62021CC0438
OPINION OF ADVOCATE GENERAL
MEDINA
delivered on 6 October 2022 (
1
)
Joined Cases C‑438/21 P to C‑440/21 P
European Commission (C‑438/21 P),
Biogen Netherlands BV (C‑439/21 P),
European Medicines Agency (C‑440/21 P)
v
Pharmaceutical Works Polpharma S.A.
(Appeal – Medicinal products for human use – Application seeking to obtain a marketing authorisation for a generic version of the medicinal product Tecfidera – Decision of the EMA not to validate the application – Previous decision of the European Commission taking the view that Tecfidera was not covered by the same global marketing authorisation as Fumaderm – Plea of illegality – Directive 2001/83 – Second subparagraph of Article 6(1) – Concept of ‘global marketing authorisation’ and its objectives – Article 10(1) – Regulatory data protection period – Regulation (EC) No 726/2004 – Decentralised application of EU pharmaceutical legislation – Principle of mutual recognition)
I. Introduction
1.
This Opinion concerns three appeals brought by the European Commission, Biogen Netherlands BV (‘Biogen’) and the European Medicines Agency (EMA) seeking to have the judgment of 5 May 2021, Pharmaceutical Works Polpharma v EMA (T‑611/18, EU:T:2021:241) (‘the judgment under appeal’) set aside. By that judgment, the General Court annulled the decision of the EMA of 30 July 2018 (‘the contested decision’), which refused to validate the application submitted by Pharmaceutical Works Polpharma S.A. (‘Polpharma’) seeking to obtain a marketing authorisation for a generic version of the medicinal product Tecfidera – Dimethyl fumarate (‘Tecfidera’).
2.
The Court of Justice has requested that two legal issues be examined, which are, to a large extent, common to the three cases. This Opinion will accordingly focus on the grounds of appeal relating to the concept of ‘global marketing authorisation’ within the meaning of the second subparagraph of Article 6(1) of Directive 2001/83, (
2
) and to the test set out by the General Court for assessing whether the two medicinal products at issue in the present case belong to the same global marketing authorisation. In essence, that test would have required the Commission, on the basis of the scientific assessment conducted by the EMA, to verify the therapeutic contribution of the components of a medicinal product previously authorised by a national competent authority for the purposes of determining whether a newly developed product fell under that same global marketing authorisation.
3.
The appeal in question provides the opportunity for the Court to clarify the requirements that apply, respectively, to the approval of the marketing of a medicinal product in the European Union and to the assessment of whether two medicinal products belong to the same global marketing authorisation. The case also allows the Court to define, within the context of that assessment, the relationship between the competences of the Commission, the EMA and the authorities of the Member State and the degree of (de)centralisation that stems from Directive 2001/83 and Regulation No 726/2004 (
3
) upon the application of EU pharmaceutical legislation.
II. Legal context
A.
Directive 2001/83
4.
Recitals 9 and 12 of Directive 2001/83 state:
‘(9)
Experience has shown that it is advisable to stipulate more precisely the cases in which the results of toxicological and pharmacological tests or clinical trials do not have to be provided with a view to obtaining authorisation for a medicinal product which is essentially similar to an authorised product, while ensuring that innovative firms are not placed at a disadvantage.
…
(12)
With the exception of those medicinal products which are subject to the centralised Community authorisation procedure established by [Regulation No 2309/93 (
4
)] a marketing authorisation for a medicinal product granted by a competent authority in one Member State ought to be recognised by the competent authorities of the other Member States unless there are serious grounds for supposing that the authorisation of the medicinal product concerned may present a risk to public health. In the event of a disagreement between Member States about the quality, the safety or the efficacy of a medicinal product, a scientific evaluation of the matter should be undertaken according to a Community standard, leading to a single decision on the area of disagreement binding on the Member States concerned. Whereas this decision should be adopted by a rapid procedure ensuring close cooperation between the Commission and the Member States.’
5.
Article 1 of Directive 2001/83 provides the following definitions of the terms ‘medicinal product’ and ‘active substance’:
‘…
2.   Medicinal product:
(a)
Any substance or combination of substances presented as having properties 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;
…’
6.
Article 6 of Directive 2001/83 states:
‘1.   No medicinal product may be placed on the market of a Member State unless a marketing authorisation has been issued by the competent authorities of that Member State in accordance with this Directive or an authorisation has been granted in accordance with [Regulation No 726/2004] …
When a medicinal product has been granted an initial marketing authorisation in accordance with the first subparagraph, any additional strengths, pharmaceutical forms, administration routes, presentations, as well as any variations and extensions shall also be granted an authorisation in accordance with the first subparagraph or be included in the initial marketing authorisation. All these marketing authorisations shall be considered as belonging to the same global marketing authorisation, in particular for the purpose of the application of Article 10(1).
…’
7.
Article 8 of Directive 2001/83 provides:
‘…
3.   The application shall be accompanied by the following particulars and documents, submitted in accordance with Annex I:
…
(c)
Qualitative and quantitative particulars of all the constituents of the medicinal product, including the reference to its international non-proprietary name (INN) recommended by the [World Health Organisation (WHO)], where an INN for the medicinal product exists, or a reference to the relevant chemical name.
…’
8.
Article 10 of Directive 2001/83 states:
‘1.   By way of derogation from Article 8(3)(i), and without prejudice to the law relating to the protection of industrial and commercial property, the applicant shall not be required to provide the results of pre-clinical tests and of clinical trials if he can demonstrate that the medicinal product is a generic of a reference medicinal product which is or has been authorised under Article 6 for not less than eight years in a Member State or in the [European Union].
A generic medicinal product authorised pursuant to this provision shall not be placed on the market until ten years have elapsed from the initial authorisation of the reference product.
…
The ten-year period referred to in the second subparagraph shall be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorisation holder obtains an authorisation for one or more new therapeutic indications which, during the scientific evaluation prior to their authorisation, are held to bring a significant clinical benefit in comparison with existing therapies.
2.   For the purposes of this Article:
(a)
“reference medicinal product” shall mean a medicinal product authorised under Article 6, in accordance with the provisions of Article 8;
(b)
“generic medicinal product” shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. In such cases, additional information providing proof of the safety and/or efficacy of the various salts, esters or derivatives of an authorised active substance must be supplied by the applicant. The various immediate-release oral pharmaceutical forms shall be considered to be one and the same pharmaceutical form. Bioavailability studies need not be required of the applicant if he can demonstrate that the generic medicinal product meets the relevant criteria as defined in the appropriate detailed guidelines.’
9.
Article 11 of Directive 2001/83 provides:
‘The summary of the product characteristics shall contain, in the order indicated below, the following information:
…
2.   qualitative and quantitative composition in terms of the active substances and constituents of the excipient, knowledge of which is essential for proper administration of the medicinal product. The usual common name or chemical description shall be used.
…’
10.
Article 30 of Directive 2001/83 states:
‘1.   If two or more applications submitted in accordance with Articles 8, 10, 10a, 10b, 10c and 11 have been made for marketing authorisation for a particular medicinal product, and if Member States have adopted divergent decisions concerning the authorisation of the medicinal product or its suspension or revocation, a Member State, the Commission or the applicant or the marketing authorisation holder may refer the matter to the Committee for Medicinal Products for Human Use, hereinafter referred to as “the Committee”, for the application of the procedure laid down in Articles 32, 33 and 34.’
11.
Article 31 of Directive 2001/83 declares:
‘1.   The Member States, the Commission, the applicant or the marketing authorisation holder shall, in specific cases where the interests of the Union are involved, refer the matter to the Committee for application of the procedure laid down in Articles 32, 33 and 34 before any decision is reached on an application for a marketing authorisation or on the suspension or revocation of a marketing authorisation, or on any other variation of the marketing authorisation which appears necessary.
…’
12.
Point 3 of Part II of Annex 1 to Directive 2001/83 provides:
‘Where the active substance of an essentially similar medicinal product contains the same therapeutic moiety as the original authorised product associated with a different salt/ester complex/derivative evidence that there is no change in the pharmaco-kinetics of the moiety, pharmaco-dynamics and/or in toxicity which could change the safety/efficacy profile shall be demonstrated. Should this not be the case, this association shall be considered as a new active substance.’
B.
Regulation No 726/2004
13.
Recitals 9 and 19 of Regulation 726/2004 declare:
‘(9)
As regards medicinal products for human use, optional access to the centralised procedure should also be provided for in cases where use of a single procedure produces added value for the patient. This procedure should remain optional for medicinal products which, although not belonging to the abovementioned categories, are nevertheless therapeutically innovative. It is also appropriate to allow access to this procedure for medicinal products which, although not innovative, may be of benefit to society or to patients if they are authorised from the outset at Community level, such as certain medicinal products which can be supplied without a medical prescription. This option may be extended to generic medicinal products authorised by the Community, provided that this in no way undermines either the harmonisation achieved when the reference medicinal product was evaluated or the results of that evaluation.
