On 23 January 2018, the European Court of Justice (CJEU) handed down its judgment in Case C-179/16 relating to an on-going saga concerning Hoffman-La Roche Ltd (Roche) and Novartis AG (Novartis) and their attempts to restrict the off-label of Avastin.
The CJEU's decision emphasises the increasingly wide application of competition law to the pharmaceutical sector. It should be welcome news, in particular to other developers of biosimilars who frequently face similar challenges and issues with regard to questions and concerns raised about the safety and efficacy of their products, even when they have been through extensive comparability studies and received marketing authorisations.
It is clear that originator companies will need to take greater care in the future to ensure any issues or safety concerns are raised in the context of a legitimate safety concern/pharmacoviligence monitoring only, and not with a view to reducing the competitive pressure of a rival's product.
Background
Avastin is a monoclonal antibody originally developed by a US subsidiary of Roche, Genentech, and granted an MA for oncological indications. At the same time as developing Avastin, Genentech also developed another monoclonal antibody (mAb), which also received an MA and was marketed as Lucentis.
Lucentis is authorised for the treatment of eye diseases (aged-related macular degeneration). Genetech licensed the commercialisation of Lucentis to Novartis, as it was already active in the field of ophthalmology, whereas Roche was not. While Avastin is authorised for treatment for oncological conditions, it is also frequently used "off-label" for the treatment of eye diseases, because it has a much lower price than Lucentis.
Fines by the Italian competition authority
In 2014, the Italian competition authority imposed two fines, each amounting to over €90 million, on both Roche and Novartis, on the grounds that they had put in place an arrangement designed to achieve an artificial differentiation between Avastin and Lucentis in breach of Article 101(1) of the TFEU (the EU's prohibition against anti-competitive agreements). Essentially, the arrangements were viewed as a form of collusive market sharing, as Avastin and Lucentis were equivalent in all respects for the treatment of eye diseases, and the arrangement was designed to achieve an artificial differentiation between them by manipulating the perception of the risks of using Avastin in the field of ophthalmology.
As a result of this behaviour, it claimed Lucentis was used in preference to Avastin, a shift which resulted in a cost increase for the Italian health service assessed at approximately €45 million in 2012 alone.
Following Roche and Novartis' appeal against the fines, the Consiglio di Stato (Council of State, Italy) referred a number of questions to the CJEU. One question focused on whether a concerted practice intended to emphasise that a medicinal product is less safe or less efficacious (without being supported by reliable scientific evidence) could be regarded as a restriction of competition by object in the light of the fact that the scientific knowledge available at the time was not conclusive as regards the product being less safe or less efficacious or not.
The Italian Court also referred questions on the approach to the relevant market definition, particularly in light of the marketing authorisations for each of the products: whether it was appropriate to frame the market definition only by reference to the MAs, or whether, as in this case, off-label use of a medicinal product for the same therapeutic indication meant that the products can be regarded as interchangeable for the purpose of defining the market.
In essence, the question was whether the off-label use of Avastin could be included in the relevant market, even where it failed to comply with the requirements laid down by the EU rules on pharmaceutical products. Roche argued that a significant proportion (the majority, even) of the Avastin intended for off-label use in Italy was serially repackaged without manufacturing authorisation and was sold to healthcare providers before the submission of individual prescriptions.
CJEU decision
On the question of market definition, the CJEU held that it was for the national courts to consider whether the off-label use was lawful.
It stated that, when defining the relevant market, the national competition authority may include medicinal products whose MA does not cover that treatment but which is used (i.e. off-label) for that purpose as it is substitutable with the approved medicinal product. In order to determine whether such a relationship of substitutability exists, the CJEU stated that the competition authority must also take into account any examination which has been undertaken by the competent authorities or courts as to whether the applicable legal provisions governing the manufacture and marketing of the product are fulfilled.
Given that pharmaceutical market definition also includes an assessment of the prescribing practices of doctors and pharmacists, it would also seem appropriate to include lawful off-label use in any market definition exercise.
The CJEU also stated that disseminating misleading information relating to adverse reactions resulting from the off-label use of a product with a view to reducing the competitive pressure it exerts on another product, could amount to a restriction of competition by object and therefore be in breach of EU competition law.
However, it emphasised that the information must be considered to be misleading. This will be a matter for the Italian court to determine, but relevant factors will be whether the purpose of the information is, first, to confuse (in this case the EMA and the Commission) and, secondly, to emphasise, in a context of scientific uncertainty, the public perception of the risks associated with the off-label (in this case of Avastin).