62022TJ0483
JUDGMENT OF THE GENERAL COURT (Fifth Chamber, Extended Composition)
24 September 2025 (
*1
)
(Public health – Medicinal products for human use – Marketing authorisation for the medicinal product Nexviadyme (avalglucosidase alfa) – Non-recognition of avalglucosidase alfa as a new active substance – Directive 2001/83/EC – Regulation (EC) No 726/2004 – Commission document ‘Notice to Applicants, Volume 2A, Procedures for marketing authorisation, Chapter 1, Marketing Authorisation’ – Standard of proof – Obligation to state reasons – Principle of good administration – Right to be heard – Decision to remove the medicinal product from the European Union Register of Orphan Medicinal Products – Regulation (EC) No 141/2000 – Regulation (EC) No 847/2000 – Significant benefit – Standard of proof – Obligation to state reasons)
In Case T‑483/22,
Sanofi BV, formerly Genzyme Europe BV, established in Amsterdam (Netherlands), represented by P. Bogaert, B. Van Vooren and V. Sturla, lawyers,
applicant,
supported by
European Confederation of Pharmaceutical Entrepreneurs (Eucope), established in Brussels (Belgium), represented by C. Schoonderbeek, lawyer,
intervener,
v
European Commission, represented by E. Mathieu, M. Owsiany-Hornung and A. Spina, acting as Agents,
defendant,
supported by
European Medicines Agency (EMA), represented by S. Drosos, H. Kerr, S.‑M. Kamo and G. Gavriilidou, acting as Agents,
intervener,
THE GENERAL COURT (Fifth Chamber, Extended Composition),
composed, at the time of the deliberations, of J. Svenningsen, President, C. Mac Eochaidh (Rapporteur), J. Laitenberger, J. Martín y Pérez de Nanclares and M. Stancu, Judges,
Registrar: P. Cullen, Administrator,
having regard to the written part of the procedure,
further to the hearing on 10 September 2024,
gives the following
Judgment
1
By its action under Article 263 TFEU, the applicant, Sanofi BV (formerly Genzyme Europe BV), seeks the partial annulment of Commission Implementing Decision C(2022) 4531 final of 24 June 2022 granting marketing authorisation for Nexviadyme – avalglucosidase alfa, a biological medicinal product for human use (‘the contested decision’), first, in so far as that decision implicitly finds that avalglucosidase alfa is not a new active substance (‘NAS’) and, second, in so far as Article 5 of that decision states that the medicinal product in question is not to be classified as an orphan medicinal product.
Legal context
The concepts of biological medicinal product and active substance
2
The third subparagraph of point 3.2.1.1 (b) of Part I of Annex I to 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 (EU) 2022/642 of the European Parliament and of the Council of 12 April 2022 (OJ 2022 L 118, p. 4) (‘Directive 2001/83’), states that a ‘biological medicinal product is a product, the active substance of which is a biological substance’.
3
Article 1(3a) of Directive 2001/83 defines an ‘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 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’.
4
According to the third subparagraph of point 3.2.1.1 (b) of Part I of Annex I to Directive 2001/83, a biological substance is a substance that is produced by or extracted from a biological source and that needs for its characterisation and the determination of its quality a combination of physico-chemical-biological testing, together with the production process and its control.
5
According to Annex I to Directive 2001/83, the starting materials of biological medicinal products may include micro-organisms, organs and tissues of either plant or animal origin, cells or fluids (including blood or plasma) of human or animal origin, and biotechnological cell constructs.
The procedure for examining applications for a marketing authorisation
6
The procedure for obtaining a marketing authorisation (‘MA’) for a medicinal product in the European Union is governed by Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Union procedures for the authorisation and supervision of medicinal products for human use and establishing a European Medicines Agency (OJ 2004 L 136, p. 1), as amended by Regulation (EU) 2019/5 of the European Parliament and of the Council of 11 December 2018 (OJ 2019 L 4, p. 24) (‘Regulation No 726/2004’) and by Directive 2001/83.
7
According to Article 3(1) of Regulation No 726/2004 and Article 6(1) of Directive 2001/83, no medicinal product may be placed on the market of the European Union or of a Member State unless an MA has been granted by the Union or the competent authorities of the Member State.
8
Regulation No 726/2004 provides for a centralised MA procedure for certain medicinal products, including those designated as ‘orphan medicinal products’ in accordance with Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products (OJ 2000 L 18, p. 1), as amended by Regulation (EU) 2019/1243 of the European Parliament and of the Council of 20 June 2019 (OJ 2019 L 198, p. 241) (‘Regulation No 141/2000’).
9
Under Article 5(2), Article 6(3) and Article 56(1)(a) of Regulation No 726/2004, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) is responsible for drawing up the EMA’s opinion on the granting of an MA for a medicinal product for human use and on any question relating to the evaluation of medicinal products for human use.
10
According to Article 9(3) of Regulation No 726/2004, the EMA is to forward the opinion of the CHMP to the European Commission, the Member States and the applicant for the MA. Under Article 9(2) of that regulation, the applicant for an MA may request a re-examination of the CHMP’s opinion.
11
The first subparagraph of Article 10(1) of Regulation No 726/2004 provides that, following receipt of the CHMP’s opinion, the Commission is to prepare a draft decision on the MA application. The fourth subparagraph of Article 10(1) of that regulation provides that where the draft decision differs from the opinion of the EMA, the Commission is to attach a detailed explanation of the reasons for those differences. The draft decision is to be forwarded to Member States and the applicant. Under Article 10(2) of that regulation, read in conjunction with Article 87 thereof, the Commission is then to take a final decision after obtaining the opinion of the Standing Committee on Medicinal Products for Human Use.
The concepts of ‘regulatory data protection period’ and ‘regulatory marketing protection period’
12
In accordance with Article 10(2)(b) of Directive 2001/83 a generic medicinal product is, in essence, 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.
13
The first and second subparagraphs of Article 10(1) of Directive 2001/83 permit the authorisation of generic medicinal products in the following terms:
‘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.’
14
According to recital 11 of Regulation No 726/2004, for medicinal products for human use, the period for protection of data relating to pre-clinical tests and clinical trials should be the same as that provided for in Directive 2001/83. Article 14(11) of Regulation No 726/2004 provides as follows:
‘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 …’
The concepts of ‘global marketing authorisation’ and ‘extension of an MA’
15
The second subparagraph of Article 6(1) of Directive 2001/83 introduces the concept of ‘global marketing authorisation’ as follows:
‘When a medicinal product has been granted an initial marketing authorisation …, 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).’
16
Article 2(4) of 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), as amended by Commission Delegated Regulation (EU) 2021/756 of 24 March 2021 (OJ 2021 L 162, p. 1) (‘Regulation No 1234/2008’), provides that, for the purposes of that regulation, ‘extension of a marketing authorisation’ or ‘extension’ means a variation which is listed in Annex I and fulfils the conditions laid down therein.
17
Annex I to Regulation No 1234/2008, entitled ‘Extensions of marketing authorisations’, provides as follows:
‘1. Changes to the active substance(s):
(a)
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;
(b)
replacement by a different isomer, a different mixture of isomers, of a mixture by an isolated isomer (e.g. racemate by a single enantiomer), where the efficacy/safety characteristics are not significantly different;
(c)
replacement of a biological active substance with one of a slightly different molecular structure where the efficacy/safety characteristics are not significantly different …
…’
Commission document entitled ‘Notice to Applicants, Volume 2A, Procedures for marketing authorisation, Chapter 1, Marketing Authorisation’
18
The Commission document entitled ‘Notice to Applicants, Volume 2A, Procedures for marketing authorisation, Chapter 1, Marketing Authorisation – July 2019 (Revision 11)’ (‘the Notice to Applicants’) was prepared by the Commission on the basis of Article 6(4) of Regulation No 726/2004 and Annex I to Directive 2001/83, in consultation with the EMA, the Member States and interested parties, and reflects the harmonised view of the Member States, the EMA and the Commission.
19
Section 2.3 of the Notice to Applicants, entitled ‘Notion of “global marketing authorisation”’, contains the following information relating to the concept of a new active substance (NAS):
‘If the medicinal product being assessed contains a modification of an existing active substance, it should be clarified during the marketing authorisation procedure whether the product contains a new active substance or not. This clarification impacts on the existence or not of a global marketing authorisation if the medicinal products belong to the same marketing authorisation holder. Request for a new active substance claim should be submitted within the initial marketing authorisation application for medicinal product containing the modified substance and will not be considered retroactively. This assessment is to be done in accordance with the definition of a new active substance provided in Annex I [to the Notice to Applicants] and the conclusion should be reflected at least in the assessment report. If the assessment report does not indicate that the product contains a new active substance, it will be considered that the product at stake contains the same active substance and belongs to the global marketing authorisation of the already authorised medicinal product(s)…’
20
Annex I to the Notice to Applicants, entitled ‘Definition of a new active substance’, states that a new chemical, biological or radiopharmaceutical active substance includes, inter alia:
–
a chemical, biological or radiopharmaceutical substance not previously authorised in a medicinal product for human use in the European Union (‘the first indent of Annex I to the Notice to Applicants’);
–
an isomer, mixture of isomers, a complex or derivative or salt of a chemical substance previously authorised in a medicinal product for human use in the European Union but differing significantly in properties with regard to safety and/or efficacy from that chemical substance previously authorised (‘the second indent of Annex I to the Notice to Applicants’);
–
a biological substance previously authorised in a medicinal product for human use in the European Union, but differing significantly in properties with regard to safety and/or efficacy which is due to differences in one or a combination of the following: in molecular structure, nature of the source material or manufacturing process (‘the third indent of Annex I to the Notice to Applicants’).
The designation of medicinal products as ‘orphan medicinal products’ and the procedure for examining applications for marketing authorisations for those medicinal products
21
It is apparent from recitals 1 and 2 of Regulation No 141/2000 that the European Union is seeking to stimulate the research, development and bringing to the market of appropriate medications by the pharmaceutical industry for conditions that occur so infrequently that the cost of developing and bringing to the market a medicinal product to diagnose, prevent or treat the condition would not be recovered by the expected sales of the medicinal product (‘orphan medicinal products’).
22
To that end, the EU legislature provided in particular in Article 8(1) of Regulation No 141/2000 that, where an MA is granted in respect of an orphan medicinal product, the European Union and the Member States are not, for a period of 10 years, to accept another application for an MA, or grant an MA or accept an application to extend an existing MA, for the same therapeutic indication, in respect of a similar medicinal product.
23
Under Article 3(1) of Regulation No 141/2000, a medicinal product is to 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 [European Union] and that without incentives it is unlikely that the marketing of the medicinal product in the [European 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 [European Union] or, if such method exists, that the medicinal product will be of significant benefit to those affected by that condition.’
24
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 that, for the purposes of the implementation of Article 3 of Regulation No 141/2000, ‘significant benefit’ means a clinically relevant advantage or a major contribution to patient care.
25
Under Article 56(1)(c) of Regulation No 726/2004 and Article 4(2)(a) and Article 5(5) and (12)(b) of Regulation No 141/2000, the Committee for Orphan Medicinal Products (COMP) of the EMA is responsible for examining any application for the designation of a medicinal product as an orphan medicinal product which is submitted to it by sponsors of candidate orphan medicinal products and for carrying out the subsequent re-assessment of compliance with the designation criteria at the stage of the MA application for the medicinal product in question.
26
Article 5(1) of Regulation No 141/2000 provides that, in order to obtain the designation of a medicinal product as an orphan medicinal product, the sponsor must submit an application to the EMA at any stage of the development of the medicinal product before the MA application is made.
27
In accordance with Article 5(4) to (9) of Regulation No 141/2000, the application is then examined by the COMP, which is to forward an opinion to the Commission, which is to take a decision, as the case may be, to include the designated medicinal product in the EU Register of Orphan Medicinal Products.
28
Article 5(12)(b) of Regulation No 141/2000 provides that a designated orphan medicinal product is to be removed from the EU Register of Orphan Medicinal Products if it is established, before the MA is granted, that the criteria set out in Article 3 of that regulation are no longer met in respect of the medicinal product concerned.
29
Where the opinion of the COMP is that the application for designation does not satisfy the criteria set out in Article 3(1) of Regulation No 141/2000, Article 5(7) of that regulation provides that the sponsor may submit detailed grounds for appeal to the COMP, which is to consider whether its opinion should be revised.
30
In accordance with Article 5(8) of Regulation No 141/2000, the final opinion of the COMP is to be forwarded to the Commission, which is to adopt a decision.
Background to the dispute
Development of the medicinal product Nexviadyme – avalglucosidase alfa
31
The applicant has since March 2006 held an MA for the medicinal product Myozyme, a biological medicinal product, the active substance of which is alglucosidase alfa. Myozyme is an enzyme replacement therapy indicated for patients with Pompe disease, a rare inherited disorder. Myozyme provides patients with the recombinant version of the acid alpha-glucosidase enzyme that they are missing.
32
In order to improve the treatment of patients suffering from Pompe disease, the applicant redesigned the molecular structure of the active substance of Myozyme, namely alglucosidase alfa, by conjugating it, that is to say, chemically linking it, with multiple copies of a synthetic glycan called ‘E13 (bis-mannose-6-phosphate-tetra-mannose glycan)’.
33
On 26 March 2014, the Commission adopted a decision by which the redesigned enzyme replacement therapy, at the time called ‘recombinant human alpha-glucosidase conjugated with multiple copies of synthetic bismannose-6-phosphate-tetra-mannose glycan’, of which the applicant is the sponsor, was designated as an orphan medicinal product for the treatment of Pompe disease and entered in the EU Register of Orphan Medicinal Products under Article 5(9) of Regulation No 141/2000.
34
In November 2015, following its request for scientific advice under Article 57(1)(n) of Regulation No 726/2004, in the version then applicable, the applicant obtained protocol assistance from the EMA concerning the development of the redesigned enzyme replacement therapy, at the time designated under the references of candidate medicinal product ‘neoGAA’ or ‘GZ402666’ (‘the protocol assistance’).
Application for marketing authorisation
35
On 11 September 2020, the applicant submitted an application to the EMA for an MA for the medicinal product ‘Nexviadyme – avalglucosidase alfa’ in accordance with the centralised procedure at EU level. The application was accompanied by an annex setting out the reasons why, according to the applicant, the active substance of Nexviadyme, namely avalglucosidase alfa, should be regarded as an NAS. The applicant also submitted two reports to the EMA in support of maintaining the designation of the medicinal product as an orphan medicinal product at the time of the granting of the MA.
36
The EMA’s assessment procedure of the file concerning the MA application commenced on 1 October 2020.
37
On 20 July 2021, a meeting was held to hear the applicant’s oral explanations.
38
On 23 July 2021, the CHMP, pursuant to Article 7 of Regulation No 726/2004, issued an opinion recommending, by consensus, that the Commission grant an MA for Nexviadyme and finding that avalglucosidase alfa was not an NAS (‘the CHMP opinion of 23 July 2021’).
39
The proposal to reject NAS status in respect of avalglucosidase alfa was based on a CHMP assessment report, also dated 23 July 2021, which stated that that substance could not be classified as an NAS, whether under the definition of that concept in the first indent of Annex I to the Notice to Applicants or under the definition thereof set out in the third indent of that annex.
40
The CHMP opinion of 23 July 2021 also stated that, in accordance with Article 5(12) of Regulation No 141/2000, the COMP would provide an opinion on whether or not to maintain the designation of Nexviadyme as an orphan medicinal product.
Re-examination of the application for NAS status
41
On 27 July 2021, the applicant, in accordance with Article 9(2) of Regulation No 726/2004, submitted a request to the EMA for a re-examination in part of the CHMP opinion of 23 July 2021, which concerned solely the refusal of NAS status for avalglucosidase alfa. On 9 September 2021, the applicant submitted its detailed grounds for re-examination.
42
On 8 November 2021, the applicant made an oral presentation to the CHMP.
43
On 11 November 2021, the CHMP adopted a final opinion by consensus, finding that avalglucosidase alfa was not an NAS (‘the final opinion of the CHMP’).
44
The final opinion of the CHMP is based on a final assessment report, also dated 11 November 2021 (‘the final assessment report of the CHMP’), which was appended to the final opinion.
45
According to the final assessment report of the CHMP, avalglucosidase alfa could not be qualified as an NAS in itself, under the definition of that concept set out in the first indent of Annex I to the Notice to Applicants, since it is structurally related to alglucosidase alfa, the previously authorised active substance of Myozyme, and its administration exposes patients to the same therapeutic moiety as alglucosidase alfa, the amino acid sequence of those two substances being the same. Nor could avalglucosidase alfa be qualified as an NAS under the definition of that concept set out in the third indent of Annex I to the Notice to Applicants owing to insufficient evidence that avalglucosidase alfa differs significantly in properties with regard to safety and/or efficacy from alglucosidase alfa.
46
The final opinion of the CHMP was forwarded to the Commission.
Designation as an orphan medicinal product
47
As regards whether or not the designation of Nexviadyme as an orphan medicinal product should be maintained, the COMP drew up a preliminary report on 9 November 2021, setting out its position on the re-assessment of compliance with the criteria for designation as an orphan medicinal product, in which it asked the applicant to justify further the significant benefit of avalglucosidase alfa over alglucosidase alfa. The applicant responded to that invitation on 22 November 2021.
