In January 2022, the US Court of Appeals for the Eleventh Circuit struck down the US Food and Drug Administration’s (FDA’s) interpretation of the scope of orphan drug exclusivity (ODE). In doing so, the Eleventh Circuit declined to adopt the agency’s “indication-specific” view of the exclusivity granted to Catalyst Pharmaceuticals, Inc. (Catalyst) and its drug Firdapse (amifampridine phosphate).1 Instead, the court held that the Orphan Drug Act (ODA) provides for a broader, “disease-specific” exclusivity. As a result, the court concluded that FDA had improperly approved a competitor product, Ruzurgi (amifampridine), from Jacobus Pharmaceutical Co. (Jacobus) during Catalyst’s ODE period. The court’s decision significantly undercuts FDA’s indication-specific view of orphan exclusivity in favor of a broader approach whereby ODE extends to the entire disease or condition for which a product is designated—even where the product has only been approved for a narrower population. The Catalyst decision thus creates a great deal of uncertainty for FDA’s Office of Orphan Products Development (OOPD) and for orphan drug sponsors, who will be eager to know whether and how the agency will apply the court’s decision to other products.
The ODA authorizes FDA to grant orphan-drug designation to a drug being developed for a “rare disease or condition,” i.e., one that affects fewer than 200,000 people in the US.2 Orphan-drug designation opens the door to several statutory incentives and benefits, the most important of which is a seven-year exclusivity period. Thus, if a sponsor of an orphan-designated drug obtains approval for a use that is consistent with its designation, the statute directs FDA not to approve a competitor application for the “same drug for the same disease or condition” for seven years (with limited exceptions not relevant here).3 By regulation, FDA has interpreted ODE more narrowly, limiting its scope to the approved “indication or use,” which is commonly narrower than the “disease or condition” giving rise to the orphan designation.4 It is this narrower view of ODE that Catalyst successfully challenged.
An Orphan “Horse Race” between Catalyst and Jacobus
The case arose from an orphan “horse race,” which can occur if two sponsors are developing the “same drug” for the same rare disease at the same time. Given the seven-year length of the ODE period—and the fact that it blocks approval of any competitor, including one that independently conducts its own clinical development program—an orphan horse race can be a high-stakes affair resulting in a “winner takes all” outcome. It appears that FDA went to unusual lengths to avoid such an outcome but in doing so may have jeopardized the agency’s ODE framework in the process.
For several years, both Catalyst and Jacobus had been developing amifampridine as an orphan drug for the treatment of Lambert-Eaton myasthenic syndrome (LEMS), a rare autoimmune disorder.5 Given the low prevalence of this disease, each sponsor had obtained orphan-drug designation, Catalyst in 2009 and Jacobus in 1990. Catalyst won the race to market, when FDA granted final approval to NDA 208078 for Firdapse (amifampridine phosphate) on November 28, 2018. According to its labeling, Firdapse was approved for the treatment of LEMS “in adults” on the basis of two pivotal trials that enrolled a total of 64 adults (aged 21 to 88 years).
At the same time, FDA was also reviewing NDA 209321 from Jacobus for its amifampridine product, Ruzurgi. Like Catalyst, Jacobus studied Ruzurgi in adult patients only, and the NDA included efficacy data from a single study that enrolled adult LEMS patients only. Notwithstanding the lack of pediatric efficacy data in the NDA, Jacobus sought approval for both pediatric and adult patients, and FDA “administratively divided” the NDA into pediatric and adult populations.
When FDA completed its review of the Jacobus NDA in May 2019, the agency predictably concluded that final approval of Ruzurgi for treatment of LEMS in adults was blocked by Firdapse’s ongoing ODE. As a result, the agency issued a tentative approval letter for this indication. But FDA did grant final approval to Ruzurgi for the treatment of LEMS in pediatric patients 6 to less than 17 years of age, notwithstanding Firdapse’s ODE. Given the limited pediatric data, it appears that FDA may have sought to avoid a “winner takes all” result in this orphan horse race. And the agency may have been influenced by reported inquiries from Senator Bernie Sanders and others who expressed concern about the pricing of amifampridine should only a single competitor obtain marketing approval.6
The Eleventh Circuit Decision
As noted above, the legal issue addressed in this case was FDA’s interpretation of the scope of the ODA’s exclusivity provision, which—like the statutory designation provision—describes a “rare disease or condition.” Thus if FDA approves an application “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 … until the expiration of seven years from the date of the approval of the approved application ….”7
Historically, FDA interpreted the scope of ODE to be indication-specific, and that longstanding interpretation was codified in the orphan drug regulations in 2013. The key regulation now provides that the scope of ODE is limited to the approved “indication or use” even if the underlying designation is for a broader “disease or condition.”8 It was on the basis of this regulation that FDA granted final approval to Ruzurgi for the treatment of LEMS in pediatric patients during the exclusivity period for Firdapse for the treatment of LEMS in adults.
Catalyst brought suit against FDA in federal district court, alleging that the ODA prohibited the agency from granting final approval to Ruzurgi, and Jacobus intervened. Specifically, Catalyst asserted that the statutory exclusivity provision precluded FDA from approving Ruzurgi because it is the “same drug” as Firdapse and treats the “same disease or condition” as Firdapse. All parties recognized that the two amifampridine products are the “same drug” for purposes of the ODA and the orphan drug regulations, so the key question was whether Firdapse’s approval for treatment of LEMS in adults would block approval of Ruzurgi for treatment of LEMS in pediatric patients.
On September 30, 2021, the Eleventh Circuit issued its opinion, which squarely rejected FDA’s approach. The appellate court determined that the ODA 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.”9 That decision became final in January 2022 with the issuance of the court’s mandate, and FDA shortly thereafter converted Ruzurgi’s final approval for the treatment of LEMS in pediatric patients to tentative approval.
The Catalyst decision will jeopardize FDA’s regulatory interpretation, and the agency must now decide whether it can or will apply its indication-specific interpretation in spite of the court’s ruling. For sponsors of approved products, FDA may have to broaden the scope of existing periods of orphan exclusivity. In turn, that could have a significant impact on development plans and strategies for investigational orphan products. All orphan drug sponsors will have to carefully monitor FDA’s response to the Catalyst case to evaluate the potential impact for their rare disease products.
5 See Lambert-Eaton Myasthenic Syndrome, National Organization for Rare Disorders (NORD), Rare Disease Database, available at https://rarediseases.org/rare-diseases/lambert-eaton-myasthenic-syndrome.
6 See, e.g., U.S. Senator Sanders urges FDA to allow older versions of $375,000 drug, Reuters Health News (Feb. 28, 2019), available at https://www.reuters.com/article/us-usa-healthcare-catalyst/u-s-senator-sanders-urges-fda-to-allow-older-versions-of-375000-drug-idUKKCN1QH1LK.