JUDGMENT OF THE GENERAL COURT (Sixth Chamber)
28 October 2020 (*)
(Medicinal products for human use — Application for marketing authorisation for the medicinal product Aplidin — plitidepsin — Commission decision refusing authorisation — Regulation (EC) No 726/2004 — Scientific evaluation of the risks and benefits of a medicinal product — Committee for Medicinal Products for Human Use — Objective impartiality)
In Case T‑594/18,
Pharma Mar, SA, established in Colmenar Viejo (Spain), represented by M. Merola and V. Salvatore, lawyers,
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(2018) 4831 final of 17 July 2018 refusing marketing authorisation under Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (OJ 2004 L 136, p. 1) for Aplidin — plitidepsin, a medicinal product for human use,
THE GENERAL COURT (Sixth Chamber),
composed of A. Marcoulli (Rapporteur), President, S. Frimodt Nielsen and R. Norkus, Judges,
Registrar: P. Cullen, Administrator,
having regard to the written part of the procedure and further to the hearing on 12 March 2020,
gives the following
Judgment
Background to the dispute
1        The applicant, Pharma Mar, SA, is a company operating in the oncology research sector. On 16 November 2004, it obtained designation of the medicinal product Aplidin, the active substance of which is plitidepsin, as an orphan medicinal product for the treatment of multiple myeloma, a serious cancer of the bone marrow, 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).
2        With a view to making an application for marketing authorisation for Aplidin, the applicant sought and obtained from the European Medicines Agency (‘the EMA’), pursuant to Article 6(1) of Regulation No 141/2000, protocol assistance in relation to the conduct of tests and trials necessary to demonstrate the quality, safety and efficacy of Aplidin.
3        On 21 September 2016, the applicant submitted to the EMA an application for marketing authorisation for Aplidin, pursuant to Article 4 of Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (OJ 2004 L 136, p. 1). The application related to the following indication: ‘in combination with dexamethasone for the treatment of relapsed/refractory multiple myeloma in adult patients who have received at least three prior regimens including bortezomib, and either lenalidomide or thalidomide’.
4        The procedure for the EMA’s assessment of the application for marketing authorisation commenced on 27 October 2016. During that procedure, the Committee for Medicinal Products for Human Use (‘the CHMP’), which is responsible, under Article 5(2) of Regulation No 726/2004, for drawing up the EMA’s opinion on any matter concerning, inter alia, the granting of marketing authorisation for a medicinal product for human use, compiled an initial list of questions for the applicant on 9 March 2017, a list of outstanding issues on 18 September 2017 and, finally, a second list of outstanding issues on 16 November 2017. Two meetings for the applicant’s oral explanations were organised on 7 November 2017 and 12 December 2017.
5        In addition, at the CHMP’s request, the Biostatistics Working Party delivered an opinion on 6 December 2017 concerning the acceptability and validity of the sensitivity analyses submitted by the applicant in order to evaluate the effect of changing treatment arms, that is to say, of transferring part of the patients tested from one treatment to another.
6        On 14 December 2017, the CHMP issued an opinion recommending that the European Commission reject the application for marketing authorisation for Aplidin. The opinion was based on the fact that the efficacy and safety of the product were not sufficiently demonstrated and that, therefore, the benefits did not outweigh the risks.
7        On 3 January 2018, the applicant submitted to the EMA a request for re-examination of the CHMP’s opinion and then, on 14 February 2018, submitted the detailed grounds for its request, pursuant to Article 9(2) of Regulation No 726/2004. It also requested that, as part of the re-examination, the EMA consult a scientific advisory group, in accordance with Article 62(1) of Regulation No 726/2004.
8        The re-examination procedure began on 15 February 2018. On 7 March 2018, a meeting was held of the Scientific Advisory Group for Oncology (‘the SAG’), which consisted of five core members, six additional experts and two patient representatives. On 19 March 2018, the SAG replied to the various questions which had been put to it.
9        On 21 March 2018, the applicant presented its oral submissions before the CHMP. On 22 March 2018, the CHMP upheld its opinion of 14 December 2017 and a draft Commission decision rejecting the application for marketing authorisation was drawn up.
10      The draft decision was discussed by the Standing Committee on Medicinal Products for Human Use set up by Article 121 of 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 assists the Commission pursuant to Article 87 of Regulation No 726/2004. Under Article 10(3)(c) of that regulation, at the request of the Kingdom of Spain, that discussion took place during a plenary meeting of that committee. The committee issued an opinion in favour of the draft.
11      On 17 July 2018, the Commission adopted Implementing Decision C(2018) 4831 final refusing marketing authorisation for Aplidin — plitidepsin (‘the contested decision’). That decision includes an annex headed ‘Scientific conclusions and grounds for refusal presented by the [EMA]’, which is consistent with the CHMP’s opinion.
