By way of background, the Orphan Drug Act (ODA) incentivizes the development of drugs and biologic products intended for the treatment of rare diseases. To obtain the benefits of the ODA, a sponsor must first obtain orphan drug designation for a drug that “is being or will be investigated for a rare disease or condition.” 21 USC 360bb(a)(1). The primary incentive of the ODA is a 7‑year period of orphan exclusivity, which is awarded to an orphan drug that is subsequently approved for the rare disease or condition for which it was designated. Under the statute, orphan exclusivity prevents FDA from approving another sponsor’s application for the “same drug for the same rare disease or condition.” Id.

In applying orphan exclusivity, the agency has historically distinguished between the “rare disease or condition” for which a drug is designated and a potentially narrower “indication or use” for which the drug is approved. By regulation, FDA has therefore limited the scope of orphan exclusivity only to the approved “indication or use,” even if the underlying designation is for a broader “disease or condition.” 21 CFR 316.31(a). FDA’s interpretation has now been called into question by the Eleventh Circuit’s decision in favor of Catalyst.

On November 12, 2009, Catalyst obtained designation for Firdapse (amifampridine phosphate) as an orphan drug for the treatment of Lambert-Eaton myasthenic syndrome (LEMS). FDA approved Catalyst’s new drug application (NDA) for Firdapse for the treatment of LEMS “in adults” on November 28, 2018, and granted Catalyst orphan exclusivity through November 28, 2025. The approval of Firdapse was based on two pivotal trials evaluating a total of 63 adults (aged 21 to 88 years).

At the time of approval of Catalyst’s product, the agency was also reviewing an NDA from Jacobus for its amifampridine product, Ruzurgi. Like Catalyst, Jacobus had previously obtained orphan designation for amifampridine for the treatment of LEMS. The Ruzurgi NDA contained efficacy data from a single study that enrolled a total of 32 adult patients with LEMS (aged 23 to 83 years), but sought approval for both adult and pediatric patients. FDA rightly concluded that approval of Ruzurgi for treatment of LEMS in adults was blocked by Firdapse’s orphan exclusivity.

Nevertheless, in May 2019 – during the 7-year exclusivity for Catalyst’s Firdapse – FDA approved Ruzurgi for the treatment of LEMS in pediatric patients 6 to less than 17 years of age, despite the limited pediatric data in the Ruzurgi NDA. Consistent with its regulations, FDA concluded that the scope of orphan exclusivity for Firdapse was limited to its approved use in adults, and the approval of Ruzurgi for pediatric patients was for a different “indication or use.”

Catalyst sued FDA in federal district court, and Jacobus intervened in support of FDA. Catalyst alleged that the ODA prohibited FDA from approving Ruzurgi because it is the “same drug” as Firdapse and treats the “same disease or condition” as Firdapse, as defined by 21 USC 360cc. Specifically, 360cc(a) states that:

…for a drug designated under section 360bb of this title for a rare disease or condition, the Secretary may not approve another application […] for the same drug for the same disease or condition for a person who is not the holder of such approved application or of such license until the expiration of seven years from the date of the approval of the approved application or the issuance of the license.” 21 USC 360cc (emphasis added).

There is no dispute that the two amifampridine products are the “same drug” for purposes of the ODA, so the key question revolved around the scope of the exclusivity.

The U.S. District Court for the Southern District of Florida applied the familiar Chevron framework to review the agency’s decision. At Chevron Step 1, the district court concluded that the ODA was ambiguous with regard to the scope of orphan exclusivity: the statutory phrase “same disease or condition” could refer to the broader disease or condition for which a drug is designated, or it could refer to the potentially narrower disease or condition for which approval was granted. At Chevron Step 2, the district court concluded that FDA’s interpretation of the ODA was reasonable. As a result, the district court deferred to FDA’s decision to approve Ruzurgi and granted summary judgment in favor of the agency.

Catalyst appealed. On September 30, 2021, the U.S. Court of Appeals for the Eleventh Circuit ruled in favor of Catalyst, finding that approval of Ruzurgi violated the existing orphan exclusivity for Firdapse. With the issuance of the court’s mandate last week, that decision has now been finalized. The appellate court concluded that the statutory exclusivity provision unambiguously “prohibits the approval of subsequent NDAs for amifampridine to treat LEMS—the ‘rare disease or condition’ designated under [21 USC 360bb]—while Catalyst holds its seven-year exclusivity.” 14 F.4^th 1299, 1311 (Sept. 30, 2021). The Eleventh Circuit’s opinion orders the case to be remanded to the district court with instructions to grant judgment in favor of Catalyst – and presumably the district court will either vacate FDA’s approval of Ruzurgi or remand to FDA to implement the court’s holding.

The impact of this decision may be straightforward with respect to the Jacobus product, but, the implications for other sponsors are less clear. FDA faces a difficult decision in deciding whether and how to implement this decision with regard to other sponsors holding orphan designation or exclusivity. For example, the agency must evaluate if its indication-specific regulations can continue to be applied and whether other approvals may need to be rescinded to be consistent with the Catalyst decision. More broadly, FDA may consider new approaches to same drug determinations or questions of clinical superiority – if the agency seeks to mitigate the reach of the Eleventh Circuit’s decision. In the meanwhile, sponsors developing orphan drugs will need to carefully evaluate the potential impact on their orphan products.

If you have any questions on orphan drug exclusivity, or on FDA’s drug product approval process more generally, please contact any of the authors of this alert or the Hogan Lovells attorney with whom you generally work.

Authored by George O'Brien, Susan Cook, Komal Nigam, and Philip Katz