delivered on 11 July 2024 (1)

Case C‑237/22 P

Mylan IRE Healthcare Ltd

European Commission

(Appeal – Medicinal products for human use – Regulation (EC) No 141/2000 – Orphan medicinal products – Significant benefit – Market exclusivity of the medicinal product Tobi Podhaler, containing the active substance tobramycin – Subsequent marketing authorisation for the medicinal product Tobramycin VVB and associated names – Derogation from the market exclusivity of the first medicinal product – Clinical superiority of the second medicinal product – Criteria)

1.‘Orphan medicinal products’ are medicinal products for the treatment of diseases that are relatively uncommon (also known as rare diseases), which makes it difficult to develop and market them profitably. To address the concerns that arise from the restricted availability of medicinal products to patients suffering from such diseases, the EU legislature has adopted a legislative framework to encourage production of those medicinal products. That framework, comprising in particular Regulation (EC) No 141/2000 (2) and Regulation (EC) No 847/2000, (3) offers several incentives to the pharmaceutical industry, including a ‘reward’ in the form of several years of market exclusivity.

2.To obtain designation as an orphan medicinal product (also referred to as ‘OMP’), and benefit from such exclusivity, the product must provide, inter alia, a significant benefit compared to other authorised treatments.

3.At the same time, the marketing exclusivity is not absolute. A derogation can be granted when, inter alia, a similar medicinal product is safer, more effective or otherwise clinically superior to the designated OMP.

4.The present case primarily concerns two medicinal products: ‘Tobi Podhaler – Tobramycin’ (‘Tobi Podhaler’) and ‘Tobramycin VVB and associated names’ (‘Tobramycin VVB’). Both products are indicated for the treatment of pulmonary infection caused by the bacterium Pseudomonas aeruginosa in cystic fibrosis patients aged six years and older.

5.More specifically, Tobi Podhaler was designated as an OMP and was subsequently granted a marketing authorisation (‘MA’) and, therefore, market exclusivity. Mylan IRE Healthcare Ltd (‘Mylan’) subsequently became the holder of that MA.

6.However, during the period of that market exclusivity, another company, UAB VVB (‘VVB’), obtained an MA for Tobramycin VVB, a product similar to Tobi Podhaler. To that end, VVB applied for, and was granted by the European Commission, a derogation from Tobi Podhaler’s market exclusivity.

7.That decision was challenged before the General Court, but the action was dismissed. By the present appeal, Mylan seeks to challenge what it claims is an erroneous interpretation of the criteria permitting a derogation from the OMP-related market exclusivity.

II. Legal framework

8. Article 3(1) of Regulation No 141/2000 states that:

‘A medicinal product shall be designated as an orphan medicinal product if its sponsor can establish:

(a) that it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in 10 thousand persons in the Community 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 Community and that without incentives it is unlikely that the marketing of the medicinal product in the Community 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 Community or, if such method exists, that the medicinal product will be of significant benefit to those affected by that condition.’

9. Article 8 of Regulation No 141/2000 provides that:

‘1. Where a marketing authorisation in respect of an orphan medicinal product is granted pursuant to Regulation (EEC) No 2309/93 or where all the Member States have granted marketing authorisations in accordance with the procedures for mutual recognition laid down in Articles 7 and 7a of Directive 65/65/EEC or Article 9(4) of Council Directive 75/319/EEC of 20 May 1975 on the approximation of provisions laid down by law, regulation or administrative action relating to medicinal products, and without prejudice to intellectual property law or any other provision of Community law, the Community and the Member States shall not, for a period of 10 years, accept another application for a marketing authorisation, or grant a marketing authorisation or accept an application to extend an existing marketing authorisation, for the same therapeutic indication, in respect of a similar medicinal product.

…

3. By way of derogation from paragraph 1, and without prejudice to intellectual property law or any other provision of Community law, a marketing authorisation may be granted, for the same therapeutic indication, to a similar medicinal product if:

(a) the holder of the marketing authorisation for the original orphan medicinal product has given his consent to the second applicant, or

(b) the holder of the marketing authorisation for the original orphan medicinal product is unable to supply sufficient quantities of the medicinal product, or

(c) the second applicant can establish in the application that the second medicinal product, although similar to the orphan medicinal product already authorised, is safer, more effective or otherwise clinically superior.’

B. Regulation No 847/2000

10. Pursuant to Article 3(2) of Regulation No 847/2000:

‘For the purposes of the implementation of Article 3 of [Regulation No 141/2000], the following definition shall apply:

“significant benefit” means a clinically relevant advantage or a major contribution to patient care.’