Procedure and forms of order sought
12      By application lodged at the Court Registry on 1 October 2018, the applicant brought the present action.
13      On 20 December 2018, the Commission filed its defence.
14      The reply and the rejoinder were lodged by the parties on 25 March 2019 and 22 May 2019, respectively.
15      By letter of 24 June 2019, the applicant submitted a request for a hearing under Article 106(2) of the Rules of Procedure of the General Court.
16      Following a change in the composition of the Chambers of the Court, the Judge-Rapporteur was assigned to the Sixth Chamber, to which the present case was accordingly allocated.
17      On a proposal from the Judge-Rapporteur, the Court (Sixth Chamber) decided to open the oral part of the procedure and, by way of measures of organisation of procedure provided for in Article 89 of its Rules of Procedure, put a number of questions to the parties, to be answered in writing. The parties complied with those measures within the prescribed period.
18      The parties presented oral argument and answered the questions put to them by the Court at the hearing on 12 March 2020.
19      By way of a measure of organisation of procedure, and taking account of the fact that, owing to the COVID-19 health crisis, some of the applicant’s advisers were not at the hearing, the Court granted the applicant the opportunity to supplement its answers to certain questions that were put to it at the hearing. The applicant complied with that measure within the period prescribed and, on 24 June 2020, the Commission submitted its observations on the answers sent by the applicant.
20      By way of a measure of organisation of procedure, the Commission was asked to reply to one question put to it by the Court. It complied with that measure on 9 July 2020, within the prescribed period.
21      The oral part of the procedure was concluded on 14 July 2020 and the request for it to be reopened submitted by the applicant on 17 July 2020 was not granted.
22      The applicant claims that the Court should:
–        annul the contested decision;
–        order the Commission to pay the costs.
23      The Commission contends that the Court should:
–        dismiss the application;
–        order the applicant to pay the costs.
Law
24      It should be noted at the outset that the EMA, which was established by Regulation No 726/2004, has as its main task the protection and promotion of public and animal health through the evaluation and supervision of medicinal products for human and veterinary use. According to the first subparagraph of Article 57(1) of that regulation, the EMA is to provide the Member States and the institutions of the European Union with the best possible scientific advice on any question relating to the evaluation of the quality, safety and efficacy of medicinal products for human or veterinary use which is referred to it. The EMA is responsible for, inter alia, coordinating the scientific evaluation of the quality, safety and efficacy of medicinal products which are subject to EU marketing authorisation procedures.
25      As regards applications for marketing authorisation for medicinal products for human use in the European Union that are submitted under the centralised procedure laid down by Regulation No 726/2004, that procedure involves the pharmaceutical company concerned submitting an application, which is the subject of an examination and an opinion on the part of the EMA, and the Commission issuing a decision on the marketing authorisation.
26      As regards the EMA’s opinion, it is clear from recital 23 and Article 5(2) of Regulation No 726/2004 that ‘exclusive responsibility’ for preparing it is conferred on the CHMP.
27      Under Article 56(2) of Regulation No 726/2004, the CHMP may establish standing and temporary working parties and also scientific advisory groups in connection with the evaluation of specific types of medicinal products or treatments to which it may delegate certain tasks associated with drawing up the scientific opinions on the application for marketing authorisation.
28      The CHMP’s final opinion, accompanied by a report describing its assessment of the medicinal product and stating the reasons for its conclusions, is to be sent to the Commission, the Member States and the applicant, in accordance with Article 9(3) of Regulation No 726/2004.
29      Under Article 10 of Regulation No 726/2004, the Commission, assisted by the Standing Committee on Medicinal Products for Human Use, set up under Article 121 of Directive 2001/83, is to prepare a draft decision within 15 days after receipt of the CHMP’s opinion. The draft decision is to be forwarded to the Member States and the applicant. The Commission is then to take a final decision in accordance with the procedure referred to in Article 87(3) of Regulation No 726/2004, which may differ from the CHMP’s opinion. In that situation, the Commission is to attach an annex setting out in detail the reasons for the differences.
30      In the present case, Article 1 of the contested decision states that the application for marketing authorisation is refused on the basis of the scientific conclusions set out in the annex to that decision, that is to say, the CHMP’s opinion and the assessment report on which it is based.
31      In so far as the contested decision taken by the Commission purely and simply confirms the EMA’s opinion drawn up by the CHMP, it follows from case-law that the content of that opinion, and also that of the assessment report upon which it is based, are an integral part of the statement of reasons for that decision, as regards in particular the scientific assessment of the medicinal product in question (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).