…
(19)
The chief task of the [EMA] should be to provide Community institutions and Member States with the best possible scientific opinions so as to enable them to exercise the powers regarding the authorisation and supervision of medicinal products conferred on them by Community legislation in the field of medicinal products. Only after a single scientific evaluation procedure addressing the quality, safety and efficacy of high-technology medicinal products has been conducted by the [EMA], applying the highest possible standards, should marketing authorisation be granted by the Community, and this should be done by means of a rapid procedure ensuring close cooperation between the Commission and Member States.’
14.
Pursuant to Article 3 of Regulation No 726/2004:
‘…
2.   Any medicinal product not appearing in the Annex may be granted a marketing authorisation by the Community in accordance with the provisions of this Regulation, if:
…
(b)
the applicant shows that the medicinal product constitutes a significant therapeutic, scientific or technical innovation or that the granting of authorisation in accordance with this Regulation is in the interests of patients or animal health at Community level.
…
3.   A generic medicinal product of a reference medicinal product authorised by the Community may be authorised by the competent authorities of the Member States in accordance with Directive 2001/83/EC and [Directive 2001/82/EC (
5
)] under [certain] conditions …
…’
15.
Article 14 of Regulation No 726/2004 states:
‘…
11.   Without prejudice to the law on the protection of industrial and commercial property, medicinal products for human use which have been authorised in accordance with the provisions of this Regulation shall benefit from an eight-year period of data protection and a ten-year period of marketing protection, in which connection the latter period shall be extended to a maximum of 11 years if, during the first eight years of those ten years, the marketing authorisation holder obtains an authorisation for one or more new therapeutic indications which, during the scientific evaluation prior to their authorisation, are held to bring a significant clinical benefit in comparison with existing therapies.’
16.
Article 57 of Regulation No 726/2004 declares:
‘1.   The [EMA] shall provide the Member States and the institutions of the Community with the best possible scientific advice on any question relating to the evaluation of the quality, safety and efficacy of medicinal products for human or veterinary use which is referred to it in accordance with the provisions of Community legislation relating to medicinal products.
…’
17.
Article 60 of Regulation No 726/2004 establishes:
‘At the request of the Commission, the [EMA] shall, in respect of authorised medicinal products, collect any available information on methods that Member States’ competent authorities use to determine the added therapeutic value that any new medicinal product provides.’
III. Facts and procedure
A.
Background to the dispute
18.
The background to the dispute is described in paragraphs 1 to 51 of the judgment under appeal. For the purposes of the present Opinion, that background can be summarised in the following undisputed facts, which are relevant to the appeal.
19.
Fumaderm is a medicinal product that was granted a marketing authorisation in Germany by the Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for Drugs and Medical Devices, Germany; ‘the BfArM’) in 1994. It was indicated for the treatment of psoriasis as a fixed combination of dimethyl fumarate (‘DMF’) and various monomethyl fumarate (‘MEF’) salts. The authorisation was requested by Fumapharm AG, an undertaking which was acquired by Biogen in 2006. Pursuant to Article 10(1) of Directive 2001/83, the regulatory data protection period of Fumaderm expired in 2004. Its marketing authorisation was nevertheless renewed by the BfArM in June 2013.
20.
Tecfidera is a mono-substance medicinal product, which contains only DMF, and not MEF. At the request of Biogen, it was authorised by the Commission on 30 January 2014 for the treatment of multiple sclerosis by virtue of Implementing Decision C(2014) 601 final granting marketing authorisation under Regulation No 726/2004 for ‘Tecfidera – Dimethyl fumarate’, a medicinal product for human use (‘the 2014 Decision’).
21.
During the assessment of the marketing authorisation application for Tecfidera, the Commission, with a view to defining the regulatory data protection status of that medicinal product, requested the Committee for Medicinal Products for Human Use (‘the CHMP’) of the EMA to assess whether Tecfidera and Fumaderm, both under Biogen’s ownership, were different medicinal products.
22.
In that regard, the CHMP took the view that DMF and MEF were different active substances as they did not share the same therapeutic moiety. Moreover, the CHMP considered that Tecfidera, inasmuch as it was composed only of DMF, and Fumaderm, which consisted of a combination of DMF and MEF, had a different qualitative composition. The CHMP thus concluded that Fumaderm and Tecfidera were different medicinal products.
23.
On the basis of the scientific findings of the CHMP, the Commission established, in the 2014 Decision, that Tecfidera had complied with the requirements set out in Directive 2001/83 and that it was appropriate to authorise its placing on the market. The Commission also provided that Tecfidera did not belong to the same global marketing authorisation as Fumaderm, within the meaning of Article 6(1) of Directive 2001/83. In that regard, recital 3 of the 2014 Decision stated:
‘Dimethyl fumarate (DMF), the active substance of “Tecfidera – Dimethyl fumarate”, is part of the composition of the authorised medicinal product Fumaderm which [consists] of DMF and calcium salt of ethyl fumarate, magnesium salt of ethyl hydrogen fumarate and zinc salt of ethyl hydrogen fumarate (MEF salts), belonging to the same marketing authorisation holder. The [CHMP] concluded that MEF and DMF are both active and are not the same active substance since they do not share the same therapeutic moiety. Therefore it is considered that Tecfidera containing DMF is different from Fumaderm the other already authorised medicinal product composed of DMF and MEF salts. Therefore “Tecfidera – Dimethyl fumarate”, the application of which was based on Article 8(3) of Directive [2001/83], and the already authorised medicinal product Fumaderm do not belong to the same global marketing authorisation as described in Article 6(1) of Directive [2001/83].’
24.
As a result of the 2014 Decision, Tecfidera was granted an independent regulatory data protection period starting from the date of the notification of that decision. Other undertakings could not therefore refer to pre-clinical and clinical data in Tecfidera’s file for 8 years or market a generic version of Tecfidera for 10 years.
25.
In 2017, Polpharma, a pharmaceutical company that develops and markets medicinal products, applied for a marketing authorisation for a generic version of Tecfidera. In its application, Polpharma claimed that the regulatory data protection period for Tecfidera had already expired, given that its authorisation should be considered to fall within the same global marketing authorisation as Fumaderm.
26.
By the contested decision, the EMA refused to validate Polpharma’s application. In particular, the EMA stated that, according to the 2014 Decision, Tecfidera and Fumaderm did not belong to the same global marketing authorisation because of their different qualitative composition in terms of active substances. The EMA also referred to the statement in recital 3 of the 2014 Decision and refused to validate Polpharma’s application for a marketing authorisation on the basis that Tecfidera’s regulatory data protection period had not expired.
B.
The application for annulment brought before the General Court and the judgment under appeal
27.
By application lodged at the Registry of the General Court, Polpharma brought an action for annulment of the contested decision.
28.
In support of its application for annulment, Polpharma raised a single plea in law, alleging that the 2014 Decision was unlawful and therefore had to be declared inapplicable in accordance with Article 277 TFEU. In essence, it considered that, in order to establish whether Tecfidera and Fumaderm differed for the purpose of the global marketing authorisation, the Commission and the EMA should have been required to assess not only the qualitative composition, in terms of active substances, of Fumaderm vis-à-vis Tecfidera, but also the existence of a relevant therapeutic contribution of the MEF in Fumaderm. As a consequence, it argued that the contested decision, which refused to validate the application for a marketing authorisation for a generic medicinal product of Tecfidera, had no legal basis and had to be annulled.
29.
In the judgment under appeal, the General Court found, in the first place, that the plea of illegality raised by Polpharma against the 2014 Decision was admissible.
30.
In its reasoning, the General Court stated, inter alia, that Polpharma was not entitled to bring a direct action for annulment against the 2014 Decision because it did not satisfy the relevant criteria established in the fourth paragraph of Article 263 TFEU. In that regard, the General Court considered, on the one hand, that Polpharma was not individually concerned by the 2014 Decision. On the other hand, it held that that decision was a regulatory act that entailed implementing measures. In any event, the General Court noted that Polpharma’s interest in seeking the annulment of the 2014 Decision was not current and vested, as required by settled case-law, but future and uncertain on the date on which it would have been entitled to bring an action for annulment against that decision.
31.
In the second place, the General Court upheld the plea of illegality and considered that, inasmuch as it was based on the 2014 Decision, the contested decision was unfounded and had to be annulled.
32.
