JUDGMENT OF THE GENERAL COURT (Ninth Chamber)

26 January 2022 ([\*](#Footnote*))

(Medicinal products for human use – Orphan medicinal products – Marketing authorisations for the medicinal products Tobramycin VVB and associated names – Derogation from the market exclusivity of Tobi Podhaler, containing the active substance tobramycin – Article 8(3)(c) of Regulation (EC) No 141/2000 – Concept of ‘significant benefit’ – Concept of ‘clinical superiority’ – Article 3(2) and (3)(d) of Regulation (EC) No 847/2000 – Duty of care – Manifest error of assessment)

In Case T‐303/16,

**Mylan IRE Healthcare Ltd,** established in Dublin (Ireland), represented by I. Vernimme, M. Campolini and D. Gillet, lawyers,

applicant,

v

**European Commission,** represented by K. Mifsud-Bonnici and A. Sipos, acting as Agents,

defendant,

supported by

**UAB VVB,** established in Kaunas (Lithuania), represented by E. Rivas Alba, V. Horcajuelo Rivera and M. Martens, lawyers,

intervener,

APPLICATION pursuant to Article 263 TFEU for annulment of Commission 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 of the Council, the marketing authorisations for ‘Tobramycin VVB and associated names’, medicinal products for human use which contain the active substance ‘tobramycin’,

THE GENERAL COURT (Ninth Chamber),

composed of M.J. Costeira, President, M. Kancheva (Rapporteur) and T. Perišin, Judges,

Registrar: I. Kurme, administrator,

having regard to the written part of the procedure and further to the hearing on 2 July 2021,

gives the following

**Judgment**

**Background to the dispute**

***TOBI and** **Tobi Podhaler***

1        In 1999, Novartis Pharmaceuticals UK obtained a marketing authorisation (‘MA’) for TOBI, a medicinal product containing the active substance tobramycin for inhalation by nebuliser, indicated for the treatment of pulmonary infection due to the bacterium *Pseudomonas aeruginosa* in cystic fibrosis patients.

2        The MA for TOBI was adopted in accordance with the national authorisation procedure provided for by the EU directives applicable at the date of the application and preceding 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 2012/26/EU of the European Parliament and of the Council of 25 October 2012 (OJ 2012 L 299, p. 1).

3        On 17 April 2003, Chiron Corporation Ltd was granted the designation as an orphan medicinal product, pursuant to 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), for the medicinal product ‘Tobramycin (inhalation powder)’, intended for the treatment of pulmonary infection in cystic fibrosis patients.

4        In order to obtain that designation, Chiron Corporation had to establish that tobramycin inhalation powder was of significant benefit to patients compared with existing therapies, including TOBI. That significant benefit was based on major contribution to patient care because tobramycin inhalation powder 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.

5        In 2006, the designation as an orphan medicinal product of the medicinal product ‘Tobramycin (inhalation powder)’ was transferred to Novartis Europharm Ltd after its acquisition of Chiron Corporation.

6        On 20 July 2011, on the basis of that designation, the European Commission adopted 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, by which Novartis Europharm obtained the MA for the medicinal product Tobi Podhaler.

7        As an orphan medicinal product, Tobi Podhaler enjoys, since its MA, a 10-year period of market exclusivity, in accordance with Article 8(1) of Regulation No 141/2000, allowing the market entry of similar competing medicinal products to be prevented, subject to certain derogations. In 2015, the market exclusivity granted to Tobi Podhaler was extended by a period of two years as a reward for compliance with an agreed paediatric investigation plan; accordingly, it expires on 25 July 2023.

***Tobramycin VVB***

8        On 2 May 2014, UAB VVB filed an MA application for the medicinal product ‘Tobramycin VVB and associated names’ (‘Tobramycin VVB’), based on a hybrid file, pursuant to Article 10(3) of Directive 2001/83 and in accordance with the decentralised procedure referred to in Article 28 of that directive. In accordance with that latter provision, the application was sent to the reference Member State, namely the Republic of Lithuania, and to the six Member States concerned by the application, namely the Republic of Bulgaria, the Republic of Estonia, the Republic of Latvia, Hungary, the Republic of Poland and Romania.

9        Since Tobramycin VVB was similar to Tobi Podhaler, as an orphan medicinal product for the same therapeutic indication, within the meaning of Article 3(3)(b) 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), UAB VVB applied for a derogation from the market exclusivity of Tobi Podhaler, in accordance with Article 8(3)(c) of Regulation No 141/2000. In that regard, it claimed that Tobramycin VVB was clinically superior, given its greater safety in a substantial part of the target population.

10      During the assessment of the dossier, the Republic of Poland stated that it could not approve the grant of an MA on the ground that the data provided by the applicant on clinical superiority had been considered insufficient and could not therefore be accepted. In that context, the decentralised procedure was sent, in accordance with Article 29(1) of Directive 2001/83, to the Coordination Group for Mutual Recognition and Decentralised Procedures. Since the Member States did not reach agreement within that coordination group, the procedure was referred to the Committee for Medicinal Products for Human Use (‘the CHMP’), in accordance with Article 29(4) of Directive 2001/83.

11      On 14 October 2015, the referral for arbitration to the CHMP was notified by the Republic of Lithuania on the basis of the concerns raised by the Republic of Poland. The latter took the view that Tobramycin VVB’s clinical superiority by comparison with Tobi Podhaler had not been demonstrated and that, consequently, it did not satisfy the conditions for a derogation, in accordance with Article 8(3) of Regulation No 141/2000, and an MA could not be granted.

12      On 18 December 2015, Novartis Europharm, having become aware of that referral procedure, sent a letter to the Chair of the CHMP, a copy of which was sent to the Commission. In that letter, Novartis Europharm expressed its concerns about that referral procedure and explained that there was no clinical data to support the finding that Tobramycin VVB was superior to Tobi Podhaler. It also stated therein that it had brought an action before the General Court, registered as Case T‐269/15, against a similar Commission decision granting a derogation from the market exclusivity of Tobi Podhaler and an MA for Vantobra, a tobramycin-based medicinal product. Finally, Novartis Europharm expressed its wish to be able to explain to the CHMP its concerns orallybefore the delivery of a final opinion.

13      On 28 January 2016, the CHMP issued, on the basis of a detailed assessment report, an opinion in which it considered that, in the context of Article 8(3)(c) of Regulation No 141/2000, read in conjunction with point (2) of Article 3(3)(d) of Regulation No 847/2000, the clinical superiority of Tobramycin VVB as compared with Tobi Podhaler in a substantial portion of the target population could be established, with the result that the objections raised by the Republic of Poland should not prevent the granting of a MA. The scientific opinion was adopted by consensus and was then sent to the Commission.

14      On 10 February 2016, Novartis Europharm reiterated its concerns to the Commission and asked it to recommend that the MA application for Tobramycin VVB be dismissed and that a meeting be held before the adoption of a final decision. That meeting took place on 9 March 2016. On 18 March 2016, Novartis Europharm provided the Commission with additional information in support of its position that the data submitted by UAB VVB in the context of its MA application and which had been taken into consideration by the CHMP were incomplete and did not justify the finding that Tobramycin VVB was clinically superior to Tobi Podhaler.

15      On 22 March 2016, the Commission contacted the European Medicines Agency (EMA) in order to ascertain whether the information provided by Novartis Europharm had an impact on the result of the scientific assessment of the referral application for Tobramycin VVB.

16      On 23 March 2016, the EMA replied that the data mentioned by Novartis Europharm were known to the CHMP and that they did not alter the CHMP’s conclusions in the referral procedure for Tobramycin VVB. The Commission informed Novartis Europharm of that reply on 8 April 2016.

***Contested decision***

17      On 4 April 2016, the Commission adopted Implementing Decision C(2016) 2083 final concerning, in the framework of Article 29 of Directive 2001/83, the marketing authorisations for ‘Tobramycin VVB and associated names’, medicinal products for human use which contain the active substance ‘tobramycin’ (‘the contested decision’).

18      By the contested decision, the Commission declared, on the basis of the CHMP’s scientific opinion, that the medicinal product Tobramycin VVB fulfilled the criteria provided for in Article 8(3) of Regulation No 141/2000, allowing a derogation from the market exclusivity rights enjoyed by Novartis Europharm by virtue of Tobi Podhaler’s status as an orphan medicinal product to be granted, and that the national MAs had to be based on information relating to the product approved during the decentralised procedure.

**Procedure and forms of order sought**

19      By application lodged at the Registry of the General Court on 14 June 2016, Novartis Europharm brought the present action.

20      On 12 July 2016, the case was assigned to the Fourth Chamber of the General Court and subsequently to the Second Chamber, by decision of 5 October 2016, pursuant to Article 27(5) of the Rules of Procedure of the General Court.

21      On 12 August 2016, the Commission lodged its defence.

22      By document lodged at the Court Registry on 28 September 2016, UAB VVB applied for leave to intervene in the present proceedings in support of the form of order sought by the Commission.

