4 December 2018 – EuG, T-329/16 (Bristol-Myers Squibb Pharma/ Commission and EMA), ECLI:EU:T:2018:878, of 5 December 2018

A. Facts

On 17 May 2012, the applicant, Bristol-Myers Squibb Pharma EEIG, submitted to the European Medicines Agency (EMA) an application for the designation of Elotuzumab as an orphan medicinal product indicated for the treatment of multiple myeloma. Multiple myeloma is a serious bone marrow cancer. By decision of the Commission of 9 August 2012, the applicant obtained the designation of the medicinal product Elotuzumab as an orphan medicinal product und Regulation No 141/2000 (‘Reg 141/2000’). The Committee for Orphan Medicinal Products of the EMA (‘COMP’) found that Elotuzumab fulfilled the criteria for designation as an orphan medicinal product according to art. 3 Reg 141/2000.

On 3 July 2015, the applicant submitted to the EMA an application for marketing authorisation (‘MA’) for the medicinal product Empliciti (Elotuzumab) pursuant to Regulation (EC) No 726/2004. Whereas the EMA’s Committee for Medicinal Products for Human Use (‘CHMP’) issued a positive opinion for the grant of an MA, the COMP issued a negative opinion on 18 February 2016, finding that the criterion under art. 3(1)(b) Reg 141/2000 was not satisfied. On 11 April, the EMA confirmed that the negative opinion of the COMP was considered final and would be forwarded to the Commission.

B. Substance

1. Third plea, alleging failure to identify the legal basis and lack of reasoning (para. 47 et seqq.)

The applicant submitted that the decision does not identify the legal basis, which constitutes an infringement of the duty to state reasons and invalidates the decision. The decision failed to mention Reg 141/2000 and referred only to Reg. 726/2004 as a legal basis.

The Court held that the obligation to identify the legal basis of an act is part of the duty to state reasons and is of constitutional significance. The extent of the obligation depends on the nature of the measure in question and on the context in which it was adopted. The statement of reasons must disclose in a clear and unequivocal fashion the reasoning followed by the institution which adopted the measure in such a way as to enable the persons concerned to ascertain the reasons for the measure, so that they can defend their rights and ascertain whether or not the decision is well founded and the European Union judicature to review the lawfulness of the measure. It is not necessary for the reasoning to go into all the relevant facts and points of law, since the question whether the statement of reasons meets the requirements of Article 296 TFEU must be assessed with regard not only to its wording but also to its context and to all the legal rules governing the matter in question.

Where a decision simply confirms the opinion of the EMA, the content of that opinion and of the assessment report are an integral part of the statement of reasons for that decision. The decision at issue complies with Article 296 TFEU in so far as it refers, in its preamble, to the COMP opinion of 8 April 2016, which itself forms an integral part of the statement of reasons for that decision, gives the reasons why the designation of Elotuzumab as an orphan medicinal product had to be withdrawn and expressly refers to Reg. No 141/2000.

2. The first part of the first plea, concerning the fact that the recently authorised medicinal product Kyprolis (Carfilzomib) was taken into account (para. 60 et seqq.)

The applicant claimed that the decision infringed art. 5(12)(b) of Reg. 141/2000 and the principle of proportionality, by taking into account, incorrectly, another medicinal product, namely Kyprolis (Carfilzomib), in the review of the significant benefit criterion under Article 3(1)(b) of that regulation. The applicant maintained that Empliciti (Elotuzumab) should not have been compared with Kyprolis (Carfilzomib), as the latter was granted an MA on 19 November 2015, that is to say, after the development programme for Empliciti (Elotuzumab) had been completed by the applicant with a view to applying for an MA for that medicinal product. Recently authorised medicinal products should not be taken into account when conducting a review under art. 5(12)(b) of Reg. No 141/2000.

It follows that the wording of art. 3(1)(b) of Reg. No 141/2000 and, in particular the phrase ‘that has been authorised in the [European Union]’, as well as the interpretation of this provision given by the Court justify the conclusion that all authorised medicinal products must be taken into account for the purpose of establishing significant benefit. The relevant regulation in the present case does not provide for any exception in that respect. If the legislature had intended to exclude medicinal products authorised after the MA application had been submitted for the medicinal product concerned and before the end of the review of the designation criteria laid down in art. 3(1)(b) of Reg. No 141/2000, it could have done so.

In the present case, the COMP was under a legal obligation to evaluate the potential significant benefit of Empliciti (Elotuzumab) compared with the authorised medicinal product Kyprolis (Carfilzomib). If the COMP had not assessed significant benefit by comparing Empliciti (Elotuzumab) with Kyprolis (Carfilzomib), it would not have been possible to establish, in accordance with art. 5(12) of Reg. No 141/2000, whether the designation criteria set out in art. 3 of the regulation were still met in so far as concerns Empliciti (Elotuzumab).

3. The second part of the first plea, concerning the alleged failure to provide conclusive evidence establishing the lack of significant benefit (para. 76 et seqq.)

