CELEX: 62018CJ0359
Appeal
Regulation (EC) No 141/2000
Orphan medicinal products
Article 5
Application for designation of a medicinal product as an ‘orphan medicinal product’
Validation
Existence of a prior marketing authorisation (MA) for the same medicinal product

By its appeal, the European Medicines Agency (EMA) asks the Court to set aside the judgment of the General Court of the European Union of 22 March 2018,
Shire Pharmaceuticals Ireland
v
EMA
(T‑80/16, not published; ‘the judgment under appeal’, EU:T:2018:165), whereby the General Court annulled the decision of the EMA of 15 December 2015 to refuse to validate the application submitted by Shire Pharmaceuticals Ireland Ltd (‘Shire’) for the designation of Idursulfase-IT as an orphan medicinal product (‘the contested decision’).

Legal context

Regulation No 141/2000
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), as amended by Regulation (EC) No 596/2009 of the European Parliament and of the Council of 18 June 2009 (OJ 2009 L 188, p. 14) (‘Regulation No 141/2000’), lays down procedures for the designation of medicinal products as orphan medicinal products and for the marketing authorisation (MA) of such products.
Recital 4 of that regulation provides:
‘orphan medicinal products eligible for incentives should be easily and unequivocally identified; it seems most appropriate to achieve this result through the establishment of an open and transparent Community procedure for the designation of potential medicinal products as orphan medicinal products’.
Article 3(1) of that regulation is worded as follows:
‘A medicinal product shall be designated as an orphan medicinal product if its sponsor can establish:
(a)      that it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in 10 thousand persons in [the European Union] when the application is made, or
that it is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition in [the Union] and that without incentives it is unlikely that the marketing of the medicinal product in [the Union] would generate sufficient return to justify the necessary investment;
and
(b)      that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorised in [the Union] or, if such method exists, that the medicinal product will be of significant benefit to those affected by that condition.’
Article 5 of Regulation No 141/2000 states:
‘1.      In order to obtain the designation of a medicinal product as an orphan medicinal product, the sponsor shall submit an application to the [EMA] at any stage of the development of the medicinal product before the [MA] is made.
2.      The application shall be accompanied by the following particulars and documents:
(a)      name or corporate name and permanent address of the sponsor;
(b)      active ingredients of the medicinal product;
(c)      proposed therapeutic indication;
(d)      justification that the criteria laid down in Article 3(1) are met and a description of the stage of development, including the indications expected.
3.      The Commission shall, in consultation with the Member States, the [EMA] and interested parties, draw up detailed guidelines on the required format and content of applications for designation.
4.      The [EMA] shall verify the validity of the application and prepare a summary report to the Committee. Where appropriate, it may request the sponsor to supplement the particulars and documents accompanying the application.
5.      The [EMA] shall ensure that an opinion is given by the Committee within 90 days of the receipt of a valid application.
6.      When preparing its opinion, the Committee shall use its best endeavours to reach a consensus. If such a consensus cannot be reached, the opinion shall be adopted by a majority of two-thirds of the members of the Committee. The opinion may be obtained by written procedure.
7.      Where the opinion of the Committee is that the application does not satisfy the criteria set out in Article 3(1), the [EMA] shall forthwith inform the sponsor. Within 90 days of receipt of the opinion, the sponsor may submit detailed grounds for appeal, which the [EMA] shall refer to the Committee. The Committee shall consider whether its opinion should be revised at the following meeting.
…’
Article 8 of that regulation sets out the conditions under which an MA may be granted to a medicinal product similar to an orphan medicinal product and states that the Commission is to determine, by means of an implementing regulation, the definition of a ‘similar medicinal product’.

Regulation (EC) No 847/2000
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) provides.
‘For the purposes of the implementation of Article 3 of Regulation (EC) No 141/2000 on orphan medicinal products, the following definition shall apply:
–        “significant benefit” means a clinically relevant advantage or a major contribution to patient care.’

Directive 2001/83
Article 1(2) and 3a 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), as amended by Directive 2011/62/UE of the European Parliament and of the Council of 8 June 2011 (OJ 2011 L 174, p. 74) (‘Directive 2001/83’), define the concepts of ‘medicinal product’ and ‘active substance’ as follows:
‘2.      Medicinal product:
(a)      Any substance or combination of substances presented for treating or preventing disease in human beings; or
(b)      Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.
…
3a.      Active substance: Any substance or mixture of substances intended to be used in the manufacture of a medicinal product and that, when used in its production, becomes an active ingredient of that product intended to exert a pharmacological, immunological or metabolic action with a view to restoring, correcting or modifying physiological functions or to make a medical diagnosis.’