First, the General Court examined the concept of ‘global marketing authorisation’ and its objectives. It also observed that, in adopting the 2014 Decision, the Commission was faced, for the first time at EU level, with the question of whether or not an authorised fixed combination medicinal product, on the one hand, and a mono-substance medicinal product based on a component of that fixed combination, on the other, belonged to the same global marketing authorisation. Moreover, it held that the Commission had to take into account the fact that the state of EU law relating to combination medicinal products and scientific knowledge was significantly different in 1994 when the BfArM granted the authorisation in favour of Fumaderm. Within that context, according to the General Court, the Commission was correct to request the CHMP to assess whether Tecfidera’s sole active substance was different from that of Fumaderm.
33.
Second, the General Court noted that, in specific cases of interest to the European Union, the Member States, the Commission, an applicant or the marketing-authorisation holder are to consult the CHMP, which is responsible for carrying out its own assessment at EU level of the medicinal product concerned, independent of that carried out by the national authorities. According to the General Court, in the context of marketing-authorisation procedures, the EMA and the Commission thus perform a particular function that is not comparable to that of the national authorities. In that regard, the principle of mutual recognition could not prevent the CHMP from examining the assessments previously carried out by a national authority or from carrying out an independent assessment. That would be particularly the case where an application for marketing authorisation is submitted at EU level for a substance which forms part of a medicinal combination authorised 15 years before at national level. After all, the question of whether Tecfidera was covered by the same global marketing authorisation as Fumaderm was a case of particular interest to the European Union in the light of the objectives pursued by Directive 2001/83, in general, and by the concept of global marketing authorisation, in particular.
34.
Third, the General Court noted that, when the 2014 Decision was adopted, the EMA and the Commission had, or could have had, information capable of rendering implausible the assumption that MEF, which formed part of Fumaderm but was not contained in Tecfidera, played a role within Fumaderm. Thus, according to the General Court, the Commission was not entitled to conclude that Tecfidera was covered by a different global marketing authorisation from Fumaderm without having verified or requested the CHMP to verify the role played by MEF in Fumaderm. In the absence of such verification and in view of the fact that the Commission had not analysed all the relevant data that had to be taken into consideration in order to establish that Tecfidera and Fumaderm were not covered by the same global marketing authorisation, the General Court concluded that the 2014 Decision was vitiated by a manifest error of assessment.
IV. Forms of order sought by the parties before the Court of Justice
35.
By their respective appeals, the Commission, Biogen and the EMA claim that the Court of Justice should set aside the judgment under appeal, dismiss the action brought at first instance and order Polpharma to pay the costs. If necessary, where the state of the proceedings does not allow the Court of Justice to give a ruling, Biogen also claims that the case should be referred back to the General Court for judgment.
36.
Polpharma claims that the Court should dismiss the appeal, confirm the judgment under appeal and order the appellants to pay the costs of the appeals.
V. Analysis
37.
In support of their appeals, the Commission, Biogen and the EMA rely, in Cases C‑438/21 P, C‑439/21 P and C‑440/21 P respectively, on four grounds, the content of which is almost identical.
38.
In essence, those grounds of appeal relate, first, to the distortion of the facts of the case and, in particular, the failure to infer the correct legal implications of the assessment carried out by the BfArM upon the renewal of the marketing authorisation of Fumaderm in 2013; second, the infringement of the second subparagraph of Article 6(1) of Directive 2001/83, concerning the concept of ‘global marketing authorisation’ and its objectives, as interpreted by the case-law of the Court; third, the infringement of the decentralised system of application of EU pharmaceutical legislation, as defined by Directive 2001/83 and Regulation No 726/2004, as well as that of the principle of mutual trust; and, fourth, the infringement of the standard of judicial review in relation to scientific assessments and scientific evidence.
39.
Furthermore, Biogen also claims an infringement of Article 277 TFEU, regarding the admissibility recognised by the General Court at first instance vis-à-vis the plea of illegality raised by Polpharma against the 2014 Decision.
40.
As requested by the Court, my analysis will focus, in the first place, on the interpretation of the concept of ‘global marketing authorisation’ and its objectives, as laid down in Article 6(1) of Directive 2001/83, to which the second ground of appeal in Cases C‑438/21 P and C‑439/21 P and the third ground of appeal in Case C‑440/21 P relate. Moreover, as the answer to be given to those grounds depends on the legal consequences to be inferred from the renewal by the BfArM of the marketing authorisation of Fumaderm in 2013, I will refer in my analysis to whether the General Court based its reasoning on an incorrect factual premiss capable of affecting the final conclusion of the judgement under appeal, as claimed by the three appellants. That is related to the first ground of appeal in Cases C‑438/21 P and C‑440/21 P, and to the third ground in Case C‑439/21 P.
41.
In the second place, I will examine whether the General Court could lawfully establish, in the light of the provisions of Directive 2001/83 and Regulation No 726/2004 and the principle of mutual recognition, that the Commission and the EMA have the competence to reassess the marketing authorisation of a fixed combination medicinal product granted by a national competent authority when faced with the decision as to whether a mono-substance medicinal product, composed of one of the substances of that fixed combination, belongs to the same global marketing authorisation. That issue relates to the third ground of appeal in Case C‑438/21 P, the fourth ground in Case C‑439/21 P and the second ground in Case C‑440/21 P, respectively.
A.
Grounds of appeal based on the infringement of the second subparagraph of Article 6(1) of Directive 2001/83 and the correctness of the factual premiss adopted by the General Court
42.
In the judgment under appeal, the General Court concluded that, ‘in so far as, despite the particular circumstances of the case, neither the CHMP nor the Commission assessed the role played by MEF within Fumaderm or requested information from the BfArM in that regard’, the 2014 Decision ‘[was] vitiated by a manifest error of assessment’. (
6
)
43.
That conclusion is based, inter alia, on the following reasoning, which results from paragraph 282 of that judgment:
‘… In view of [(i)] the objectives of global marketing authorisations, [(ii)] the EU law applicable to combination medicinal products in 1994 and the development of scientific knowledge between 1994 and 2014, [(iii)] the particular function performed by the EMA and the Commission, and [(iv)] the data available, or which could have been available, to them which rendered implausible the theory that MEF played a role within Fumaderm …, it must be held that the Commission was not entitled to conclude that Tecfidera was covered by a different global marketing authorisation than Fumaderm, which had previously been authorised, without verifying or requesting the CHMP to verify whether and, if necessary, how, the BfArM had assessed the role of MEF within Fumaderm, or without requesting the CHMP to verify the role played by MEF within Fumaderm.’
44.
The appellants claim that the previous finding of the General Court is vitiated by several errors of law, inasmuch as it entails that the Commission and the EMA would have had to reassess the therapeutic contribution of MEF within Fumaderm, a nationally authorised medicinal product, for the purposes of deciding whether Tecfidera belonged to the same global marketing authorisation.
45.
In essence, they submit that that obligation of reassessment is not supported by the wording of the second subparagraph of Article 6(1) of Directive 2001/83, nor by the legislative aims underlying the concept of ‘global marketing authorisation’. Pursuant to that provision, a comparison of the qualitative composition of two medicinal products, as established in their respective marketing-authorisation decisions, would be appropriate to determine whether both products fall under the same global marketing authorisation. In that regard, they also argue that, in the judgment under appeal, the General Court unlawfully used an assessment pertinent to the approval of the marketing of a medicinal product as the basis of the assessment as to whether two medicinal products belong to the same global marketing authorisation. Moreover, the approach of the General Court would give rise to two diverging concepts of ‘global marketing authorisation’, depending on whether the authorisation to place a medicinal product on the market is granted at national or EU level. Finally, the appellants challenge the existence of a risk of abuse by innovators when requesting the authorisation of medicinal products composed of substances with no real therapeutic contribution, making it possible to obtain extra regulatory data protection periods by removing those substances in a subsequent medicinal product.
46.
Polpharma contests the arguments put forward by the appellants. It considers that the General Court correctly concluded that, for the purpose of establishing whether Tecfidera and Fumaderm differed as medicinal products, the Commission was required to assess the therapeutic contribution of MEF in Fumaderm. Moreover, Polpharma argues that, when faced with an application for marketing authorisation for an active substance which forms part of a previously authorised combination medicinal product, the assessment as to whether there is a difference between that combination and the isolated active substance depends on whether the individual active substances in the combination provide a significant and relevant therapeutic contribution within that combination. In that regard, Polpharma submits that it is inappropriate to regard two products as different merely because one of them contains a particular compound that has some kind of pharmaceutical effect that is not present in the product with which it is being compared. Otherwise, it would be too easy for a marketing authorisation holder to obtain a long period of additional regulatory data protection by adding or removing, when extending the product to a new therapeutic indication, a substance that is pharmaceutically active but clinically irrelevant.
