REMS Program Challenges Manufacturers, Providers

Published on: 
BioPharm International, BioPharm International-09-01-2010, Volume 23, Issue 9
Pages: 40–45

Too many REMS cause headaches for doctors and the industry.

Drug safety has come under fire, prompting the US Food and Drug Administration to take a closer look at its program for establishing Risk Evaluation and Mitigation Strategies (REMS). Charges of safety problems with GlaxoSmithKline's diabetes treatment Avandia (rosoglitazone) prompted advisory committee members to request a restrictive REMS to keep the drug on the market. Recent scrutiny of new anti-obesity therapies indicates that manufacturers will need to present fairly extensive REMS plans to get on the market in the first place. And the ongoing debate over devising a class-wide REMS for long-acting opioids reflects the difficulties in imposing safeguards on prescribing widely used therapies associated with dangerous abuse.

Jill Wechsler

Although manufacturers are willing to implement costly and cumbersome programs to meet FDA postmarketing safety requirements, doctors, pharmacists, and other healthcare providers are alarmed by the proliferation of new requirements for drug prescribing and dispensing. The most restrictive REMS programs 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 manufacturers, feel that the program is being overused, raising costs and interfering with patient treatment. Health providers regard all the new educational and patient registration programs as a significant burden on their operations and on the healthcare system. Similarly, payers are concerned about added costs, while consumers are caught between their desire for access to treatment and the need to avoid adverse events.

These issues have been debated at recent advisory committee meetings to evaluate proposed drugs, as well as at a two-day FDA public meeting in July on the REMS program. The shape and scope of REMS requirements has become a central topic related to revising the Prescription Drug User Fee program (PDUFA), and significant changes are likely to be included in the user fee renewal legislation slated for enactment by 2012.



At the July public meeting, Janet Woodcock, director of the 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 the FDA is looking for guidance from all stakeholders on "how we might remodel our house." The FDA also published a draft guidance in October 2009 on what information manufacturers should include in REMS proposals, and the FDA is reviewing comments on this plan.

Everyone at the meeting acknowledged the importance of REMS in ensuring safe drug use, while highlighting 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 Elements to Assure Safe Use (ETASU). The general complaint is that there are too many REMS of all kinds, and that the FDA should more clearly explain the need for special risk management requirements. So far, the FDA has approved more than 120 REMS, including 15 with ETASU.

Pharmacists, physicians, and healthcare leaders outlined a host of burdens and costs imposed by multiple REMS requirements. Physicians cited multiple educational and training programs that they consider redundant and unnecessary. Oncologists have been particularly vocal in opposing added educational requirements, noting that they are well trained in using highly toxic chemotherapies. Pharmacists described how training, tracking compliance, and patient counseling takes time and interferes with pharmacy operations.

Probably the most objectionable REMS feature for pharmacists and providers is the limited distribution systems for high-risk therapies that permit prescribing by only certain well-informed specialists and dispensing by specialty pharmacies that can verify appropriate use and patient understanding of 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.


Pharmaceutical and biotechnology companies would like the FDA to shoulder more responsibility for explaining the need for educational and distribution requirements to providers. The Pharmaceutical Research and Manufacturers of American (PhRMA) proposes that the FDA 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.

Another industry goal is to streamline the process for making modifications in established REMS by reducing those changes that require prior approval. The policy creates unnecessary delays and wastes FDA resources, said Andrew Emmett of the Biotechnology Industry Organization (BIO). He proposed a tiered approach to REMS modifications that would allow sponsors to merely notify FDA of administrative and technical changes and limit prior approval to those revisions that affect the main goals, timetable, or implementation system of a REMS.

A main change sought by manufacturers is to separate MedGuides from the REMS program. Before FDAAA was enacted in 2007, MedGuides were considered part of labeling, and not related to specific risk management plans. Manufacturers preparing MedGuides now also have to establish program goals, monitor how well pharmacists and providers distribute the information, and develop timetables for assessing the plans. There's a lot of paperwork for both the industry and the FDA. Pharmacists say there are too many different MedGuides for patients, sometimes different ones on the same drug for pharmacists and physicians. In some situations, such as with kidney dialysis, patients have to review the same risk information at every monthly treatment session, a requirement that physicians find burdensome and ineffective. But pulling MedGuides out of REMS requires legislation, as would a move by the FDA to establish a single document for describing drug benefits and risks.

Woodcock acknowledged that paper MedGuides are not the optimal way to provide patients with information and said that the FDA plans to develop a patient information leaflet that is more informative and uses modern communication science. A number of stakeholders support that approach, urging the FDA to devise templates or standardized formats for MedGuides to reduce provider and patient confusion, and to better focus on the information that patients really need.


Although manufacturers welcome provider support for curbing the scope and number of REMS, they are leery about third parties playing a more prominent role in REMS development and approval, a main goal of pharmacists, physicians, and health plans. At the public meeting, providers called for a more transparent process for REMS development so that doctors and pharmacists would 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 the FDA could consult third parties on REMS proposals. Before approving a drug for market, confidentiality restrictions prevent the FDA from indicating that a REMS is even under discussion, explained Jane Axelrad of CDER. John Jenkins, director of CDER's Office of New Drugs (OND) queried: "How can we meet early with sponsors to discuss REMS and avoid delay, when consumers see early agreement on REMS lacking in transparency?"

An added issue is whether REMS programs erect barriers to generic drug development and follow-on biologics. There is general agreement that generic and innovator products should use a shared risk management system to avoid unnecessary multiple approaches, but achieving that goal raises issues about who controls the risk program and how costs should be shared.

FDAAA specifies that a REMS should not block generics from coming to market and includes provisions providing considerable relief for generics makers in REMS implementation. But generics makers complain that limited distribution systems required by highly restrictive REMS programs prevent innovators from releasing products for bioequivalence testing needed to develop generic versions of the drug. Health plans and payers fear similar problems for developers of follow-on biologics, which generally involve more risky therapies that will be subject to more restrictive REMS requirements.

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634,