‘“clinically superior” means that a medicinal product is shown to provide a significant therapeutic or diagnostic advantage over and above that provided by an authorised orphan medicinal product in one or more of the following ways:

(1) greater efficacy than an authorised orphan medicinal product (as assessed by effect on a clinically meaningful endpoint in adequate and well controlled clinical trials). Generally, this would represent the same kind of evidence needed to support a comparative efficacy claim for two different medicinal products. Direct comparative clinical trials are generally necessary, however comparisons based on other endpoints, including surrogate endpoints may be used. In any case, the methodological approach should be justified;

(2) greater safety in a substantial portion of the target population(s). In some cases direct comparative clinical trials will be necessary;

(3) in exceptional cases, where neither greater safety nor greater efficacy has been shown, a demonstration that the medicinal product otherwise makes a major contribution to diagnosis or to patient care.’

III. Facts and the decision of the Commission

12.The factual circumstances are set out in paragraphs 1 to 38 of the judgment under appeal. (4) For the purposes of the present Opinion, I would state the following.

13.In 1999, Novartis Pharmaceuticals UK obtained an MA for TOBI, a medicinal product which is indicated for the treatment of pulmonary infection due to the bacterium Pseudomonas aeruginosa in cystic fibrosis patients aged six years or older. (5) When TOBI received its MA, Regulation No 141/2000 was not yet in force.

14.In 2003, when that regulation was in force, the designation as an OMP was granted for the medicinal product ‘Tobramycin (inhalation powder)’ (corresponding to the medicinal product Tobi Podhaler), (6) which was also intended for the treatment of pulmonary infection in cystic fibrosis patients aged six years or older. Since that medicinal product is similar to TOBI, the sponsor of Tobi Podhaler had to show, in order to obtain the OMP designation, that Tobi Podhaler provided a significant benefit as compared with TOBI. That condition was met because Tobi Podhaler was much easier to administer.

15.That orphan designation was later transferred to Novartis Europharm Ltd.

16.When the Commission granted an MA to Tobi Podhaler in 2011, (7) that decision triggered a 10-year period of market exclusivity, which was then extended by two years. (8) That period of market exclusivity, in principle, prevents the market entry, during that period, of similar medicinal products, subject to certain derogations including a similar product being clinically superior.

17.In 2016, relying on that ground for derogation, the Commission granted an MA for the medicinal product Tobramycin VVB to VVB. In adopting that decision (‘the decision at issue’), (9) the Commission relied, in application of the corresponding rules, on the scientific opinion of the Committee for Medicinal Products for Human Use which concluded that Tobramycin VVB was clinically superior to Tobi Podhaler because it was safer for a substantial part of the population since it resulted, simply put, in a lower incidence of cough and the need to discontinue the treatment. (10)

18.In 2016, Novartis Europharm filed an action by which it requested, inter alia, the annulment of the decision at issue on the grounds, inter alia, of the alleged infringement of its market exclusivity rights.

19.The Commission, supported by VVB, asked the General Court to dismiss that action.

20.Following the transfer of the MA relating to the medicinal product Tobi Podhaler to Mylan, that company was authorised to substitute itself for Novartis Europharm in the proceedings before the General Court.

21.By the judgment under appeal, the General Court dismissed the action. (11)

22.By its appeal, lodged on 4 April 2022, Mylan (‘the appellant’) asks the Court of Justice, first, to declare the appeal admissible and well founded. Second, it asks the Court of Justice to set aside the judgment under appeal. Third, it asks the Court of Justice to annul the decision at issue, if the state of the proceedings so permits, or, in the alternative, to refer the case back to the General Court. Fourth, Mylan requests the Court of Justice to order the Commission to pay the costs which it has incurred both in the proceedings before the General Court and before the Court of Justice. Lastly, it requests the Court of Justice to order VVB to pay its own costs in respect of both stages of the proceedings.

23.The Commission and VVB submitted responses on 15 June 2022 by which they ask the Court to dismiss the appeal and order the appellant to pay the costs.

24.On 22 August 2022, Mylan lodged a reply after having received an authorisation from the Court to that effect. On 3 October 2022, the Commission and VVB lodged their respective rejoinders.

25.Meanwhile, the Court granted the application for leave to intervene in support of the Commission, which had been submitted by the European Medicines Agency (EMA). (12) In its statement in intervention, EMA asks the Court to dismiss the appeal and order the appellant to pay its costs. Mylan and the Commission submitted observations on that statement in intervention on 14 and 6 December 2022, respectively.

26.Mylan, VVB, the Commission and EMA presented oral argument at a hearing that took place on 20 September 2023.

27.The present appeal relies on two grounds of appeal. First, Mylan alleges that the General Court erred in the interpretation of the concept of clinical superiority within the meaning of Article 8(3)(c) of Regulation No 141/2000. Second, Mylan alleges an error of law due to insufficient reasoning.

