JUDGMENT OF THE GENERAL COURT (Seventh Chamber)
16 May 2019 (*) (1)
(Medicinal products for human use — Article 3(1)(b) of Regulation (EC) No 141/2000 — Definition of ‘significant benefit’ — Availability of orphan medicinal products — Article 5(12)(b) of Regulation No 141/2000 — Commission decision to remove a medicinal product from the Register of Orphan Medicinal Products — Error of assessment — Error of law — Legitimate expectations)
In Case T‑733/17,
GMP-Orphan (GMPO), established in Paris (France), represented by M. Demetriou QC, E. Mackenzie, Barrister, L. Tsang and J. Mulryne, Solicitors,
applicant,
v
European Commission, represented by K. Petersen and A. Sipos, acting as Agents,
defendant,
ACTION pursuant to Article 263 TFEU seeking the partial annulment of Commission Implementing Decision C(2017) 6102 final of 5 September 2017 granting marketing authorisation under Regulation (EC) No 726/2004 of the European Parliament and of the Council for ‘Cuprior-trientine’, a medicinal product for human use, in so far as the Commission decided, in Article 5 of that decision, that that medicinal product no longer satisfied the criteria laid down in Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products (OJ 2000 L 18, p. 1) to be registered as an orphan medicinal product and that the European Union Register of Orphan Medicinal Products should be updated accordingly,
THE GENERAL COURT (Seventh Chamber),
composed of V. Tomljenović, President, E. Bieliūnas and A. Kornezov (Rapporteur), Judges,
Registrar: P. Cullen, Administrator,
having regard to the written part of the procedure and further to the hearing on 13 December 2018,
gives the following
Judgment
Background to the dispute
1 On 19 March 2015, the European Commission adopted a decision by which trientine tetrahydrochloride, sponsored by the applicant, GMP-Orphan (GMPO), was designated as an orphan medicinal product for the treatment of Wilson’s disease and entered into the European Union Register of Orphan Medicinal Products in accordance with Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products (OJ 2000 L 18, p. 1) (‘the 2015 designation decision’).
2 On 7 December 2015, the applicant submitted an application for marketing authorisation in respect of that medicinal product under the name Cuprior — trientine (‘Cuprior’).
3 On 20 September 2016, the applicant also submitted a report to the European Medicines Agency (EMA) and, more specifically, to the Committee for Orphan Medicinal Products provided for in Article 4 of Regulation No 141/2000 (‘the COMP’), on the maintenance of the designation as an orphan medicinal product of Cuprior at the time of granting the marketing authorisation.
4 On 23 May 2017, following an exchange of correspondence between the applicant and the COMP, the latter adopted an opinion in which it concluded that the criteria for designation of the medicinal product Cuprior as an orphan medicinal product, set out in Article 3(1)(b) of Regulation No 141/2000, had not been satisfied on the ground that that product did not provide a significant benefit, in particular in comparison with dihydrochloride trientine (‘the reference product’) which had been granted marketing authorisation in the United Kingdom since 1985.
5 On 30 June 2017, the applicant requested that the COMP’s opinion of 23 May 2017 be revised in accordance with Article 5(7) of Regulation No 141/2000.
6 On 20 July 2017, the COMP adopted a final opinion in which it upheld the conclusions reached in its opinion of 23 May 2017 (‘the final opinion’). In particular, the COMP stated that satisfactory methods of treatment of the condition in question had already been authorised in one Member State of the EU and that the sponsor had not provided sufficient evidence to demonstrate the lack of availability of the reference product in the EU.
7 On 5 September 2017, the Commission adopted Decision C(2017) 6102 final granting marketing authorisation under Regulation (EC) No 726/2004 of the European Parliament and of the Council for Cuprior — trientine, a medicinal product for human use (‘the contested decision’). Article 1 of that decision states that the marketing authorisation provided for in Article 3 of Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (OJ 2004 L 136, p. 1) is granted for the medicinal product Cuprior, the characteristics of which are summarised in Annex I to that decision, and that that medicinal product is to be registered in the European Union register of medicinal products under reference EU/1/17/1199.
8 However, on the basis of the COMP’s final opinion, the Commission decided that the criteria for designation as set out in Article 3 of Regulation No 141/2000 were no longer met in respect of Cuprior and that, therefore, it could not be classified as an orphan medicinal product (recital 4). Consequently, Article 5 of the contested decision states that the ‘medicinal product [Cuprior] shall not be classified as [an] orphan medicinal product’ and that ‘the [European Union] Register of Orphan Medicinal Products should be updated accordingly’.
9 On 12 September 2017, Cuprior was removed from the Register of Orphan Medicinal Products.
Procedure and forms of order sought
10 By application lodged at the Court Registry on 2 November 2017, the applicant brought the present action.
11 On the same day, the applicant made an application for interim measures, which was rejected by order of 23 November 2018, GMPO v Commission (T‑733/17 R, not published, EU:T:2018:839).
12 On 19 January 2018, the Commission lodged its defence.
13 The parties lodged the reply and the rejoinder on 12 March and 27 April 2018 respectively.
14 The applicant claims that the Court should:
– annul Article 5 of the contested decision;
– order the Commission to classify Cuprior as an orphan medicinal product and update the European Union Register of Orphan Medicinal Products accordingly;
– order the Commission to pay the costs.
