The first European judgments regarding Orphan Medicinal Products

31 January 2011

Mary Smillie


The first judgments considering Orphan Drugs on a European level were handed down by the General Court on 9 September 2010.

The Orphan Medicinal Products Regulation No 141/2000 (“the Regulation”) was adopted on 16 December 1999 to make effective treatments available for patients suffering from rare diseases in the European Union.  The Regulation establishes a regime of incentives and rewards for the development of orphan drugs.  An applicant submits the application for orphan designation to the European Medicines Agency (EMA), and the Committee on Orphan Medicinal Products (COMP) reviews the application to see whether the application meets the requirements to be designated as an orphan drug. 

The criteria which must be met are set out in Article 3(1) of the Regulation:

‘A medicinal product shall be designated as an orphan medicinal product if its sponsor can establish:

(a) that it is intended for the diagnosis, prevention or treatment of a life‑threatening or chronically debilitating condition affecting not more than 5 in 10 000 persons in the Community when the application is made, or
that it is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition in the Community and that without incentives it is unlikely that the marketing of the medicinal product in the Community would generate sufficient return to justify the necessary investment; and

(b) that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorised in the Community or, if such method exists, that the medicinal product will be of significant benefit to those affected by that condition.’

If the COMP decides that the application does not meet the criteria, the EMA informs the applicant who can appeal the decision which is referred back to the COMP.  The EMA then submits the final opinion of the COMP to the Commission, who have 30 days to issue the final decision to state whether or not orphan status is granted.

If it is granted the medicinal product is entered in the Community Register of Orphan Medicinal Products.  The applicant can then proceed with its Marketing Authorisation application (which is mandated to use the Centralised Procedure) to the EMA and get the advantages that orphan status confers such as reduced fees, free scientific advice and ten years Market Exclusivity.

The two judgments handed down by the General Court on 9 September 2010 concerned challenges to decisions made by the Commission in 2007.

Case T-74/08 Now Pharm AG v European Commission

Now Pharm AG (Luxembourg) developed the product “Chelidonii radix special liquid extract” branded “Ukrain” for the treatment of cancer of the pancreas.  It was first produced in 1975.  It is administered intravenously and reportedly accumulates selectively in the primary tumour and the metastases.  As a result of auto-fluorescence under UV light, it is thus said to be able to help distinguish between healthy tissue and malignant tissue during laser treatment/surgery.  A Marketing Authorisation application for Ukrain was refused by Austria in 2002.

An application for orphan designation was submitted to the EMA on 6 February 2007.  Following the procedure, the Commission followed the EMA’s opinion and adopted its decision on 4 December 2007 not to give an orphan designation.  The negative opinion was based on the finding that satisfactory methods of treatment of pancreatic cancer have been authorised in the Community and the sponsor did not demonstrate that this treatment would significantly benefit those affected by the condition, over currently authorised treatments, neither through a clinically relevant advantage in terms of efficacy or safety nor through a significant contribution to patient care.

In deciding on the challenge to this decision by Now Pharm, the General Court considered that broad discretion must be given to the Commission where decisions are taken on technical evaluations involving complex scientific data.  The role of the Court is to verify that the Commission has followed the rules of procedure, has not made an error in assessment of the facts and has not misused its powers.  The opinion of the COMP is not binding on the Commission, but it has decisive importance.  The results of four published studies had been discussed but were considered to have methodological problems.  Therefore the Commission considered that the assertion by the applicant of a significant treatment benefit was not sufficiently supported by the evidence available.  There were doubts about the plausibility of the published data.  The Commission sought further information from the authors of the clinical studies on methodology and results.  The COMP sought the opinion of two experts at the appeal stage, who agreed with the conclusions made.

The Court, rejecting the challenge to the Commission’s decision, concluded that it was futile for the applicant before it to reiterate its view that Ukrain conferred a significant benefit when the COMP and both experts consulted during the initial procedure and appeal found that the four studies relied on had serious methodological problems.  By doing so the applicant had not demonstrated that the Commission had made a manifest error.