1. The wording of Article 6(1) of Directive 2001/83
47.
As regards the issue of whether the wording of Article 6(1) of Directive 2001/83 supports the interpretation adopted by the General Court, I must recall, from the outset, that the first subparagraph of that provision establishes, as a prerequisite for any medicinal product to be placed on the market of a Member State, the issuing of a marketing authorisation. Either the competent national authorities, in accordance with Directive 2001/83, or the Commission, pursuant to Regulation No 726/2004, may grant that authorisation.
48.
In turn, the second subparagraph of Article 6(1) of Directive 2001/83 declares that, ‘when a medicinal product has been granted an initial marketing authorisation in accordance with the first subparagraph, any additional strengths, pharmaceutical forms, administration routes, presentations, as well as any variations and extensions shall also be granted an authorisation in accordance with the first subparagraph or be included in the initial marketing authorisation. All these marketing authorisations shall be considered as belonging to the same global marketing authorisation, in particular for the purpose of the application of Article 10(1) [of Directive 2001/83]’.
49.
It thus results from Article 6(1) of Directive 2001/83 that, other than setting out the requirement to obtain an authorisation for the marketing of a medicinal product in the European Union, that provision defines the types of subsequent developments to an original medicinal product, the authorisations of which are viewed as part of the same ‘global marketing authorisation’. That entails, for the most part, that a single regulatory data protection period, as laid down in Article 10(1) of Directive 2001/83, applies to those developments starting on the date of authorisation of the first product. (
7
)
50.
A defining element of the concept of ‘global marketing authorisation’ is therefore its close link with the regulatory data protection status attributed to medicinal products and their modifications. (
8
) After all, the second subparagraph of Article 6(1) of Directive 2001/83 was inserted into that directive (
9
) in order to codify the existing case-law of the Court in relation to the categories of authorisations that would not give rise to a different medicinal product, but would rather be considered to be covered by the regulatory data protection period triggered by the initial authorisation of a medicinal product. (
10
) In that regard, the object of that provision is to prevent the prolongation of the regulatory data protection period of an existing product on the basis of mere variants undeserving of its benefit.
51.
For the present case, it is important to point out that the modification of the qualitative composition of an authorised medicinal product, in terms of active substances, does not appear to fall under the specific categories of authorisations laid down in the second subparagraph of Article 6(1) of Directive 2001/83 – namely, additional strengths, pharmaceutical forms, administration routes, presentations or variations and extensions.
52.
First, those categories must be considered to be listed in an exhaustive manner. Recital 9 of Directive 2001/83 highlights that the second subparagraph of Article 6(1) thereof is intended to ‘stipulate more precisely the cases’ in which the results of tests or clinical trials do not have to be provided to obtain the authorisation for a medicinal product which is essentially similar to an authorised one. Considerations of legal certainty thus motivated the adoption of that provision, which invites an interpretation that it sets out a closed number of authorisations that are not entitled to an independent regulatory data protection period.
53.
Next, it is clear that a difference in the qualitative composition of two medicinal products does not constitute an ‘additional strength’, a term that, as follows from Article 1(22) of Directive 2001/83, refers to ‘the content of the active substances expressed quantitatively per dosage, per unit of volume or weight according to the dosage form’. It also does not constitute a ‘pharmaceutical form’, that is to say, the way in which a medicine is presented – table capsule, solution for injection, cream, and so forth. (
11
) Nor does it refer to an ‘administration route’ or a ‘presentation’, terms which respectively cover the way in which a medicine is given – orally, intravenously, subcutaneously, and so forth (
12
) – and the differences in the pharmaceutical form, strength and pack size of a medicinal product – for instance, the number of pills in the packaging. (
13
)
54.
Furthermore, the modification of the qualitative composition of a medicinal product cannot be classified as ‘any variations and extensions’ within the meaning of the second subparagraph of Article 6(1) of Directive 2001/83.
55.
In that respect, I observe that Regulation No 1234/2008 (
14
) describes the modifications of a medicinal product that are to be classified as a variation or an extension of an initial market authorisation. (
15
) In particular, regarding changes in active substances, point 1(a) of Annex I to that regulation provides that an extension of a marketing authorisation results from the ‘replacement of a chemical active substance by a different salt/ester complex/derivative, with the same therapeutic moiety, where the efficacy/safety characteristics are not significantly different’. (
16
)
56.
It stems from that definition that, for a modification of a medicinal product to be recognised as an extension – and not as a newly developed product subject to a standalone marketing authorisation – the active substance(s) of that product cannot be replaced by other substance(s) having a different therapeutic moiety. (
17
)
57.
In that regard, it might be worth noting, first, that Article 1 of Directive 2001/83 defines the term ‘active substance’ as 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. According to that same definition, active substances are those that intend to exert a pharmacological, immunological or metabolic action with a view to restoring, correcting or modifying physiological functions or to make a medical diagnosis. It follows that a component of a medicinal product can be considered to be an active substance where it displays a therapeutic contribution within that product.
58.
In addition, in line with the appellants’ observations, the therapeutic moiety of an active substance is the part of the molecule of that substance that, after administration to the patient, is responsible for its physical or pharmacological action. (
18
) For that reason, active substances that do not share the same therapeutic moiety are, by definition, different. Moreover, where a change in an active substance exposes a patient to a different therapeutic moiety, then a new medicinal product, different from a previous one, is considered to be created. That also means that medicinal products that diverge in their active substance(s) are different medicinal products.
59.
The Court has already ruled on the importance of the therapeutic moiety for the purposes of establishing a difference between active substances in the SmithKline Beecham case. (
19
) Moreover, other EU rules employ the therapeutic moiety criterion to determine the sameness or difference between medicinal products. (
20
)
60.
It follows from the above considerations that a modification of the qualitative composition of a medicinal product, in terms of active substances, cannot be subsumed into any of the categories of authorisations established by the second subparagraph of Article 6(1) of Directive 2001/83. Consequently, medicinal products presenting a qualitative differentiation do not fall under the same global marketing authorisation.
61.
The previous interpretation finds a clear endorsement in the Opinion delivered in the Novartis case by Advocate General Bobek, to which I adhere. (
21
)
62.
In that Opinion, Advocate General Bobek pointed out that the concept of ‘global marketing authorisation’ is based on the identity of two elements: the marketing authorisation holder and the active substance(s). (
22
) In his view, if the marketing authorisation holder or the active substance changes, then the same global marketing authorisation no longer applies. (
23
) He further stated that a marketing authorisation granted for a medicinal product based on a different active substance with respect to an initial medicinal product cannot be seen as a development of a previous existing medicinal product, but, as an innovation, merits a different regulatory data protection period. Finally, by reference to the Notice of Applicants for medicinal product authorisations, (
24
) he identified the separation of an active substance from a previous combination as a situation in which the same global marketing authorisation would not apply. (
25
)
63.
Contrary to the position adopted in the judgment under appeal, (
26
) I think that, in the judgment delivered in the Novartis case, the Court confirmed that the concept of ‘global marketing authorisation’ does not englobe changes in the qualitative composition of a medicinal product. Admittedly, the Court did not rule on a case concerning a fixed combination medicinal product and a mono-substance medicinal product. The medicinal products at issue in that case contained only one active substance, which was, incidentally, the same. (
27
) However, the Court underlined that a change in the therapeutic indication of the same active substance had to be considered to be a variation within the meaning of that regulation, which entailed, pursuant to the second subparagraph of Article 6(1) of Directive 2001/83, that both medicinal products fell under the same global marketing authorisation. (
28
) It can be logically inferred from the Court’s ruling that two medicinal products with a different qualitative composition cannot be considered to be a variation and, consequently, cannot be considered either to belong to the same global marketing authorisation.
64.
In the light of the foregoing, I must conclude that the wording of Article 6(1) of Directive 2001/83 shows that the concept of ‘global marketing authorisation’ does not apply to changes to medicinal products that constitute a modification to their qualitative composition in terms of active substances. Rationally, that applies to a mono-substance medicinal product, composed of one active substance, and a fixed-combination product, composed of at least two active substances with different moieties. A comparison of their qualitative compositions therefore appears to be a suitable methodology for the purposes of determining whether those two medicinal products fall under the same global marketing authorisation pursuant to the second subparagraph of that provision.
2. The objectives of global marketing authorisations
65.
