Advisory Committee Sides With FDA: King/Acura's Acurox Fails To Prevent Abuse

The public forum did no favors for Acurox, as advisory committee members questioned whether adding niacin to oxycodone would really deter abuse.

King Pharmaceuticals and Acura Pharmaceuticals' attempts to use a joint advisory committee review of Acurox , their abuse-resistant formulation of oxycodone, to get around FDA's initial rejection in a "complete response" letter backfired when the panel sided with the agency.

"We already turned the drug down, but the company said we disagree with your interpretation of the data, so we brought it before the advisory committee," Bob Rappaport, director of FDA's Division of Anesthesia and Analgesia Products, said at the April 22 meeting.

The lopsided 19-1 vote against the niacin-containing formulation of the immediate-release opioid by the Anesthetic and Life Support Drugs Committee and Drug Safety and Risk Management Advisory Committee underscores the difficulty drug companies are having in developing abuse-resistant formulations of opioid analgesics that FDA will approve.

King itself has run into considerable problems before in this area, with its long-acting products. Its abuse-resistant Embeda (long-acting morphine/naltrexone) was delayed to create a Risk Evaluation and Mitigation Strategy and its abuse-resistant extended-release oxycodone Remoxy received a "complete response" letter in December 2008 (Also see "FTC Lets King Buy Alpharma Now That Antitrust Problem Is Resolved – But New Embeda Delay Adds Risk To Acquisition" - Pink Sheet, 4 Jan, 2009.).

The company received the "complete response" letter for Acurox on June 30, 2009. According to the sponsors' briefing materials for the advisory committee meeting, FDA looked at the clinical trial data and "questioned the incidence of flushing in pain patients and the relative effectiveness of niacin to minimize the potential for oxycodone abuse."

By bringing the NDA before a public venue, King and Acura were able to receive support from advocacy groups for drug abuse victims and pain patients - with about 20 speakers during the public comment section of the meeting calling for FDA to approve the drug. But the demonstration of the need for the product on the market was not enough to sway the panel.

Instead, the committee was hung up on the same issues as FDA - that the niacin component was not sufficient to defeat abuse, while its inclusion in the formulation could cause discomfort for actual pain patients.

Niacin Fails As An Abuse Deterrent

All the FDA speakers hammered home the point that the sponsors had not proven that adding niacin (vitamin B3) to Acurox to create an unpleasant flushing sensation was enough to deter abusers from taking it, because the effect is tolerable and can be suppressed by eating or taking aspirin or a non-steroidal anti-inflammatory drug.

"There is complete obliteration of these effects [flushing] by food," Igor Cerny, a senior clinical analyst with FDA's Division of Anesthesia and Analgesia Products, said. "The effects are mildly unpleasant but tolerable; tolerability improves in a fed state."

"This fairly easy way to circumvent the potential abuse deterrent properties of Acurox calls into serious question the efficacy of the added niacin," Cerny stated. "We believe the applicant has failed to justify the addition of niacin."

Citing published studies, Kenneth Sommerville, vice president of clinical development at King, argued, "In no instance did aspirin or an NSAID abolish flushing. The effect is dose dependent and incomplete. Food also mitigates the effect, but in a variable and incomplete way."

But the questions to the sponsor from the advisory committee members were tough, if not hostile. The flushing "is the mildest drug side effect I've ever heard of," Michael Yesenko of the HHS Substance Abuse and Mental Health Services Administration said. Noting that one of the oral abuse liability studies found that 23 percent of the subjects would still like to take Acurox as opposed to unadulterated oxycodone despite the flushing effect, he added, "How is that a deterrent?"

On the other hand, Charles Cleeland, University of Texas M.D. Anderson Cancer Center, expressed concern that legitimate patients might be reluctant to take Acurox due to the niacin flushing effect. "What is the physician-patient interchange going to look like ... if the physician has to say, here are these pills, but don't take too many because it's going to get you?"

"All drugs have a side effect profile," replied Lynn Webster, medical director of the Lifetree Clinical Research and Pain Clinic, on behalf of the sponsor. "Like any other drug, you have to have a dialogue about how to manage the side effects."

Another problem was that the drug "liking" scale used in the clinical trials had not been validated, Lewis Nelson, New York University School of Medicine, noted. Overall, he said, "the whole concept seems too vague. It doesn't pass the smell test."

Other Anti-Abuse Aspects Of Acurox Are Effective, Panel Says

Still, there was a note of regret in the advisory committee vote against approval, in part because alongside the niacin to discourage oral abuse, Acurox also contains sodium lauryl sulfate to make sniffing the drug in crushed form unpleasant, and an excipient to turn it into a gel that can't be injected easily if dissolved in liquid. Indicating that she would have voted for approval if those were the only abuse-deterrent additives in Acurox, Almut Winterstein, University of Florida said, "I wish it didn't have niacin."

"We did not have different conclusions than the sponsor" on these aspects, Sharon Hertz, deputy director of FDA's Division of Anesthesia and Analgesia Products, said. "We thought the effects on snorting and studies evaluating the physical properties in an attempt to get this to be injectable were fine. We thought the tests supported the underlying concepts."

But in answer to FDA's question about whether the studies assessing the effects of niacin on drug "liking" had been conducted appropriately, the committees generally agreed they had not, and as for changing the study design to make it acceptable, "I wouldn't waste my time," John Farrar, University of Pennsylvania, said. For future abuse liability studies, the drug "liking" concept may be too vague, he said. "We have to study what would make Johnny not take the pill."

- Martin Berman-Gorvine ([email protected])