Court of Justice of the European Communities (including Court of First Instance Decisions)

JUDGMENT OF THE GENERAL COURT (Eighth Chamber)

23 September 2020 (*)

(Medicinal products for human use – Marketing authorisation for medicinal products for human use containing omega-3 acid ethyl esters – Variation of the terms of the authorisation – First paragraph of Article 116 of Directive 2001/83/EC – Manifest error of assessment – Proportionality)

In Case T‑472/19,

BASF AS, established in Oslo (Norway), represented by E. Wright, Barrister, and H. Boland, lawyer,

applicant,

v

European Commission, represented by L. Haasbeek and A. Sipos, acting as Agents,

defendant,

APPLICATION pursuant to Article 263 TFEU for annulment of Commission Implementing Decision C(2019) 4336 final of 6 June 2019 concerning, in the framework of Article 31 of Directive 2001/83/EC of the European Parliament and of the Council, marketing authorisations of medicinal products for human use containing ‘Omega-3 acid ethyl esters’ for oral use in secondary prevention after myocardial infarction,

THE GENERAL COURT (Eighth Chamber),

composed of J. Svenningsen, President, R. Barents (Rapporteur) and T. Pynnä, Judges,

Registrar: E. Coulon,

gives the following

Judgment

 Legal framework

1        The procedure for reviewing a marketing authorisation (‘MA’) for a medicinal product is governed, in the European Union, inter alia, by 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), which has been amended on several occasions.

2        The first paragraph of Article 6(1) of Directive 2001/83, as amended by Article 54 of Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ 2006 L 378, p. 1), provides, inter alia, that no medicinal product may be placed on the market of a Member State unless a marketing authorisation has been issued by the competent authorities of that Member State.

3        Article 31(1) of Directive 2001/83, as amended by Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 (OJ 2010 L 348, p. 74), provides:

‘The Member States, the Commission, the applicant or the [MA] holder shall, in specific cases where the interests of the Union are involved, refer the matter to the Committee [for Medicinal Products for Human Use] for application of the procedure laid down in Articles 32 [to] 34 before any decision is reached on an application for a[n MA] or on the suspension or revocation of a[n MA], or on any other variation of the [MA] which appears necessary.’

4        Article 32(1), (2) and (5) of Directive 2001/83, as amended by Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 (OJ 2004 L 136, p. 34), states:

‘1.      When reference is made to the procedure laid down in this Article, the Committee [for Medicinal Products for Human Use] shall consider the matter concerned and shall issue a reasoned opinion within 60 days of the date on which the matter was referred to it.

However, in cases submitted to the Committee [for Medicinal Products for Human Use] in accordance with Articles 30 and 31, this period may be extended by the Committee [for Medicinal Products for Human Use] for a further period of up to 90 days, taking into account the views of the applicants or the [MA] holders concerned.

In an emergency, and on a proposal from its Chairman, the Committee [for Medicinal Products for Human Use] may agree to a shorter deadline.

2.      In order to consider the matter, the Committee [for Medicinal Products for Human Use] shall appoint one of its members to act as rapporteur. The Committee [for Medicinal Products for Human Use] may also appoint independent experts to advise it on specific questions. When appointing experts, the Committee [for Medicinal Products for Human Use] shall define their tasks and specify the time limit for the completion of these tasks.

…

5.      Within 15 days after its adoption, the [European Medicines] Agency [(EMA)] shall forward the final opinion of the Committee [for Medicinal Products for Human Use] to the Member States, to the Commission and to the applicant or the [MA] holder, together with a report describing the assessment of the medicinal product and stating the reasons for its conclusions.

In the event of an opinion in favour of granting or maintaining an … [MA for] the medicinal product concerned …, the following documents shall be annexed to the opinion:

(a)      a draft summary of the product characteristics, as referred to in Article 11;

(b)      any conditions affecting the authorisation within the meaning of paragraph 4(c);

(c)      details of any recommended conditions or restrictions with regard to the safe and effective use of the medicinal product;

(d)      the proposed text of the labelling and leaflet.’

5        Article 33 of Directive 2001/83, as amended by Directive 2004/27, provides:

‘Within 15 days of the receipt of the opinion, the Commission shall prepare a draft of the decision to be taken in respect of the application, taking into account [EU] law.

In the event of a draft decision which envisages the granting of [MA], the documents referred to in Article 32(5), second subparagraph shall be annexed.

Where, exceptionally, the draft decision is not in accordance with the opinion of the [EMA], the Commission shall also annex a detailed explanation of the reasons for the differences.

The draft decision shall be forwarded to the Member States and the applicant or the [MA] holder.’

6        Article 34 of Directive 2001/83, as amended by Directive 2004/27, provides:

‘1.      The Commission shall take a final decision in accordance with, and within 15 days after the end of, the procedure referred to in Article 121(3).

2.      The rules of procedure of the Standing Committee established by Article 121(1) shall be adjusted to take account of the tasks incumbent upon it under this Chapter.

Those adjustments shall entail the following provisions:

(a)      except in cases referred to in the third paragraph of Article 33, the opinion of the Standing Committee shall be given in writing;

(b)      Member States shall have 22 days to forward their written observations on the draft decision to the Commission. However, if a decision has to be taken urgently, a shorter time limit may be set by the Chairman according to the degree of urgency involved. This time limit shall not, otherwise than in exceptional circumstances, be shorter than 5 days;

(c)      Member States shall have the option of submitting a written request that the draft Decision be discussed in a plenary meeting of the Standing Committee.

Where, in the opinion of the Commission, the written observations of a Member State raise important new questions of a scientific or technical nature which have not been addressed in the opinion delivered by the [EMA], the Chairman shall suspend the procedure and refer the application back to the [EMA] for further consideration.

The provisions necessary for the implementation of this paragraph shall be adopted by the Commission in accordance with the procedure referred to in Article 121(2).

