Orphan Drugs, a successful regulation after all? Or just about to experience its pitfalls?

On  December 5, 2018, the General Court ruled in favor of the European Commission in an action brought by Bristol-Myers Squibb Pharma (BMS) against the Commission and the European Medicines Agency (EMA) in the case, T‑329/16, read here. The application in question was made pursuant to Article 263 TFEU for annulment of an act adopted by the Commission removing Elotuzumab from the Community Register of orphan medicinal products for human use and/or of a possible act adopted by the Commission or the EMA determining that Elotuzumab no longer met the criteria for designation as an orphan medicinal product when the marketing authorisation was granted for the medicinal product Empliciti (Elotuzumab) under Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products (OJ 2000 L 18, p. 1). For those  IPKat readers who may not be familiar with the term, an “orphan drug” is a medicinal product intended for diagnosis, prevention or treatment of life-threatening or very serious diseases or disorders that are rare. A disease or disorder is defined as "rare" in Europe when it affects less than 1 in 2,000 citizens.

This cat awaits with anxiety the next step in the application of the
Oprhan Drug Regulation

The application of the Regulation and the grant of an Orphan Drug Designation

The procedure for obtaining an Orphan Drug Designation  (“ODD”)  is in practice a two-step procedure. The first step consists of the actual application of an orphan drugs designation, while the second one concerns its “maintenance” during the Marketing Authorization (MA) procedure. This second step is not expressly stated in any of the provisions of the Regulation; what the Regulation provides  is 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. Although not explicitly stipulated, the Commission has interpreted this to mean that an ab initio review of the Orphan Drug Regulation requirements has to be performed in order for the ODD to be maintained.

The maintenance of the ODD 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 a MA.

The central requirement  for the ODD to be preserved is that of “significant benefit”. This means that there is no other satisfactory therapy for the condition, or if there is one (or more), then the product in question has a significant benefit over the existing therapy. The question (and the difficulty) that arises is  to prove what the “significant benefit” consists of and above all how this will be proven. In the initial ODD application, the Commission accepts the presumption of a significant benefit, taking into account that the medicinal product in question is still in a premature phase in its product cycle .. However, in the MAA phase, the COMP requires direct comparative data, something that is not always feasible,  particularly regarding new products and the fact that MA files are confidential until the grant of the MA.

Background to the case

BMS was successful in its Orphan Drugs designation application, filed in August 2012. The Commission granted an OD to elotuzumab for the treatment of multiple myeloma (a very serious cancer disease). In 2015, when BMS submitted a MAA for Empliciti, the medicinal product including elotuzumab, the Commission made a new examination of whether the substance in question fulfills the criteria of the Oprhan Drug Regulation. Unfortunately (for BMS) the Commission had already granted a MA for a new medicinal product, Kyprolis (carfilzomib), for the treatment of the same disease. The COMP asked BMS to demonstrate the significant benefit of Empliciti over Kyprolis. In the absence  of other more concrete direct comparison data,  BMS submitted a scientific discussion on the significant benefit of the substance elotuzumab over that of carfilzomib. The COMP did not consider the submitted data to be satisfactory and thus concluded that elotuzumab’s significant effect was not shown, leading thus to its removal from the Community OD register.

The grounds for an action for annulment

BMS's action for annulment of the decision 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. The most important part of the decision concerns the violation of Article 5(12)(b) of the Orphan Regulation. In this respect BMS presented three major arguments:

(a) 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.,  several  months after the submission of the MAA for elotuzumab. Adopting such a broad perspective would, according to BMS, call into question compliance with the principle of proportionality and run counter the objectives of the Orphan Drug Regulation. “Proportionality” mean that the action of the EU must be limited to what is necessary to achieve the objectives of the Treaties. Furthermore, such a comparison would be unfair because it would mean that the applicant would not have enough time to collect all the necessary data.

The Court referred to its ruling in Now Pharm v Commission, T‑74/08, where it held  that the orphan drug in question is to be compared with all medicinal products that have been authorized in the EU (without  exception), and that both  Articles 5(12) and 7(3) of the Regulation provide as the deadline for the examination of the designation criteria (i.e.,  the date  on  which the Commission is to determine whether the OD fulfills the requirements of the Orphan Drug Regulation), the MA grant date and not that of the MAA.

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. As such, 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.

(b) Conclusive evidence should show that Empliciti is no longer of significant benefit, not that it is of significant benefit:. In fact, BMS claims that 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.

In this respect, the Court repeated the obligation under 5(12)(b) to review the OD criteria before granting an MA, and that the above-mentioned provision, read together with Article 7(3), provides that the COMP must proceed to a complete re-evaluation of the designation criteria. This assessment shall be new and independent of the one previously performed during the initial ODD. The Court thus 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.

(c) 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 did not share BMS’s approach, stating that taking into consideration the complex scientific assessment that needs to be done in such cases, the Commission usually endorses the opinions of the COMP. The Court is to rule solely on the proper functioning of the COMP, the internal consistency of the opinion and the statement of reasons contained. The Court is to examine only whether the scientific findings are linked to the conclusions drawn with regards to the fulfillment of the Orphan Drug Regulation criteria. 

Thoughts

It seems that the last word has not been yet spoken  in the matter and the industry awaits (if not expects) an appeal of the Court’s ruling. The launch of a public consultation for the Orphan Drugs Regulation, revealing the interest of the Commission in the application of the Regulation,     suggests that a revision of the Regulation might in fact be underway. That makes a ruling from  the  CJEU more desirable than ever. In this respect, the interpretation from the CJEU would be more than desirable not only for the specific provisions at stake in this case, but also with respect to other provisions, such as f Article 8(3)(1)of the Orphan Drugs Regulation, which provides   for  exceptions to the exclusivity granted by the ODD.