US FDA Must Explain How It Defines ‘Innovation’ In Awarding Hatch/Waxman Exclusivity, Court Says
Executive Summary
Agency's decision that Indivior’s Sublocade blocked Braeburn’s long-acting buprenorphine formulation Brixadi lacked ‘substantive guideposts’ in how innovation is defined for purposes of deciding scope of three-year exclusivity, US judge says.
The US Food and Drug Administration must set forth a standard by which a drug’s “innovation” is defined in determining whether Hatch/Waxman new product exclusivity blocks approval of a subsequent product, a US federal judge has ruled in a dispute related to buprenorphine depot injection formulations.
The agency’s decision that the monthly formulation of Braeburn Pharmaceuticals Inc.'s Brixadi (buprenorphine extended-release injection) cannot be approved until three-year exclusivity for Indivior PLC’s Sublocade expires failed to define the limits of the latter product’s innovation, Judge Beryl Howell of the US District Court for the District of Columbia said in a 22 July memorandum opinion.
The court remanded the case for the FDA to reconsider, “with deliberate speed,” whether Braeburn’s application for the monthly depot version of Brixadi is eligible for final approval.
“The FDA’s judgment about whether Sublocade and Brixadi Monthly are meaningfully different was made against the backdrop of an approach to defining Sublocade’s innovation that lacked substantive guideposts, and, consequently, against a possibly overly narrow vision of what ‘differences are relevant for purposes of this analysis,’” the court said.
“Once the FDA made its unguided decision that Sublocade’s innovation was a monthly depot to treat moderate-to-severe OUD [opioid use disorder], any other difference was necessarily irrelevant, even if those differences make Brixadi Monthly available to a patient population, for example, that Sublocade is not,” the court said.
The court remanded the case for the FDA to reconsider “with deliberate speed” whether Braeburn’s application for the monthly depot version of Brixadi is eligible for final approval.
Brixadi’s Path Blocked
Braeburn sued the FDA in April, challenging the agency’s decision that Brixadi, which is tentatively approved, was blocked from market by Sublocade’s three-year exclusivity, which runs until 30 November 2020. (Also see "Blocked By Sublocade: Braeburn Sues To Get Brixadi Buprenorphine Formulation Onto Market" - Pink Sheet, 10 Apr, 2019.)
The agency determined that Sublocade’s unexpired exclusivity blocked Brixadi because both are monthly buprenorphine products indicated for treating moderate-to-severe opioid use disorder. The agency rejected Braeburn’s view that the scope of Sublocade’s exclusivity should be limited to its specific formulation, and that differences in indications, treatment regimens and dosing between the two drugs are relevant for purposes of the exclusivity analysis.
The Brixadi weekly depot formulation falls outside of Sublocade’s conditions of approval, however, and could be approved upon submission of appropriate labeling, the FDA said. Braeburn has declined to pursue approval of only the weekly formulation, asserting that the weekly and monthly formulations function as an integrated system.
Indivior intervened in Braeburn’s lawsuit as a defendant.
No Standard For Determining Innovation
Whether an existing drug’s exclusivity precludes final approval of a subsequent product depends upon the overlap between “the conditions of approval” of the two products, Judge Howell said.
Finding the meaning of the term “conditions of approval” to be ambiguous in the statute, the court examined whether the FDA reasonably construed the statutory language.
In a letter decision on Brixadi Monthly, the agency interpreted “the conditions of approval” to limit exclusivity to situations in which a follow-on product shares the “innovation” supported by the first product’s “new clinical investigations essential to approval,” the court said.
“In other words, a follow-on drug product cannot be approved within three years of the first product’s approval, no matter the two products’ differences, if the latter product incorporates the first’s innovative features,” the court said. “To determine a drug product’s innovative features, the FDA compares what changes an exclusivity-eligible drug product has made relative to any drug products previously approved to administer the same active moiety or moieties.”
Although the FDA’s interpretation suggests that it identifies “the conditions of approval” as a subset of a drug product’s features entitling it to exclusivity, the letter decision “gives short shrift to how the FDA arrived at is chosen statutory construction,” the court said.
“Describing a feature as an ‘innovation’ risks becoming an empty label if the agency lacks a standard by which innovation is determined.” – US Judge Beryl Howell
“Describing a feature as an ‘innovation’ risks becoming an empty label if the agency lacks a standard by which innovation is determined,” the court said.
