US FDA’s Transfer Policy For Orphan Drug Designation Under Scrutiny

Braeburn Pharmaceuticals says awarding Indivior’s opioid use disorder treatment Sublocade seven-year orphan exclusivity that flows from a 1994 orphan drug designation for Subutex would be an abuse of the system. The US FDA said it is carefully considering whether Sublocade qualifies for exclusivity ‘within the context of the opioid public health emergency.’

The US FDA’s approach to transferring orphan drug designation from a sponsor’s original product to a follow-on formulation is under scrutiny in the face of the opioid crisis.

In an April 5 citizen petition, Braeburn Pharmaceuticals Inc. requests the FDA revoke orphan drug designation for Indivior PLC’s Sublocade, a long-acting depot formulation of buprenorphine, for the treatment of opioid addiction. The agency also should refuse to grant the drug seven-year orphan exclusivity, the petition states.

The FDA said it is carefully considering if Sublocade qualifies for orphan exclusivity and is committed to an expedited review of the matter.

Braeburn’s own depot formulation of buprenorphine, Brixadi, received tentative approval Dec. 21 but is blocked from coming to market by Sublocade’s three-year Hatch-Waxman exclusivity, which expires in November 2020. Braeburn is suing the FDA over the scope of that exclusivity period. (See sidebar.)

Separately, however, Braeburn is seeking to preempt an FDA award of orphan exclusivity for Indivior’s product.

The Orange Book listing for Sublocade does not include any information about orphan drug exclusivity. However, FDA’s orphan products database lists Sublocade jointly with Subutex, Indivior’s older sublingual tablet formulation of buprenorphine.

Subutex received orphan drug designation in June 1994 for treatment of opioid addiction in opiate users. It was approved in October 2002 for treatment of opioid dependence in patients 16 years and older. Its seven-year orphan drug exclusivity expired in October 2009, and the drug is no longer marketed.

The FDA’s orphan drug designation database includes the same June 1994 designation date for Sublocade, which was approved in November 2017 for treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for a minimum of seven days. The database lists the orphan drug exclusivity end date as “TBD,” or to be determined.

A Feb. 28 letter from Division of Anesthesia, Analgesia and Addiction Products Director Sharon Hertz to Braeburn concerning the dispute over Sublocade’s three-year marketing exclusivity references Indivior’s orphan drug designation for buprenorphine.

“If Sublocade qualifies for orphan drug exclusivity, that exclusivity may further affect the timing of approval for Brixadi,” Hertz said.

‘Not A Bona Fide Orphan Drug’

Braeburn’s citizen petition seeks to head off such an occurrence.

“Braeburn was dismayed to learn from FDA that Sublocade may be granted ODE [orphan drug exclusivity], which could prevent any other buprenorphine product intended to treat OUD [opioid use disorder] from coming to market” until December 2024, the petition states.

“This would be a major mistake not only because Sublocade obviously does not qualify as a bona fide orphan drug, but also because Indivior already obtained and used its ODE for Subutex (and Suboxone) from 2002 through 2009 to generate extraordinary and long-dated financial returns.”

“Incredibly, Indivior now appears to be seeking a second, successive exclusivity period for Sublocade based upon the same 1994 ODD that triggered the first exclusivity period for Subutex,” the petition states. “This is a blatant attempt to abuse the orphan drug system by engaging in inappropriate and offensive ‘evergreening’ of ODE, contrary to the intent of Congress.”

The basis for the FDA’s original grant of orphan drug designation to Subutex was highly unusual in that it was based on the sponsor’s assertion that there was no reasonable expectation it would recover development and marketing costs for the drug in its first seven years after approval, the petition states.

“This 1993 assertion, which turned out to be wildly inaccurate, has absolutely no relevance to whether Sublocade, which was approved nearly 25 years later, qualifies as an orphan drug in 2019,” the petition states.

Informal Policy With Potentially ‘Devastating Effects’

The FDA’s decision to transfer Subutex’s orphan drug designation to Sublocade appears to stem from an informal policy that allows certain sponsors to transfer orphan designation granted for one drug to a subsequent version of that drug without submitting either a separate request for designation, or a plausible hypothesis that the follow-on drug is clinically superior to the first drug, the petition states.