23      By letter of 25 October 2016, Novartis Europharm asked the Court to stay the present proceedings pending the ruling in Case T‐269/15, *Novartis Europharm* v *Commission*, which it had lodged with the Court on 28 May 2015.

24      The President of the Second Chamber of the General Court, after hearing the Commission, decided on 21 November 2016 to stay the proceedings, pursuant to Article 69(c) of the Rules of Procedure, pending the decision closing the proceedings in Case T‐269/15.

25      By order of 15 May 2019, *Novartis Europharm* v *Commission* (T‐269/15, not published, EU:T:2019:361), the Court decided that there was no longer any need to adjudicate in Case T‐269/15.

26      By letter of 16 May 2019, the Court questioned Novartis Europharm as to the next procedural step which it wished to take in the present action. On 14 June 2019, it informed the Court that it wished to continue the proceedings in this case. It also informed the Court that it had entered into an agreement for the transfer of the MA relating to the medicinal product Tobi Podhaler with Mylan IRE Healthcare Ltd and that that transfer was yet to be formalised.

27      On 28 June 2019, following requests submitted by Novartis Europharm and after obtaining the opinion of the EMA, the Commission adopted two decisions. The first is Implementing Decision C(2019) 5071 final, by which the designation as an orphan medicinal product of ‘Tobramycin (inhalation powder)’, entered in the Community Register of Orphan Medicinal Products under number EU/3/03/140, was transferred from Novartis Europharm to Mylan IRE Healthcare. The second decision is Implementing Decision C(2019) 5072 final, by which the MA granted to Novartis Europharm by the Implementing Decision of 20 July 2011, referred to in paragraph 6 above, for Tobi Podhaler, entered in the Register of Medicinal Products of the European Union under number EU/1/10/652, was transferred to Mylan IRE Healthcare. By those transfers, Mylan IRE Healthcare became the effective holder of the designation as an orphan medicinal product of Tobi Podhaler and of its MA and, therefore, of the market exclusivity granted to that medicinal product. Pursuant to Article 297 TFEU, those implementing decisions took effect on the date of their notification to Mylan IRE Healthcare, namely 1 July 2019.

28      By document lodged at the Court Registry on 5 July 2019, Mylan IRE Healthcare applied to substitute itself for Novartis Europharm as applicant in the present case.

29      Following a change in the composition of the Chambers of the Court by decision of 23 October 2019, the Judge-Rapporteur was assigned to the Ninth Chamber, to which the present case was accordingly allocated.

30      By order of 18 December 2019, *Novartis Europharm* v *Commission* (T‐303/16, not published, EU:T:2019:908), the Court authorised Mylan IRE Healthcare to substitute itself for Novartis Europharm as applicant in the present case and reserved the costs.

31      On 30 January 2020, the applicant lodged the reply. On 7 April 2020, the Commission lodged the rejoinder.

32      By order of 10 March 2020, the President of the Ninth Chamber of the General Court granted UAB VVB leave to intervene. On 2 June 2020, UAB VVB lodged its statement, in relation to which the applicant lodged its observations on 24 July 2020.

33      The parties presented oral arguments and answered the questions put to them by the Court at the hearing on 2 July 2021. On 16 July 2021, at the request of the Court, UAB VVB and the Commission lodged their observations on the pleas of inadmissibility raised at the hearing, to which the applicant replied on 9 August 2021.

34      Following the death of Judge Berke on 1 August 2021 and by decision of the President of the General Court of 23 August 2021, the present case was assigned to a new Judge-Rapporteur sitting in the Ninth Chamber.

35      By decision of the President of the Ninth Chamber of the General Court of 12 August 2021, a new judge was designated to complete the Chamber.

36      On 16 September 2021, the parties having informed the Court that they did not request a new hearing and the Court considering that it had sufficient information, the President of the Ninth Chamber decided to close the oral part of the procedure.

37      The applicant claims that the Court should:

–        annul the contested decision;

–        order the Commission and UAB VVB to pay the costs.

38      The Commission, supported by UAB VVB, contends that the Court should:

–        dismiss the action;

–        order the applicant to pay the costs.

**Law**

***Admissibility***

39      The Commission and UAB VVB, without formally raising an objection of inadmissibility under Article 130 of the Rules of Procedure, submitted, for the first time at the hearing and subsequently in writing at the Court’s request, a plea of inadmissibility in respect of the present action.

40      As regards the Commission’s plea of inadmissibility, it should be noted that it stated in its written observations of 16 July 2021 that it did not maintain it. Therefore, there is no longer any need for the Court to respond to it.

41      As regards the form of order sought by UAB VVB, it should be borne in mind that, in accordance with the fourth paragraph of Article 40 of the Statute of the Court of Justice of the European Union and Article 142 of the Rules of Procedure, the intervention is to be limited to supporting, in whole or in part, the form of order sought by one of the main parties. Those provisions do not, however, preclude the intervener from using arguments which differ from those of the party which it supports, provided that those arguments do not alter the framework of the dispute and that the intervention is still intended to support the form of order sought by that party (see judgment of 12 July 2018, *Austria* v *Commission*, T‐356/15, EU:T:2018:439, paragraph 55 and the case-law cited).

42      In the present case, UAB VVB, as an intervener, has no standing to put forward claims which have not been maintained by the Commission and the Court is therefore not required to examine the plea of inadmissibility which it raises (see, to that effect, judgment of 13 April 2011, *Germany* v *Commission*, T‐576/08, EU:T:2011:166, paragraph 39 and the case-law cited).

43      The plea of inadmissibility raised by UAB VVB must therefore be rejected.

***Substance***

44      In support of its action, the applicant relies on two pleas in law, alleging, first, infringement of Article 8(1) and (3) of Regulation No 141/2000 and, second, breach of the duty of care.

*The first plea in law alleging infringement of Article 8(1) and (3) of Regulation No 141/2000*

45      The applicant claims, in essence, that the contested decision infringes the market exclusivity rights it enjoys in respect of Tobi Podhaler pursuant to Article 8(1) of Regulation No 141/2000, in that the conditions set out in Article 8(3) of that regulation for granting a derogation from market exclusivity rights in favour of Tobramycin VVB are not fulfilled.

46      In view of the arguments put forward by the applicant, the Court considers it appropriate to divide the first plea into three complaints. The first complaint alleges that the data in the EAGER study, which is the pivotal study on which the CHMP relied, are insufficient to support a finding of clinical superiority. The second complaint alleges that errors of assessment were made in the assessment of the clinical superiority of Tobramycin VVB as compared with Tobi Podhaler. The third complaint alleges failure to observe the objective and system of Regulation No 141/2000.

–       *The first complaint alleging that the data from the EAGER study were insufficient to support a finding of clinical superiority*

47      First of all, the applicant claims that the applicant for the MA for Tobramycin VVB did not conduct any clinical studies comparing Tobramycin VVB with Tobi Podhaler and that the derogation relies on an extrapolation of the results of the EAGER study, which had been submitted by Novartis Europharm in its MA application for Tobi Podhaler and which compared TOBI with Tobi Podhaler; the latter thus benefited from market exclusivity for orphan medicinal products on account of the significant benefit it offered as compared with TOBI.

48      Next, the applicant submits that the EAGER study, which seems to be the pivotal study on which the CHMP relied to reach the conclusion that Tobramycin VVB is clinically superior to Tobi Podhaler, was not designed or powered to demonstrate superiority in terms of safety, to compare specific adverse events (such as a cough), or to analyse subgroups (depending on, for example, disease severity) but rather to assess the overall safety profile of Tobi Podhaler as compared with TOBI. Accordingly, the applicant takes the view that the EAGER study cannot provide the necessary evidence and definitive answers to demonstrate the clinical superiority of TOBI/Tobramycin VVB over Tobi Podhaler or to obtain a derogation from market exclusivity rights.

49      Lastly, in its reply, the applicant states that the Commission, by not taking into account the other existing scientific data, the Republic of Poland’s opinion regarding the inadequacy of the data produced on the superiority of Tobramycin VVB or even the fact that no research and development programme or pre-clinical or clinical study were generated to justify that superiority, endorsed the CHMP’s opinion without having carried out its own scientific assessment and thus infringed its obligation to state reasons by adopting the contested decision, while the assessment which it contains is based solely on the EAGER study.

50      The Commission and UAB VVB dispute those arguments.

51      First, the applicant asserts that the scientific assessment which concluded that Tobramycin VVB was superior to Tobi Podhaler was not sufficiently substantiated, given the lack of clinical trials comparing those two medicinal products or of a genuine research and development programme.

52      Under Article 10(3) of Directive 2001/83, in cases where a medicinal product, authorised at the end of a so-called ‘hybrid’ procedure, does not fall within the definition of a generic medicinal product as provided in paragraph 2(b) of Article 10 or where the bioequivalence cannot be demonstrated through bioavailability studies or in case of changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration, vis-à-vis the reference medicinal product, the results of the appropriate pre-clinical tests or clinical trials are to be provided.