According to settled case-law, for the purposes of interpreting a provision of EU law, it is necessary to consider not only the wording of such provision, but also its context and the objectives of the rules of which it is part. (
29
) Regarding the concept of ‘global marketing authorisation’ – and the regulatory data protection period which lies at its core – the overarching objective is to ensure a fair balance between the protection of innovative companies and general interests that are served by the marketing of generic medicinal products. As indicated in the judgment under appeal, (
30
) that objective would be jeopardised if the producer of an original medicinal product were able to extend indefinitely the regulatory data protection period and thus prevent producers of generic medicinal products from using that product as a reference product.
66.
In that regard, I should point out from the outset that the classic approaches to interpretation other than literal approach, such as contextual and teleological approach, are to be employed when a mere reading of the text of a provision leads to ambiguity or illogical outcomes. (
31
) It cannot reshape the wording of a norm that is clear to the point of undermining legal certainty and predictability.
67.
In the present case, inasmuch as no element from the wording of the second subparagraph of Article 6(1) of Directive 2001/83 suggests that the concept of ‘global marketing authorisation’ applies to medicinal products presenting a qualitative differentiation, in terms of active substances, in my view, the objectives of that provision cannot by themselves serve to require more than a qualitative comparison of those products when assessing whether they belong to the same global marketing authorisation. Those objectives cannot either serve to establish an obligation on the Commission and the EMA to reassess the qualitative composition of a medicinal product already authorised by a national competent authority.
68.
In any event, I agree with the appellants that the reliance on the objectives of the second subparagraph of Article 6(1) of Directive 2001/83 cannot justify adding the procedure that EU pharmaceutical legislation expressly sets out for the initial authorisation of medicinal products in the European Union to the realm of global marketing authorisations.
69.
Indeed, the qualitative composition of a medicinal product in terms of active substances forms part of the file that an applicant for a marketing authorisation has to submit to the competent authority in accordance with Article 8(3)(c) of Directive 2001/83. That provision requires an applicant for a marketing authorisation to submit the ‘qualitative and quantitative particulars of all the constituents of the medicinal product’ in question. It also forms part of the summary of product characteristics – also referred to as the SmPC – for the medicinal product, which is attached to its marketing authorisation, pursuant to Article 11(2) of Directive 2001/83, and which, according to the case-law, has to be approved together with the marketing authorisation. (
32
)
70.
The evaluation of the qualitative composition of a medicinal product in terms of active substances, including the pharmacological action and the therapeutic contribution of those substances, is therefore within the remit of the competent authority, either at national or at EU level. That authority has the obligation to examine the proposition by an applicant that the active substance(s) of a product, as defined in Article 1 of Directive 2001/83, (
33
) generates a pharmacological, immunological or metabolic effect that can be demonstrated. Failing this, that marketing authorisation is not granted.
71.
For a fixed combination medicinal product, this involves the assessment of whether its active substances have a documented therapeutic contribution within the combination, which also means that it must be demonstrated that the active substances in the combination are not the same. As the appellants’ submit, if this is not demonstrated, a product is not authorised as a fixed combination medicinal product, but rather as a medicinal product containing only one active substance.
72.
It follows that the reassessment of the qualitative composition in terms of active substances of an authorised medicinal product, including the documented therapeutic contribution of each active substance in a fixed combination product, does not appear to be required by the objectives that underlie the analysis of whether or not two medicinal products belong to the same global marketing authorisation. Although it is true, as the Commission points out, that that analysis is dependent on the competent authorities having correctly identified the active substances of each of those products, that does not mean that, when assessing the applicability of a global marketing authorisation, a verification must be carried out as to the composition of the initial medicinal product in terms of active substance(s).
73.
Polpharma argues that, for the purposes of assessing whether a fixed combination medicinal product and a mono-substance medicinal product belong to the same global marketing authorisation, it should not only be proven that there exists a mere therapeutic contribution of each of the components of the former product. The objectives of the second subparagraph of Article 6(1) of Directive 2001/83 would require that contribution to be ‘significant and relevant’ from a clinical point of view. However, in that regard, I would like to highlight that, in the judgement under appeal, the General Court did not conclude that the 2014 Decision was vitiated by a manifest error due to the lack of assessment by the BfArM of a ‘significant’ or ‘relevant’ therapeutic contribution of MEF in Fumaderm. The General Court only stated that, due to the particular circumstances of the case, it was uncertain that the German national authority had actually established the existence of any role of MEF within that medicinal product. Within that context, the General Court concluded that the Commission should have assessed the role played by MEF within Fumaderm or, at least, requested information form the BfArM in that regard. For that reason, I think that Polpharma’s argument is of no consequence in the context of the present appeal, given that the General Court did not precisely uphold its argument in first instance.
74.
To my mind, the previous considerations applies notwithstanding the possible risk, identified by the General Court, that a pharmaceutical undertaking adds an active substance of no clinical relevance to a combination product so as to take it out subsequently in order to create a new product with a separate regulatory data protection period. Apart from being theoretical in the case at issue, given the absence of concrete evidence in that regard, competent authorities must be assumed to be capable of dealing with flawed or abusive applications for marketing authorisations. Consequently, that risk of manipulation cannot justify a departure from the clear wording of Article 6(1) of Directive 2001/83, or a questioning of the system of decentralised authorisation and mutual recognition defined by that directive and Regulation No 726/2004, as I shall argue below.
75.
In the light of the considerations above, I do not think that the objectives of global marketing authorisations can serve as the basis to require more than a qualitative comparison of two medicinal products when assessing whether they belong to the same global marketing authorisation or to justify the conclusion that a reassessment of the qualitative composition of an authorised medicinal product by the Commission or the EMA is required when deciding whether a newly developed product belongs to that same global marketing authorisation.
3. The ‘particular circumstances’ indicated by the General Court
76.
In my view, the conclusion of the General Court in the judgment under appeal does not necessarily stand, as a matter of principle, in opposition to the abovementioned interpretation of the wording and objectives of Article 6(1) of Directive 2001/83. As indicated above, a combined reading of paragraphs 282 and 293 of the judgment under appeal shows that the General Court considered the present case to be subject to the condition of ‘particular circumstances’ – namely that, in the light of the EU law applicable to combination medicinal products in force in 1994, it was uncertain whether the BfArM had evaluated the therapeutic contribution of MEF in Fumaderm when granting it authorisation. That essentially means that, for the General Court, a doubt remained as to whether the German national authority had assessed in 1994 whether MEF were actually an active substance, displaying a documented therapeutic contribution within that medicinal product. (
34
)
77.
However, on the assumption that the fundamental premises of that conclusion are correct, I consider that the appellants are right to claim that the General Court did not take into account a fact, present in that court’s file, (
35
) that would have had a decisive impact within the context of the reasoning of the judgment under appeal.
78.
Indeed, the last assessment made regarding Fumaderm by the BfArM was not carried out upon its authorisation in 1994, but upon the renewal of its marketing authorisation in June 2013. As a result, contrary to the assumption of the General Court in the judgment under appeal, a new scientific assessment of the efficacy and safety of Fumaderm was adopted prior to the 2014 Decision and following the applicable legal framework at that time.
79.
I should point out that the framework applicable in 2013 to the renewal of the marketing authorisation of Fumaderm includes, for instance, Article 24 of Directive 2001/83, which establishes the obligation incumbent on the national competent authorities to consider, during that assessment, a ‘consolidated version of the file in respect of quality, safety and efficacy, including the evaluation of data contained in suspected adverse reactions reports and periodic safety update reports submitted in accordance with Title IX, and information on all variations introduced since the marketing authorisation was granted’. (
36
) Moreover, under Article 117(1) of Directive 2001/83, the national competent authorities are bound to prohibit and to withdraw from the market any medicinal product the qualitative and quantitative composition of which was not as declared. Lastly, the Notice to Applicants applicable at the time of the renewal of the marketing authorisation for Fumaderm stated that renewals of marketing authorisations had to be conducted ‘on the basis of a re-evaluation of the risk-benefit balance’, for which the holder had to provide ‘the national competent authority with a consolidated version of the file in respect of quality, safety and efficacy’. (
37
)
80.
Therefore, as the Commission and the EMA submit, during the renewal of the Fumaderm marketing authorisation in 2013, the BfArM was obliged to take into account all relevant scientific information that emerged between 1994 and June 2013, and to apply the means of assessing scientific information following the standards of June 2013, and not 1994. In addition, the BfArM was required to apply the same regulatory framework as that applicable to the 2014 Decision, namely the ‘1996 Guideline on clinical development of fixed combination medicinal products’, which was updated in 2009. (
38
) In the judgment under appeal, the General Court indeed cites that guideline to demonstrate that it was only after the authorisation of Fumaderm in 1994 that EU legislation set out the obligation to establish a documented therapeutic contribution of the active substances in a fixed combination medicinal product. (
39
) Therefore, the BfArM should have made an assessment in 2013 as to whether MEF had a documented therapeutic contribution within Fumaderm, as required by that regulatory framework.