3.      The decision as referred to in paragraph 1 shall be addressed to all Member States and reported for information to the [MA] holder or applicant. The concerned Member States and the reference Member State shall either grant or revoke the [MA], or vary its terms as necessary to comply with the decision within 30 days following its notification, and they shall refer to it. They shall inform the Commission and the [EMA] accordingly.’

7        The first paragraph of Article 116 of Directive 2001/83, as amended by Directive 2010/84, states:

‘The competent authorities shall suspend, revoke or vary a[n MA] if the view is taken that the medicinal product is harmful or that it lacks therapeutic efficacy, or that the risk-benefit balance is not favourable, or that its qualitative and quantitative composition is not as declared. Therapeutic efficacy shall be considered to be lacking when it is concluded that therapeutic results cannot be obtained from the medicinal product.’

 Background to the dispute

8        In 2001, the ‘Omega-3 acid ethyl esters 90 1000 mg capsule’ was approved as a therapeutic indication in the context of secondary prevention treatment after myocardial infarction, by type II variation of the existing MA. 

9        On 15 March 2018, the Kingdom of Sweden applied to the European Medicines Agency (EMA) under the procedure referred to in Article 31(1) of Directive 2001/83, on the ground that, ‘in recent clinical trials, no clinical benefit of omega-3 acid ethyl ester containing products ha[d] been demonstrated in prevention after myocardial infarction, and that these products lack[ed] efficacy in this indication’.

10      The procedure referred to in Article 31(1) of Directive 2001/83 was therefore initiated on 22 March 2018 and was conducted by the Committee for Medicinal Products for Human Use (‘the CHMP’). On 13 December 2018, the CHMP adopted an opinion in which it recommended that the risk-benefit balance of medicinal products containing omega-3 acid ethyl esters for oral use in secondary prevention after myocardial infarction was not favourable.

11      In accordance with Article 32(4) of Directive 2001/83, the MA holders for omega-3 acid ethyl esters, including the applicant, BASF AS, were heard by the CHMP.

12      Following that hearing, the re-examination procedure was initiated on 17 February 2019.

13      The CHMP, in its recommendation of 28 March 2019 set out in its final opinion, reiterated its conclusion that the risk-benefit balance of medicinal products containing omega-3 acid ethyl esters for oral use in secondary prevention after myocardial infarction at the dose of one gram per day was not favourable.

14      On 6 June 2019, the European Commission adopted Implementing Decision C(2019) 4336 final concerning, in the framework of Article 31 of Directive 2001/83, the MAs for medicinal products for human use containing omega-3 acid ethyl esters for oral use in secondary prevention after myocardial infarction (‘the contested decision’). Under that decision, the Member States must, in essence, vary the MAs for medicinal products for human use containing omega-3 acid ethyl esters, by removing from those MAs the indication concerning the oral use of those medicinal products in secondary prevention after myocardial infarction. The names of the medicinal products referred to in Annex I to the contested decision are, inter alia, Omacor, Zodin and Dualtis. The decision also contains the names of the MA holders for those medicinal products.

 Procedure and forms of order sought

15      By application lodged at the Court Registry on 9 July 2019, the applicant brought the present action.

16      By separate document lodged at the Court Registry on the same day, the applicant lodged an application for interim relief pursuant to Articles 278 and 279 TFEU, seeking, in essence, suspension of the operation of the contested decision and an order for the Commission to pay the costs.

17      By order of 19 August 2019, BASF v Commission (T‑472/19 R, not published, EU:T:2019:555), the General Court dismissed the applicant’s application for suspension of operation of the contested decision and reserved the costs. The appeal brought against that order was dismissed by order of 26 February 2020, BASF v Commission (C‑773/19 P(R), not published, EU:C:2020:113), and the applicant was ordered to pay the costs.

18      The Commission lodged a defence at the Court Registry on 23 September 2019. The applicant lodged a reply at the Court Registry on 4 December 2019. The Commission lodged a rejoinder at the Court Registry on 20 January 2020.

19      Acting upon a proposal of the Judge-Rapporteur, the General Court (Eighth Chamber) decided to rule on the action without an oral part of the procedure.

20      The applicant claims that the Court should:

–        annul the contested decision in its entirety or in so far as it concerns the applicant;

–        order the Commission to pay the costs.

21      The Commission contends that the Court should:

–        dismiss the action as inadmissible in part and, in any event, as unfounded;

–        order the applicant to pay the costs.

 Law

 Admissibility of the action

22      The Commission submits that the application must be regarded as being in part inadmissible. It notes that the contested decision is addressed to the Member States and contains, in Annex I thereto, the list of medicinal products based on omega-3 fatty acids to which that decision applies and the names of the MA holders for those medicinal products. Consequently, since the contested decision is not addressed to the applicant, the applicant must show either that the contested decision is of direct and individual concern to it, or that that decision is a regulatory act that is of direct concern to it and does not entail implementing measures.

23      The Commission contends that the applicant cannot base its action on the fact that it is manifestly individually concerned by the contested decision, on the ground that that decision applies to the medicinal products Omacor, Dualtis and Zodin, Dualtis and Zodin being identical to Omacor.

24      The Commission observes that, although the applicant established that Pronova Biopharma Norge AS (listed as the MA holder in Annex I to the contested decision) had changed its name to BASF AS, it did not provide evidence that it had concluded licensing agreements with the MA holders for the medicinal products Omacor and Dualtis in Croatia and Zodin in Greece.

25      Since Commission decisions terminating a re-examination procedure under Article 31(1) of Directive 2001/83 are ‘severable on a per product basis’, it must be concluded, according to the Commission, that the application can be declared admissible only in so far as it concerns the products Omacor and Zodin in respect of which Pronova Biopharma Norge, the predecessor in title of the applicant, is listed as the MA holder in the Member States concerned in the list in Annex I to the contested decision.

