Orphan designation: the General Court clarifies the meaning of significant benefit


Last month the General Court issued its judgment in case T-773/17 (available here) dismissing the action brought by GMP-Orphan. The claimant sought the annulment of the decision of the European Commission granting a marketing authorisation for its product “Cuprior” (trientine tetrahydrochloride), a medicinal product for human use for the treatment of Wilson’s disease, and establishing that the criteria for orphan designation were no longer met in respect of Cuprior which led to the product’s removal from the Register of Orphan Medicinal Products.

GMP-Orphan obtained orphan designation for trientine tetrahydrochloride for the treatment of Wilson’s disease in March 2015.  However, in May 2017, at the time of Cuprior’s orphan designation maintenance review when the marketing authorisation application was being assessed, the EMA’s Committee for Orphan Medicinal Products (COMP) concluded that the product did not provide a significant benefit.  In particular, when it compared it with dihydrochloride trientine, the reference product of Cuprior’s hybrid application under Article 10(3) of Directive 2001/83/EC, which has been the subject of a marketing authorisation in the United Kingdom since 1985.  The reference product was at least as clinically effective as Cuprior and the application for marketing authorisation for Cuprior was based on pre-clinical tests and clinical trials of the reference product.  The applicant alleged that a possible marketing authorisation for Cuprior as an orphan medicinal product in all Member States could constitute a “major contribution to patient care” and thus a significant benefit within the meaning of article 3(1)(b) of Regulation No 141/2000 and article 3(2) of Commission Regulation (EC) No 847/2000 to patients with Wilson’s disease throughout the EU in comparison with the reference product, which was only authorised in the United Kingdom.

The General Court concluded that no provision either in Regulation No 141/2000 or Commission Regulation (EC) No 847/2000 provides that a marketing authorisation at EU level for an orphan medicine constitutes per se a significant benefit in comparison with treatment based on an existing medicine, which is as effective and already authorised, albeit in only one Member State.

In order to be able to show significant benefit by reason of a “major contribution to patient care”, the Court clarified that the comparative analysis between the new product and the existing one must establish not only that the new product provides a benefit to patients and that it contributes to their care, but also that the benefit is ‘significant’ and that that contribution is ‘major’.  The expected advantage of the new product must exceed a certain quantitative or qualitative threshold so that it may be considered ‘significant’ or ‘major’.  In this regard, a sponsor cannot rely on presumptions or general assertions, as assumptions of significant benefit of a medicine as a “major contribution to patient care” have to be based on an analysis of concrete evidence in each individual case.

The Court also established that the fact that a medicine is not authorised at EU level but only in one Member State does not prevent the Member States in which that product is not authorised from enabling that product to be imported into their territories (article 5(1) of Directive 2001/83/EC).  In the case of dihydrochloride trientine, there are national importation schemes that enable the product to be imported lawfully even if it is not authorised in the Member State of importation.  This does not constitute “off-label” use, as alleged by the applicant, but the use of the medicinal product in a Member State other than in which it has been authorised in accordance with the therapeutic indications for which the reference product had been authorised.  The applicant had tried to show that, despite the existence of regulatory pathways for importing dihydrochloride trientine in most Member States, there were ‘logistic and administrative’ obstacles preventing effective access to the product.  The COMP conducted its own inquiry and the results revealed that regulatory mechanisms for importing the product existed in at least 26 Member States, that it could be imported and was in fact imported in accordance with article 5(1) of Directive 2001/83/EC.  Furthermore, the COMP reached the conclusion that the survey submitted by the applicant did not sufficiently show that there were availability problems with dihydrochloride trientine and that the lack of reimbursement of said product in the Member State of importation could not be taken into account in the assessment of significant benefit.  The Court gave a high probative value to the COMP’s inquiry and concluded that the COMP did not err in law by taking into account the existence of national importation schemes enabling the lawful importation of the reference product.

Even though the Court seems to have set a high bar for the purposes of showing details of the supply or availability problem when the argument for significant benefit is based on an increase in supply or availability of the existing medicinal product, the decision is not too surprising if we bear in mind that dihydrochloride trientine had been approved in Europe (albeit in a single Member State) for the treatment of Wilson’s disease since 1985 and that GMP-Orphan only had to carry out two comparative pharmacokinetic studies with cross-over design and a retrospective, single centre cohort survey to support Cuprior’s marketing authorisation application.  The outcome for Cuprior may have been different if it had been “truly” worthy of the 10-year orphan market exclusivity reward that the legislator considered necessary to stimulate the research and development required to bring appropriate medicines for rare conditions to the market which would not be developed under normal market conditions.

It remains to be seen whether the decision will be appealed or not.