Extended Risk Management Proposals Challenge Manufacturers

The FDA seeks new strategies for improving the safe use of opioids and other high-risk medicines, including erythropoiesis stimulating agents.
Jul 01, 2009
Volume 22, Issue 7

Jill Wechsler
The abuse and misuse of opioid painkillers is out of control, and the US Food and Drug Administration wants to stem this serious public health crisis. Previous risk mitigation programs have failed to halt inappropriate use of these drugs, prompting the FDA to put more teeth into the Risk Evaluation and Mitigation Strategies (REMS) program established by the FDA Amendments Act of 2007 (FDAAA). FDA has called on manufacturers and other interested parties to help devise workable REMS that will ensure continued access to medications essential for patients suffering from chronic pain, while also curbing inappropriate prescribing, unintentional overdosing, and intentional abuse.

The opioid REMS project reflects the FDA's interest in building on the host of provisions in FDAAA designed to enhance the FDA's ability to ensure the safety of drugs and biologics through the entire product lifecycle. In addition to the REMS program, the statute gives the agency power to require postapproval label changes when new safety issues arise and to crack down on manufacturers that fail to conduct agreed-on post-marketing studies. FDAAA also requires more extensive listing of clinical studies and study results on the public web site—another way to ensure that safety issues arising in clinical studies are fully disclosed to regulators and the public.

Implementing the FDAAA REMS program has been complex and time-consuming because it has required the FDA to assess and update existing risk management programs for dozens of therapies, as well as develop new policies to fit its enhanced authorities. Last March, the FDA identified some 24 manufacturers with drugs and biologics already on the market, such as thalidomide, mifepristone, eculizumab, and smallpox vaccine, that had risk management plans in place and thus were "deemed" to have REMS.

Under FDAAA, a REMS still may consist of just a medication guide and a timetable for evaluation after 18 months, 3 years, and 7 years following approval. More elaborate REMS programs require a communication plan for conveying safety information to prescribers, pharmacists, and patients through "Dear Doctor" letters and notices to medical societies, state licensing boards, and medical journals. Drugs with notable safety concerns also have to establish "Elements to Assure Safe Use," which can include special training or certification of healthcare providers and pharmacists; limited distribution programs that dispense only to patients who meet certain criteria; patient monitoring to identify adverse reactions; and enrollment of patients in registries for long-term oversight.

Most of the "deemed REMS" products already were complying with many of the REMS provisions, but manufacturers had to submit proposals describing how their programs fit REMS requirements. Over the past 18 months, the FDA has approved REMS for some 50 drugs and biologics—those already on the market and new treatments.


The contemplated REMS for all extended-use opioids exceeds other drug risk management efforts by applying to some 24 brand and generic opioid products, including fentanyl patches and oral drugs formulated with oxycodone, hydromorphone, methadone, morphine, and oxymorphone. Some 23 million prescriptions of these extended-release painkillers are dispensed annually to about four million patients in the US, according to data from SDI.

Even more opioid products are subject to abuse. The Substance Abuse and Mental Health Services Administration (SAMHSA) reports that in 2007, more than 12 million Americans over age 12 took pain relievers for nonmedical use, a trend that has boosted substance abuse programs. These long-acting opioids are linked to serious adverse events, such as respiratory distress, if prescribed to inappropriate patients or in too-high doses. They also are open to abuse because they can be crushed or dissolved to permit a large dose to be taken at once. The FDA did not include immediate-release (IR) painkillers in the current initiative, as they are less associated with safety problems and abuse, but some patient advocates want all opioids to be placed under more strict controls.

Federal officials do not want to pull these products off the market because they can manage chronic, severe pain with fewer doses a day than IR products. However, 10 years of risk management for Purdue Pharma's OxyContin (oxycodone) and other painkillers have not stemmed the serious adverse reactions and overdosing. Now, the FDA and manufacturers hope that more extensive and coordinated information on product risks and expanded training for health professionals will reduce prescribing to patients unable to tolerate strong medicines and curb abuse.

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