Case C‑291/22 P
Debrégeas et associés Pharma SAS (D & A Pharma)
v
European Commission
and
European Medicines Agency (EMA)
Judgment of the Court (Fourth Chamber) of 14 March 2024
(Appeal – Medicinal products for human use – Application for marketing authorisation – Independence of experts consulted by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) – Article 41 of the Charter of Fundamental Rights of the European Union – Right to good administration – Requirement of objective impartiality – Criteria for verifying the absence of conflict of interest – EMA’s policy on competing interests – Activities as principal investigator, consultant or strategic adviser for the pharmaceutical industry – Rival products – Re-examination procedure – Regulation (EC) No 726/2004 – Articles 56, 62 and 63 – EMA Guidelines – Consultation of a scientific advisory group (SAG) or an ad hoc expert group)
1. Approximation of laws – Medicinal products for human use – Marketing authorisation – Requirement of impartiality and independence of members of the scientific committees and experts of the European Medicines Agency (EMA) – Scope – Experts consulted by the Committee for Medicinal Products for Human Use – Criteria for establishing the existence of a conflict of interest – Failure to observe the requirement of objective impartiality – Obligation to provide proof of specific indications of bias – None
(Charter of Fundamental Rights of the European Union, Art. 41(1); European Parliament and Council Regulation No 726/2004, Art. 63(2))
(see paragraphs 73-76, 78-80)
2. Approximation of laws – Medicinal products for human use – Marketing authorisation – Requirement of impartiality and independence of members of the scientific committees and experts of the European Medicines Agency (EMA) – Discretion of the EMA – Limits
(Charter of Fundamental Rights of the European Union, Arts 41(1), 51(1) and 52(1); European Parliament and Council Regulation No 726/2004, Art. 57(1))
(see paragraphs 84-88)
3. Approximation of laws – Medicinal products for human use – Marketing authorisation – Requirement of impartiality and independence of members of the scientific committees and experts of the European Medicines Agency (EMA) – Existence of competing interests – Rival product – Concept – Assessment of interchangeability or substitutability – Criteria
(Charter of Fundamental Rights of the European Union, Art. 41(1); European Parliament and Council Regulation No 726/2004)
(see paragraphs 97-102)
4. Approximation of laws – Medicinal products for human use – Marketing authorisation – Procedure for reviewing the opinion of the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) – Request for consultation of a scientific advisory group established in the therapeutic area of a product – Evaluation of the creation of such a group to be carried out by the Committee for Medicinal Products for Human Use – Failure to consult that group despite its existence – Discretion of the Committee for Medicinal Products for Human Use manifestly exceeded
(European Parliament and Council Regulation No 726/2004, Art. 62(1))
(see paragraphs 142-150, 157)
Résumé
The Court of Justice upholds the appeal brought by Debrégeas et associés Pharma SAS (D & A Pharma) (‘D & A Pharma’) against the judgment of the General Court in D & A Pharma v Commission and EMA (‘the judgment under appeal’). (1) In doing so, it clarifies the scope of the principles to be respected in the procedure conducted by the European Medicines Agency (EMA) for the evaluation of medicinal products.
The applicant submitted an application for a conditional marketing authorisation (‘MA’) to the EMA, under Regulation No 507/2006, (2) for the medicinal product Hopveus. The Committee for Medicinal Products for Human Use (‘the CHMP’) issued an unfavourable opinion on that application. Following a request for re-examination of that opinion submitted under Regulation No 726/2004, (3) the CHMP convened an ad hoc expert group, in which, inter alia, an expert who was simultaneously a principal investigator for the medicinal product AD 04 participated. Since that expert group also delivered an unfavourable opinion, the Commission refused the application for a conditional MA on 6 July 2020 (‘the contested decision’).
Following the dismissal by the General Court of its action against the contested decision, the appellant brought the present appeal against the judgment under appeal.
Findings of the Court
(i) The claim to set aside the judgment under appeal
The Court of Justice recalls that the objective impartiality of the CHMP, and therefore of the EMA, is compromised where a conflict of interest on the part of one of the members of the CHMP is likely to result from an overlap of functions, irrespective of the personal conduct of that member. Such a failure to fulfil obligations is liable to render unlawful the decision adopted by the Commission at the end of the procedure. The objective impartiality of the CHMP is also compromised where an expert who is in a situation of conflict of interest is part of the expert group that is consulted by that committee in the context of the re-examination leading to the opinion of the EMA and the Commission’s decision on the MA application.