15 The Commission contends that the Court should:
– dismiss the action as inadmissible in part and, in any event, as unfounded;
– order the applicant to pay the costs.
Law
The second head of claim
16 The Commission argues that the applicant’s second head of claim by which it requests that the Court orders the Commission to classify Cuprior as an orphan medicinal product and to update the European Union Register of Orphan Medicinal Products accordingly is inadmissible. In the Commission’s view, that head of claim fails to comply with Article 266 TFEU and the relevant case-law.
17 The applicant submits that the second head of claim is admissible, since, if the Court were to hold that Cuprior satisfies the designation criteria as an orphan medicinal product, it could then decide that the only decision that the Commission could consequently adopt is to classify Cuprior as an orphan medicinal product and to update the European Union Register of Orphan Medicinal Products.
18 According to the case-law, in the context of a review of legality on the basis of Article 263 TFEU, the Court has no jurisdiction to issue directions to the institutions, bodies, offices and agencies of the European Union, even where they concern the manner in which its judgments are to be complied with. It is for the institution concerned, under Article 266 TFEU, to adopt the measures required to give effect to a judgment delivered in an action for annulment (see judgment of 30 May 2013, Omnis Group v Commission, T‑74/11, not published, EU:T:2013:283, paragraph 26 and the case-law cited).
19 It must be stated that, by its second head of claim, the applicant requests that the Court, in essence, orders the Commission to classify Cuprior as an orphan medicinal product and to update the European Union Register of Orphan Medicinal Products accordingly. Since the Court does not have such jurisdiction, that head of claim must be rejected.
Substance
20 In support of its action, the applicant relies on four pleas in law, alleging, first, an error of law in the interpretation of the term ‘significant benefit’ within the meaning of Article 3(1)(b) of Regulation No 141/2000, second, an error of law and a manifest error of assessment in the application of Article 3(1)(b) of Regulation No 141/2000, third, an error of law and a breach of the principles of protection of legitimate expectations and procedural fairness and, fourth, a manifest error of assessment of the evidence adduced by the applicant.
21 It is appropriate to examine, first of all and together, the first and the fourth plea, since the arguments raised in those pleas overlap and complement each other.
The first and fourth pleas, alleging an error of law in the interpretation of the term ‘significant benefit’ within the meaning of Article 3(1)(b) of Regulation No 141/2000 and a manifest error of assessment of the evidence adduced by the applicant
22 By its first plea, the applicant claims that the COMP and the Commission erred in law by refusing to recognise that possible marketing authorisation for Cuprior as an orphan medicinal product in all Member States could constitute 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 of 27 April 2000 laying down the provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product and definitions of the concepts ‘similar medicinal product’ and ‘clinical superiority’ (OJ 2000 L 103, p. 5) to patients with Wilson’s disease in comparison with the reference product, which is authorised only in the United Kingdom.
23 The applicant maintains that the Communication from the Commission on Regulation (EC) No 141/2000 of the European Parliament and of the Council on orphan medicinal products (OJ 2003 C 178, p. 2; ‘the 2003 Communication’) makes clear that authorisation in all Member States, as opposed only to a limited number of Member States, provides a significant benefit, and that an imminent expectation of an EU-wide marketing authorisation may be sufficient to maintain an assumption of significant benefit. In that regard, the applicant claims that the significant benefit may, in accordance with Article 3(1)(b) of Regulation No 141/2000 and Article 3(2) of Regulation No 847/2000, be either clinical or a major contribution to patient care. The second limb of that definition thus encompasses any development that adds to the ability of physicians to care for patients, provided that it is a sufficiently important development. Accordingly, a substantial increase in the availability of a trientine-based therapy, the only treatment option for some patients with Wilson’s disease, would provide them with a significant benefit in the form of a major contribution to the care they receive. Even if the reference product constitutes appropriate medication for those patients, their needs would not be met, if, as a matter of fact, they do not have access to it. That finding is also apparent from the Guideline on the format and content of applications for designation as orphan medicinal products and on the transfer of designations from one sponsor to another, updated on 27 March 2014 (ENTR/6283/00 Rev 4; ‘the 2014 Guideline’).
24 The fact that, in most Member States, patients may, in principle, have access to the reference product in the context of national schemes adopted pursuant to Article 5(1) of Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (OJ 2001 L 311, p. 67) (‘national importation schemes’) does not suffice, according to the applicant, to preclude the existence of a significant benefit, since, in the framework of those schemes, the use of that product would amount to ‘unlicensed use’. Thus, and by analogy, the 2003 Communication specifies that the off-label use of an authorised medicinal product cannot be considered to be a satisfactory method. Similarly, the COMP’s approach creates unequal access to trientine because the availability of the national importation schemes and the conditions governing their application depend entirely upon the non-harmonised national systems of the Member States. Moreover, taking into account such schemes is inconsistent with the objective of the EU legislature to provide for strict and harmonised marketing authorisation procedures.
25 Consequently, according to the applicant, by failing to have regard to the 2003 Communication and the 2014 Guideline, the COMP concluded arbitrarily that there was no ‘inherent assumption’ of significant benefit where a medicinal product was authorised in a larger number of Member States than the reference product.
