麻豆传媒

An FDA advisory committee voted unanimously Thursday that the risks of a novel amphetamine designed to deter abuse outweighed the benefits, concluding it may in fact be misused and could be even more dangerous than conventional stimulant medications for attention deficit-hyperactivity disorder (ADHD).

The panel also voted 19-2, with two abstentions, that drugmaker Arbor Pharmaceuticals did not adequately address the safety of AR19 (amphetamine sulfate), with many panelists noting that the drug appeared safe when administered orally, but that high levels of talc and polyethylene oxide in the drug's composition could be toxic if taken through snorting or injection.

The of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee also concluded with a 15-8 vote that Arbor did not adequately demonstrate AR19 would deter intravenous use, and voted 19-4 that it did not adequately demonstrate it would deter intranasal use.

In fact, the product's ability to deter manipulation was "slim to nonexistent," while the risks of the excipients were "too high and uncharacterized" to establish safety, said panel member Steven B. Meisel, PharmD, of M Health Fairview in Minneapolis.

The immediate release, pellets-in-capsule drug contains the same active ingredient as Arbor Pharmaceuticals' currently-approved , but with physical and chemical barriers to deter non-oral intake.

Many panelists agreed that an abuse-deterrent amphetamine would be beneficial. But the likely impact on abuse would be relatively small, they said.

Moreover, the vast majority of amphetamine abuse occurs through the oral route, and non-oral misuse often starts with oral misuse, said Sonia Hernandez-Diaz, MD, MPH, DrPH, of the Harvard T.H. Chan School of Public Health in Boston. AR19 was not proposed to deter oral abuse.

"I think this approach would make sense if manipulation were working very well and [AR19] was the only amphetamine on the market," Hernandez-Diaz added.

The conclusions of the panel may come as no surprise after the skeptical review FDA staff gave the product received in advance of Thursday's meeting. Agency scientists wrote that it was feasible to extract a minimum reinforcing dose (10 mg amphetamine per mL over 1 minute) suitable for injection when using higher doses of AR19.

Arbor's own studies aimed at determining whether manipulation could allow the drug to be snorted showed that ordinary household tools couldn't significantly reduce particle size. But with modifications, one tool was able to crush AR19 particles down to snortable size.

Philip Posner, PhD, the panel's patient representative from Gainesville, Florida, voted yes to both the intranasal and intravenous deference questions. He argued the evidence showed users would be far less likely to abuse AR19 compared to other stimulants on the market.

"When you compare this product with everything else that's on the market, or that students can get elsewhere, I think they're going to take the easy way out," Posner said. "They're not going to go through the excess work of emptying capsules, crushing tablets, and putting them in powder form to snort."

That view failed to persuade Karim Anton Calis, PharmD, MPH, of the National Institutes of Health (NIH), who voted no on all four questions and said individuals seeking to misuse drugs will find a way regardless.

"Unfortunately, there are creative individuals and methods of manipulation that can subvert that and those can be very quickly disseminated on social media," Calis said.

FDA staff had faulted several of Arbor's studies, including one measuring "drug liking" that failed to meet its pre-specified margin. "When you set up a study with an endpoint and you fail to meet the endpoint, to me that is pretty telling there is not adequate evidence," Meisel said.

Panelists also discussed the appropriateness of approving an abuse-deterrent formulation of an amphetamine in general, as AR19 would have been the first such product to receive this classification from the FDA.

The panel generally agreed that nonmedical use of stimulants was a public health threat, especially for adolescents and college students. However, many were cautious of the "abuse-deterrent" classification, especially after another FDA panel recently concluded that the abuse-deterrent formulation of Oxycontin (oxycodone) introduced in 2010 has not lessened overall abuse.

Jon E. Zibbell, PhD, of RTI International in Atlanta, Georgia, argued that the "abuse-deterrent" classification is ill-defined and that public health interventions -- such as reducing prescribing, implementing preventive drug use education in schools, and universal needle exchange access -- may be more effective in reducing abuse.

The drugmaker and panelists agreed that the term "abuse-deterrent" may further stigmatize patients and lead to a false sense of security that the product is "abuse-proof."

"This is a chemical response to a chemical problem," Zibbell said. "It seems like ADFs [abuse-deterrent formulations] are creating more harm."

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