53      It follows from that article that appropriate clinical trials do not have to be provided for medicinal products which fall within the definition of a generic medicinal product or where bioequivalence can be demonstrated or where the active substances, therapeutic indications, strength, pharmaceutical form or route of administration have not changed vis-a-vis the reference medicinal product.

54      Therefore, the MA of a medicinal product which contains an active substance or combination of active substances included in a reference medicinal product, where it is not a generic medicinal product, for which the so-called ‘abridged’ authorisation procedure is laid down in Article 10(1) of Directive 2001/83, may be obtained at the end of the so-called ‘hybrid’ procedure provided for in Article 10(3) of that directive. That procedure thereby allows the applicant for an MA, upon the expiry of the period of protection of the data derived from the pre-clinical tests and clinical trials provided in the submission of an MA dossier for the reference medicinal product, to rely on those data in part and in part on new data which it will have to produce and which stem from pre-clinical tests and clinical trials covering the changes made to the medicinal product in question by comparison with the reference medicinal product (see, to that effect, Opinion of Advocate General Saugmandsgaard Øe in *Abraxis Bioscience*, C‐443/17, EU:C:2018:1020, point 79).

55      In the present case, the MA application concerns the medicinal product Tobramycin VVB, available in the form of a solution for inhalation by nebuliser (300 mg/5 ml) and the active substance of which is tobramycin. In that application, Nebcin, a solution for injection for the purpose of data exclusivity, and TOBI, a tobramycin solution for inhalation by nebuliser (300 mg/5 ml), were designated as reference medicinal products for the purposes of the summary of product characteristics and clinical comparison.

56      Furthermore, Tobi Podhaler is an orphan medicinal product available in the form of capsules containing dry powder for inhalation (28 mg) using a portable device, with tobramycin as an active substance.

57      The three medicinal products at issue, TOBI, Tobi Podhaler and Tobramycin VVB, thus contain the same active substance, tobramycin, and are intended for the same therapeutic indication, namely the treatment of chronic pulmonary infections due to the bacterium *Pseudomonas aeruginosa* in cystic fibrosis patients aged 6 years or older.

58      In the MA application at issue, UAB VVB designated, inter alia, TOBI as the reference medicinal product and therefore relied in part on data relating to that medicinal product, on the EAGER study comparing TOBI and Tobi Podhaler and on *ex post* analyses comparing the safety profiles of those medicinal products by subgroups (children, adolescents and adults), namely the 2014 Geller study. In that regard, Annex II to the contested decision states that, as Tobramycin VVB contains the same qualitative and quantitative composition and the same pharmaceutical form as TOBI, clinical studies to demonstrate therapeutic equivalence can be waived in accordance with the EMA’s scientific guidelines (EMEA/CHMP/QWP/49313/2005 Corr. and CPMP/EWP/4151/00 Rev.1).

59      According to those scientific guidelines mentioned in Annex II to the contested decision relating to inhalation and nasal products and on the requirements for clinical documentation for orally inhaled products, therapeutic equivalence between two medicinal products, namely efficacy and equivalent safety, does not have to be demonstrated by studies where those medicinal products fulfil similar or identical criteria with regard to the active substance, strength, qualitative and quantitative composition and inhalation device.

60      Since it is apparent from paragraphs 55 to 57 above that Tobramycin VVB and TOBI have the same active substance, the same therapeutic indication, the same strength (300 mg/5 ml), the same pharmaceutical form (inhalation solution) and the same route of administration (nebuliser), studies demonstrating the therapeutic equivalence of those two medicinal products were therefore not necessary. Accordingly, the clinical trials concerning TOBI could be submitted in the MA application for Tobramycin.

61      In any event, the applicant’s arguments do not demonstrate that the Commission made a manifest error of assessment in concluding that the clinical studies were not necessary for a medicinal product with the same characteristics as a reference medicinal product.

62      The applicant merely asserts that studies specific to Tobramycin VVB were necessary, but it does not dispute that pre-existing data could be used or that the medicinal products at issue had the same active substance, the same therapeutic indication, the same pharmaceutical form, the same strength and the same route of administration. Moreover, it acknowledges itself that Tobramycin VVB is a hybrid copy of TOBI and that it was authorised in accordance with the procedure referred to in Article 10(3) of Directive 2001/83.

63      Therefore, the applicant’s argument that UAB VVB should have supplied its own clinical trials on Tobramycin VVB cannot succeed.

64      Secondly, it was found in Annex II to the contested decision that, since Tobramycin VVB is comparable to TOBI, the data on efficacy and safety available for TOBI could be extrapolated to Tobramycin VVB.

65      In that regard, first of all, it must be held, as is apparent from Annex II to the contested decision, that the EAGER study is a randomised, open-label phase 3 trial to assess the safety and efficacy of Tobi Podhaler as compared with Tobi. The primary criterion of that study was the assessment of safety, whereas efficacy, which was also assessed, was merely the secondary criterion.

66      Since it is established in paragraph 60 above that Tobramycin VVB is a medicinal product displaying the same characteristics as TOBI, the Commission cannot be criticised for having extrapolated the safety profile of TOBI to that medicinal product.

67      The identity of composition implies that the safety profile of those medicinal products is identical and, therefore, the data in the EAGER study could be used to assess the safety of Tobramycin VVB.

68      Furthermore, the applicant’s argument that the EAGER study was not designed to demonstrate that TOBI was superior to Tobi Podhaler cannot succeed either.

69      Where one study seeks to compare the adverse events for patients of two medicinal products, findings establishing that one product has more, less or as many adverse events as the other will inevitably ensue. Thus, the very principle of such a comparison seeks to determine to what extent a medicinal product is ‘superior’, ‘equivalent’ or ‘inferior’ to another, depending on the events analysed and the conclusions drawn therefrom. Therefore, one study cannot be designed solely to demonstrate the superiority of one medicinal product over another.

70      Thirdly, as regards the question whether the data in the EAGER study could be used to establish the clinical superiority of Tobramycin VVB over Tobi Podhaler, it should be noted that point (2) of Article 3(3)(d) of Regulation No 847/2000 provides, in its definition of clinically superior medicinal product, that the superior safety of a similar medicinal product as compared with an authorised orphan medicinal product may be established, in certain cases, without direct comparative clinical trials.

71      Since it is apparent from paragraphs 66 and 67 above that it was possible to use the data on the TOBI safety profile to assess Tobramycin VVB’s safety profile because of the identity of their characteristics, the CHMP cannot be criticised for having used the EAGER study comparing TOBI’s safety profile with that of Tobi Podhaler.

72      Since it was possible to extrapolate the safety profile of TOBI to Tobramycin VVB and direct clinical trials are not always necessary to determine the superior safety of a similar medicinal product as compared withan orphan medicinal product, the assessments carried out for the purposes of the comparison between TOBI and Tobi Podhaler could also be extrapolated to Tobramycin VVB, the composition of which is identical to that of TOBI, for the purposes of its comparison with Tobi Podhaler.

73      Fourthly, in its observations on the statement in intervention, the applicant does not dispute that pre-existing studies may be used to obtain a derogation from market exclusivity, but it submits that they should thus establish a new benefit, and not merely confirm what was already known at the time market exclusivity was granted.

74      In that regard, it should be noted that the scientific assessment relating to the superiority of Tobramycin VVB over Tobi Podhaler in a substantial portion of the target population is based on the clinical data stemming from the EAGER study and on the *ex post* analyses, namely the 2014 Geller study.

75      It must be stated that the 2014 Geller study was carried out after the 2011 MA for Tobi Podhaler and that, as the CHMP states in its conclusions, the *ex post* analyses of the profile of undesirable events in different age groups confirmed the results of the EAGER study, namely that all adverse events and a cough occur more frequently in Tobi Podhaler patients in all age groups.

76      That conclusion is also confirmed, as the Commission observes, by the lack of changes made to Section 4.4 of the summary of the characteristics of Tobi Podhaler, which provides for a special warning according to which a cough may occur in the event of use of Tobi Podhaler and that, if it persists, the doctor should consider the use of an approved tobramycin solution for inhalation by nebuliser. TOBI is therefore recommended as an alternative treatment. Thus, there is no new evidence showing that the finding of a greater cough incidence rate in Tobi Podhaler patients is incorrect.

77      Furthermore, it is also apparent from the file that the other studies to which the applicant refers assessed the efficacy and safety profile of Tobi Podhaler only, in particular as compared with a placebo. As the Commission argues, although they were known and taken into account by the CHMP (see paragraph 16 above), those studies did not allow a direct comparisonbetween TOBI Podhaler and a tobramycin solution for inhalation by nebuliser like Tobramycin VVB and were consequently less relevant than the data from the EAGER study for the purpose of that comparison.

78      Therefore, the trends observed in the EAGER study are not assumptions, since they were confirmed by the *ex post* analyses. It is therefore without committing a manifest error of assessment that it was concluded that the differences in terms of safety observed in the EAGER trial and the *ex post* analyses of Tobramycin VVB and Tobi Podhaler, which favour the former as far as concerns the occurrence of cough and discontinuation of treatment, are relevant and support the superiority of Tobramycin VVB in terms of safety in patients intolerant to Tobi Podhaler.