Background to the dispute and the contested decision
It is apparent from paragraph 9 of the judgment under appeal that the main reason for the EMA’s adoption of the contested decision was that Shire’s application for the designation of Idursulfase-IT, the active substance of which is idursulfase, as an orphan medicinal product for the treatment of Hunter syndrome, did not comply with Article 5(1) of Regulation No 141/2000.
The EMA stated that the active substance idursulfase obtained designation as an orphan medicinal product for the treatment of Hunter Syndrome in 2001, and that an MA as an orphan medicinal product for Elaprase, containing that active substance, had been issued in January 2007 for the treatment of patients suffering from Hunter Syndrome.

The procedure before the General Court and the judgment under appeal
By an application lodged at the Registry of the General Court on 23 February 2016, Shire brought an action seeking the annulment of the contested decision.
In support of its appeal, Shire relied on a single plea in law, claiming infringement of Regulation No 141/2000.
By the judgment under appeal, the General Court upheld that plea in law and annulled the contested decision.

Forms of order sought by the parties before the Court
The EMA claims that the Court should:
–        set aside the judgment under appeal;
–        dismiss the action for annulment as being unfounded, and
–        order Shire to pay the cost of proceedings, including those incurred in the procedure before the General Court.
Shire contends that the Court should:
–        dismiss the appeal; and
–        order the EMA to pay the costs.
The European Commission claims that the judgment under appeal should be set aside, the action for annulment should be dismissed and Shire ordered to pay the costs.

The appeal

The first ground of appeal, alleging infringement of Article 5 of Regulation No 141/2000

Arguments of the parties
By the first part of its first ground of appeal, the EMA claims that the General Court, in paragraph 51 of the judgment under appeal, erred in law by interpreting separately rather than together Article 5(1) and (2) of Regulation No 141/2000. That error of law undermines the effectiveness of the provision.
The EMA considers that Article 5(1) of Regulation No 141/2000 places on it an obligation to check whether an application for designation as an orphan medicinal product is already covered by an earlier application for an MA. Article 5(2) of that regulation sets out a list of documents to be submitted for that purpose. The aim of that provision is to enable the EMA Secretariat to verify that the application for designation contains sufficient information for its scientific assessment by the Committee for Orphan Medicinal Products (‘COMP’) on the basis of easily applied criteria.
That interpretation is supported by recital 4 of Regulation No 141/2000 which states that ‘orphan products eligible for incentives should be easily and unequivocally identified’. The purpose of the term ‘eligible for’ is to determine whether a medicinal product can obtain orphan designation. That designation is reserved for medicinal products which have not been the subject of a previous MA application. It is essential that the EMA Secretariat is guided by an exhaustively defined set of simple and unequivocal criteria. Such criteria are those set out in Article 5(2) of Regulation No 141/2000.
The interpretation adopted by the General Court is problematic having regard to the above. In order to circumvent Article 5(1) of Regulation No 141/2000, it would be sufficient for a company to allege inconsequential differences between the product included in the application for designation and a medicinal product for which an MA application had previously been lodged.
The EMA claims that the General Court erred in appearing to accept, in paragraphs 62 and 64 of the judgment under appeal, that the excipients and the method of administration should be taken into account when examining the risk of an overlap with Article 5(1) of Regulation No 141/2000. According to the EMA, the General Court’s interpretation would lead to such differences making it possible to validate an application for designation as an orphan medicinal product. The EMA Secretariat cannot be expected to check whether medicinal products are to be considered to be identical on the basis of criteria that are not laid down in EU legislation.
By the second part of its first ground of appeal, the EMA claims that the General Court erred in law, in paragraphs 58 and 64 of the judgment under appeal, by taking the concept of a ‘medicinal product’ defined in Article 1(2) of Directive 2001/83 as the relevant test in order to determine whether there is any overlap between an application for designation as an orphan medicinal product and a previous MA application. That interpretation is contrary to Article 5(1) and (2) of Regulation No 141/2000, from which, read together, it is clear that the relevant criteria for assessing whether an application for designation impinges on a previous MA application are the name of the sponsor, the active substance and the proposed therapeutic indication.
The concept of ‘medicinal product’, defined in Article 1(2) of Directive 2001/83, serves to determine which products fall within the scope of that directive. The validation procedure that is the subject of Article 5(1) of Regulation No 141/2000 has a different objective, namely to determine whether there is an overlap between an application for designation of an orphan medicinal product and a previous MA application. It is not therefore appropriate to refer to the definition of the concept of ‘medicinal product’, derived from Directive 2001/83, but to define the concept of ‘sameness’ by referring to the legal instruments to which that concept is relevant.
According to the EMA, it is important not to conflate the notions of ‘sameness’ and ‘similarity’ of medicinal products. Whereas the former is used in the context of the validation procedure laid down in Article 5(1) of Regulation No 141/2000, and must meet the criteria of Article 5(2) of that regulation, the latter is used for the purposes of Article 8 of that regulation and was defined by Regulation No 847/2000.
Shire disputes those arguments.
The Commission maintains that the first ground of appeal is well founded.

