Recent Developments in Off-Label Use
Off-label use has become a hot topic in the EU, particularly when promoted by governments or national health systems for economic reasons in circumstances where an approved alternative is available.
The current interest has been stimulated, in particular, by the actions of the Italian and French authorities, who introduced cost-saving policies in 2014, to permit bevacizumab (Avastin) to be prescribed for ophthalmic indications, particularly wet age-related macular degeneration (AMD), despite the availability of ranibizumab (Lucentis) authorised for intravitreal injection for the treatment of such conditions. Avastin and Lucentis have a similar mechanism of action, but Avastin is indicated only for intravenous administration in oncology (for the treatment of colon, breast and kidney cancers).
Following the introduction of these controversial policies in Italy and France, the European Commission received a number of questions from member states and other stakeholders in relation to the issues and their associated legal and medical implications. In January 2015, EFPIA, EUCOPE and EuropaBio filed a complaint against the Italian law of May 2014 which provides for reimbursement of medicinal products used off-label even though a licensed alternative is available.1 A further complaint was issued in September 2015 in relation to the French RTU system, which allows the French medicines regulator to issue a temporary recommendation for use of a product in an unauthorised indication, for economic purposes, notwithstanding the existence of an authorised alternative treatment.2
These complaints highlight the inconsistency between the strict regulatory process for authorisation of medicinal products, based on a full and harmonised set of particulars and rigorous assessment of quality, safety and efficacy for the purposes of specific medical conditions, and the promotion by national authorities of unauthorised indications for products which have not been subject to those stringent requirements for economic reasons. The position set out by EFPIA, EUCOPE and EuropaBio is also in line with the 2012 decision of the CJEU3 which considered the supply of unlicensed medicinal products under article 5(1) of Directive 2001/83/EC, to "fulfil special needs" of particular patients. In that case, the CJEU specially stated that financial considerations cannot, in themselves, lead to recognition of the existence of special needs capable of justifying the unlicensed use of a medicinal product in preference to a product with a marketing authorisation for the indication in question.
The policies in Italy and France have resulted in litigation in the national courts. Most recently, in February 2017, the Conseil d'Etat, the French Administrative Supreme Court, rejected a challenge by Novartis against the RTU issued by the French authorities recommending use of off-label Avastin in wet AMD, despite the availability of Novartis' product, Lucentis.4 The Conseil d'Etat concluded that the provisions of the French Public Health Code were in line with EU law, as the case law of the CJEU5 shows that pursuant to article 5(1) of the Directive, an authorised medicinal product may, in certain circumstances, be used off-label, notably if its active ingredient is different from that of the product authorised for such indication, provided that the prescribing doctor deems it indispensable to use this medicine to meet the therapeutic needs of his patient.
Given this context, the Commission has finally published a much awaited report, which describes a study on off-label use of medicinal products in the EU (the Study).6 The Study provides a factual analysis of this practice across the EU, including its legal framework, its prevalence (usually cited as around 20 percent of prescriptions), a description of its drivers and a review of the existing and potential policy tools that could be used to better regulate the practice.
While the purpose of the Study was principally to describe the situation from a factual perspective, some sectors, particularly the pharmaceutical industry, have been disappointed with lack of consideration given to important issues such as off-label prescribing in the context of licensed alternatives and the promotion of off-label prescriptions for purely financial reasons. The widespread criticism of the policies of the authorities in Italy and France in relation to off-label prescribing, together with the fact that such policies have been supported by their respective courts, reflects uncertainty in this area and demonstrates an urgent need for clarification at the EU level.
The Study: Drivers of Off-Label Use
The Study lists a number of reasons why off-label use is so prevalent in the EU:
- Regulatory incentives: Directive 2001/83/EC provides for one additional year of marketing protection if a new indication is registered in the first eight years after an authorisation is granted, provided this new indication brings significant clinical benefit over existing therapies. However, this additional year of marketing protection provides only limited benefit, particularly as doctors may prescribe a product off-label even without a company investing in such new indications. Furthermore, generic competition, low prices for off-patent medicines and increases in regulatory requirements mean there may be little incentive for a company to make such an investment.
- Supply issues: Disruption in the manufacturing of a product or its withdrawal (for commercial or safety reasons) from the market can provoke a need for off-label use of a different product. Similarly, some products (or some indications) may be authorised in some member states but not in others, or a product may be authorised but not made available, triggering the need for off-label prescribing of available products.