The opinion expressed by the expert group convened by the CHMP has a potentially decisive influence on the EMA’s opinion and, through that opinion, on the Commission’s decision. Each member of that group may, where appropriate, significantly influence the discussions and deliberations that take place on a confidential basis within that group.
Therefore, contrary to what the General Court held, a conflict of interest on the part of a member of the expert group consulted by the CHMP substantially vitiates the procedure. The fact that, at the end of its discussions and deliberations, that group of experts expresses its opinion collegially does not remove such a defect.
Persons whose affairs are handled by an EU institution, body, office or agency cannot be required to prove specific indications of bias. Objective impartiality is assessed on the basis of criteria that are independent of the specific conduct of the experts concerned.
As regards those criteria, which must make it possible to ensure the impartiality and independence of persons contributing to the preparation of the EMA’s scientific opinions, the Court of Justice notes, first, that, in order to enable the EMA to pursue effectively the objective assigned to it, and in view of the complex technical assessments that it has to make, its broad discretion is reflected in the definition of those criteria.
However, notwithstanding the existence of that broad discretion and the importance of the public interest pursued, the EMA is, in the exercise of its powers, bound by the requirements of the Charter of Fundamental Rights of the European Union, which states that any limitation on the exercise of rights and freedoms must respect the essence of those rights and freedoms and the principle of proportionality.
It follows that, even though the objective of general interest relating to the need for the best possible scientific advice may justify a mitigation of the requirement of objective impartiality of persons, a requirement that stems from the fundamental right to sound administration, the EMA must respect the essence of that fundamental right and the principle of proportionality. In particular, it cannot be accepted that that agency, on the pretext of wishing to maximise the number of experts available, lays down restrictions on the exercise of their mandate that appear insufficient to guarantee an impartial procedure. That would be the case if experts whose activities revealed a current interest in relation to a rival product of the product concerned were allowed to be members of the expert group convened by the CHMP for the purposes of re-examining the MA application for that product.
Secondly, the Court finds that the EMA’s policy on competing interests defines the concept of ‘rival product’ as a ‘medicinal product that targets a similar patient population with the same clinical purpose (i.e. to treat, prevent or diagnose a particular condition) and constituting potential commercial competition’.
That definition reflects the criterion used in the case-law of the Court of Justice to assess whether two pharmaceutical products are in competition on a given market. According to that case-law, that is the case where, for the same therapeutic indication, those products are interchangeable or substitutable.
It is therefore on the basis of an examination to determine whether, in the event that AD 04 and Hopveus are marketed, those products, both of which have been developed for the purpose of treating alcohol dependence, would present such a degree of interchangeability or substitutability that it would be necessary to determine the existence or absence of potential commercial competition between those two products.
That assessment of interchangeability or substitutability need not be carried out solely in relation to the objective characteristics of those products. The examination of potential commercial competition between the products at issue must be based on an overall assessment of the factors that may be taken into account in order to assess whether patients and their prescribing doctors will be able to view one product as a valid alternative to the other.
By excluding the possibility of commercial competition on the ground that AD 04 and Hopveus have different clinical objectives and target different groups of patients, namely, as regards the former, those who intend to limit their alcohol consumption and, as regards the latter, those who intend to stop that consumption altogether, the General Court did not carry out such an overall assessment.
In that regard, the Court of Justice considers that the mere difference in intensity in the scope of the therapeutic action between two products intended to treat the same pathology is precisely likely to encourage certain patients suffering from that pathology to replace, in the course of their treatment, one of those products with the other depending on changes in their symptoms or considerations of therapeutic expediency and efficacy from their prescribing doctors.
Consequently, the General Court failed to examine whether those products were likely to compete with each other in the light, in particular, of the fact that changes in the treatment of the same patient may lead his or her doctor to prescribe those two products alternately during that treatment, depending on the symptoms and considerations of therapeutic appropriateness and efficacy.