26      The applicant, which states that it participated actively in the procedure referred to in Article 31(1) of Directive 2001/83 leading to the contested decision, states that it demonstrated that Pronova BioPharma Norge had changed its name on 4 July 2018 to become BASF and that, on 21 September 2018, the name of the MA holder for most of the Omacor and Zodin medicinal products marketed in the European Economic Area had been varied in order to take account of that change of name. Furthermore, a licensing agreement was concluded by the applicant, first, with Mylan Hrvatska d.o.o, which holds the MA for Omacor and Dualtis in Croatia, where it markets those products, and, secondly, with Ferrer-Galenica SA, which holds the MA for Zodin in Greece, where it markets it that product.

27      The applicant concludes from the foregoing considerations that it is directly and individually concerned by the contested decision.

28      Furthermore, the applicant adds that it disputes the plea of inadmissibility raised by the Commission in that it cannot bring its action with regard to all the medicinal products covered by the contested decision, since its action is based on the fact that the contested decision has no legal basis.

29      First, it should be noted that, although the applicant seeks the annulment of the contested decision not only in so far as it concerns the applicant, but also in so far as it concerns the other MA holders for medicinal products listed in Annex I to that decision, it has neither established nor alleged that it has standing to bring the action on behalf of those other MA holders, with the result that, even if the contested decision were to be annulled, it could be annulled only in part in so far as that decision concerns the applicant. Thus, in any event, the annulment sought could take effect only with regard to the medicinal products for which the applicant is the holder of the MA or MAs (see, to that effect, judgment of 27 March 2019, August Wolff and Remedia v Commission, C‑680/16 P, EU:C:2019:257, paragraph 48) or exercises the rights of the holder or holders of those MAs under contractual arrangements.

30      The applicant claims nevertheless that its action should be declared admissible in its entirety, since it is based on the fact that the contested decision has no legal basis.

31      In that regard, it must be held that that argument is clearly wrong, since, even if the contested decision has no legal basis, the applicant has still not shown that it has standing to bring proceedings for the benefit of the other MA holders for the medicinal products concerned by that decision.

32      Secondly, it should be noted that the applicant has demonstrated that it was the MA holder for the medicinal products Omacor and Zodin, following the change of name that had taken place, which, moreover, the Commission does not dispute. It follows that the applicant is individually and directly concerned by the contested decision in so far as it applies to medicinal products in respect of which it has shown that it is the MA holder.

33      Thirdly, since the applicant has not, in the course of the proceedings, produced evidence of the licensing agreement allegedly concluded between it and, Mylan Hrvatska, as regards the MA for Omacor and Dualtis in Croatia, and, Ferrer Galenica, as regards Zodin in Greece, as it submitted in its action, the examination of the action must be limited to those medicinal products in respect of which it is established that the applicant is the successor in title of Pronova BioPharma Norge and which are referred to in paragraph 32 above.

34      The mere reference by the applicant, in a footnote to its reply, to the fact that it manufactures and is the owner in Greece of the medicinal product Zodin, information which is directly available on the website of Greek national medicinal product organisations, is insufficient for the purposes of demonstrating that it is directly and individually concerned, since the Court is not required to seek evidence of such individual concern, such as licensing agreements or any other information that is available on the internet.

35      Moreover, the fact that the medicinal products Dualtis and Zodin are identical to Omacor also does not mean that the applicant has standing to bring proceedings on that basis alone.

36      The action must therefore be declared admissible only as regards the medicinal products in respect of which the applicant is the MA holder and which are referred to in the contested decision as belonging to the company, Pronova Biopharma Norge, to which the applicant is now the successor in title. As to the remainder, the claims for annulment must be dismissed as inadmissible on the basis that the applicant has no standing to bring proceedings for the annulment of the contested decision in so far as it concerns persons other than the applicant.

 Substance

37      As a preliminary point, although the applicant did not formally set out pleas in law in its application in support of its action, contrary to the provisions of Article 76(d) of the Rules of Procedure of the General Court, it is apparent from the application that it sought to rely, as the Commission rightly pointed out, on two pleas in law alleging, first, infringement of the first paragraph of Article 116 of Directive 2001/83 and, secondly, infringement of the principle of proportionality.

38      Moreover, it must be noted that, at the stage of the reply, the applicant expressly endorsed that finding.

 First plea in law, alleging infringement of the first paragraph of Article 116 of Directive 2001/83

39      As a preliminary point, the applicant states that it is not asking the Court to re-examine the CHMP’s scientific conclusions. It relies only on the absence, in EU law, of a valid legal basis for the contested decision.

40      The applicant submits that the CHMP considered that the risk-benefit balance presented by Omacor was not favourable, so that it was necessary to vary the MA in order to remove the indication for oral use in secondary prevention after myocardial infarction. In its view, it is for the Commission to prove that the medicinal product concerned is harmful or lacks therapeutic efficacy, that the risk-benefit balance is not favourable or that its qualitative and quantitative composition is not as declared. The Commission has not succeeded in showing that any of those conditions was satisfied. The applicant adds that it is not for it to prove the continued efficacy of Omacor, as, according to the applicant, is submitted by the CHMP, in an attempt to reverse the burden of proof.

41      The applicant maintains that neither the CHMP’s final assessment report, nor the CHMP’s final opinion, nor the contested decision succeeded in proving, on the basis of relevant and statistically significant clinical data, that the robustness of the study methodology or the results of the study generated in the context of a trial carried out in 1999, entitled GISSI-Prevenzione, were no longer valid or reliable, with the result that Omacor lacks efficacy. It adds that the CHMP relies in its opinion on vague and general observations.

42      According to the applicant, the CHMP cannot have the power to issue an ex post facto opinion on a study, even though the original assessor, with substantially greater and more appropriate resources at its disposal, considered it appropriate to grant an MA to a medicinal product such as Omacor.

43      Lastly, the applicant notes that the Commission merely refers to the presumed weakness of the GISSI-Prevenzione trial, which is apparent from the assessment report, and that it relied solely on a study which is insufficiently substantiated, namely the OMEGA study, and on additional studies which presented only ‘some relevance’ for the purposes of the prescription of Omacor in the prevention of myocardial infarction.