48
On 20 December 2021, the COMP issued an opinion recommending, by consensus, that Nexviadyme be removed from the EU Register of Orphan Medicinal Products (‘the COMP opinion of 20 December 2021’).
49
According to the COMP, the significant benefit, within the meaning of Article 3(1)(b) of Regulation No 141/2000, of Nexviadyme over Myozyme, the latter being a satisfactory method of treating Pompe disease, was not duly demonstrated. That opinion was accompanied by a COMP position, also dated 20 December 2021, on the re-assessment of compliance with the criteria for designation as an orphan medicinal product.
Re-examination of the COMP opinion of 20 December 2021
50
On 21 March 2022, the applicant submitted detailed grounds to the EMA in support of an appeal against the COMP opinion of 20 December 2021 under Article 5(7) of Regulation No 141/2000.
51
On 12 April 2022, the applicant made an oral presentation to the COMP.
52
On 26 April 2022, the COMP adopted, by consensus, a final opinion and a final position (‘the final opinion of the COMP’ and ‘the final position of the COMP’, respectively), confirming the initial recommendation that Nexviadyme should be removed from the EU Register of Orphan Medicinal Products, on the ground that the criterion for designation laid down in Article 3(1)(b) of Regulation No 141/2000, namely the significant benefit of Nexviadyme over Myozyme, had not been established.
53
The final opinion of the COMP was sent to the Commission.
54
On 3 May 2022, a meeting took place between the applicant and the Commission’s services.
55
On 23 May 2022, the Commission prepared a draft decision envisaging the granting of an MA for Nexviadyme, which it submitted to the Standing Committee on Medicinal Products for Human Use, in accordance with Article 10 of Regulation No 726/2004.
56
On 8 June 2022, there was a further meeting between the applicant and the Commission’s services.
Contested decision
57
On 24 June 2022, the Commission adopted the contested decision, ‘having regard to the opinions of the [EMA], formulated on 11 November 2021 by the [CHMP] and on 26 April 2022 by the [COMP]’ (fifth paragraph of the introduction to that decision).
58
Article 1 of the contested decision states that the MA provided for in Article 3 of Regulation No 726/2004 is granted for the medicinal product ‘Nexviadyme – avalglucosidase alfa’.
59
However, Article 5 of the contested decision states that the ‘medicinal product “Nexviadyme – avalglucosidase alfa” shall not be classified as [an] orphan medicinal product’ and that ‘the [European Union] Register of Orphan Medicinal Products should be updated accordingly’.
60
Moreover, the contested decision does not make any explicit reference to the NAS status of avalglucosidase alfa.
Events after the adoption of the contested decision
61
On 1 July 2022, the applicant asked the EMA to provide it with copies of internal EMA documents and communications relating to the file on Nexviadyme and of communications between the EMA and the Commission relating to that file between April and June 2022 (‘the request for access to the file’). Subsequently, the scope of that request for access to the file was limited to documents relating to the assessment of NAS status and of the purported significant benefit of avalglucosidase alfa. On 2 and 8 September 2022, the EMA provided the applicant with 42 documents in two batches.
62
On 18 November 2022, the EMA published, for public consultation, a draft reflection paper on criteria to be considered for the evaluation of NAS status of biological substances.
Forms of order sought
63
The applicant claims that the Court should:
–
annul in part the contested decision, first, in so far as that decision provides implicitly that avalglucosidase alfa is not an NAS and, second, in so far as Article 5 of that decision provides that the medicinal product Nexviadyme – avalglucosidase alfa is not to be classified as an orphan medicinal product;
–
order the Commission to bear the costs.
64
The Commission contends that the Court should:
–
dismiss the application;
–
order the applicant to pay the costs.
65
The European Confederation of Pharmaceutical Entrepreneurs (Eucope) claims that the Court should uphold the action for annulment.
66
The EMA contends that the Court should:
–
dismiss the application;
–
order the applicant to pay the costs.
Law
67
In the contested decision, and on the basis of two separate scientific assessments carried out respectively by the two different competent scientific committees of the EMA, the Commission granted an MA for the biological medicinal product for human use Nexviadyme – avalglucosidase alfa, without granting it certain regulatory advantages.
68
First, it is implicit from the contested decision that the active substance of Nexviadyme, namely avalglucosidase alfa, was not granted NAS status, thus precluding the medicinal product from benefiting from a regulatory data protection period of 8 years and a regulatory marketing protection period of 10 years under Article 14(11) of Regulation No 726/2004.
69
In that regard, the CHMP considered that avalglucosidase alfa could not be considered as an NAS in itself and that the evidence submitted by the applicant in support of its claim for NAS status for avalglucosidase alfa, the active substance of Nexviadyme, in relation to alglucosidase alfa, the active substance of an already authorised medicinal product, namely Myozyme, the MA of which is also held by the applicant, was insufficient, with that finding being endorsed by the Commission.
70
Second, Nexviadyme was not granted orphan status, thus precluding the medicinal product from benefiting from a 10-year period of market exclusivity under Article 8(1) of Regulation No 141/2000. In that regard, the COMP considered the evidence submitted to maintain the designation of the medicinal product Nexviadyme as an orphan medicinal product, at the time of granting the MA, insufficient, that finding also being endorsed by the Commission.
71
In support of its action, the applicant puts forward three pleas in law. The first two pleas in law concern the implied refusal of NAS status for avalglucosidase alfa. The first plea alleges infringement of Article 10(1) of Directive 2001/83, Article 14(11) of Regulation No 726/2004, manifest error of assessment and an inadequate statement of reasons. The second plea alleges infringement of the principle of good administration, as laid down in Article 41 of the Charter of Fundamental Rights of the European Union (‘the Charter’). The third plea concerns the withdrawal of Nexviadyme’s designation as an orphan medicinal product. That plea alleges infringement of Article 5(12)(b) of Regulation No 141/2000, manifest error of assessment and an inadequate statement of reasons.
72
As a preliminary point, the Court considers it appropriate to set out certain considerations on the standard of review relevant both to the implied refusal of NAS status for avalglucosidase alfa and to the withdrawal of Nexviadyme’s designation as an orphan medicinal product.
Preliminary considerations on the standard of judicial review
73
The decisions by which the Commission decides whether or not a medicinal product is to be granted an MA – including whether or not it contains an NAS – or whether or not it constitutes an orphan medicinal product are adopted following scientific opinions that are issued by two EMA committees, namely the CHMP and the COMP.
74
In that context, a distinction must, as a general rule, be drawn between the review that the EU judicature may be called upon to carry out of the formal legality of the scientific opinions of the EMA’s committees and of the Commission’s exercise of its discretion (see, to that effect, judgment of 19 December 2019, Vanda Pharmaceuticals v Commission, T‑211/18, EU:T:2019:892, paragraph 50 and the case-law cited).
75
As regards the judicial review of the opinions of the EMA’s committees – and by extension of the assessment reports of the committees – the Court cannot substitute its own assessment for that of those committees. Only the proper functioning of the committee, the internal consistency of the opinion and the statement of reasons contained in it can be subject to judicial review. As regards the latter aspect, the review consists of examining whether those documents contain a statement of reasons from which it is possible to ascertain the considerations on which they are based and whether they establish a comprehensible link between the medical or scientific findings and the conclusions (see, to that effect, judgments of 5 December 2018, Bristol-Myers Squibb Pharma v Commission and EMA, T‑329/16, not published, EU:T:2018:878, paragraph 99, and of 19 December 2019, Vanda Pharmaceuticals v Commission, T‑211/18, EU:T:2019:892, paragraph 53 and the case-law cited).
76
As regards the Commission’s exercise of its discretion, it is apparent from settled case-law that, where the EU authorities have a broad discretion, in particular as to the assessment of highly complex scientific and technical facts in order to determine the nature and scope of the measures which they adopt, review by the EU judicature is limited to verifying whether there has been a manifest error of assessment or a misuse of powers, or whether those authorities have manifestly exceeded the limits of their discretion. In such a context, the EU judicature cannot substitute its assessment of scientific and technical facts for that of the EU authorities on which alone the FEU Treaty has placed that task (see, to that effect, judgment of 19 December 2019, Vanda Pharmaceuticals v Commission, T‑211/18, EU:T:2019:892, paragraph 51 and the case-law cited).
77
The discretion of the EU authorities, which implies limited judicial review of its exercise, does not concern only the nature and scope of the measures to be taken but also, to some extent, the finding of the basic facts. However, even though such judicial review is of limited scope, it requires that the EU authorities must be able to show before the EU judicature that in adopting the act they actually exercised their discretion, which presupposes the taking into consideration of all the relevant factors and circumstances of the situation the act was intended to regulate (see, to that effect, judgment of 19 December 2019, Vanda Pharmaceuticals v Commission, T‑211/18, EU:T:2019:892, paragraph 52 and the case-law cited).
78
Furthermore, it is apparent from the case-law that, in so far as a decision purely and simply confirms the EMA’s opinion, the content of that opinion, and also that of the assessment report on which it is based, should be considered as an integral part of the statement of reasons for that decision, with regard in particular to the scientific assessment of the medicinal product in question (see judgments of 5 December 2018, Bristol-Myers Squibb Pharma v Commission and EMA, T‑329/16, not published, EU:T:2018:878, paragraph 54 and the case-law cited, and of 19 December 2019, Vanda Pharmaceuticals v Commission, T‑211/18, EU:T:2019:892, paragraph 32 and the case-law cited).
79
In the present case, the contested decision purely and simply confirms, first, the final opinion of the CHMP recommending that an MA be granted to Nexviadyme and that NAS status should not be granted to the active substance of that medicinal product and, second, the final opinion of the COMP recommending that Nexviadyme be removed from the EU Register of Orphan Medicinal Products.
80
In addition, in accordance with the case-law cited in paragraph 78 above, the final assessment report of the CHMP and the final position of the COMP, on which the final opinion of the CHMP and the final opinion of the COMP are based, are an integral part of the statement of reasons for the contested decision.
81
Accordingly, the Court’s judicial review, in particular an examination that there is no manifest error of assessment, must be carried out in respect of all the considerations set out in the final opinions of the CHMP and the COMP, the final assessment report of the CHMP and the final position of the COMP (see, to that effect, judgments of 5 December 2018, Bristol-Myers Squibb Pharma v Commission and EMA, T‑329/16, not published, EU:T:2018:878, paragraph 98, and of 19 December 2019, Vanda Pharmaceuticals v Commission, T‑211/18, EU:T:2019:892, paragraph 54).
The first plea in law, alleging infringement of Article 10(1) of Directive 2001/83 and Article 14(11) of Regulation No 726/2004, manifest error of assessment and an inadequate statement of reasons
82
By the first plea, the applicant criticises the Commission and the EMA for not finding that the changes which it had made to the molecular structure of alglucosidase alfa, namely the addition of synthetic glycans, justified recognising avalglucosidase alfa as an NAS. This plea comprises three limbs. The first two limbs concern the implied refusal of NAS status for avalglucosidase alfa under the definition of an NAS set out in the first indent of Annex I to the Notice to Applicants. The third limb concerns the implied refusal of NAS status for avalglucosidase alfa under the NAS definition set out in the third indent of that annex.
The second limb and the second complaint of the third limb of the first plea, alleging an inadequate statement of reasons as regards failure to satisfy the conditions set in the first and third indents of Annex I to the Notice to Applicants
83
By the second limb and by the second complaint of the third limb of the first plea, which it is appropriate to examine together and at the outset, the applicant claims that the statement of reasons in the final assessment report of the CHMP with regard to the examination of the NAS status of avalglucosidase alfa under the first and third indents of Annex I to the Notice to Applicants is not sufficient to support the contested decision’s implied refusal of that status.
84
As regards the NAS assessment of avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants, the applicant submits that the CHMP’s reasoning is contradictory since that committee, while it claimed to apply the NAS definition given in that indent ‘verbatim’, in fact applied the concepts of ‘therapeutic moiety’, ‘main molecular entity’, ‘basic structural element’ and ‘amino acid sequence’, which do not appear in that indent.
85
In addition, the applicant complains that the CHMP and the Commission failed to respond to all the arguments put forward in its detailed grounds for re-examination. It alleges deficiencies in the statement of reasons as regards extrapolating the criteria applicable to chemical active substances to a biological active substance, in particular ‘therapeutic moiety’; as regards previous assessments of claims of NAS status for other medicinal products; as regards the legal and regulatory nature of the criteria for determining NAS status; and as regards the advice provided by the CHMP in 2015 in the framework of the protocol assistance. It also complains of inadequacies in the reasoning as regards the relevance of Regulation No 1234/2008 on variations to the terms of MAs, as regards the principles applicable to ‘biosimilar’ substances, and as regards the regulations on orphan medicinal products, namely Regulation No 141/2000 and Regulation No 847/2000, as amended by Commission Regulation (EU) 2018/781 of 29 May 2018 (OJ 2018 L 132, p. 1).
86
With respect to the assessment of the NAS status of avalglucosidase alfa under the third indent of Annex I to the Notice to Applicants, the applicant complains, inter alia, that the CHMP did not give a detailed explanation for the strict approach it took with regard, in particular, to the data on the results of the secondary and tertiary endpoints of a study called ‘COMET’, which compared avalglucosidase alfa and alglucosidase alfa (‘the COMET study’).
87
The Commission, supported by the EMA, disputes those arguments.
88
The obligation to state reasons constitutes an essential procedural requirement which must be distinguished from the question whether the statement of reasons is well founded, which is a question of the substantive legality of the contested measure (judgments of 22 March 2001, France v Commission, C‑17/99, EU:C:2001:178, paragraph 35, and of 20 September 2019, ICL-IP Terneuzen and ICL Europe Coöperatief v Commission, T‑610/17, EU:T:2019:637, paragraph 47).
89
According to settled case-law, the statement of reasons required by the second paragraph of Article 296 TFEU must be appropriate to the act at issue and must disclose in a clear and unequivocal fashion the reasoning followed by the institution which adopted the measure in question, in such a way as to enable the persons concerned to ascertain the reasons for the measure and to enable the competent court to exercise its power of review. The requirements to be satisfied by the statement of reasons depend on the circumstances of each case, in particular the content of the measure in question, the nature of the reasons given and the interest which the addressees of the measure, or other parties to whom it is of direct and individual concern, may have in obtaining explanations. It is not necessary for the reasoning to go into all the relevant facts and points of law, since the question whether the statement of reasons meets the requirements of Article 296 TFEU must be assessed with regard not only to its wording but also to its context and to all the legal rules governing the matter in question (see judgment of 19 December 2019, Vanda Pharmaceuticals v Commission, T‑211/18, EU:T:2019:892, paragraph 60 and the case-law cited).
90
In addition, where the persons concerned are involved in the process by which a measure comes about, the requirement to state reasons may be circumscribed, since they acquire information through their involvement (judgments of 21 July 2011, Etimine, C‑15/10, EU:C:2011:504, paragraph 116, and of 1 February 2013, Polyelectrolyte Producers Group and Others v Commission, T‑368/11, not published, EU:T:2013:53, paragraph 101).
91
In the present case, the implied refusal in the contested decision of NAS status for avalglucosidase alfa, as evidenced by there being no recognition of that status in the decision in question, is based on the final assessment report of the CHMP and the final opinion of the CHMP, which are an integral part of that decision.
92
It is apparent from that report and opinion that the scientific considerations and reasons for finding that avalglucosidase alfa was not an NAS under the NAS definition, given in the first or third indent of Annex I to the Notice to Applicants, have been provided by the authors thereof.
93
Indeed, in section 5.3. of its final assessment report, under the heading ‘CHMP position on Ground #1’, the CHMP sets out its overall conclusions on the detailed grounds for re-examination of the claim for NAS status for avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants.
94
First of all, the CHMP outlined the assessment it had carried out, observed that avalglucosidase alfa was a development of alglucosidase alfa, an already authorised active substance, and mentioned certain texts that the applicant had referred to in the claim for NAS status for avalglucosidase alfa. It also explained the ‘verbatim’ approach it took to the first indent of Annex I to the Notice to Applicants. Thus, the CHMP considers that an active substance not previously authorised in a medicinal product for human use in the European Union is an NAS under the first indent of Annex I to the Notice to Applicants where, from a structural point of view, it is not related to any other authorised substance. Such a substance is considered to be new in itself if the administration of that substance would not expose patients to the same therapeutic moiety as that of an already authorised substance. If, on the other hand, the active substance being assessed is related to an already authorised active substance and patients are exposed to the same therapeutic moiety, the CHMP considers that the claim for NAS status should be assessed under the third indent of Annex I to the Notice to Applicants.
95
The CHMP then explained the approach it takes in the case of biological active substances based on proteins and the addition of structures to what the committee deems to be the basic structural element of a protein, namely its amino acid sequence. It observed that that approach was consistent with that taken for chemical active substances and in the case of previous claims for NAS status for biological active substances, including in particular those relating to Rekovelle and Zinbryta. In the present case, the CHMP found that avalglucosidase alfa exposed the patient to the same therapeutic moiety as alglucosidase alfa, since their basic structural element – their amino acid sequences – was the same and the synthetic glycans conjugated to the amino acid backbone of avalglucosidase alfa were not considered to be part of the basic structural element. The clinical impact of the added synthetic glycans in terms of safety or efficacy had therefore to be assessed under the third indent of Annex I to the Notice to Applicants. More specifically, the impact of the increased affinity of avalglucosidase alfa observed in vitro with respect to receptor binding and increased cellular uptake in comparison to alglucosidase alfa, the clinical effect of which was not known, would be examined in the context of the third indent of that annex.