26 Lastly, the applicant claims that the COMP disregarded the fact that, even if the reference product could be imported under national importation schemes, there are, in practice, barriers to obtaining that product such as, for example, ‘administrative’ hurdles arising from the lack of a valid marketing authorisation across the EU. The COMP was therefore required to take into account the practical benefits that Cuprior would provide if it was authorised across the EU.
27 By its fourth plea, the applicant claims that the COMP committed a manifest error of assessment in evaluating the evidence put forward by the applicant in the course of the administrative procedure in order to establish that Cuprior provides a significant benefit to patients. This concerns the following evidence:
– long-term studies carried out in Germany on the treatment of patients with Wilson’s disease according to which the proportion of patients requiring treatment with trientine, who experience serious side effects with other treatments available (namely D-penicillamine), is 20 to 30%; a document entitled ‘[European Association for the Study of the Liver] Clinical Practice Guidelines: Wilson's disease’, published in the Journal of Hepatology in 2012, according to which there was a clear impact on the health of those patients because Wilson’s disease can be fatal if not properly treated; and the fact, acknowledged by the COMP in its final opinion, that for some patients, trientine-based medicinal products are the only treatment;
– the results of a survey carried out on the basis of the replies given by national medicinal product regulatory agencies in 26 Member States, 18 doctors from 15 Member States and patient associations from 11 Member States which show that, despite the existence of routes of access to the reference product in nearly all Member States, this does not result in appropriate supply or availability of the medicinal product in question, and the fact, mentioned by doctors and patient associations, that low prescription rates for treatment with the reference product in certain Member States were due to the lack of authorisation for that product, to the fact that it was not reimbursed by national health systems, and to the practical (logistical) difficulties relating to the importation of that product, which show that patients’ needs are unmet, even if, in theory, they may have access to the reference product as a result of national importation schemes.
28 However, according to the applicant, the COMP wrongly rejected that evidence on the sole basis of the information that it had gathered informally from national regulatory agencies.
29 The Commission disputes the applicant’s arguments.
30 First, it should be noted that the procedure relating to orphan medicinal products divides into two separate phases. The first phase covers the designation of the product as an orphan medicinal product; the second covers marketing authorisation for the product that has been designated as an orphan medicinal product and the market exclusivity attaching to it (judgment of 9 September 2010, Now Pharm v Commission, T‑74/08, EU:T:2010:376, paragraph 33).
31 With regard to the procedure for designation as an orphan medicinal product, Article 3 of Regulation No 141/2000 sets out the criteria which a potential product must meet in order to be recognised as an orphan medicinal product. The first assumption of Article 3(1)(b) of Regulation No 141/2000 provides that the sponsor of the orphan medicinal product must in particular establish that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question by the product for which an application for designation as an orphan medicinal product has been made that has been authorised in the European Union. If such a method exists, the legislature has made provision, in the second assumption of Article 3(1)(b) of Regulation No 141/2000, for the designation as an orphan medicinal product of any potential medicinal product for the treatment of the same condition provided its sponsor can establish that the medicinal product will be of significant benefit to patients affected by that condition (judgment of 9 September 2010, Now Pharm v Commission, T‑74/08, EU:T:2010:376, paragraph 34).
32 The term ‘significant benefit’ is defined in Article 3(2) of Regulation No 847/2000 as ‘a clinically relevant advantage or a major contribution to patient care’. In the context of the second assumption of Article 3(1)(b) of Regulation No 141/2000, applicable in the present case, establishing significant benefit takes place in the context of a comparison with an existing authorised medicinal product or method. The ‘clinically relevant advantage’ and the ‘major contribution to patient care’, which enable the potential orphan medicinal product to be described as being of significant benefit, can be established only by comparison with treatments that have already been authorised (see, to that effect, judgment of 22 January 2015, Teva Pharma and Teva Pharmaceuticals Europe v EMA, T‑140/12, EU:T:2015:41, paragraph 64 and the case-law cited).
33 As for the second phase of the procedure, namely that of marketing authorisation for an orphan medicinal product, it starts, where relevant, after the product concerned has been designated as an orphan medicinal product. It is apparent from Article 5(12)(b) of Regulation No 141/2000 that, when reviewing an application for marketing authorisation, it is necessary to ascertain whether the criteria laid down in Article 3 of that regulation are still satisfied. As provided in Article 5(12)(b) of Regulation No 141/2000, a designated orphan medicinal product is to be removed from the Register of Orphan Medicinal Products if it is established before the marketing authorisation is granted that those criteria are no longer met in respect of the medicinal product concerned.
34 Thus, where a sponsor submits an application for marketing authorisation in respect of a designated orphan medicinal product, he triggers at the same time a procedure for re-evaluating the designation criteria. The responsibility for assessing whether the designation criteria have been met lies with the COMP, which must issue an opinion in that regard. In this case, the Commission did not depart from the COMP’s opinion and therefore endorsed the findings of that opinion. Accordingly, the judicial review which falls to the Court must be carried out in respect of all the considerations set out in that opinion, which forms an integral part of the contested decision (see, to that effect, judgment of 5 December 2018, Bristol-Myers Squibb Pharma v Commission and EMA, T‑329/16, not published, EU:T:2018:878, paragraph 98).