44      The Commission submits that that plea must be rejected.

45      As a preliminary point, it should be recalled that the first paragraph of Article 116 of Directive 2001/83 provides that the competent authorities are to suspend, revoke or vary an MA if the view is taken that the medicinal product is harmful or that it lacks therapeutic efficacy, or that the risk-benefit balance is not favourable, or that its qualitative and quantitative composition is not as declared.

46      Those conditions of variation, suspension or revocation of an MA are alternative and not cumulative (judgments of 11 December 2014, PP Nature-Balance Lizenz v Commission, T‑189/13, not published, EU:T:2014:1056, paragraph 41, and of 19 September 2019, GE Healthcare v Commission, T‑783/17, EU:T:2019:624, paragraph 44). They must also be interpreted in accordance with the general principle, set out in the case-law, that the protection of public health must unquestionably take precedence over economic considerations (judgments of 19 April 2012, Artegodan v Commission, C‑221/10 P, EU:C:2012:216, paragraph 99, and of 19 September 2019, GE Healthcare v Commission, T‑783/17, EU:T:2019:624, paragraph 44).

47      Furthermore, the precautionary principle, which is a general principle of EU law, authorises the competent authorities, where there is uncertainty, to take appropriate measures in order to prevent certain potential risks for public health, safety and the environment without having to wait until the reality and seriousness of those risks become fully apparent (see judgment of 19 September 2019, GE Healthcare v Commission, T‑783/17, EU:T:2019:624, paragraph 45 and the case-law cited; see also, to that effect, judgment of 3 December 2015, PP Nature-Balance Lizenz v Commission, C‑82/15 P, not published, EU:C:2015:796, paragraph 21) or, in particular, concerning the re-examination of an existing MA, without waiting for the risks to materialise to the detriment of patients.

48      Consequently, in accordance with the precautionary principle, the health risks which the grounds set out in the first paragraph of Article 116 of Directive 2001/83 aim to prevent need not be specific, but only potential (judgment of 19 September 2019, GE Healthcare v Commission, T‑783/17, EU:T:2019:624, paragraph 46; see also, to that effect, judgments of 10 April 2014, Acino v Commission, C‑269/13 P, EU:C:2014:255, paragraph 59, and of 3 December 2015, PP Nature-Balance Lizenz v Commission, C‑82/15 P, not published, EU:C:2015:796, paragraph 23).

49      In that scheme, the first paragraph of Article 116 of Directive 2001/83 confers rights on undertakings which are MA holders, since it ensures the retention of the MAs as long as the existence of one of the conditions for the variation, suspension or withdrawal of those MAs is not established (see, to that effect, judgment of 19 April 2012, Artegodan v Commission, C‑221/10 P, EU:C:2012:216, paragraph 96). It follows that, as regards the burden of proof, it is for the competent authority, in this case the Commission, to establish that the conditions relating to the revocation, suspension or modification of an MA, set out in the first paragraph of Article 116 of Directive 2001/83, are met (judgments of 7 March 2013, Acino v Commission, T‑539/10, not published, EU:T:2013:110, paragraph 79, and of 19 September 2019, GE Healthcare v Commission, T‑783/17, EU:T:2019:624, paragraph 47).

50      In view of the precautionary principle, the Commission may nevertheless merely provide serious and conclusive evidence which, without ruling out scientific uncertainty, gives reasonable grounds for doubting the harmlessness of the medicinal product concerned, its therapeutic effect, the existence of a favourable risk-benefit balance or the qualitative and quantitative composition declared (judgments of 3 December 2015, PP Nature-Balance Lizenz v Commission, C‑82/15 P, not published, EU:C:2015:796, paragraph 23; of 7 March 2013, Acino v Commission, T‑539/10, not published, EU:T:2013:110, paragraph 66; and of 19 September 2019, GE Healthcare v Commission, T‑783/17, EU:T:2019:624, paragraph 48).

51      However, the decision to vary, suspend or revoke an MA for a medicinal product is justified only where that decision is substantiated by new, objective, scientific or medical data (judgments of 26 November 2002, Artegodan and Others v Commission, T‑74/00, T‑76/00, T‑83/00 to T‑85/00, T‑132/00, T‑137/00 and T‑141/00, EU:T:2002:283, paragraphs 174, 177 and 191 to 194; of 11 December 2014, PP Nature-Balance Lizenz v Commission, T‑189/13, not published, EU:T:2014:1056, paragraphs 44 and 75; and of 19 September 2019, GE Healthcare v Commission, T‑783/17, EU:T:2019:624, paragraph 49).

52      In that respect, the competent authority is obliged to refer to the main reports and scientific expert opinions on which it relies and to explain, in the event of a significant discrepancy, the reasons why it has departed from the conclusions of the reports or expert opinions supplied by the undertakings concerned. That obligation is particularly strict in cases of scientific uncertainty. The consultation is to be inter partes and transparent in order to ensure that the substance considered has undergone an in-depth and objective scientific assessment, based on using the most representative scientific theories and scientific positions put forward by the relevant pharmaceutical laboratories (judgment of 19 September 2019, GE Healthcare v Commission, T‑783/17, EU:T:2019:624, paragraph 50; see also, to that effect, judgments of 26 November 2002, Artegodan and Others v Commission, T‑74/00, T‑76/00, T‑83/00 to T‑85/00, T‑132/00, T‑137/00 and T‑141/00, EU:T:2002:283, paragraph 200; and of 11 December 2014, PP Nature-Balance Lizenz v Commission, T‑189/13, not published, EU:T:2014:1056, paragraph 52).

53      That being so, it should be recalled, as the applicant accepted in its application, that the Court cannot substitute its own assessment for that of the CHMP. Its power of judicial review is exercised only over the lawfulness of its operation, and over the internal consistency and reasoning of the CHMP’s opinion. With regard to the latter element, the courts may only examine whether the opinion contains a statement of reasons from which it is possible to ascertain the considerations on which the opinion is based, and whether it establishes a comprehensible link between the medical or scientific findings and their conclusions (see, to that effect, judgments of 11 December 2014, PP Nature-Balance Lizenz v Commission, T‑189/13, not published, EU:T:2014:1056, paragraph 52, and of 19 September 2019, GE Healthcare v Commission, T‑783/17, EU:T:2019:624, paragraph 51).

