On December 5, 2018, the General Court (Court) ruled in favor of the European Commission in a case brought by Bristol-Myers Squibb Pharma (BMS) against the Commission and the European Medicines Agency (EMA) (T‑329/16). BMS had sought the annulment of the Commission's decision to remove Empliciti (elotuzumab) from the Community Register of orphan medicinal products following the “procedure for maintenance of the orphan designation.” During that procedure, the Committee for Orphan Medicinal Products (COMP) asked BMS to show the significant benefit of Empliciti over Kyprolis, a medicinal product that had been authorized several months after the submission of the marketing authorization application (MAA) for Empliciti. Despite the lack of data available on Kyprolis, BMS tried to provide such a comparison, but the COMP concluded that it was not sufficient and recommended the removal of the orphan designation.

The Court's ruling in favor of the Commission supports an application of the “procedure for maintenance of the orphan designation” (which was informally created by the Commission pursuant to Article 5(12) of the Orphan Regulation) that disregards how impossible it is for companies to produce the stringent comparative evidence required by the COMP even though data on newly authorized medicinal products is not yet publicly available.

Increasingly, evidence has become a key concern for companies developing orphan medicinal products. The success of the Orphan Regulation has led to the development and marketing of many medicinal products designed for rare diseases, which multiplies the number of products that must be taken into account for significant benefit purposes. In addition, many more companies are developing orphan drugs, which makes it more common than in the past to have competing orphan drugs being assessed for approval more or less at the same time. Given the level of evidence required by the COMP, demonstrating significant benefit over a product that has been authorized a couple of years ago is challenging; bringing such evidence for a medicinal product authorized a few months ago is basically impossible. The confidentiality of the MA procedure until the granting of the MA, the time required to get effective access to documents in the MA dossier and the time necessary to complete the pricing and reimbursement procedure(s) de facto lead to a lack of publicly available data for more than a year after the granting of a MA.     

In August 2012, the Commission decided that elotuzumab met the criteria for orphan designation (OD) set forth in Article 3 of the Orphan Regulation and granted an OD to elotuzumab for the treatment of multiple myeloma. However, in 2015-2016, when BMS sought marketing authorization (MA) for Empliciti, a medicinal product containing elotuzumab, the Commission revisited whether elotuzumab met the OD criteria, decided that it no longer did and withdrew the OD.

In Europe, a medicinal product obtains an orphan status in two steps: the orphan status is (i) granted and (ii) then “maintained” at the time of MA if the Commission concludes once again that the OD criteria are met.

The maintenance of the OD at the time of MA is not expressly set forth by the Orphan Regulation. The regulation simply states that a designated orphan medicinal product must be removed from the Community Register if it is established, before the MA is granted, that the designation criteria are no longer met. The Commission interpreted those legal provisions as requiring a systematic review of an OD right before the grant of an MA.

That review may lead to the withdrawal of the OD.  Indeed, the designation criteria include the so-called “significant benefit”—i.e., there is no other satisfactory therapy for the condition, or, if there is one (or more), the future product will bring a significant benefit over the existing therapy. The significant benefit must be demonstrated by means of a comparison between the existing therapy(ies) and the future medicinal product. At the time of granting of the OD, the Commission considers that presumptions are sufficient because the company has not yet fully developed its future medicinal products. However, at the time of MA, the COMP requires direct comparative data, i.e., head-to-head studies. Because direct comparison is not always possible, the COMP, in certain cases, will accept indirect comparative data. However, in rare cases, even indirect comparisons are not feasible due to lack of publicly available data, especially for newly authorized medicinal products.

In practice, the company submits the comparative data for the maintenance of the OD with the MAA. If a new medicinal product is authorized after that date, it is very difficult, if not impossible, to generate direct comparative data and, sometimes, even indirect comparative data. On the one hand, the MA procedure is confidential, and the MA dossier is not accessible up until the granting of the MA. On another hand, the pricing and reimbursement procedure(s) delays the effective marketing of the new products and thereby “real world” safety and efficacy data and scientific publication. 