Findings of the Court
In order to give a ruling on both parts of the first ground of appeal, it must be recalled that, when an application for the designation of a medicinal product as an orphan medicinal product is submitted to it, the EMA is required to verify its validity, under Article 5(4) of Regulation No 141/2000. That verification concerns compliance with the conditions laid down in Article 5(1) and (2) of that regulation.
Under Article 5(1) of Regulation No 141/2000, an application for designation of a medicinal product as an orphan medicinal product must be submitted to the EMA ‘before the [MA application] is made’ for the same medicinal product. It is therefore precluded that a medicinal product for which an MA application has previously been lodged can be the subject of an application for designation as an orphan medicinal product.
Article 5(2) of Regulation No 141/2000 requires two categories of information to be supplied in support of the application for designation. The first of these, under subparagraphs (a) to (c) of that provision, relates to the name of the sponsor, the active ingredient of the medicinal product and the proposed therapeutic indication. It thus makes it possible to identify the essential characteristics of the medicinal product in question in order, in particular, to enable the EMA to ensure that that medicinal product has not already been the subject of an application for an MA.
The purpose of the second category of information referred to in Article 5(2)(d) of Regulation No 141/2000 is to establish that the designation criteria in Article 3(1) of that regulation are met. In that regard, that provision requires that the medicinal product for which designation is sought is intended for the diagnosis, prevention or treatment of a condition considered to be orphan and for which there is no satisfactory method already authorised in the European Union or, if there is such a method, that the medicinal product will be of significant benefit to those affected by that condition.
It is thus apparent from a combined reading of Article 3(1) and Article 5(2) of Regulation No 141/2000 that if, for a given therapeutic indication, there is already a medicinal product for which an MA has been issued, the sponsor seeking orphan designation for a further medicinal product in respect of that therapeutic indication must establish that the latter will be of significant benefit to patients in relation to the former medicinal product. Furthermore, in the light of Article 5(1) of Regulation No 141/2000, it is also for the sponsor in such a situation to show that the second medicinal product is not identical to the first medicinal product. In the case of the same medicinal product, the consequence of the rule laid down in Article 5(1) of that regulation would be to invalidate the application for designation of that medicinal product as an orphan due to the fact that it already has a marketing authorisation.
By its first ground of appeal, the EMA submits that it follows from a combined reading of Article 5(1), (2) and (4) of Regulation No 141/2000 that, when examining the validity of an application for designation, those provisions require it to ascertain whether the medicinal product in question is identical to a medicinal product already authorised by taking into consideration the active ingredients and therapeutic indications of those medicinal products, to the exclusion of all other factors. The EMA submits that those criteria are the only criteria set out in Article 5(2)(b) and (c) of that regulation and that, because of their simplicity, they are the only ones that can be taken into consideration at that stage of the designation procedure.
However, it should be noted that verification of the criteria in Article 3(1) of Regulation No 141/2000 does not fall within the scope of the EMA’s review of the validity of the application for designation. Pursuant to Article 4 and Article 5(5) to (7) of that regulation, responsibility for that verification lies with the COMP.
The rationale for that allocation of powers lies in the technical and scientific nature of the criteria set out in Article 3(1) of that regulation. Those criteria entail complex and nuanced analyses, particularly where it is a question of assessing whether the medicinal product in question provides a significant benefit for patients compared with a medicinal product which has already been authorised.
For the same reasons, taking account of the link established between Article 3(1) and Article 5(2) of Regulation No 141/2000, the exclusive competence of the COMP extends to verifying the identity of the medicinal product which is the subject of the application for designation with a medicinal product which has already been authorised, in a situation such as that in the present case.
It is true that Article 5(2) of Regulation No 141/2000 mentions only the active ingredients and the therapeutic indications among the matters to be provided in support of an application for designation. However, this cannot lead to the conclusion that, in the situations described in paragraph 31 above, the fact that the medicinal products in question have the same active substance is sufficient for those medicinal products to be considered to be identical and, consequently, to the rejection of the application for designation.
As held by the General Court, in paragraph 58 of the judgment under appeal, the terms ‘medicinal product’ and ‘active substance’ cover two distinct concepts, defined in Article 1 of Directive 2001/83. As the active substance is a component of a medicinal product, it should not be confused with the medicinal product itself. It is therefore necessary to examine all other relevant factors, in addition to the active substance, in order to determine whether those medicinal products are identical.
That allocation of powers between the EMA and the COMP is without prejudice to the outcome of the designation procedure. It is not therefore capable of undermining the effectiveness of Article 5(1) of that regulation.
The General Court did not therefore err in law in holding, in paragraph 51 of the judgment under appeal, that:
‘The EMA is required to verify, at this stage of the proceedings, the validity of the application, pursuant to Article 5(4) of Regulation No 141/2000. Thus, it must check, on the one hand, whether the application was submitted at any stage of the development of the medicinal product before the application for marketing authorisation was made, as required by Article 5(1) of that regulation and, on the other, whether the application is accompanied by the information and documents referred to in Article 5(2) of the regulation. Following that verification, the EMA may, where appropriate, request the sponsor to supplement the particulars and documents accompanying the application. If the application complies with the requirements laid down in Article 5(1) and (2) of Regulation No 141/2000, the EMA is obliged to validate and transmit it, next, to the Committee on Orphan Medicinal Products.’
As regards the criticisms made in the context of the first ground of appeal against paragraphs 62 and 64 of the judgment under appeal, it must be stated that, in paragraph 62 of that judgment, the General Court found, on the basis of the file before it, that ‘Elaprase differs from Idursulfase-IT in its composition, method of administration and therapeutic effects’. After examining each of those points in turn in paragraphs 62 to 63 of the judgment under appeal, the General Court reiterated, in paragraph 64 of that judgment, that ‘it does not appear, at the validation stage of the … application, that Idursulfase-IT is the same medicinal product as Elaprase.’  Those factual assessments are not subject to review by the Court of Justice in appeal proceedings. The arguments of the EMA against paragraphs 62 and 64 of the judgment under appeal are therefore inadmissible.
It follows from all of those considerations that the first ground of appeal must be dismissed as in part inadmissible and in part unfounded.

