CELEX: 62017TJ0733
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

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Procedure and forms of order sought
By application lodged at the Court Registry on 2 November 2017, the applicant brought the present action.
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
).
On 19 January 2018, the Commission lodged its defence.
The parties lodged the reply and the rejoinder on 12 March and 27 April 2018 respectively.
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.
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
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Substance
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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
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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
).
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
).
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
and the case-law cited).
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.
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
).
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.
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.
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.
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.
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’.
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.
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.
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).
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.
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.
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.
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.
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.
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
and the case-law cited).
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.
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.
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.
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.
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.
The first plea must therefore be rejected as unfounded.
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.
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
and the case-law cited).
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.
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.
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.
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
and the case-law cited).
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.
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.
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.
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.
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.
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.
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.
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’.
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.
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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.
The fourth plea must therefore also be rejected as unfounded.
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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.
E. Coulon
Registrar
V. Tomljenović
President
(
*1
)	Language of the case: English.
(
)	Only the paragraphs of the present judgment which the Court considers it appropriate to publish are represented here.