32      In support of the form of order sought in the application, the applicant raises five pleas in law, alleging, first, breach of the obligation requiring impartial examination of the application for marketing authorisation by the members of the SAG; second, breach of the principle of good administration; third, infringement of Article 12 of Regulation No 726/2004 and breach of the principle of equal treatment; fourth, infringement of the duty to state reasons; and, fifth, infringement of the rights of the defence.
33      The first plea is divided into two parts. The first part alleges a lack of impartiality on the part of certain members of the SAG.
34      The applicant states that the impartiality requirements applicable to the EU institutions extend to the experts consulted by those institutions and that the requirement that those experts are impartial is especially important since the contested decision is based on complex, technical assessments.
35      The applicant contests the participation in the vote of two experts of the SAG on the ground that, according to the document headed ‘Mandate, objectives and rules of procedure for the Inter-Committee Scientific Advisory Group (SAG) for Oncology’ of 25 April 2014 (‘the rules applicable to the SAG’) and the document headed ‘[EMA] policy on the handling of competing interests of scientific committees’ members and experts’ of 6 October 2016 (‘the policy of 6 October 2016’), they declared interests that are incompatible with an impartial assessment of the application for marketing authorisation, which should have led to their exclusion from the SAG.
36      The first of those experts is a professor, vice-chairperson of the SAG and one of the five core members, who was employed by a university institute (‘the institute’), a renowned educational establishment in the medical field. According to the applicant, the institute exercises a significant influence over the university hospital of the same name (‘the university hospital’) and over a professional clinical research centre, which should be classified as clinical research organisations and, therefore, pursuant to Section 3.2.2 of the policy of 6 October 2016, treated as pharmaceutical companies. On account of that influence, the institute is not caught by the exclusion granted to research institutes and should itself be classified as a pharmaceutical company for the purposes of assessing conflicts of interest. The applicant also claims that the institute is closely involved in the development of the medicinal product CellProtect, which is indicated for the treatment of multiple myeloma.
37      According to the applicant, the declared interests of a second professor, one of the six additional experts of the SAG, should likewise have precluded his participation in the SAG because he is an employee of the institute. The applicant adds that, in view of the particular circumstances of the present case connected with the current and multiple interests of that professor in the development of rival products to the medicinal product Aplidin, the EMA should have applied the policy of 6 October 2016 more strictly, since that policy relates solely to the declaration of interests in the medicinal product being examined and not in rival products.
38      In the reply, the applicant states that the EMA did not examine whether the economic activities pursued by the experts in question were compatible with their mandate within the SAG, even though information about those activities was publicly available. It adds that the EMA rules which seek to prevent conflicts of interest are inadequate, particularly as regards the examination of an orphan medicinal product.
39      The Commission notes that the applicant disputes the objective impartiality of the SAG. It contends that, since the SAG is not directly involved in the decision-making regarding the application for marketing authorisation, its lack of impartiality, even if it were established, would not affect the CHMP’s assessment or the legality of the contested decision. In particular, the Commission contends that the distinction between the scientific evaluation, which falls within the EMA’s mandate, and the decision-making, which is a matter for the Commission, already is a guarantee that the evaluation is impartial. It also relies on the fact that the SAG is merely a consultative body, that its involvement in the process is not obligatory, and that, in the present case, the SAG became involved at the applicant’s request.
40      With regard to the participation of certain members of the SAG in the ‘voting session’, the Commission states that SAG members do not vote but only draw conclusions and that they are not involved in the CHMP’s deliberations. It adds that the procedure set out in the policy of 6 October 2016 was fully complied with and correctly applied as regards the two experts in question. It submits that the main purposes of the institute and of the university hospital are, respectively, those of a medical university and medical research centre and those of a hospital participating in medical research and education. On that ground, they are both excluded from the definition of a pharmaceutical company set out by the policy of 6 October 2016, on the basis of the last paragraph of that definition. In addition, according to the Commission, the applicant has not proven that those bodies exercise, for the purpose of the third paragraph of the definition, a significant influence in the decision-making processes of pharmaceutical companies, in the present case a professional clinical research centre and a production unit for advanced therapy medicinal products. In the Commission’s view, the fact that that centre and unit are located on the university hospital premises does not prove such influence. It adds that the fact that the university hospital and the institute are involved in the clinical trials of CellProtect, a rival medicinal product to Aplidin, does not make those establishments in their entirety pharmaceutical companies within the meaning of the policy of 6 October 2016. It also states that the applicant has not proven that the university hospital and the institute exercise a significant influence over the company responsible for CellProtect. Accordingly, the Commission concludes that the two experts in question declared their interests properly and that they were permitted to participate fully in the SAG. In the rejoinder, the Commission adds that the plea in law, raised in the reply, alleging that the policy of 6 October 2016 is insufficient is new and therefore inadmissible.