96
Lastly, the CHMP explained why it rejected the relevance of the texts referred to by the applicant other than Annex I to the Notice to Applicants, namely Regulations Nos 1234/2008 and 847/2000 and the Guideline on similar biological medicinal products, those documents having a different scope and not providing any guidance on how to substantiate NAS status.
97
In section 5.3. of its final assessment report, under the heading ‘CHMP position on Ground #2’, the CHMP sets out its overall conclusions on the detailed grounds for re-examination of the claim for NAS status for avalglucosidase alfa under the third indent of Annex I to the Notice to Applicants.
98
In that regard, first of all, the CHMP found that the non-clinical and pre-clinical data did not support the NAS claim for avalglucosidase alfa, whether in terms of efficacy or safety. In that context, it stated, inter alia, that it was difficult to assess the potency of avalglucosidase alfa in the absence of data on efficacy in relation to dose and that it was not clear why the increased potency of avalglucosidase alfa did not translate into increased efficacy consistently.
99
Next, as regards the COMET study, it is apparent from the final assessment report of the CHMP (in particular sections 2.6.5. and 2.6.6.) that the primary objective of that study was to determine the effect of avalglucosidase alfa, as compared with alglucosidase alfa, on respiratory muscle strength, as measured by percentage predicted forced vital capacity (‘FVC’) at week 49. The COMET study constituted the main evidence for the safety and efficacy of avalglucosidase alfa and was considered to be an adequate basis for drawing robust conclusions on the comparative efficacy of avalglucosidase alfa compared to alglucosidase alfa. Since avalglucosidase alfa was expected to be at least as efficacious as alglucosidase alfa – the first-ranked hypothesis – that study was to test, in the first place, as a primary statistical objective, the non-inferiority of avalglucosidase alfa in relation to alglucosidase alfa, with regard to that primary endpoint, at a 5% level of statistical significance.
100
In the second place, once non-inferiority had been demonstrated, the COMET study was to test, as a second-ranked hypothesis, the superiority of avalglucosidase alfa with regard to the same primary endpoint and at the same level of statistical significance.
101
In the third place, if the superiority of avalglucosidase alfa were demonstrated with regard to the primary endpoint, superiority testing was to be carried out with regard to various secondary endpoints (six minutes of walking, respiratory function, motor function and quality of life).
102
In the present case, it is apparent from the final assessment report of the CHMP that although the COMET study did indeed demonstrate the non-inferiority of avalglucosidase alfa in relation to alglucosidase alfa with regard to the primary endpoint, namely forced vital capacity as measured by percentage predicted FVC at week 49 and at the required level of statistical significance, that study did not provide a statistically significant result with respect to the second-ranked hypothesis, that is to say, the superiority of avalglucosidase alfa over alglucosidase alfa with regard to that same primary endpoint.
103
It is in that context that, in its overall conclusions on the third indent of Annex I to the Notice to Applicants, and specifically in its considerations on the clinical efficacy of avalglucosidase alfa, the CHMP stated that clinical trials on rare diseases were subject to the usual methodological rules of having a hierarchy of hypotheses and that deviations from those rules had to be pre-planned, fully justified and included in the study protocol. However, in the present case the applicant had neither pre-specified nor prospectively justified ‘the use of less conventional methods’. The CHMP stated that, consequently, claims of the superiority of avalglucosidase alfa based on secondary endpoints in the COMET study or on sensitivity or post hoc analyses had not been agreed from a methodological point of view.
104
Furthermore, apart from the fact that the post hoc analyses carried out by the applicant in order to support the clinical efficacy data had not been planned in advance, the CHMP identified other limitations affecting those analyses, some of them being potentially biased, not providing additional information or being of an exploratory or descriptive nature. As regards the long-term efficacy of avalglucosidase alfa, the CHMP noted that the data did not appear to show a continuous improvement, but rather stabilisation, and that it was difficult to conclude on a difference between that substance and alglucosidase alfa. While observing that the majority of the experts of the ad hoc expert group, which the CHMP had consulted at the applicant’s request, were of the view that clinically meaningful improvements had been reached with regard to clinical endpoints relating, inter alia, to respiration, mobility, motor function and quality of life, the CHMP remained of the opinion that ‘all subsequent statistical tests for the secondary endpoints in the pre-specified hierarchy could not formally be carried out under adequate experiment wise type-1-error control’.
105
Thus, the CHMP explained why the results of the secondary and tertiary endpoints of the COMET study had limited probative value for establishing significant differences between avalglucosidase alfa and alglucosidase alfa.
106
Lastly, as regards clinical safety, the CHMP considered that, due to limitations on robustness of the data, the impact of changes to the molecular structure of avalglucosidase alfa compared to that of alglucosidase alfa could not be established. It also noted that the ad hoc expert group had not reached any firm conclusions on an improved safety profile of Nexviadyme as compared to Myozyme. The CHMP concluded that no clinically significant difference could be demonstrated in terms of efficacy and safety between the two substances. Consequently, the CHMP maintained its view that avalglucosidase alfa, considered in relation to alglucosidase alfa, previously authorised as a medicinal product in the European Union, could not be qualified as an NAS.
107
Section 7 of the final assessment report of the CHMP recommends, following the re-examination, inter alia, that avalglucosidase alfa is not to be qualified as an NAS, either in itself or in comparison to alglucosidase alfa, a previously authorised substance, due to insufficient evidence being provided to demonstrate that avalglucosidase alfa differs significantly in properties with regard to safety and/or efficacy from alglucosidase alfa.
108
Furthermore, section 1 of the final opinion of the CHMP states that that committee, having examined the MA application and the detailed grounds for re-examination, as set out in the final assessment report of the CHMP, considers that avalglucosidase alfa is not an NAS.
109
In the light of the factors set out in paragraphs 93 to 108 above, the final assessment report of the CHMP and the final opinion of the CHMP, on which the implied refusal in the contested decision of NAS status for avalglucosidase alfa is based, are not vitiated by an inadequate statement of reasons. As a matter of fact, they contain a statement of reasons which meets the requirements of the case-law cited in paragraph 89 above.
110
In addition, the statement of reasons in the overall conclusions of the CHMP following its re-examination of the claim for NAS status for avalglucosidase alfa adds to the information provided, inter alia, in the protocol assistance and in the procedure which led to the CHMP’s opinion and assessment report of 23 July 2021, and follows the exchanges between the applicant and the CHMP at the oral explanations of 20 July and 8 November 2021. It is therefore strengthened by the context, which was well known to the applicant, of which it was part, in terms of the case-law cited in paragraph 90 above.
111
Lastly, the statement of reasons for the contested decision with regard to the implied refusal of NAS status for avalglucosidase alfa complies with Article 296 TFEU since it refers to the final opinion of the CHMP, which itself, along with the assessment report on which it is based, forms an integral part of that decision.
112
The Court’s findings in paragraphs 109 and 111 above are not undermined by the fact that neither the CHMP nor the Commission took an explicit stance on each of the arguments made by the applicant in its detailed grounds for re-examination. As observed in paragraph 89 above, the case-law does not require the statement of reasons to go into all the relevant facts and points of law, and the CHMP and the Commission cannot therefore be required to adopt a position on each of the arguments set out in the detailed grounds for re-examination.
113
In the light of the foregoing considerations, the second limb and the second complaint of the third limb of the first plea must be rejected as unfounded.
114
In accordance with the case-law cited in paragraph 89 above, the Court’s findings in paragraphs 109, 111 and 113 above are without prejudice to possible errors of law or manifest errors of assessment on the part of the CHMP or the Commission. The merits of the approach and the scientific findings made will be assessed in paragraphs 115 to 228 below.
The first limb of the first plea, alleging errors in finding that the conditions laid down in the first indent of Annex I to the Notice to Applicants were not met
115
The applicant, supported by Eucope, submits, in essence, that the implied refusal in the contested decision of NAS status for avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants is based on the application of incorrect criteria. Denying that status on an erroneous basis infringes the principles of the periods of regulatory data protection and regulatory marketing protection laid down in Article 10(1) of Directive 2001/83 and Article 14(11) of Regulation No 726/2004, read in conjunction, if necessary, with the second subparagraph of Article 6(1) of Directive 2001/83. This limb is composed, in essence, of two complaints.
116
The Commission, supported by the EMA, disputes those arguments.
– The first complaint of the first limb of the first plea, alleging an error in the relevant legal point of reference for the assessment of the NAS status of avalglucosidase alfa
117
By a first complaint, the applicant, supported by Eucope, submits that the CHMP and the Commission erred in law in assessing the NAS status of avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants by disregarding the criteria set out in point 1(c) of Annex I to Regulation No 1234/2008 for the purposes of that assessment.
118
In that regard, relying on paragraphs 66 and 69 of the judgment of 28 June 2017, Novartis Europharm v Commission (C‑629/15 P and C‑630/15 P, EU:C:2017:498), and paragraphs 85 to 88 of the judgment of 16 March 2023, Commission and Others v Pharmaceutical Works Polpharma (C‑438/21 P to C‑440/21 P, EU:C:2023:213), the applicant, supported by Eucope, submits that given that the purpose of the assessment of NAS status is to determine whether a new medicinal product may be covered by the global marketing authorisation of an earlier medicinal product, the criteria for NAS designation under Annex I to the Notice to Applicants should be read in conjunction with the criteria in point 1 of Annex I to Regulation No 1234/2008. Accordingly, when the molecular structure of a biological active substance is more than ‘slightly’ different from that of the previously authorised substance, it cannot be regarded as a modification of that latter substance for the purposes of point 1(c) of Annex I to Regulation No 1234/2008 and should be classified as an NAS under the first indent of Annex I to the Notice to Applicants. It follows that differences between biological active substances are not determined on the basis of their therapeutic moiety, reduced to their amino acid sequence, since therapeutic moiety is not referred to in point 1(c) of Annex I to Regulation No 1234/2008, but on the basis of differences in their molecular structure.
119
The Commission, supported by the EMA, disputes that line of argument.
120
The Court observes that the error of law as raised by the applicant relates, in essence, to disregard of the relevant legal point of reference for assessing the NAS status of avalglucosidase alfa.
121
As regards questions of law, the Court can only carry out full judicial review (see, to that effect, judgment of 23 September 2020, Medac Gesellschaft für klinische Spezialpräparate v Commission, T‑549/19, EU:T:2020:444, paragraph 47). That is the case with regard to the concept of ‘NAS’.
122
In the present case, the application for the recognition of NAS status for avalglucosidase alfa was made in the context of a full and independent MA application, as provided for in Article 8(3) of Directive 2001/83, for Nexviadyme, pursuant to Article 3(1) of Regulation No 726/2004, point 4 of Annex I to that regulation and on the basis of Annex I to the Notice to Applicants. It was not made as part of an application for the extension of an existing MA, that of Myozyme, under point 1(c) of Annex I to Regulation No 1234/2008.
123
In those circumstances, the applicant cannot claim, by arguing a contrario, that point 1(c) of Annex I to Regulation No 1234/2008 is the relevant legal point of reference for assessing the NAS status of avalglucosidase alfa and that, consequently, the CHMP and the Commission erred in law by disregarding the criteria laid down therein.
124
That is all the more the case since the applicant stated, in response to a written question from the Court and at the hearing, first, that its position did not consist in considering that any modification of an active substance that would not constitute an extension for the purposes of Annex I to Regulation No 1234/2008 would lead to the recognition of an NAS and acknowledged, second, that there were situations in which a medicinal product might fall ‘between two stools’.
125
Apart from the fact that Regulation No 1234/2008 does not define the concept of ‘NAS’ and does not contain any elements capable of supporting the arguments made by the applicant and Eucope, the Court observes that, as the Commission and the EMA rightly submit, the regulatory procedures for an application for extension of an MA on the basis of Regulation No 1234/2008 and for an application for an MA on the basis of Regulation No 726/2004, accompanied by an application for the recognition of NAS status under Annex I to the Notice to Applicants, may not be treated as the same since they are based on different legal bases and dossiers.
126
In an application for an extension of an MA under point 1(c) of Annex I to Regulation No 1234/2008, the extension applicant is seeking to demonstrate that, despite the replacement of the biological active substance with a biological active substance with a slightly different molecular structure, the efficacy or safety characteristics of those two active substances are not significantly different. Accordingly, on the basis of a dossier and specific evidence provided by the extension applicant for those purposes, the CHMP is required, first, to assess the extent of the differences in the molecular structure of the two biological active substances in order to ensure that the molecular structure of the active substance replacing the first substance is in fact only ‘slightly different’ from that of the substance being replaced and, second, to verify the claimed absence of significant differences as regards the efficacy or safety characteristics of those two substances.
127
By contrast, in the present case the applicant was seeking to differentiate avalglucosidase alfa from alglucosidase alfa.
128
The purpose of the MA application under Regulation No 726/2004, accompanied by the request for recognition of NAS status for avalglucosidase alfa under Annex I to the Notice to Applicants, was therefore different from that which would have been involved in an application to extend an existing MA.
129
In that regard, it is irrelevant that the rapporteur, in the re-examination by the CHMP, when carrying out the assessment under the first indent of Annex I to the Notice to Applicants, initially adopted an approach based on Regulation No 1234/2008 or that the co-rapporteur observed at the re-examination stage that ‘glucooptimisation’ is not compatible with the biosimilar approach and that avalglucosidase alfa and alglucosidase alfa could not be considered ‘biosimilars’.
130
First, neither Regulation No 1234/2008, nor Article 10(4) of Directive 2001/83 nor the Guideline on similar biological medicinal products are relevant to assessing the NAS status of avalglucosidase alfa.
131
Second, in accordance with recital 23 and Article 5(2), Article 56(1)(a) and Article 61(7) of Regulation No 726/2004, the ‘exclusive responsibility’ for the preparation of the EMA’s opinions on all questions concerning medicinal products for human use is vested in the CHMP, which expresses itself by means of scientific opinions or recommendations adopted by consensus or by an absolute majority of its members. Consequently, a distinction must be drawn between any intermediate documents drawn up by the co-rapporteurs and the final assessment report of the CHMP on which the contested decision is based, since only that final assessment report reflects the final opinion of the CHMP (see, to that effect, judgment of 19 December 2019, Vanda Pharmaceuticals v Commission, T‑211/18, EU:T:2019:892, paragraphs 37, 38, 47 and 48).
132
As regards the concept of ‘NAS’, the first paragraph of section 3 of Part II of Annex I to Directive 2001/83 contains a negative definition of an NAS in so far as that paragraph provides that 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 is to be demonstrated. Should this not be the case, that association is to be considered as a new active substance.
133
Accordingly, different associations of the same therapeutic moiety which would result in the same safety/efficacy profile as an original authorised product preclude those associations from being considered as NAS.
134
Apart from those indications, a definition of the concept of ‘NAS’ is given in Annex I to the Notice to Applicants. As regards biological active substances, according to the first indent of that annex, a biological NAS comprises a biological substance not previously authorised in a medicinal product for human use in the European Union. According to the third indent of that annex, a biological NAS comprises a biological substance previously authorised, but differing significantly in properties with regard to safety and/or efficacy, due to differences in one or a combination of the aspects listed therein, namely the molecular structure, the nature of the source material or the manufacturing process.
135
While the Notice to Applicants is not legally binding, it must be accorded some weight in the interpretation of EU pharmaceutical legislation, in particular where the EU legislation proves to be imprecise and complex technical questions are at stake (see, to that effect, Opinion of Advocate General Jacobs in SmithKline Beecham, C‑74/03, EU:C:2004:541, point 92).
136
Having regard to the legal basis of the MA application and the request for recognition of NAS status in the present case, and in the absence of a more precise definition of the concept of ‘NAS’ for biological active substances laid down by the EU legislature, the CHMP and the Commission were entitled, without erring in law, to assess the NAS status of avalglucosidase alfa in the light of the definition of that concept in Annex I to the Notice to Applicants.
137
Given the foregoing considerations, the CHMP and the Commission did not err in law by disregarding, for assessing the NAS status of avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants, the criteria set out in point 1(c) of Annex I to Regulation No 1234/2008.
138
It follows that the first complaint of the first limb of the first plea in law must be rejected as unfounded.
– The second complaint of the first limb of the first plea, alleging errors in the application of the first indent of Annex I to the Notice to Applicants
139
By a second complaint, the applicant, supported by Eucope, claims that there are manifest errors in the CHMP’s application, endorsed by the Commission, of the first indent of Annex I to the Notice to Applicants.
140
In that context, the applicant submits that a verbatim application of the first indent of Annex I to the Notice to Applicants should have led to a finding that avalglucosidase alfa, the active substance of Nexviadyme, was an NAS under that indent, the active substance of Myozyme being alglucosidase alfa. It adds that the connection between the assessment of NAS status and the regulatory data and marketing protection periods precludes a presumption that a substance is not new unless proven otherwise. Furthermore, the first indent of Annex I to the Notice to Applicants does not require the new substance to bring about an improvement when compared with the existing previously authorised active substance. Lastly, regulatory data protection period and regulatory marketing protection period rights are a direct legal consequence of the granting of an MA under Article 14(11) of Regulation No 726/2004.
