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FDA’s Proposed Risk Evaluation and Mitigation Strategy (REMS) for Opioids

A brief overview and critique.
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Prescription drug abuse has become a major public health issue with increasing attention from media, community outcry, and government agencies.1,2 Nevertheless, chronic pain remains a serious public health concern in the U.S. and must remain a priority despite fears of diversion and abuse of pain medications, and the regulatory scrutiny that may follow.3-6 At this point in time, large changes loom on the horizon, including a recent spate of congressional hearings, government inquiries, in-creased regulatory actions, and reme-dial legislation.7-12

The Mandate

As a result of an amendment to the Food, Drug and Cosmetic Act enacted in 2007, the Food and Drug Administration (FDA) has been mandated to require, under certain conditions, drug sponsors to implement specific measures to mitigate safety risks in the use of their products. Perhaps for the first time in the history of the Act, the statutory definition of an adverse event was broadened to include drug abuse as well as accidental or intentional drug overdose.13

In 2009, the FDA called upon a number of manufacturers of specific long-acting opioids to develop a “class-wide” Risk Evaluation and Mitigation Strategy (REMS)—a unique historical event for the FDA. The group, called the Industry Working Group (IWG), was given immunity from prosecution under the anti-trust statutes and subsequently held a number of meetings and set up subcommittees to develop language and recommendations for specific aspects of the class-wide REMS. In November of 2009, the IWG asked stakeholders to a special meeting to review and critique a proposed class-wide REMS program.

The current juncture in history may be a crossroads for both the FDA and the pharmaceutical industry. Any form of a proposed REMS program will be expensive and will require resources from industry and government. However, what happens if REMS is a failure? Will it ever achieve the goals set by the FDA and hoped for by the public, media, and Congress? Will we be able to maintain patient access to these medications while minimizing prescription drug abuse? Unfortunately REMS, in its present form, will be ineffective and a likely failure.

Critique of REMS

The goal of the REMS program is to decrease “abuse, misuse, addiction and overdose deaths.”14 While this is a laudable goal, major problems are evident upon further investigation. At this time, there are no universally-acceptable definitions for any of these terms. On the surface, overdose deaths might be considered fairly straightforward. However, if the death occurred with a long-acting opioid in combination with heroin use, or if the dead person had consumed a bottle of vodka along with taking an opioid, do these constitute “overdose deaths”? Since most overdose deaths are due to polypharmacy, how is the action of just one chemical or pharmaceutical to be separated out as the “clear cause” of the overdose death? Does the death need to occur as a primary result of opioid use or is having any amount of opioid in the serum sufficient? Without clear definitions there can be no outcomes measurements and, without clear and measureable outcomes, there is no way to ascertain achievement of the goals set by the FDA. Therefore, the first step in developing a meaningful REMS program must be to define the terms.

Once a common terminology is accepted, it becomes necessary to elucidate clear outcomes. Outcomes measurements for “abuse and misuse” of scheduled and prescription medications have been difficult to develop. A large part of this is due to the illicit nature of these activities. It seems clear that existing databases, once identified, might be used and collated to get a better idea of the outcomes desired. For example, prescription monitoring programs, autopsy and coroner report data, law enforcement data, and other databases could be reviewed and used to evaluate the goal terms. Even here, however, we must proceed knowing that each of these data sources is limited and will have pitfalls.

It is not clear what the FDA plans on doing if the rates of abuse and other indicators increase or don’t change. Will long-acting opioids be taken off the market, as has been suggested in some FDA meetings? Will the FDA require a separate REMS program for each separate long-acting opioid product (of which there are currently more than thirty)? This would be a draconian move, causing untoward harm and suffering for tens of thousands of patients around the country. So the issue of clear measurable outcomes is critical.

The procedural goals of REMS (i.e., Medication Guide, Communication Guide and education) are severely flawed. If the goal of the REMS is to reduce abuse, misuse, addiction and overdose deaths, then prescriber patterns must change. Changing prescribing behavior is very difficult and it is clear that medication guides and communication guides have yet to show efficacy for encouraging change. There is a paucity of evidence that such guides change physician or patient behavior. Further, education in the traditional lecture format is unlikely to result in significant changes in behavior.

Patient Responsibility

The issue of patient responsibility has received little attention in the medical literature or in the media. While physicians and prescribers can be educated and sales of scheduled medications can be restricted, this will not stop patients from engaging in irresponsible behavior. In fact, many of those who are dying are not patients at all but substance abusers trying to become intoxicated. It is critical that patients also have education on the proper use, storage and disposal of these medications. That education should be unique, creative and in multiple formats. In addition, the patient should demonstrate some understanding of that educational material. Pharmacists have a critical and pivotal role in this process as well. Pharmacists should also have to undergo education and, again, this should be unique and creative.

Adverse Shift In Prescribing

There are myriad other issues that have yet to be thought out before implementing a REMS program. For instance, would REMS inadvertently encourage an increase in the use of Schedule III opioids? Since hydrocodone is both the most prescribed and abused opioid in the United States, will there be a leftward shift from long-acting to the short acting drugs? Also, what about legitimate patient access to these medications? By definition we must restrict access if we are to achieve the goals of REMS but trying to maintain current access and achieve goal reductions is likely impossible. Another missed opportunity under the current REMS proposal is the lack of clear policy statements about the need to increase addiction programs and in-patient beds for addiction treatment.

Last updated on: February 21, 2011
First published on: July 1, 2010