28.At the Court’s request, the present Opinion will address the first ground of appeal only. For that purpose, and given the technical nature of the present case, I will begin by explaining the relevant elements of the applicable regulatory framework and linking them with the main facts of the case (A). On that basis, I will then set out the reasons that lead me to conclude that the first ground of the appeal should be rejected (B).

The relevant regulatory elements and the main facts

It follows from Article 3(1) of Regulation No 141/2000 that, for a medicinal product to be considered to be an ‘orphan’, it either must be intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10 thousand persons in the European Union (prevalence criterion), or (irrespective of the prevalence of the condition concerned) must be a product the marketing of which is unlikely, without incentives, to generate sufficient return to justify the necessary investment (return on investment criterion).

That provision sets out two scenarios that may lead to a medicinal product being designated as orphan.

The first scenario arises when the sponsor of the product establishes that there exists no satisfactory method of diagnosis, prevention or treatment of the condition concerned. However, when such a method exists, the designation as an OMP can still be granted when the sponsor establishes that that product will be of significant benefit to those affected by the condition (second scenario).

The latter scenario is relevant in the present case.

Tobi Podhaler is a medicinal product similar to TOBI. In order to obtain a designation as orphan, its sponsor, therefore, had to establish the existence of a significant benefit as compared to treatments already authorised, such as TOBI.

The concept of significant benefit is defined in Article 3(2) of Regulation No 847/2000 as ‘a clinically relevant advantage or a major contribution to patient care’.

In the present case, the significant benefit offered by Tobi Podhaler consisted in the fact that it constituted ‘a major contribution to patient care’, within the meaning of Article 3(2) of Regulation No 847/2000, because it ‘significantly reduced delivery time of the medicinal product by comparison with TOBI and it could be used with a portable delivery system, leading to added convenience for patients and potentially an improvement in compliance with the treatment’. (13) Indeed, as the case file indicates, and as Mylan in particular has explained in the present proceedings, TOBI is a liquid product to be used for inhalation therapy with a nebuliser, a device that weighs between 1.5 and 2 kg, whereas Tobi Podhaler consists of a dry powder to be administrated with a portable inhalation device that weighs 20 grams. Moreover, it takes longer to administer TOBI, as opposed to Tobi Podhaler.

It should be added that the data gathered to demonstrate the significant benefit of Tobi Podhaler (in order to obtain the OMP designation and later the MA as an OMP) (14) also revealed that Tobi Podhaler posed a higher risk of incidence of cough than TOBI and led to a higher rate of discontinuation of treatment in all relevant age groups (children, adolescents, adults). That intolerance was known at that stage and was included in the summary of the characteristics of Tobi Podhaler, which introduced a special warning and recommended the use of TOBI in the event of intolerance. (15) At the same time, those adverse effects did not preclude the finding that ‘Tobi Podhaler offered efficacy and safety comparable to TOBI’, (16) and that, as the General Court observed, in essence, ‘those profiles were [thus] found to be comparable or similar for the population taken as a whole’. (17)

Turning now to the issue of marketing exclusivity, such as the one granted on account of the designation of (and market authorisation for) Tobi Podhaler as an OMP, that exclusivity is not absolute, as has already been observed. This follows from Article 8(3) of Regulation No 141/2000 which provides that it is possible to grant an MA for a similar medicinal product in respect of the same therapeutic indication where, inter alia, ‘the second applicant’ (such as VVB) can establish that its product (such as Tobramycin VVB), ‘although similar to the orphan medicinal product already authorised [such as Tobi Podhaler], is safer, more effective or otherwise clinically superior’. (18)

It was on that ground of clinical superiority that VVB was granted a derogation from the market exclusivity granted to Tobi Podhaler and received an MA for Tobramycin VVB. In that regard, the Commission concluded, more specifically, that Tobramycin VVB was clinically superior to Tobi Podhaler in that it provided ‘greater safety in a substantial portion of the target population’. This is a specific criterion of clinical superiority expressly laid down in Article 3(3)(d)(2) of Regulation No 847/2000 (which explains, together with Article 3(3)(d)(1) and (3), the provisions of Article 8(3)(c) of Regulation No 141/2000 and on which I will comment more extensively later in this Opinion).

With that in mind, the present case may appear somewhat intricate because Tobramycin VVB is, in fact, a generic copy of TOBI, as can be seen from the judgment under appeal (19) and as has been repeatedly observed in the present proceedings. That fact made it possible for VVB to rely on the data previously gathered in respect of TOBI, including those previously used for the comparison between TOBI and Tobi Podhaler. (20) Those data made it possible to conclude that, like TOBI, Tobramycin VVB is safer than Tobi Podhaler for a part of the target population, and thus clinically superior to Tobi Podhaler, because it does not entail adverse effects in the form of cough and discontinuance of the treatment.