79      Fifthly, as regards the failure to take into account the Republic of Poland’s opinion concerning the insufficiency of the data produced on the superiority of Tobramycin VVB, it is sufficient to note that, in the light of the foregoing, the applicant cannot validly complain that the Commission considered that the data produced were sufficient to demonstrate the superiority of Tobramycin VVB.

80      In those circumstances, the Republic of Poland’s objections made in the course of the administrative procedure cannot demonstrate that the data produced are insufficient.

81      Therefore, the applicant’s arguments alleging that the data in the EAGER study are insufficient to support a finding of clinical superiority of Tobramycin and infringement of the resulting obligation to state reasons must be rejected as unfounded.

82      Consequently, the first complaint of the first plea must be rejected as unfounded.

–       *The second complaint alleging errors of assessment in the assessment of the clinical superiority of Tobramycin VVB over Tobi Podhaler*

83      In the first place, the applicant claims that the concepts of ‘significant benefit’ and ‘clinical superiority’ both govern the market exclusivity granted to orphan medicinal products. Those concepts are based on the same criteria, that is to say a demonstration of greater efficacy, greater safety or a major contribution to patient care.

84      In the second place, according to the applicant, although a claim of significant benefit as compared with existing therapies or clinical superiority overan authorised orphan medicinal product can be based on a single one of those criteria, the scientific assessment should take account of all the product characteristics which may, positively or negatively, affect safety, efficacy and contribution to patient care. Thus, the alleged benefits of a product are assessed in the light of the overall benefit/risk balance of the products concerned and never in the light of one of those criteria in isolation.

85      In the third place, the applicant claims that clinical superiority based on greater safety should be demonstrated for the patient population as a whole or at least for a substantial portion of that population so that the overall benefit/risk balance is improved.

86      Consequently, the applicant takes the view that, in the present case, the reasoning in the scientific assessment annexed to the contested decision is contradictory.

87      First, the applicant submits that the finding in the contested decision that TOBI, and therefore Tobramycin VVB, provides greater safety than Tobi Podhaler is inconsistent with the assessment procedure of Tobi Podhaler. The applicant takes the view that the concepts of ‘significant benefit’ and ‘clinical superiority’ cannot be interpreted as meaning that Tobi Podhaler, which was found to provide a significant benefit to patients by comparison with TOBI because of its major contribution to patient care, could, at the same time and based on the same clinical data, namely the EAGER study, be considered clinically inferior to TOBI or to Tobramycin VVB due to its inferior safety, since the finding that Tobi Podhaler provided a significant benefit as compared with TOBI was conditional on the safety profile of TOBI and Tobi Podhaler being comparable and the EMA expressly stated that that condition had been satisfied.

88      Secondly, the applicant submits that, by referring to the incidence of cough as an ‘adverse event’ and to ‘intolerance’ and ‘discontinuation’, the CHMP does not draw any conclusion as to the severity of the cough, so that it is therefore difficult to determine how the data in the EAGER study on the incidence of cough were incorporated into the CHMP’s finding regarding the clinical superiority of Tobramycin VVB.

89      Thirdly and lastly, the applicant notes that the Commission made a manifest error in the assessment of the criterion of the substantial portion of the target population by endorsing the CHMP’s opinion according to which at least 10% of the target population may not be able to use Tobi Podhaler due to intolerance, whereas it is apparent from the EAGER study that only 3.9% of patients discontinued Tobi Podhaler treatment due to a cough.

90      The Commission and UAB VVB dispute the applicant’s arguments.

91      As a preliminary point, in the first place, it should be recalled that Regulation No 141/2000 was adopted with a view to promoting the development of effective treatments for patients suffering from rare diseases in the European Union. That regulation introduces a system of initiatives to encourage pharmaceutical companies to invest in the research, development and marketing of medicinal products intended for the diagnosis, prevention or treatment of rare diseases, namely orphan medicinal products. It also lays down the criteria and procedure to be followed for the designation of certain medicinal products as orphan medicinal products.

92      In that regard, it should be noted that the procedure relating to orphan medicinal products divides into two separate phases. The first phase covers the designation of the product as an orphan medicinal product; the second covers the MA for the product that has been designated as an orphan medicinal product and the market exclusivity attaching to it (see judgment of 16 May 2019, *GMPO* v *Commission*, T‐733/17, EU:T:2019:334, paragraph 30 and the case-law cited).

93      With regard to the procedure for designation as an orphan medicinal product, Article 3 of Regulation No 141/2000 sets out the criteria which a potential medicinal product must meet in order to be recognised as an orphan medicinal product. The first assumption of Article 3(1)(b) of Regulation No 141/2000 provides that the sponsor of the orphan medicinal product must in particular establish that there exists no satisfactory method of diagnosis, prevention or treatment of the condition concerned by the product for which an application for designation as an orphan medicinal product has been made that has been authorised in the European Union. If such a method exists, the legislature has made provision, in the second assumption of Article 3(1)(b) of Regulation No 141/2000, for the designation as an orphan medicinal product of any potential medicinal product for the treatment of the same condition provided its sponsor can establish that the medicinal product will be of significant benefit to patients affected by that condition (see judgment of 16 May 2019, *GMPO* v *Commission*, T‐733/17, EU:T:2019:334, paragraph 31 and the case-law cited).

94      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 context of the second assumption of Article 3(1)(b) of Regulation No 141/2000, applicable in the present case, establishing significant benefit takes place in the context of a comparison with an existing authorised medicinal product or method. The ‘clinically relevant advantage’ and the ‘major contribution to patient care’, which enable the potential orphan medicinal product to be described as being of significant benefit, can be established only by comparison with treatments that have already been authorised (see judgment of 16 May 2019, *GMPO* v *Commission*, T‐733/17, EU:T:2019:334, paragraph 32 and the case-law cited). That interpretation is confirmed by the 2003 Communication from the Commission on Regulation No 141/2000 (OJ 2003 C 178, p. 2), in which it is stated that ‘the applicant is required to establish significant benefit compared with an existing authorised medicinal product or method at the time of designation’ (judgment of 9 September 2010, *Now Pharm* v *Commission*, T‐74/08, EU:T:2010:376, paragraph 44).

95      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).

96      Furthermore, the criteria laid down in Article 3(1) of Regulation No 141/2000 must be met, first, where the medicinal product is designated as an orphan product and entered in the Community Register of Orphan Medicinal Products, pursuant to Article 3(1) of Regulation No 141/2000, read in conjunction with Article 5(9) thereof. Second, those criteria must continue to be met when the medicinal product designated as an orphan product is granted an MA as an orphan medicinal product since, pursuant to Article 5(12) of the regulation, a medicinal product which, before the MA is granted, fails to meet the criteria laid down in Article 3(1) of the regulation, must be removed from the register (judgment of 22 January 2015, *Teva Pharma and Teva Pharmaceuticals Europe* v *EMA*, T‐140/12, EU:T:2015:41, paragraph 66).

97      The second stage of the procedure thus occurs, where relevant, after the product concerned has been designated as an orphan medicinal product. It should be borne in mind in that regard that it follows from Article 5(12)(b) of Regulation No 141/2000 that, when reviewing an MA application, it is necessary to ascertain whether the criteria laid down in Article 3 of that regulation are still met. As provided in Article 5(12)(b) of Regulation No 141/2000, a designated orphan medicinal product is to be removed from the Register of Orphan Medicinal Products if it is established before the MA is granted that those criteria are no longer met in respect of the medicinal product concerned (judgment of 16 May 2019, *GMPO* v *Commission*, T‐733/17, EU:T:2019:334, paragraph 33).

98      Accordingly, where a sponsor submits an MA application in respect of a designated orphan medicinal product, he or she triggers at the same time a procedure for re-evaluating the designation criteria. The responsibility for assessing whether the designation criteria have been met lies with the Committee for Orphan Medicinal Products (‘the COMP’), which must issue an opinion in that regard (see judgment of 16 May 2019, *GMPO* v *Commission*, T‐733/17, EU:T:2019:334, paragraph 34 and the case-law cited).

99      It should also be recalled that, in accordance with Article 8(1) of Regulation No 141/2000, once marketing authorisation has been granted for an orphan medicinal product, the competent authorities must not, for a period of 10 years, accept another application for a marketing authorisation in respect of a similar medicinal product for the same therapeutic indication or indications included in the designation of the product as an orphan medicinal product (judgment of 22 January 2015, *Teva Pharma and Teva Pharmaceuticals Europe* v *EMA*, T‐140/12, EU:T:2015:41, paragraph 67).

100    As is apparent from recital 8 of Regulation No 141/2000, that regulation nevertheless seeks to circumscribe that period of exclusivity in order not to prejudice existing intellectual property rights and, in the interests of patients, not to prevent the marketing of a medicinal product similar to the orphan product which could be of significant benefit to those affected by the condition in question (judgment of 3 March 2016, *Teva Pharma and Teva Pharmaceuticals Europe* v *EMA*, C‐138/15 P, not published, EU:C:2016:136, paragraph 28).