141
In addition, the applicant, supported by Eucope, submits that the CHMP and the Commission, when assessing NAS status for avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants, erred in applying an approach based on the concepts of ‘therapeutic moiety’, ‘main molecular entity’, ‘basic structural element’ and ‘amino acid sequence’. Those concepts have no legal basis since they are included in neither the European Union’s pharmaceutical legislation nor in Annex I to the Notice to Applicants. The approach adopted of assessing whether avalglucosidase alfa exposes patients to the same therapeutic moiety as an already authorised substance is based on an unjustified extrapolation of the criteria applicable to chemical active substances to biological active substances. Furthermore, the concept of ‘therapeutic moiety’ is not appropriate for assessing the NAS status of biological active substances and is more difficult to apply to them because of their nature and structural complexity.
142
In any event, if the concept of ‘therapeutic moiety’ were applicable to biological active substances, it ought to be interpreted as extending to all the parts of the active substance which contribute to the therapeutic functioning of the medicinal product or which are not inert, in accordance with paragraphs 30, 43 and 44 of the judgment of 20 January 2005, SmithKline Beecham (C‑74/03, EU:C:2005:39), point 14 of the Opinion of Advocate General Jacobs in SmithKline Beecham (C‑74/03, EU:C:2004:541), and point 58 of the Opinion of Advocate General Medina in Joined Cases Commission and Others v Pharmaceutical Works Polpharma (C‑438/21 P to C‑440/21 P, EU:C:2022:758), which, in this case, applies to the added synthetic glycan structures.
143
In that context, the applicant, supported by Eucope, submits that the specific nature of the medicinal product as a biological medicinal product and an enzyme replacement therapy, and the objective of determining NAS status and the objective of stimulating innovation pursued by EU pharmaceutical legislation, and in particular through the regulatory data protection period and the regulatory marketing protection period, mean that changes to the active substance that affect the therapeutic functionality of the medicinal product should be classified as an NAS under the first indent of Annex I to the Notice to Applicants. For enzyme replacement therapy, where the enzyme administered must function in the same way as the endogenous enzyme, innovation has to result from elements other than the enzyme. In the present case, the added synthetic glycans contribute to the therapeutic functioning of Nexviadyme in terms of the uptake of the active substance necessary to transfer the administered enzyme and in terms of the potency of the medicinal product, which was recognised by the ad hoc expert group in the final assessment report of the CHMP and in the summary of product characteristics of the medicinal product.
144
Lastly, the applicant submits that other considerations confirm its argument that changes to the active substance that affect the therapeutic functionality of the medicinal product should be classified as an NAS under the first indent of Annex I to the Notice to Applicants, namely the NAS assessments carried out in respect of the medicinal products Rekovelle and Zinbryta, the advice provided to it by the CHMP in the protocol assistance, and the EMA’s Guideline on similar biological medicinal products.
145
The Commission, supported by the EMA, disputes those arguments.
146
The Court observes that the errors raised by the applicant relate, in essence, to the methodology applied by the CHMP and the Commission when assessing the NAS status of avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants and concern the relevance and scope of the scientific concepts employed in that context.
147
As a preliminary point, it must be stated that the Notice to Applicants does not provide any detailed guidance on how the CHMP and the Commission should interpret or apply the definition of an NAS under the first or third indent of Annex I to that notice for biological active substances. The same is true of the judgments and Opinions referred to by the applicant (see paragraphs 118 and 142 above). In any event, the cases giving rise to those judgments and Opinions did not concern procedures for the recognition of NAS status, but related to other regulatory procedures.
148
It follows that the CHMP and the Commission enjoy broad discretion when interpreting and applying the NAS definition set out in Annex I to the Notice to Applicants, the evaluations required involving the assessment of highly complex scientific and technical facts.
149
Nevertheless, as regards the overall framework of the evaluation, it is apparent from the scheme of the definition of an NAS in Annex I to the Notice to Applicants, that an applicant for an MA, who claims the existence of a biological NAS, is required to demonstrate that the active substance under assessment has not been previously authorised in a medicinal product for human use in the European Union (first indent of Annex I to the Notice to Applicants) or, as the case may be, or failing that, that the substance differs significantly in properties with regard to safety and/or efficacy from a previously authorised substance, this being due to differences in one or a combination of aspects, namely the molecular structure, the nature of the source material or the manufacturing process (third indent of Annex I to the Notice to Applicants).
150
In order to determine whether an active substance is to be considered as not previously authorised, the CHMP must ascertain whether the applicant for the grant of NAS status has adduced proof that the substance covered by its application should be distinguished from the already authorised substance owing to changes made to it. If no such proof is provided, the CHMP will assess the impact on properties with regard to safety and/or efficacy of the differences, inter alia, in molecular structure, on the basis of the dossier and the specific evidence submitted for that purpose by the MA applicant.
151
In the present case, as set out in paragraphs 94 to 96 above, the CHMP stated that an active substance that is not previously authorised in a medicinal product for human use in the European Union is an NAS under the first indent of Annex I to the Notice to Applicants where, from a structural point of view, it is not related to any other already authorised substance, such an active substance being considered as new in itself, if its administration does not expose patients to the same therapeutic moiety as that of an already authorised substance. However, if the active substance which is claimed to be new is related to an already authorised active substance and patients are exposed to the same therapeutic moiety, the CHMP considers that the application for NAS status should be assessed under the third indent of Annex I of the Notice to Applicants. The CHMP found that avalglucosidase alfa was not an NAS in relation to alglucosidase alfa under the first indent of that annex since those substances were related from a structural point of view and shared the same therapeutic moiety. The committee referred to the fact that that approach was to be found in a CHMP document of 17 December 2015, entitled ‘Reflection paper on the chemical structure and properties criteria to be considered for the evaluation of new active substance (NAS) status of chemical substances’ (‘the 2015 reflection paper on the NAS status of chemical substances’), and in earlier NAS assessments relating to biological medicinal products, such as Rekovelle and Zinbryta. The CHMP also stated that, for qualification as an NAS, the main molecular entity had to be demonstrated ‘to be more than slightly different from the basic structural element(s) contained in a medicinal product authorised in the EU (that is, at the EU level or national level)’. It stated that the main molecular entity was considered to be the basic structural element or elements without added functional structures.
152
For proteins, the amino acid sequence was considered to be the basic structural element and proteins containing differences in the amino acid sequence would normally be considered as NAS. The CHMP observed that trivial changes to the basic structural element would not warrant NAS status being granted. It explained that where a molecular structure with the same basic structural element is produced but has additional post-translational modifications, such a structure would normally be considered as a known active substance, unless it can be shown that those modifications have a clinical impact in terms of safety or efficacy, such an impact being evaluated under the third indent of Annex I to the Notice to Applicants.
153
Similarly, the CHMP considered that where additional molecular structures are chemically attached to the basic structural element and such structures are not present in the authorised product, the whole molecule would normally be considered as a known active substance, unless it can be shown that those modifications have a clinical impact in terms of safety or efficacy, such an impact being evaluated under the third indent of Annex I to the Notice to Applicants.
154
In the light of the considerations set out in paragraphs 147 and 148 above, the Court must determine whether the arguments put forward by the applicant and Eucope are capable of demonstrating a manifest error on the part of the CHMP and the Commission, with regard to the methodology applied and the scientific concepts employed for assessing the NAS status of avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants, or indeed of demonstrating that those authorities failed to take into consideration all the relevant factors and circumstances related to the application for recognition of that status.
155
First of all, the Court notes that the applicant confirmed, in the annex to its MA application setting out the reasons why avalglucosidase alfa was to be regarded as an NAS, that that substance constituted a modification of alglucosidase alfa, an already authorised substance, and that the two substances differed owing to the glycans that were chemically added to the alglucosidase alfa molecule.
156
It is with regard to that information that the CHMP examined whether avalglucosidase alfa was a new active substance in itself on the basis of a verbatim application of the first indent of Annex I to the Notice to Applicants. The applicant submits in that regard that a verbatim application of that kind should have led to the granting of NAS status to avalglucosidase alfa. That claim must, however, be rejected since it is based on a misreading of the final assessment report of the CHMP. It was in fact made clear in that report that a verbatim application meant that account had to be taken of the structural links between the substances under examination and their therapeutic moieties.
157
Furthermore, the CHMP’s methodological choice with regard to the first indent of Annex I to the Notice to Applicants, endorsed by the Commission, that, in essence, the fact that an active substance has not been previously authorised is not sufficient in and of itself to grant that substance NAS status under that indent, despite that indent not requiring the candidate active substance to bring about an improvement in comparison to a previously authorised active substance, cannot be regarded as a choice that manifestly exceeded the limits of those authorities’ discretion, having regard to the scheme of that annex. The first indent of that annex cannot be read in isolation from the third indent, otherwise the latter would be deprived of its effectiveness. Moreover, that methodological choice is supported by the scheme of EU pharmaceutical legislation and the case-law.
158
In that regard, EU pharmaceutical legislation explicitly envisages, at least in the context of the authorisation of generic medicinal products, and therefore in a context involving regulatory data and marketing protection periods, a rule that an active substance with some variations is the same as the active substance without those variations. Thus, Article 10(2)(b) of Directive 2001/83, in defining a generic medicinal product, provides that 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’ and that ‘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’. Accordingly, differences between one active substance and another do not preclude those substances from being regarded as constituting the same active substance.
159
Indeed, the Court observes that a similar rule may be found in the CHMP document of 18 October 2012 entitled ‘Reflection paper on considerations given to designation of a single stereo isomeric form (enantiomer), a complex, a derivative, or a different salt or ester as new active substance in relation to the relevant reference active substance’. That document states that for the purposes of designation as an NAS only, the default position is that an enantiomer, complex, derivative or a different salt or ester is not different from the reference active substance, unless demonstrated to be otherwise.
160
It follows that the applicant cannot succeed with its argument that the link between the NAS assessment and the periods of regulatory data and marketing protection precludes a rule to the effect that a biological active substance is not new unless proven otherwise.
161
Similarly, the case-law does not support the applicant’s argument as regards the interpretation of the first indent of Annex I to the Notice to Applicants, according to which regulatory data protection period and regulatory marketing protection period rights are a direct legal consequence of the granting of an MA under Article 14(11) of Regulation No 726/2004.
162
It is apparent from reading recital 11 of Regulation No 726/2004 in conjunction with Article 13(1) thereof that an MA granted under that regulation confers the same rights and obligations as one granted in accordance with Article 6 of Directive 2001/83.
163
According to the case-law, the existence of a global marketing authorisation within the meaning of the second subparagraph of Article 6(1) of Directive 2001/83 means, in essence, that a single regulatory data protection period, as provided for in Article 10(1) of that directive, applies to the developments of a medicinal product already authorised provided for in that Article 6 from the date of authorisation of that medicinal product. Therefore, by preventing the prolongation of the regulatory data protection period of an existing product on the basis of mere variants undeserving of its benefit, the second subparagraph of Article 6(1) of Directive 2001/83 seeks to ensure a fair balance between the protection of innovative companies and general interests that are served by the marketing of generic medicinal products (judgment of 16 March 2023, Commission and Others v Pharmaceutical Works Polpharma, C‑438/21 P to C‑440/21 P, EU:C:2023:213, paragraph 92).
164
It follows that situations exist in which, notwithstanding the investments of the pharmaceutical company concerned in the research and development of potential improved medicinal products, the granting of an MA does not lead to the recognition of an additional period of regulatory data protection.
165
In a situation where the CHMP and the Commission have concluded that the benefit-risk balance of a candidate biological medicinal product, which is intended to be an improvement on an existing authorised biological medicinal product, is positive, such that an MA should be granted to that candidate medicinal product, then the automatic grant of NAS status under the first indent of Annex I to the Notice to Applicants and the benefits flowing therefrom to the active substance of that medicinal product, even though it is a modification of the active substance of the already authorised existing medicinal product, that is to say regardless of any assessment, for the purpose of recognising that status, of the impact of the modification on the safety and/or efficacy properties of the active substance, as compared to those of the already authorised substance, would run counter to the objectives referred to in paragraph 92 of the judgment of 16 March 2023, Commission and Others v Pharmaceutical Works Polpharma (C‑438/21 P to C‑440/21 P, EU:C:2023:213) and the scheme of Annex I to the Notice to Applicants.
166
In the present case, Nexviadyme received an MA since its benefit-risk balance was positive. Nevertheless, an automatic grant of NAS status to avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants, solely on the basis of the added glycan structures, would have entailed a period of regulatory data and marketing protection for Nexviadyme, without there having been any assessment, for the purpose of recognising that status, of the impact of those added glycan structures on the safety and/or the efficacy properties of avalglucosidase alfa as compared to alglucosidase alfa, even though Myozyme has already benefited from those regulatory advantages.
167
Next, the applicant and Eucope submit that the CHMP and the Commission erred in applying a methodology based on the concepts of ‘therapeutic moiety’, ‘main molecular entity’, ‘basic structural element’ and ‘amino acid sequence’ for assessing the NAS status of avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants.
168
In that regard, given the highly scientific and complex nature of the assessment of whether one biological active substance must be distinguished from another, which involves an assessment of the differences between those substances, the CHMP and the Commission enjoy broad discretion as regards identification of the specific scientific concepts to be taken into consideration. Consequently, the fact that the concepts of ‘therapeutic moiety’, ‘main molecular entity’, ‘basic structural element’ and ‘amino acid sequence’ have not been defined in EU pharmaceutical legislation does not preclude their being taken into account as part of a complex scientific assessment. Similarly, the CHMP and the Commission could legitimately employ therapeutic moiety restricted to the amino acid sequence when comparing two biological active substances in order to determine whether the substance concerned by the NAS application was different from the other one.
169
As regards the concept of ‘therapeutic moiety’ in particular, which was employed by the CHMP and the Commission and which, according to the applicant and Eucope, is an unjustified extrapolation to biological active substances of a concept that applies to chemical active substances, it is true that the 2015 reflection paper on the NAS status of chemical substances states that biological active substances are excluded from its scope.
170
However, the Court considers that the scientific approach adopted for chemical active substances in the framework of the first indent of Annex I to the Notice to Applicants, consisting of ascertaining the structural links between an already authorised active substance and an active substance contained in a candidate medicinal product, as well as their respective therapeutic moieties, cannot be precluded for biological active substances solely on the ground that those latter substances are not covered by the 2015 reflection paper on the NAS status of chemical substances. That fact does not suffice to deprive of plausibility the CHMP’s view that that approach was appropriate. Although they bear the burden of proof, neither the applicant nor Eucope have provided any scientific data or evidence to establish the manifestly erroneous or inappropriate character of extrapolating an approach initially established for chemical active substances to biological active substances. Nor has the applicant explained why the absence of guidelines on the NAS status of biological active substances is a bar to such an extrapolation.
171
In any event, the concept of ‘therapeutic moiety’ was explicitly used by the EU legislature in the context of essentially similar medicinal products, referred to in the first paragraph of section 3 of Part II of Annex I to Directive 2001/83, in connection with a negative definition of the concept of ‘NAS’ (see paragraphs 132 and 133 above). However, section 4 of Part II of Annex I to Directive 2001/83 on similar biological medicinal products does not refer to the concept of ‘NAS’. Accordingly, no conclusion can be drawn from the absence of any reference to the concept of ‘therapeutic moiety’ in that provision.
172
Similarly, it is irrelevant that the concept of ‘therapeutic moiety’ has been explicitly used in the context of certain changes to chemical active substances that would fall within the concept of an ‘extension of an MA’ referred to in point 1(a) of Annex I to Regulation No 1234/2008, but not in the corresponding provision relating specifically to biological medicinal products or active substances. Point 1(c) of Annex I to that regulation, which sets out the changes to biological active substances that would fall within the concept of an extension of an MA, does not detail the specific scientific concepts that should be taken into account in the assessments entailed by that provision as regards the molecular structure of a biological active substance. Consequently, that provision in no way calls into question the relevance of the concept of ‘therapeutic moiety’ as far as biological medicinal products or active substances are concerned. The same applies to the relevance of the concepts of ‘main molecular entity’, ‘basic structural element’ or ‘amino acid sequence’ referred to in the final assessment report of the CHMP, which are clearly concerned with characterising the molecular structure of the active substance.
173
Next, as regards, first, the specific application of the concept of ‘therapeutic moiety’ in the present case, having regard to the broad discretion enjoyed by the CHMP and the Commission, the fact that that concept is, according to the applicant and Eucope, more easily used in the context of chemical medicinal products, or ought to have been interpreted more broadly, does not substantiate any manifest error in the assessment of avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants. In any event, in its reply to a written question from the Court, the applicant acknowledged that the concept of ‘therapeutic moiety’ may be used for biological active substances, even though it disputes the use of that concept for assessing whether a biological active substance is an NAS.