41      The Commission also states that, in striking a balance between preventing conflicts of interest and sourcing the necessary expertise, the policy of 6 October 2016 does not provide for restrictions on participating in SAG meetings based on interests relating to rival products to the product being examined or for specific rules on orphan medicinal products.
42      As a preliminary observation, it should be recalled that the institutions, bodies, offices and agencies of the Union are obliged to observe the fundamental rights guaranteed by EU law.
43      According to well-established case-law, where the institutions, bodies, offices and agencies of the Union have a wide discretion, observance of the guarantees conferred by the EU legal order in administrative procedures is of even more fundamental importance (judgments of 21 November 1991, Technische Universität München, C‑269/90, EU:C:1991:438, paragraph 14, and of 6 November 2008, Netherlands v Commission, C‑405/07 P, EU:C:2008:613, paragraph 56). Those guarantees include, inter alia, the right to sound administration enshrined in Article 41 of the Charter of Fundamental Rights of the European Union (see judgment of 27 March 2019, August Wolff and Remedia v Commission, C‑680/16 P, EU:C:2019:257, paragraph 24 and the case-law cited).
44      Article 41(1) of the Charter of Fundamental Rights states, inter alia, that every person has the right to have his or her affairs handled impartially by the institutions, bodies, offices and agencies of the Union.
45      In that regard, it should be noted that the need for impartiality, required of the institutions, bodies, offices and agencies in carrying out their tasks, is intended to guarantee equality of treatment, which is at the heart of the European Union. That requirement is intended, inter alia, to avoid a situation where there could be a conflict of interest on the part of officials or agents acting on behalf of those institutions, bodies, offices and agencies. Having regard to the fundamental importance of ensuring the independence and probity of EU institutions, bodies, offices and agencies as regards both their internal functioning and external reputation, the requirement of impartiality covers all circumstances which an official or agent who is called upon to decide on an issue must reasonably regard as being of such a nature as to be viewed by third parties as a possible source of impairment of his or her independence in that matter (see judgment of 27 March 2019, August Wolff and Remedia v Commission, C‑680/16 P, EU:C:2019:257, paragraph 26 and the case-law cited).
46      Accordingly, it is incumbent upon those institutions, bodies, offices and agencies to comply with both components of the requirement of impartiality, which are, first, subjective impartiality, by virtue of which no member of the institution concerned may show bias or personal prejudice, and second, objective impartiality, under which there must be sufficient guarantees to exclude any legitimate doubt as to possible bias on the part of the institution concerned (see judgment of 27 March 2019, August Wolff and Remedia v Commission, C‑680/16 P, EU:C:2019:257, paragraph 27 and the case-law cited).
47      In the present case, the applicant does not claim that the two SAG experts in question showed bias or personal prejudice. The applicant’s arguments must therefore be regarded as seeking to establish a lack of objective impartiality resulting from the two experts’ conflicts of interest. According to the applicant, those conflicts of interest should have led to the experts being excluded from the SAG meeting under the terms of the policy of 6 October 2016 or the more general principle of impartiality.
48      Against that background, it is necessary to examine, first, the claim that the two experts in question had conflicts of interest and then, if required, its bearing on the validity of the procedure that led to the adoption of the contested decision (see, to that effect, judgment of 19 September 2019, GE Healthcare v Commission, T‑783/17, EU:T:2019:624, paragraph 180).
The claim that there were conflicts of interest
49      First of all, it should be noted that, under Article 63(2) of Regulation No 726/2004:
‘Members of the Management Board, members of the committees, rapporteurs and experts shall not have financial or other interests in the pharmaceutical industry which could affect their impartiality. They shall undertake to act in the public interest and in an independent manner, and shall make an annual declaration of their financial interests. All indirect interests which could relate to this industry shall be entered in a register held by the Agency which is accessible to the public, on request, at the Agency’s offices.
The Agency’s code of conduct shall provide for the implementation of this Article with particular reference to the acceptance of gifts.
Members of the Management Board, members of the committees, rapporteurs and experts who participate in meetings or working groups of the Agency shall declare, at each meeting, any specific interests which could be considered to be prejudicial to their independence with respect to the items on the agenda. These declarations shall be made available to the public.’
50      Section 7.5 of the rules applicable to the SAG sets out the guarantees of independence of the SAG experts. It reiterates, in essence, Article 63(2) of Regulation No 726/2004 and states that the policy of 6 October 2016 is applicable to the SAG experts.