101    Accordingly, Article 8(3) of Regulation No 141/2000 provides that it is possible to derogate from the 10-year exclusivity period and grant an MA for a similar medicinal product in respect of the same therapeutic indication and to do so in three cases, namely (i) where the holder of the MA for the original orphan product consents or (ii) where he or she is unable to supply sufficient quantities of the medicinal product and (iii) where the second applicant can establish that his or her product, ‘although similar to the orphan medicinal product already authorised, is safer, more effective or otherwise clinically superior’ (judgment of 3 March 2016, *Teva Pharma and Teva Pharmaceuticals Europe* v *EMA*, C‐138/15 P, not published, EU:C:2016:136, paragraph 29). Moreover, Article 8(3) of Regulation No 141/2000 does not establish any order of priority among the three situations where a derogation may be applied under Article 8(1) of that regulation (judgment of 22 January 2015, *Teva Pharma and Teva Pharmaceuticals Europe* v *EMA*, T‐140/12, EU:T:2015:41, paragraph 75).

102    It is also apparent from the factors referred to above that although the market exclusivity provided in Article 8(1) of Regulation No 141/2000 is reserved for orphan medicinal products alone, the derogations exhaustively set out in Article 8(3) of the regulation relate to any similar medicinal product within the meaning of Regulation No 847/2000, irrespective of whether or not the product is an orphan product (judgment of 3 March 2016, *Teva Pharma and Teva Pharmaceuticals Europe* v *EMA*, C‐138/15 P, not published, EU:C:2016:136, paragraph 31).

103    In the second place, as regards the scope and extent of judicial review in this area, it is clear from the case-law that, where the Commission must undertake complex technical or scientific assessments, it enjoys broad discretion. In such a situation, judicial review is confined to determining whether the relevant procedural rules have been complied with, whether the facts established by the Commission are correct and whether there has been a manifest error of appraisal of those facts or a misuse of powers (see, 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 96, and of 16 May 2019, *GMPO* v *Commission*, T‐733/17, EU:T:2019:334, paragraph 56 and the case-law cited).

104    In order to establish that an institution committed a manifest error in assessing complex facts such as to justify the annulment of a measure, the evidence adduced by the applicant must be sufficient to make the factual assessments used in that act implausible. Subject to that review of plausibility, it is not the Court’s role to substitute its assessment of complex facts for that made by the entity which adopted the decision. The abovementioned limits to the review by the Courts of the European Union do not, however, affect their duty to establish whether the evidence relied on is factually accurate, reliable and consistent, whether that evidence contains all the information which must be taken into account in order to assess a complex situation, and whether it is capable of substantiating the conclusions drawn from it (see judgment of 11 February 2015, *Spain* v *Commission*, T‐204/11, EU:T:2015:91, paragraphs 32 and 33 and the case-law cited).

105    In the third place, a feature of the procedure introduced by Article 5 of Regulation No 141/2000 is the essential part assigned to an objective and in-depth scientific assessment by the COMP of the effect of the potential medicinal products considered. Since the Commission is not in a position to carry out scientific assessments of the efficacy or harmfulness of a medicinal product during the orphan medicinal product designation procedure, the aim of the mandatory consultation of the COMP is to provide the Commission with the evidence of scientific assessment which is essential for it to be able to determine, in full knowledge of the facts, the appropriate measures to ensure a high level of public health protection. Thus, although the COMP’s opinion does not bind the Commission, it is nonetheless extremely important. In that regard, it is apparent from Article 5(8) of Regulation No 141/2000 that a case in which a decision is not in accordance with the COMP’s opinion was envisaged as constituting an exceptional situation. That is why, in a complex scientific area such as that of orphan medicinal products, in the majority of cases the Commission endorses the opinions of the COMP unless it has other adequate sources of information in the field in question (see, to that effect, judgment of 9 September 2010, *Now Pharm* v *Commission*, T‐74/08, EU:T:2010:376, paragraphs 75 and 112).

106    In the present case, it is apparent from recital 4 and Article 1 of the contested decision that the Commission authorised the marketing of Tobramycin VVB for the reasons set out in the CHMP report in Annex II to the contested decision. It must therefore be held that the Commission did not depart from the CHMP’s opinion and endorsed the findings therein.

107    Accordingly, the Court’s limited review referred to in paragraph 103 above must be conducted in respect of all the considerations contained in the contested decision, and also those to which it refers, including the annexes, containing inter alia the CHMP’s opinion, which form an integral part of the contested decision (see, to that effect, judgment of 11 June 2015, *Laboratoires CTRS* v *Commission*, T‐452/14, not published, EU:T:2015:373, paragraph 60 and the case-law cited).

108    It should also be noted that the applicant does not dispute that Tobramycin VVB is a similar medicinal product, within the meaning of Article 3(3)(b) of Regulation No 847/2000, to the orphan medicinal product Tobi Podhaler and that, therefore**,** marketing it requires a ground for derogation from the market exclusivity of Tobi Podhaler to be established, pursuant to Article 8(3) of Regulation No 141/2000.

109    It should also be noted that Tobramycin VVB was authorised on the basis of safety superiority in a substantial portion of the target population, in accordance with the derogation provided for in Article 8(3)(c) of Regulation No 141/2000, read in conjunction with point (2) of Article 3(3)(d) of Regulation No 847/2000.

110    It is in the light of those considerations that the arguments put forward by the applicant in support of the second complaint of the first plea in law must be examined.

111    In substance, the applicant claims that the Commission misinterpreted the concept of ‘significant benefit’, referred to in Article 3(2) of Regulation No 141/2000, and the concept of ‘clinical superiority’, referred to in Article 8(3) of that regulation, which led to inconsistencies and contradictions in the assessment of the medicinal products at issue.

112    In the first place, in order to determine whether or not the Commission made manifest errors of assessment in reaching the conclusion in the contested decision that Tobramycin VVB is clinically superior to Tobi Podhaler, it is necessary to define the assessment criteria on which that conclusion was based.

113    First, it should be noted that the concept of ‘significant benefit’ appears in Article 3(1)(b) of Regulation No 141/2000 and constitutes a condition for obtaining the designation of orphan medicinal product having regard to all the other existing medicinal products which must still be in existence at the time of the MA giving rise to the market exclusivity of the orphan medicinal product. Thus, if the medicinal product in question does not satisfy that condition, assessed by the COMP, it will not be able to obtain the designation of orphan medicinal product; however, this will not prevent the grant of a possible MA as a medicinal product without specific designation. As noted in paragraph 94 above, that concept is defined in Article 3(2) of Regulation No 847/2000 as ‘a clinically relevant advantage or a major contribution to patient care’.

114    Second, the concept of ‘clinical superiority’ appears in Article 8(3)(c) of Regulation No 141/2000 and constitutes one of the conditions under which a derogation from the market exclusivity of an orphan medicinal product may be granted to a similar medicinal product, whether orphan or not (see paragraph 102 above). In the event of a negative assessment of that condition, for which the CHMP is responsible, the medicinal product in question will not be able to obtain its MA, prohibited due to the market exclusivity of the orphan medicinal product. A clinically superior medicinal product is defined in Article 3(3)(d) of Regulation No 847/2000 as follows:

‘“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 ... or

(2)      greater safety in a substantial portion of the target population(s) ... or

(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.’

115    Although both those concepts have different purposes and scope, parts of the definitions are similar, such as ‘clinically relevant advantage’, ‘clinical superiority’, ‘major contribution to patient care’, which are found, in essence, in the definition of the two concepts. It is therefore necessary to ascertain whether the criteria for assessing significant benefit are the same as those for clinical superiority, as the applicant claims.

116    First, it is apparent from the Proposal for a European Parliament and Council Regulation (EC) on orphan medicinal products (OJ 1998 C 276, p. 7) that the Commission had used the same wording of ‘safer, more effective or clinically superior’ medicinal product in Articles 3 and 8 of that proposal for a regulation. Following amendments during the procedure for the adoption of the regulation, the EU legislature preferred the concept of ‘significant benefit’ as a criterion for designation as an orphan medicinal product and the concept of ‘safer, more effective or clinically superior’ as a criterion for derogating from market exclusivity, which shows the importance attached to the difference between those two assessment criteria.

117    In the second subparagraph of paragraph 2 of Section B, entitled ‘Explanation of the main amendments’, of the explanatory memorandum to the amended proposal for a European Parliament and Council Regulation on orphan medicinal products (OJ 2000 C 177 E, p. 1), the Commission explains that, ‘since clinical superiority is difficult to establish at the very early stage of development when designation as an orphan medicinal product is likely to take place, this term has been removed from Article 3 and replaced by the notion that, in situations where there is already an existing treatment for an orphan condition, significant benefit to those affected by the condition should be demonstrated’.

