Abuse-Resistant Opioids: How Much Deterrence Is Enough For A Labeling Claim?

FDA advisory committee will consider post-market study plans for King's Embeda and Purdue's reformulated OxyContin.

How much deterrence is enough to label a drug as abuse-deterrent?

The answer to that question will be key to determining FDA's standard for labeling a drug as abuse deterrent and to designing post-market trials so they demonstrate the effectiveness of anti-abuse formulations in curbing recreational use of opioids.

Any incremental reductions in abuse are valuable, Division of Anesthesia and Analgesia Products Director Bob Rappaport said in a briefing memo to members of the Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees who will meet Oct. 21-22 to discuss post-market trial design issues for anti-abuse formulation opioids.

But in designing a large epidemiological study to demonstrate whether an abuse-deterrent formulation (ADF) works, he pointed out, "it is essential to understand what degree of decrease in abuse and its consequences would be sufficient to conclude that the product is actually abuse deterrent in the community" and can be labeled as such.

"It is essential that the product labeling is accurate and that promotion by the manufacturer be based on explicit or implicit language in that label that is not misleading," he said. Otherwise, the medical and patient communities could be misled about a drug's abuse potential and the existing public health crisis could worsen, he noted.

King And Purdue Each To Present Suite Of Post-Market Studies

As the focus of the meeting is trial design, FDA has invited King Pharaceuticals and Purdue Pharma to discuss studies they are developing to show whether their anti-abuse products prevent abuse. King's Embeda contains extended release morphine sulfate coupled with a sequestered naltrexone hydrochloride inner core that is released when the drug is chewed, crushed or dissolved and blunts the psychoactive effects of the morphine ('Chew On This: FDA OK's Tamper-Resistant Morphine, Embeda,' 'The Pink Sheet' DAILY, Aug. 13, 2009). Purdue's reformulated Oxycontin (oxycodone hydrochloride controlled release) is formulated to make breaking, crushing or chewing more difficult and to form a viscous gel when dissolved ('FDA Okays Purdue's Newer OxyContin; Payors And Physicians Chew On Drug's Benefit,' 'The Pink Sheet' DAILY, April 6, 2010).

King is proposing five studies and Purdue is looking at seven. The studies are in early draft form and FDA has not yet provided any feedback on them, so the panel will not vote on whether they are appropriate.

Rather, Rappaport says, they are to be considered as examples of possible designs, metrics and outcomes during a discussion "intended to define a current gold-standard study (or studies) for the evaluation of the impact of products designed to be abuse deterrent on actual abuse in the community."

To identify that standard, FDA is looking for committee input on a range of issues: the most effective and efficient metrics and surveillance systems for evaluating the impact of abuse-deterrent formulations and whether new surveillance systems are needed; how to evaluate the ADF's impact on the numerous populations and methods of administration involved in opioid abuse and misuse; appropriate comparators; how to evaluate novel analgesics introduced in an ADF; an adequate duration for a post-market study; and the aspects of King's and Purdue's proposals that would be applicable to ADF products in general.

In addition to aiding sponsors of potential ADFs, the panel's discussion on how much deterring power the formulations must have and how to measure that power will help FDA determine how to assess the impact of a Risk Evaluation and Mitigation Strategy for long-acting and extended-release opioids.

As part of that effort, FDA already is collaborating with several federal agencies to determine ways to measure changes in non-medical use of opioids, opioid-related overdose, addiction and dealth and in doctors' prescribing patterns ('Sponsors Will Need New Databases And Metrics To Determine Success of Opioids REMS,' 'The Pink Sheet' DAILY, June 29, 2010).

-Cathy Dombrowski ([email protected] )