51      The policy of 6 October 2016 sets out, in section 4.1, its objectives, namely to strike the right balance between preventing conflicts of interest and providing the best expertise for the evaluation and supervision of medicinal products in the European Union. Section 4.2.1.2 provides that involvement of the individual in the EMA’s activities is restricted taking into account three factors, namely the nature of the declared interest, the timeframe during which such an interest occurred, and the type of activity. The last of those criteria involves taking into account the group in which the individual is involved (scientific committee, such as the CHMP, working party or scientific advisory group) as well as his or her duties (inter alia, chairperson, vice-chairperson, member or expert). Those restrictions are set out in a table in an annex to the policy of 6 October 2016.
52      According to section 4.2.1.2 of the policy of 6 October 2016, employment by a pharmaceutical company during the term of the mandate or assignment within the EMA or the existence of financial interests in the pharmaceutical industry is incompatible with involvement in the EMA’s activities.
53      In addition, section 3.2.2 of the policy of 6 October 2016 defines a pharmaceutical company as:
‘any legal or natural person whose focus is to research, develop, manufacture, market and/or distribute medicinal products. For the purpose of this policy, the definition includes companies to which activities relating to the research, development, manufacturing, marketing and maintenance of medicinal products (which might also be carried out in house) are outsourced on a contract basis.
In this regard CROs [clinical research organisations] or consultancy companies providing advice or services relating to the above activities, fall under the definition of a pharmaceutical company.
Legal or natural persons which do not fall within the scope of the above definition but (i) control (i.e. own a majority stake in, or otherwise exercise a significant influence in the decision-making processes of the relevant pharmaceutical company), (ii) are controlled by or (iii) are under common control of a pharmaceutical company, shall be considered as pharmaceutical companies for the purposes of this policy.
Independent researchers and research organisations including universities and learned societies are excluded from the scope of the present definition.’
54      The applicant submits that the institute, the employer of the two SAG experts in question, exercises a significant influence in decision-making processes of pharmaceutical companies, within the meaning of the policy of 6 October 2016, namely the university hospital and a professional clinical research centre. Furthermore, the applicant submits that the institute is closely involved in the development of CellProtect, a rival medicinal product to Aplidin. According to the applicant, the institute should have been regarded, for the purposes of implementing the policy of 6 October 2016, as a pharmaceutical company and the experts in question, as employees of the institute, should have been regarded as having financial interests in a pharmaceutical company and, therefore, excluded from the SAG.
55      In that regard, first, it should be noted that the applicant does not dispute the sincerity of the declarations of interest made by the experts in question, but takes issue with the EMA’s assessment of them, which it submits was incomplete, particularly having regard to information that was publicly available, such as information on the institute’s website.
56      Second, it is apparent from the declarations of interest made by the experts in question that the first stated he was employed by the institute and the second gave, as his employer, the name of the institute and the university hospital without specifying whether he was employed by one and/or the other. The Commission, in its reply to the written questions put to it by the Court, stated that, at the date of the SAG meeting, and as was apparent from the curricula vitae of the individuals in question, the first professor was employed by the institute, where he held a professorship, and by the university hospital, where he was a consultant in oncology. Similarly, the second professor was employed by both the institute and the university hospital where he was a specialist in haematology.
57      Third, in so far as the applicant submits that the university hospital, which is one of the employers of the experts in question, should be classified as a pharmaceutical company within the meaning of the policy of 6 October 2016, it is apparent from the material before the Court that that hospital is one of the largest university hospitals in Europe. As a university hospital, it performs a threefold role of care, education and research. For that purpose, it collaborates with the institute in the areas of research and education. The two entities have common personnel and share common equipment, particularly in respect of clinical research.
58      The parties are in disagreement as to whether the exclusion in the last paragraph of the definition of a pharmaceutical company, reproduced in paragraph 53 above, applies to the university hospital. The Commission takes the view that, given its task of university research, the university hospital must be treated as a research institute for the purposes of the policy and, on that basis, be excluded from the definition. The applicant takes the view, on the other hand, that, as a derogation, the exclusion must be interpreted strictly and cannot, therefore, be extended to university hospitals. However, as the parties confirmed in their written replies to a question put to them by the Court, they are in agreement that the university hospital falls within the definition of a pharmaceutical company given by the policy of 6 October 2016 if it controls such a company.
59      In that regard, it is apparent from the material before the Court that the university hospital is home to a cell therapy centre whose aim is to support and facilitate the development by researchers, clinicians and industrial companies of advanced therapy medicinal products. The cell therapy centre makes research infrastructure and personnel available, in particular for pharmaceutical companies. It is common ground that the centre carries out clinical trials at the request of pharmaceutical companies. It is apparent from Annexes A 25 to A 27 to the application and from the statements made by the Commission in paragraph 46 of the rejoinder and paragraph 10 of the written replies referred to in paragraph 17 above that the centre also has a production unit for advanced therapy medicinal products which manufactures medicinal products as outsourced by pharmaceutical companies. That finding cannot be called into question by the Commission’s statement, in paragraph 4 of its written reply of 9 July 2020, that the cell therapy centre, which contains the production unit for medicinal products, is not involved in the manufacturing of medicinal products, which clearly conflicts with the material before the Court referred to above.
