Recent US Court Decision Threatens Orphan Exclusivity and Marketing Approval for Certain Orphan Drugs

In yet another high profile loss for the Food and Drug Administration (FDA or Agency) in a challenge to the Agency’s interpretation of the Orphan Drug Act (ODA), the Eleventh Circuit’s decision in Catalyst Pharmaceuticals, Inc. v. FDA has the potential to significantly broaden the scope of orphan drug exclusivity for drugs that receive marketing approval for orphan indications that are narrower than their orphan-designated conditions.¹ If applied across existing and pending orphan exclusivities, this decision could fundamentally change the current planning and expectations of many companies reliant on, or seeking to work around, such exclusivities.

At issue in the case was whether orphan drug exclusivity awarded to a drug approved for a use that is narrower than the full orphan-designated disease or condition should be limited to the drug’s approved use or should more broadly cover the full scope of the orphan-designated condition. FDA’s longstanding interpretation of the ODA, as codified in the Agency’s orphan drug regulations, is that the scope of orphan drug exclusivity is specific to the orphan indication for which a drug obtains marketing approval and does not cover an orphan use or population for which a drug may be designated but is not approved for marketing. In Catalyst, the Eleventh Circuit interpreted the ODA such that orphan exclusivity awarded to an amifampridine drug approved for Lambert-Eaton myasthenic syndrome (LEMS) in adults should have blocked the approval of an amifampridine same drug for the treatment of LEMS generally, including for treatment in a pediatric LEMS population for which the protected drug is not even approved. In response to the Catalyst decision, FDA earlier this month revoked the pediatric LEMS approval of the amifampridine drug in question. It remains to be seen whether FDA will apply the Catalyst decision beyond the drugs that were the subject of the case. As further detailed herein, absent a timely legislative fix, a broad application of the Catalyst decision could have far-reaching implications, including the potential to result in revocation of marketing approvals for certain orphan drugs or indications.

The Catalyst case pertains to FDA’s 2019 approval of Jacobus Pharmaceutical Company Inc.’s (Jacobus) Ruzurgi® (amifampridine) for pediatric use in LEMS. Ruzurgi is considered the “same drug” as Catalyst Pharmaceuticals’ (Catalyst) Firdapse® (amifampridine). In 2009, Catalyst received orphan designation for amifampridine for the treatment of LEMS. In November of 2018, Catalyst received marketing approval for Firdapse for the treatment of LEMS in adults. Under the orphan drug provisions of the Federal Food, Drug and Cosmetic Act (FDCA), a drug that is designated for a rare disease or condition and then subsequently obtains marketing approval for that rare disease or condition is entitled to a 7-year period of orphan-drug exclusivity during which, with certain exceptions (e.g., a demonstration of clinical superiority), FDA may not approve a drug considered the same drug for the same rare disease or condition.² To qualify for orphan drug exclusivity, FDA must not have previously approved the same drug for the same orphan condition or the sponsor of the subsequent drug must demonstrate that its drug is clinically superior to any previously approved same drug.³ Under FDA’s existing 21 C.F.R. Part 316 orphan drug regulations, orphan drug exclusivity protects only the approved indication or use of a designated drug. If approval of an orphan-designated drug is limited to only particular indication or uses within the rare disease or condition for which the drug was designated, and the sponsor later receives marketing approval for additional indications or uses within the rare disease or condition, FDA will recognize a new orphan exclusivity for these new (not previously approved) indications or uses.⁴

