This case comment was first published by lawtext.com in Bioscience Law Review, Volume 17, Issue 2. Its content has been reproduced with the permission of lawtext.com.
GMP-Orphan v European Commission
On 16 May 2019, in Case T–733/17, GMP-Orphan (GMPO) v Commission, the EU General Court considered the interpretation of the term ‘significant benefit’ within the meaning of Regulation (EC) No 141/2000 (‘the Orphan Regulation’). The General Court upheld the European Commission (‘the EC’) decision to remove Cuprior-trientine (‘Cuprior’) from the Register of Orphan Medicinal Products (‘the Register’), on the basis that the sponsor, GMP-Orphan (‘GMPO’), could not meet the Significant Benefit Test within the meaning of Article 3 of the Orphan Regulation. The court was clear that marketing authorisation of a new orphan medicinal product at EU level did not constitute per se a significant benefit where an existing product, which was equally effective, was available, regardless of the fact that it is only authorised in one Member State.
Overview of Orphan Data Exclusivity
A key right for pharmaceutical developers is that of data exclusivity. On one hand, developers who carry out extensive clinical trials in order to seek a marketing authorisation (‘MA’) for a medicinal product should be rewarded with the fruits of their labour. On the other hand, insisting that a full dossier of clinical data is prepared for generic products, or for similar but ‘improved’ versions of products already approved, is onerous and hampers the availability of cost-effective medicines. The EU regime, therefore, allows developers of new products a period of ‘data exclusivity’, after which third parties can adopt that clinical data in support of applications for MAs of their own. In order to incentivise development of drugs for serious but rare diseases, a special form of exclusivity right, ‘orphan exclusivity’, is offered to orphan medicinal products. Orphan exclusivity differs from data exclusivity in that it prevents a regulatory authority from accepting or granting an application for a similar medicinal product during the ten-year duration of the orphan exclusivity.
Under Article 3, for a medicinal product to be designated as an orphan medicinal product, the sponsor must establish:
- that it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition;
- the condition affects not more than five in 10,000 persons in the EU when the application is made, or it is unlikely that the marketing of the medicinal product in the EU would generate sufficient return to justify the necessary investment; and
- there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorised in the EU (limb one) or if such method exists, the medicinal product will be of significant benefit to those affected by that condition (limb two) (‘the Significant Benefit Test’).
Background of the Disease and Product in Suit
Wilson’s disease is a genetic condition that causes a build-up of copper in the body. It affects 0.6 people in 10,000 (far lower than the 5/10,000 threshold laid down by Article 3).
Three pre-existing medicinal products in the EU were approved for the treatment of Wilson’s disease before Cuprior:
- penicillamine – which is effective but to which some people are allergic;
- zinc acetate – which is only recommended for use once the symptoms of Wilson’s disease have been brought under control, and not in the initial stages of Wilson’s disease; and
- trientine di-hydrochloride (TETA 2HCL available in 150mg scored tablets) (‘the Reference Product’) – which can be used at onset in patients who cannot take penicillamine.
The Reference Product was granted market authorisation in the United Kingdom in 1985. Whilst it is not authorised elsewhere other than in the United Kingdom, it is in practice exported to Germany, France, Greece, Norway, Switzerland, Austria and Ireland. However, supply is restricted to named patients only.
GMPO subsequently began development of Cuprior, a trientine tetra-hydrochloride (TETA 4HCL) product available in 300mg capsules. Cuprior is very similar to the Reference Product, in that it has the same active moiety (trientine) and the same mechanism of action.
GMPO sponsored Cuprior’s designation as an orphan medicinal product for the treatment of Wilson’s disease on the basis that this satisfied Article 3. In March 2015, the EC designated Cuprior as an orphan medicinal product: Wilson’s disease is a chronically debilitating condition that affects fewer than five in 10,000 people, and Cuprior can be used in the initial stages of the disease in patients who cannot take penicillamine. It is expected to be more widely available than the Reference Product, to which access is limited.
In December 2015, GMPO applied for a MA for Cuprior. GMPO did so by relying in part on the clinical data in respect of the Reference Product, to which it added bridging data (a procedure that was possible given the close similarity between the pharmaceutical substances). The GMPO marketing authorisation was, therefore, granted pursuant to Article 10(3) the ‘hybrid generic’ route. As such it had no data exclusivity of its own, which is why retaining orphan exclusivity was critically important on this product.
In September 2016, in order to maintain the orphan designation of Cuprior, GMPO submitted a report to the European Medicines Agency. The report included various data on Wilson’s disease and the medicine’s significant benefit, in order to demonstrate that it continued to meet the requirements of Article 3.