174
Second, as regards the application of the concepts of ‘main molecular entity’, ‘basic structural element’ and ‘amino acid sequence’, as observed in paragraph 155 above, the applicant has confirmed that avalglucosidase alfa is a modification of alglucosidase alfa, which is an already authorised substance, and that the two substances differ in the chemical addition of glycans to the alglucosidase alfa molecule, the latter therefore being the basic structure of those two substances. In addition, the applicant itself acknowledges that the amino acid sequence is the primary structure or building block of a protein. Consequently, it does not appear to be manifestly incorrect to consider that the amino acid sequence constitutes the basic structural element of avalglucosidase alfa. Furthermore, it is common ground that the amino acid sequences of avalglucosidase alfa and alglucosidase alfa are identical. It follows that they share the same basic structural element.
175
Lastly, the Court finds that the specific nature of Nexviadyme as a biological medicinal product and an enzyme replacement therapy was indeed taken into account. The final assessment report of the CHMP in fact states that Nexviadyme is a biological product and that avalglucosidase alfa, like alglucosidase alfa, is an enzyme replacement therapy.
176
In that regard, even if, in the case of an enzyme replacement therapy, the enzyme administered must function in the same way as the endogenous enzyme, such that any developments intended to improve the safety or efficacy of the medicinal product must be made to elements other than the enzyme, then in the light of the wording of Annex I to the Notice to Applicants, the scheme of EU pharmaceutical legislation and the case-law as set out in paragraphs 149, 157, 158 and 163 above, the applicant has not shown that the CHMP and the Commission manifestly exceeded the limits of their discretion by adopting an approach by which such developments were to be examined under the third indent of Annex I to the Notice to Applicants. Such an approach means that it is possible to assess their real contribution in terms of significant differences with regard to safety and/or efficacy.
177
Indeed, as observed in paragraph 166 above, the granting of NAS status to avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants would mean that Nexviadyme would enjoy a period of regulatory data and marketing protection, without there being any requirement, for recognition of that status, to assess the impact of the modifications in avalglucosidase alfa, as compared with alglucosidase alfa, the active substance of Myozyme, even though Myozyme has already enjoyed those regulatory advantages. As is apparent from the positions defended by the applicant before the CHMP, and as it acknowledged in response to questions put by the Court, Nexviadyme and Myozyme are both enzyme replacement therapies indicated for the same rare disease, which provide patients with the recombinant version of the enzyme which they lack, and their active substances both contain glycans that are necessary for the uptake of the enzyme administered. Moreover – this not being challenged by the applicant – the final assessment report of the CHMP states that Nexviadyme does not exert a novel mechanism of action as compared with Myozyme.
178
In the light of the foregoing considerations, the CHMP and the Commission did not manifestly exceed the limits of their discretion or fail to take into consideration all the relevant factors and circumstances of the application for recognition of NAS status under the first indent of Annex I to the Notice to Applicants by rejecting the approach advocated by the applicant and Eucope, according to which changes to an active substance affecting the therapeutic functionality of the medicinal product would automatically lead to the recognition of NAS status under that indent for the substance thus modified.
179
That finding is not invalidated by the applicant’s other arguments.
180
No manifest error is demonstrated, regarding the approach applied and the scientific concepts used, from the fact that the wording of the definition of the concept of ‘NAS’ in the second indent of Annex I to the Notice to Applicants, concerning chemical active substances, is in part different from the wording of the third indent of that annex concerning biological active substances (see paragraph 20 above). Indeed, the applicant does not make clear what conclusion should be drawn from the partly different wording of the second and third indents of Annex I to the Notice to Applicants.
181
In so far as the applicant refers to previous assessments of NAS status, claiming that those carried out in respect of the biological medicinal products Rekovelle and Zinbryta confirm that the amino acid sequence is not the only relevant criterion to be taken into account in assessing whether a biological active substance may be classified as an NAS under the first indent of Annex I to the Notice to Applicants and that modifications to the active substance which impact the therapeutic functionality of the medicinal product should be classified as an NAS under that first indent, the Court observes that the final assessment report of the CHMP states that the approach adopted in relation to avalglucosidase alfa was consistent with that employed in those earlier assessments, and that the amino acid sequences of the candidate biological active substances in question were the same as those of the active substances of medicinal products that were already authorised in the European Union.
182
It is not clear from the few selected general observations, which in the case of Rekovelle were expressed in the conditional, taken from the European public assessment reports on the medicinal products and referred to by the applicant, that the CHMP took a different approach in the cases of Rekovelle and Zinbryta. The applicant’s line of argument relating to the assessment of the NAS status of the active substances of those medicinal products relates to the CHMP’s consideration of the ‘potency’ associated with modifications to an already authorised active substance. However, it is not clear from the extracts of the reports cited by the applicant whether the CHMP took that aspect into account under the first indent of Annex I to the Notice to Applicants, as the applicant claims, or under the third indent of that annex, which would then be in line with the practice referred to and followed by the CHMP in the present case.
183
It follows that the applicant has failed to establish that the CHMP adopted a manifestly different approach in the assessment of the NAS status of avalglucosidase alfa when compared to the assessments of the active substances of Rekovelle and Zinbryta.
184
In addition, and for the same reasons as set out in paragraph 131 above, it is irrelevant that at the stage of the initial examination procedure the co-rapporteur recommended that data supporting the significant impact of the increase in the level of bis-M6P on cellular binding should be provided in order to support the claim for NAS status for avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants. Furthermore, the opinions of co-rapporteurs, even if they differ from the opinion and assessment report subsequently adopted by the CHMP, cannot establish a lack of consistent practice as regards the assessment of biological active substances.
185
The applicant also submits that the advice provided to it by the CHMP in response to question 11, which it had asked in the context of the protocol assistance, confirms that changes to the active substance that affect the therapeutic functionality of the medicinal product should be classified as an NAS under the first indent of Annex I to the Notice to Applicants.
186
In that regard, the Court observes that the introductory part of the protocol assistance provided to the applicant in 2015 states that ‘the response given by the CHMP is based on the questions and supporting documentation submitted by the [a]pplicant, considered in the light of the current state of the art in the relevant scientific fields.’
187
Question 11 raised by the applicant in its request for protocol assistance did not relate to the possible NAS status of neoGAA, a first stage of development of avalglucosidase alfa, as compared with alglucosidase alfa. It concerned the possible similarity or lack thereof of neoGAA and BMN-701, another enzyme replacement therapy for Pompe disease being developed at that time by another company. The applicant had asked whether neoGAA and BMN-701 could be regarded as ‘not similar in the context of [A]rticle 3 of [Regulation] No 847/2000, with regard to the mechanism of action and the principle molecular structural features of both products’.
188
Moreover, the Court observes that the CHMP’s remarks in response to question 11 are drafted in the conditional, which shows their provisional nature at that time as regards the specific question asked.
189
It follows that the CHMP did not in any way confirm that the glycan structures of avalglucosidase alfa would be relevant for the NAS assessment under the first indent of Annex I to the Notice to Applicants. In any event, the protocol assistance provided in the present case cannot have a binding effect on the CHMP’s assessment of a separate, subsequent claim submitted in the context of an MA application, based on other scientific data, for the granting of NAS status to avalglucosidase alfa.
190
Lastly, the applicant submits that the EMA Guideline on similar biological medicinal products confirms its view that modifications to the active substance that affect the therapeutic functionality of the medicinal product should be classified as an NAS under the first indent of Annex I to the Notice to Applicants. An active substance that is not regarded as ‘similar’ to that of a reference biological medicinal product for the purposes of Article 10(4) of Directive 2001/83 cannot be regarded as being ‘the same’ as an already authorised substance when applying the ‘global authorisation’ concept and the regulatory data protection and marketing protection periods, the latter being directly relevant in the light of the abovementioned article of Directive 2001/83.
191
In that regard, the Court observes that the applicant did not submit its MA application for Nexviadyme on the basis of the MA procedure for biosimilar medicinal products provided for in Article 10(4) of Directive 2001/83, but on the basis of a separate regulatory procedure, such that the Guideline on similar biological medicinal products, published by the EMA under the last paragraph of section 4 of Part II of Annex I to Directive 2001/83, cannot be of relevance.
192
In the light of the foregoing considerations, the second complaint of the first limb of the first plea must be rejected as unfounded.
193
Consequently, the first limb of the first plea must be rejected as unfounded.
The third limb of the first plea, alleging errors in the finding that the conditions laid down in the third indent of Annex I to the Notice to Applicants were not met
194
The applicant argues that the CHMP applied an overly strict standard of proof for assessing the NAS status of avalglucosidase alfa under the third indent of Annex I to the Notice to Applicants. In addition, the final assessment report of the CHMP is vitiated by manifest errors of assessment inasmuch as the application of an incorrect standard of proof led the CHMP to consider that the evidence provided by the applicant did not suffice to demonstrate that avalglucosidase alfa differed significantly in properties with regard to safety and/or efficacy from alglucosidase alfa, since no clinically significant difference had been identified. In particular, the CHMP failed to take into account the clinical data on the secondary endpoints of the COMET study. Furthermore, the CHMP failed to consider the available quality data on avalglucosidase alfa in their totality.
195
In the reply, the applicant claims that the contested decision also infringes the principle of equal treatment.
196
The Commission, supported by the EMA, disputes those arguments.
197
As regards the standard of proof, the essential function of evidence is to establish the relevant facts to the requisite legal standard. The specific requirements relating to the quality of the evidence therefore do not, in principle, affect the standard of proof required (see to that effect, judgment of 13 July 2023, Commission v CK Telecoms UK Investments, C‑376/20 P, EU:C:2023:561, paragraph 77 and the case-law cited).
198
The third indent of Annex I to the Notice to Applicants states that a biological NAS includes a biological substance previously authorised in a medicinal product for human use in the European Union, but differing significantly in properties with regard to safety and/or efficacy which is due to differences, inter alia, in molecular structure.
199
It should be observed that neither the EU pharmaceutical legislation nor Annex I to the Notice to Applicants specifies the standard of proof required for the granting of NAS status to a biological active substance.
200
The applicant does not dispute that, for the purpose of applying the third indent of Annex I to the Notice to Applicants, it was required to provide the necessary evidence to establish the existence of an NAS. However, it submits that the standard of proof required by the CHMP was too high. It argues that the granting of NAS status under that indent does not require that the results of a clinical trial must clearly demonstrate that the active substance is significantly better in terms of efficacy or safety than the previously authorised active substance. The standard of proof which should have been applied involves determining, on the basis of all the available data and on a balance of probability, whether there are sufficient indications of a significant difference, in relation to the already authorised biological active substance, in safety or efficacy. That standard of proof is compatible with point 1(c) of Annex I to Regulation No 1234/2008, in the light of which the third indent of Annex I to the Notice to Applicants should be interpreted. Furthermore, the principle of proportionality requires such an approach because it is possible that certain data might not be available at the time of the grant of the MA and because of the difficulties inherent in collecting data in the case of medicinal products intended for the treatment of very rare conditions.
201
However, what the applicant is in fact seeking to do by its arguments is to set aside the criterion, which is explicitly expressed in the third indent of Annex I to the Notice to Applicants, that the active substance under assessment must differ ‘significantly’ in properties with regard to safety and/or efficacy from the previously authorised substance.
202
The assessment of significant differences in the properties of two active substances with regard to safety and/or efficacy is based on a thorough, objective and adversarial assessment of the highly complex scientific and technical facts put forward by an applicant, which, by their very nature, are not always free of scientific uncertainty, but which require the CHMP, bound by its duty to provide the best possible scientific advice, to adopt a position according to its assessment of those factors and of the plausibility of the conclusions drawn therefrom.
203
In addition, the expected effect on the properties of the active substance under assessment as regards safety and/or efficacy of the differences, in particular in the molecular structure of that substance, must go beyond a certain quantitative or qualitative threshold before those properties may be considered to differ ‘significantly’ from those of the already authorised substance.
204
It follows that establishing significant differences with regard to safety and/or efficacy in comparison with the relevant previously authorised biological substance must, as with any claim relating to medicinal products, be based on appropriate and reliable evidence. Furthermore, that evidence must enable the CHMP, and subsequently the Commission, to find that there are differences with regard to safety and/or efficacy between the two substances and that those differences are significant, that is to say that they involve a positive clinical impact going beyond mere non-inferiority, otherwise recognition of NAS status under the third indent of Annex I to the Notice to Applicants must be refused.
205
Consequently, and contrary to what the applicant claims, ‘sufficient indications’ cannot suffice. Moreover, where there are doubts as to the reliability of the data provided in support of the existence of significant differences and the conclusions drawn therefrom by the applicant, the competent authorities must be able to favour refusing the grant of NAS status.
206
In that context, the applicant cannot succeed with its argument that the less strict standard of proof which it suggests is supported by point 1(c) of Annex I to Regulation No 1234/2008 and the similarity of the wording of that provision with that of the third indent of Annex I to the Notice to Applicants, read in the light of the case-law referred to in paragraph 118 above.
207
Apart from the fact that Regulation No 1234/2008 does not contain any guidance in that regard, a claim for NAS status for an active substance under Annex I to the Notice to Applicants and an application for the extension of an MA are made in the framework of two different regulatory procedures, which cannot be treated as the same.
208
Similarly, the applicant cannot succeed with its argument based on the principle of proportionality and the difficulties inherent in collecting data for medicinal products intended for the treatment of very rare conditions. Since even such difficulties cannot serve to relax the requirements relating to establishing the quality, safety and efficacy of a medicinal product for the grant of an MA, the applicant fails to explain why those same difficulties would mean that ‘indications’ of significant differences with regard to safety and/or efficacy would be sufficient to establish the actual existence of such differences and, consequently, to permit the recognition of NAS status under the third indent of Annex I to the Notice to Applicants.
209
Also, it is true that the inherent complexity of the assessment of the clinical effects of an active substance is a factor which must be taken into account when assessing the plausibility of the conclusions drawn as to the claimed effects of an active substance. However, such complexity does not, of itself, have an impact on the standard of proof which is required (see, by analogy, judgment of 13 July 2023, Commission v CK Telecoms UK Investments, C‑376/20 P, EU:C:2023:561, paragraph 78 and the case-law cited).
210
Furthermore, the criterion that the active substance under evaluation must differ ‘significantly’ in properties with regard to safety and/or efficacy from the already authorised substance is justified by the necessity not to prolong or, as in the present case, not unduly to start new periods of regulatory data and marketing protection (see, to that effect, judgment of 16 March 2023, Commission and Others v Pharmaceutical Works Polpharma, C‑438/21 P to C‑440/21 P, EU:C:2023:213, paragraph 92).
211
In the light of the foregoing considerations, the Court finds that the applicant has not established that the CHMP failed to have regard to the applicable standard of proof with respect to the assessment of the NAS status of avalglucosidase alfa under the third indent of Annex I to the Notice to Applicants.
212
Next, as regards the alleged manifest errors of assessment in the final assessment report of the CHMP, the Court considers that the CHMP, in finding that the tests for the secondary endpoints pre-specified in the statistical analysis plan of the COMET study ‘could not formally be carried out under adequate experiment wise type-1-error control’, sought to verify and ensure the scientific and methodological reliability of the conclusions that could be drawn from the results of that study. Indeed, it is apparent from the documents before the Court that warnings and reservations of a similar nature had been signalled during the initial and the re-examination procedure.
213
Thus, the final assessment report of the CHMP, just like the CHMP assessment report of 23 July 2021, refers to the implications of the hierarchical testing of the COMET study with regard to the ‘interpretability’ of the data relating to the secondary and tertiary endpoints of that study. The reports also refer to the fact that, from a methodological perspective, it is not permissible to indicate, on the basis of that study, that avalglucosidase alfa provides an advantage over alglucosidase alfa.
214
As it is, the applicant has failed to explain how a finding of non-inferiority demonstrates the existence of significant differences with regard to efficacy and/or safety. Nor does it explain how the CHMP was wrong to follow the agreed hierarchy of tests.
215
In addition, as stated in paragraph 76 above, the EU authorities have broad discretion to determine the nature and scope of the measures which they adopt, in particular where they involve highly complex scientific and technical assessments, as is the case at hand. The Court therefore cannot substitute its own assessment for that of those authorities. Such assessments certainly include both the scientific evidence relevant to the assessment of the NAS status of biological active substances and the methodological rigour to be applied in interpreting scientific data.
216
Furthermore, the applicant’s argument that the CHMP did not take into account all the available data cannot succeed. The applicant has failed to identify any item of evidence which the CHMP failed to examine. In addition, it is apparent from the considerations in paragraphs 98, 103 and 106 above that the CHMP explained the various reasons why, taken individually or together, the evidence produced was not sufficient to establish the existence of significant differences with regard to efficacy and/or safety of avalglucosidase alfa as compared with alglucosidase alfa.
217
In the light of the above, the CHMP and the Commission did not commit any manifest error of assessment in considering that the evidence provided was not sufficient for the granting of NAS status to avalglucosidase alfa under the third indent of Annex I to the Notice to Applicants.
