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In September, King Pharmaceuticals, Inc. launched the first of the so–called “abuse deterrent” formulations of an opioid analgesic: EMBEDA™ (morphine sulfate and naltrexone hydrochloride) extended release capsules. There is no evidence to date that the naltrexone in EMBEDA™ reduces the abuse liability of the product, and the approval for EMBEDA™ did not include any “abuse deterrent” labeling. Nevertheless, researchers now have the first opportunity to gather epidemiological data to examine the potential impact of particular “abuse deterrent” properties on the actual rate of abuse and abuse patterns of a drug. This has implications not only for King but also for other pharmaceutical companies that are developing opioid medications formulated to deter abuse.
“Product–specific epidemiological data on abuse of prescription medications can assist researchers in developing and testing novel approaches to improving the risk/benefit profile of pharmaceuticals with abuse potential,” explains Stephen Butler, Ph.D., Senior Vice President and Chief Science Officer of Inflexxion. “In addition, our research team has been investigating whether it is possible to develop an accurate pre–approval estimate of a formulation’s ‘attractiveness for abuse,’ similar to other estimates of how a drug will perform post–launch, such as animal and laboratory testing, human pharmacokinetic studies, or other types of abuse liability studies. The data on EMBEDA™ and other ‘abuse–deterrent’ formulations should prove to be illuminating.”
Below is an article describing two new research studies conducted to explore the potential for estimating an opioid medication’s attractiveness for abuse pre–launch, the results of which will be published in the journal Pain Medicine.
In addition, for those following regulatory developments relevant to opioid risk management, we provide brief commentary on the FDA′s first draft guidance on REMS, Guidance for Industry: Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications.
We hope you find this issue of NAVIPPRO Signal useful. If you have any questions about NAVIPPRO or our research, please feel free to contact us.
Sincerely,
The NAVIPPRO team
Estimating an opioid medication′s attractiveness for abuse
Inflexxion has conducted extensive research to develop a scientifically valid approach to estimating the “attractiveness for abuse” of an opioid medication prior to launch. This includes a pair of studies to:
- Refine and test the Opioid Attractiveness Technology Scaling (OATS) method, developed to identify, from a drug abuser’s point of view, the particular features of a prescription opioid relevant to its attractiveness for recreational use; and
- Derive an estimate of attractiveness for abuse of a not-yet-marketed opioid medication formulated to deter abuse: Remoxy®, a controlled-release oxycodone for moderate-to-severe chronic pain (Pain Therapeutics/King Pharmaceuticals, Inc.)
“The methods developed in these studies allow us not only to derive an estimate of a product′s attractiveness for abuse prior to launch, but also to track how attractive abusers find a drug when they have had a chance to actually use/abuse it — that is, post–launch. We anticipate, based on some prior findings, that attractiveness for abuse is a dynamic property of a product that may change over time,” says Dr. Butler.
Following are brief descriptions of findings from these studies:
Study 1: Refining and testing OATS — Building on previous research to develop a model of attractiveness for abuse of prescription opioids, this study resulted in a model that addresses limitations of the previous model, and accounts for some of the variance in abusers′ directly rated preferences for specific products. The findings suggest that the formulation of an opioid analgesic product may be a more important factor for those interested in extracting the active ingredient of a product and using alternative routes of administration, possibly to enhance the onset and intensity of the high. Therefore, new “abuse–deterrent” formulations that alter the physical and/or chemical properties of the drug to prevent extraction may be most likely to impact the attractiveness for abuse of that drug for those who snort, smoke, or inject prescription opioids.
Study 2: Estimating the attractiveness for abuse of a not–yet–marketed “abuse–deterrent” opioid medication — Using the OATS method, this study derived an estimate of attractiveness for abuse of Remoxy®, which revealed significant differences between Remoxy® and OxyContin® (Purdue Pharma LP), Percocet® (Endo Pharmaceuticals), and Vicodin® (Abbott Laboratories), but not Talwin® NX (Sanofi-aventis), which was identified in the prior study as a highly unattractive drug for recreational purposes. The method showed promise, and if it can be validated post–launch, it may prove to be useful for estimating, pre–launch, the extent to which a drug will be seen (at least initially) by abusers as relatively unattractive for abuse. (See poster [PDF].)
