EU Ruling likely to set an increase in off-label use of medicinal products.
Managing partner of the law firm Herbert Smith Freehills in Italy, Laura Orlando is one of Italy’s leading life sciences specialists, with a focus on IP and regulatory matters. Together with Sara Balice, one of the firm’s senior associates they examine the Court of Justice of the European Union’s (CJEU) ruling on the Reimbursement of off-label medicinal products.
It is the responsibility of EU Member States to control off-label use of medicinal products.
Under EU Legislation (Directive 2001/83/EC, the “Directive”), a medicinal product may only be placed on the market of a Member State if a marketing authorisation has been issued by the competent authorities. The terms under which a medicinal product can be used safely and efficaciously are described in the product information, which is an integral part of the marketing authorisation process.
Off-label use refers to any intentional use of an authorised product not covered by the terms of its marketing authorisation.
A study report on the off-label use of medicinal products in the EU published by the European Commission in 2017 revealed that various drivers provoke off-label use of medicinal products. These drivers relate to the marketing authorisation process, post-marketing authorisation events (e.g. disruption in manufacturing, withdrawal from the market), pricing and reimbursement, aspects connected with the work of healthcare professionals, and patient-related factors, as shown in the figure below.
It is the responsibility of EU Member States to control off-label use of medicinal products. EU rules do not prohibit off-label prescription of medicines and their repackaging for such use but do require that they comply with the conditions laid down in those rules.
Under Italian law, further to an amendment introduced in 2014 (Law 79/2014), off-label medicinal product can be reimbursed by the Italian national healthcare insurance system (NHS) not only if no other therapeutic alternative is available but also in order to reduce expenditure, notwithstanding the existence and market availability of a valid therapeutic alternative.
The above-mentioned Italian law has been the subject of a recent decision of the CJEU in Novartis Farma v Italian Medicines Agency (AIFA), Roche Italia et al. case (C-29/17). The Court answered, in essence, that such law is not contrary to EU law on medicinal products.
The case involved two medicinal products – Avastin and Lucentis – marketed, respectively, by Roche and Novartis. Avastin is authorised for cancer treatment and Lucentis for eye diseases. Avastin was also frequently used off-label to treat eye diseases and was included in the Italian list of authorised, reimbursable off-label products – known as “List 648”. When Lucentis was authorised for the treatment of eye diseases in 2012, Avastin was excluded from List 648.
In 2014, the Italian competition authority fined both Roche and Novartis for having created an artificial differentiation between Avastin and Lucentis when they were equivalent for the treatment of eye diseases. After the competition case, AIFA reinserted Avastin as reimbursable after repackaging by the pharmacies for its off-label treatment of eye diseases, because Avastin had to be extracted from its original vial and divided into single-use syringes for intravitreal injection. Italian Law 79/2014 was then introduced, which essentially granted AIFA the power to authorise off-label use of medicinal products (under certain conditions) if warranted by public interest (including for financial reasons) even where a valid therapeutic alternative was available.
Novartis challenged AIFA’s decision to insert Avastin in List 648 but the decision was upheld by the Regional Administrative Court for Lazio. Novartis lodged an appeal with the Italian Council of State, which referred the case to the CJEU. The Italian Council of State essentially asked for clarification on whether:
- a national law, which encourages off-label use of medicinal products – regardless of specific patient needs and even when an authorised medicinal product for the same treatment already exists – by including medicinal products in the national list of NHS-reimbursed medicinal products, is in contrast with the Directive;
- once Avastin has been repackaged for off-label use according to national law, it falls within the scope of the Directive;
- a national law, which grants AIFA the power to monitor drugs like Avastin for its off-label use is in contrast with Regulation (EC) 726/2004.
The CJEU decision ruled that:
- The repackaging of Avastin in pharmacies for the purpose of its off-label use does not significantly change its composition, form or other fundamental characteristics. Therefore, repackaged Avastin still falls within the scope of the Directive.
- The Directive does not impact the national law that allows Avastin to be repackaged for its off-label treatment of ophthalmological indications, provided that the process of repackaging is prescribed by a doctor via an individual prescription and carried out by pharmacists.
- Regulation (EC) 726/2004 does not conflict with national law, under which AIFA has the power to monitor off-label products to safeguard patient safety, provided that its implementation reinforces the pharmacovigilance system introduced by Regulation No 726/2004.
This decision confirms that the Directive prohibits neither off-label use nor the repackaging of medical products for off-label use provided that it complies with the Directive. However, the CJEU did not expressly address the question whether off-label use of a medicinal product is permitted under the Directive for the sole purpose of reducing the NHS spend when medicinal products authorised for that specific therapeutic indication are already available on the market. The position of the Advocate General was clearer as he opined that (i) off-label use should be permitted insofar as it is necessary for therapeutic reasons (even when an authorised medicinal product for the same treatment already exists), and (ii) a national law that allows physicians to prescribe off-label products for the sole purpose of cost-saving would be contrary to the Directive.
It is likely that in the circumstances we will see an increase in off-label use.