REMS: When Elephants Prance, Ants Take a Pounding

At a meeting last Friday, December 4, 2009, the U.S. Food and Drug Administration (FDA) called upon pharmaceutical company representatives to report on their progress in developing a REMS (Risk Evaluation and Mitigation Strategy) for extended-release or long-acting opioid analgesic products containing oxycodone, morphine, methadone, and other agents. Concerned about what are perceived as high rates of misuse, abuse, addiction, and overdose with these powerful pain relievers, this is the first time the FDA has demanded a REMS program for an entire class of drugs.

Most, but not all, companies manufacturing the involved analgesics had joined together in an Industry Working Group (IWG) to wrestle with the problems of reducing abuse of the drugs while still maintaining access for patients who thrive on the pain relievers. The FDA had provided little guidance on required solutions, and IWG members had spent countless hours in meetings to arrive at a preliminary plan. At the Friday meeting, IWG representatives proposed a phased-in approach, including educational handouts for patients and training for prescribers to better educate them about the proper and safe use of opioid analgesics. This sounds simple enough, but there are several complications...

1. As the IWG pointed out, the problems themselves — eg, misuse, abuse, addiction, overdose — are often poorly defined and available data are confusing and faulty. We have previously observed that those problems seem to have already leveled-off [see post 9/16/09]. And, in the total picture, the problems are of relatively small proportions; which, we acknowledged, “is actually a testament to the effectiveness of the FDA in evaluating, approving, and monitoring medications that are essentially safe when properly prescribed and taken as directed on the product labeling” [see post 9/12/09]. However, during the meeting, the shortcomings of the data were not fully considered.


2. Some of the problems with opioids for the most part do not involve the patients for whom the drugs were prescribed; rather they are public health and community issues. Whether pharmaceutical companies should be held accountable for these problems such as non-medical use or abuse and whether they fall within the purview of the FDA are questionable. These implications were mentioned but not addressed at the meeting.


3. Not only is the FDA demanding that the IWG come up with solutions to the alleged problems but that they measure the effectiveness of their REMS program in changing behavior. While assessing whether or not a new program works seems worthwhile, nobody knows exactly how to do this and there is a high likelihood that it cannot be done effectively or accurately. Despite this, the burden is clearly on the IWG to come up with solutions that will satisfy the FDA.


4. There are no easy solutions for how people can be forced to behave in more responsible ways regarding opioid medications, or how practitioners can be made to acquire more and better education on safely prescribing the drugs. In their presentations, it was apparent that the IWG had considered these issues and that “making” people — whether professionals, patients, or the public — attend to education and change their behavior is a daunting task.

IWG representatives posed many questions to the FDA panel, which went unanswered. And, at several points during the meeting, the concept of “unintended consequences” was noted by both FDA and IWG representatives, which is of great concern. There is a very real possibility that an unintended result of the REMS process will be LESS access to vital opioid analgesics by patients who need them. We have previously noted how already announced REMS programs for Onsolis® [see post 7/17/09] and the not-yet-approved Exalgo™ [see post 9/26/09] are actually designed to restrict distribution of those products. If this is the direction REMS will be taking, rather than trying to satisfy newly imposed educational and registration requirements some practitioners may opt out of prescribing the whole class of opioid analgesics. And, two additional issues are puzzling:

• After receiving more than 2,000 comments, the FDA apparently feels that they need more data and public input on the opioid REMS issue and has extended the time for comment submission to next October, 2010. And, they say that there will be more meetings, perhaps next spring. Yet, the FDA is urging the IWG to continue work on their opioid REMS, and to possibly start implementing their plans as soon as possible. Meanwhile, as noted above, separate REMS already have been introduced and proposed for Onsolis and Exalgo, respectively. These conflicting and confusing actions do not make sense.


• At no time has cost been mentioned; what will it cost to develop, implement, and evaluate the opioid REMS programs? How might these costs be reflected in product prices, and will patients still be able to afford the analgesics? It seems ironic that, at a time when Congress is wrestling with how to create a more cost-effective healthcare system in America, the FDA is encouraging a course of action that could significantly increase medication costs.

Throughout the meeting last Friday, it was clear that FDA representatives were in the positions of authority and are determined that the IWG proceed despite the obstacles. It also is well known that the FDA can remove the opioid analgesics in question from the marketplace entirely if they are not satisfied with the IWG’s REMS solutions. So, we did not sense that this was an equitable coming together of government and industry to partner in solving mutually agreed upon problems. Meanwhile, those at most risk are the millions of patients with chronic pain who, as a result, could end up with fewer effective treatment options.

— correspondent Stewart B. Leavitt, MA, PhD

Addendum: The agenda and presentation slides from this meeting are available [click here]. The webcast of the whole meeting is available [here]. If you would like to submit a comment directly to the FDA Docket: "Risk Evaluation and Mitigation Strategies for Certain Opioid Drugs; Notice of Public Meeting; Reopening of Comment Period (Document ID FDA-2009-N-0143-1061)" — click here.