Until now, if a Sponsor intended to request orphan designation with 7 years of marketing exclusivity for a drug that has already been granted orphan designation, FDA has followed the Code of Federal Regulations (CFR), including the condition described in 21CFR §316.34(c): “If a drug is otherwise the same drug as a previously approved drug for the same use or indication, FDA will not recognize orphan-drug exclusive approval if the sponsor fails to demonstrate upon approval that the drug is clinically superior to the previously approved drug.” [Detailed definitions of “clinically superior” and “same drug” are provided in 21CFR §316.3(b)(3) and 21CFR §316.3(b)(14), respectively.] Essentially, the process involved the Sponsor presenting “a plausible hypothesis that its drug may be clinically superior to the first drug” at the time that orphan designation is requested. Then at the time of marketing approval, in accordance with 21CFR §316.34(c), the Sponsor must have demonstrated clinical superiority of its drug compared to the first drug in order to be eligible for 7 years of marketing exclusivity.

Depomed, Inc. challenged this interpretation of the statute. Briefly, Depomed apparently presented a plausible hypothesis for clinical superiority of its gabapentin product (Gralise) compared with the previously approved gabapentin product (Neurontin) at the time that orphan designation was requested. However, Depomed, the Sponsor, failed to demonstrate clinical superiority in the clinical studies conducted for approval of its product Therefore, in 2011 when FDA granted marketing approval for Gralise, marketing exclusivity as a result of the orphan designation was not granted. Abbot/Depomed challenged this position in court.

The US District Court upheld Depomed’s contention that the statute had been overinterpreted, and that any drug that received orphan designation is eligible for marketing exclusivity upon approval. This is regardless of whether the drug lived up to its promise of clinical superiority over a previously approved drug. FDA appealed this decision but withdrew its appeal on 12 November 2014, implying that FDA will abide by the courts findings.

The implication for drug products seeking approval via the 505(b)(2) regulatory pathway that are targeted to orphan populations is significant. And almost all applications that may be affected by this ruling will be 505(b)(2) applications. This is because clinical superiority is not required for new molecular entities (approved via the (505(b)(1) regulatory pathway), and because generic products cannot claim superiority over their respective Reference Listed Drug. On the surface, it could be viewed that the standard for obtaining the exclusivity that accompanies orphan designation and drug approval has been lowered. A Sponsor need only provide a plausible hypothesis for clinical superiority at the time of the orphan designation request, and ultimately get their product approved. The requirement to actually demonstrate clinical superiority prior to marketing authorization apparently no longer exists. In some cases, the chance that a Sponsor’s product may appear to be a plausible candidate for clinical superiority may be improved if the request for orphan designation is made at an early stage in the development program before a lack of clinical superiority may be evident. Orphan designation may be granted before an IND has even been opened, a time at which little may be known about the superiority of the Sponsor’s formulation over the approved drug product.

However, it seems more likely that FDA’s Office of Orphan Product Development will alter their modus operandi to accommodate the court’s ruling yet restrict exclusivity for new or improved drugs for orphan populations. The court noted that FDA has control over the process as FDA is responsible for granting both orphan designation and marketing approval, the 2 requirements for exclusivity. FDA could delay the designation of a drug product as orphan until clinical superiority has been demonstrated, or even raise the standard required for a plausible hypothesis of clinical superiority. Ultimately, the effect on Sponsors seeking approval for a previously approved drug via the 505(b)(2) pathway is likely to be a delay in obtaining orphan designation. This could reduce the attractiveness of the drug product to potential investors, introduce uncertainty in the scope of the clinical program, and delay or reduce the tax incentives associated with orphan designation. If developing a previously approved drug for an orphan population, Sponsors are advised to seek the advice of a partner that frequently submits orphan requests, such as Premier Consulting, to get the best advice on the timing of submission of the orphan request, based on the available data, to minimize these consequences.