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EU Court says off-label treatments must not be considered when assessing the significant benefit criterion in orphan drugs

Carmeliet Tine
Tine Carmeliet

Senior Associate


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30 November 2020

On 23 September 2020, the General Court of the European Union (GC) annulled a decision of the European Commission (Commission) that had withdrawn the orphan drug status of Trecondi (Treosulfan).

This is an important decision as, for the first time, the GC has disagreed with the Commission’s restrictive approach to finding a “significant benefit” in the context of the application of the Orphan Regulation. This ruling clearly excludes off-label use from being considered a satisfactory method, and limits the comparison for significant benefit purposes to medicinal products authorised for the same indication(s), including target populations, as the future medicinal product.


By a decision of 23 February 2004, Medac Gesellschaft für klinische Spezialpräparate mbH (Medac) received an orphan designation for a Treosulfan-based medicinal product indicated for ‘conditioning treatment prior to haematopoietic progenitor cell transplantation’.

On 13 October 2017, Medac submitted to the Committee for Orphan Medicinal Products (COMP) a report on the maintenance of the designation of Treosulfan as an orphan medicinal product. However, in December 2018, the COMP concluded that Medac had not established that Treosulfan would be of significant benefit in comparison with the already existing melphalan- and cyclophosphamide-based medicinal products.

For reference, Article 3(1)(b) of Regulation No 141/2000 (Orphan Regulation) provides for two alternative criteria for the designation of a medicinal product as an orphan medicinal product: (i) there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorised in the EU, or, (ii) if such a method exists, the medicinal product in question will be of significant benefit, compared with existing satisfactory methods, to those affected by that condition.

In June 2019, the Commission granted the marketing authorisation, but, based on the COMP’s final opinion, decided that Trecondi-treosulfan no longer met the criteria for orphan designation. Medac subsequently appealed to the GC, alleging an error of law in the interpretation of the concept of ‘satisfactory method’ within the meaning of Article 3(1)(b) of the Orphan Regulation.

GC’s judgment

To recall, in order for a medicinal product to constitute a ‘satisfactory method’, it must be ‘authorised’ in the EU for the same orphan ‘condition’ as that covered by the medicinal product for which a marketing authorisation as an orphan medicinal product is sought.

In its landmark judgment, the GC stated that “the off-label use of a medicinal product cannot be regarded, in the light of the foregoing, as being ‘authorised’ and that, consequently, a medicinal product used off-label cannot constitute a ‘satisfactory method … that has been authorised in the [European Union]’ within the meaning of Article 3(1)(b) of Regulation No 141/2000.” The GC thereby stressed that medicinal product used off-label cannot constitute a “satisfactory method” against which the treosulfan-based product had to be compared under the Orphan Regulation since the summaries of product characteristics (SmPC) evidenced different intended treatment conditions and patient populations.

The GC stipulates that the purpose of the Orphan Regulation, is precisely to provide incentives for the research, development and placing on the market of medicinal products intended to treat conditions which occur so infrequently that the pharmaceutical industry would be unwilling to develop medicinal products to diagnose, prevent or treat them under normal market conditions. Therefore, according to the GC, “the exclusion of a potential medicinal product from the benefits provided for by the Orphan Regulation on the ground that ‘satisfactory methods’ exist only for a portion of the rare conditions covered by it is contrary to the intended purpose”.


This ruling indeed clearly excludes off-label use from being considered a satisfactory method. It can also be argued that in addition to off-label use, the GC’s reasoning could applies to pharmacy preparations. The Medac ruling will in any event enable pharmaceutical companies to oppose the choice of ‘satisfactory methods’ imposed by the COMP, and reduce the comparisons mandated with their future orphan medicinal products.

It is expected that the Commission will appeal this decision to the European Court of Justice. In this respect, it will be interesting to see how this decision will impact future COMP assessment, and whether, if at all, it will influence the current review of the OMP Regulation. We expect the draft proposal of this significant reform of the OMP Regulation to be published in the beginning of next year.