35 In the light of the above, it should be pointed out that, in these proceedings, the applicant relies on the second assumption set out in Article 3(1)(b) of Regulation No 141/2000. It therefore recognises that in this case there are satisfactory methods of treatment which have already been authorised in the European Union for patients with Wilson’s disease, including in particular the reference product. It is common ground in that regard, as the applicant confirmed at the hearing, that the reference product is at least as clinically effective as Cuprior and that the application for marketing authorisation for Cuprior was based on pre-clinical tests and clinical trials of the reference product.
36 The applicant essentially submits, in its first plea, that imminent marketing authorisation for Cuprior, valid for the whole of the European Union, constitutes an ‘inherent assumption’ of significant benefit within the meaning of the second assumption of Article 3(1)(b) of Regulation No 141/2000, of Article 3(2) of Regulation No 847/2000, of the 2003 Communication and of the 2014 Guideline, since the reference product is authorised in only one Member State.
37 First, it should be noted in that regard that no provision either in Regulation No 141/2000 or Regulation No 847/2000 provides that marketing authorisation at EU level for an orphan medicinal product constitutes per se a significant benefit in comparison with treatment based on an existing medicinal product, which is as effective and already authorised, albeit in only one Member State.
38 Second, as provided in Article 3(2) of Regulation No 847/2000, the term ‘significant benefit’ is defined as ‘a clinically relevant advantage or a major contribution to patient care’. In this case, as Cuprior does not provide any clinical advantage in comparison with the reference product, it is the assumption of a ‘major contribution to patient care’ on which the applicant relies.
39 It is apparent from that definition that the comparative analysis between the new medicinal product and the reference product must establish not only that the new product provides a benefit to patients and that it contributes to their care, but also that that benefit is ‘significant’ and that that contribution is ‘major’. The expected advantage of that new medicinal product must therefore exceed a certain quantitative or qualitative threshold in order that it may be considered to be ‘significant’ or ‘major’.
40 A sponsor must therefore demonstrate, on the basis of concrete and substantiated evidence and information, that its medicinal product provides a significant benefit, that is to say that it ensures a major contribution to patient care in comparison with the reference product, and is not able to rely in that regard on presumptions or assertions of a general nature.
41 The mere fact that the reference product is authorised in only one Member State does not mean that patients in other Member States do not have legal access to that product and that their needs are unmet. Similarly, the fact that a medicinal product is authorised at EU level does not in itself mean that the medicinal product has, in fact, been made available in all Member States. Indeed, there may also be availability problems with respect to medicinal products authorised at EU level.
42 Third, that conclusion is borne out by the 2003 Communication. It is apparent from Section A.4 thereof that assumptions of significant benefit of a medicinal product as a ‘major contribution to patient care’ are necessarily based on an analysis of concrete evidence in each individual case. More specifically, the assumptions of significant benefit on which the sponsor relies must be ‘supported by available data [or] evidence supplied by the [sponsor]’ (second and third paragraphs) and the sponsor must ‘explain why [the supply or availability problem] results in the unmet needs of patients’ whilst substantiating those claims by ‘qualitative and quantitative references’ (fourth paragraph).
43 Although the fifth paragraph of Section A.4 of the 2003 Communication states that, ‘with respect to potential availability of the product to the [EU] population, a medicinal product that is authorised and available in all Member States may constitute a significant benefit compared with a similar product that is authorised in a limited number of Member States only’, it must be stated that that passage relates to medicinal products which are not only ‘authorised’ but also ‘available’ in all Member States. Moreover, that passage merely states that such a medicinal product ‘may’ constitute a significant benefit. Consequently, although that passage of the 2003 Communication acknowledges that a potential EU marketing authorisation may constitute a significant benefit, this remains only a possibility which must be substantiated, on a case-by-case basis, by concrete evidence, as is apparent also from the aforementioned passages of the 2003 Communication (see paragraph 42 above), and not a mandatory stipulation or a legal presumption.
44 At the hearing, the applicant acknowledged that it cannot rely on the assumption described in the ninth paragraph of Section A.4 of the 2003 Communication either, since that assumption is not applicable to the circumstances of the present case. In this case, the reference product has been authorised on the United Kingdom market since 1985 and thus well before the 2015 designation decision, so that it cannot reasonably be argued that the sponsor of the reference product sought, by the national authorisation in question, to block imminent marketing authorisation for Cuprior. The assumption described in the ninth paragraph of Section A.4 of the 2003 Communication is not therefore applicable to the present case.
45 The applicant nonetheless relies on the 10th paragraph of Section A.4 of the 2003 Communication, according to which ‘the imminent expectation of a [marketing authorisation at EU level] as compared with the existence of a national authorisation [for the same medicinal product] in one or a limited number of Member States may be sufficient to maintain an assumption of significant benefit’. However, even if that paragraph is intended to apply in circumstances other than those described in the ninth paragraph of Section A.4 of the 2003 Communication, circumstances which are not relevant to this case, it is sufficient to note that that paragraph also merely indicates a possibility rather than a mandatory stipulation or a legal presumption.
46 Fourth, the 2014 Guideline also supports that conclusion. Thus, Section D.3 of that document essentially reiterates what is stated in the 2003 Communication. That section acknowledges, on the one hand, that a medicinal product that is authorised in all Member States ‘may’ constitute a significant benefit as compared to a product that is authorised in a limited number of Member States only, but that, on the other hand, justifications provided by the sponsor aimed at establishing the potential increase in supply or availability must be examined in the light of whether these justifications could lead to a clinically relevant significant benefit for patients in all Member States.
