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FDA’s Risk Evaluation and Mitigation Strategies Program

Proceed with Extreme Caution
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The Food and Drug Administration’s new and evolving Risk Evaluation and Mitigation Strategies (REMS) program may be the greatest threat to pain care in decades. The under-treatment of chronic pain is already a public health issue1 and, if the FDA is not careful, the situation will become critical. Chronic pain impacts the lives of 100 million Americans2 and costs the United States economy an estimated $100 billion per year.3 The human cost of under-treatment is incalculable.

The Food and Drug Administration Amendments Act (FDAAA) of 2007 gave the FDA authority to require pharmaceutical companies to provide and implement risk management strategies (REMS) for their medications to ensure benefits outweigh risks.4 In February, 2009, the FDA sent letters to pharmaceutical companies informing them of the need to create REMS for long-acting and extended-release opioid pain medication.4 The process has been ongoing with meetings over the past year between the FDA, sponsors (pharmaceutical companies), and stakeholders (patient, physician, and pharmacist organizations/ associations).5

On December 4, 2009, the Industry Working Group (IWG), which represents 22 pharmaceutical companies, met with the FDA Opioid REMS Steering Committee in a public forum.6 The meeting was recorded and is available to view online at The approximately 3.5 hour video provides insight into the fluidity of the process and the views and concerns of sponsors, stakeholders and the FDA.

At the beginning of the video, it was stated by FDA’s John K. Jenkins, MD, Director, Office of New Drugs that opioid REMS are being required as a result of increasing adverse opioid outcomes. Four specific adverse outcomes were later identified—abuse, misuse, addiction, and fatal overdose. Sidney Schnoll, MD, PhD, who represents the IWG and was one of many speakers, informed the FDA panel that according to government statistics7 the rate of nonmedical use of prescription pain killers had leveled off between 2002 and 2008. FDA members expressed sur-prise and were unaware of these statistics and requested more information. In addi-tion, Dr. Schnoll pointed out there were multiple definitions of “abuse,” “misuse,” “addiction” and “overdose” and that defi-nitions must first be agreed upon in order to accurately collect and interpret data.

It is worrisome that FDA members responsible for opioid REMS were not aware of statistics regarding nonmedical use of prescription pain killers, and that no firm definitions for “abuse,” “misuse,” “addiction” and “overdose” had been established despite the fact that FDAAA was signed into law in 2007. Although there are many problems surrounding REMS, these two items are foundational. Crucial decisions are made based upon vital statistics and if FDA personnel are not aware of these numbers it would be difficult for them to make informed and thoughtful choices. Moreover, not having defined essential terms makes it close to impossible for parties to communicate about pertinent issues. This is very basic and should have been resolved at the start of the process.

Although serious questions remain, the FDA has approved REMS for two opioids, Embeda® (morphine sulfate and naltrexone hydrochloride; King Pharmaceuticals) and Onsolis® (fentanyl buccal soluble film; Meda Pharmaceuticals)8 and, ac-cording to the FDA website, “…(FDA) intends to approve REMS for Actiq® (oral transmucosal fentanyl citrate; Cephalon Inc.) and Fentora® (fentanyl buccal tablet; Cephalon Inc.) in the coming months.”9 Onsolis, Actiq and Fentora all contain the opioid fentanyl and are instant-release oral medications for acute pain,9-11 while Embeda is an extended-release drug for chronic pain.12 Both instant- and ex-tended-release opioids are utilized in pain management.13,14

Embeda is a new drug with unique physical features12 that may make it less prone to abuse and its REMS15 may reflect this. The REMS for Onsolis16 are very onerous and may result in fewer physicians prescribing the drug and fewer patients benefiting. Since Actiq and Fentora are similar to Onsolis, one could anticipate highly restrictive REMS for these drugs also. If restrictive REMS spread to other pain medications, a decreasing number of physicians will likely prescribe opioids and fewer patients will receive adequate care. In other words, there will be less pain medication available and a dwindling pool of healthcare providers willing to prescribe them. Those reductions would result in increased human suffering for tens of millions of individuals with pain.

REMS threaten to further degrade treatment for people in pain who may already be undertreated. Educating both physician and patient about drug safety and opioid pharmacology, including risks and benefits, is essential but a balanced approach is needed to avoid patient harm. The causes of drug abuse, misuse, addiction and overdose are varied and complex17-22 and there are no simple solutions. However, restricting access to opioids for people who need them to treat chronic and acute pain is definitely the wrong answer.

The FDA is asking for public comment regarding REMS. Please express your views by going to the following website and clicking on “submit comments” at the top right portion of the web page near the image of the paper and pencil: home.html#documentDetail?R=09000 06480a44cce.

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