In the light of the above, it may appear puzzling that the conclusion as to the clinical superiority of Tobramycin VVB over Tobi Podhaler, on account of its greater safety with regard to a substantial part of the target population, was reached only after it had been concluded that the safety (and efficacy) profile of Tobi Podhaler is equivalent to the safety profile of TOBI, where the same must be held also in respect of Tobramycin VVB because it is a generic copy of TOBI.

The General Court addressed that aspect of the case and held that ‘the fact that Tobi Podhaler provides, for the population as a whole, a significant benefit justified by a major contribution to patient care … since those benefits outweigh the risks of adverse events[,] is not inconsistent with the fact that, at the same time and on the basis of the same data, Tobramycin VVB offers greater safety for patients with a potential intolerance to Tobi Podhaler, who amount to a substantial portion of the target population’. (21) On that basis, it rejected Mylan’s argument alleging that the Commission’s conclusion as to the clinical superiority of Tobramycin VVB over Tobi Podhaler was inconsistent.

In the present proceedings, Mylan maintains that a product cannot be considered to be of ‘significant benefit’ in comparison to another one, while being at the same time clinically inferior. The essence of the first ground of its appeal consists in criticising the General Court’s interpretation of the condition of clinical superiority, set out in Article 8(3)(c) of Regulation No 141/2000, because that court failed to adopt what the appellant considers to be a ‘global’ approach vis-à-vis the three (alternative) criteria underlying that concept (these are, concisely, greater efficacy, greater safety in a substantial part of the target population, or major contribution to patient care). (22)

I will now go on to explain why that claim, and, therefore, the first ground of the appeal, must be rejected.

Why the first ground of the appeal should be rejected

The appellant contests, in essence, the statement that the General Court made in paragraph 132 of the judgment under appeal.

In that paragraph, the General Court commented on the concept of clinical superiority and focused, more specifically, on the criterion of ‘greater safety in a substantial portion of the target population(s)’. I would recall that this is a specific criterion of clinical superiority, laid down in Article (3)(3)(d)(2) of Regulation No 847/2000 (which fleshes out the rule set out in Article 8(3)(c) of Regulation No 141/2000), (23) on which the Commission relied in the case at hand to grant the MA for Tobramycin VVB to VVB, in derogation from the market exclusivity enjoyed by Tobi Podhaler.

In that context and in that paragraph, the General Court held that ‘point (2) of Article (3)(3)(d) of Regulation No 847/2000 expressly lays down the criterion of greater safety “in a substantial portion of the target population(s)”’ and concluded that ‘that criterion of clinical superiority must be assessed individually, without establishing an overall benefit/risk balance for the population as a whole, as is the case for significant benefit’.

The appellant considers that that statement is inconsistent with a statement made in paragraph 124 of the judgment under appeal.

In that paragraph, the General Court (primarily) commented on the concept of significant benefit and noted, inter alia, that the criteria on which the assessment of significant benefit is based ‘must be assessed as a whole on the basis of a weighting and overall evaluation of the benefit/risk balance’.

The reason why the appellant is of the view that the statement in paragraph 132 (with which it disagrees) is inconsistent with that made in paragraph 124 (with which – as I understand it – the appellant agrees) is that, in its view, both concepts (significant benefit and clinical superiority) are based on the same criteria (efficacy, safety and major contribution to patient care), and are therefore interchangeable, and must accordingly be assessed in the same way.

Instead – according to the appellant – the General Court adopted, incorrectly, an ‘individual’ approach vis-à-vis the concept of clinical superiority, meaning that it considered that the satisfaction of only one of the three criteria – in this instance, a greater safety in a substantial part of the target population – was sufficient for the condition of clinical superiority to be met (without assessing the overall balance of all the criteria). On the other hand, the General Court required (correctly according to the appellant), a ‘global’ assessment of the same criteria in connection with the concept of significant benefit, meaning that the overall balance of the three criteria must be positive for the condition of significant benefit to be met.

That differentiated approach means, in the appellant’s view, that the condition of clinical superiority is subject to less strict criteria than the condition of significant benefit, which, however, is not justified and results in a situation that is inconsistent with the teleological interpretation of the derogation regime set out in Article 8(3) of Regulation No 141/2000 and the interests of patients.

I will start addressing those arguments by commenting briefly on the appellant’s premiss that both concepts at issue are interchangeable and on the nature of the relevant criteria (1). I will then explain that the appellant’s position is based on a misreading of the paragraphs of the judgment under appeal referred to above (2). I will conclude by clarifying that, contrary to what is argued by the appellant, the result reached by the General Court in the judgment under appeal is consistent with the objective pursued by Regulation No 141/2000 (3).