81.
In that regard, for the sake of completeness, it is worth noting that the renewal of a marketing authorisation by the BfArM is regulated under Paragraph 31(3) of the Arzneimittelgesetz (Law on medicinal products), (
40
) which states that ‘[a marketing authorisation] … is to be prolonged based on an application … on condition that none of the grounds of refusal pursuant to [Paragraph 25(2)(5a)] exist’. In turn, Paragraph 25(2)(5a) of the Law on medicinal products declares that ‘the competent higher federal authority may only refuse to grant the marketing authorisation if … in the case of a medicinal product containing more than one active substance, insufficient grounds are provided to demonstrate that each active substance contributes towards a positive assessment of the medicinal product, whereby the special features of the particular medicinal product should be considered in a risk evaluation’.
82.
It follows that, contrary to the assertion made by the General Court in the judgment under appeal, there was no reason to doubt that the BfArM would have taken into account, when the marketing authorisation of Fumaderm was renewed in 2013, the regulatory standards that were applicable at the time of the renewal following which a determination could have been made that the qualitative composition of that medicinal product was appropriately verified.
83.
According to settled case-law, in an appeal case, the Court of Justice in principle does not have jurisdiction to establish the facts or to examine the evidence which the General Court confirmed in support of those facts. However, exceptions to this principle apply where the findings of a particular judgement under appeal rely on a substantive inaccuracy that is apparent from the documents which were submitted at first instance. Such inaccuracy must be obvious from the documents in the Court’s file, without there being any need to carry out a new assessment of the facts and the evidence. (
41
)
84.
In the present case, for the reasons explained above, I invite the Court of Justice to signal the absence of any analysis of the renewal of the marketing authorisation for Fumaderm in 2013, inasmuch as the reasoning of the judgment under appeal is based on the factual premiss that that medicinal product was assessed for the first and only time in 1994. By way of consequence, I also invite the Court to consider that the present case was not made subject to the condition of ‘particular circumstances’, as established by the General Court, in a manner which suggests that the BfArM assessment as regards Fumaderm could be outdated or could have failed to apply the relevant regulatory criteria.
85.
Finally, because the conclusion reached by the General Court in paragraph 293 of the judgement under appeal (
42
) cannot be justified in the light of the ‘particular circumstances’ of the present case, nor rooted in the wording or in the objectives of ‘global marketing authorisations’, as defined in Directive 2001/83, I take the view that the second ground of appeal in Cases C‑438/21 P and C‑439/21 P and the third ground of appeal in Case C‑440/21 P, on the one hand, and the first ground of appeal in Cases C‑438/21 P and C‑440/21 P and the third ground in Case C‑439/21 P, on the other, should be upheld.
B.
Ground of appeal based on the infringement of the principle of conferral of powers and the principle of mutual recognition
86.
As stated above, in paragraph 282 of the judgment under appeal, the General Court considered that, ‘in view of … the particular function performed by the EMA and the Commission’, (
43
) the latter should have asked the CHMP to verify the role played by MEF within Fumaderm, either on its own or through the BfArM.
87.
That finding stems from the analysis set out in paragraphs 219 to 238 of the judgment under appeal, in which the General Court examined several recitals and provisions of Directive 2001/83 and Regulation No 726/2004 supporting the conclusion that, in its view, the Commission and the EMA perform a particular function that should have obliged them to seek a verification of the therapeutic effect of MEF within Fumaderm.
88.
In those same paragraphs, the General Court states that the ‘principle of mutual recognition relied on by the EMA cannot […] prevent, following the submission of an application for marketing authorisation under the centralised procedure, the CHMP from examining the assessments previously carried out by a national authority or from itself carrying out an independent assessment’.
89.
The appellants contest both findings. They argue, first, that the reasoning of the judgement under appeal is manifestly incorrect in the light of the provisions of Directive 2001/83 and Regulation No 726/2004, which were relied on by the General Court. Second, they submit that the relevant Union legislation and case-law expressly acknowledge the principle of mutual recognition of previous scientific assessments – in particular, from national competent authorities – which the findings of the General Court directly undermine and contradict.
90.
In turn, Polpharma considers that the findings of the General Court are at no way inconsistent with the functioning of the system of decentralised application of EU pharmaceutical legislation. It states that the General Court’s decision does not amount to calling into question the assessment conducted by BfArM in relation to Fumaderm, because that national authority never performed any assessment related to the scope of the global marketing authorisation of that medicinal product. Moreover, it submits that the appellants’ submissions are based on a strict reading of the provisions of Directive 2001/83 and Regulation No 726/2004, as cited by the General Court.
1. The provisions of Directive 2001/83 and Regulation No 726/2004 relied on by the General Court
91.
It is important to understand, in the first place, that, in order to avoid ultra vires conduct, any institution or agency of the European Union must derive its competence from a legal act and state a legal basis for the decision to be adopted. In the judgment under appeal, the General Court relied on three sets of provisions for the purpose of establishing the obligation to reassess or verify, in the context of a global marketing authorisation, the correctness of the assessment by a national authority of the qualitative composition, in terms of active substances, of the initial medicinal product. Those sets of provisions are:
–
first, recital 12 and Article 30(1) of Directive 2001/83 and recital 17 of Regulation No 726/2004, which relate to the so-called ‘arbitration referral’;
–
second, Article 31 of Directive 2001/83, which concerns the EU referral procedure; and
–
third, recital 19 and Article 57(1) and Article 60 of Regulation No 726/2004, which relate to the EMA’s obligation to provide the best possible scientific advice and the power granted to the Commission to collect information from Member States on the ‘added therapeutic value’ of new medicinal products.
92.
In my view, in the absence of an express power granted to the Commission and the EMA under Directive 2001/83 or Regulation No 726/2004, the provisions cited by the General Court cannot be relied upon – not even under a combined reading – to maintain that the Commission had the competence in the present case to reassess the qualitative evaluation carried out by the BfArM at the time of the authorisation of the medicinal product Fumaderm and even less so at the time of the renewal of that authorisation in 2013.
93.
The first set of recitals and provisions cited – namely recital 12 and Article 30(1) of Directive 2001/83 and recital 17 of Regulation No 726/2004 – refer to the importance of resolving, through a centralised system of assessment and decision, any disagreement that might arise between Member States as to the authorisation of a particular medicinal product under the mutual recognition and decentralised procedure. More specifically, those provisions concern the situation in which Member States disagree about the grant of a marketing authorisation by a national authority of another Member State on the ground of a potential serious risk to public health. Only in the event that, within the context of a threat to public health, such disagreement cannot be resolved among the Member States concerned must the issue be referred to the EMA on the basis of Article 29(4) of Directive 2001/83.
94.
By contrast, the present case concerns a medicinal product authorised solely in one Member State. Therefore, there was no mutual recognition or decentralised procedure, no dispute regarding the effects on human health of Fumaderm, and no disagreement between any Member States so as to justify the application of Article 29(4) of Directive 2001/83.
95.
Under the second set of provisions cited, the General Court referred to Article 31(1) of Directive 2001/83, which governs the European Union interest referral procedure. As the Commission and the EMA explain in their written observations, that procedure concerns products authorised in more than one Member State. It may be triggered ‘in specific cases where the interests of the Union are involved’, when ‘the Member States, the Commission, the applicant or the marketing authorisation holder … refer the matter to the [CHMP] before any decision is reached on an application for a marketing authorisation or on the suspension or revocation of a marketing authorisation, or on any other variation of the marketing authorisation which appears necessary’.
96.
I observe that the scope of application of Article 31(1) of Directive 2001/83 was the subject matter of the judgment of the General Court in August Wolff and Remedia v Commission, (
44
) in which that court held that it is only when authorisations of the same medicinal product are granted in several Member States and there is uncertainty surrounding their active substance that the concept of ‘interests of the Union’ assumes its full role. That concept is applicable in situations where a medicinal product is authorised in more than one Member State. A referral under Article 31(1) of Directive 2001/83 may not be triggered in respect of products that are authorised solely in one Member State.
97.
In the present case, I do not think that the link drawn by the General Court between Article 31(1) of Directive 2001/83 and the competence of the Commission to verify the file relating to a product that is authorised solely in one Member State is supported by that provision.
98.
In relation to the third set of provisions cited by the General Court, reference is made to Article 60 of Regulation No 726/2004, which is linked to the gathering of information that Member States have at their disposal for the purpose of evaluating the added therapeutic value of a new medicinal product in matters relating to pricing and reimbursement. In my view, it is clear that that provision does not confer on the Commission the power to verify a scientific assessment, made at national level, that was conducted with a view to placing a medicinal product on the market on the territory of that Member State.