The applicant further submitted that the decision at issue infringed art. 5(12)(b) of Reg. No 141/2000 and the principle of proportionality, by relying, incorrectly, on data that did not clearly demonstrate that Empliciti (Elotuzumab) did not provide significant benefit as compared with Kyprolis (Carfilzomib). However, in order to withdraw the orphan designation from Empliciti (Elotuzumab), there would have had to be solid and conclusive evidence that the medicinal product has no significant benefit, which was not the case. The COMP considered that the available data comparing Empliciti (Elotuzumab) and Kyprolis (Carfilzomib) were inconclusive. Therefore, the COMP erred as regards the standard of proof.

The Court held that the responsibility for assessing whether such an application meets the designation criteria lies solely with the COMP, which must issue a scientific opinion on the initial designation. An MA will confer entitlement to market exclusivity only if the COMP has confirmed that the objective designation criteria (art. 3 Reg. 141/2000) are met. In the absence of conclusive evidence proving significant benefit at the time of the MA, the COMP is required to conclude that Commission remove the medicinal product concerned. In order to avoid such removal, the sponsor must provide sufficient data to establish significant benefit. In casu it is clear from the COMP opinion that the applicant did not produce sufficient data to enable it to be established that Empliciti (Elotuzumab) was still of significant benefit to those affected by the condition in question. The available data comparing Empliciti (Elotuzumab) with Kyprolis (Carfilzomib) were conclusive as to the fact that the former medicinal product was not of significant benefit by comparison with the latter. The Court found that the applicant had no valid grounds for criticising the COMP for not basing its decision on conclusive evidence.

4. The third part, alleging the application of an overly rigid test for the assessment of significant benefit (para. 89 et seqq.)

The applicant submitted that the decision at issue infringed art. 5(12)(b) of Reg. 141/2000 and the principle of proportionality by applying, incorrectly, an overly rigid test to assess the significant benefit concerned. The COMP should have: (i) conducted a more global assessment, focusing on all of the evidence that could substantiate its claim of significant benefit; (ii) used the general criterion of benefit for the patient; and (iii) applied a standard of proof that did not require conclusive proof and could allow for estimates and assumptions based on the available data, especially when taking into account the relevant circumstances, including the practical impossibility for the applicant of producing new comparative data.

The Court held that the procedure for the designation of orphan medicinal products was an administrative procedure involving complex scientific assessments. In that area of orphan medicinal products, in most cases the Commission endorses the opinions of the COMP unless it has other adequate sources of information in the field in question. Where the Commission must undertake complex technical and/or scientific assessments, it enjoys broad discretion. As part of its judicial review, the EU Courts only determine

• whether the relevant procedural rules have been complied with,
• whether the facts established by the Commission are correct and
• whether there has been a manifest error of appraisal of those facts or a misuse of powers.

As a consequence, although the COMP’s opinion does not bind the Commission, it is nonetheless extremely important. In the present case, the COMP’s assessment and its opinion of 8 April 2016 comply with the requirements laid down in the legislation governing orphan medicinal products and do not infringe art. 5(12)(b) of Reg. 141/2000. Indeed, it is apparent from that opinion that the COMP applied the criteria for establishing whether there was a significant benefit strictly.

5. The second plea, alleging infringement of Article 5(12)(b) of Regulation No 141/2000, read in conjunction with Article 5(8) of that regulation (para. 106 et seqq.)

The applicant submitted that the mentioned provisions were infringed as no formal Commission decision was taken to withdraw the designation of Elotuzumab as an orphan medicinal product. A formal decision was necessary because: (i) the initial designation was made by means of a decision; (ii) the EMA had no power to take a decision under art. 5(12) of Reg. No 141/2000; and (iii) the 2003 Communication from the Commission confirms that a Commission decision is necessary.

The Court found that even if the decision to withdraw the orphan designation may form part of the decision granting or amending the MA, together in one and the same instrument, that does not mean that the withdrawal decision may take the form of an implied decision. As the decision granting the initial designation, in the present case the Commission’s implementing decision of 9 August 2012, takes an express form, so must the decision withdrawing that designation, so that the withdrawal decision must also take an express form. By failing to adopt the decision withdrawing the orphan designation of Elotuzumab in an express form, the Commission failed to fulfil its duty to comply with the formal requirements for the adoption of the acts concerned in the procedure for the withdrawal of the designation at issue and, in particular, the duty laid down in art. 5(8) of Reg. No 141/2000.

However, the Court found that this is not sufficient to lead to the annulment of the decision at issue. It held that applicants have no legitimate interest in the annulment of a decision on the ground of a procedural defect where annulment of the decision can only lead to the adoption of another decision identical in substance to the decision annulled. Moreover, in casu, the procedural defect established did not infringe the applicant’s rights of defence. The applicant was fully aware of and understood the reasons for the withdrawal of the designation at issue.

The three pleas examined were rejected in their entirety and the action therefore dismissed in its entirety.