The concepts at issue and the nature of the relevant criteria

First, much of the discussion in the present proceedings has revolved around the question whether the concept of significant benefit and the concept of clinical superiority are interchangeable (as argued by Mylan) or whether they are different (as argued by VVB, the Commission and EMA).

I am of the view that, for the purposes of the present case, that question can be addressed rather briefly. Although the same three criteria (better safety, better efficacy and major contribution to patient care) are relevant for both of these concepts, as the General Court observed, in essence, and as is not contested here, this does not mean that those concepts are interchangeable, contrary to what is argued by Mylan.

In that respect I observe that there are textual differences in the manner in which those three criteria are addressed. In particular, the definition of significant benefit in Article 3(2) of Regulation No 847/2000 is more open-ended, given that it does not refer to the specific criteria of safety and efficacy but to a more general term of ‘clinically relevant advantage’. (24) Moreover, the explanation in the previous section makes it clear that both concepts appear in different contexts and have, accordingly, a different purpose. (25)

It is true that, rather puzzlingly, recital 8 of Regulation No 141/2000, refers to significant benefit although the derogation from the market exclusivity (to which issue that recital relates) relies on the concept of clinical superiority. (26) I am not sure how that inconsistency can be explained and the travaux préparatoires do not shed light on that question either. (27) That said, I disagree with the appellant that it attests to the interchangeability of the concepts at issue. The question whether those concepts are interchangeable must be assessed in the light of the relevant wording, purpose and context in which they may appear. While recitals constitute a useful tool of interpretation to that effect, they cannot supplant the main regulatory text. In that respect, I have already briefly explained the way in which that regulatory text makes both concepts different.

Second, a significant part of the discussion in the present case has also revolved around the question whether the three relevant criteria (better safety, efficacy and major contribution to patient care) are, in the respective contexts of the concepts at issue, alternative or cumulative.

As regards the concept of significant benefit, there is nothing in the judgment under appeal to suggest that the General Court required the cumulative application of the criteria concerned. The General Court was clear when it held that those criteria are not cumulative. (28) That said, the interpretation of that concept is not as such at issue in the present appeal.

What is relevant is that the General Court reached the same conclusion as regards the criteria in the context of the concept of clinical superiority (the interpretation of which is

at issue in the present appeal). (29) That conclusion is, in my view, fully consistent with the clear wording of Article (3)(3)(d) of Regulation No 847/2000 (cited in point 11 above), and in particular with the use of the conjunction ‘or’ in the definition given there. (30) Thus, the fact that one of the three criteria of clinical superiority specified therein (greater efficacy, or greater safety in a substantial part of the target population, or major contribution to patient care) is satisfied is sufficient to conclude that a medicinal product is clinically superior to a given OMP.

60.That said, the appellant explains that it is not arguing that the three criteria for clinical superiority are cumulative, but is of the view that their overall balance should be assessed and should be positive in order for a derogation from an OMP’s market exclusivity to be granted. It follows from its arguments, as I understand them, that a ‘global assessment’ would in this instance have required an increased efficacy to be demonstrated in respect of Tobramycin VVB (in addition to its increased safety in a substantial part of the population).

61.That argument amounts, however, to saying that the two criteria for clinical superiority concerned – better safety and better efficacy – must, in fact, be applied cumulatively (despite the appellant arguing to the contrary). That position is contradicted by the wording of Article 3(3)(d) of Regulation No 847/2000, as I have already explained.

62.Lastly, contrary to what the appellant suggests, I do not see how the use of the expression ‘advantage over and above’ in the definition of the concept of clinical superiority given in Article 3(3)(d) of Regulation No 847/2000 affects my conclusion as set out above. I agree with VVB that that argument is not sufficiently substantiated. It follows, in any event, from the above provision that the ‘advantage over and above’ is to be shown in one of the three ways which are then specified, namely greater efficacy, greater safety in a substantial part of the target population, or major contribution to patient care. The expression ‘advantage over and above’, therefore, does not affect the alternative nature of those criteria.

63.That said, it seems to me that the appellant’s distinction between what it qualifies as a ‘global’ and an ‘individual’ approach supposedly established by the General Court in paragraphs 124 and 132 of the judgment under appeal, respectively, results from a misreading of the references by the General Court to ‘overall evaluation of the benefit/risk balance’ (paragraph 124, in connection with significant benefit), on the one hand, and the lack of need to establish ‘an overall benefit/risk balance for the population as a whole’ (paragraph 132, in connection with clinical superiority), on the other.

64.I will address that issue now.

65.I have to admit that the implications of the distinction set out in point 63 of this Opinion may not be immediately clear. However, they will become clearer once the passages concerned are placed in their proper context.

66.As VVB, the Commission and EMA have argued, in particular during the hearing, the reference to the ‘overall evaluation of the benefit/risk balance’ in respect of the condition of significant benefit (paragraph 124 of the judgment under appeal) is in response to the explanation given in paragraphs 122 and 123 of the judgment under appeal.

