SILVER SPRING, Md. – Members of two FDA advisory committees on Wednesday narrowly favored approval for SpecGx's putatively abuse-deterrent oxycodone product MNK-812, with plenty of arguments both for and against.
With a 10-7 vote, the FDA's Anesthetic and Analgesic Drug Products and Drug Safety and Risk Management Advisory committees gave lukewarm backing to the immediate-release oxycodone tablet, which is formulated to resist abuse by injection or snorting.
A larger majority (12-5) agreed that MNK-12 could be labeled as deterring abuse by the nasal route, but most members (10-7) did not think deterrence of intravenous injection was sufficiently proven.
Developer SpecGx, a unit of Mallinckrodt Pharmaceuticals, designed the tablet to be difficult to crush and to become a viscous gel in liquid environments. The product also contains compounds that effervesce in water, making it disagreeable to snort.
Mallinckrodt is seeking an indication for management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. If approved, the company has said it will cease production of its current branded and generic formulations of non-abuse deterrent formulation immediate-release single-entity oxycodone tablets -- including Roxicodone and generic oxycodone -- and replace them with this drug.
Mallinckrodt submitted a New Drug Application in January following two Phase I pharmacokinetic studies conducted to demonstrate bioequivalence to the FDA-approved drug Roxicodone (at a 15-mg dose of the new drug), and a human abuse potential study.
In testimony Wednesday, the company described its efforts to document abuse deterrence. In a study of 38 recreational opioid users who inhaled MNK-812, oxycodone IR or placebo, participants reported statistically significantly less drug liking for MNK-812 and reported statistically significantly less willingness to try it again compared with oxycodone.
The FDA countered that these nasal effects were most prominent within the first 15 minutes of inhalation and declined substantially within an hour. Additionally, an FDA researcher testified that, in the agency's own tests, they were able to recover up to 60% of oxycodone from 30 mg MNK-812 tablets with some physical manipulation and 5 mL of an unnamed household solvent, generating a syringeable dose in about an hour. Investigators extracted more than 80% of oxycodone from the tablets when soaked in 30 mL of common solvent.
These mixed results prompted debate among committee members, with some questioning whether the short-term nasal irritation would be enough to quell people with serious opioid use disorders, as well as on how to define abuse deterrence. As in previous meetings on supposedly abuse-deterrent opioids (10 of which are now approved), some members questioned whether such labeling would create a false sense of security for prescribing physicians, while others said the drug is a step in the right direction.
Brian T. Bateman, MD, MSc, of Harvard Medical School and Brigham and Women's Hospital, said he voted yes because of MNK-812's bioequivalence to Roxicodone. "IR [immediate-release] oxycodone is widely abused so there's a clear need for abuse deterrent formulations," he said. "While the abuse deterrent properties are perhaps not as robust as we might like, it is an important advance over existing formulations." Others agreed.
But one of the "no" voters, Jon F. Zibbell, PhD, of the Behavioral Health Research Division of RTI International in Atlanta, argued that there are already other drugs on the market for pain. In earlier debate, he noted that the gel components of MNK-812 could be overcome by adding the drug to larger amounts of water, potentially creating a large enough volume of drug to be shared intravenously and cause a public health risk.
Suzanne B. Robotti, executive director of DES Action USA and founder and president of the MedShadow Foundation, also voted against the drug's approval. "If the distribution of the drug could be limited to those who prescribed it appropriately and used it appropriately, I would feel differently but there's a very predictable expectation that there will be illegal abusive use. I don't believe the drug is a big enough step forward to warrant the risk that it causes." She also argued that manufacturers for this and similar drugs have done little to deter abuse via the oral route.
An FDA official noted that the opioid crisis is still a problem, with data indicating oxycodone was misused by 3.9 million individuals in the U.S. in 2016; 35% of people entering treatment for opioid use disorder that year reported abusing oxycodone within the previous month.
Existing abuse-deterrent opioid products have not been widely adopted, said Sharon Hertz, MD, director of the FDA's Division of Anesthesia, Analgesia, and Addiction Products for the Office of Drug Evaluation II: "This may reflect several factors, including cost and a sense by prescribers that it might be insulting to prescribe such a product to a trusted patient."
There is also a lack of evidence that abuse-deterrent analgesic products have had the intended effect of reducing abuse, she added: "While there have been publications making a number of such assertions, no company has actually submitted the post-marketing data to support labeling statements that [abuse deterrent formulations] have the intended effect."
Mallinckrodt is committed to conducting such testing, said Martha Sclicher, PhD, vice president of R&D for the company.