After four years, the effectiveness of the FDA’s mandatory Risk Evaluation and Mitigation Strategies (REMS) program remains open to question because drug companies have failed to comply with key reporting requirements and the agency lacks adequate enforcement authority to take action against them, according to a report by the Department of Health and Human Services’ Office of Inspector General (OIG).

Nearly one-fourth of the drug companies with medications in the REMS program were found to be in violation of legislatively approved timetables for data reporting, according to the OIG report. Furthermore, less than 15% of the companies had met all of the safety goals stipulated in their products’ REMS.

As for the FDA, the agency has reviewed only one of 32 drugs whose REMS contain “elements to assure safe use” (ETASU)—usually reserved for medications on the higher end of the risk spectrum—a reporting gap that has undermined any assessment of the merits of that REMS program component.

These issues “raise concerns about the overall effectiveness of the REMS program,” the OIG concluded in its Feb. 13, 2013 report.

Under the Food and Drug Administration Amendments Act of 2007 and subsequent legislation, the FDA has been granted legal authority to require drug and biological product manufacturers or sponsors to establish a REMS program whenever the agency determines that one is necessary to ensure that a product’s therapeutic benefits outweigh its risks. REMS programs typically include additional medication guides, patient package inserts, communications plans for health care providers and one or more ETASUs, such as patient and prescriber registries, specific training for prescribers and practitioners, or certifications in health care settings.

Some REMS programs have become controversial, such as those involving erythropoietin-stimulating agents and long-lasting, extended-release opioids. The main objections to the REMS programs often revolve around delays in access to medications that can result when complicated REMS requirements are implemented. Drug manufacturers, which are responsible for REMS, have noted that they can only advise but not control physician and patient behavior when it comes to prescribing practices and medication adherence.

The OIG reviewed 199 REMS approved by the FDA between March 25, 2008, when the program officially began, and Dec. 31, 2011. The OIG selected 49 sponsor assessments and interviewed FDA officials about them. OIG found that nearly half of the assessments (23 of 49) were missing information that the FDA had requested. For example, one drug sponsor did not report the number of pharmacies that had been “deauthorized” to dispense its drug because of noncompliance with the REMS. The same sponsor also did not report the amount of the drug shipped to health care providers compared with actual patient orders. (The company was not identified in the report.)

Failure to report requested (i.e., voluntary) information is not the only potential weak point in REMS reporting and assessment, according to the OIG report. Federally required (i.e., mandatory) timetables for report submission, for example, were often missed. Indeed, more than 20% of the completed REMS assessments (10 of 49) had been submitted by sponsors after the dates specified in the timetables (three to 70 days late, with a median of 17 days).

This presents a multipronged problem with regard to FDA oversight. first, when drug companies fail to provide voluntary information, FDA lacks authority to take enforcement action against them. Second, even in cases where the aqency does have enforcement authority—for example, when drug companies fail to comply with mandatory items that carry the force of federal law—FDA is not exercising that authority, according to the OIG. And this is despite the fact that the agency has powerful enforcement tools at its disposal: it can, for example, apply penalties such as barring the involved drug from interstate commerce and imposing civil fines of up to $250,000 per violation, and up to $10 million for continued violations.

The OIG recommended that FDA should seek authority from Congress to take action when even voluntary items are not being met. The FDA “did not explicitly concur,” the OIG report noted, “but agreed that it should be considered if another opportunity arises” to make legislative changes to the REMS program.

Overall, according to the OIG report, only seven of the 49 REMS evaluated had met all of their goals, whereas 21 had not. Of the remaining 21, the FDA could not determine whether 17 had met the goals, and had not assessed the other four.

Because the FDA had evaluated only one of 32 drugs having ETASUs, it “has limited data to demonstrate that the remaining REMS with ETASUs effectively ensure safe use of drugs or meet statutory requirements to minimize burdens on patients and the health care system,” noted the OIG. In its comments, the FDA replied it had spent much of the past three years developing and implementing the REMS program.

The OIG stated that the FDA needs to develop a plan to “identify, develop, validate, and assess the effectiveness of REMS.” The report also said that the FDA should identify REMS that are not meeting their goals and work with sponsors to correct deficiencies; evaluate one ETASU per year as required by law; work with sponsors to obtain missing information; and complete its own reviews within 60 days. The FDA agreed with these recommendations.

The nation’s branded drug industry association did not have much to say about the OIG’s findings. “We look forward to reviewing the report and continuing to work with FDA to help ensure that REMS effectively improve the safety of medicines while not unnecessarily burdening patients and health care professionals,” said Matthew Bennett, the senior vice president of Pharmaceutical Research and Manufacturers of America.

Silver Lining?

James M. Hoffman, PharmD, a medication safety officer at St. Jude Children’s Research Hospital, in Memphis, Tenn., pointed to a dropoff in REMS programs as evidence that the initiative is working. Since its inception in 2008, 199 REMS have been created; by 2012, only 99 were still in place. That falloff “is evidence of the FDA’s work to refine the program,” Dr. Hoffman said. “Keep in mind that some REMS (those with ETASUs) are designed to enable drugs to be on the market that would otherwise be withdrawn for safety risks. Thus, REMS continue to [help maintain] access to important therapies, which is a clear success.”

Others disagree. REMS programs “have no precedent, and even though they seem like ‘good ideas,’ to my knowledge, they have never been shown to improve patient safety or reduce harm,” said David S. Craig, PharmD, the director of the pain and palliative care residency program at the H. Lee Moffitt Cancer Center and Research Institute, in Tampa, Fla. “The FDA is doing its best with the new authority given to them, but I think they also don’t really want to monitor and oversee both the implementation and impact all of these REMS programs. In addition, they have very [few] tools to evaluate the impact and outcome of any REMS and also likely lack the manpower to ensure that all drug manufacturers are carcomplying with the requirements.”

Bonnie Kirschenbaum, MS, FASHP, a health care consultant based in Breckenridge, Colo., said the concept of REMS “has merit.” After all, “one really can’t argue [against] educating prescribers, pharmacists and patients about using a drug in the most advantageous and safest way possible.” Unfortunately, the REMS program has been weakened, she said, by ongoing controversy over how to interpret the specific components of the program and the overcomplication of its implementation. “This has significantly diminished any possible returns we might have gotten from this initiative, however well-intentioned it may be.”