54      It is in the light of those considerations that the applicant’s arguments must be examined. Those arguments relate to the assessment of both the risks and benefits of products containing omega-3 acid ethyl esters, which formed the basis of the contested decision.

55      Since the Commission took the view, in the contested decision, that the MA in each of the Member States concerned had to be varied on the ground that the risk-benefit balance was unfavourable, it is necessary to examine whether, in making that finding, the Commission committed a manifest error of assessment.

56      It should be noted that it is apparent from the documents before the Court that products containing omega-3 acid ethyl esters obtained an MA in 2001, which was based on the results of an open-label study, that is to say, a study in which both the patients and the investigators knew which patients took omega-3 and which patients did not. That 1999 study, entitled GISSI-Prevenzione, concerned the examination of 11 324 patients between 1993 and 1995.

57      As is apparent from the information provided by the Commission, which is not disputed by the applicant, that open-label trial had two co-primary endpoints: the first co-primary endpoint included all-cause death, non-fatal myocardial infarction and non-fatal stroke; and the second co-primary endpoint related to cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.

58      In relation to the first co-primary endpoint, 12.6% of patients on omega-3 had an event corresponding to that endpoint, whereas 13.9% of patients who did not receive omega-3 had such an event. In relation to the second co-primary endpoint, 9.7% of patients on omega-3 had an event corresponding to that endpoint, whereas 10.8% of patients who did not receive omega-3 had such an event.

59      The treatment efficacy of omega-3, although modest, as is apparent from those figures, was regarded nevertheless as sufficient to permit the grant of an MA.

60      The GISSI-Prevenzione study thus states:

‘In this study, there was a relative risk reduction for one of the two primary [major cardiovascular events] MACE endpoint[s] (death, non-fatal … [myocardial infarction] and non-fatal stroke) of 10% with a rather poor precision (upper … [confidence interval] 0.99[%]), whereas for the other primary endpoint including cardiovascular (CV), instead of all-cause death, statistical significance was not achieved.’

61      However, since the GISSI-Prevenzione study new clinical trials have been conducted, from which new data could be extracted and used regarding the efficacy of omega-3 treatment in secondary prevention after an infarction. The scientific conclusions in that regard are set out in Annex II to the CHMP’s opinion and are based on the assessment of the scientific data in the CHMP’s scientific report. According to the contested decision, the Commission relied on the scientific assessment carried out by the CHMP, as is apparent both from that decision and from Annex II thereto.

62      Thus, in so far as, in the present case, the contested decision purely and simply confirms the CHMP’s opinion, which is referred to in recital 4 of the decision, the content of that opinion and also that of the assessment reports on which it is based are an integral part of the statement of reasons for that decision, as regards in particular the scientific assessment of omega-3 acid ethyl esters (see, to that effect, judgments of 18 December 2003, Olivieri v Commission and EMEA, T‑326/99, EU:T:2003:351, paragraph 55, and of 11 June 2015, Laboratoires CTRS v Commission, T‑452/14, not published, EU:T:2015:373, paragraph 60).

63      It is apparent from Annex II to the contested decision that the risk-benefit balance in respect of omega-3 acid ethyl esters is now unfavourable following new studies which, through a more rigorous methodology (the monitoring group, in particular), reached a different conclusion from that reached in the GISSI-Prevenzione study.

64      Contrary to what the applicant claims, the variation of the MA for omega-3 acid ethyl esters should not result from proof of the claim that the GISSI-Prevenzione trial was weak, but must, on the contrary, be based on knowledge of new data which allow the beneficial effect of omega-3 acid ethyl esters in prevention after myocardial infarction to be called into question.

65      It must be stated that the CHMP’s assessment report lists, in point 2.2.1, all the randomised clinical trials that were conducted, including the GISSI-Prevenzione trial, and it is apparent from that report that new studies, including the OMEGA trial, which is also referred to in the contested decision, facilitated the finding that the risk-benefit balance of omega-3 in secondary treatment after myocardial infarction was unfavourable.

66      As is apparent from the CHMP’s assessment report, the OMEGA trial, which began 10 years after the GISSI-Prevenzione trial, was a randomised, placebo-controlled, double-blind multicentre trial conducted in Germany between 2003 and 2007. The objective of that trial was to study the rate of sudden cardiac death in patients who had survived myocardial infarction, by testing one of the effects of medicinal products containing omega-3 acid ethyl esters. One group of patients was treated with omega-3 fatty acids, whilst the other group was given a placebo. For the purposes of that study, the primary endpoint taken into consideration was sudden cardiac death of patients who had previously had a myocardial infarction. Two secondary endpoints were total mortality and major adverse cerebrovascular and cardiovascular events defined as total mortality, re-infarction and strokes in surviving patients.

67      It follows, in particular, from Figure 2 which is set out in the CHMP’s assessment report that sudden cardiac death was observed in 1.5% of patients in both groups, with the result that that identical rate showed that there was no difference between patients who had followed a treatment based on omega-3 fatty acids and those who were treated solely with a placebo.

68      In addition, as regards death from all causes, 4.6% of those deaths were observed in patients on omega-3 and 3.7% in patients given a placebo. Furthermore, major adverse cerebrovascular and cardiovascular events were observed in 10.4% of patients on omega-3 and 8.8% of patients given a placebo.

69      Accordingly, that data highlighted, first, a lack of efficacy or relative efficacy of omega-3 in preventing total mortality and, secondly, the occurrence of major adverse cerebrovascular and cardiovascular events. In those circumstances, the Commission, as it adopted the CHMP’s opinion, did not commit a manifest error of assessment in taking the view, in the contested decision and on the basis of those data, that the OMEGA trial had not made it possible to confirm the results of the GISSI-Prevenzione trial or to establish the efficacy of medicinal products based on omega-3 acid ethyl esters in secondary prevention after myocardial infarction.

