REMS Regulation Provokes Anger in Provider Community

September 2010, Vol 1, No 4

Silver Spring, MD—Risk Evaluation and Mitigation Strategies (REMS) are required from some drug manufacturers as part of a new US Food and Drug Administration (FDA) regulation designed to draw the attention of sponsors, providers, and patients to the likelihood of severe adverse events accompanying certain drugs and biologic agents.

Going beyond the usual drug label, REMS are required for certain drugs, depending on:

  • Number of persons likely to use a drug
  • Severity of the disease for which the drug is intended
  • Expected benefit of a drug weighed against its possible adverse effects
  • Duration of treatment
  • Seriousness of side effects
  • When new safety data are available
  • If the drug or biologic agent is a new molecular entity.

Although the cancer community is affected by REMS to the greatest extent, no one is pleased to be further entangled in government red tape. Negative reactions to REMS have been many and loud; therefore, the FDA held a meeting to address questions and concerns on July 27 and 28 at its Silver Spring, MD, headquarters.

The 250 attendees represented a wide range of those affected—drug manufacturers (also called “sponsors” under the legislation), providers, professional societies, and patient advocacy groups. The consensus was that the FDA is teetering on a tightrope between protecting patient safety and imposing new barriers to access. The latter provoked much scarcely contained anger from attendees.

Janet Woodcock, MD, director of the FDA Center for Drug Evaluation and Research, acknowledged the problems. “FDA regulates sponsors, but we have no control over how they influence providers and prescribers,” she said. “REMS is not perfect, but it’s enforceable. We can order compliance with those who agree to abide by the restrictions, but we cannot make people agree to participate in the REMS program. It’s awkward.”


The FDA Amendments Act (FDAAA) of 2007 created REMS. In essence, it permits the FDA to establish stronger regulations, which require sponsors to ensure that the benefits of a drug outweigh its risks. REMS applies to new drug applications as well as to already approved drugs that are deemed by the FDA to carry significant risk.

REMS requirements include a medication guide (MG), a communication plan (CP), and elements to assure safe use (ETASU).

The MG is similar to a drug label but provides more extensive information and is dispensed with the drug. This must be given to patients to inform them of possible serious adverse events, as well as the importance of strict adherence to the dosing regimen.

The CP is designed for healthcare providers. It explains safety protocols and contains information about training materials; prescribing proce dures; patient–physician agreements; in formed consent; patient education materials; medical monitoring; and data collection forms and procedures.

The ETASU are a series of additional requirements that must be commensurate with a specific, serious risk but must not be unduly burdensome to patients. They require that the prescriber and pharmacist be educated about the specific risks of a drug and be certified to prescribe and/or dispense it. In some cases, prescribers are required to counsel patients about risk, enroll them in a registry, ask that they sign a prescriber–patient agreement to ensure full awareness of risk, and monitor them closely for signs of toxicity.

Furthermore, some drugs with ETASU requirements are only permitted to be dispensed from certain registered pharmacies. ETASU is the most stringent REMS requirement, and can preclude approval if the sponsor does not comply.

All REMS include a timetable for submission of risk and benefit assessment at 18 months, 3 years, and 7 years. Drugs with ETASU requirements can have more frequent assessments. The onus of assessment falls on the manufacturer.

Concerns and Problems

During the 2 years after the FDAAA became effective on March 25, 2008, the FDA approved 110 REMS for new drugs and biologic agents. The majority (68%) required an MG only, and just 10 necessitated ETASU. Nevertheless, stakeholders across the healthcare system have expressed concerns about REMS.

Many see REMS as a burden on the provision of care. Prescribers complain about having to enroll in several programs, obtain a variety of certifications, and provide additional counseling to patients. These restrictions can interfere with the way medicine is practiced, and they are costly—and not reimbursed, according to some physicians.

Another concern is REMS’ potential negative effect on patient access to therapies. Advocacy groups are concerned that physicians may choose to not participate in REMS, thus denying patients access to certain drugs.