67.Those paragraphs make it clear that because the significant benefit was claimed, in this instance, on the basis of major contribution to patient care for the entire target population, EMA and the Committee for Orphan Medicinal Products required, in the process which led to the OMP designation of Tobi Podhaler, the safety and efficacy of that product to be at least equivalent (to TOBI). (31) In the light of that requirement (which is not as such at issue in the present case) and given that the significant benefit was claimed for the entire target population, as already noted, that made it necessary, as I understand it, to carry out an ‘overall evaluation of the benefit/risk balance’ (for the entire target population).

68.By contrast, the ground of clinical superiority claimed by Tobramycin VVB at issue in the present case was better safety in a substantial part of the target population. That is an explicit ground for the establishment of clinical superiority provided for in Article 3(3)(d)(2) of Regulation No 847/2000, as I have already explained and as is emphasised by VVB.

69.I would recall that the target population for all three medicinal products at issue are patients aged six years and older with cystic fibrosis caused by the bacterium Pseudomonas aeruginosa. However, when Tobi Podhaler was assessed in comparison to TOBI, the adverse effects of cough were recorded in all relevant groups, namely children, adolescents and adults. That subset of the target population, within the meaning of that provision – patients in all relevant age groups suffering from the adverse effects at issue – was thus identified as the subset in respect of which Tobramycin was considered to be clinically superior to Tobi Podhaler.

70.It is, in my view, this specific aspect of the case that explains why, in paragraph 132 of the judgment under appeal, the General Court concluded that the criterion for clinical superiority at issue (‘greater safety in a substantial portion of the target population(s)’) (32) ‘must be assessed individually, without establishing an overall benefit/risk balance for the population as a whole as is the case for significant benefit’. (33)

71.Indeed, the clinical superiority of Tobramycin VVB over Tobi Podhaler had to be established only by reference to better safety for the given subset of the target population (as this was allowed by the applicable rules, namely Article 3(3)(d)(2) of Regulation No 847/2000), whereas the significant benefit, in terms of ease of administration of Tobi Podhaler over TOBI (and, by extension, over Tobramycin VVB), as well as the equivalence in terms of safety and efficacy, were to be established by reference to the entire target population.

72.In that regard, I do not think that the General Court erred in law in interpreting the condition of clinical superiority laid down in Article 8(3)(c) of Regulation No 141/2000 and set out in more detail in Article 3(3)(d) of Regulation No 847/2000. It follows from the foregoing that it is indeed possible to arrive at the conclusion that, for a given subset of the target population, as described above, Tobramycin VVB is safer than Tobi Podhaler because it does not trigger the adverse effects at issue, without contradicting the conclusion that Tobi Podhaler’s safety profile is equivalent to the safety profile of TOBI/Tobramycin VVB for the entire target population. As was held by the General Court and as has been noted by VVB, the fact that the safety profiles of both medicinal products are comparable for the population taken as a whole does not mean that they are equivalent for all subsets of that population. (34)

73.That conclusion is, moreover and in my view, fully consistent with the objective pursued by Regulation No 141/2000, contrary to what is argued by Mylan. I will address that last aspect of the present case below.

3. Considerations of the objective pursued by Regulation No 141/2000

74.The appellant raises two arguments that consist in claiming that the judgment under appeal hinders the attainment of the objective pursued by Regulation No 141/2000, namely ensuring that patients suffering from rare diseases and whose medical needs are unmet have access to adequate treatment. (35)

75.First, the appellant argues that the failure, by the General Court, to adopt a ‘global approach’ vis-à-vis the concept of clinical superiority goes against the interests of patients because it may result in medicinal products with an overall negative balance being placed on the market. This would occur should a product A (challenging the market exclusivity of an OMP product B) prove to be safer for 10% of the target population but less safe for the remaining 90% than product B.

76.I note that addressing that argument would, in principle, require a clarification of whether, irrespective of the criterion for clinical superiority that is being relied on, the other (two) criteria must be evaluated as being at least equivalent. EMA explained in detail during the hearing that a reply in the affirmative as regards the criteria of safety and efficacy follows organically from the assessment conducted in such a context.

77.That said, I do not think that the facts underlying the present appeal make it necessary to study that question in depth. It is true that when the greater safety in a substantial part of the target population of a medicinal product is established, that does not however necessarily answer the question whether it has at least an equivalent safety profile in respect of the rest of the population. However, I understand that in the present case that equivalence was established. It follows from the above explanation that, because Tobramycin VVB is a generic copy of TOBI and because it had been established that the efficacy and safety profiles of TOBI and Tobi Podhaler are comparable, it is difficult to see how the decision at issue could have resulted in the authorisation of a medicinal product (Tobramycin VVB) that would be, in those respects, worse than Tobi Podhaler.