218
Lastly, in so far as the applicant submits that the contested decision infringes the principle of equality of treatment, since the EMA applied a more flexible standard of proof in dossiers other than that of Nexviadyme and allows a different, more flexible standard of proof for advanced therapy medicinal products, it should be borne in mind that it is apparent from the provisions of Article 76(d), in conjunction with Article 84(1), of the Rules of Procedure of the General Court that, inter alia, no new plea in law or argument may be introduced in the course of proceedings unless it is based on matters of law or of fact which come to light in the course of the procedure (see, to that effect, judgment of 15 July 2015, Dennekamp v Parliament, T‑115/13, EU:T:2015:497, paragraph 80), or it is a plea or argument that amplifies a plea put forward previously, whether directly or by implication, in the original application, and which is closely connected therewith (see, to that effect, judgment of 11 July 2013, Ziegler v Commission, C‑439/11 P, EU:C:2013:513, paragraph 46).
219
In the present case, it was not until the reply that the applicant, on the basis of one of the documents it received in September 2022 in response to its request for access to the file and on the basis of the draft reflection paper published on 18 November 2022, claimed that the CHMP had applied a more flexible standard of proof in the past and permitted a more flexible standard of proof for advanced therapy medicinal products and that, consequently, it had infringed the principle of equal treatment in the present case.
220
Accordingly, although that claim cannot be regarded as amplifying the third limb of the first plea as set out in the application, the matters of law and of fact which it contains came to light after the action was brought, such that it must be regarded as admissible.
221
In that regard, the principle of equal treatment requires that comparable situations not be treated differently and different situations not be treated in the same way unless such treatment is objectively justified (see judgment of 19 December 2019, Vanda Pharmaceuticals v Commission, T‑211/18, EU:T:2019:892, paragraph 159 and the case-law cited).
222
In the present case, the applicant has not identified in its written pleadings any other assessment of a biological active substance under the third indent of Annex I to the Notice to Applicants in which a more flexible standard of proof was applied.
223
That finding is not invalidated by the purely speculative line of argument put forward by the applicant on the basis of remarks in a document entitled ‘MLT dashboard’, issued by the EMA’s Medicines Leadership Team (MLT). There is nothing to indicate that those remarks concerned assessments of the NAS status of biological active substances under the third indent of Annex I to the Notice to Applicants, let alone ones in which the pivotal study formally failed.
224
In any event, since the scientific data relating to purported differences in the properties of one active substance compared to another with regard to efficacy and/or safety depend on the particular dossier submitted to the EMA and must be assessed individually, there can be no question of comparable situations (see, to that effect and by analogy, judgment of 19 December 2019, Vanda Pharmaceuticals v Commission, T‑211/18, EU:T:2019:892, paragraph 160).
225
Lastly, section 4.3.2. of the draft reflection paper of 18 November 2022 likewise does not substantiate an infringement of the principle of equal treatment.
226
It is true that section 4.3.2. of the draft reflection paper of 18 November 2022 refers to the possibility of justifying a claim for NAS status under the third indent of Annex I to the Notice to Applicants for advanced therapy medicinal products on the basis of ‘plausible scientific grounds’ and by justifying how the differences in molecular structure, nature of the source material or manufacturing process ‘may significantly impact’ the safety and/or efficacy profile of the active substance.
227
However, the applicant acknowledges that Nexviadyme is not an advanced therapy medicinal product and does not explain how it is comparable to such a medicinal product. In that regard, it is apparent from section 3.2. of the reflection paper of 18 November 2022 that claims for NAS status for biological substances in connection with structural differences that are insufficient for a claim to that status under the first indent of Annex I to the Notice to Applicants, require ‘evidence’ of significant differences in the properties of the active substance with regard to efficacy and/or safety. Accordingly, even if the applicant had demonstrated that the EMA permitted a different, more flexible standard of proof for advanced therapy medicinal products, it would not thereby have established a difference in treatment to the detriment of Nexviadyme.
228
In the light of the foregoing considerations, the complaint of an infringement of the principle of equal treatment must be rejected as unfounded and the third limb of the first plea must therefore be rejected in its entirety.
229
Since all the limbs of the first plea have been rejected as unfounded, the first plea must be rejected in its entirety.
The second plea in law, alleging breach of the principle of good administration, as enshrined in Article 41 of the Charter
230
By the second plea, the applicant argues that the procedures for the initial examination and the re-examination of its application for NAS status for avalglucosidase alfa do not comply with the principle of good administration, as enshrined in Article 41 of the Charter. This plea is divided into four limbs.
The first limb of the second plea, alleging infringement of the requirement of objective impartiality
231
The applicant submits that the EMA, during the initial examination and re-examination procedures for its application for NAS status for avalglucosidase alfa, imposed its view on the CHMP that that status should be refused, and that the discussion on the NAS status of avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants took place ‘behind the scenes’. It explained at the hearing that it was thereby raising an infringement of the requirement of objective impartiality.
232
The Commission, supported by the EMA, disputes those arguments.
233
The requirement of objective impartiality requires the institution to offer sufficient guarantees to exclude any legitimate doubt as to possible bias (see, to that effect, judgment of 27 March 2019, August Wolff and Remedia v Commission, C‑680/16 P, EU:C:2019:257, paragraph 27 and the case-law cited).
234
In order to show that the organisation of an administrative procedure does not ensure sufficient guarantees to exclude any legitimate doubt as to possible bias, it is not necessary to prove lack of impartiality. It is sufficient for a legitimate doubt to arise which cannot be dispelled (see, to that effect, judgment of 27 March 2019, August Wolff and Remedia v Commission, C‑680/16 P, EU:C:2019:257, paragraph 37).
235
In the present case, the applicant, in support of the purported failure to comply with the requirement of objective impartiality relating to the assessment of the NAS status of avalglucosidase alfa, refers to the minutes of CHMP meetings and certain documents it received in response to its request for access to the file.
236
First of all, the applicant submits, as regards the initial examination of the NAS claim for avalglucosidase alfa, that it is apparent from page 11 of the document entitled ‘Early Background Summary for Marketing Authorisation application’ of 13 October 2020 that the EMA took the position from the beginning of the procedure that the glycan structure was not relevant for the assessment of NAS status under the first indent of Annex I to the Notice to Applicants.
237
That document contains the following passage:
‘In particular, for [the] avalglucosidase alfa NAS claim, any changes in improved binding and uptake would be expected to translate into significant differences in safety and/or efficacy. Examples of significant differences are changes in dosing frequency, improved efficacy, changes in contraindications etc. Examples of insignificant differences are changes in [pharmacokinetics] alone, widening of patient population to sub-groups not previously studies etc.’
238
In that regard, the Court observes that, in accordance with Article 56(1)(f) of Regulation No 726/2004, the Secretariat of the EMA is to provide technical, scientific and administrative support for the committees of that agency and ensure appropriate coordination between them. In accordance with Article 22 of the Rules of Procedure of the CHMP, the assistance includes technical and scientific support to rapporteurs and legal and regulatory support to the CHMP.
239
The ‘Early Background Summary for Marketing Authorisation application’ was drawn up by the EMA Secretariat, during the initial examination procedure, in the context of the latter’s support to the CHMP. It was not binding on the CHMP.
240
Furthermore, the passage cited by the applicant does not indicate that the glycan structure is not relevant for the review of NAS status under the first indent of Annex I to the Notice to Applicants. In addition, that passage must be read in context. In the introductory part of that document, on the procedural and regulatory aspects, it is stated that the applicant had requested NAS status for avalglucosidase alfa and had provided comparative data for comparison with alglucosidase alfa in order to support the claim for that status under the first indent. The introductory part states that such data should only be required if the substance had previously been authorised in a medicinal product for human use in the European Union, namely in the framework of the third indent of Annex I to the Notice to Applicants. That part states that ‘only in the case avalglucosidase alfa is considered the same biological substance as alglucosidase alfa from a quality perspective, the clinical and non clinical data to support the significant safety and/or efficacy should be assessed to support the NAS claim’. It follows that, as the EMA submits, the ‘Early Background Summary for Marketing Authorisation application’ indicates that the pathway of the first indent of Annex I to the Notice to Applicants and that of the third indent of that annex were both open in the present case for assessing the application for NAS status.
241
In any event, since the exclusive responsibility for preparing the EMA’s opinions on all questions relating to medicinal products for human use is vested in the CHMP, which expresses itself by means of scientific opinions or recommendations adopted by consensus or by an absolute majority of its members, an argument based on an isolated passage, cited out of context, from the ‘Early Background Summary for Marketing Authorisation application’ issued by the EMA Secretariat must be rejected as unfounded.
242
Next, the applicant argues that it is apparent from page 4 of the document entitled ‘EMA Product team peer review of the day-80 assessment reports for Avalglucosidase alfa’ of 8 January 2021 that the final determination of the NAS status of avalglucosidase alfa under the first indent was ‘delegated’ to the Biologics Working Party.
243
That document contains the following passage:
‘[The Biologics Working Party] should discuss if the NAS claim according to [the first indent] could be still [be] pursued by the company (requiring further justification) or it is not acceptable. Should [the Biologics Working Party] reject a claim according to [the first indent], in order to claim … NAS status, the applicant can consider a claim according to the third indent of the [Notice to Applicants], requiring significant differences in safety and/or efficacy. It is noted that the applicant has already submitted some non-clinical and clinical information that the [r]apporteurs [have] reviewed and currently [consider] not sufficient. The evaluation of the NAS status of avalglucosidase alfa with regard to [the third indent] (safety and efficacy) is not within the remit of [the Biologics Working Party] but a multidisciplinary issue and, therefore, it should be further discussed by the CHMP.’
244
In that regard, the Court observes that that document was also drawn up by the EMA Secretariat, during the initial examination procedure, in the framework of the support which that secretariat provides to the CHMP, and was not binding on the CHMP.
245
Moreover, in accordance with Article 56(2) of Regulation No 726/2004 and Article 15(1) of the Rules of Procedure of the CHMP, the CHMP may establish standing and temporary working parties. Article 6(8) of the CHMP’s Rules of Procedure empowers the CHMP to consult an advisory group when evaluating a product. Furthermore, Article 15(4) and (5) of those rules of procedure provides that the CHMP is to review the mandate and objectives of each working party at least every three years and that, whenever considered appropriate, the CHMP is to consult its working parties on any scientific issue related to their fields of expertise. As regards the delegation of tasks, Article 15(5) of the CHMP’s Rules of Procedure provides that the committee may also delegate certain tasks associated with the scientific evaluation of applications or drafting of guidelines to the relevant working parties. The tasks identified by the CHMP should be included in the work programme of each working party to be adopted by the CHMP.
246
In the present case, it is apparent from section 2 of the rules of procedure of the Biologics Working Party, entitled ‘Mandate and objectives’, that it was established in order to provide recommendations to the CHMP on all matters relating directly or indirectly to the quality aspects of biological medicinal products. It is responsible for providing support to the CHMP in the evaluation of dossiers, inter alia, by providing it with reports on all MA applications prior to the CHMP’s opinion and so as to maintain the consistency of evaluations. It may also, at the request of the CHMP, provide scientific advice on general and product-specific matters related to the quality aspects of biological medicinal products.
247
It follows that the Biologics Working Party had a mandate to provide recommendations to the CHMP regarding the claim of NAS status for avalglucosidase alfa submitted in the framework of the MA application for Nexviadyme, that mandate being set out in the rules of procedure of that working party.
248
In addition, the passage cited by the applicant does not serve to support the conclusion that the final determination of the NAS status of avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants was ‘delegated’ to the Biologics Working Party or that the EMA imposed its point of view on the CHMP. It merely indicates a question which the working group was to address, while explaining that, if the claim for NAS status under the first indent of Annex I to the Notice to Applicants were rejected, the pathway of the third indent of that annex would remain open. The passage cited by the applicant must be read in context. It is apparent from the passages immediately preceding that cited by the applicant that, owing to the submission of some information on efficacy and safety, it was unclear whether or not the applicant intended to make a claim for NAS status under the third indent of Annex I to the Notice to Applicants, that it had been informed, prior to the submission of its MA application, that a claim to NAS status under the first indent of that annex would be difficult and that, in essence, certain aspects of the co-rapporteurs’ assessment reports at the ‘day-80’ stage of the procedure were inconsistent or unclear.
249
It follows that the argument based on a passage taken in isolation and cited out of context from the document entitled ‘EMA Product team peer review of the day-80 assessment reports for Avalglucosidase alfa’, issued by the EMA Secretariat, must be rejected as unfounded.
250
Next, as regards the minutes of the CHMP meeting of July 2021, which took place over several days, it should be stated that that meeting was held as part of the initial assessment procedure of the application for NAS status for avalglucosidase alfa and, therefore, before the adoption of the initial opinion of the CHMP on 23 July 2021. The fact that the minutes of that meeting describe avalglucosidase alfa as a ‘known’ substance, even in a passage referring to the applicant’s oral explanations of 20 July 2021, cannot constitute evidence of a biased initial examination by the CHMP. Minutes are generally approved only at the end of a meeting or after it and it was indeed after the oral explanations referred to above that the CHMP adopted its initial opinion, including the initial rejection of the applicant’s claims regarding the NAS status of avalglucosidase alfa. In any event, it is apparent from the file that the minutes of the CHMP meeting of July 2021 were not published until October 2021, namely after the adoption of the initial opinion. It follows that those minutes, drawn up in circumstances that are not known, cannot allow conclusions to be drawn as to the possible lack of objective impartiality on the part of the CHMP at the time of that meeting.
251
Similarly, the mere fact that the agendas and minutes of CHMP meetings during the procedure for re-examination of the NAS application classified avalglucosidase alfa as a ‘known’ active substance does not lead to the conclusion that that procedure did not offer sufficient guarantees to exclude any legitimate doubt as to possible bias on the part of the EMA, its secretariat or the CHMP.
252
Such documents are intended solely to provide basic information on the topics to be discussed and the action to be taken and, in the case of minutes, to summarise the actions taken in the past, the stage which the discussions have reached and, as necessary, the various action points adopted. Since the CHMP had already issued an initial opinion recommending that avalglucosidase alfa should not be classified as an NAS, the description of that substance as a ‘known’ substance in the agendas and minutes of meetings during the re-examination procedure was merely an immediate reminder of the subject matter of the re-examination concerned by the meeting.
253
Lastly, the applicant’s argument based on page 3 of the document entitled ‘Rolling Reader’s Guidance – Re-examination’ of November 2021, namely that the EMA had already concluded that avalglucosidase alfa was not an NAS under the first indent of Annex I to the Notice to Applicants, cannot succeed.
254
That document contains the following passage:
‘A substance is considered to be new in itself (i.e. first indent) when the administration of the applied active substance would not expose patients to the same therapeutic moiety as already authorised active substance(s) in the European Union. Cases where active substances are structurally related and where the administration of the applied active substance does expose patients to the same therapeutic moiety, fall under the third indent.
Taking this principle in account during the assessment of the molecular structure and the different points raised by the [a]pplicant, it is concluded that avalglucosidase alfa is not considered to qualify as a new active substance under [the first indent] of the NAS definition. Any potential impact to clinical efficacy or safety is assessed under the claim [under the third indent].’
255
The EMA asserts, without being contradicted on that point by the applicant, that that document was not prepared by its secretariat, but by the rapporteur at the re-examination stage, and that it is intended only to summarise the stage of the discussions at that time at the level of the CHMP, by presenting the rapporteur’s point of view, that of the co-rapporteur and the comments received from the rest of the CHMP members.
256
It follows that the passage from the ‘Rolling Reader’s Guidance – Re-examination’ cited by the applicant does not serve to support the conclusion that the EMA imposed its point of view on the CHMP. Furthermore, that passage must be read in context, namely as reflecting the state of the debate taking place at that time within the CHMP. It shows that the rapporteur and co-rapporteur agreed at the re-examination stage on the quality assessment of avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants. It summarises the rapporteur’s position that that substance could qualify as an NAS under the third indent of Annex I to the Notice to Applicants. It states that the unanimous position of the CHMP members was that avalglucosidase alfa could not be granted NAS status under the first indent of Annex I to the Notice to Applicants.
257
In the light of the foregoing considerations, the first limb of the second plea must be rejected as unfounded.
The second limb of the second plea, claiming that the CHMP made use of a document to which the applicant was refused access
258
The applicant complains that the CHMP, as a reference point during the procedures for the initial examination and the re-examination of its application for NAS status for avalglucosidase alfa, took account of a draft reflection paper on the criteria to be considered for the evaluation of the NAS status of biological substances, which was subsequently published for consultation on 18 November 2022, to which it was denied access.
259
The Commission, supported by the EMA, disputes those arguments.
260
According to the case-law, infringement of the right of access to the file during the procedure prior to the adoption of a decision that has an adverse effect can result in the annulment of the contested decision only if there was a chance, albeit slight, that disclosure of the documents in question might have caused the administrative procedure to have a different result if the person concerned had been able to rely on them during that procedure (see, to that effect, judgment of 16 February 2012, Council and Commission v Interpipe Niko Tube and Interpipe NTRP, C‑191/09 P and C‑200/09 P, EU:C:2012;78, paragraph 174).
261
In the present case, the applicant submits, in support of its line of argument, that a draft reflection paper on the criteria to be considered for the evaluation of the NAS status of biological substances was referred to in the CHMP (co)rapporteurs’ report of 7 July 2021; during its oral explanations in the course of the initial examination; in a presentation to the Biologics Working Party during the latter’s meeting of October 2021 in the re-examination procedure, and in the report by that working party of 28 October 2021.
262
In that context, it should be borne in mind that intermediate evaluation reports and documents must be distinguished from the assessment reports adopted by the CHMP that reflect the opinion of that committee.