The agency adequately explains when a product’s characteristics are not innovative, such as if the feature already has been proven safe and effective in conjunction with a prior drug application, the court said. “Yet, that definition is incomplete as it provides only a threshold for a characteristic to be deemed innovative.”
“The FDA needs a rationale, based in the statute, to define the boundaries of a drug product’s innovation,” the court said. “Without any intelligible decisional principle for identifying innovation, the FDA’s standard simply supplants the ambiguous phrase ‘the conditions of approval’ for the ambiguous term ‘innovation.’”
The FDA has not explained what legal or scientific standard it applied to define Sublocade’s innovation in the broad manner set forth in the letter decision, the court said.
“Why is dosing interval a way in which Sublocade’s innovation is limited, but the drug product’s high-loading dose of 300 mg, the patient population on which it was tested, or other details of its specific treatment regime, are not? Leaving questions like that unexplored is especially pertinent given that both the FDCA and the FDA appreciate that drugs’ characteristics may differ in multiple important dimensions.”
The court acknowledged that the Brixadi Monthly attributes that Braeburn believes put the product outside the scope of Sublocade’s innovation “might not, in fact, do so. That possibility does not save the agency’s decision.”
“Rather, to analyze properly whether Brixadi Monthly is ‘for the conditions of approval’ of Sublocade, the FDA must first explain what separates the elements of the essential clinical investigations incorporated into the definition of a drug product’s innovation from those that are irrelevant, and why the identified dividing line reasonably applies” to the statutory exclusivity provision, the court said.
Inconsistent Treatment
Separately, the court said the FDA’s letter decision must be vacated as arbitrary and capricious because it was inconsistent with the exclusivity determination involving an earlier product, Titan Pharmaceuticals Inc.'s Probuphine (buprenorphine subdermal implant), which is distributed by Braeburn.
The agency limited Probuphine’s defined innovation, in part, by the patient population that participated in the essential clinical trial, but it failed to follow this same approach for Sublocade, the court said.
“If the Letter Decision had been consistent, Sublocade’s innovation might have been defined as something akin to ‘monthly depot injection for the treatment of OUD in new-to-treatment patients following one week of titration on oral buprenorphine.’ With that definition of innovation, the reach of Sublocade’s exclusivity might have been different.”
Orphan Exclusivity Questions Await
In a statement, Braeburn President and CEO Mike Derkacz said the court’s decision is an important step toward making Brixadi available to health care providers and patients. “We look forward to working expeditiously with FDA to get Brixadi on the market as soon as possible.”
The FDA said it is reviewing the court’s decision and it would be premature to comment on the case at this time.
Indivior said it is continuing to review the decision and its options.
At the time Braeburn filed its lawsuit, the firm also petitioned the FDA to revoke Sublocade’s orphan drug designation and refuse to grant the Indivior drug seven-year orphan exclusivity. (Also see "US FDA’s Transfer Policy For Orphan Drug Designation Under Scrutiny" - Pink Sheet, 10 Apr, 2019.) The agency has not yet taken action on the petition.
It remains unclear whether an FDA Reauthorization Act requirement that a sponsor demonstrate clinical superiority to an already-approved version of the same drug would apply to Sublocade, which received orphan designation prior to FDARA but was approved after the statute was enacted.
In the federal litigation, Indivior had argued that Braeburn lacks standing to challenge the FDA’s letter decision because the Sublocade new product exclusivity determination is not causing any harm to Braeburn that is separate from the impact of Sublocade’s right to orphan drug exclusivity through 2024.
Judge Howell said Indivior’s argument was unconvincing and based on a “hypothesized future event” because, as the company acknowledges, the FDA has not decided whether Sublocade is even entitled to orphan drug exclusivity.
Although Indivior maintains that Sublocade’s right to orphan exclusivity is certain, not speculative, Judge Howell saw it differently. It remains unclear whether an FDA Reauthorization Act requirement that a sponsor demonstrate clinical superiority to an already-approved version of the same drug would apply to Sublocade, which received orphan designation prior to FDARA but was approved after the statute was enacted, the court said.
“Moreover, even if Sublocade were found to be clinically superior to past versions of the same drug, the FDA might determine that Brixadi Monthly is clinically superior to Sublocade and thus not subject” to Sublocade’s orphan drug exclusivity, the court said.