In the case of Firdapse, because the product’s 2018 marketing approval was limited to treatment of LEMS in adults, FDA, in accordance with its regulations, limited the product’s orphan exclusivity to treatment of LEMS in adults. As a result, Firdapse’s orphan exclusivity would not work to block approval of a same drug in pediatric patients with LEMS. This meant that a sponsor of a same drug could potentially obtain marketing approval for treatment of LEMS in pediatric patients without having to demonstrate clinical superiority over Firdapse. This is precisely what ended up transpiring with Jacobus’ drug Ruzurgi. Ruzurgi received orphan designation for the treatment of LEMS in 1990. In 2017, Jacobus submitted its first NDA for Ruzurgi, but the NDA was rejected. In June 2018, Jacobus re-filed its NDA. Jacobus included a label stating that the safety and effectiveness of Ruzurgi had been established in patients 6 to <17 years of age, and that use in that population is supported by evidence from studies in adults with LEMS. In reviewing the NDA, FDA recognized that Firdapse had exclusivity for the treatment of LEMS in adults. Because of this, FDA administratively divided Jacobus’ NDA into two parts: one for the treatment of LEMS in pediatric patients and one for the treatment of LEMS in adults “to allow for independent action in these populations.” Following its review, FDA approved Ruzurgi in May of 2019 in LEMS patients 6 to < 17 years of age. FDA concluded that approving Ruzurgi for pediatric patients with LEMS constituted a different “indication or use” from Firdapse’s approval for adult patients with LEMS.  

Catalyst filed suit against FDA basing its claims on two premises. First, Catalyst argued that the plain language of the ODA prohibited FDA from approving Ruzurgi because it is the same drug as Firdapse and treats the “same disease or condition.” Second, Catalyst argued that the Ruzurgi labeling was false or misleading because it suggests the drug can be used in adults patients, notwithstanding that Ruzurgi only obtained approval to treat pediatric patients. Catalyst also objected to several aspects of FDA’s decision to administratively divide Jacobus’ NDA, including asserting that Jacobus never expressed interest in a pediatric-only approval and that Jacobus did not conduct clinical trials in children.

The US District Court for the Southern District of Florida ruled in favor of FDA, granting the Agency’s motion for summary judgment. The district court held that the ODA statutory phrase “same disease or condition” is ambiguous, concluding that “it is unclear whether that phrase refers to the use for which the drug is approved after it submits its [NDA]’—here, LEMS for adults—‘or the disease or condition for which it . . . received orphan [drug] designation’—LEMS for all patients.”⁵ The district court thus deferred to FDA’s interpretation of the phrase, finding that the interpretation was reasonable.

On appeal, the Eleventh Circuit held that by its express language, the relevant provisions of the ODA provide exclusivity and protection from others marketing the same drug for the rare disease or condition for which the orphan drug was designated. The court concluded the following:

We hold therefore that the disease referred to in the phrase “same disease or condition” is the “rare disease or condition” for which the drug received designation under § 360bb. We further hold that the phrase “same disease or condition” in § 360cc of the Orphan Drug Act is not ambiguous, as it plainly refers back to the term—“rare disease or condition”—used earlier in the same statutory provision In this case, § 360cc prohibits the approval of subsequent NDAs for amifampridine to treat LEMS—the “rare disease or condition” designated under § 360bb—while Catalyst holds its seven-year exclusivity. Unless one of the three statutory exemptions applies—and there is no record evidence to suggest that any do apply—it is irrelevant if the subsequent NDA is intended to address only a subset of the population for LEMS.⁶

The Eleventh Circuit further determined that “based on these undisputed facts and record evidence, the FDA’s approval of Ruzurgi was contrary to the unambiguous language of the Orphan Drug Act” in that Catalyst “held the exclusive right to market, Firdapse, an orphan drug, for a period of seven years in order to treat the rare autoimmune disease, LEMS.”⁷ The court determined that the district court therefore erred in finding that the statutory phrase “same disease or condition” was ambiguous and also erred in giving deference to FDA’s interpretation of the statute. The Eleventh Circuit thus reversed the district court’s decision and remanded with instructions to grant summary judgment in Catalyst’s favor. On January 7, 2022, the Eleventh Circuit denied a petition for rehearing en banc, and on January 18 and 20, the United States Supreme Court and the Eleventh Circuit, respectively, denied motions to stay issuance of the mandate. The mandate was issued on January 28, 2022, and the district court subsequently entered judgment for Catalyst on January 31.