60      According to the Commission, in view of its activities, the cell therapy centre, of which the production unit for medicinal products forms part, is a pharmaceutical company within the meaning of the policy of 6 October 2016. However, the Commission takes the view that the applicant has not demonstrated that that categorisation also applies to the university hospital in that the university hospital controls the centre. The Commission also contends that the fact that the centre and production unit for medicinal products are located within the university hospital does not mean that the university hospital can be classified, as a whole, as a pharmaceutical company. According to the Commission, a distinction should be made between, on the one hand, personnel working at the cell therapy centre and production unit for medicinal products, who should be regarded as working for a pharmaceutical company and, on the other hand, personnel of the university hospital, including the experts in question, who do not work within those entities. That would be the case even if it were proven that the university hospital controls the cell therapy centre, particularly since the centre is not involved in the marketing of medicinal products. A different interpretation of the policy of 6 October 2016 would, in the Commission’s view, lead to disproportionate consequences.
61      In that regard, first, it is true that, for the purposes of the first two paragraphs of the definition of pharmaceutical company given by the policy of 6 October 2016, only personnel of the university hospital who work at the cell therapy centre are, in view of the functions of the centre, liable to be in a position of conflict of interest. Nevertheless, under the terms of that policy, the fact that a legal or natural person, irrespective of that person’s principal purpose, controls a pharmaceutical company is sufficient for that person to be classified as a pharmaceutical company, without it being necessary to distinguish between its various activities. In addition, according to the policy, the nature of the activities of the pharmaceutical company under control and, in particular, whether that company is charged with tasks relating to the research or development of medicinal products or whether it markets them, are irrelevant.
62      Second, as stated in paragraph 59 above, the cell therapy centre is an advanced therapy centre located at the university hospital. It is apparent from Annexes A 25 to A 27 to the application that the hospital has a unit which runs core facilities offering services to, inter alia, the institute and other public entities, but also to the private sector, and that the cell therapy centre is one of the facilities offered.
63      The information contained in the annexes referred to in paragraph 62 above constitutes strong evidence adduced by the applicant capable of proving that the cell therapy centre, which is a pharmaceutical company within the meaning of the policy of 6 October 2016, is answerable to the university hospital, which is responsible for managing the centre, and that, accordingly, the centre is placed under the control of the hospital within the meaning of the policy. There is no material before the Court capable of calling into question the evidence adduced by the applicant. In particular, contrary to the Commission’s assertion, the diagram showing how the cell therapy centre operates, reproduced in Annex A 27 to the application, is not such as to prove that it is an entity which is separate from, and merely housed within, the university hospital. When questioned on that point at the hearing, the Commission moreover stated that, according to its understanding, the hospital merely houses the cell therapy centre, but acknowledged that it had no information on the status of the centre. In reply to a written question put to it by the Court by means of a measure of organisation of procedure, the Commission reiterated that ‘it is the understanding of the Commission that [the cell therapy centre] is a separate entity within the university hospital’, but that it did not have any evidence demonstrating that they are ‘separate legal entities’.
64      Accordingly, having been presented with strong evidence indicating that one of the employers of the experts in question could, in view of the activities of an entity linked to it, be classified as a pharmaceutical company within the meaning of the policy of 6 October 2016 and, therefore, that the experts could have a conflict of interest owing to the identity of their employer, it was for the Commission to adduce any evidence capable of calling into question the applicant’s submissions in order to remove the doubt thus created. However, the Commission has put forward no evidence to that effect.
65      It follows from the foregoing that the fact that the experts in question were employed by the university hospital may give rise to a legitimate doubt as to the existence of a conflict of interest for the purposes of section 4.2.1.2 of the policy of 6 October 2016.
66      Fourth, it is apparent from the documents before the Court that the cell therapy centre in question is responsible both for carrying out phase I clinical trials of the medicinal product CellProtect and for manufacturing that medicinal product in its production unit. It is common ground that that medicinal product is a rival medicinal product to Aplidin, that is to say, according to the policy of 6 October 2016, a medicinal product that targets a similar patient population with the same clinical objective and constituting potential commercial competition. It should be noted, in that regard, that Aplidin was designated as an orphan medicinal product for the treatment of multiple myeloma on 16 November 2004 and that, as is clear from the SAG opinion, there are few, if any, alternative treatments on the market.
