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Shire v EMA: Has the CJEU adopted another 'evergreen' orphan?

Peter O’Sullivan obtained a first class honours BCL and LLM from UCC, and is currently pursuing an BPharm/MPharm Degree in UCC. He has previously been published regarding online selling in the King’s Inns Law Review (Vol. VI) and Emergency Medicines in COLR. His LLM research focused on the regulation of internet pharmacy in the EU. In this letter, he considers the recent CJEU ruling in Shire, which pertains to orphan designations of medicinal products.

A fully referenced article is available here.


Dear Editor,

On 29 July, the Court of Justice of the European Union (CJEU) upheld the General Court’s ruling that new medicinal products containing the same ‘active substance’ as existing orphan medicines are entitled to their own separate ten year market exclusivity, if they satisfy the criteria under the Orphan Regulation. The judgments explain substantive provisions of the legislation and the European Medicines Agency’s (EMA) role in applying them.

In this case, the EMA refused to validate Shire’s 2015 application for orphan designation of ‘Idursulfase-IT’. This is an intrathecal version of idursulfase designed for patients suffering from a severe form of Hunter Syndrome with accompanying ‘cognitive disorders’. The EMA argued that the application was too late because a ‘general’ orphan designation for idursulfase (2001) for Hunter Syndrome, and a market authorisation (MA) for Elaprase® (2007 intravenous formulation), had already been granted to Shire. To decide otherwise would infringe Elaprase® MA under Article 5(1) of the Orphan Regulation.

In dismissing the appeal, the CJEU affirmed the position that when validating orphan designation applications, the remit of the EMA, in verifying whether the same medicinal product is already the subject of MA, is ‘purely administrative’ in scope (per Article 5(1) and Article 5(4)). Under Article 5(2) of the Orphan Regulation, the EMA is supplied with ‘two categories’ of information from the sponsor to assist them in their determination:

1) Article 5(2)(a)-(c): name of sponsor, active ingredient, and proposed therapeutic indication.

2) Article 5(2)(d): justification that criteria in Article 3(1) are satisfied. In this case, Article 3(1)(b) is of relevance, as it requires the sponsor to establish that the medicinal product in question is for an orphan condition for which there is no satisfactory authorised treatment or, if such treatment exists, that the medicinal product will be of ‘significant benefit’ compared to authorised treatment. In the latter situation, the sponsor must also establish that the second medicinal product is not ‘identical’ to the first.

The EMA argued that, in assessing whether a medicinal product was ‘identical’, it was confined to the ‘exhaustively defined….simple and unequivocal criteria’ of ‘active substance’ and ‘indication’, i.e. category one above. The Court considered that limiting the identity of a medicinal product to these criteria would be insufficient grounds to refuse an orphan designation. The General Court’s position that ‘medicinal product’ and ‘active substance’ are distinct concepts (the latter being a component of the former), and are afforded individual legal definitions under the Medicinal Product’s Directive 2001/83, was reiterated. As a result, ‘all other relevant factors’ must be accounted for when the EMA is making an assessment on a ‘medicinal product’, and not merely the above two criteria. This view was in light of the ‘combined reading’ of Article 5(2) and 3(1) which requires a sponsor to provide evidence of lack of sameness and a ‘significant benefit’.

A key issue before the Courts is who determines whether a medicinal product provides a ‘significant benefit’. The Court held that, given the ‘technical and scientific nature’ of this criterion, it is the Committee for Orphan Medicinal Products (COMP) who is allocated this exclusive competence under Article 4 and 5(5)-(7) of the Orphan Regulation. The consequence of this for a case such as Shire, is that when ‘significant benefit’ is claimed, the characterisation of what constitutes the ‘identity’ of a medicinal product is extended to the purview of COMP and not to the EMA. As a result, provided the conditions under Article 5(1) and (2) above are satisfied, the EMA is obliged to validate an application and furnish it to the COMP.

In dismissing the last ground of appeal as unfounded, the Court agreed with the lower court that the definition of ‘medicinal product’ under Article 1(3b) of Medicinal Product’s Directive encompasses excipients as well as active substance. The factual findings that Elaprase® and Idursulfase-IT are different ‘medicinal products’ based on their ‘composition, method of administration and therapeutic effect’ was not subject to the review by the CJEU.

It is unfortunate, in this author’s view, that concerns regarding potential misuse in granting an additional ten year market exclusivity were not appealed before the CJEU. The concern raised before the General Court was that companies may be incentivised to strategically delay releasing their improved products before the original product’s exclusivity expires in an effort to ‘evergreen’ their monopoly. This would be contrary to the Regulation’s purpose of incentivising innovation in rare diseases. The General Court was not persuaded, and strictly applied the provisions of the Regulation to dismiss this argument. The General Court relied on the controversial Teva ruling, where generic entry was refused because Novartis was granted an independent exclusivity period for a similar medicinal product covering the same indication as its previous reference medicine. Article 8(3)(a) allows for derogation when similar orphan medicines are permitted MA where consent from the MA holder is obtained. In both Shire and Teva the Courts opted for robust interpretations of the legislation which may result in situations where companies are rewarded for shrewdly overcoming legal hurdles as opposed to innovative endeavours.

In 2016, the Council of Europe noted the following potential concerns regarding the current orphan regime:

the increasing trend of MA of new medicinal products for small indications, including, in some cases, the authorisation of a single product for ‘segmented’ patient groups within a disease area, and the authorisation of one substance for several rare diseases, and in this respect notes with concern that companies may seek very high prices while the added value of some of these products is not always clear.

While Shire is a welcome decision in terms of incentivising further research by pharmaceutical companies into enhancing their own medicinal products, it may also have the unintended consequence of fostering an environment where pharmaceutical companies stratify their patient populations in an effort to extend their market exclusivity period in an ‘evergreen’ manner. While the COMP is tasked with zealously preventing such ‘artificial’ categorisation attempts, it is conceivable that, in light of the narrative in Shire, some of these attempts may not be preventable.

Is mise le meas,

Peter O’Sullivan

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