Extension of REMS requirements by FDA raises provider, manufacturer concerns


FDA appears to be requesting some kind of Risk Evaluation and Mitigation Strategy on most new drug products.

Key Points

FDA appears to be requesting some kind of Risk Evaluation and Mitigation Strategy (REMS) on most new drug products. That approach is generating fears from drug and biotechnology manufacturers, as well as from pharmacists, health plans and payers, that too many REMS will impose added burdens and costs on drug sponsors and on the nation's healthcare system.

The REMS program is one of several enhanced post-marketing safety provisions established by the FDA Amendments Act of 2007 (FDAAA) to better ensure appropriate drug use. The legislation also strengthened FDA's ability to require manufacturers to make labeling changes, to conduct post-approval studies, and to publish clinical trial results. The aim is to better inform healthcare providers and patients about the safety and efficacy of drugs after they become available in the market.

Since the program went into effect in March 2008, FDA has negotiated more than 100 REMS programs with drug sponsors as part of the new drug application approval process. FDA further determined that 16 existing drugs that had restrictive risk management programs prior to enactment of the FDAAA were "deemed" to have REMS under the new policy. The number of REMS programs could grow even more if FDA determines that additional risk management strategies are needed for other already-approved drugs based on the emergence of new safety information.

The most risky drugs, about 10 under the current program, have to establish REMS programs with Elements to Assure Safe Use (ETASU). Those may require training and certification of health professionals; limited distribution of the drug to certain healthcare settings; patient monitoring and testing; and enrollment of patients in registries for long-term evaluation.

In addition, all REMS programs, even MedGuide-only versions, require periodic assessment to determine if they are meeting goals or need to be modified.

Adding to the burden is a growing number of drug-class REMS, which are more complex to establish and administer. In February FDA finalized a REMS for erythropoiesis-stimulating agents (ESAs) used in cancer treatment, and called for a class-wide REMS for long-acting beta-agonists. Additional REMS may be launched for anti-seizure therapies and for antidepressants. Most controversial is the proposed multi-product REMS for long-acting opioid drugs, which has been embroiled in FDA-industry negotiations for more than a year. The aim of the initiative is to decrease abuse and misuse of these high-risk drugs, but it has been difficult to develop meaningful metrics for such behavior and to obtain reliable data on drug-related overdoses or deaths.


These issues have not created a serious problem for providers so far because most REMS with restricted distribution and other complex management requirements have involved drugs for relatively small patient populations. But the prospect of mega-REMS for opioids and other drug classes raises fears among pharmacists and health plans that too many diverse postmarketing drug safety programs will impose a burden on the healthcare system and on patients, and that this will drive up costs and limit access to therapies. Hospitals and clinics report that they have to assign a specific person to oversee dispensing of ESAs, and physicians complain that they have to register for additional training before they can prescribe ESAs to cancer patients.

Oncologists, in particular, are upset that they were not consulted in developing the REMS for ESAs administered to cancer patients. Unlike the process being used to develop a class-wide REMS for long-acting opioids, FDA negotiated the plan directly with Amgen for Aranesp (darbepoetin alfa) and Johnson & Johnson, marketer of Procrit (epoetin alfa). The American Society of Clinical Oncology complained to FDA that requiring oncologists to enroll in pharma educational programs on the importance of limiting use of ESAs for cancer patients is a "duplicative requirement," and that oncologists should have had an opportunity to help develop or review the policy.

Kaiser Permanente filed a citizens petition with FDA in December 2009 stating the need for health plans to have a seat at the table when FDA and drug companies discuss REMS design to ensure that these programs don't raise problems for healthcare providers and pharmacies. Requiring consumers to obtain medicines through select doctors or from specialty pharmacies can increase costs for health plans and for consumers and may limit access to needed drugs, Kaiser stated, noting that these issues raise questions about the overall benefits of the REMS program. The health plan proposes more transparency in the REMS development process by requiring FDA advisory committee review of significant REMS proposals before they are adopted. And FDA should evaluate established REMS programs at least annually and make these assessments public to help doctors and patients weigh treatment decisions.

Similar concerns were raised by providers and pharmacists at an FDA public meeting in April to hear comments from stakeholders on how to revise or improve the Prescription Drug User Fee Program (PDUFA), which is up for reauthorization in 2012. A main theme from pharmacy organizations was the need for more uniformity in the structure and requirements of REMS. The American Society of Health-System Pharmacists called for standardization of REMS to prevent disruption to patient care, and the American Pharmacists Association proposed using existing technologies and infrastructure to link REMS to prescriber and pharmacist workflows. Any required training for physicians and pharmacists should be coordinated, as should the establishment of patient registries.


Pharmaceutical companies similarly would like more uniformity and predictability in REMS requirements to avoid wasted efforts in drug development and to prevent delay in FDA approval of new drug applications.

Janet Woodcock, director of the Center for Drug Evaluation and Resarch, admits that the REMS program "needs work," but attributes recent new drug approval delays to a host of added burdens on the agency related to implementing the FDAAA, and not just to REMS. In comments at the annual meeting of the Food and Drug Law Institute in April, Woodcock was optimistic that some of these problems would diminish by turning REMS evaluation into a regular part of the approval process, and not have it "as something new tacked on at the end."

Ideally, REMS could become an important tool for obtaining more information on drug utilization and outcomes and for detecting drug contamination or diversion, according to a report from the Institute for Alternative Futures on "Optimal Futures for REMS." But to be useful, the program needs standard requirements and uniform methods for REMS design and implementation, especially for restricted distribution systems. Ultimately, REMS should be linked to electronic medical records, to health plans and programs, and to adverse event surveillance systems in order to bolster the collection of needed information on drug response and clinical effects of treatment for different patient populations.

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

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