67      Admittedly, it is not apparent from the declarations of interest of the experts in question, the sincerity of which the applicant does not dispute, that those experts carry out an activity within the cell therapy centre. Nevertheless, the employment relationship between those experts and the university hospital may be such as to be viewed by third parties as capable of affecting their independence in the matter in so far as the university hospital participates, via that centre, in the development of a rival medicinal product to Aplidin.
68      It should be noted in that regard that, in order to show that the organisation of an administrative procedure does not ensure sufficient guarantees to exclude any legitimate doubt as to possible bias, it is not necessary to prove lack of impartiality. It is sufficient for a legitimate doubt to arise which cannot be dispelled (judgment of 27 March 2019, August Wolff and Remedia v Commission, C‑680/16 P, EU:C:2019:257, paragraph 37).
69      In addition, the legitimate doubts as to the independence of the experts in question owing to their employment relationship with the university hospital are increased with regard to the second professor since, in his declaration of interests, he declared, under his current activities, a consultancy in relation to the medicinal product CellProtect, and activities as principal investigator and investigator, respectively, for Daratumumab and Isatuximab, which are medicinal products indicated for multiple myeloma. It is common ground that the latter two medicinal products are, like CellProtect, rival medicinal products to Aplidin within the meaning of the policy of 6 October 2016.
70      Against that background, it is necessary to examine whether, in the particular circumstances of the present case, the fact that the two experts in question were employed by the university hospital and one of them performed activities aimed at developing rival medicinal products to Aplidin is such as to affect the validity of the procedure that led to the adoption of the contested decision.
The effect of the alleged conflicts of interest concerning the experts on the validity of the procedure
71      As a preliminary point, it should be noted that the Commission is not justified in maintaining that the lack of impartiality of certain members of the SAG, even if proven, would not be such as to vitiate the contested decision on the sole ground that that decision was adopted not by the CHMP but by the Commission at the end of a procedure which involved the Standing Committee of Medicinal Products for Human Use.
72      It follows from case-law that, where a number of EU institutions, bodies, offices and agencies are given separate responsibilities of their own in the context of a procedure that is liable to result in a decision adversely affecting a party, each of those entities is required, in respect of its own activities, to comply with the requirement of objective impartiality. Consequently, even where only one of them has breached that requirement, such a breach is liable to render the decision adopted by the other at the end of the procedure at issue unlawful (judgments of 20 December 2017, Spain v Council, C‑521/15, EU:C:2017:982, paragraph 94, and of 27 March 2019, August Wolff and Remedia v Commission, C‑680/16 P, EU:C:2019:257, paragraph 28).
73      Similarly, the sole fact that the SAG is a consultative body responsible for issuing an opinion to the CHMP and that its members are not involved in the deliberations on the CHMP’s opinion is not such as to preclude a breach by the SAG of the requirement of objective impartiality from affecting the validity of the procedure.
74      The requirement of impartiality to which the EU institutions, bodies offices and agencies are subject also extends to experts consulted in that regard (judgment of 9 September 2010, Now Pharm v Commission, T‑74/08, EU:T:2010:376, paragraph 88 and the case-law cited; see also, to that effect, judgment of 22 November 2018, Brahma v Court of Justice of the European Union, T‑603/16, EU:T:2018:820, paragraph 149 (not published)). Accordingly, the fact that the opinion issued is not binding on the authority responsible for adopting the decision is not in itself such as to relieve the body that issued the opinion from its obligation to observe the principle of impartiality (see, to that effect, judgment of 5 July 2016, Commission v Hristov, T‑26/15 P, EU:T:2016:390, paragraph 46).
75      In the present case, it is necessary to examine whether, given the interests of the two SAG experts in question, the procedure implemented in the particular circumstances of the case gave the applicant sufficient guarantees to exclude any legitimate doubt as to possible bias. To that end, it is necessary to consider the SAG’s influence on the conduct and outcome of the procedure for granting marketing authorisation as well as any responsibilities of their own that the two experts had within the SAG.
76      First, as regards the SAG’s influence on the conduct and outcome of the procedure for granting marketing authorisation, it should be noted that, pursuant to Article 56(2) of Regulation No 726/2004, the CHMP may establish scientific advisory groups in connection with the evaluation of specific types of medicinal products or treatments. The CHMP established the SAG to answer specific questions concerning oncology and haematology. Accordingly, under section 3 of the rules applicable to the SAG, the SAG is responsible for ‘providing an independent recommendation on scientific and technical matters related to products under evaluation through centralised regulatory procedures and referrals or any other scientific issue relevant to the work of the committees’. According to section 4 of those rules, the SAG is composed of core members, who ensure continuity and consistency within the SAG, and, where necessary, to ensure a sufficient number of experts and relevant expertise in the field to be discussed, additional experts. Additional experts may be called upon to participate in a given meeting or series of meetings on a specific issue about which they have relevant professional education, training and experience, therefore bringing additional expertise in specific domains.
