that the way member states are dealing with off-label use is not harmonised.” The study does not provide any particular recommendations at this stage, but its conclusions will be further assessed by Commission services and discussed with the member states. In response to the study report which recognises that “off-label use of medicines at the healthcare system level can also be driven by financial reasons”, industry associations EFPIA, EUCOPE and EuropaBio issued a statement reiterating their fierce opposition of promoting off-label use for economic reasons.
Following an October 2013 Resolution from the European Parliament calling on the EMA to develop guidelines on the off-label use of medicines, in 2014 the European Commission commissioned a study in order to understand the ramification of the issue of off-label use of medicinal products. The study, which was commissioned to the Dutch National Institute for Public Health and the Environment (Nivel) and the European Public Health Alliance (EPHA), was intended to gather information in order to identify the need for coordination of off-label use of medicines at the EU level, focusing on the one hand on – scientific – public health aspects, and on the other hand on the – legal – regulatory framework for the off-label use of medicines.
The study concludes that off-label use in the EU is common practice in both the hospital and outpatient setting, is of interest in clinical areas which represent unmet medical needs (such as oncology/haematology, psychiatry and rheumatology), and is particularly high within the paediatric population. It identifies the following driving factors of off-label use: (i) the limited incentives for pharmaceutical companies to extend the labelling of existing medicinal products (i.e., an extra year of market protection if a new indication is registered in the first eight years after approval, provided it brings significant clinical benefit over existing therapies), (ii) the unavailability of some products due to economic reasons, (iii) pricing and reimbursement, and (iv) the fact that there is sometimes no other choice than prescribing off-label.
Even though the study does not provide specific recommendations, it sets forth a couple of potential measures, both nationally and at EU level, that could be taken in the field of off-label use. According to the study, 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.” During an expert meeting, stakeholders suggested that, the EU could (i) explore possibilities of including other evidence than industry-based randomised controlled trials (e.g. evidence from monitoring patient cohorts) for the approval of off-label indications, (ii) provide guidance for member states on off-label use (e.g. on elements to be included in treatment guidelines), and (iii) create incentives for pharmaceutical companies to register new indications for existing products.
The study also examined some national policy tools such as the French temporary recommendations for use (RTU) regime and specific reimbursement measures in Italy that allowed Roche’s anticancer medicine Avastin (bevacizumab) to be reimbursed for the non-approved indication of wet age-related macular degeneration (AMD) despite the availability of Novartis’ authorised (but much more expensive) medicinal product Lucentis (ranibizumab) – legislation with respect to which industry has complained to the European Commission in respectively 2015 and 2014. In this respect, the report merely recognises that “beyond purely therapeutically motivated decisions, off-label use of medicines at the healthcare system level can also be driven by financial reasons” and that “budget control at member state level and the sustainability of healthcare systems can be achieved by prescribing a cheaper off-label option.”
In a joint statement published on 2 March, industry associations EFPIA, EUCOPE and EuropaBio expressed its regret for “the lack of emphasis in the report on the fact that off-label use poses additional risks for patient safety which appear all the more unacceptable when alternative on-label treatments are available and not used for financial reasons” while underlining that “the report highlights the negative impact of off-label use for the regulatory system mentioning that it creates uncertainties regarding the liability of healthcare professionals, undermines the EU market authorisation process and discourages R&D.” The statement notes that the pharmaceutical industry “fully recognise[s] the affordability challenges faced by healthcare systems under pressure from rising healthcare demand” but “cannot accept measures that could compromise public health.” For these reasons, the industry bodies “emphasise the fact that the reimbursement of off-label medicines for economic reasons when on-label products exist is not an acceptable policy option.”
However, industry is facing an uphill battle, even more since on 24 February 2017 the French Administrative Supreme Court rejected the request of Novartis and Roche to annul the RTU for Avastin because it considered that the RTU served public health by requiring strict precautions for the off-label use of Avastin.