47 Fifth, the fact that a medicinal product 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 providing for legal mechanisms in order to enable that product to be imported into their territories. In accordance with recital 30 of Directive 2001/83, it must be possible for a person established in one Member State to receive from another Member State a reasonable quantity of medicinal products intended for his personal use. In that vein, Article 5(1) of Directive 2001/83 provides that a Member State may, in accordance with legislation in force and to fulfil special needs, exclude from the provisions of that directive and thus from the prohibition set out in Article 6(1) thereof medicinal products supplied in response to a bona fide unsolicited order, formulated in accordance with the specifications of an authorised healthcare professional and for use by an individual patient under his responsibility.
48 The Court of Justice has had occasion to point out that it is apparent from all the conditions set out in Article 5(1) of Directive 2001/83, read in the light of the fundamental objectives of the directive, and in particular the objective of seeking to safeguard public health, that the exception provided for in that provision can only concern situations in which the doctor considers that the state of health of his individual patients requires that a medicinal product be administered for which there is no authorised equivalent on the national market or which is unavailable on that market (see judgment of 23 January 2018, F. Hoffmann-La Roche and Others, C‑179/16, EU:C:2018:25, paragraph 57 and the case-law cited).
49 In this case, it is not disputed that there are national importation schemes which enable the reference product to be imported lawfully even if it is not authorised in the Member State of importation. These schemes therefore permit medicines without a granted marketing authorisation in the relevant Member State to be prescribed for use in the treatment of the patients concerned.
50 Contrary to what the applicant claims, in the present case, the use in question, in the framework of those schemes, is not ‘off-label’ use of the reference product, but solely its use in a Member State other than that in which it has been authorised, and precisely in accordance with the actual therapeutic indications for which the reference product has been authorised. The analogy that the applicant seeks to draw between ‘off-label’ use and use in accordance with the therapeutic indications in a Member State other than that in which the reference product has been authorised must therefore fail.
51 The applicant’s argument that the taking into account of such national importation schemes for the purposes of examining whether there is a significant benefit creates unequal access to the reference product because that access is governed by rules, which sometimes differ, applied by each Member State and is therefore inconsistent with the objective of the EU legislature to set up, at EU level, strict and harmonised marketing authorisation procedures must also fail. The relevance of those schemes cannot be denied solely because they have been set up on the basis of an exception, namely that laid down in Article 5(1) of Directive 2001/83, or because the rules governing their application are not harmonised at EU level. Whether those schemes in fact guarantee sufficient and effective access to the reference product is another question entirely and depends on the examination of the particulars of each case, this point being the subject indeed of the fourth plea. Similarly, taking into account such schemes in no way calls into question the centralised procedure at EU level for marketing, but is intended to establish whether, in fact, patients with the condition at issue are able to have access to the reference product.
52 Accordingly, the COMP did not err in law, in its final opinion, on which the Commission based the contested decision, by taking into account the existence of national importation schemes enabling the lawful importation of the reference product.
53 It follows, in the light of all the foregoing considerations, that the fact that a medicinal product may be authorised at EU level does not permit the conclusion or even the presumption that it will be of significant benefit within the meaning of the second assumption of Article 3(1)(b) of Regulation No 141/2000, of Article 3(2) of Regulation No 847/2000, of the 2003 Communication and of the 2014 Guideline, in comparison with the reference product, on the sole ground that the latter is authorised in only one Member State.
54 The first plea must therefore be rejected as unfounded.
55 With respect to the fourth plea, it must be examined whether the contested decision is vitiated by an error of assessment in that the COMP concluded that the evidence adduced by the applicant was insufficient to establish the assumption of a significant benefit. In that regard, the COMP found that the applicant had not sufficiently established the lack of availability of the reference product in the European Union and that, consequently, the assertion that Cuprior would significantly increase the availability of the treatment could not be accepted.
56 In that context, it has been held that, where the Commission must undertake complex technical or scientific assessments, it enjoys broad discretion. In such a situation, judicial review is confined to determining 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 (see judgment of 9 September 2010, Now Pharm v Commission, T‑74/08, EU:T:2010:376, paragraph 111 and the case-law cited).
57 However, in the present case, the Court finds that the COMP’s opinion, on which the contested decision is based, does not undertake complex technical or scientific assessments, but is essentially based on findings of fact regarding the availability within the European Union of the reference product. The judicial review by the Court must therefore be full in the present case.
58 In this instance, first, it should be noted that the COMP conducted its own inquiry relating to the availability of the reference product in the EU Member States. The results of that inquiry revealed that regulatory mechanisms for importing the reference product exist in at least 26 Member States and that that medicinal product could therefore be imported or was in fact imported, in accordance with Article 5(1) of Directive 2001/83.
59 The applicant does not appear to dispute the accuracy of the information thus collected by the COMP in the context of that inquiry. By contrast, it takes issue with the fact that the COMP relied on ‘informal communications’ between members of the COMP and national regulatory authorities. The applicant therefore appears, at least implicitly, to call into question the probative value of that inquiry.