Thirdly, the Court of Justice observes that the EMA must, in any event, interpret and apply its policy on competing interests in a manner consistent with the Charter of Fundamental Rights of the European Union.
In the present case, the policy relating to competing interests imposes on experts who have a current competing interest as principal investigator a mitigating measure, according to which they may, in procedures relating to the ‘medicinal product concerned’, be involved ‘only in the discussions’, without participating in the ‘final deliberations and voting’. That mitigation measure cannot, without disproportionately limiting the protection of objective impartiality, be interpreted or applied as meaning that an expert who is at the same time the principal investigator for a rival product of the product concerned may participate in the work of an expert group that is consulted by the CHMP in the procedure for re-examination of an MA application for the product concerned.
Such participation, by its very nature, would be inappropriate in order to ensure that the re-examination procedure in question is conducted impartially. A refusal to grant an MA for the rival product under re-examination is likely to be of considerable commercial interest to the company at the instigation and/or under the sponsorship of which such an expert carries out his or her activity as principal investigator.
It follows that the judgment under appeal is vitiated by an error of law, in that the General Court’s interpretation of the policy relating to competing interests is incompatible with the principle of objective impartiality.
Similarly, the restrictions – within the meaning of the policy on competing interests – imposed on experts cannot, contrary to what the General Court held, be interpreted and applied as meaning that a consultant or strategic adviser for individual medicinal products of a pharmaceutical company may be a member of the ad hoc expert group convened by the CHMP for the purpose of re-examining the MA application submitted for a rival product of one of those individual medicinal products. Such an interpretation is also incompatible with the principle of objective impartiality.
Accordingly, the plea alleging failure to observe the principle of objective impartiality is well founded and justifies the setting aside of the judgment under appeal.
(ii) The action before the General Court
The Court of Justice observes, first of all, that it follows from the guidelines on the re-examination procedure that the EMA undertakes that the CHMP will systematically consult a scientific advisory group (‘SAG’) when the applicant for re-examination requests such consultation, in good time and on a duly motivated basis. It is also apparent from this that the SAG referred to for that purpose must be the one established in the therapeutic area to which the product in question belongs, and that an ad hoc expert group will be convened if no SAG is established in that area.
The CHMP must, in its capacity as the competent committee of the EMA, apply the rules of conduct laid down by that agency, which include the guidelines on the re-examination procedure. It is settled case-law that, in adopting rules of conduct and announcing by publishing them that they will apply to the cases to which they relate, an EU institution, body, office or agency imposes a limit on the exercise of its discretion.
In view of the self-imposed limitation on the EMA’s discretion, the Court finds that the CHMP manifestly exceeds the limits of that discretion where it decides to convene an ad hoc expert group, even though it has established that the therapeutic indication of the product at issue falls, at least predominantly, within a therapeutic area for which a SAG has been established, or where it decides to convene an ad hoc expert group on the basis of elements that already relate to the substantive treatment, by the CHMP, of the request for re-examination or on hypothetical considerations.
The Court notes, in that regard, that consultation of the SAG enables the CHMP to receive an opinion drawn up by the permanent experts of that SAG. Furthermore, that ‘core’ group of the SAG may be supplemented by additional experts who are specialised in dealing with specific issues raised by the questions that the CHMP intends to ask. Consultation of such an expert group comprising, on the one hand, a group which ensures, by its permanent nature and its balanced composition, continuity and consistency in the treatment of dossiers and, on the other hand, additional experts specialised in dealing with specific issues raised in the context of the re-examination, ensures that the ‘best possible scientific opinion’ is drawn up, and thus enables the EMA to comply with the task entrusted to it.
In those circumstances, the convening, in a therapeutic area for which a SAG is established, of an ad hoc expert group cannot be accepted on the basis of the CHMP’s consideration that an ad hoc expert group would be better able to answer its questions than the SAG established, where appropriate reinforced by additional experts.
The Court infers from this that the decision to convene an ad hoc expert group instead of the SAG on Psychiatry constitutes a defect vitiating the procedure for adopting the opinion of the EMA. Consequently, the procedure for adopting the contested decision is itself vitiated by a formal defect.
Consequently, the Court annuls the contested decision.