118    In that regard, it should be noted that that consideration on the part of the Commission was incorporated into its 2003 communication on Regulation No 141/2000, referred to in paragraph 94 above. It states therein that, as there may be little or even no clinical experience with the orphan medicinal product in question, the justification for significant benefit is likely to be made on assumptions of benefit made by the sponsor. It also lists examples of assumptions of justification for significant benefit such as formulation or route of administration, expected benefits to a particular population sub-set, expectations of an improved safety profile, more favourable pharmacokinetic properties or problems of supply or availability.

119    The recommendation of the COMP of 2 March 2010 on the elements required to support the medical plausibility and the assumption of significant benefit for an orphan designation (EMA/COMP/15893/2009) adds, referring to the 2000 Commission Guideline on the format and content of applications for designation as orphan medicinal products and on the transfer of designations from one sponsor to another (ENTR/6283/00), that, ‘in general a demonstration of potentially greater efficacy, an improved safety profile, and/or more favourable pharmacokinetic properties than existing methods may be considered to support the notion of significant benefit’. That recommendation of the COMP then clearly gives information on the significant benefit based on assumptions of improved efficacy, improved safety and major contribution to patient care.

120    Consequently, 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.

121    Secondly, it should be noted that both the elements of the definition of significant benefit laid down in Article 3(2) of Regulation No 847/2000 and the assessment criteria relating thereto are linked by the coordinating conjunction ‘or’, with the result that, contrary to what the applicant claims, those criteria cannot be cumulative. Thus, in order to establish the significant benefit of a medicinal product for which an application for designation as an orphan medicinal product has been made, it is sufficient to show that one of those criteria is satisfied.

122    Moreover, it is stated, in the Commission’s letter of 17 March 2011 to the EMA, that the COMP always considered in that case that, in order to maintain significant benefit, it was essential to demonstrate equivalent efficacy and safety. In Annex A.11 to the application, relating to the position of the EMA and of the COMP of 17 December 2010 on the review of the criteria for designation of Tobi Podhaler as an orphan medicinal product with a view to maintaining its designation and MA, it is stated that designation as an orphan medicinal product was granted in 2003 on the basis of satisfactory argumentation by the sponsor of Tobi Podhaler justifying the assumption that tobramycin (inhalation powder) may be of potential significant benefit for the treatment of a lung infection due to *Pseudomonas aeruginosa* in cystic fibrosis patients, on account of a contribution to patient care (reduction of delivery time, improved convenience, better delivery system, improvement in compliance with the treatment regime). However, it had been held that it was essential for the maintenance of that designation and the justification of the significant benefit that, at the time of the MA, when all the relevant data were available, it was confirmed that Tobi Podhaler offered efficacy and safety comparable to TOBI.

123    In the light of those considerations, if significant benefit is justified by the criterion of ‘major contribution to patient care’, the sponsor will also have to show that the medicinal product for which he or she intends to seek designation as an orphan medicinal product is at the very least equivalent, or in any event non-inferior to the medicinal products already authorised in terms of efficacy and safety.

124    It follows from the foregoing that the assessment criteria for the efficacy, safety and major contribution to justify significant benefit are identical to the criteria for clinical superiority, are not cumulative and must be assessed as a whole on the basis of a weighting and overall evaluation of the benefit/risk balance.

125    In the present case, particularly following the EAGER study comparing Tobi Podhaler with TOBI, the COMP concluded in its position referred to in paragraph 122 above, first, that the condition of non-inferiority (more effective or at least similar effects) of Tobi Podhaler as compared with TOBI for all patients who participated in the clinical trials was satisfied, without which the significant benefit would not have been proved, secondly, that a major contribution to patient care based on portability, convenience and administration time justified the significant benefit, without that benefit being restricted to a specific group of patients, thirdly, that (i) Tobi Podhaler and TOBI were not entirely comparable in specific subgroups, but Tobi Podhaler was statistically non-inferior to TOBI in all the population tested, and (ii) with their differences, both treatments were of value in an important proportion of patients across all evaluated age categories, fourthly, that, in terms of the benefit/risk balance, the benefits of Tobi Podhaler (improved convenience, portability and shorter duration of administration) outweigh the potential increased risk of adverse events (such as a cough), in particular in the adult patients most affected by those effects which increase the discontinuation rate but for whom a tolerability warning has been included in Section 4.4 of the summary of product characteristics of Tobi Podhaler, fifthly, that in terms of major contribution to patient care, the assessment of convenience and overall satisfaction was much more favourable for Tobi Podhaler than for TOBI, and therefore, sixthly, that Tobi Podhaler is of significant benefit for the persons affected by the orphan disease, justified by a major contribution to patient care owing to a reduction in the administration time of the active substance and a more convenient form of administration.

126    In the second place, in order to determine whether the finding that Tobramycin VVB was superior to Tobi Podhaler is consistent with the comparison made between TOBI and Tobi Podhaler in the course of the latter’s MA, it is necessary to examine the assessment criteria applied to Tobramycin VVB as regards its clinical superiority.

127    First of all, it should be borne in mind that, as was established in paragraphs 51 to 81 above in the context of the first complaint of the first plea in law, the EAGER study was sufficient to support the finding that Tobramycin VVB was clinically superior and an extrapolation of the results of that study was permitted. Consequently, the conclusions drawn from the COMP’s opinion of 17 December 2010 cited in paragraph 125 above, reproduced in substance in the CHMP’s opinion annexed to the contested decision of which it forms an integral part, on the basis of the EAGER study comparing TOBI with Tobi Podhaler, are applicable in the context of a comparison between Tobramycin VVB and Tobi Podhaler.

128    Moreover, as stated in paragraph 108 above, the applicant does not dispute that Tobramycin VVB is a medicinal product similar to the orphan medicinal product Tobi Podhaler and that its MA requires a derogation from the market exclusivity of Tobi Podhaler.

129    In the present case, as is apparent from the contested decision, Tobramycin VVB was authorised on the basis of a finding of clinical superiority based on the criterion of greater safety in a substantial portion of the target population, in accordance with the derogation provided for in Article 8(3)(c) of Regulation No 141/2000, read in conjunction with point (2) of Article 3(3)(d) of Regulation No 847/2000.

130    First, it must be pointed out that the clinical superiority of a medicinal product must be demonstrated, first, solely in relation to the orphan medicinal product which benefits from exclusivity (unlike all the medicinal products authorised for significant benefit) to which it is similar within the meaning of Article 3(3)(b) of Regulation No 847/2000 and, second, following the grant of the MA and market exclusivity of the orphan medicinal product, having regard to the public health objective of Regulation No 141/2000, which, despite market exclusivity, is also intended not to prevent a better or safer medicinal product from being marketed in the interests of patients, as established in the case-law cited in paragraph 100 above.

131    Secondly, it must be noted that, like the criteria for assessing significant benefit (see paragraph 121 above), the assessment criteria of clinical superiority are also non-cumulative because of the coordinating conjunction ‘or’ which separates them.

132    Thirdly, 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)’. It follows 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 (see paragraphs 123 and 124 above).

133    Thus, the applicant’s argument that clinical superiority based on greater safety must be demonstrated for the whole target population or, at least, for a substantial portion of that population in such a way that the benefit/risk balance is improved is incorrect.

134    Fourthly, the applicant claims that it is inconsistent and illogical to conclude that Tobi Podhaler provides a significant benefit in comparison with TOBI or Tobramycin VVB for one of the criteria and, at the same time and on the basis of the same data, that TOBI or Tobramycin VVB is clinically superior to Tobi Podhaler for another criterion, since the comparability of the efficiency and safety profiles of the two medicinal products at issue was a condition justifying the significant benefit of Tobi Podhaler.

135    It should be noted that that alleged inconsistency had also been raised by the Commission in its letter of 17 March 2010 to the EMA, which had replied on 30 March 2011 that ‘the efficacy profile of Tobi Podhaler [was] non inferior to that of Tobi’ and that ‘taking into account all available safety data included in all studies submitted, both medicinal products [had] a similar safety pattern’, thus ensuring that there was no inconsistency in the conclusions of the COMP and the CHMP.

136    It should be noted in that regard that, contrary to what the applicant claims, even if those profiles were found to be comparable or similar for the population taken as a whole, that does not mean that they are equivalent for all subsets of that population.

137    It is apparent from Annex II to the contested decision, in terms of safety, on the basis of the EAGER study, that, first, Tobi Podhaler posed a higher risk of incidence of cough than TOBI or Tobramycin VVB (48.4% as opposed to 31.1%), secondly, amongst those 13% of patients who had discontinued Tobi Podhaler treatment, 3.9% had discontinued it because of a cough, as opposed to 1% of the 8% of patients who had discontinued TOBI or Tobramycin VVB treatment and, thirdly, cough events were suspected to be related to the medicinal product in 25.3% of Tobi Podhaler patients and 4.3% of TOBI or Tobramycin VVB patients. On the basis of the *ex post* analyses carried out in the 2014 Geller study, which compared the safety profile of the two medicinal products at issue by reference to age subgroups (children, adolescents, adults), the results of the EAGER study were confirmed, with the result that, first, a cough occurs more frequently in all age groups in Tobi Podhaler patients than in TOBI or Tobramycin VVB patients, secondly, the discontinuance rates for Tobi Podhaler patients are higher in each age group than the abandonment rates for TOBI or Tobramycin VVB patients, in particular in adults (32.7% as opposed to 18.9%, of which 17.3% as opposed to 9.1% discontinued treatment because of an adverse event) and, thirdly, differences in cough incidence rates in favour of TOBI or Tobramycin VVB are confirmed in all age groups, with the smallest difference being in adult patients (45% as opposed to 34%).