60 It should be pointed out in that regard that, according to settled case-law, the principle which prevails in EU law is that of the unfettered evaluation of evidence and it is only the reliability of the evidence before the Court which is decisive when it comes to the assessment of its value. In addition, in order to assess the probative value of a document, regard should be had to the credibility of the account it contains and, in particular, to the person from whom the document originates, the circumstances in which it came into being, the person to whom it was addressed and whether, on its face, the document appears to be sound and reliable (see, to that effect, judgment of 31 May 2018, Kaddour v Council, T‑461/16, EU:T:2018:316, paragraph 107 and the case-law cited).
61 In the present case, it must be stated that the information gathered in the context of the COMP’s inquiry was from official and reliable sources, namely national regulatory authorities, which have the experience to enable them to assess whether or not there are any supply problems and to know the procedures established for the purposes of importing the reference product. The results of that inquiry were presented in a summary table of 15 June 2016, entitled ‘Availability of trientine in Member States according to COMP members review, EMA/317599/2017’ appended as Annex A.7 to the application, which contains specific and verifiable information, by Member State.
62 Moreover, the COMP is a collective body composed of one member designated by each Member State, three members designated by the Commission to represent patient organisations, three members nominated by the Commission acting on a proposal by the EMA and a Chairman, and one member nominated by the States of the European Economic Area (EEA) (recital 6 of Regulation No 141/2000). The COMP is therefore formed by a college representing all Member States together with patient organisations, thus enabling it to form an opinion on the basis of national experiences acquired by both national regulatory authorities and patient organisations.
63 Consequently, and in the absence of any substantiated argument to the contrary by the applicant, the Court considers that the COMP’s inquiry is of high probative value.
64 Second, as regards the evidence adduced by the applicant before the COMP, the applicant has sought to show that, despite the existence of regulatory pathways for importing the reference product in most Member States, there were ‘logistical and administrative’ obstacles preventing effective access to that product. In that regard, the applicant relied on the results of a survey that it undertook itself on the basis of the replies given by the national medicinal product regulatory agencies of 26 Member States, 18 doctors from 15 Member States and patient associations from 11 Member States. It documented the replies in a summary table, appended as Annex 10 to the application, which places the Member States into three groups, namely those in which availability of the reference product is ‘limited[/absent]’ (7 Member States), those in which availability is ‘moderate’ (4 Member States) and those in which availability is ‘good’ (9 Member States). According to the results of that survey, the availability problems identified in the 11 Member States with ‘limited[/no]’ or ‘moderate’ availability are due to the lack of reimbursement of the reference product and to supply problems.
65 After examining the results of that survey, the COMP reached the conclusion that the survey did not sufficiently show that there were availability problems in respect of the reference product. More specifically, the COMP stated that it could not take account, in the assessment of whether or not there was a significant benefit, of considerations related to lack of reimbursement of the reference product in the Member State of importation. Moreover, according to the COMP, the applicant had not provided any additional evidence capable of proving the existence of objective shortages of supply beyond, on the one hand, the lack of reimbursement in some Member States and, on the other hand, the administrative burden entailed by having to arrange importation.
66 As regards the first type of obstacle, namely obstacles arising from lack of reimbursement of the reference product in the Member State of importation, it should be borne in mind that the reimbursement of a medicinal product by the health systems of the Member States falls within the exclusive competence of the Member States. Thus, the fact that the reference product is authorised only in one Member State does not necessarily mean that it is therefore excluded from any reimbursement by the national health system of the Member State of importation. By way of example, it is apparent from the COMP’s inquiry, mentioned in paragraph 58 above, that the reference product is reimbursed in Germany.
67 Moreover, as the applicant conceded at the hearing, nor does obtaining a marketing authorisation at EU level mean that Cuprior would be reimbursed under national health schemes. Furthermore, the applicant does not provide any material capable of showing that Cuprior would probably be reimbursed by national health systems, or to what extent, once a marketing authorisation at EU level has been obtained for it.
68 As regards the second type of obstacle, on which the applicant relies, namely obstacles of an ‘administrative or logistical’ nature, it must be stated that the applicant’s arguments in that respect are not sufficiently substantiated. The applicant merely cites some examples, that are set out in its survey, which is referred to in paragraph 64 above, according to which there is a requirement in certain Member States to obtain prior authorisation which must be renewed periodically or according to which there are unspecified delays in the supply of the reference product, without however showing that the manner in which the national importation schemes function imposes an unreasonable administrative burden on the patient in terms of waiting times, costs or steps to be taken, which might jeopardise the effectiveness of those programmes and, hence, the timely supply of the reference product. As was noted in paragraphs 39 and 40 above, the sponsor must establish not only that its medicinal product provides a benefit or contributes to patient care, but also that that benefit is ‘significant’ and that that contribution is ‘major’.
69 Moreover, the information gathered by the applicant in its survey must, in any event, be compared with the information which emerges from the COMP’s inquiry, which, as this Court has stated, is of high probative value (see paragraph 63 above). That inquiry does not refer to any significant obstacle to access to the reference product in the Member States concerned.