To implement the Catalyst decision, FDA earlier this month in effect revoked the Ruzurgi NDA approval, by converting the prior final approval to a tentative approval.⁸ A tentative approval reflects that a drug otherwise meets the statutory requirements for approval but cannot be approved because of another drug’s unexpired regulatory exclusivity or patent protection. In a letter dated February 1, 2022, FDA explained that it was taking this action in response to the Eleventh Circuit decision in Catalyst.⁹

As the Eleventh Circuit appears to interpret the ODA in Catalyst, once an orphan-designated drug is approved for marketing and receives orphan exclusivity, the orphan exclusivity provides protection against the full scope of the orphan-designated disease or condition irrespective of whether the drug received marketing approval for the full disease or a condition or for a use narrower than the full disease or condition. If FDA applies this decision beyond Ruzurgi, it could have significant implications for other similarly situated drugs that currently hold orphan exclusivities narrower in scope than their orphan-designated conditions as well as for sponsors of competitor products.

Perhaps the most significant consequence of a broad application of Catalyst is that it could lead to the revocation of approvals of an unknown number of orphan drugs. At issue would be those drugs that received marketing approval for use in a subset of patients for which an orphan exclusivity-protected same drug is designated but not approved. If FDA interprets the ODA such that the orphan exclusivity awarded to an orphan-designated drug covers the full scope of the orphan-designated condition regardless of whether the drug obtains approval only for a narrower use, then sponsors of such drugs could argue that FDA erred in approving same drug competitors for uses covered by the broader orphan designation for the orphan exclusivity-protected drug. One context where FDA may be required to more immediately make a decision on how broadly to apply the Catalyst decision is with respect to the approvability of pending marketing applications. For example, sponsors with pending NDAs/BLAs for orphan indications where a same drug has unapproved orphan exclusivity could now arguably be blocked from approval even if only seeking approval for a use within the orphan-designated condition that does not overlap with the use for which the same drug with unexpired exclusivity is approved. Under the broader Catalyst interpretation of orphan exclusivity, any such drugs with pending marketing applications could now require a demonstration of clinical superiority to obtain marketing approval.

Sponsors of drugs approved for an orphan indication narrower than their orphan designations may view the Catalyst decision as a positive in that it would broaden the scope of protection from approval of competitor same drugs. However, Catalyst could also have potential adverse implications for sponsors of such products, including with respect to whether future label expansions of their drugs would qualify for new periods of orphan exclusivity. As explained above, under FDA’s current orphan drug regulations, an orphan-designated drug can qualify for multiple periods of orphan drug exclusivity if the drug first receives marketing approval for a use narrower than the full scope of the designated condition and then subsequently receives approval for an additional use within the scope of the orphan designated condition. If FDA applies the Catalyst decision beyond Firdapse and Ruzurgi, FDA could seek to revoke the subsequent orphan exclusivity periods for drugs that benefitted from more than one period of orphan exclusivity for a single orphan designated condition. Such a move could conceivably open the door for marketing approval for drugs that are currently blocked by such orphan exclusivities held by a competitor same drug. Moreover, such a move could have implications for sponsors that may have invested time and resources into developing their orphan drugs for additional uses within the scope of an orphan-designated condition on the assumption that the use(s) in development would qualify for additional 7-year periods of orphan exclusivity if approved.

Given the potential implications of the Catalyst decision, we expect that FDA will seek to work with Congress to seek an amendment the FDCA orphan drug provisions – perhaps as part of the upcoming reauthorization of user fees—to specify that orphan exclusivity is limited to the specific indication for which an orphan-designated drug obtains approval. In the interim, Catalyst has likely opened the door for FDA to face various additional legal challenges relating to prior and pending approvals of orphan-designated drugs.

© Arnold & Porter Kaye Scholer LLP 2022 All Rights Reserved. This Advisory is intended to be a general summary of the law and does not constitute legal advice. You should consult with counsel to determine applicable legal requirements in a specific fact situation.