70      Unlike the GISSI-Prevenzione study, the OMEGA trial was a placebo-controlled double-blind trial, which meant that neither of the two groups, nor the investigators and the staff of the promoter or of the instigator, knew the treatment assigned to each of the patients subject to the OMEGA trial, which, according to the CHMP, constituted an advantage over the GISSI-Prevenzione study.

71      In that regard, in its assessment report, the CHMP wrote as follows:

‘However, ignoring double blind by using no treatment as comparator (as in GISSI-P[revenzione]) ignores another important concept in clinical trials, i.e. the use of a (blinded) comparator in order to control the … effects [other] than [those arising from] the investigational drug, and deviation [from this] principle should only be needed or suitable “when it is difficult or impossible to avoid” (ICH E10 guideline on Choice of control group in clinical trials).’

72      Those scientific considerations, which appear in the CHMP’s assessment report, which were endorsed in the contested decision and which were referred to by the Commission before the Court, were also not disputed by the applicant in its reply.

73      Furthermore, as is apparent from the CHMP’s assessment report, the standard treatment for secondary prevention after myocardial infarction has substantially evolved since the GISSI-Prevenzione trial was conducted. In that trial, at most 5% of the patients received lipid-lowering therapy before receiving omega-3. Furthermore, although statin use increased during the trial, only 28% to 29% of patients at 6 months and 44% to 46% at 42 months were on statins. Beta-blockers, which are prescribed for most patients after myocardial infarction, were used in only 37% to 44% of patients in that trial.

74      On the other hand, as is also apparent from the CHMP’s assessment report, ‘the OMEGA trial started 10 years after the GISSI-P[revenzione] trial, and the management of MI patients [patients who had undergone a myocardial infarction] ha[s] advanced considerably over this period’. Furthermore, ‘dissimilar to [the] GISSI-P[revenzione] [trial], almost all patients received statins, beta-blockers and antiplatelet drugs’.

75      Nor have those findings been challenged by the applicant in response to the arguments put forward by the Commission.

76      Lastly, the applicant has also not challenged the three other trials conducted since the GISSI-Prevenzione trial, namely the GISSI-HF, Origin and SU.FOL.OM studies, which were conducted between 2003 and 2012, and the meta-analysis carried out in 2018 by Aung et al, the results of which also appear in the CHMP’s assessment report.

77      In that regard, the applicant cannot merely claim that the OMEGA trial was not sufficiently substantiated and that ‘the set of new data on which the European Commission relies to adopt the contested decision is insufficient and cannot be considered to provide serious and conclusive evidence to conclude on the efficacy of Omacor in the prevention of myocardial infarction’. Indeed, the applicant relies only on general considerations, which, in reality, consist of mere assertions.

78      It should be borne in mind that, as is apparent from the settled case-law referred to in paragraph 53 above, the Court’s power of judicial review is exercised only over the lawfulness of the CHMP’s operation, and over the internal consistency and reasoning of the CHMP’s opinion.

79      Thus, in the present case, the applicant cannot merely make vague and imprecise assertions that a study is unsubstantiated. On the contrary, it must either highlight the lack of internal consistency of the CHMP’s opinion or its reasoning in relation to that study, or demonstrate, which it has failed to do, that that study lacked probative value or relevance for the purposes of the re-examination of the MA previously granted.

80      Furthermore, the applicant claims not only that the CHMP considered that Omacor’s safety profile remained positive, but also that there is no evidence in the CHMP’s final assessment report to support the conclusion that that product is no longer therapeutically effective in any of the therapeutic indications for which it is authorised.

81      In that regard, it should be noted that, since the applicant does not refer to a specific part of the CHMP’s report in order to corroborate the fact that Omacor’s safety profile remained positive, it is once again only an unsupported assertion, an assertion which is contradicted, in particular, by Annex II to the contested decision, according to which, ‘in view of all the available data, the CHMP considered that the evidence that supported the authorisation of omega-3 in secondary prevention after MI [myocardial infarction] suffered from some methodological limitations and was weak [and that] the efficacy in th[at] indication was not demonstrated in subsequent and more robust clinical trials’. The applicant cannot therefore claim, without adducing tangible evidence in support of its claims, that Omacor’s safety profile remained positive.

82      Moreover, it must be pointed out that, in any event, the variation of the MA was not upheld, in the contested decision, because of the alleged lack of therapeutic efficacy of omega-3 acid ethyl esters, but because the risk-benefit balance was now regarded as unfavourable.

83      It also follows from the foregoing that, contrary to the applicant’s assertion that the CHMP does not have power to give an ex post facto opinion in the context of a trial that the initial assessor, with substantially greater and more appropriate resources at its disposal, considered to be adequate for the purposes of supporting an MA for Omacor, it is, on the contrary, for the CHMP to take all the necessary measures on the basis of new analyses and recent data allowing re-examination and, if necessary, to test the relevance of keeping the MA initially granted in place.

84      In that regard, contrary to what is claimed by the applicant, the grant of an MA cannot have the effect of ‘freezing’ the situation and preventing the CHMP from calling into question the MA thus granted, since the issue of the grant of the MA is before that committee and since analyses, publications or any other documentation make it possible to find, in the context of that referral, that the conditions for granting the MA are no longer met, in particular on account of the risk-benefit balance which has tipped to the point where it has now become unfavourable.

85      While it is true, as the applicant notes, that, once an MA has been granted to a medicinal product, it is for the CHMP to demonstrate that the risk-benefit balance is unfavourable, that does not prevent the CHMP from being able, on the basis of the factors referred to in paragraph 84 above and in order not to deprive the first paragraph of Article 116 of Directive 2001/83 of any effect, to draw conclusions different from those which justified the grant of the earlier MA which is the subject of re-examination by the CHMP.