78.Second, the appellant argues that the conclusion that a generic medicinal product (such as Tobramycin VVB) is clinically superior to an OMP (such as Tobi Podhaler) means that derogations from market exclusivity can be granted in the absence of any investment in research. I understand that argument as reflecting the appellant’s position that, because developing a generic medicinal product does not require investment into research, that precludes the possibility of a generic medicinal product being introduced on the market by way of derogation from the market exclusivity granted in respect of an OMP. I further understand that argument as saying that, because the objective pursued by Regulation No 141/2000 is also to reward pharmaceutical companies for their investment into research with a view to developing OMPs, the rewards offered by that regulation cannot be granted to companies which do not make such investment.

79.In that respect, I would recall that the possibility of obtaining an MA, and therefore market exclusivity, for a medicinal product designated as an OMP was intended by the EU legislature to be a financial reward for the pharmaceutical industry for deciding to engage in what is considered to be, prima facie, a non-profitable activity.

80.By contrast, that logic does not underlie Article 8(3) of Regulation No 141/2000, which introduces a possibility of obtaining a derogation from the market exclusivity of an OMP. Indeed, that possibility was not intended by the EU legislature to be a reward for investment into research, but to place a limit on that reward in the explicit interest of patients, as follows from recital 8 of that regulation. (36)

81.I would note that the positive result of an OMP application may lead to (an artificially and purposefully created) monopoly in the market of medicinal products that may temporarily prevent the access of patients to similar medicinal products, including to the generic versions of pre-existing products over which the given designated OMP is shown to have a significant benefit. (37) In that regard, the EU legislature has decided to limit that monopoly by preserving the possibility of introducing on the market medicinal products that are clinically superior including, as in this instance, when that clinical superiority is relevant for a substantial part of the target population. Whether the significantly better treatment is, in this context, offered by a medicinal product the development of which has not required investment into research is not, in my view, relevant. What matters is whether the circulation on the market of such a product complies with the applicable conditions and is thus consistent with the abovementioned public-health objective of ensuring access by patients affected by the rare disease concerned to significantly better treatment. In that context, it should not be forgotten that the overall objective of the regulatory framework of orphan medicinal products is to address the unmet needs of such patients.

82.Finally, the same reasons lead me to reject the appellant’s argument that by adopting the definition of clinical superiority in Article 3(3)(d)(2) of Regulation No 847/2000, the Commission altered the scope of Article 8(3)(c) of Regulation No 141/2000. Irrespective of the admissibility of that argument, which for that matter was raised in the reply and does not explicitly raise a plea of illegality, I consider that it follows sufficiently from the arguments presented above that rather than altering the scope of the concept defined in Article 8(3)(c) of Regulation No 141/2000, its definition given in Article 3(3)(d)(2) of Regulation No 847/2000 is fully consistent with the abovementioned objective pursued by the EU legislature.

83.Therefore, I am of the view that the considerations of the objective pursued by Regulation No 141/2000 do not affect the conclusion that I have reached in point 72.

VI. Conclusion

84.For those reasons, and without prejudice to the examination of the second ground of appeal, I propose that the Court of Justice find that the General Court did not err in its interpretation of the concept of clinical superiority under Article 8(3)(c) of Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products and that the first ground of the appeal must therefore be rejected.

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(1) Original language: English.

(2) Regulation of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products (OJ 2000 L 18, p. 1).

(3) Commission Regulation 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).

(4) Judgment of 26 January 2022, Mylan IRE Healthcare v Commission (T‑303/16, EU:T:2022:25) (‘the judgment under appeal’).

(5) Cystic fibrosis is a genetic disease that leads to chronic infection of the lungs, the chronic infection with Pseudomonas aeruginosa being its typical feature. ‘It can induce damage to the lung tissue and respiratory insufficiency, which is life threatening.’Public summary of opinion on orphan designation Tobramycin (inhalation powder) for the treatment of Pseudomonas aeruginosa lung infection in cystic fibrosis, European Medicines Agency, 6 February 2015, EMA/COMP/4684/2003 Rev.3.

(6) Paragraphs 3 to 6 of the judgment under appeal.

(7) Implementing Decision C(2011) 5394 final granting marketing authorisation under Regulation (EC) No 726/2004 of the European Parliament and of the Council for ‘Tobi Podhaler – Tobramycin’, an orphan medicinal product for human use.

(8) As a reward for compliance with an agreed paediatric investigation plan. See Article 37 of Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ 2006 L 378, p. 1). The market exclusivity at issue thus expired in July 2023, as Mylan also observed during the hearing. However, the present litigation relates to the facts preceding that date.