263
The outline draft reflection paper was not referred to in either the assessment report of the CHMP of 23 July 2021 or the final assessment report of the CHMP after re-examination.
264
Furthermore, the Court points out that textual similarities in the various reports drawn up during the initial examination procedure and in the re-examination procedure cannot constitute an irregularity (see, to that effect and by analogy, judgments of 9 September 2010, Now Pharm v Commission, T‑74/08, EU:T:2010:376, paragraph 95, and of 11 December 2014, Faita v EESC, T‑619/13 P, EU:T:2014:1057, paragraph 32).
265
Similarly, the fact that scientific considerations are applied in an assessment of an application for NAS status, while they may also appear in an outline draft reflection paper that is not yet available to the public because it has not been adopted by the CHMP, cannot constitute an irregularity.
266
It is apparent from the third subparagraph of Article 61(1) of Regulation No 726/2004 and Article 6(1) of the Rules of Procedure of the CHMP that it is on the basis of their experience and in connection with the objective of providing the best possible scientific advice that the members of the CHMP are appointed and the various CHMP rapporteurs and co-rapporteurs and the members of their teams of assessors are designated. Accordingly, those individuals cannot be expected to set aside scientific approaches, knowledge and practices which may appear to them to be relevant and which, moreover, have been recommended to them by a working party responsible for providing them with support, solely on the ground that those approaches, that knowledge and those practices appear in an outline draft reflection paper.
267
In any event, the applicant has not shown that communication of the outline draft reflection paper would have affected the content of the contested decision, the applicant not having adduced any conclusive evidence in that regard. It was only at the hearing that the applicant stated that it could possibly have raised additional arguments in order to cast doubt on the emphasis placed by the CHMP on the amino acid sequence. However, the scientific approach ultimately adopted by that committee was set out clearly throughout the procedure and was not changed. Consequently, even if it were considered that failure to communicate that outline constitutes a procedural irregularity, it would have no effect on the lawfulness of the contested decision.
268
In the light of the foregoing considerations, the second limb of the second plea must be rejected as unfounded.
The third limb of the second plea, based on failure to communicate to the applicant the EMA’s recommendations to the rapporteur and co-rapporteur of the CHMP
269
The applicant complains that the EMA did not give it access to the recommendations that the agency had provided to the CHMP’s rapporteur and co-rapporteur during the re-examination of its application for NAS status for avalglucosidase alfa. Two passages in the co-rapporteur’s re-examination report of 1 October 2021 on the grounds for re-examination appear to show that the CHMP’s subsequent assessment was steered by those recommendations.
270
Thus, as regards the ground for re-examination concerning the legal and regulatory nature of the NAS assessment criteria, the applicant refers to section 4.3. of the co-rapporteur’s assessment report on the grounds for re-examination of 1 October 2021. The co-rapporteur observed that the EMA had stated in its comments to him that ‘there is no need to address these issues’ and that ‘the assessment should focus only on scientific grounds’.
271
As regards the ground for re-examination that the principle of similarity, as provided for in Regulation No 847/2000 applicable to orphan medicinal products, confirms the NAS status of avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants, the applicant refers to section 4.11. of the report referred to in paragraph 270 above. The co-rapporteur observed that the ‘EMA states that the definitions used are those of the Orphan Regulation’ and that, however, ‘these fall outside the considerations to be held for NAS assessment, and as such should be disregarded’. The EMA had also stated that ‘a statement could be added to the [assessment report] to the effect that [principal molecular structural features] considerations, as provided in orphan legislation, are not necessarily applicable [to an] NAS assessment which does not deal with market exclusivity’.
272
The applicant states that the second of the co-rapporteur’s observations, cited in paragraph 271 above, is to be found in section 5.3. of the final assessment report of the CHMP, which states that ‘the principal molecular structural features (PMSF) considerations, as provided in orphan legislation, are not applicable [to an] NAS assessment since it does not deal with market exclusivity’.
273
The Commission, supported by the EMA, disputes those arguments.
274
As observed in paragraph 238 above and as the applicant acknowledges, the EMA Secretariat is responsible for providing technical, scientific and administrative support to that agency’s committees, which includes technical and scientific support to rapporteurs and legal and regulatory support to the CHMP.
275
The Court notes that the EMA Secretariat provided legal support to the CHMP rapporteurs during the re-examination procedure that is not provided for in the Rules of Procedure of the CHMP, in the form, according to the Commission’s written pleadings, of ‘internal clarifications of [a] legal nature’. Nevertheless, in the absence of any argument raised by the applicant in that regard, that fact cannot constitute a ground for annulment of the contested decision. Indeed, the applicant has stated that it did not object to such guidance.
276
Furthermore, it is not apparent from the documents before the Court that the applicant sought access to the legal clarifications in question during the re-examination procedure and it has not explained how the failure to communicate those clarifications to it automatically had a specific adverse effect on it.
277
Moreover, the aspects of the applicant’s arguments covered by those clarifications, namely the legal and regulatory nature of the criteria of the NAS assessment and the relevance of the definitions set out in Regulation No 847/2000, had already been raised and rejected during the initial examination and in the assessment report of the CHMP of 23 July 2021 accompanying the opinion of the CHMP of 23 July 2021. Accordingly, there is nothing to suggest that communication of those clarifications would have affected the content of the contested decision, the applicant not having adduced any conclusive evidence in that regard. Consequently, even if it were considered that the failure to communicate those clarifications constitutes a procedural irregularity, that circumstance cannot lead to annulment of the contested decision.
278
In the light of the foregoing considerations, the third limb of the second plea must be rejected as unfounded.
The fourth limb of the second plea, alleging failure to inform the applicant of the role and work of the Biologics Working Party
279
The applicant submits that it was not properly informed of the role and opinion of the CHMP’s Biologics Working Party in the procedures for the initial examination and the re-examination of its application for NAS status for avalglucosidase alfa. Nor were its views heard by that working party. In addition, the EMA should have sent it the report of the Biologics Working Party of 28 October 2021 earlier, instead of communicating it only in June 2022, after a request to that effect. The Biologics Working Party played a decisive role in the re-examination of its application for NAS status for avalglucosidase alfa under the first indent of Annex I of the Notice to Applicants and the involvement of that working party changed the approach initially proposed by the rapporteur at the re-examination stage. Furthermore, the Biologics Working Party did not have a mandate to assume such a role in the absence of a renewal of the group’s work plan by the CHMP.
280
The Commission, supported by the EMA, disputes those arguments.
281
The applicant’s argument that it was not properly informed of the role of the Biologics Working Party and that that working party did not have a mandate to provide recommendations to the CHMP with regard to the NAS claim for avalglucosidase alfa submitted in the context of the MA application for Nexviadyme cannot be accepted.
282
The rules of procedure of the CHMP and of the Biologics Working Party are public documents that are accessible on the EMA’s website, such that the applicant was in a position to acquaint itself with the role and mandate of that working party. Furthermore, the applicant itself provided the Court with the rules of procedure of the Biologics Working Party.
283
As stated in paragraphs 246 and 247 above, the Biologics Working Party was established in order to provide recommendations to the CHMP on ‘all matters’ relating, directly or indirectly, to the quality aspects of biological medicinal products and is responsible for providing support to the CHMP in the evaluation of dossiers by providing it with reports on ‘all marketing authorisation applications … prior to opinion’. The mandate to provide recommendations to the CHMP regarding claims for NAS status is set out in the rules of procedure of the Biologics Working Party and not in its annual work plan.
284
Moreover, there is nothing in the file to show that the mandate of the Biologics Working Party was altered between 13 December 2018 and 11 November 2021, namely between the date of adoption of the rules of procedure of that working party and the date of adoption of the final opinion and the final assessment report of the CHMP. More specifically, there is no indication that the CHMP amended the mandate of the Biologics Working Party as part of the triennial review of that mandate under Article 15(4) of the Rules of Procedure of the CHMP (see paragraph 245 above).
285
It follows that there is no lack of transparency nor any absence or exceeding of the mandate of the Biologics Working Party as regards the CHMP’s consultation of that working party.
286
Next, as regards the possibility for an MA applicant to be heard by the Biologics Working Party, the case-law states that the right to be heard requires that the addressees of decisions which significantly affect their interests should be placed in a position in which they can effectively make known their views on the accusation made against them forming the basis of the contested measure (see, to that effect, judgment of 19 December 2019, Probelte v Commission, T‑67/18, EU:T:2019:873, paragraph 86 and the case-law cited).
287
In that regard, Article 13(1) of the CHMP’s Rules of Procedure provides that oral explanations may be provided by the applicant for an MA to working parties or scientific advisory groups when the CHMP has delegated tasks associated with the scientific evaluation to a working party or a scientific advisory group. However, as pointed out in paragraph 248 above, the applicant has not established that the final determination of the NAS status of avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants was ‘delegated’ to the Biologics Working Party.
288
Section 2 of the Biologics Working Party’s rules of procedure states, in the framework of the support that it provides to the CHMP in the evaluation of dossiers that ‘where deemed necessary by the [Biologics Working Party]/CHMP, oral clarification meetings may be held’ with MA applicants. Section 6.3. of the rules of procedure of the Biologics Working Party provides that ‘when considered appropriate by the [Biologics Working Party], oral presentations by companies can be made during working party meetings on matters directly related to the activities of the working party, following agreement of the CHMP’.
289
Since those provisions are expressed in non-mandatory terms and give discretion to the Biologics Working Party, a decision to invite the applicant to provide oral explanations fell to that working party, if necessary with the agreement of the CHMP.
290
That conclusion is not invalidated by the fact that the EMA is required, in the exercise of its powers, under Article 51(1) of the Charter, to respect the rights and principles referred to therein (see, to that effect, judgment of 14 March 2024, D & A Pharma v Commission and EMA, C‑291/22 P, EU:C:2024:228, paragraphs 87 and 112).
291
The opinion of the Biologics Working Party does not constitute an individual measure which would affect the applicant adversely for the purposes of Article 41(2)(a) of the Charter. Such an opinion is merely an intermediate act that is preparatory to the opinion of the CHMP and the contested decision. Furthermore, the applicant did not have a general or absolute right to make oral observations above the possibility provided for by Directive 2001/83, Regulation No 726/2004 and the rules of procedure of the CHMP and the Biologics Working Party.
292
In the light of the foregoing considerations, it must be found that the applicant’s right to be heard was not infringed by the fact that it did not have the opportunity to express its views orally before the Biologics Working Party.
293
In any event, it is apparent from the file that the applicant was able to express its position on the NAS status of avalglucosidase alfa at the initial examination and re-examination stage, both in writing and during the oral explanations before the CHMP on 20 July and 8 November 2021, and at meetings with the Commission. In addition, it makes no claim that the contested decision is based on scientific considerations on which it was unable to express its views before the adoption of that decision.
294
As regards the complaint that the EMA did not send the Biologics Working Party report of 28 October 2021 to the applicant until June 2022, after a request was made to that effect, even though the report had a decisive impact on the outcome of the assessment of its NAS application for avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants, it is sufficient to observe that the considerations of that working party that were considered relevant by the co-rapporteurs at the re-examination stage and, subsequently, by the CHMP were included in the Rapporteurs’ Joint Assessment Report of the Grounds for the Re-examination Procedure of 2 November 2021 and in the final assessment report of the CHMP. The applicant does not deny having received those documents in good time.
295
Furthermore, no irregularity may be inferred from the fact that, in the re-examination of the assessment of the NAS status of avalglucosidase alfa under the first indent of Annex I to the Notice to Applicants, the rapporteur, who had initially considered that avalglucosidase alfa could be an NAS under that indent of Annex I to the Notice to Applicants on the ground that the difference in its molecular structure from that of alglucosidase alfa was more than slight, as provided for in Regulation No 1234/2008, adopted the position of the Biologics Working Party in her report on the grounds for re-examination of 8 October 2021.
296
It is true that the exercise of the role of rapporteur entails taking on an important role in preparing the opinion which the CHMP is called upon to issue and the rapporteur appointed by that committee has responsibilities of his or her own in that procedure for issuing an opinion (see, to that effect, judgment of 27 March 2019, August Wolff and Remedia v Commission, C‑680/16 P, EU:C:2019:257, paragraphs 33 and 34).
297
Nevertheless, in the present case, the re-examination rapporteur stated that she considered it as pragmatic to incorporate the position of the Biologics Working Party in her report of the grounds for re-examination of 8 October 2021, in view of timetable constraints. There was nothing to prevent the rapporteur from so doing if she shared the conclusions of the Biologics Working Party. In any event, it is not inconceivable that an expert may change their mind on a question relating to the evaluation of a medicinal product.
298
In that regard, the minutes of the meeting of the Biologics Working Party of October 2021, at the stage of the re-examination of the application for NAS status, indicate that a vote intended to clarify the trend of opinion within that working party showed that a majority of its members considered that avalglucosidase alfa was not an NAS under the first indent of Annex I to the Notice to Applicants and that that conclusion was subsequently endorsed by all the members of the working party and by the rapporteur at the re-examination stage.
299
In the light of the foregoing considerations, the fourth limb of the second plea must be rejected as unfounded.
300
Since all the limbs under the second plea have been rejected as unfounded, the second plea must be rejected in its entirety.
The third plea in law, alleging infringement of Article 5(12)(b) of Regulation No 141/2000, manifest error of assessment and inadequate statement of reasons
301
By the third plea in law, the applicant challenges Article 5 of the contested decision in that the Commission decided that Nexviadyme should not be classified as an orphan medicinal product. According to the applicant, the COMP imposed an overly strict standard of proof when assessing whether the criterion of significant benefit, for maintaining the designation of Nexviadyme as an orphan medicinal product at the time of granting the MA, was still met. While the examination of the criteria for finding a significant benefit is strict, a ‘weighing of probabilities’ is required. However, the structure and reasoning of the final position of the COMP are deficient in that the committee did not conduct a review of the totality of the evidence, by weighing the overall probabilities. The COMP therefore did not address all the aspects that ought to have been taken into account and made a manifest error of assessment. Lastly, the applicant claims that the errors affecting the assessment of the NAS status of avalglucosidase alfa by the CHMP also vitiate the COMP’s assessment of the significant benefit of Nexviadyme as compared to Myozyme.
302
The Commission, supported by the EMA, disputes those arguments.
303
First, it should be observed that the procedure relating to orphan medicinal products is divided into two separate phases. The first phase covers the designation of the product as an orphan medicinal product; the second, at issue in the present case, covers the MA for the medicinal product that has been designated as an orphan medicinal product and the market exclusivity attaching to it. Under Article 5(12)(b) of Regulation No 141/2000, a designated orphan medicinal product is to be removed from the EU Register of Orphan Medicinal Products if it is established before the MA is granted that the designation criteria are no longer met in respect of the medicinal product concerned. Thus, where a sponsor submits an MA application in respect of a designated orphan medicinal product, it triggers at the same time a procedure for re-evaluating compliance with the designation criteria (see judgment of 23 September 2020, Medac Gesellschaft für klinische Spezialpräparate v Commission, T‑549/19, EU:T:2020:444, paragraphs 43 to 45 (not published) and the case-law cited).
304
Article 3(1)(b) of Regulation No 141/2000 lays down alternative criteria for the designation of a medicinal product as an orphan medicinal product. Those are that either there is no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorised in the European Union (first situation) or, if such a method exists, as in the present case, the medicinal product in question will be of significant benefit to those affected by that condition (second situation).
305
It should be observed that, when classifying a medicinal product as an orphan medicinal product, the concept of ‘significant benefit’ is defined in Article 3(2) of Regulation No 847/2000 as meaning ‘a clinically relevant advantage or a major contribution to patient care’.
306
According to the case-law, in the context of the second situation in Article 3(1)(b) of Regulation No 141/2000, applicable in the present case, establishing significant benefit takes place in the context of a comparison with an existing authorised medicinal product or method. The ‘clinically relevant advantage’ and the ‘major contribution to patient care’, which enable the potential orphan medicinal product to be described as being of significant benefit, can be established only by comparison with treatments that have already been authorised (see judgment of 16 May 2019, GMPO v Commission, T‑733/17, EU:T:2019:334, paragraph 32 and the case-law cited).
307
It is also apparent from Article 3(1)(b) of Regulation No 141/2000 and the spirit underlying the system established by that regulation that the criteria for a finding of a significant benefit are strict. The development of a medicinal product which is of significant benefit in comparison with the medicinal product already authorised for the treatment of the same condition involves, for the undertaking working on it, investment in research and development of the potential improved medicinal product. An undertaking cannot thus merely develop a similar medicinal product in order to obtain its designation as an orphan medicinal product, marketing authorisation, and the concomitant market exclusivity (see judgment of 22 January 2015, Teva Pharma and Teva Pharmaceuticals Europe v EMA, T‑140/12, EU:T:2015:41, paragraph 65 and the case-law cited).
308
The responsibility for assessing whether an application for designation as an orphan medicinal product meets the designation criteria lies solely with the COMP, which must issue a scientific opinion on the initial designation. An MA will confer entitlement to market exclusivity, within the meaning of Article 8 of Regulation No 141/2000, only if the COMP has confirmed, at the conclusion of its scientific assessment, that the objective designation criteria set out in Article 3(1) of the regulation are met (see, to that effect, judgment of 5 December 2018, Bristol-Myers Squibb Pharma v Commission and EMA, T‑329/16, not published, EU:T:2018:878, paragraph 82).