99.
Finally, and in a similar vein, recital 19 and Article 57(1) of Regulation No 726/2004 do not militate in favour of power being conferred by the General Court on the Commission and the EMA. The first sentence of recital 19 merely states that the EMA is to ‘provide [EU] institutions and Member States with the best possible scientific opinions’. That sentence thus requires the agency to abide by a standard of scientific excellence when adopting its opinions in the context of the procedures that empower the EMA to do this. However, it does not establish any power of the EMA in this regard vis-à-vis the Member States. For its part, Article 57(1) of Regulation No 726/2004 sets out a standard of excellence and an obligation to advise on questions relating to the evaluation of the quality, safety and efficacy of medicinal products. Yet, the wording of that provision makes it clear that standard and obligation applies to ‘any question … referred to it in accordance with the provisions of [EU] legislation relating to medicinal products’, which means that an express competence needs to stem from Regulation No 726/2004 for Article 57(1) thereof to be applied.
100.
For all of the reasons described above, to my mind, the General Court was not entitled to conclude that the Commission and the EMA perform a ‘particular function’, which would specifically permit – or even oblige – either body to reassess the marketing authorisation of a fixed combination medicinal product granted by a national competent authority following a decision having been made as to whether a mono-substance medicinal product composed of one of the substances of that fixed combination belongs to the same global marketing authorisation.
2. The principle of mutual recognition of previous scientific assessments of medicinal products
101.
In the second place, it is important to note that, as the General Court itself has declared in its case-law, Directive 2001/83 and Regulation No 726/2004 ‘form a uniform, harmonised set of rules in so far as concerns the substantive law applicable to the authorisation of medicinal products’, whereby, ‘irrespective of the procedure [– at national or EU level –] medicinal products must satisfy the same substantive requirements and may claim the same protection’. (
45
) Indeed, the principle of mutual recognition of previous scientific assessments of medicinal products emanates from the fact that both the EU authorities and the national competent authorities are subject to the same fully harmonised rules, with the purpose, as pointed out by the EMA, to create a common market for medicinal products.
102.
I observe further that, irrespective of the procedure followed for the authorisation of a medicinal product – national or centralised – the harmonised nature of EU pharmaceutical legislation is reflected in recital 14 of Regulation No 726/2004. That recital declares that ‘provision should be made for the quality, safety and efficacy criteria in [Directives 2001/83 and 2001/82] to apply to medicinal products authorised by the [European Union] and it should be possible to assess the risk-benefit balance of all medicinal products when they are placed on the market, at the time of the renewal of the authorisation and at any other time the competent authority deems appropriate’.
103.
Regarding the principle of mutual recognition of previous scientific assessments, it is worth noting, in line with the EMA’s observations, that recital 9 of Regulation No 726/2004 states that the Commission may authorise, at the centralised level, generic medicinal products where the reference medicinal product has been authorised either by the Commission, via the centralised procedure, or by a national competent authority, via the mutual recognition or decentralised procedures. In the context of the centralised authorisation of a generic medicinal product, that same recital requires the Commission to refrain from undermining the harmonisation achieved when the reference medicinal product was – either centrally or nationally – authorised.
104.
The principle of mutual recognition of previous scientific assessments was also the main subject-matter of the judgments rendered by the Court in the Synthon (
46
) and Astellas (
47
) cases. In the first of those judgements, the Court found that it cannot be accepted that a Member State in receipt of an application for mutual recognition is entitled – outside of the situation where there is a risk to public health referred to in Article 29 [of Directive 2001/83] – to carry out a fresh assessment of the data on essential similarity which the reference Member State relied on in accepting an abridged application. According to the Court, not only would such an interpretation run counter to the very wording of Articles 28 and 29 of Directive 2001/83, but it would render those provisions redundant. If a Member State which was asked to recognise an authorisation already granted by another Member State could make that recognition subject to a second assessment of all or part of the application for authorisation, that would deprive the mutual recognition procedure established by the EU legislature of all meaning and seriously compromise the attainment of the objectives of Directive 2001/83. (
48
) Even though that judgment results from a dispute concerning the national authorities of different Member States, the same interpretation should apply when the Commission and the EMA are involved.
105.
Besides, it follows from the judgment in Astellas that the competent courts of Member States do not have jurisdiction to assess, on the application of a producer of generic medicinal products, the compatibility with Directive 2001/83 of a decision granting marketing authorisations adopted in another Member State. A parallel approach must apply a fortiori to the bodies of the European Union, namely the Commission and the EMA, which, unless expressly provided for by the applicable legislation, should not contest the decisions adopted by the Member States. Indeed, as the Commission submits, the Astellas case-law invites the interpretation that a generic company requesting the marketing authorisation for its product – be it at national or at EU level – has the possibility of challenging the decision granting a marketing authorisation for the initial medicinal product before the national courts in the Member State where that authorisation was granted. That possibility also exists in relation to the decision to renew the marketing authorisation adopted by national authorities, which makes it possible to challenge the assessment made by that authority in relation to the qualitative composition of the medicinal product at issue.
106.
On the basis of the above considerations, it is clear that, not only Member State authorities, but also European Union bodies, should be obliged to recognise the previous scientific assessments relating to a given medicinal product, unless there are specific reasons related to public health – for instance, doubts surrounding the safety of the product – that would result in the triggering of a new assessment. As already indicated, that consideration relies on the existence of the same legislative and regulatory framework, which is intended to lead to the same outcome and that eliminates, for this reason, the need to verify the previous assessment of competent authorities.
107.
For all the abovementioned reasons, I take the view that the principle of mutual recognition should be interpreted in the present case as preventing the imposition of an obligation on the Commission and the EMA to verify the therapeutic relevance of MEF within Fumaderm, given that that would entail reassessing the qualitative composition of that medicinal product, for which a market authorisation had been granted by the BfArM.
108.
Moreover, given the absence of an express competence recognised under Directive 2001/83 and Regulation No 726/2004, I conclude that the General Court could not lawfully establish that the Commission and the EMA had the competence to reassess the marketing authorisation of a fixed combination medicinal product granted by a national competent authority following the decision as to whether a mono-substance medicinal product composed of one of the substances of that fixed combination belongs to the same global marketing authorisation.
109.
The third ground of appeal in Case C‑438/21 P, the fourth ground of appeal in Case C‑439/21 P and the second ground of appeal in Case C‑440/21 P should therefore be upheld by the Court.
C.
Final remarks
110.
At points 85 and 109 of the present Opinion, I propose the Court to uphold the grounds of appeal submitted by the appellants based, first, on the infringement of the second subparagraph of Article 6(1) of Directive 2001/83 and the absence of particular circumstances justifying the conclusion adopted by the General Court in the judgment under appeal and, second, the infringement of the principle of conferral of powers and mutual recognition. The judgment under appeal should consequently be set aside.
111.
Under the first paragraph of Article 61 of the Statute of the Court of Justice of the European Union, if the decision of the General Court is quashed, the Court of Justice may give final judgment in the matter where the state of the proceedings so permits. That is my position in the present case. Absent the infringements established, the General Court would have found that the Commission correctly concluded in the 2014 Decision that Fumaderm and Tecfidera, inasmuch as they are different medicinal products, did not belong to the same global marketing authorisation. Consequently, the plea of illegality invoked by Polpharma in first instance would have been dismissed and the contested decision would have not been annulled.
112.
Finally, under Article 184(2) of the Rules of Procedure of the Court of Justice, the Court is to make a decision as to costs where the appeal is well founded and the Court itself gives final judgment in the case. Under Article 138(1) of the Rules of Procedure, which applies 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. In the present case, since the appellants have applied for Polpharma to be ordered to pay the costs of the proceedings before the General Court and the Court of Justice, and since Polpharma should be, in my view, unsuccessful in its pleadings, Polpharma should be ordered to pay the appellant’s costs and its own costs both at first instance and on appeal.
VI. Conclusion
113.
In the light of the foregoing, I suggest that the Court:
–
set aside the judgment of the General Court of the European Union (Seventh Chamber, Extended Composition) of 5 May 2021, Pharmaceutical Works Polpharma v EMA (T‑611/18, EU:T:2021:241);
–
dismiss the action for annulment brought by Pharmaceutical Works Polpharma S.A. at first instance;
–
order Pharmaceutical Works Polpharma S.A. to pay the costs.
(
1
)	Original language: English.
(
2
)	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 2011 L 311, p. 67), as subsequently amended.
(
3
)	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).
