No Sleep ‘Til District Court: Jazz Sues FDA Over Sodium Oxybate Clinical Superiority Determination

July 24, 2023By Sara W. Koblitz

Neither Jazz Pharmaceuticals nor Avadel CNS Pharmaceuticals has taken the battle of sodium oxybate—a drug approved to treat narcolepsy—lying down.  After suing each other in patent litigation and Avadel’s suit against FDA challenging the Agency’s authority to compel patent certifications, it’s Jazz’s turn to sue FDA.  This time, rather than use codes and patent certifications, the fight is over orphan drug exclusivity (“ODE”), with Jazz challenging FDA’s clinical superiority decision concerning sodium oxybate in the treatment of narcolepsy.  Specifically, FDA determined that Avadel’s Lumryz can “break” Jazz’s ODE because it is “clinically superior” based on Lumryz’s “major contribution to patient care,” rendering it not “the same drug” under the Orphan Drug Act.  With that decision, Jazz lost its ODE, allowing Avadel’s sodium oxybate product to compete with Jazz’s long before the expiration of the ODE covering Jazz’s most recent product, Xywav, in 2027.

Approximately six weeks after FDA approved Lumryz and issued its clinical superiority decision, Jazz filed a Complaint against FDA in the District Court of D.C. asking the Court to set aside FDA’s approval of Lumryz, alleging that FDA did not have statutory authority to use clinical superiority to break ODE and that FDA’s approval of Lumryz was arbitrary and capricious.  Like in the multitude of Orphan Drug Act cases preceding this one, Jazz alleges that FDA’s authority under the Orphan Drug Act was limited by the statutory language.  Its main argument is that Congress included only two exceptions to FDA’s restriction barring FDA from granting new approvals during the ODE period: the inability to provide sufficient quantities of a drug and consent from the ODE holder.  Though the Orphan Drug Act (now) includes a clinical superiority clause, Jazz argues that it is not a third exception to ODE.  Jazz also argues that, notwithstanding the language that instructs FDA to promulgate regulations implementing the clinical superiority provisions at 21 U.S.C. § 360cc(c), the statute does not permit FDA to promulgate regulations to use clinical superiority to break ODE.

Taking another stab at the plain language of the statute, Jazz argues that FDA does not have the authority to interpret the term “same drug” in its implementing regulations, as the term is not ambiguous.  Specifically, Jazz notes that the clinical superiority provisions in the Orphan Drug Act “does not authorize FDA to use a determination of clinical superiority as a basis to find that two drugs are not ‘the same drug’ for purposes of [ODE].”   In other words, Jazz states, the “‘different drug’ fiction is the linchpin of OOPD’s [ODE] analysis,” but the distinction between “same drug” based on clinical superiority is “inconsistent with the statute. . . .”

More specific to the facts of this case than the governing statute, Jazz argues that OOPD’s determination that Lumryz is clinically superior to Xywav is inconsistent with FDA’s regulations.  Essentially, Jazz argues that FDA’s determination is based on “greater efficacy,” which is not supported by the types of evidence FDA requires for such a determination—namely, head-to-head comparative studies.  Though FDA framed its clinical superiority decision as a Major Contribution to Patient Care (“MC-to-PC”) superiority finding, Jazz believes that it is actually a greater efficacy argument in disguise.  Because the premise of FDA’s determination—that not needing to awaken to take a second dose will provide medical benefits to narcolepsy patients by improving their sleep architecture and reducing disrupted or fragmented sleep—it must be a comparative effectiveness finding.  And, because comparative effectiveness claims must be supported by substantial evidence—one or more adequate and well-controlled clinical trials—FDA’s decision cannot stand as Avadel never conducted a comparative clinical trial of Xywav and Lumryz.  Thus, Jazz argues, there is no evidence that Lumryz is more effective than Xywav.

Perhaps the most notable assertion is that FDA deviated from Agency policy with respect to clinical superiority in determining that a drug need not be comparable in safety to break ODE on efficacy or MC-to-PC grounds.  In the ODE determination, FDA explained that “one drug can demonstrate a [MC-to-PC] over a previously approved drug even if the drug is not as effective or safe in every respect as the previously approved drug.”  Jazz believes that FDA precedent precludes that position and thus FDA departed from established policy, which FDA denied ever existed.  Jazz, however, cites to the preamble to the 2011 revised implementing regulations for the Orphan Drug Act, which states that MC-to-PC is a narrow category that is applicable and “meaningful only when the subsequent drug [product] provides safety or effectiveness comparable to the approved drug.”  Thus, Jazz contends that FDA has had a longstanding policy that comparable safety is necessary for an MC-to-PC clinical superiority finding.  Jazz points to several other examples of such a requirement, including Procysbi (the brief states that OOPD “observed that an ‘[i]nherent’ part of a major contribution to patient care finding was a threshold requirement that the new drug ‘would maintain a similar or improved adverse event profile and similar efficacy’”) and Ravicti (which, the brief states, FDA rejected the MC-to-PC request “because there was ‘a lack of objective evidence to support [the sponsor’s] claim that [Ravicti] would have comparable safety and effectiveness profiles as those of [the existing phenylbutyrate products].’”

Jazz also asserts that FDA failed to disclose or explain three prior memos in the Lumryz administrative record that found that Lumryz does not provide a MC-to-PC.  In rejecting Avadel’s argument for Priority Review, Jazz explains that FDA must have determined that Lumryz did not represent a “significant improvement” over existing therapies, including Xywav, and thus the clinical superiority determination conflicts with the Priority Review determination.  Jazz argues, essentially, that the change in position was the product of a pressure campaign within the Agency.  But rather than disclose these conflicting analyses, Jazz contends that FDA “conceal[ed] the existence” of these prior determinations.

Finally, Jazz argues that the ODE determination was arbitrary and capricious and an abuse of discretion because FDA ignored relevant scientific considerations.  FDA did not seek input from Jazz or Avadel, and neither had an opportunity to “comment on FDA’s thinking because FDA did not share it.”  Consequently, FDA made its determination without informed comments from the affected stakeholder, which Jazz says is “an indispensable feature of well-reasoned agency decisionmaking.”  The record also does not reflect consultation with the requisite experts, and FDA ignored some of the risks associated with elevated sodium intake, which is precisely the benefit provided by Xywav.  Additionally, Jazz says, FDA exaggerated the importance of once-nightly dosing because the idea that Lumryz allows narcolepsy patients to achieve “normal” sleep is scientifically baseless and unsupported.

Avadel has intervened as a Defendant, and neither FDA nor Avadel has yet to respond to the Complaint.  Our best guess is that FDA will argue that it has broad authority to interpret the provisions of the Orphan Drug Act and interpret “clinical superiority” and “same drug” as it sees fit.  Though FDA has a losing streak when it comes to the Orphan Drug Act, this case is a bit of an uphill battle for Jazz because Congress did include a clinical superiority provision in the Orphan Drug Act as of 2017, and FDA has broad discretion to categorize the basis of its clinical superiority decisions (i.e. greater efficacy, greater safety, or MC-to-PC), and even wider discretion to make MC-to-PC determinations, “which are evaluated on a case-by-case basis for each drug product.”  Such discretion is typically carte blanche for FDA in these types of cases, but again FDA’s track record with the Orphan Drug Act is pretty bleak.  We will keep on watching, as this case is one that might keep us up at night.