309
It is apparent from a reading of Article 5(12)(b) of Regulation No 141/2000 in conjunction with Article 7(3) of the regulation that at the time of the MA the COMP is to carry out a complete re-evaluation of the designation criteria in a factual situation that is different from that which led to the initial designation. In order to determine whether the medicinal product in question meets those criteria at the time of the MA, that new assessment must take account of evidence that has come to light since the grant of the initial designation, including new medicinal products which have been authorised in the meantime or new scientific and medical data on clinical trials and studies subsequent to the initial designation (see, to that effect, judgment of 5 December 2018, Bristol-Myers Squibb Pharma v Commission and EMA, T‑329/16, not published, EU:T:2018:878, paragraph 83).
310
It follows that there must be a positive finding that the significant benefit criterion referred to in Article 3(1) of Regulation No 141/2000 is met once again at the time of the MA. In order to confirm in its opinion that the orphan designation attributed to the medicinal product concerned should be maintained, the COMP must satisfy itself, scientifically and objectively, that the significant benefit criterion is met. Accordingly, in the absence of conclusive evidence proving significant benefit at the time of the MA, the COMP is required to conclude that the designation criteria laid down in Article 3 of the regulation are no longer met and, therefore, recommend that the Commission remove the medicinal product concerned from the EU Register of orphan medicinal products. Thus, in order to avoid such removal, the sponsor must provide sufficient data to establish significant benefit, in the light of the new circumstances prevailing at the time the MA is granted (judgment of 5 December 2018, Bristol-Myers Squibb Pharma v Commission and EMA, T‑329/16, not published, EU:T:2018:878, paragraph 84).
311
Furthermore, it is apparent from the case-law that the comparative analysis between the new medicinal product and the existing methods or medicinal products authorised in the European Union, namely, in the present case, Myozyme, must establish not only that the new product provides a benefit to patients and that it contributes to their care, but also that that benefit is ‘significant’ and that that contribution is ‘major’. The expected advantage of that new medicinal product must therefore exceed a certain quantitative or qualitative threshold in order that it may be considered to be ‘significant’ or ‘major’ (see, to that effect, judgment of 16 May 2019, GMPO v Commission, T‑733/17, EU:T:2019:334, paragraph 39).
312
A sponsor must therefore demonstrate, on the basis of concrete and substantiated evidence and information, that its medicinal product provides a significant benefit, that is to say that it provides a clinically significant advantage or ensures a major contribution to patient care in comparison with the reference product, and is not able to rely in that regard on presumptions or assertions of a general nature (see, to that effect, judgment of 16 May 2019, GMPO v Commission, T‑733/17, EU:T:2019:334, paragraph 40).
313
In the present case, and in so far as the applicant submits that the statement of reasons in the final position of the COMP is inadequate, it must be stated that, in sections 6 and 7 of that document, the committee set out the scientific and methodological considerations and reasons why it considered that the additional evidence provided by the applicant in its detailed arguments seeking revision of the opinion of the COMP of 20 December 2021, taken in isolation or together, was not sufficient to establish that Nexviadyme provides a significant benefit in comparison with Myozyme.
314
First of all, the COMP examined two additional analyses relating to the COMET study data. The first of those analyses was intended to demonstrate, in essence, that the results of the COMET study were not a chance finding and that the fact that that study did not provide a statistically significant result for the assumption of the superiority of avalglucosidase alfa was due to an outlier patient. The second was intended to demonstrate, in essence, that there was a meaningful difference favouring Nexviadyme when the endpoints relating to muscle respiratory force (corresponding to percentage predicted FVC) and the six-minute walk test were considered together.
315
Nevertheless, the COMP stated that it had reservations regarding the conclusions drawn by the applicant with regard to the first of the additional analyses referred to in paragraph 314 above on the ground that it was based on an insufficiently convincing approach from a methodological point of view and one that was clinically unjustified, given the lack of justification for excluding the patient in question and the lack of control for type 1 errors. It concluded that, on balance, the COMET study had failed to establish formally the superiority of Nexviadyme and that the additional analyses, although statistically significant, were not sufficient to establish the significant benefit of Nexviadyme given the limitations identified. In that context, it also noted that the Biostatistics Working Party, which had been consulted, recommended that any favourable opinion as regards significant benefit should be based on the totality of evidence, rather than a change in statistical methods. The COMP stated that ‘for the reasons explained in this report, … the additional analyses (the totality of the evidence)’ were not sufficient for establishing significant benefit.
316
As regards the second of the additional analyses referred to in paragraph 314 above, the COMP considered that an approach under the methodology of that analysis, namely the ‘win ratio’, was not justified on clinical grounds where, as in the present case, there was no ‘competition’ between the endpoints relating to FVC and the six-minute walk test. It also observed that when the CHMP had taken ‘win ratio’ analyses into account for other products, this had involved situations in which the primary analyses had been met. In line with its conclusion regarding the first additional analysis, it found that claims of the superiority of Nexviadyme based on secondary, sensitivity or post hoc analyses, such as the ‘win ratio’ analysis, were not sufficiently compelling from a methodological point of view and were not justified on clinical grounds, such that they could not establish significant benefit.
317
Next, as regards the simulation study intended to predict the percentage of patients on Nexviadyme and Myozyme who would require ventilation or a wheelchair in the future and as regards patient-reported outcomes in relation to basic mobility-related activities, which, according to the applicant, show that Nexviadyme is likely to delay patients’ needs for assisted ventilation or wheelchairs and lead to meaningful improvements in patients’ symptoms and physical functioning, the COMP found, respectively, that the data were speculative due to their extrapolation over the long term and were potentially biased. The simulation study ‘could not possibly be considered to be conclusive evidence’ of the significant benefit of Nexviadyme, while the ‘patient-reported outcomes’ did not suffice to establish significant benefit.
318
The COMP also explained that the data related to the claim of a clinically significant benefit for young children declining on Myozyme did not allow conclusions to be drawn on the effectiveness of Nexviadyme, in particular owing to the small sample size and the impact of child development according to age. The data are ‘of [an] exploratory or descriptive nature’. Moreover, the COMET study had not demonstrated a clear benefit of switching to Nexviadyme for adult patients who had had only a modest response to Myozyme. Accordingly, it had not been robustly demonstrated for those two sets of patients that switching to Nexviadyme improved outcomes. In addition, claims relating to a less frequent administration of Nexviadyme in relation to Myozyme could not be accepted, since the posology was similar for both medicinal products, namely intravenous infusion every two weeks. Better efficacy had to be shown on the basis of conclusive evidence and could not be presumed on the basis of less frequent administration. As regards a qualitative survey of patients who switched to Nexviadyme after declining on Myozyme, the COMP considered that although the preliminary data showed positive effects from Nexviadyme, the survey had a small sample size and there was no control data or systematic and objective measuring of muscle strength or respiratory function, meaning that the data could not be considered reliable in order to support the superiority of Nexviadyme over Myozyme.
319
As regards the purportedly improved safety profile of Nexviadyme as compared to Myozyme, the COMP considered that no firm conclusions could be drawn from the data provided, owing to the small sample size, confounding factors resulting from the exposure of certain patients to Myozyme and the absence of long-term comparative data as all patients in the Myozyme placebo group had switched to Nexviadyme.
320
Lastly, the COMP concluded that, ‘on balance’, in view of the significant limitations identified in the data submitted, the latter could not be considered to be conclusive evidence for establishing the existence of significant benefit, ‘whether taken in isolation or in combination and in their totality’, or for overcoming the formal failure of the COMET study to show in a robust manner the superiority of Nexviadyme over Myozyme.
321
In the light of the considerations set out in paragraphs 313 to 320 above, the final position of the COMP and the final opinion of the COMP, on which Article 5 of the contested decision is based, contain a statement of reasons which meets the requirements of the case-law cited in paragraph 89 above.
322
That finding is not invalidated by the absence of any explicit reference in the final position of the COMP to the conclusions of the ad hoc expert group. The positive considerations on Nexviadyme referred to by that expert group were in essence reproduced in the detailed arguments submitted by the applicant. It follows that even though the COMP did not refer to them in its final position, that does not mean that they were not known to that committee and that they had no impact on the outcome of its scientific assessment (see, to that effect and by analogy, judgment of 26 January 2022, Mylan IRE Healthcare v Commission, T‑303/16, not published, EU:T:2022:25, paragraph 179).
323
It should be added that in so far as the applicant refers to the MLT dashboard, issued by the EMA’s Medicines Leadership Team, in which it is stated that the CHMP had accepted formally failed studies on the basis of consistent positive trends across primary and secondary endpoints, the COMP, in its examination of the second of the additional analyses relating to the COMET study data referred to in paragraph 314 above, namely the ‘win ratio’ analysis, expressly rejected the applicant’s line of argument justifying the relevance of that analysis on the ground that, in the ‘win ratio’ studies taken into consideration by the CHMP relating to other medicinal products, the primary analyses had been met (see paragraph 316 above).
324
Next, as regards the applicant’s argument that the COMP imposed an overly strict standard of proof, it should be observed that since the COMP, at the time of the MA, carries out a complete re-evaluation of the designation criteria in a factual situation that is different from that which led to the grant of the initial designation, while taking account of evidence that has come to light since the grant of that initial designation, including new scientific and medical data relating to clinical trials and studies subsequent to the initial designation, it is not possible to infer any general presumption from Regulation No 141/2000 as to the existence or absence of a significant benefit provided by the medicinal product. Accordingly, the requirements for the adducing of evidence, including the standard of proof, do not vary according to the type of recommendation adopted by the COMP on the question of whether or not to maintain the designation as an orphan medicinal product.
325
While the Court has held that the test for finding significant benefit is ‘strict’ and that there has to be ‘a positive finding’ thereof, on the basis of ‘conclusive evidence proving significant benefit at the time of the MA’, of ‘sufficient data to establish significant benefit’, or of ‘concrete and substantiated evidence and information that [the] medicinal product provides a significant benefit,’ and that the expected advantage of the medicinal product ‘must therefore exceed a certain quantitative or qualitative threshold’ (see the case-law cited in paragraphs 307 and 310 to 312 above), those statements reflect the essential function of evidence, which is to establish the relevant facts to the requisite legal standard.
326
In that context, the analysis is based on a thorough, objective and adversarial comparative assessment of the highly complex scientific and technical facts put forward by the sponsor, which, by their very nature, are not always free of scientific uncertainty, but which require the COMP, bound by its duty to provide the best possible scientific advice, to adopt a position according to its assessment of those factors and of the plausibility of the conclusions drawn therefrom as to the significant benefit of the medicinal product under assessment.
327
In the present case, the applicant, by its arguments set out in paragraphs 192 to 201 of the application, has not disputed the merits of any of the COMP’s assessments of the additional evidence which it had provided in its detailed arguments seeking revision of the opinion of the COMP of 20 December 2021. Thus it may not criticise the final position of the COMP on the ground that that committee applied an overly strict standard of proof or assessed the evidence of the significant benefit of Nexviadyme in isolation, without carrying out a more overall evaluation. In any event, it fails to provide any explanation of how a more overall evaluation of that evidence could have established significant benefit, when the COMP, following the structure of the applicant’s detailed arguments, found that none of that evidence, whether taken in isolation or in combination and in its totality, could be considered to be conclusive data for establishing the existence of significant benefit. It follows that the complaint challenging the contested decision on the basis of an overly strict application of the criteria for establishing significant benefit must be rejected as unfounded. For the same reasons, the applicant has failed to show that the COMP’s assessments are vitiated by a manifest error of assessment. Similarly, the complaint alleging that the COMP did not examine all the aspects which should have been taken into account and that it committed a manifest error of assessment must be rejected.
328
Lastly, in so far as the applicant claims that the alleged errors of the CHMP with regard to the assessment of the NAS status of avalglucosidase alfa vitiate the COMP’s assessment, it is sufficient to state that the examination of the first and third limbs of the first plea shows that there is no error of law or manifest error of assessment.
329
Likewise, no irregularity may be inferred from the interaction between the EMA Secretariat and the COMP as to the consistency of the latter’s opinion with that of the CHMP, namely the passage from the MLT dashboard cited by the applicant, according to which ‘the COMP in [its] assessment was informed (after regulatory and legal advice) that diverging from the CHMP scientific assessment would not be recommended’ and that ‘a negative COMP opinion was adopted on [a] similar basis as the CHMP conclusion’.
330
As observed in paragraph 238 above, in accordance with Article 56(1)(f) of Regulation No 726/2004, the EMA Secretariat is responsible for providing technical, scientific and administrative support to that agency’s committees and ensuring coordination between them.
331
In addition, the third, eighth and tenth indents of Article 15(1) of the COMP’s rules of procedure, in the versions applicable from the date of submission of the MA application for Nexviadyme until the date of adoption of the final opinion and of the final position of the COMP on maintaining the designation of that medicinal product as an orphan medicinal product, provided by the Commission in response to a measure of organisation of procedure, confirm that the support provided by the EMA Secretariat to the COMP includes legal and regulatory support and that the EMA Secretariat is also responsible for ensuring the scientific and regulatory consistency of the opinions and recommendations of that committee and the sharing of all relevant information between the COMP and the CHMP.
332
In the light of all the foregoing considerations, the third plea in law must be rejected and, accordingly, the action must be dismissed in its entirety.
Costs
333
Under Article 134(1) of the Rules of Procedure, the unsuccessful party is to be ordered to pay the costs if they have been applied for in the successful party’s pleadings. Since the applicant has been unsuccessful, it must be ordered to pay the costs, in accordance with the form of order sought by the Commission.
334
In accordance with Article 138(1) of the Rules of Procedure, the Member States and institutions which have intervened in the proceedings are to bear their own costs. Under Article 1(2)(g) of the Rules of Procedure, the term ‘institutions’ means the institutions of the European Union referred to in Article 13(1) TEU and the bodies, offices or agencies established by the Treaties, or by an act adopted in implementation thereof, which may be parties before the General Court. It follows that the EMA is to bear its own costs.
335
Eucope is to bear its own costs in accordance with Article 138(3) of the Rules of Procedure.
On those grounds,
THE GENERAL COURT (Fifth Chamber, Extended Composition)
hereby:
1.
Dismisses the action;
2.
Orders Sanofi BV to bear its own costs and to pay those incurred by the European Commission;
3.
Orders the European Medicines Agency (EMA) and the European Confederation of Pharmaceutical Entrepreneurs (Eucope) to bear their own costs.
Svenningsen
Mac Eochaidh
Laitenberger
Martín y Pérez de Nanclares
Stancu
Delivered in open court in Luxembourg on 24 September 2025.
V. Di Bucci
Registrar
S. Papasavvas
President
Table of contents
Legal context
The concepts of biological medicinal product and active substance
The procedure for examining applications for a marketing authorisation
The concepts of ‘regulatory data protection period’ and ‘regulatory marketing protection period’
The concepts of ‘global marketing authorisation’ and ‘extension of an MA’
Commission document entitled ‘Notice to Applicants, Volume 2A, Procedures for marketing authorisation, Chapter 1, Marketing Authorisation’
The designation of medicinal products as ‘orphan medicinal products’ and the procedure for examining applications for marketing authorisations for those medicinal products
Background to the dispute
Development of the medicinal product Nexviadyme – avalglucosidase alfa
Application for marketing authorisation
Re-examination of the request for NAS status
Designation as an orphan medicinal product
Re-examination of the COMP opinion of 20 December 2021
Contested decision
Events after the adoption of the contested decision
Forms of order sought
Law
Preliminary considerations on the nature and scope of the judicial review
The first plea in law, alleging infringement of Article 10(1) of Directive 2001/83 and Article 14(11) of Regulation No 726/2004, manifest error of assessment and an inadequate statement of reasons
The second limb and the second complaint of the third limb of the first plea, alleging an inadequate statement of reasons as regards failure to satisfy the conditions set in the first and third indents of Annex I to the Notice to Applicants
The first limb of the first plea, alleging errors in finding that the conditions laid down in the first indent of Annex I to the Notice to Applicants were not met
– The first complaint of the first limb of the first plea, alleging an error in the relevant legal point of reference for the assessment of the NAS status of avalglucosidase alfa
– The second complaint of the first limb of the first plea, alleging errors in the application of the first indent of Annex I to the Notice to Applicants
The third limb of the first plea, alleging errors in the finding that the conditions laid down in the third indent of Annex I to the Notice to Applicants were not met
The second plea in law, alleging breach of the principle of good administration, as enshrined in Article 41 of the Charter
The first limb of the second plea, alleging infringement of the requirement of objective impartiality
The second limb of the second plea, claiming that the CHMP made use of a document to which the applicant was refused access
The third limb of the second plea, based on failure to communicate to the applicant the EMA’s recommendations to the rapporteur and co-rapporteur of the CHMP
The fourth limb of the second plea, alleging failure to inform the applicant of the role and work of the Biologics Working Party
The third plea in law, alleging infringement of Article 5(12)(b) of Regulation No 141/2000, manifest error of assessment and inadequate statement of reasons
Costs
(
*1
)	Language of the case: English.