Extended Risk Management Proposals Challenge Manufacturers

Published on: 
BioPharm International, BioPharm International-07-01-2009, Volume 22, Issue 7
Pages: 40–45

The FDA seeks new strategies for improving the safe use of opioids and other high-risk medicines, including erythropoiesis stimulating agents.

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.

Jill Wechsler

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 ClinicalTrials.gov 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.

To get the project started, the FDA invited 16 brand and generic firms, including Purdue and Johnson & Johnson's Ortho-McNeil-Janssen, to a meeting in March to discuss the goals and design of a REMS for the opioid class. An Industry Working Group of 25 companies was formed to hash out the details of a class REMS program. Another agency meeting in February with physicians, pharmacists, and patient advocates similarly aimed to elicit support from these groups for the opioid REMS project. FDA officials explained how the FDA and other government agencies regulate pain medications and how a class REMS program might be established.

Everyone voiced his or her proposals and concerns at an open public meeting in May. A panel headed by Douglas Throckmorton, deputy director of the Center for Drug Evaluation and Research (CDER), and John Jenkins, director of CDER's Office of New Drugs, heard from parents of teens who died from OxyContin overdoses, who demanded removal of these dangerous painkillers from the market. Representatives of the pain community, though, insisted on continued access to these medicines, and warned that restricted distribution systems and complex oversight programs could be harmful to patients and costly to the healthcare system.

Physicians supported additional training and certification for pain management, but raised concerns about potentially redundant educational programs. Pharmacists and distributors said they already had tight controls and tracking systems to prevent drug diversion and advised that any certification program should fit pharmacy workflows and be tied to the existing Drug Enforcement Agency (DEA) registration system. Hospital and nursing home pharmacists, moreover, sought exemptions from REMS restrictions for their closed treatment systems that they consider less open to abuse.

The opioid class REMS is unique in that it requires brand and generic manufacturers to collaborate on devising a single shared system to monitor safety and risks of dozens of products. Manufacturers supported the shared-system concept, but there is tension over how much cooperation there will be among competitors, including brand and generic firms. Some elements of the program may involve collaborative efforts, such as a system for confirming that patients have received appropriate information on pain treatment.


FDA officials hope to present a REMS proposal to advisory committees later this year. Meanwhile, Jenkins suggested that there might be some immediate actions that manufacturers could take while the agency finalizes and tests a long-term program. After the FDA issues a REMS proposal for these drugs, it will be up to each manufacturer to file an implementation plan and carry it out. The FDA says it won't hold up the review and approval of new opioid products in the pipeline while REMS development goes on, and will continue to grant priority review status to drugs in this class to speed new products to market.

Success with the opioid REMS may encourage similar FDA initiatives to enhance the safety of other risky medicines. The FDA is working with Amgen on a REMS for erythropoiesis stimulating agents. Manufacturers of botulinum toxin products have been advised to implement REMS programs to alert prescribers and patients to serious adverse events associated with expanded product uses. In recent years, the FDA has requested stronger label warnings and other risk management strategies for widely used drugs that raise safety concerns, such as COX-2 inhibitors, antidepressants, and anti-epileptics, and more REMS programs may be on the horizon for these widely used products.

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, jwechsler@advanstar.com