The second ground of appeal, alleging infringement of Article 1(2) of Regulation No 2001/83

Arguments of the parties
By its second ground of appeal, put forward in the alternative, the EMA disputes paragraphs 60 and 62 of the judgment under appeal. It submits that the General Court relied on an incorrect interpretation of the concept of ‘medicinal product’, as defined in Article 1(2) of Directive 2001/83. The General Court took the view that Elaprase and Idursulfase-IT are different medicinal products insofar as they do not have the same excipients or the same method of administration. The concept of medicinal product defined in that provision refers neither to the excipients nor to the method of administration, but focuses on the concept of active substance. Accordingly, the General Court was not entitled to refer to those factors in order to conclude that there were differences between two products.
Shire disputes that second ground of appeal.
The Commission maintains that the second ground of appeal is well founded.

Findings of the Court
In paragraph 60 of the judgment under appeal, the General Court held that ‘a medicinal product also contains, in addition to one or more active substances, excipients, which are defined in Article 1(3b) of Directive 2001/83 as “any constituent of a medicinal product other than the active substance and the packaging material”
’
.
By its second ground of appeal, the EMA does not put forward any argument specifically to show that paragraph 60 of the judgment under appeal is vitiated by an error of law. The second ground of appeal is therefore substantially the same as the first ground of appeal, which has been rejected as unfounded. It must therefore, for the same reasons, be rejected as unfounded.
In view of the factual nature of the assessments made by the General Court in paragraph 62 of the judgment under appeal, the line of argument directed against that paragraph is inadmissible, as has already been held in paragraph 40 above.
It follows that the second ground of appeal is in part inadmissible and in part unfounded and must, in consequence, be rejected.
Having regard to all of the foregoing considerations, the appeal must be dismissed in its entirety.

Costs
In accordance with the Article 184(2) of the Rules of Procedure of the Court, where the appeal is unfounded, the Court is to make a decision as to costs. Under Article 138(1) of those rules, applicable to appeal proceedings by virtue of Article 184(1) thereof, the unsuccessful party is to be ordered to pay the costs if they have been applied for in the successful party’s pleadings.
Article 140(1) of the Rules of Procedure, which applies to the procedure on appeal by virtue of Article 184(1) thereof, provides that the Member States and institutions which have intervened in the proceedings are to bear their own costs.
Since Shire has applied for costs to be awarded against the EMA and the latter has been unsuccessful, it must be ordered to pay the costs.
The Commission, intervener at first instance, must bear its own costs.
On those grounds, the Court (Eighth Chamber) hereby:
1.
Dismisses the appeal;
2.
Orders the European Medicines Agency (EMA) to bear its own costs and to pay the costs incurred by Shire Pharmaceuticals Ireland Ltd;
3.
Orders the European Commission to bear its own costs.
Biltgen
Malenovský
Fernlund
Delivered in open court in Luxembourg on 29 July 2019.
A. Calot Escobar

F. Biltgen
Registrar

President of the Eighth Chamber
*
Language of the case: English.