On review, the Committee for Orphan Medicinal Products (‘the COMP’) decided that the criteria for designation of Cuprior under Article 3 were not all met. Specifically, Cuprior did not satisfy the Significant Benefit Test. The COMP was satisfied that Cuprior provides a significant benefit over penicillamine, as Curprior can be taken by patients who cannot take penicillamine. It was also satisfied of a significant benefit over zinc acetate, as Cuprior (unlike zinc acetate) can be used in the early stages of Wilson’s disease. However, the COMP was not satisfied of any significant benefit over its own Reference Product, and so the COMP refused to maintain the orphan designation.
GMPO then requested that the COMP review its opinion. However, the COMP upheld the opinion, again on the basis that satisfactory methods of treatment for the condition had already been authorised and that GMPO had not provided sufficient evidence to demonstrate the lack of availability of its Reference Product in the EU. This decision was later adopted by the EC and Cuprior was removed from the Register in September 2017.
GMPO then appealed to the General Court and requested that Cuprior be classified as an orphan medicinal product, arguing that the court should annul the EC’s decision and order the EC to classify Cuprior as an orphan medicinal product and update the Register.
The Significant Benefit Test and the General Court Decision
The assessment of Cuprior turns on the Significant Benefit Test: does Cuprior provide a significant benefit to those affected by Wilson’s disease over existing methods of diagnosis, prevention or treatment of that condition, more particularly the Reference Product?
GMPO submitted that the Cuprior MA would provide significant benefit because the Reference Product was only authorised in the United Kingdom. Accordingly, an increased availability of trientine-based therapy, as the only treatment option for some patients with Wilson’s disease, would provide significant benefit. GMPO also pointed out that even if the Reference Product could be imported, practically there remain administrative hurdles in gaining access to the Reference Product.
The court revisited the definition of significant benefit which is defined as ‘a clinically relevant advantage or a major contribution to patient care’ under Article 3(2) of the Orphan Regulation. The court clarified that on the data, Cuprior does not provide any clinical advantage in comparison to the Reference Product (indeed, as a hybrid generic product it uses the same active moiety and method of action). Therefore, GMPO relied on Cuprior providing a major contribution to patient care through its increased availability in the Community. The court held that to meet this criterion, the comparison between both new and Reference Product must establish that the new product provides a benefit to patients, that it contributes to their care and that the benefit is ‘significant’ and the contribution ‘major’. This could be demonstrated on the basis of concrete and substantiated evidence.
The court was clear that a mere fact that the Reference Product was only authorised in the United Kingdom did not mean that the patients in other Member States did not have legal access to that product. The authorised Member State can provide the legal mechanisms to enable product import. Conversely, the court was of the view that the fact that a medicinal product was authorised at EU level does not necessarily mean it is made available in all Member States.
It was recognised that the COMP, in their assessment, took into account the existence of national importation schemes to enable this lawful importation of the Reference Product.
The General Court clearly stated that the fact a medicinal product may be authorised at EU level does not permit the conclusion or presumption that it will be of significant benefit in comparison with the Reference Product being authorised in only one Member State.
The Court’s Jurisdiction
The court, during the course of the judgment, also considered their jurisdiction under Article 263 TFEU, clarifying that they had no jurisdiction to order the classification of Cuprior as an orphan medicinal product and for the EC to update the Register.
The court reiterated the judgment of Now Pharma v Commission (T–74/08) stating that judicial review of the EC is confined to determining whether the relevant procedural rules have been complied with, whether the facts established by the EC are correct and whether there has been a misuse of power. The court found that the EC’s decision was based on findings of fact regarding the availability of the Reference Product in the EU.
Brexit and the Orphan Regulation
Post-Brexit, the UK Government anticipates that there will be a UK system for rare disease medicinal products with orphan status, as is the case in the current EU system. Orphan medicines are to be transferred to the UK system. Overall, the orphan criteria would still be based upon the criteria under Article 3 of the Orphan Regulation and the evaluation of compliance with orphan criteria would be conducted in parallel with the review of quality, safety and efficacy of the medicine at the time of the Market Authorisation application, similar to the current framework. Recent EU General Court decisions relating to the operation of the Orphan Regulation will, therefore, still be of use in navigating the law in the United Kingdom in the immediate future.
'Case comment: GMP-Orphan v European Commission' originally published in Bioscience Law Review, Volume 17 Issue 2.
Article co-authored by Shayna-Radhika Patel.