Pharmacy organizations have complained about the fact that there is no compensation for the extra work stemming from REMS regulations.

Manufacturers also perceive the burden of REMS as substantial. A drug’s sponsor must establish the education and certification programs and monitor REMS. It has no control, however, over other participants in the system, and cannot force them to comply with REMS requirements.

The FDA Acknowledges Problems

Even before the July meeting, the FDA recognized problems and attempted to set a course by drafting guidance for industry.1 This document considered issues such as the goal of REMS programs and what factors are pertinent to REMS (and how can they be measured).

Other considerations include how ETASU will affect patients’ access to some drugs. Will they really improve safety—or diminish it? Can they be standardized? And how will they affect the healthcare delivery system?

Other issues noted by Dr Woodcock include the advantages and disadvantages of various REMS drug distribution systems; monitoring and assessment; ameliorating the burden of cost to all participants; and maintaining patient privacy.

Panelists Voice Concerns

Sandra Adamson Fryhofer, MD, an internist in Atlanta, GA, and member of the American Medical Association (AMA) Council on Science and Public Health, agreed with the FDA that REMS is probably necessary, but said that the AMA is concerned about the process of implementation and the significant burdens it will place on physicians. She noted that the organization polled its members and found that 50% of them will refuse to prescribe drugs that require REMS. “One third of oncologists say they won’t even register as REMS prescribers,” she added.

Mitchell S.Y. Cohen, Esq, an attorney at Kaiser Permanente, and Jeffrey K. Francer, Esq, Assistant General Counsel for the Pharmaceutical Research and Manufacturers of America, agreed that 3 major principles should guide REMS implementation. These include:

  • The process of calculating risks and benefits should be easy for patients to understand
  • Data about evaluation of REMS should be shared with all concerned, as should efforts taken to mitigate burdens on all participants
  • Use of MGs and CPs should be reasonable, and confidentiality of patient information must be ensured.

Several speakers were concerned that patients might refuse a drug after reading the MG. Thomas H. Hostetter, MD, a practicing nephrologist and past president of the American Society of Nephrology, was the most outspoken. In discussing erythropoiesis-stimulating agents (ESAs), he noted that there are 350,000 patients undergoing dialysis in the United States, and they all receive ESAs in varying doses. “The medication guides emphasize only risks, and if patients read, in practically the first sentence, that they might die from taking ESAs, they might refuse them— and then miss the clear benefits of these drugs,” he said.

Michael Lazarus, MD, a nephrologist at Fresenius Medical Care North America in Waltham, MA, added that ESAs are used in oncology as well as nephrology, but in much higher doses; therefore, the risks are greater. “But the medication guide does not distinguish among types of ESA use, and the same guide is given to all patients, regardless of diagnosis and treatment plan,” Dr Lazarus said. “This is confusing.”

Every speaker noted that REMS will add significantly to the costs of drug manufacturing, prescribing, dispensing, and providing patient care. Several concerns were generated by ETASU. According to Dr Fryhofer, their rigor may make physicians shy away from certain drugs and use less effective ones. “The purpose of REMS is increased safety, not decreased access to therapy,” she said. “Therefore, ETASUs should be developed with input from specialty physicians.”

In addition, ETASU will erect new barriers between patients and providers, and worsen the ones that already exist, noted Karen Kiefer, of the New Jersey chapter of the American Pain Management Nurse/Physician Association.

Several pharmacists said that restrictive distribution programs can interfere with pharmacy practice. They advocated for compensation to pharmacies for the additional cost of administering REMS in general, and ETASU in particular.

Others voiced concern that, because ETASU are not standardized, they can increase administrative, evaluative, and safety problems. Also, everyone affected by ETASU will experience increased demands on their time.


  1. Guidance for Industry Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications. Rockville, MD; Food and Drug Administration: September 2009.

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