- Lack of authorised alternatives: The prescriber may have no choice but to prescribe off-label in circumstances where particular patient groups were not included in the clinical trials and are therefore not reflected in the SmPC for particular products.
- Cost: The most controversial drivers for off-label use are related to pricing and reimbursement. In this context, the study recognises that pricing may be the reason for off-label use in those cases where the on-label product is more expensive than the off-label product and both are reimbursed. Further, there are circumstances where the off-label use of a product is reimbursed while use of the on-label product is not, leading to off-label prescribing despite the availability of the on-label product.7
The Study: Policy Options to Provide Further Guidance and Certainty Around Off-Label Use
On the basis of these findings, the Study identifies a number of policy tools that could be used to better regulate off-label use:
- Regulating off-label prescription for specific products: Competent authorities might evaluate the risk-benefit profile of the medicine in its off-label use; only medicines with a favourable risk-benefit profile would be granted a permit to be prescribed off-label, as currently occurs in Hungary and France. In France, patients should be monitored through a protocol, and the marketing authorisation holder is required to collect safety and efficacy information, and to provide all available data to the regulatory authorities. Such systems serve to increase patient safety, and strengthen the prescriber's position with regards to liability. Their downside is that a refusal may be disadvantageous for individual patients, as off-label use may be prohibited, based on an evaluation of the average risk/benefit ratio across the population, rather than in an individual patient. The option also encounters reluctance from some companies and physicians due to the burden that these reporting obligations entail.
- Monitoring data on efficacy and safety: Data, other than from industry-based randomised controlled trials, could be accepted as evidence for applications for authorisations; for example by accepting monitoring data on efficacy and safety, real-world data from patient registries, or pharmacovigilance data. However, in order to ensure patient safety, it should be clear which quality standards apply for these data to be acceptable.
- EU guidance to assist with development of national guidelines of off-label prescribing: EU Guidance could be provided to establish a common ground for national treatment guidelines in member states.
- Treatment guidelines for specific products: Off-label prescription could be regulated using protocols or professional standards prepared by the relevant professional bodies on specific off-label use, as is the case in the Netherlands. Such guidelines would provide information on the risk-benefit balance of the product, so prescribers and patients could make an informed decision.
- Incentives for pharmaceutical companies to register new indications: The authorisation of new indications enhances patient safety and supports prescription by healthcare professionals. Industry stakeholders argued that additional incentives should be added to the EU legal framework to reward the investment needed to develop new indications, although other stakeholders considered the current incentives (including those under the Paediatric Regulation and the Orphan Drug Regulation) to be sufficient.
- Reimbursement measures: Reimbursement systems could be amended to allow for off-label use, including: (i) reimbursing off-label use where a product is included in treatment guidelines, (ii) reimbursing off-label use for which there is no competitor on the market; and/or (iii) reimbursing off-label use where the off-label product is less expensive than its on-label competitor. The last option caused controversy among stakeholders. The authors of the Study noted the decision of the CJEU in European Commission v. Poland8, which confirmed that the exemption to the requirement for a medicinal product to be supplied in accordance with a marketing authorisation, under Article 5 of Directive 2001/83/EC, cannot be applied for financial reasons only. They commented that
"it can be debated whether allowing reimbursement of off-label use in case it is less expensive than its on-label competitor is (always) against the medical need of an individual patient. Moreover, medicinal products may become available to patients who otherwise would not have access to these medicines."
The Study states that industry was opposed to this option, but does not present any analysis of its lack of consistency with the EU medicines regulatory framework.
- Awareness campaigns: Healthcare professionals and patients could be informed about off-label use via awareness campaigns. However, campaigns for healthcare professionals were not considered useful, as needs differ per country and per specialism. Nor were they considered useful for patients, as off-label use is not relevant for a large majority of patients.
It remains to be seen how the Commission will respond to these suggestions, and what, if any, changes will be implemented. None of the proposals involve implementing the same rigorous standard for assessment as that required by the European Directive to place a product on the market. In the meantime, the circumstances in which off-label use is permitted and even promoted by national authorities in the different member states shows substantial divergence.
Conseil d'Etat, 1st–6th Chambers, 24 February 2017, No. 392459.