70 Third, with respect to the applicant’s arguments that, for 20 to 30% of all patients with Wilson’s disease, the only possible treatment is a trientine-based medicinal product and, for those patients, the lack of such treatment may be fatal, as the evidence referred to in the first indent of paragraph 27 above allegedly shows, it is sufficient to observe that it is not disputed that for certain patients the only possible treatment is a trientine-based treatment and that the lack of such treatment could be fatal. However, the COMP correctly observed that those data do not show that there is a lack of availability in the European Union of the reference product, which is as effective in treating those patients, or that those patients are incorrectly treated.
71 Accordingly, the Court considers that the COMP did not make an error of assessment in finding that the sponsor had not provided sufficient supporting information to establish that there was an availability problem and that patients with Wilson’s disease in the European Union were not correctly treated by means of products which have already been authorised, including by regulatory routes of access in accordance with Article 5(1) of Directive 2001/83. Consequently, the contested decision, which endorses the COMP’s final opinion, is not vitiated by an error of assessment either.
72 The fourth plea must therefore also be rejected as unfounded.
The second plea, alleging an error of law or a manifest error of assessment in the application of Article 3(1)(b) of Regulation No 141/2000
73 By its second plea, the applicant claims that the COMP erred in law or committed a manifest error of assessment by finding that Cuprior did not satisfy the requirements laid down in Article 3(1)(b) of Regulation No 141/2000 because the applicant had not established that the insufficient availability of the reference product within the European Union would cause harm to patients. Once the insufficient availability was established in the present case, there was no need to also show that it led to a failure to meet patient needs or caused patient harm.
74 The Commission disputes the applicant’s arguments.
75 It must be stated in that regard that the applicant’s arguments in support of its second plea are based on the premiss that it has demonstrated the insufficient availability of the reference product in the EU and that it cannot be required to show, in addition, that that insufficiency causes patient harm. However, that premiss has not been proved in the present case, as is apparent from the Court’s analysis of the first and fourth pleas. The second plea of the action is therefore ineffective.
76 In any event, as is apparent from paragraph 32 above, in accordance with Article 3(2) of Regulation No 847/2000, the term ‘significant benefit’ means inter alia a ‘major contribution to patient care’. It follows that the expected contribution of the medicinal product in question must always be assessed by reference to the care needed by patients. Thus, if an alleged increase in the availability of a medicinal product does not result in patients’ real needs being met or, conversely, if the current state of supply causes no harm to patients, the assumption of a significant benefit is not established.
77 The second plea must therefore be rejected.
The third plea, alleging an error of law and a breach of the principles of protection of legitimate expectations and procedural fairness
78 The applicant claims that, by relying on the Commission notice of 18 November 2016 on the application of Articles 3, 5 and 7 of Regulation No 141/2000 on orphan medicinal products (OJ 2016 C 424, p. 3, ‘the 2016 Notice’), instead of the 2003 Communication, whereas the 2016 Notice was not applicable ratione temporis either to the application for marketing authorisation filed on 7 December 2015, or to the report on the maintenance of the designation as an orphan medicinal product in respect of Cuprior submitted on 20 September 2016, the COMP erred in law and infringed the principles of protection of legitimate expectations and procedural fairness.
79 According to the applicant, first of all, unlike the 2016 Notice, the 2003 Communication expressly recognises that a significant benefit could be based on an increase in supply or availability and that a product that is authorised in all Member States may constitute a significant benefit in comparison with a product that is authorised in only one Member State. Next, by requiring the applicant to establish the existence of ‘patient harm’, the COMP actually applied the 2016 Notice which alone refers to such a requirement. Lastly, the COMP adopted an overly restrictive approach to the evidence that the applicant should adduce to establish ‘objective supply shortages’ or a ‘systematic shortage’, thus disregarding the letter and spirit of the 2003 Communication. By contrast, the COMP should have required only that the applicant establish that the assumptions which resulted in the initial designation of trientine tetrahydrochloride as an orphan medicinal product remain valid and had not changed at the time of the application for marketing authorisation.
80 The Commission disputes the applicant’s arguments.
81 In the first place, as regards the argument alleging the error of law that the COMP allegedly committed by actually applying the 2016 Notice instead of the 2003 Communication, it should be pointed out at the outset that it was the 2003 Communication which was in force on the date of the application triggering the marketing authorisation procedure for Cuprior, filed on 7 December 2015, and at the time of submission of the report on the maintenance of the designation as an orphan medicinal product of that medicinal product, submitted on 20 September 2016. Since the 2016 Notice, which replaces the 2003 Communication, was published in the Official Journal of the European Union on 18 November 2016, the COMP was entitled to take it into consideration only after that date. The 2003 Communication is therefore applicable ratione temporis to the present case.
82 However, the Court notes that the COMP made no reference whatsoever to the 2016 Notice in its final opinion. Moreover, there is nothing to suggest that the COMP applied the 2016 Notice implicitly.
83 According to Section B.5 of the 2016 Notice, significant benefit should not be based on ‘possible increased supply [or] availability due to shortages of existing authorised products or to existing products being authorised in only one or a limited number of Member States. (Exceptions may be made if the sponsor has evidence of patient harm)’.
84 In that regard, first of all, it must be stated that, in its final opinion, the COMP concluded not that significant benefit could not be based on the fact that the reference product was authorised only in one Member State, unless patient harm was proved — which might suggest that the COMP had actually applied the 2016 Notice — but that the applicant had not demonstrated the existence of an availability problem in respect of the reference product.