(
4
)	Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products (OJ 1993 L 214, p. 1).
(
5
)	Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products (OJ 2001 L 311, p. 1).
(
6
)	See paragraph 293 of the judgment under appeal.
(
7
)	See also judgment of 28 June 2017, Novartis Europharm v Commission (C‑629/15 P and C‑630/15 P, EU:C:2017:498, paragraphs 69 and 72), where the Court specified that the second subparagraph of Article 6(1) of Directive 2001/83 covers all developments of the original medicinal product, irrespective of their authorisation procedures, namely through the variation of an initial marketing authorisation for that medicinal product or through the grant of a separate marketing authorisation.
(
8
)	See, in that regard, Opinion of Advocate General Bobek in Joined Cases Novartis Europharm v Commission (C‑629/15 P and C‑630/15 P, EU:C:2016:1003, point 32 and 33).
(
9
)	See, in that respect, Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use (OJ 2004 L 136, p. 34). See also paragraph 176 of the judgment under appeal.
(
10
)	See, in that regard, judgment of 3 December 1998, Generics (UK) and Others (C‑368/96, EU:C:1998:583, paragraph 44, 53 and 56), and of 29 April 2004, Novartis Pharmaceuticals (C‑106/01, EU:C:2004:245, paragraph 69). In essence, that case-law referred to whether the research of a new indication alone or a different pharmaceutical form for the same active substance changed the product and justified a new regulatory data protection period. In the latter of those judgments, the Court concluded that such changes are variants of the same product, which do not attract a new regulatory data protection period.
(
11
)	See the non-contested definition provided by the EMA on its website, available at https://www.ema.europa.eu/en/glossary/pharmaceutical-form.
(
12
)	See the non-contested definition provided by the EMA on its website, available at https://www.ema.europa.eu/en/glossary/route-administration.
(
13
)	See European Medicines Agency pre-authorisation procedural advice for user of the centralised procedure (version of 20 June 2022), Sub-section 4.7.2 ‘Presentations’, p. 122.
(
14
)	Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products (OJ 2008 L 334, p. 7), which replaced Commission Regulation (EC) No 1085/2003 of 3 June 2003 concerning the examination of variations to the terms of a marketing authorisation for medicinal products for human use and veterinary medicinal products falling within the scope of Council Regulation (EEC) No 2309/93 (OJ 2003 L 159, p. 24). See also judgment of 28 June 2017, Novartis Europharm v Commission (C‑629/15 P and C‑630/15 P, EU:C:2017:498, paragraph 69).
(
15
)	As the appellants point out, the distinction between ‘variations’ and ‘extensions’ is made in the light of the complexity of assessment required in each case and the level of risk to human health arising from the possible effect of the change(s) to the product on the quality, safety and efficacy of the product. The minor category consists of variations of type I, whereas the major category consists of extensions, for which Article 19 of Regulation No 1234/2008 requires that the same assessment procedure be followed as for the grant of the original marketing authorisation.
(
16
)	Emphasis added.
(
17
)	For a list of the variations authorised for the medicinal product Tecfidera since the adoption of the 2014 Decision, see Tecfidera: EPAR – Procedural steps taken and scientific information after the authorisation, available at https://www.ema.europa.eu/en/documents/procedural-steps-after/tecfidera-epar-procedural-steps-taken-scientific-information-after-authorisation_en.pdf.
(
18
)	Gerstenblith, B.A., ‘An “active ingredient” of a drug must be present when the drug is administered’, Journal of Intellectual Property Law & Practice, vol. 6(2), February 2011, pp. 69-71.
(
19
)	Judgment of 20 January 2005, SmithKline Beecham (C‑74/03, EU:C:2005:39, paragraph 43 and 44), where a pharmaceutical undertaking contested the granting of a marketing authorisation to a generic medicinal product on the ground that that product was not essentially similar to the reference product. In that case, the Court held that an application for a marketing authorisation of a medicinal product is to be handled under the abridge procedure where the product at issue contains the same therapeutic moiety as the reference product but combined with another salt. See ‘Products may be essentially similar with same active substance in different salts’, EU Focus, 2005, 159, pp. 19-20.
(
20
)	See, for instance, Commission Regulation (EU) 2018/781 of 29 May 2018 amending Regulation (EC) No 847/2000 as regards the definition of the concept ‘similar medicinal product’ (OJ 2018 L 132, p. 1).
(
21
)	Opinion of Advocate General Bobek in Joined Cases Novartis Europharm v Commission (C‑629/15 P and C‑630/15 P, EU:C:2016:1003).
(
22
)	Ibid., point 43, citing, in that regard, Manley, M.I., and Vickers, M., Navigating European Pharmaceutical Law, Oxford University Press, Oxford, 2015, p. 264, point 8.33.
(
23
)	Ibid., point 46.
(
24
)	Notice to Applicants, Volume 2A: Procedures for marketing authorisation, Chapter 1: Marketing authorisation, July 2015, point 2.3, p. 9. See, also, the current version, of July 2019, of this same document.
(
25
)	Ibid., point 45.
(
26
)	See paragraph 292 of the judgment under appeal.
(
27
)	The problem was that, first, the two medicinal products had been authorised by the granting of a separate marketing authorisation and, second, the dosages and therapeutic indications were not the same.
(
28
)	In particular, in its judgment of 28 June 2017, Novartis Europharm v Commission (C‑629/15 P and C‑630/15 P, EU:C:2017:498, paragraph 66), the Court held that the words ‘any variations and extensions’ in the second subparagraph of Article 6(1) of Directive 2001/83 refer to a ‘variation to the terms of a marketing authorisation’ or an ‘extension of the marketing authorisation’, within the meaning of Commission Regulation (EC) No 1085/2003 of 3 June 2003 concerning the examination of variations to the terms of a marketing authorisation for medicinal products for human use and veterinary medicinal products falling within the scope of Regulation No 2309/93 (OJ 2003 L 159, p. 24). That regulation preceded Regulation No 1234/2008, cited in point 55 above.
(
29
)	Judgment of 16 November 2016, Hemming and Others (C‑316/15, EU:C:2016:879, paragraph 27 and the case-law cited).
(
30
)	See paragraph 176 of the judgment under appeal.
(
31
)	See, in that regard, Opinions of Advocate General Léger in Schulte (C‑350/03, EU:C:2004:568, points 84 to 88 and the case-law cited), and of Advocate General Bobek in European Federation for Cosmetic Ingredients (C‑592/14, EU:C:2016:179, point 37 and the case-law cited).
(
32
)	See, in that regard, judgment of 14 December 2011, Nycomed Danmark v EMA (T‑52/09, EU:T:2011:738, paragraph 71).
(
33
)	See point 57 above.
(
34
)	The reasoning of the General Court is further elaborated in paragraphs 181 to 218 of the judgment under appeal, in which it is stated inter alia that ‘the content of the guidelines relating to combination medicinal products and the scope of information requested from applicants evolved significantly between the date of the marketing authorisation for Fumaderm (9 August 1994) and the day when the implementing decision of 30 January 2014 was adopted’.
(
35
)	See the EMA’s defence before the General Court, paragraph 37 and Annex B.2.
(
36
)	Emphasis added.
(
37
)	See the Notice of Applicants in its version of November 2005, applicable in 2013.
(
38
)	CHMP/EWP/240/95 Rev. 1 (19 February 2009), available at https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-development-fixed-combination-medicinal-products-revision-1_en.pdf.
(
39
)	See paragraphs 205 to 207 of the judgement under appeal.
(
40
)	BGBl. 2005 I, No 73, p. 3394, as subsequently amended. An English version of the Law on medicinal products is available at https://www.gesetze-im-internet.de/englisch_amg/.
(
41
)	Order of 31 March 2011, Mauerhofer v Commission (C‑433/10 P, not published, EU:C:2011:204, paragraphs 69 and 71).
(
42
)	See point 42 of the present Opinion.
(
43
)	Emphasis added.
(
44
)	Judgment of 20 October 2016, August Wolff and Remedia v Commission (T‑672/14, EU:T:2016:623). See, in particular, paragraphs 59 to 66 of that judgment.
(
45
)	See, in that regard, judgment of 15 September 2015, Novartis Europharm v Commission (T‑472/12, EU:T:2015:637, paragraphs 74 and 76).
(
46
)	Judgment of 16 October 2008, Synthon (C‑452/06, EU:C:2008:565).
(
47
)	Judgment of 14 March 2018, Astellas Pharma (C‑557/16, EU:C:2018:181) (‘the judgment in Astellas’).
(
48
)	Judgment of 16 October 2008, Synthon (C‑452/06, EU:C:2008:565, paragraphs 31 and 32).