BMS found itself in this difficult situation. It had submitted the MAA in July 2015 and, in November 2015, the Commission authorized a new medicinal product, Kyprolis (carfilzomib), for the treatment of multiple myeloma. The COMP asked BMS to demonstrate the significant benefit of Empliciti over Kyprolis. BMS submitted a scientific discussion on the significant benefit of elotuzumab over carfilzomib. Although the CHMP, the EMA committee in charge of the scientific assessment of MAAs, gave a positive opinion on the MA, the COMP gave a negative opinion on the maintenance of the OD on the grounds that BMS did not demonstrate a significant benefit of Empliciti over Kyprolis. BMS appealed that negative opinion, but the COMP maintained its initial opinion. The Commission granted an MA for Empliciti, and, a few days later, the Community Register of orphan medicinal products no longer included elotuzumab. On the same day, elotuzumab was listed on the Community Register of non-active orphan medicinal products.

BMS's action for annulment was based on (i) violation of Article 5(12)(b) of the Orphan Regulation in conjunction with the principle of proportionality; (ii) violation of Article 5(12)(b) in conjunction with Article 5(8); and (iii) failure to identify the legal basis and to state reasons. We focus on the first plea—violation of Article 5(12)(b) of the Orphan Regulation in conjunction with the principle of proportionality—as it touches on “core” principles of the European orphan system.

BMS's plea was divided in three arguments.

(i) Kyprolis may not be taken into account in the review of the significant benefit because it was authorized after the submission of the MAA for Empliciti: BMS claimed that Empliciti should not have been compared with Kyprolis because Kyprolis was authorized on November 19, 2015, i.e. after the submission of the MAA for Kyprolis. Taking medicinal products authorized after the submission of the MAA into account for significant benefit purposes:

  • Jeopardizes compliance with the principle of proportionality and the attainment of the objective of the Orphan Regulation (to encourage pharmaceutical laboratories to invest in research and development of new products by granting them market exclusivity).
  • Is unfair because there is not enough time to submit sufficient data, particularly if a direct comparison is to be made.

After first recalling that a significant benefit must be drawn from a comparison of the future medicinal product with medicinal products that have already been authorized (9 Sept. 2010, Now Pharm v Commission, T‑74/08), the Court noted that:

  • The wording of Article 3(1)(b) of the Orphan Regulation, in particular the phrase “that has been authorised in the [European Union],” as well as the Court's interpretation of this provision justify the conclusion that all authorized medicinal products must be taken into account for establishing the significant benefit. The Orphan Regulation does not provide for any exception, and, if the legislature had intended to exclude medicinal products authorized after the submission of the MAA, it could have done so;
  • Neither Article 5(12) nor Article 7(3) of the Orphan Regulation refer to the MAA but rather to the MA, and the date on which the MA is granted is the deadline for establishing whether the designation criteria are still met;
  • Not comparing the medicinal products authorized after the submission of the MAA with the future medicinal product could result in infringing Article 7(3), which prohibits the grant of an MA for therapeutic indications that do not meet the designation criteria;
  • Pursuant to Article 7(3), in combination with Article 5(12), the designation criteria must be reviewed before an MA is granted, so the relevant time for establishing whether those criteria are still met is the time at which an MA is granted for that product;

… and concluded that the COMP was under a legal obligation to evaluate the potential significant benefit of Empliciti as compared with Kyprolis. If the COMP had not assessed significant benefit by comparing Empliciti with Kyprolis, it would not have been possible to establish, in accordance with Article 5(12), whether Empliciti still met the designation criteria.

The Court also decided that the principle of proportionality was not breached because the assessments concerning the significant benefit criterion were carried out objectively, from a purely scientific point of view, so that the COMP had no scope for discretion as regards to recommending to the Commission to remove the medicinal product from the Community Register of orphan medicinal products.

(ii) Conclusive evidence should show that Empliciti is no longer of significant benefit, not that it is of significant benefit: According to BMS, the Commission's decision relied, incorrectly, on data that did not clearly demonstrate that Empliciti did not provide significant benefit compared to Kyprolis. Indeed,

  • According to the wording of Article 5(12)(b), at the time of MA, compelling evidence is needed that the designated medicinal product is no longer of significant benefit compared with other authorized medicinal products, not that the designated medicinal product is of significant benefit.
  • By applying an incorrect criterion, the EMA implemented the procedure under Article 5(12) in a manner that went beyond what was appropriate and necessary to achieve the objective of the Orphan Regulation.