138    Consequently, in view of the negative impact of the adverse events, and in particular of a cough, on the target population, the Commission cannot be criticised for having concluded that a portion of the target population would not be able to use Tobi Podhaler because of the development of intolerance. Moreover, it should be noted that that intolerance was known and included in Section 4.4 of the summary of the characteristics of Tobi Podhaler, which introduces a special warning and recommends the use of TOBI in the event of intolerance. Tobramycin VVB may therefore present a new alternative solution to Tobi Podhaler, in particular in Estonia, Latvia and Lithuania, where TOBI, which could have been used for patients who are intolerant to Tobi Podhaler, is not authorised, but also to TOBI, which, in any event, as the applicant acknowledges, no longer enjoys any regulatory protection.

139    Nor did the Commission make a manifest error of assessment in concluding, in the light of the conclusions of the studies taken together, first, that a cough was described as a ‘very common’ adverse event, which means, in terms of percentage, that it occurs at a frequency of at least 10% (1 out of 10 persons) and, second, that those 10% could be regarded as a substantial portion of the target population within the meaning of Article 3(3)(d) of Regulation No 847/2000. Therefore, the applicant’s argument that only 3.9% of patients discontinued use of Tobi Podhaler because of a cough, and not 10%, is unfounded, since the fact that at least 10% of patients develop a cough means that potentially all or some of those patients could also develop an intolerance justifying the use of the alternative medicinal product. It is therefore incorrect to take into account only the rate of patients who discontinued Tobi Podhaler because of the cough incidence, which, moreover, still remains higher than in TOBI or Tobramycin VVB patients.

140    Lastly, the Commission cannot be criticised for having considered that the differences in terms of inhalation duration (namely the criterion of major contribution to patient care in relation to which Tobi Podhaler presents a clear advantage compared with TOBI or Tobramycin VVB) are not relevant in the context of the assertion of clinical superiority based on greater safety. The fact that Tobi Podhaler has advantages in terms of administration has no impact on patients who may develop an intolerance to Tobi Podhaler, since they would not be able to use it or benefit from its advantages.

141    Accordingly, the fact that Tobi Podhaler provides, for the population as a whole, a significant benefit justified by a major contribution to patient care due to a reduction in the administration time of the active substance and a more convenient form of administration 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. Consequently, the applicant’s argument that Tobramycin VVB cannot be clinically superior to Tobi Podhaler in terms of safety is unfounded.

142    In the light of the foregoing, the second complaint of the first plea must be rejected as unfounded.

–       *The third complaint, alleging failure to observe the objective and system of Regulation No 141/2000*

143    The applicant claims that, by adopting the contested decision, which authorises the marketing of Tobramycin VVB through a derogation from its market exclusivity, the Commission is putting at risk the entire system and *ratio legis* of Regulation No 141/2000, by discouraging the pharmaceutical industry from investing in costly research and development programmes required for bringing on the market new orphan medicinal products.

144    Similarly, the applicant submits that proper respect for the market exclusivity of orphan medicinal products, a derogation from which should be interpreted strictly, and a restrictive approach to those rights are also in the interest of patients suffering from rare conditions, since investments by pharmaceutical undertakings in research and development of future treatments for rare conditions are based on them, the interest of patients having a central role in the system established by Regulation No 141/2000.

145    The Commission and UAB VVB dispute the applicant’s arguments.

146    First of all, it should be recalled that, in view of the fact that certain health conditions are so rare that the pharmaceutical industry is not inclined to develop medicinal products intended for their diagnosis, prevention or treatment under normal market conditions because of the excessive costs of developing and marketing in the light of the predicted sales of those medicinal products, the objective of Regulation No 141/2000, laid down in Article 1 thereof, is to establish a procedure for the designation of those medicinal products as orphan medicinal products and to provide incentives to encourage pharmaceutical companies to invest in research, development and marketing of those orphan medicinal products.

147    In that regard, the market exclusivity provided for by Article 8(1) of Regulation No 141/2000 is the most significant incentive under the regulation to which an authorised orphan medicinal product is entitled (judgment of 11 June 2015, *Laboratoires CTRS* v *Commission*, T‐452/14, not published, EU:T:2015:373, paragraph 77).

148    Next, as is apparent from the case-law cited in paragraph 100 above, Regulation No 141/2000 also seeks to circumscribe the period of exclusivity of an orphan medicinal product in the interest of patients and public health by grounds for derogation laid down in Article 8(3), in order not to prevent the marketing of a medicinal product similar to the orphan medicinal product which could provide a significant advantage to persons suffering from the conditions concerned.

149    It follows that the MA for a medicinal product similar to an orphan medicinal product, which satisfies the conditions set out in Article 8(3) of Regulation No 141/2000 and which therefore benefits patients, is consistent with the objectives of that regulation.

150    Given that, in the present case, it is apparent from paragraphs 111 to 141 above that the assessment relating to the superiority of Tobramycin VVB over Tobi Podhaler is not vitiated by a manifest error of assessment, it must be held that the contested decision, in that it finds in favour of granting an MA for Tobramycin VVB, satisfies the conditions for derogation laid down in Article 8(3)(c) of Regulation No 141/2000 and, therefore, the public health objective pursued by that regulation.

151    In the light of the foregoing, the third complaint of the first plea in law must be rejected as unfounded and, accordingly, the first plea must be rejected in its entirety.

*The second plea in law, alleging breach of the duty of care*

152    The applicant submits, in substance, that, in the procedures relating to the application of Article 8(3) of Regulation No 141/2000, the holder of the MA and of the market exclusivity rights of an orphan medicinal product has the right to request compliance with the duty of care, also known as the principle of diligence, since that duty creates an obligation on the part of the bodies, both of the Member States and of the European Union, to protect the rights of individuals in substantive and procedural matters. Therefore, the applicant submits that the contested decision was adopted in breach of the duty of care in that, first, it was not consulted during the scientific assessment and, second, the CHMP did not take into account all the available clinical data.

153    In the first place, the applicant takes the view that many of the deficiencies in the assessment and decision-making procedure could have been avoided if it had been consulted by the EMA or the CHMP during the scientific assessment of the application for derogation.

154    In its view, in order to benefit fully from the rewards which Regulation No 141/2000 offers, sponsors of orphan medicinal products should have the right to be heard or consulted in any application procedure for a derogation from its orphan product market exclusivity rights. The applicant takes the view that, in the present case, its consultation was crucial, since the derogation procedure, first, solely concerned a direct comparison between two of its own medicinal products and in respect of which it has the most complete knowledge and information, thus preventing the assessment of a clinical superiority claim from being limited to the information provided by the applicant for a derogation and, second, was based on the assessment and interpretation of the clinical data produced by Novartis Europharm in the context of the MA application for Tobi Podhaler.

155    In the second place, the applicant claims that the CHMP reached a conclusion on the clinical superiority of TOBI or Tobramycin VVB over Tobi Podhaler by taking into account only the clinical data of the EAGER study, produced by Novartis Europharm, although that study does not reflect all the existing clinical data and safety data.

156    In that regard, the applicant refers to several studies, as well as to an actual case study published in the scientific literature, which should have been taken into consideration, since they show that the frequency of the cough adverse event is highly variable in the various studies, depending on the study design, study duration, patient population, so that it is difficult or even impossible to predict the true frequency of cough depending on patients and treatment by Tobi Podhaler or tobramycin inhalation solution. According to the applicant, those factors should also have been taken into consideration when interpreting the clinical data.

157    The applicant also claims that the absence of any reference to those other studies in the CHMP’s opinion confirms that only the clinical data for the EAGER study were assessed by the CHMP. It adds that the CHMP does not explain the reasons why it did not take into account the other studies or respond to the concerns of the Republic of Poland and Novartis Europharm in relation to the insufficient nature of the data provided by UAB VVB regarding the clinical superiority of Tobramycin VVB. It submits that the Commission should, by virtue of its obligation to verify the consistency and reasoning of the opinion, have asked the CHMP to explain why it was not necessary to take other scientific studies into account and why they had no effect. According to the applicant, the outcome of the procedure may have been different if the CHMP had taken into account other scientific data and not solely the EAGER study.

158    Accordingly, the applicant takes the view that, by failing to take into account and failing to assess impartially all the relevant information, the CHMP breached its duty of care and, therefore, infringed the principle of impartiality.

