General Court confirms strict significant benefit test on the grant of an orphan marketing authorisation

The General Court has confirmed in its judgment in Bristol-Myers Squibb Pharma EEIG v European Commission and European Medicines Agency (Case T-329/16) that the European Medicines Agency should take account of recently authorised medicinal products in determining whether a product under assessment should retain its orphan designation on the grant of a marketing authorisation.

In the European Union, orphan medicinal products are usually granted orphan designation early on in their development. This entitles their sponsors to some of the benefits conferred by the Orphan Regulation, such as protocol assistance at a reduced charge and other fee waivers. The key incentive of orphan designation is, however, the award of a ten year period of market exclusivity on the grant of a marketing authorisation. During this period, the European Medicines Agency will not accept an application for a marketing authorisation for a similar medicinal product in the same indication unless the latter product can be shown to offer a significant benefit to patients affected by the orphan condition over existing therapies.

But, if the original orphan designation had also been granted on the basis that the product offered a significant benefit to patients with an orphan condition over existing therapies, the sponsor will have to prove that the criterion of significant benefit is still met at the end of the development phase and just before the grant of a marketing authorisation.

The problem for sponsors is that other products may have begun to be researched in the same indication after their own development plans were settled. Surprising new research findings, perhaps strong phase II clinical trial data, might enable a rival product to “leapfrog” a candidate that was expected to be granted marketing authorisation first. If that second product is unexpectedly granted a marketing authorisation before the first product, the first product will have to prove that it offers a significant benefit over that product. It may be very challenging to produce robust evidence of significant benefit in such a short time, especially if direct comparative clinical evidence is required.

Bristol-Myers Squibb argued before the General Court that an interpretation of the Orphan Regulation that produced this result was unfair and was likely to defeat the point of the orphan market exclusivity incentive by deterring investment in the development of treatments for rare diseases. BMS argued that the EMA had applied scientific criteria that were too strict in coming to their conclusion that the BMS’ product, Empliciti® (elotuzumab), no longer offered a significant benefit to patients with multiple myeloma once Amgen’s Kyprolis® (carfilzomib) had been granted a marketing authorisation two months earlier. BMS also tried to persuade the Court that when orphan designation is reviewed again just before the grant of a marketing authorisation the burden of proof should shift to the EMA, which would need to show compelling evidence that the product is no longer of significant benefit.

The General Court rejected BMS’ arguments and re-emphasised that it “is apparent from the wording of the Orphan Regulation and the spirit underlying the system established by [it] that the criteria for a finding of significant benefit are strict.”

The General Court was clear that:

“ …at the time of the MA the COMP is to carry out a complete re-evaluation of the designation criteria in a factual situation that is different from that which lead to the initial designation. In order to determine whether the medicinal product in question meets those criteria at the time of the MA, that new assessment must take account of evidence that has come to light since the granting of the initial designation, including new medicinal products that have been authorised in the meantime. Thus, if it is shown that the basis on which the initial designation was granted has changed, in particular where that designation was based on a significant benefit which no longer exists due to the existence of new authorised medicinal products at the time of the MA, the medicinal product must be removed from the Community Register of orphan medicinal products, as stated on the 2003 Communication from the Commission.”

The effect of the Court’s ruling is that the Commission decision to grant BMS a marketing authorisation in respect of Empliciti®, while at the same time removing the product from the Community Register of designated orphan medicinal products, was upheld. Empliciti® will not benefit from orphan market exclusivity but, since it is considered to be a new active substance in the opinion of the Committee for Human Medicinal Products, it will benefit from 10 years of regulatory data protection.