Case T-264/07 CSL Behring GmbH v European Commission and the EMA

CSL Bering GmbH applied for orphan status of its medicinal product “human fibrinogen” on 13 March 2007.  CSL Bering already had marketing authorisations (MAs) approved for this product in Germany (1966), Portugal (1978), Czech Republic and Austria (1994), the Netherlands (1997), Hungary (1998) and Romania (1999). 

The EMA sent CSL Bering a letter within seven days to say that the application was invalid for a number of reasons but particularly because of the MAs that it already held.  The applicant and EMA met to discuss the problem in more depth and a new application was submitted to which the EMA again replied promptly to say that the second application was invalid because the applicant already held MAs for the product. The applicant did not claim that the product was of significant benefit, and the indication in the orphan drug application was identical to that authorised in the MAs already held by it. 

In challenging the Commission decision before the General Court CSL Bering put forward two pleas to establish that the contested decision was unlawful.  The first is that Article 5(1) of the Regulation had been incorrectly interpreted and second that Article 5(1) of the Regulation and Article 2(4)(a) of its implementing Regulation, Commission Regulation No 847/2000, (“the Implementing Regulation”), were unlawful. 

As to the first ground, Article 5(1) of the Regulation requires that “in order to obtain the designation of a medicinal product as an orphan medicinal product, the sponsor shall submit an application to the Agency (EMA) at any stage of the development of the medicinal product before the application for marketing authorisation is made”.  The Court held accordingly that if the medicinal product for which an application for designation as an orphan medicinal product already has a MA, it cannot be designated as an orphan medicinal product for the same indication.  However, Article 5(1) in no way prevents an application for designation as an orphan medicinal product for a medicinal product which already had MA being submitted in respect of a new therapeutic indication. 

As to the second ground, Article 2(4)(a) of the Implementing Regulation expressly permits an application for orphan designation of a medicinal product which has already been authorised if the application concerns a new therapeutic indication.  The five arguments that Article 5(1) of the Regulation and Article 2(4)(a) of the Implementing Regulation are unlawful that were put forward (infringement of property rights, impairment of freedom to pursue a trade or profession, lack of justification for that infringement of property rights, and impairment of freedom to pursue a trade or profession and infringement of the principle of equal treatment and infringement of the principle of protection of legitimate expectations) were all rejected by the Court.

Regarding the infringement of property rights argument the Court said at paragraph 100: “In the present case, the fact that it may become impossible for the applicant to make use of its right to use the procedure for mutual recognition in a situation where a competing undertaking obtains market exclusivity for an improved medicinal product is a possible consequence of the implementation of Regulation No 141/2000. Nevertheless, such a consequence can in no way be regarded as impairing the very substance of the property right or of the freedom to pursue a trade or profession. The restriction on the economic exploitation of human fibrinogen developed more than 40 years ago by the applicant does not represent a disproportionate or intolerable sacrifice when compared with the objectives of public interest pursued by the European Union legislature.”

The Court concluded on the issue of protection of legitimate expectations that “a prudent and discriminating trader must be in a position to foresee that, in a field such as that of the research and development of effective treatments for patients suffering from rare diseases, the European legislature may be called upon to encourage research, inter alia, by way of an award of market exclusivity to a pharmaceutical undertaking which has developed the treatment with the most significant benefit”. 


The Court in upholding the decisions of the EMA and the Commission has made it clear that the aim of the Regulation is to give incentives, which includes the significant incentive of 10 years market exclusivity for the indication, to companies who are developing innovative therapies to treat patients with rare diseases.  A product receiving orphan status must be of significant benefit to those patients suffering from the disease over existing therapies. 

The Court has made it clear that the Regulation is not intended for old products, other than where a new indication for an existing product is discovered, nor to give additional protection to existing MA holders.