Condition Critical: Court Interprets Orphan Drug Exclusivity Broadly

February 17, 2022By Sara W. Koblitz

Because a drug is designated an “Orphan” if it is intended to treat a “rare condition,” the condition itself always has been integral to Orphan Drug Exclusivity.  Indeed, the condition for which the product is intended to treat dictates the prevalence calculation by which FDA determines eligibility for an Orphan Drug Designation.  But the scope of Orphan Drug Exclusivity has always been based on the indication for which the product has been approved.  In yet another blow to FDA’s implementation of the Orphan Drug Act—specifically Orphan Drug Exclusivity—the Eleventh Circuit, in Catalyst v. FDA, ruled that limiting Orphan Drug Exclusivity to the indication, rather than the condition designated, is inconsistent with the plain language of the statute.  And last week, FDA officially withdrew approval of an amifampridine drug product approved for a pediatric subset of an Orphan-protect condition due to this broadened scope of Orphan Drug Exclusivity.

In 2009, Catalyst’s drug Firdapse (amifampridine phosphate) received Orphan Drug Designation for Lambert-Eaton Myasthenic Syndrome (“LEMS”), and FDA subsequently approved Firdapse in November 2018 for the treatment of LEMS in adults with 7 years of Orphan Drug Exclusivity.  However, a competitor, Jacobus, had developed its own amifampridine product for the treatment of LEMS, Ruzurgi, which it had been giving away for free under FDA’s Expanded Access provisions.  But, anticipating Catalyst approval and with it the end to Expanded Access, Jacobus submitted an NDA for approval of Rugurzi in August 2017, which FDA Refused to File, and Jacobus refiled in June 2018.  Given the timing, FDA recognized that the Firdapse Orphan Drug Exclusivity would block approval of Ruzurgi for the treatment of LEMS in adults, so FDA “administratively divided” Jacobus’s NDA into two parts: one for the treatment of adults and one for the treatment of pediatric patients to “allow for independent action in these populations.”  In so doing, FDA believed that it could approve Ruzurgi for the treatment of pediatric patients because Catalyst’s Orphan Drug Exclusivity was limited only to the indication for which Firdapse was approved: LEMS in adults.  Thus, the Agency could and would approve Ruzurgi for pediatric patients in May 2019—notwithstanding the fact that Jacobus had performed no clinical trial in children, that the LEMS pediatric patient population was negligible, and that the clinical testing reflected that Ruzurgi clearly was intended to be used in adults.

Upon Ruzurgi approval, Catalyst sued FDA alleging multiple violations of the Administrative Procedure Act.  Catalyst argued that the plain language of the Orphan Drug Act prohibited FDA from approving the “same drug” for the “same disease or condition” as Firdapse, and FDA’s approval of Ruzurgi approved the “same drug” (amifampridine) for the “same disease or condition” (LEMS) as Firdapse.  In other words, Catalyst argued that LEMS is a single disease or condition, and thus the scope of its exclusivity covered the entire LEMS condition regardless of whether patients are adults or children.  Catalyst also argued that the Ruzurgi labeling is “false or misleading” because it suggests that the drug could be used for adult patients with LEMS even though Ruzurgi was approved only in pediatric patients.

After a magistrate recommendation, the District Court for Southern Florida held that “same disease or condition” in the Orphan Drug Act is ambiguous and deferred to FDA’s interpretation, which awarded Orphan Drug Exclusivity based on the approved indication rather than the designated condition; the Court also found that the allegations of false or misleading labeling targeting adults were not supported by law.  Catalyst appealed up to the Eleventh Circuit.