86      In the reply, the applicant added that, in its defence, the Commission had referred to ‘well-documented safety concerns’ which justified the variation of the MA granted, although the existence of such safety concerns is not apparent from the CHMP’s assessment report. It follows, according to the applicant, that the Commission relied on considerations other than those set out in that assessment report, so that its position differs from that of the CHMP. The Commission therefore based the contested decision on information that had not previously been made available either to the CHMP or to the applicant.

87      Thus, according to the applicant, it cannot be maintained that the Commission followed the opinion of the CHMP even though at the same time it reached a different conclusion regarding the safety of omega-3 fatty acid medicinal products. The Commission may either follow in full the opinion of the CHMP or depart from it. However, if it departs from the opinion, it must state the reasons justifying that divergence. Furthermore, the applicant requests the Court, first, to adopt measures instructing the Commission to produce the information on which it relied in order to conclude that there were ‘well-documented safety concerns’ regarding the products, next, to invite the Commission to reply to certain questions relating to that conclusion and, lastly, to adopt measures of inquiry for the purposes of disclosing that information.

88      In that regard, contrary to what the applicant claims, no divergence can be found between the contested decision and the reasoning adopted by the Commission in the present proceedings.

89      As the Commission states, the fact that the CHMP found that the safety profile of Omega-3 seemed to be well characterised and that no new safety concerns relating to Omega-3 had been raised does not imply that the CHMP found that there were no safety concerns in respect of Omega-3, as those concerns were identified in the assessment report.

90      The CHMP’s assessment report contains the following findings:

‘Omega-3 fatty acid should be used with caution in patients with known sensitivity or allergy to fish …

The most frequent undesirable effects (Common ≥ 1/100 to < 1/10) are gastrointestinal disorders including abdominal distension, abdominal pain, constipation, diarrhoea, dyspepsia, flatulence, eructation, gastro-oesophageal reflux disease, nausea or vomiting.

…

In the last PSUSA for omega-3-acid-ethyl esters of omega-3 acids, “increase in bleeding time in patients with haemorragic diathesis or receiving treatment with anticoagulants” and “increase in hepatic enzymes that require monitoring in hepatic patients” w[ere] included as identified risks.’

91      It also follows from Annex II to the final opinion of the CHMP that:

‘With respect to safety, the PRAC concluded, in the last PSUSA (January 2017) that no new safety issues had emerged. In general, it can be concluded that the safety profile seems well characterised. As discussed above, in the last PSUSA for omega-3-acid-ethyl esters, “increase in bleeding time in patients with haemorrhagic diathesis or receiving treatment with anticoagulants” and “increase in hepatic enzymes that require monitoring in hepatic patients” w[ere] included as identified risks. The increase in bleeding time may be relevant for patients post MI [myocardial infarction] most of which are on single or dual antiplatelet therapy and/or on anticoagulants post MI [myocardial infarction] or for associated diseases.’

92      As the Commission rightly points out, the finding that the ‘safety profile of omega-3 is well-documented’, which is set out following the description of all the relevant risks, cannot be interpreted as meaning that omega-3 has no risks, but as a confirmation of the data concerning omega-3, including those relating to its risks, an analysis which is, moreover, indispensable in the examination of the profile of a medicinal product and its inherent risk-benefit balance. Indeed, the determination of a risk-benefit balance necessarily implies that the risks associated with the use of a medicinal product must be weighed against the advantages, in terms of efficacy, that the medicinal product is capable of procuring for the patients for whom it is intended.

93      Although, prior to the adoption of the contested decision, the safety concerns in respect of omega-3 acid ethyl esters were regarded as being offset by the advantages which they provided in terms of their efficacy, the additional examinations enabled the CHMP to highlight, in the risk-benefit balance, the lack of benefits of omega-3 acid ethyl esters in secondary prevention treatment after myocardial infarction in the light, moreover, of the risks they presented, which were sufficiently documented.

94      The applicant is therefore wrong to claim that there is a discrepancy between the Commission’s position and that which is set out in the contested decision or even between the position adopted by the CHMP and the contested decision.

95      In light of the foregoing considerations, it is not necessary, in that regard, to order measures of inquiry or to put questions to the Commission in order to determine the factors on which the Commission relied in order to adopt an allegedly different position from that of the CHMP or from that adopted in the contested decision.

96      Furthermore, in the reply, the applicant relied on a new meta-analysis, entitled ‘Marine Omega-3 supplementation and cardiovascular disease: an updated meta-analysis of 13 randomised controlled trials involving 127 477 participants’, concerning the effects of medicinal products containing omega-3 acid ethyl esters on the reduction of cardiovascular diseases. The applicant requests the Court to take account of that study, which was not annexed to the application, on the ground that it was published after the applicant brought its action on 9 July 2019.

97      According to the applicant, that meta-analysis demonstrates the relevance of omega-3 acid ethyl esters on the reduction of cardiovascular diseases, in so far as it was observed that marine omega-3 supplementation led to statistically significant risk reductions of myocardial infarction at a fixed point in time and that risk reductions appeared to be linearly related to omega-3 dosage. In addition, after conducting sensitivity analyses that excluded open-label studies, the point estimates remained unchanged for most of the endpoints for cardiovascular disease.

98      In that regard, it should be borne in mind that, as held in paragraph 53 above, the Court cannot substitute its own assessment for that of the CHMP. Its power of judicial review is exercised only over the lawfulness of its operation, and over the internal consistency and reasoning of the CHMP’s opinion. With regard to the latter element, the courts may only examine whether the opinion contains a statement of reasons from which it is possible to ascertain the considerations on which the opinion is based, and whether it establishes a comprehensible link between the medical or scientific findings and their conclusions.

99      It follows that the Court cannot take into consideration evidence other than that available to the CHMP at the time when it issued its opinion and the Commission at the time of the contested decision. Thus, the Court cannot assess the lawfulness of that decision in the light of the observations and documents submitted by the applicant after the adoption of that decision. Consequently, the lawfulness of the contested decision cannot be examined by taking into consideration new information arising after its adoption.