85 Next, the mere fact that, in its final opinion, the COMP states that the applicant failed to prove the existence of patient harm, a factor referred to in the 2016 Notice, does not mean that the COMP applied that notice, since, as is stated in paragraph 76 above, the term significant benefit is to be assessed, in any event, by reference to the care which patients actually need.
86 Lastly, the applicant’s argument based on the fact that, in a provisional position of 11 April 2017 (document EMA/COMP/453124/2016, appended as Annex A.8 to the application), the COMP mentioned that, ‘in the light of the upcoming changes in the acceptability of the arguments of limited availability in the new “Notice to Applicants” from the European Commission, the committee should discuss if this aspect of major contribution to patient care in this maintenance procedure shall still be accepted’ cannot succeed. In that passage, the COMP does not refer to the 2016 Notice. Moreover, that passage appears in a document which contains only a provisional opinion which merely states that the COMP should further discuss the abovementioned issue and that, therefore, no final position had been adopted in that regard.
87 In any event, by that argument, the applicant is in actual fact suggesting that if the COMP had adhered to the 2003 Communication, the conclusion that it would have reached would have been different. However, as is apparent from the analysis in paragraphs 35 to 71 above, the contested decision is not vitiated by any error of law and of assessment as regards the interpretation and application in the present case of the term ‘significant benefit’ within the meaning in particular of the 2003 Communication. Accordingly, the applicant’s argument that the COMP wrongly applied the 2016 Notice instead of the 2003 Communication must be considered ineffective.
88 In the second place, it should be borne in mind that Article 5(12)(b) of Regulation No 141/2000 provides for the possibility of removing a designated orphan medicinal product from the EU Register of Orphan Medicinal Products if it is established before the marketing authorisation is granted that the designation criteria are no longer met. According to Section B.2.1 of the 2003 Communication, ‘the sponsor is requested to inform the [EMA] and to submit a report on the criteria that led to the designation of the product as an orphan medicinal product and updated information on the current fulfilment of these criteria’. Section D.3 of the 2014 Guideline also states that the level of evidence or data required by the COMP at that stage of the procedure will be ‘higher … than at the time of designation’.
89 It follows that the COMP was entitled and was even obliged, to re-examine the designation criteria at the stage of the application for marketing authorisation. At the end of that review, the COMP may reach a conclusion different from that which led it to accept the designation of the medicinal product as an orphan medicinal product. Otherwise, the marketing authorisation procedure would be meaningless.
90 Accordingly, the applicant cannot reasonably complain that the COMP reached a conclusion different from that which it had adopted when it accepted the designation of the product as an orphan medicinal product, particularly since, as is stated in paragraph 88 above, at the stage of the application for marketing authorisation, the level of evidence and data required is higher than at the time of the initial designation.
91 In the third place, as regards the alleged infringement of the principle of protection of legitimate expectations, it should be recalled that the protection of legitimate expectations extends to any person with regard to whom an institution of the European Union has given rise to justified hopes and that a person may not plead a breach of that principle unless the administration has given him precise assurances (see order of 4 July 2013, Menidzherski biznes reshenia, C‑572/11, not published, EU:C:2013:456, paragraph 30 and the case-law cited).
92 In whatever form it is given, information which is precise, unconditional and consistent and comes from authorised and reliable sources constitutes assurances capable of giving rise to such hopes (see judgment of 14 March 2013, Agrargenossenschaft Neuzelle, C‑545/11, EU:C:2013:169, paragraph 25 and the case-law cited).
93 Also according to the case-law, economic operators are not justified in having a legitimate expectation that an existing situation which is capable of being altered by the EU institutions in the exercise of their discretionary power will be maintained (judgment of 29 November 2016, T & L Sugars and Sidul Açúcares v Commission, T‑103/12, not published, EU:T:2016:682, paragraph 150).
94 Neither the COMP nor the Commission had at any time provided the applicant with precise assurances that Cuprior would obtain marketing authorisation or that it would be maintained on the list of orphan medicinal products. In particular, the 2015 designation decision was not capable of giving rise to a legitimate expectation on the part of the applicant that that designation would necessarily be followed by the maintenance of such a designation for the medicinal product at issue and by the award of marketing authorisation.
95 Lastly, since the applicant puts forward no independent argument in support of the complaint alleging breach of the principle of ‘procedural fairness’, it is not necessary to respond separately to that complaint. In any event, it should be pointed out that the applicant was afforded the opportunity to submit its observations on all the matters that the COMP had indicated to be relevant prior to the adoption of the final opinion.
96 Consequently, the third plea must be rejected as unfounded.
97 In the light of all the foregoing, the action must be dismissed in its entirety.
Costs
98 Under Article 134(1) of the Rules of Procedure of the General Court, the unsuccessful party is to be ordered to pay the costs if they have been applied for in the successful party’s pleadings. Since the applicant has been unsuccessful, it must be ordered to pay the costs, including those incurred in the proceedings for interim measures, in accordance with the form of order sought by the Commission.
On those grounds,
THE GENERAL COURT (Seventh Chamber)
hereby:
1. Dismisses the action;
2. Orders GMP-Orphan (GMPO) to pay the costs, including those incurred in the proceedings for interim measures.
Tomljenović | Bieliūnas | Kornezov |
Delivered in open court in Luxembourg on 16 May 2019.