The Court considered that:

  • Article 5(12)(b) requires a review of the OD criteria before an MA is granted, so the company triggers a procedure for re-evaluating those criteria when it submits an MAA for a designated orphan medicinal product;
  • The responsibility for assessing whether the OD criteria are met lies solely with the COMP, which must issue a scientific opinion on the initial OD. An MA will confer entitlement to market exclusivity only if the COMP has confirmed, at the conclusion of its scientific assessment, that the designation criteria are met. According to Article 7(3), the MA granted for an orphan medicinal product covers only those therapeutic indications that fulfill the criteria set out in Article 3;
  • It is apparent from a reading of Article 5(12)(b) in conjunction with Article 7(3) that at the time of the MA the COMP must carry out a complete re-evaluation of the designation criteria in a factual situation that is different from that which led to the initial OD. That new assessment must take into account evidence that has come to light since the grant of the initial OD, including new medicinal products that have been authorized in the meantime. Thus, if it is shown that the basis on which the initial OD was granted has changed—in particular where that OD was based on a significant benefit that no longer exists due to the existence of new authorized medicinal products at the time of the MA, the future medicinal product must be removed from the Community Register;

… and concluded that there must be a positive finding that the significant benefit criterion is met once again at the time of the MA. In order to confirm its initial opinion, the COMP must satisfy itself, scientifically and objectively, that the significant benefit criterion is met. In the absence of conclusive evidence proving significant benefit at the time of MA, the COMP is required to conclude that the designation criteria are no longer met. Therefore, in order to avoid such removal, the company must provide sufficient data to establish significant benefit in light of new circumstances prevailing at the time the MA is granted.

(iii) The test for the assessment of significant benefit is overly rigid: BMS claimed that the Commission applied, incorrectly, an overly rigid test to assess the significant benefit. Even though the COMP had to verify whether the available data supported the conclusion that Empliciti offered significant benefit compared with Kyprolis, the COMP should not have fixed an overly rigid test for evidence of significant benefit but instead should have (i) conducted a more global assessment, focusing on all of the evidence that could substantiate its claim of significant benefit; (ii) used the general criterion of benefit for the patient; and (iii) applied a standard of proof that did not require conclusive proof and could allow for estimates and assumptions based on the available data, especially when taking into account the relevant circumstances, including the practical impossibility for the applicant to produce new comparative data.

The Court disagreed with BMS.

It noted that the procedure for OD is an administrative procedure involving complex scientific assessments and that, in most cases, the Commission endorses the opinions of the COMP unless it has other adequate sources of information in the field concerned. In addition, according to case law, where the Commission must undertake complex technical and/or scientific assessments, it enjoys broad discretion. As part of their judicial review, EU courts must determine whether the relevant procedural rules have been complied with, whether the facts established by the Commission are correct and whether there has been a manifest error of appraisal of those facts or a misuse of powers (9 Sept.2010, Now Pharm v Commission, T‑74/08). With the Commission having endorsed the findings of the COMP opinion, the judicial review of that opinion, in particular the Court’s review as to whether there has been a manifest error of assessment, had to be carried in respect of all the considerations set out in that opinion, which forms an integral part of the decision at issue.

In addition, the Court cannot substitute its own assessment for that of the COMP. It is only the proper functioning of the COMP, the internal consistency of the opinion and the statement of reasons contained therein that are subject to judicial review. The Court is empowered only to examine whether the COMP 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 and/or scientific findings and its conclusions (26 Nov. 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). In the BMS case, the COMP opinion contains a statement of reasons from which it is possible to ascertain the considerations on which the opinion is based and to establish a comprehensible link between its conclusions and the medical and/or scientific findings. It cannot therefore be validly claimed that the statement of reasons in that opinion is vitiated by unlawfulness in that regard.

Finally, the wording of Article 3(1)(b) and the spirit underlying the orphan system create strict criteria for a finding of significant benefit. In the BMS case, it is apparent from the COMP opinion that the COMP applied strictly the criteria for establishing whether there was a significant benefit, and there was no manifest error of assessment in that regard.

Let's hope that BMS decides to appeal the decision of the General Court and that the European Court of Justice gives an interpretation of the relevant legal provisions that not only recognizes the evidence issue but also the objective of the Orphan Regulation. This is especially important as the European Commission has launched a public consultation on the Orphan Regulation, thereby indicating a possible revision of that legislation, and if such a revision were to happen, the EU legislature would most likely codify the European case law.