In reviewing the statutory interpretation argument, the Eleventh Circuit determined that the term “same drug or condition” in the Orphan Drug Exclusivity statutory provisions, codified at 21 U.S.C. § 360cc(a), is not ambiguous and plainly refers to the “rare disease or condition” for which the drug “was designated under 21 U.S.C. § 360bb.”  Thus, the scope of the Orphan Drug Exclusivity is limited to the designated disease or condition under 21 U.S.C. § 360bb rather than the indication approved.  Because the disease for which Firdapse was designated was LEMS—not LEMS in adults—and because LEMS is the same disease in all patients—adult or pediatric—FDA could not approve another sponsor’s NDA for amifampridine for the treatment of LEMS in any patient population.  Thus, absent a demonstration of clinical superiority, the Court held that FDA’s approval of Ruzurgi during the Firdapse 7 years of Orphan Drug Exclusivity violated the APA.  As a result of this decision, FDA officially withdrew approval of the Jacobus NDA in February 2022.

On the facts of this case, it is difficult to criticize the Eleventh Circuit’s decision.  Jacobus did not do any pediatric testing yet received approval in pediatrics less than a year into Catalyst’s 7 years of Orphan Drug Exclusivity.  FDA’s push to approve Ruzurgi seemed to be a clever attempt to introduce competition and bring costs down in reaction to congressional pressure after Catalyst announced it would raise prices of the drug, upsetting Congress and leading to a hearing.  But clearly FDA’s ploy backfired.  (And indeed, there is little question that this was a ploy.  FDA rarely “administratively divide[s]” an NDA, and FDA has rejected designations of pediatric subsets for orphan drugs in light of PREA since 2018.)  To FDA’s chagrin, rather than embracing the questionable de facto subset at issue here to address pricing concerns, the Court broadened the scope of all Orphan Drug Exclusivity.

Catalyst invested the money to legally bring an important product to market for an orphan population—exactly what Congress intended with the Orphan Drug Act and exactly what Orphan Drug Exclusivity was intended to reward—but FDA’s actions immediately undercut any return on that investment.  Rubbing salt into that wound is that Jacobus did minimal (if any) testing in the intended patient population, raising questions of how much of an investment Jacobus actually made.

Keep in mind, Jacobus could have tried to break Catalyst’s Orphan Drug Exclusivity.  In that case, Jacobus would need to demonstrate clinical superiority.  But Jacobus could not do that because Ruzurgi is identical to Firdapse, because the condition does not differ in adults and kids, and because Jacobus performed no clinical testing in kids.  In other words, there is no basis for breaking Firdapse exclusivity.  And there is no basis for a pediatric orphan subset, as any orphan subset requires that a “characteristic or feature of the drug (e.g., mechanism of action, toxicity profile, prior clinical experience) why the drug will be limited to use in the subset of question.”  Obviously, that could not occur here where the drug products in question are identical.  The Court’s decision here, given the facts, is equitable and in accordance with the Act.

On the other hand, the implications here are much broader than Catalyst or LEMS.  Now, the entire designated condition represents the scope of Orphan Drug Exclusivity even if the product is indicated for a narrower condition.  It encourages sponsors to seek as broad a designation as possible—assuming the population can stay under 200,000—to ensure the broadest market protection possible; the larger the designation, the wider blockade on market entry.  Blocking approval for the entire designated condition where initial approval is only for a narrow indication would effectively deprive patients falling under the broader condition but not the specifiorc indication to use products off-label, depriving potentially vulnerable patients of important dosing and warning information.  Did Congress really intend for the Orphan Drug Act to block approval for orphan subsets?

Nevertheless, the Court had a tough call to make.  And FDA is not happy with this decision, which is not surprising since the last thing FDA needs is another big L.  But like in the Depomed litigation, FDA’s reading of the Orphan Drug Act went too far, and, like the Depomed litigation, it will take an act of Congress to overturn this decision.  Through the grapevine, we’ve heard that legislative fixes to this decision are being shopped around Congress.  For such a fix to be effective, Congress will need to clarify the language and expressly limit the scope of exclusivity to that approved indication.  But, until then, as Quiet Riot once said (in an entirely different context), the scope of Orphan Drug Exclusivity is “Condition Critical” (rather than indication indispensable?).