77      It follows that the SAG is a group of experts that is highly specialised in the condition treated by the medicinal product being examined.
78      In addition, in accordance with Article 62(1) of Regulation No 726/2004, as regards medicinal products for human use, scientific advisory groups are consulted either on the initiative of the CHMP or, if there is a re-examination of the CHMP’s opinion, on the initiative of the applicant for marketing authorisation. While the SAG is therefore not involved in all procedures for marketing authorisation, its involvement in the re-examination procedure gives an applicant for marketing authorisation a guarantee that the opinion of a group of experts that is highly specialised in the field in question can be obtained, as the applicant has stated. In the present case, the SAG was involved in the procedure at the re-examination stage, at the request of the applicant, which sought the implementation of the guarantee provided by Regulation No 726/2004.
79      Furthermore, it should be noted that, according to the last subparagraph of Article 62(1) of Regulation No 726/2004, the re-examination procedure may deal only with the points of the CHMP’s opinion initially identified by the applicant. In the present case, at the request of the CHMP, the SAG gave its opinion on the grounds for refusing marketing authorisation contained in the CHMP’s opinion of 14 December 2017 in the light of the grounds for the applicant’s request for re-examination, and replied to certain questions raised by the CHMP. The SAG’s opinion was taken into consideration by the CHMP in the re-examination procedure and is reproduced in full in the CHMP’s assessment report.
80      It follows from the foregoing that the SAG was involved in the context of the guarantee provided to the applicant by Regulation No 726/2004, as a group of experts that was highly specialised in the field of the medicinal product at issue. It gave its opinion on the grounds put forward by the CHMP for refusing the application for marketing authorisation of Aplidin, and the opinion was taken into consideration by the CHMP in the re-examination procedure. Accordingly, the SAG’s opinion could have had an influence on the conduct and outcome of the procedure which led to the adoption of the contested decision.
81      Second, as regards responsibilities particular to the experts in question, the SAG, which met on 7 March 2018, was composed of five core members, one of whom was the first professor, six additional experts, including the second professor, and two patient representatives, who, as the applicant states, did not have any medical expertise.
82      As vice-chairperson of the SAG, the first professor chaired the meeting on 7 March 2018. On that basis, he was responsible, under the provisions of section 7.1 of the rules applicable to the SAG, for leading the group’s discussions and, at the end of the discussions, for summarising the group’s answers to be sent to the CHMP. Those provisions also make clear that he was responsible for proposing to the CHMP the list of additional experts who were to attend the meeting of 7 March 2018, those experts being selected on the basis of their expertise from a list of names provided by the Member States to the EMA pursuant to Article 62(2) of Regulation No 764/2004. While it is apparent from section 7.4 of the rules applicable to the SAG that the vice-chairperson is to be assisted in that task by the SAG Secretariat and the national competent authorities, it is for the vice-chairperson to propose the list of experts to the CHMP. Lastly, the first professor was also responsible for ensuring that there were no conflicts of interest concerning the experts prior to the meeting of the group.
83      It follows that, as vice-chairperson of the SAG who chaired the meeting of that group, the first professor had responsibilities of his own in the opinion procedure, including the proposing of additional experts, one of whom was the second professor, who was also employed by the university hospital.
84      In the light of all of those factors, it must be concluded that, owing to the SAG’s potential influence on the conduct and outcome of the procedure for granting marketing authorisation and to the first professor’s important role within that committee, as chair of the meeting of 7 March 2018, his participation in the SAG, as well as that of the second professor, lead to the conclusion that, owing to the employment relationship between those two professors and the university hospital in the circumstances set out in paragraph 67 above and the activities of the second professor referred to in paragraph 69 above, the procedure that led to the adoption of the contested decision did not provide sufficient guarantees to exclude any legitimate doubt as to possible bias.
85      It follows that the first part of the first plea must be upheld and the contested decision must, for that reason, be annulled without the need to adjudicate on the second part of the first plea or the remaining pleas in the application.
Costs
86      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 Commission has been unsuccessful, it must be ordered to pay the costs, in accordance with the form of order sought by the applicant.
On those grounds,
THE GENERAL COURT (Sixth Chamber)
hereby:
1.      Annuls Commission Implementing Decision C(2018) 4831 final of 17 July 2018 refusing marketing authorisation under Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, for Aplidin — plitidepsin, a medicinal product for human use;
2.      Orders the Commission to pay the costs.
Marcoulli
Frimodt Nielsen
Norkus
Delivered in open court in Luxembourg on 28 October 2020.
E. Coulon
M. van der Woude
Registrar
President
*      Language of the case: English.