“Although this policy is briefly mentioned on FDA’s website, it is not set forth or explained in any FDA regulation or guidance document,” the petition states. Furthermore, it is unclear when this policy was adopted because the FDA has applied it in some recent cases but not in other older situations, Braeburn said.

“The precise scope of FDA’s informal policy, therefore, is unclear. However, it does not seem to incorporate any time limits between ODD transfers,” the petition states. “In other words, as far as Braeburn can tell, FDA will transfer ODD regardless of how long ago (or on what basis) the original ODD was granted, and irrespective of any other considerations or intervening developments.”

Granting orphan drug exclusivity to Sublocade “would have devastating public health consequences by blocking any and all future buprenorphine products from coming to market for seven years (no earlier than December 2024) – in the middle of one of the worst opioid epidemics in US history,” the petition states. “This would also result in monopoly pricing. Such an outcome would represent an historic abuse of the Orphan Drug Act.”

Eligibility For Exclusivity Under Review

The FDA told the Pink Sheet it designated buprenorphine as an orphan drug for treatment of opiate addiction in 1994 based on information from the sponsor that, at that time, there was no reasonable expectation the R&D costs of the drug could be recovered by sales in the US.

“The decision was based on a rarely used provision of the Orphan Drug Act allowing designation based on this economic criterion,” the FDA said. “Under the statute, that evaluation was based on information and facts as of the date designation was requested in 1994.”

Whether Sublocade qualifies for orphan status and seven-year exclusivity is being considered “within the context of the opioid public health emergency and with consideration to our regulatory authority.” – FDA

Orphan designation attaches to a molecule, or more precisely the active moiety, not to particular drug products, the FDA said. “In other words, once buprenorphine is designated as an orphan drug for the treatment of opiate addiction, all future approvals of the same active moiety for that indication from the sponsor holding designation may be eligible for orphan exclusivity.” However, the FDA added: “This is something the agency is currently assessing.”

The FDA's evaluation of whether Sublocade qualifies for orphan status and exclusivity is ongoing “within the context of the opioid public health emergency and with consideration to our regulatory authority,” the agency said.

During the pendency of any orphan exclusivity period, newer versions of the same drug for the same use can be approved if those versions are clinically superior to previous formulations, the FDA said. Such clinically superior versions also may be eligible for their own period of orphan exclusivity. “These provisions give sponsors incentives to innovate/bring better versions of orphan drugs to market,” the agency said.

Even assuming that Sublocade were eligible for orphan exclusivity, the FDA said it would be misleading to suggest that all future buprenorphine products would be blocked from approval. “For example, buprenorphine products that are clinically superior to Sublocade would not be blocked by its orphan exclusivity.”

“The agency recognizes that, in general, the nation is in urgent need of new and better treatment options for opioid use disorder, and FDA remains committed to helping advance development of new treatments, promote novel formulations or delivery mechanisms of existing drugs to support patients.”

Indivior’s View

Indivior told the Pink Sheet that it originally submitted a request for orphan drug designation for buprenorphine (Subutex) “in accordance with the agency’s longstanding policies. The FDA exercised its independent judgment at that time, and fully agreed with Indivior that buprenorphine should be so designated for the treatment of opioid addiction in opiate users.”

Sublocade also was granted orphan drug designation in accordance with the FDA’s policies, the company said. “The agency is currently reviewing whether Sublocade is entitled to orphan drug exclusivity based on its previous orphan drug designation.”

Indivior said it has made substantial investment and worked for eight years to develop Sublocade, and was rewarded with three years of marketing exclusivity for performing new clinical studies necessary to support the drug’s approval.

“The entire regulatory framework in the US is structured to encourage such research into groundbreaking medicines and to allow companies to both cover their costs and to incentivize the next generation of research and development,” Indivior said. “Furthermore, the market for treatment of OUD is highly competitive, with over a dozen products currently on the market, including multiple generic versions of buprenorphine.”

On April 7, the US Department of Justice announced a federal grand jury indictment of Indivior for allegedly deceiving healthcare providers and benefit programs into believing that Suboxone (buprenorphine/naloxone sublingual film) was safer, less divertible, and less abusable than other opioid-addiction treatment drugs.

The indictment alleges that Indivior announced it was discontinuing the tablet form of Suboxone based on concerns about pediatric exposure, when in fact company executives knew the primary reason was to delay FDA approval of generic tablet forms of the drug. (See sidebar.)