100    Lastly, contrary to what the applicant claims, since, relying on the CHMP’s opinion, the Commission was entitled to consider that the risk-benefit balance was unfavourable, there is no need to examine the arguments seeking to demonstrate that the medicinal product is not harmful, that therapeutic efficacy is not lacking and that the qualitative and quantitative composition of the medicinal product is as declared.

101    Since, as is apparent from paragraph 46 above, the conditions of the first paragraph of Article 116 of Directive 2001/83 are alternative and not cumulative, it is sufficient that one of those conditions is satisfied in order for the competent authorities to be able to suspend, withdraw or vary an MA.

102    It follows that the applicant’s arguments that the medicinal product is not harmful, that therapeutic efficacy is not lacking  and that the qualitative and quantitative composition of the medicinal product is as declared are ineffective.

103    It follows from all the foregoing that the first plea in law must be rejected, without it being necessary, as requested by the applicant, to order the Commission to provide the information on which it relied in order to conclude that there were ‘well-documented safety concerns’ concerning the products, or to request the Commission to reply to certain questions relating to that conclusion, or to adopt measures of inquiry for the purposes of disclosing that information.

 Second plea in law, alleging breach of the principle of proportionality

104    The applicant submits that, in order not to infringe the principle of proportionality, the Commission should have adopted the measures necessary in the circumstances of the present case and which were appropriate in order to attain the objective pursued.

105    The applicant also argues that the Court should add another element to its examination of whether the principle of proportionality was observed, in that the Commission should have selected the least onerous measure to achieve a specific objective.

106    According to the applicant, even if there had been concerns regarding the efficacy or the risk-benefit balance of Omacor, the Commission would have been required to consider measures that could or would have addressed those concerns and which would have been less restrictive than those adopted in the contested decision.

107    The Commission contends that that plea must be rejected.

108    It should be borne in mind that it has been consistently held that the principle of proportionality is one of the general principles of EU law. In accordance with that principle, acts of the institutions of the European Union must not exceed the limits of what is appropriate and necessary in order to attain the objectives legitimately pursued by the measure in question; where there is a choice between several appropriate measures, recourse must be had to the least onerous, and the disadvantages caused must not be disproportionate to the aims pursued (judgments of 13 November 1990, Fedesa and Others, C‑331/88, EU:C:1990:391, paragraph 13; of 5 May 1998, United Kingdom v Commission, C‑180/96, EU:C:1998:192, paragraph 96; and of 11 December 2014, PP Nature-Balance Lizenz v Commission, T‑189/13, not published, EU:T:2014:1056, paragraph 111).

109    As regards judicial review of those conditions in the present case, it must be stated that the EU legislature has a discretion in this area, so that, according to settled case-law, decisions concerning the application of the criteria of efficacy, safety and quality of a medicinal product are the result of complex assessments in the medico-pharmacological field, which are subject to limited judicial review. Where an EU institution is called upon to make complex assessments it enjoys a wide measure of discretion, the exercise of which is subject to a judicial review restricted to verifying that the measure in question is not vitiated by a manifest error or a misuse of powers and that the competent authority did not clearly exceed the bounds of its discretion (see judgments of 21 January 1999, Upjohn, C‑120/97, EU:C:1999:14, paragraph 34 and the case-law cited, and of 11 December 2014, PP Nature-Balance Lizenz v Commission, T‑189/13, not published, EU:T:2014:1056, paragraph 34 and the case-law cited).

110    In the present case, it must at this juncture be pointed out that the applicant does not refer to any measure that would have been less restrictive than the withdrawal of the MA for medicinal products containing omega-3 acid ethyl esters in secondary prevention following infarction. On the other hand, it submits that it is apparent from the analysis which it carried out that the CHMP and the Commission, in the contested decision, have not demonstrated that, unlike the situation in 2001, when the medicinal product was authorised for the first time for use in post-myocardial infarction indication, that medicinal product is now devoid of therapeutic effect or that the risk-benefit balance of that medicinal product is no longer favourable.

111    Thus, even though the applicant states, in its reply, that it did not submit that the CHMP failed to consider taking less restrictive alternative measures, but that it infringed the principle of proportionality by varying the existing MA for Omacor by removing the indication for oral use in secondary prevention after myocardial infarction, it merely relies on the infringement of that principle without in any way indicating the existence of any less restrictive measures which could have been implemented in the light of a situation in which the risk-benefit balance of omega-3 acid ethyl esters was considered to be unfavourable in secondary prevention after myocardial infarction.

112    In any event, it must be borne in mind that the first paragraph of Article 116 of Directive 2001/83 requires the competent authorities to suspend, withdraw or vary the MA where the risk-benefit balance is regarded as negative (see paragraph 7 above) and that, consequently, in the circumstances of the present case, the measure seeking variation of the MA initially authorised appears, in the absence of any indication from the applicant on that point, the least restrictive measure for the medicinal products concerned which may continue to be prescribed for uses other than secondary prevention after myocardial infarction.

113    Thus, in the present case, since, as was held in the examination of the first plea, the Commission did not make a manifest error of assessment as regards the risk-benefit balance in question, it could, without infringing the principle of proportionality, consequently decide to require the withdrawal of the MA for medicinal products containing omega-3 acid ethyl esters in respect of secondary prevention after myocardial infarction.

114    It follows from the foregoing that the second plea in law must be rejected and the action dismissed in its entirety.

 Costs

115    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 pleading. Since the applicant has been unsuccessful, it must be ordered to pay the costs, including those incurred in the proceedings for interim measures, in accordance with the form of order sought by the Commission.

On those grounds,

THE GENERAL COURT (Eighth Chamber)

hereby:

1.      Dismisses the action;

2.      Orders BASF AS to pay the costs, including the costs relating to the interlocutory proceedings.

Delivered in open court in Luxembourg on 23 September 2020.

*      Language of the case: English.

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