159    The Commission and UAB VVB dispute the applicant’s arguments.

160    As a preliminary point, it should be noted first of all that the guarantees afforded by the European Union legal order in administrative proceedings include, in particular, the principle of sound administration, enshrined in Article 41 of the Charter of Fundamental Rights of the European Union, which entails the duty of care, that is, the duty of the competent institution to examine carefully and impartially all the relevant aspects of the individual case (see, to that effect, judgments of 27 September 2012, *Applied Microengineering* v *Commission*, T‐387/09, EU:T:2012:501, paragraph 76 and the case-law cited, and of 16 September 2013, *ATC and Others* v *Commission*, T‐333/10, EU:T:2013:451, paragraph 84 and the case-law cited).

161    Furthermore, the requirement of impartiality to which the EU institutions are subject also extends to experts consulted in that regard. In particular, where an expert is requested to give an opinion on the effects of a medicinal product, it is necessary for that expert to perform his or her task impartially (see judgment of 9 September 2010, *Now Pharm* v *Commission*, T‐74/08, EU:T:2010:376, paragraph 88 and the case-law cited).

162    It should also be observed that the Commission must be recognised as enjoying broad discretion in the areas in which it must undertake complex technical or scientific assessments. In the context of its judicial review, the EU judicature must determine whether the relevant procedural rules have been complied with, whether the facts established by the Commission are correct and whether there has been a manifest error of appraisal of those facts or a misuse of powers (see paragraph 103 above).

163    Furthermore, in the context of Directive 2001/83, the procedure for issuing an MA is conceived as a bilateral procedure involving only the applicant and the competent authority. It is a procedure between the applicant and the administration, during which the latter must take into account the applicant’s interest in obtaining an MA and the public interest in protecting human health. The applicant, as a third party, is not entitled to participate in that procedure or set itself up as an interlocutor of the CHMP or of the Commission in regard to the assessment of the scientific data relating to the medicinal product in question (see, to that effect, judgments of 23 October 2014, *Olainfarm*, C‐104/13, EU:C:2014:2316, paragraph 34 and the case-law cited, and of 18 December 2003, *Olivieri* v *Commission and EMEA*, T‐326/99, EU:T:2003:351, paragraph 94).

164    Nevertheless, it must be observed that there is no provision in Directive 2001/83, applicable to this case, which prohibits the Commission, before issuing an MA, from following a procedure during which persons other than the applicant for the MA are able to submit their observations to it so as to enable it to fulfil its duty to check, in the interests of public health, whether all the information relating to the scientific assessment of the medicinal product in question, whether it be favourable or unfavourable to the product, has indeed been made available to it. The fact that those rules do not contain any provision to that effect cannot prevent the Commission from obtaining information from a third party where such a course of action is indispensable in order to safeguard public health (see, to that effect and by analogy, judgment of 18 December 2003, *Olivieri* v *Commission and EMEA*, T‐326/99, EU:T:2003:351, paragraph 73).

165    Furthermore, according to settled case-law, the right to be heard in all proceedings is affirmed not only in Articles 47 and 48 of the Charter of Fundamental Rights, which ensure respect for both the rights of the defence and the right to fair legal process in all judicial proceedings, but also in Article 41 thereof, which guarantees the right to good administration. Article 41(2) of the Charter of Fundamental Rights provides that the right to good administration includes, inter alia, the right of every person to be heard before any individual measure which would affect him or her adversely is taken (see, to that effect, judgment of 5 October 2016, *ECDC* v *CJ*, T‐395/15 P, not published, EU:T:2016:598, paragraph 54 and the case-law cited).

166    Respect for the right to be heard is, in all proceedings initiated against a person which are liable to culminate in a measure adversely affecting that person, a fundamental principle of EU law which must be guaranteed even in the absence of rules governing the proceedings in question. That principle 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, judgments of 19 December 2019, *Probelte* v *Commission*, T‐67/18, EU:T:2019:873, paragraph 86 and the case-law cited).

167    However, according to the case-law, an infringement of the right to be heard does not affect the validity of the contested decision where it is not established that the procedure could have led to a different result without that alleged irregularity (see, to that effect, judgment of 14 May 2019, *Marinvest and Porting* v *Commission*, T‐728/17, not published, EU:T:2019:325, paragraph 57 and the case-law cited).

168    In the present case, the applicant claims, in essence, breach of the duty of care in so far as the contested decision, first, was adopted without the EMA or the CHMP consulting it during the scientific assessment of the application for a derogation and, second, is based only on the EAGER study and on none of the other scientific studies which it mentioned.

169    First, the applicant submits that, by virtue of its market exclusivity, it has a right to be consulted during the MA procedure, since the grant of a derogation from that market exclusivity, relating to scientific assessments produced by the applicant and to its own medicinal products, is of direct and individual concern to it. That consultation is justified not only with regard to its interests as a result of the derogation procedure, but also in the context of the duty of care of the competent authorities, since it has a thorough knowledge of its own medicinal products at issue.

170    In that regard, it should be noted that, even though no particular provision provides specifically for consultation of the applicant during the MA procedure for a medicinal product under Directive 2001/83, the Commission gave it the opportunity to express its point of view on several occasions.

171    It is thus apparent from the file that, despite the lack of a reply from the CHMP to the letter of 18 December 2015, in which the applicant expressed its concerns regarding the MA procedure for Tobramycin VVB and sought to explain these to the CHMP orally, the Commission, in response to the letter of 10 February 2016 in which the applicant reiterated its concerns, granted it a meeting on 9 March 2016, for which the applicant thanked it on 10 March 2016, and the applicant provided it with additional information by letter of 18 March 2016 (see paragraphs 12 and 14 above).

172    Thus, the Commission cannot be criticised for having heard the applicant at a late stage of the procedure, when the scientific assessment had already been completed, given that, in any event, the applicant, as it itself acknowledges, was able to submit its observations before the adoption of the final decision.

173    In any event, in the light of those circumstances, the applicant was able, during the MA procedure for Tobramycin VVB, to express its point of view and defend its interests.

174    Therefore, the applicant’s argument relating to the lack of consultation during the MA procedure for Tobramycin VVB must be rejected.

175    Secondly, the applicant disputes the CHMP’s scientific assessment in that it failed to take into consideration all the available data concerning the products at issue.

176    In that regard, it should be noted that, following the meeting of 9 March 2016 and the letter of 18 March 2016, in which the applicant disputes the clinical superiority of Tobramycin VVB over Tobi Podhaler and the derogation from market exclusivity, the Commission contacted the EMA. In a letter of 22 March 2016, the Commission asked the Chair of the CHMP whether the applicant’s information, including the additional studies to which it referred, had an impact on the result of Tobramycin VVB’s scientific assessment. In a letter of 23 March 2016, the Chair of the CHMP replied that the information provided by the applicant was known to the CHMP, the studies mentioned therein having been examined in various procedures, and that they did not alter the CHMP’s conclusions in the referral procedure (see paragraphs 15 and 16 above).

177    The Commission cannot therefore be criticised for not having paid particular attention to that information or for not ensuring that it had all been taken into consideration before the adoption of the final MA decision of 4 June 2016, namely the contested decision.

178    It follows that the applicant’s argument that the consideration of those data could have led to a different result is unfounded, even if it had been consulted before the adoption of the CHMP’s scientific assessment (see paragraphs 169 to 173 above).

179    In any event, the applicant adduces no evidence to show that those data were not taken into account. Even though the additional studies and arguments on which it relied are not expressly mentioned in the CHMP’s opinion, that does not call into question the fact that those data were known to the CHMP and had no impact on the outcome of the scientific assessment.

180    It should be noted in that regard that those data were examined during various regulatory procedures which gave rise to several CHMP opinions, so that they were well known to the CHMP. Furthermore, as was established in paragraphs 76 and 77 above, first, in the absence of a change in the characteristics of Tobi Podhaler relating to cough, the higher incidence rate of cough observed with Tobi Podhaler is not incorrect and, second, the studies referred to by the applicant are less relevant than the EAGER study, because they related solely to the reaction of patients to whom Tobi Podhaler or a placebo was prescribed.

181    The Commission therefore did not infringe the duty of care or the principle of impartiality by not asking the CHMP for the reasons for the lack of impact of those data and for not taking them into account.

182    In the light of all the foregoing considerations, the second plea in law must be rejected as unfounded and, accordingly, the action must be dismissed in its entirety.

**Costs**

183    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 bear its own costs and to pay those incurred by the Commission and by UAB VVB, in accordance with the form of order sought by them, including those relating to the procedure for the replacement of a party.

On those grounds,

THE GENERAL COURT (Ninth Chamber)

hereby:

1.      **Dismisses the action;**

2.      **Orders Mylan IRE Healthcare Ltd to bear its own costs and pay those incurred by the European Commission and by UAB VVB, including those relating to procedure for the replacement of a party.**

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| Costeira | Kancheva | Perišin |

Delivered in open court in Luxembourg on 26 January 2022.

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| E. Coulon | | M. van der Woude |

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| Registrar | | President |

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[\*](#Footref*)      Language of the case: English.