CJEU upholds withdrawal of orphan designation based on increased availability

The EU’s General Court, whose jurisdiction includes the judicial review of decisions made by the EU institutions such as European Medicines Agency, has recently considered an interesting application in relation to a medicinal product that had been granted orphan designation on the little used basis that its significant benefit lay in its potential authorisation in all member states. The product was subsequently granted a marketing authorisation having applied via the route for generic approval, making it, unusually, a generic orphan medicinal product.

In its decision of 16th May 2019, the General Court dismissed an action by GMP-Orphan (GMPO) for annulment of a Commission decision revoking the status of orphan medicinal product for trientine tetrahydochloride, known as “Cuprior-trientine” (Cuprior), a medicinal product for the treatment of Wilson’s disease. The Commission decided that Cuprior did not satisfy the criteria for orphan medicinal products, as set out in Regulation (EC) No 141/2000 (the Orphan Regulation), and in particular, that it did not provide a significant benefit, especially when compared to dihydrochloride trientine (the Reference Product), which had been authorised in one EU Member State since 1985. The Commission found that that GMPO had not provided sufficient evidence to prove the lack of availability of the Reference Product in the EU. Cuprior was therefore removed from the Register of Orphan Medicinal Products and GMPO sought judicial review of the Commission’s decision.

GMPO relied on the second limb of Article 3(1)(b) of the Orphan Regulation to establish orphan status, namely that Cuprior was of significant benefit to patients affected by the condition. “Significant benefit” is defined in Article 3(2) of Regulation No 847/2000 as “a clinically relevant advantage or a major contribution to client care”.

GMPO argued that authorisation in all Member States (compared to authorisation in a limited number) provides a significant benefit, and that an expectation of EU-wide marketing authorisation constitutes an “inherent assumption” of significant benefit within the meaning of the Orphan Regulation. Section A.4 of the Communication from the Commission on Regulation (EC) No 141/2000 of the European Parliament and of the Council on orphan medicinal products (the 2003 Communication) states that “with respect to potential availability of the product to the Community population, a medicinal product that is authorised and available in all Member States may constitute a significant benefit compared with a product that is authorised in a limited number of Member States only”.

The Court stated that marketing authorisation at EU level does not constitute per se a significant benefit compared to a treatment based on an existing medicinal product which is effective and authorised, albeit that it is only authorised in one Member State. Section A.4 of the 2003 Communication indicates a possibility rather than a mandatory stipulation or legal presumption. The fact that the Reference Product is authorised in only one Member State does not necessarily mean that patients in other Member States do not have access to the product. Likewise, the fact that a medicinal product is authorised at EU level does not in itself mean that the product has been made available to patients in all Member States. The Court acknowledged that whilst potential EU-wide marketing authorisation may constitute a significant benefit, this must be assessed on a case-by-case basis, with reference to concrete evidence.

The Court considered that no error of assessment had been made in finding that GMPO had not provided sufficient supporting information to establish that there was an availability problem of the Reference Product, and that patients with Wilson’s disease in the EU were not properly treated by the Reference Product. The Court stated that the fact that the Reference Product is authorised in only one Member State does not mean that it is excluded from reimbursement by the national health system of the Member State of importation (in fact, the Reference Product is reimbursed in Germany). Further, obtaining marketing authorisation at EU level does not necessarily mean that Cuprior will be reimbursed under national health schemes, and GMPO did not provide any evidence showing that it would.

The Court therefore found that Cuprior did not offer a “significant benefit” to patients suffering from Wilson’s disease, and dismissed GMPO’s application.

The General Court was careful to base its decision on its analysis of the meaning and effect of section A.4 of the 2003 Communication. It is impossible to know to what extent its decision may have been influenced by a perception that a generic medicinal product may not be an appropriate recipient of the reward of 10 years orphan market exclusivity. That reward is offered in recognition of the commercial uncertainties of investment in the research and development costs attaching to orphan medical products but here the sponsors had done little or no additional research and relied on the evidence supporting a product approved as long ago as 1985. On the other hand, it would be hard to construct a set of facts that more clearly falls within Section 4A. Such tension between the spirit and the letter of the Orphan Regulation may invite an appeal to the CJEU.

This article was co-authored by Charlotte Eaton.