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Risk management, drug safety raise challenges for sponsors and healthcare providers


Intense public scrutiny of drug safety issues is prompting FDA to take a closer look at its program for establishing Risk Evaluation and Mitigation Strategies. Healthcare providers, as well as pharmaceutical companies, believe that the program is being overused, raising costs, and interfering with patient treatment.

Key Points

Intense public scrutiny of drug safety issues is prompting FDA to take a closer look at its program for establishing Risk Evaluation and Mitigation Strategies (REMS). The most restrictive REMS programs include Elements to Assure Safe Use (ETASU) and are intended to apply only to those very high-risk products that cannot come to market without special safety controls. But healthcare providers, as well as pharmaceutical companies, believe that the program is being overused, raising costs, and interfering with patient treatment.

REMS are at the center of ongoing discussions about drug safety and the approval of new medical products. In the highly publicized review of risks associated with GlaxoSmithKline's diabetes treatment Avandia (rosiglitazone), advisory committee members recommended keeping the drug on the market, provided that FDA impose strict controls on prescribing through a highly restrictive REMS. FDA followed their recommendations in late September. Recent scrutiny of new anti-obesity therapies indicates that sponsors of these drugs will need to present fairly extensive REMS plans to get on the market; advisory committee members opposed approval of Vivus's Qnexa in July largely because its slim REMS outline for a voluntary program to prevent pregnancy was considered inadequate.

And the ongoing debate over devising a class-wide REMS for long-acting opioids reflects the difficulties in imposing added safeguards on high-risk therapies that are in high demand by patients. Despite more than a year of collaborative efforts by manufacturers and multiple consultations with stakeholders, in July the members of 2 advisory committees voted overwhelmingly (25 to 10) to reject FDA's proposed classwide REMS plan, which relies on a voluntary educational program for prescribers to curb illegal use of these drugs. The practitioners and academics on the panels said that FDA's plan is too weak and unlikely to stop unsafe use of these potentially dangerous products; they proposed that sponsors institute mandatory training for prescribers that is linked to assessment of competencies and licensure.


These issues were discussed recently at an FDA public meeting. Janet Woodcock, director of FDA's Center for Drug Evaluation and Research (CDER), acknowledged that the REMS program established by the FDA Amendments Act of 2007 (FDAAA) "is not perfect" and that FDA is looking for input from all stakeholders on "how we might remodel our house." FDA also published a draft guidance in October 2009 on what information manufacturers should include in REMS proposals and is reviewing comments on that document.

Everyone at the meeting acknowledged the importance of REMS in assuring safe drug use. They also highlighted the unintended consequences of added postmarketing requirements at both ends of the REMS spectrum: more diverse Medication Guides, as well as a growing number of highly restricted REMS with ETASU. So far, FDA has approved more than 120 REMS, including 15 with ETASU, a number that Woodcock acknowledged has led to a proliferation of restrictions and requirements.

Pharmacists, physicians, and healthcare leaders outlined a host of burdens and costs imposed by multiple REMS and the paperwork involved in documenting compliance. Physicians complained of redundant and unnecessary educational and training programs.

Oncologists have been particularly vocal in opposing added educational requirements, noting that they are well trained to use chemotherapies that can be highly toxic. Pharmacists described how training, tracking compliance, and patient counseling takes time and may interfere with pharmacy operations.

Probably the most objectionable REMS feature for pharmacists and providers is the limited distribution systems for high-risk drugs that permit prescribing by only certain well-informed specialists and dispensing by designated specialty pharmacies that can verify appropriate use and patient understanding of the risks. Retail pharmacists complain that such systems steer patients away from regular pharmacies, while hospitals and health plans cite added costs and difficulties in obtaining therapies from restricted sources.


The solutions to these problems are not obvious. While some stakeholders seek more standardization and uniformity in REMS plans to minimize diverse educational programs, manufacturers generally fear that a one-size-fits-all approach will not work for so many different products with varying indications for different patient groups. Pharma companies would like FDA to play a larger role in explaining to providers the need for educational and distribution requirements and spell out in action letters on new drugs why a REMS is needed, what risks are being addressed, and why other risk management tools are insufficient to protect patients. Manufacturers would like to simplify MedGuide production, and providers agree that there are too many different MedGuides for patients to review, often repeatedly. Woodcock acknowledged that paper MedGuides are not the optimal way to provide patients with information and said that FDA plans to develop a patient information leaflet using modern communication science. A proposal from industry is to separate MedGuides from the REMS program, as it was prior to enactment of FDAAA in 2007. However, pulling MedGuides out of REMS requires Congressional action, as would an FDA effort to establish a single document for describing drug risks and benefits.

While manufacturers and providers agree on a number of proposals for curbing the scope and number of REMS, they differ over whether healthcare professionals should play a more prominent role in REMS development and approval, something that pharmacists, physicians, and health plans are demanding. At the public meeting, providers called for a more transparent REMS development process so that they will be aware of upcoming risk management programs and have an opportunity to weigh in early on specific proposals.

It's not clear, though, how or when FDA could consult third parties on REMS proposals. Prior to approving a drug for market, confidentiality restrictions prevent FDA from indicating that a REMS is even under discussion, explained Jane Axelrad of CDER. "How can we meet early with sponsors to discuss REMS to avoid delay," queried John Jenkins, director of CDER's Office of New Drugs (OND), "whereas consumers see early agreement on REMS lacking in transparency?"

An added issue is whether REMS programs erect barriers to generic drug development and marketing. There is general agreement that generic and innovator products should use a shared risk management system to avoid unnecessary multiple approaches. Achieving that goal, however, raises issues about who controls the risk program and how costs should be shared-both for REMS developed for drugs prior to generic competition, and those that are modified after generic competition comes in. Generics makers complain that brand firms use restrictive REMS to block access to drugs needed to test new generics; health plans and payers fear similar tactics by developers of follow-on biologics, which generally involve more risky therapies that likely will be subject to restrictive REMS requirements.


Added support for REMS and other postmarketing drug safety programs, such as the proposed safety initiative for long-acting opioids, could come from FDA's Safe Use initiative. The agency launched Safe Use last November to encourage agency collaboration with healthcare providers, patient groups, and other government agencies on programs to promote the safe use of medical products. FDA aims to identify specific cases involving drugs associated with potential harm and to devise plans to work with hospitals, doctors, nurses, patient groups, and others on ways to mitigate these risks. These could involve distributing information to consumers, improving packaging and dosing devices, and other strategies used in REMS programs.

FDA's hands are tied somewhat in its ability to impose drug safety and educational programs on providers. The agency has authority only to regulate drug manufacturers, and not health professionals or the practice of medicine. FDA thus cannot require a medical society to add certain information on a new drug to a medical education program, or mandate that physicians take a certain training program. Imposing REMS requirements on regulated companies, however, may put the agency in the awkward position of requiring manufacturers to "influence healthcare," Woodcock commented. Many healthcare providers and payers are leery of manufacturer involvement in continuing medical education programs, yet REMS initiatives are needed to ensure safe use of drugs throughout the healthcare system.

Many of these issues will be discussed further related to revising the Prescription Drug User Fee Act (PDUFA). Pharma companies and healthcare professionals have begun to build the case for REMS reform, with an eye on the user fee renewal legislation slated for enactment by 2012.

Ms Wechsler is a Washington-based reporter specializing in federal and state healthcare issues.

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