(9) Implementing Decision C(2016) 2083 final of 4 April 2016, concerning, in the framework of Article 29 of Directive 2001/83/EC of the European Parliament and Council, the marketing authorisations for ‘Tobramycin VVB and associated names’, medicinal products for human use which contain the active substance ‘tobramycin’.

(10) See, especially, paragraphs 18 and 137 of the judgment under appeal.

(11) Referred to in footnote 4 above.

(12) Order of the President of the Court of 22 September 2022, Mylan IRE Healthcare v Commission (C‑237/22 P, EU:C:2022:726).

(13) Paragraph 4 of the judgment under appeal.

(14) It should be added that the fact that a medicinal product is designated as an OMP does not automatically make it possible to place it on the market. To achieve that result, its sponsor has to apply for, and be granted, an MA. See Article 5(1) of Regulation No 141/2000. These are two different stages, as explained in paragraph 92 et seq. of the judgment under appeal.

(15) Paragraphs 137 and 138 of the judgment under appeal.

(16) Paragraph 122 in fine and paragraph 135 of the judgment under appeal.

(17) Paragraph 136 of the judgment under appeal.

(18) Article 8(3)(c) of Regulation No 141/2000. Emphasis added.

(19) See paragraphs 58 and 59 of the judgment under appeal.

(20) That aspect was contested by Mylan in the proceedings before the General Court but that claim was dismissed and is not covered by the present appeal.

(21) Paragraph 141 of the judgment under appeal. Emphasis added.

(22) I note that without raising a formal plea of inadmissibility, the Commission observes that there is an overlap between the arguments raised by the appellant before the General Court and those raised here. Although I agree as to that overlap, I do not think that it makes the first ground inadmissible. Indeed, the appellant explains in what respect the conclusion of the General Court is based, in its view, on an erroneous interpretation of the legal concept at issue. See, to that effect, judgment of 10 April 2014, Acino v Commission (C‑269/13 P, EU:C:2014:255), paragraph 37 and the case-law cited.

(23) See point 11 above.

(24) I note that in paragraph 120 of the judgment under appeal the General Court held that: ‘the findings of significant benefit and clinical superiority are based on the same criteria, namely demonstration of greater efficacy, greater safety or major contribution to patient care’. As has just been noted, I agree that those criteria are, in general, relevant for both concepts at issue, but I am not sure whether the open-ended definition of the concept of significant benefit leads to the conclusion that that concept is necessarily limited to those criteria. See also the Commission notice on the application of Articles 3, 5 and 7 of Regulation (EC) No 141/2000 on orphan medicinal products (OJ 2016 C 424, p. 3), p. 5.

(25) VVB, the Commission and EMA commented extensively on the differences between both concepts, including when it comes to the respective scopes of assessment or the consequences that follow when the respective conditions of significant benefit or clinical superiority are not met. However useful that explanation may be, in general, I do not consider it necessary to address those differences in full for the purpose of the present case.

(26) The last sentence of that recital states that ‘in the interest of patients, the market exclusivity granted to an [OMP] should not prevent the marketing of a similar medicinal product which could be of significant benefit to those affected by the condition.’ Emphasis added.

(27) See, for the historical context more generally paragraphs 116 and 117 of the judgment under appeal and the amended proposal for a European Parliament and Council Regulation (EC) on orphan medicinal products (COM/99/0298 final).

(28) Paragraph 121 of the judgment under appeal.

(29) Paragraph 131 of the judgment under appeal.

(30) And with the terms specifying that ‘a significant therapeutic or diagnostic advantage over and above that provided by an authorised orphan medicinal product’ is to be shown ‘in one or more of the following ways’. Emphasis added.

(31) I note that the Commission notice referred to in footnote 24 above observes (at p. 6), in the context of significant benefit, that ‘to be regarded as making a major contribution to patient care, the product should at least be equivalent in terms of efficacy, safety and benefit/risk balance as compared with the authorised medicinal products’.

(32) Emphasis added.

(33) Emphasis added.

(34) Paragraph 136 of the judgment under appeal.

(35) See recital 2 of Regulation No 141/2000 which states that ‘patients suffering from rare conditions should be entitled to the same quality of treatment as other patients; it is therefore necessary to stimulate the research, development and bringing to the market of appropriate medications by the pharmaceutical industry …’.

(36) See footnote 26 above.

(37) See, to that effect, the Commission notice cited in footnote 24, p. 6, Section 6, penultimate paragraph. It is probably for that reason that the General Court has repeatedly held that the criteria for the OMP designation are strict. See the judgment under appeal, paragraph 95 and the case-law cited, and judgment of 9 September 2010, CSL Behring v Commission and EMA (T‑264/07, EU:T:2010:371), paragraph 94. See also Commission notice referred to in footnote 24, p. 5, Section 5.