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Over the past year, a number of pharmaceutical firms have been pursuing a pharmacological approach to combating opioid abuse, submitting new drug applications (NDAs) for formulations specifically designed to deter tampering and abuse. A key question in the applications for approval has been whether, at this point in time, the FDA will allow the use of a label indicating that a formulation is either “abuse-deterrent” or “tamper resistant.”
Below, Kevin Zacharoff, M.D., Director of Medical Affairs at Inflexxion, discusses how the FDA has responded, and explores the challenges ahead for companies seeking to demonstrate the capacity of their products to deter misuse, abuse, or tampering.
“In my view, what we’re seeing in the FDA′s responses so far is indicative of a larger trend, where the need for systems to monitor the actual use of products over time is becoming increasingly evident,“ says Zacharoff. “How do you establish that a formulation is ‘abuse-deterrent’? Regardless of the intrinsic, physical characteristics of a formulation, an ongoing, epidemiologically-based approach is necessary for a real-world, dynamic measurement of the capacity to deter abuse.”
Read on for the full essay, and stay tuned for future issues as we explore developments that are changing the shape of pharmaceutical risk management.
Sincerely,
The NAVIPPRO team
Demonstrating the capacity of an opioid to deter abuse
How do we establish that a formulation is truly “abuse deterrent”?
By Kevin Zacharoff, M.D.
On March 3rd, Acura Pharmaceuticals, Inc. and King Pharmaceuticals, Inc. announced that the FDA had accepted its new drug application (NDA) for the immediate-release opioid analgesic Acurox® with a priority review classification.
What makes the announcement especially noteworthy is that Acurox is among a number of new products that have been formulated to resist or deter common methods of misuse and abuse. With priority review, it may serve as a bellwether in this arena, helping to clarify key questions for companies seeking approval of abuse-deterrent formulations. Among them: How will the FDA handle labeling of these medications? If the Agency does not approve the use of an “abuse-deterrent” label, how will the sponsors convey the potential benefit of these formulations?
So far, the FDA has demonstrated caution in approving abuse-deterrent formulations. In May, the Agency held a hearing on Purdue’s reformulated version of OxyContin, and the company has signaled that it will continue to work with the FDA on its NDA. In October, Abbott Laboratories received a Complete Response Letter about its extended-release form of Vicodin; it is also continuing work, but has suspended plans to market the drug in 2009.
Two other formulations are currently under consideration for approval: King’s Remoxy, an extended-release formulation of oxycodone, and Embeda, a preparation of morphine sulfate and naltrexone HCI. In December, the FDA requested more nonclinical data to support Remoxy’s application. It also delayed approval for Embeda pending further evaluation of the sponsor’s plans for minimizing risks. It remained unclear whether an explicit “tamper resistant” or “abuse deterrent” designation would be part of an approved label for either medication.
In the case of Acurox, the Agency has specifically addressed the issue of labeling. According to a media release on the NDA, the FDA has indicated that “an explicit claim of abuse deterrence requires the demonstration of an actual reduction in product abuse by patients or drug abusers in routine clinical practice, after approval“ (emphasis added).
The Agency may instead allow on the label inclusion of 1.) information about the physical properties of the product that may deter abuse, and/or 2.) information from laboratory and clinical studies designed to simulate the relative difficulty of abusing product candidates using Acura's Aversion Technology.
What are the big-picture implications? In my view, what we’re seeing in the FDA′s responses so far is indicative of a larger trend, where the need for systems to monitor the actual use of products over time is becoming increasingly evident. How do you establish that a formulation is “abuse-deterrent”? Regardless of the intrinsic, physical characteristics of a formulation, an ongoing, epidemiologically-based approach is necessary for a real-world, dynamic measurement of the capacity to deter abuse.
The reason is that while a product may indeed be more difficult to tamper with, and have the demonstrated potential to deter abuse, we cannot fully verify that potential until after it hits the market, when extrinsic factors can come into play. Or, as Deborah Leiderman M.D., puts it in the roundtable discussion on abuse deterrence that we published in Issue #4 of this newsletter, “The designations of ‘abuse resistant’ or ‘abuse/tamper deterrent’ are theoretical or hypothetical characteristics that require empiric validation in the community.”
Suppose, for instance, that clinicians misinterpret an “abuse deterrent” label, and prescribe these “safe” medications inappropriately. The result could be misuse of powerful medications. “If physicians did not adhere to principles of appropriate prescribing and modified their practices based upon the perception of reduced risk of these drug products, this could be viewed as an unintended consequence of product labeling,” says Leiderman. “That is why there needs to be a cautious, step-wise approach to labeling of these modified formulations.”
We don′t know yet exactly how the FDA will proceed with regard to labeling of abuse-deterrent drugs. But the bottom line is that we’re moving beyond the days when the majority of industry and regulatory involvement in ensuring drug safety took place before the drugs hit the market. Today, in the world of Risk Evaluation and Mitigation Strategy (REMS), there is increasing recognition that a better understanding of how medications are actually being used has enormous potential benefits for public health. With the right programs in place for monitoring use, opioid medications with the capacity to minimize risk or deter abuse or misuse could have an important role in helping us effectively treat pain while keeping our patients and the public safe.
At Inflexxion, our focus is on risk management that incorporates accurate, real-time data about the use of opioid and stimulant medications. If you would like to talk to us about our experience working with companies to develop risk management plans, please feel free to contact me.
About NAVIPPRO
The National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO) is a public health-oriented risk management solution that integrates the four key components of an effective Risk Evaluation and Mitigation Strategy (REMS): national, real-time, product-specific surveillance; signal detection; signal verification; and empirically validated prevention and intervention programs.
NAVIPPRO began in 2001 with a series of grants from the National Institute on Drug Abuse (NIDA). In 2005, Endo Pharmaceuticals became the founding industry sponsor of NAVIPPRO and in 2006 Alpharma Pharmaceuticals LLC. (now King Pharmaceuticals, Inc.) became the second industry founder. Since that time other pharmaceutical companies have become subscribers. With NIDA’s continued support of ongoing research and product development, NAVIPPRO is constantly evolving to meet our goal of advancing public health.
American Pain Society: 28th Annual Scientific Meeting
May 7, 2009 San Diego, California
The College on Problems of Drug Dependence: CPDD 71st Annual Meeting
June 20, 2009 Reno, Nevada
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- NAVIPPRO Roundtable: Abuse Deterrence
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The NAVIPPRO team gratefully acknowledges the support of the NIH, King Pharmaceuticals, Inc., and Endo Pharmaceuticals in the development of NAVIPPRO.
The NAVIPPRO team gratefully acknowledges the support of the NIH, King Pharmaceuticals, Inc., and Endo Pharmaceuticals in the development of NAVIPPRO.
The contents of this newsletter are for informational purposes only and are not intended to be a substitute for professional medical advice, diagnosis or treatment. Reliance on any information provided in this newsletter is at your own risk.
You should consult your physician or other qualified health provider if you have questions about a medical condition. If you think you have a medical emergency, call your doctor or 911 immediately.
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