FDA issues guidance for industry on REMS
On September 30, 2009, the FDA issued the first draft guidance for industry [PDF] regarding Risk Evaluation and Mitigation Strategies (REMS). The document provides industry with guidance on the format and content of proposed REMS, including:
- requirements for REMS documentation;
- content for REMS assessments and proposed modifications; and
- timelines for assessment and evaluation.
In analyzing the significance of the guidance document for pharmaceutical risk management, it's important to consider historical and contextual factors.
The FDA gained the authority to require REMS with the passage of the FDA Amendments Act (FDAAA) 2007. The FDAAA contains numerous provisions that are intended to ensure that the public is better informed about drug safety and that the FDA has the tools necessary for reducing risks and unsafe drug use. This additional authority expands the roles of both the FDA and the industry in ensuring that the benefits of a particular drug product continue to outweigh the risks. It is clear that each must take a more active approach to ensuring drug safety, with an emphasis on pharmacovigilance throughout the lifecycle of a particular product.1 However, to date there has been considerable uncertainty about exactly how the REMS authority would translate into practice.
Recent developments provide additional information with respect to REMS and opioid medications with abuse potential. The FDA has approved two unique, branded opioid analgesics with REMS: Onsolis™, an oral transmucosal fentanyl product intended for management of breakthrough pain in patients with cancer, and EMBEDA™, an extended–release morphine sulfate capsule containing naltrexone. In addition, the FDA Advisory Committee reviewed New Drug Applications (NDAs) and proposed REMS for two new opioid formulations: Exalgo™ (hydromorphone HCl) extended–release tablets and OxyContin™ (oxycodone hydrochloride controlled–release) reformulated tablets. Finally, the FDA has reopened until October 19, 2010 the public comment period for the development of what is expected to be a class–wide REMS for certain extended–release opioid medications.
Onsolis™ was approved with a medication guide, a communication plan, and a restricted distribution program that requires enrollment by the prescriber, pharmacy, distributor, and patient. EMBEDA™ was approved with an interim REMS requiring a medication guide and communication plan. Meanwhile, at the Advisory Committee meeting on the NDA for Exalgo™, one of the questions the Committee asked was whether the REMS program should be similar to that of Onsolis™, similar to that of EMBEDA™, or a unique program. The FDA is expected to make a decision about the NDAs for Exalgo™ and OxyContin™ reformulated tablets, including proposed REMS, in the near future.
Given these developments, how do we interpret the FDA's current draft guidance for industry?
According to Theresa Cassidy, M.P.H., Director of Epidemiology at Inflexxion, while issuing the draft guidance may be an “important first step” in providing a roadmap for the transition to the new REMS environment, “it's clear from the decisions that the FDA is making with regard to opioid formulations that this new approach to risk management is continuing to evolve, and REMS is simply not a ‘one–size–fits–all’ solution.”
This, says Cassidy, means that many questions remain, not least of which is how the REMS for particular opioid medications may impact patients.
“The goal of REMS programs is to balance the risk-benefit profile of pharmaceuticals with the potential for abuse, but members of the public health community are still questioning whether the REMS for certain products will result in restricting access to opioid medications for patients who require these medications,” Cassidy says. “This is of particular concern when it comes to patients who require these medications for the treatment of chronic pain.”
References
1Leiderman, D.L. (in press). Risk management of drug products and the U.S. Food and Drug Administration: Evolution and context. Drug and Alcohol Dependence.
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, Shire Development, Inc. has joined in supporting the program, including providing founding sponsorship for the CHAT component. With NIDA’s continued support of ongoing research and product development, NAVIPPRO is constantly evolving to meet our goal of advancing public health.
- Estimating an opioid medication’s attractiveness for abuse
- FDA issues guidance for industry on REMS
- References
- About NAVIPPRO
- NAVIPPRO
- Surveillance
- Signal detection
- Signal verification
- Prevention & intervention
- DETER Model
- About Inflexxion
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Support
The NAVIPPRO team gratefully acknowledges the support of the NIH, King Pharmaceuticals, Inc., Endo Pharmaceuticals, and Shire Development, Inc.in the development of NAVIPPRO.
The NAVIPPRO team gratefully acknowledges the support of the NIH, King Pharmaceuticals, Inc., Endo Pharmaceuticals, and Shire Development, Inc. 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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