Regulatory Focus™ > News Articles > Government Report Shows Endemic Deficiencies in REMS Assessments

Government Report Shows Endemic Deficiencies in REMS Assessments

Posted 13 February 2013 | By Alexander Gaffney, RAC

A new report just published by the Department of Health and Human Services (DHHS) claims that the US Food and Drug Administration (FDA) lacks sufficient data to determine whether one of its flagship postmarketing safety methods, Risk Evaluation and Mitigation Strategies (REMS), is actually effective at ensuring product safety.


REMS plans were instituted in 2007 under the FDA Amendments Act, and were seen as a response to a number of product safety scandals, most notably Merck's Vioxx (rofecoxib). For drugs where the risks of a product outweigh its potential benefits, FDA generally requires sponsors to submit REMS proposals detailing a range of control measures, including elements to ensure safe use (ETASU), medication guides (MedGuides), communication plans, implementation systems and plans for conducting periodic assessments of the REMS plan.

Under FDAAA, FDA has fairly wide latitude in deciding when REMS plans should be required, and which elements should be included within them. Since they first came into effect in 2008, FDA has approved more than 200 of the plans, and has even used REMS to approve some infamous drugs like thalidomide.

Companies are required to submit data showing the effectiveness of their REMS strategy every 18 months, at the three- and seven-year marks, and less frequently thereafter if FDA still requires ongoing data. In addition, sponsors are also encouraged to institute continuous improvement processes.

As the DHHS report explains, "Sponsors of brand-name drugs must submit their assessments of REMS for FDA's review according to the timetable in the approved REMS."

In his book, REMS for US Drug Development, REMS expert Ed Tabor explains that these assessments are actually the only common element between all REMS classes. "A proposed assessment schedule must be included in the Proposed REMS; if accepted by FDA, the schedule is then confirmed in the NDA approval letter," Tabor writes. "A REMS assessment must also be submitted in situations where FDA is about to ask for a modification to a REMS due to new safety or efficacy information."

Not Working as Intended

But if the plan was to allow FDA to determine on an ongoing basis the effectiveness of each REMS plan, that's not how it's worked out in practice, says the DHHS report.

The problem, they explain, is that FDA is largely unable to determine the efficacy of such plans as the result of a lack of submitted data. That's because while companies are required to submit data regarding the efficacy of plans, FDA doesn't have the authority to require sponsors to submit specific information regarding the REMS' effectiveness, according to DHHS.

"At the time of our review, assessments of REMS with ETASUs were required to include an evaluation of the extent to which each ETASU is meeting the goal stated in the REMS in addition to complying with the approved timetable," DHHS explained. "Under current amendments to FDCA, all REMS assessments must include, with respect to each goal of the REMS, an assessment of the extent to which REMS are meeting the goals or of whether the goals or REMS should be modified."

However, FDAAA and subsequent legislation do "not require sponsors to include additional information about the effectiveness of REMS in assessments." 

DHHS Report

Case-in-point: Of the 49 REMS plans active in 2012 and reviewed by DHHS, "nearly half … did not include all information requested in FDA assessment plans, and 10 were not submitted to FDA within required timeframes," OIG wrote.

At present, that assessment is supposed to include information regarding whether the ETASU is working as intended, if the REMS is too burdensome and ways the REMS could be made more efficient and effective.

Twenty-three of the studies reviewed by DHHS did not include all of the information requested by FDA. For example, one sponsor reportedly did not include the number of pharmacies that were no longer authorized to dispense their pharmaceutical product as the result of non-compliance, and also neglected to include information regarding the number of patient orders. Both pieces of data are critical to FDA's understanding about compliance and safety trends, DHHS said.

Of the 23 violations noted, 10 regarded ETASUs, eight regarded communication plans and five regarded medication guides.

DHHS explained that even noting these deficiencies, FDA lacks the authority necessary in many cases to take enforcement actions against sponsors that do not report information. Information regarding the extent to which ETASUs met the REMS goal is required, however, but seven sponsors neglected to include that information.

FDA Failures and Recommendations

Ten of the deficient sponsors identified by DHHS had failed to submit their assessments to FDA in the required timeframe. DHHS noted that while FDA has the authority to go after these sponsors under federal law, it has never done so.

DHHS' report noted a number of more practical deficiencies as well. Of the 22 risk mitigation-related deficiencies noted by DHHS in its report, 19 were repeat offenses from their respective prior reports, indicating that many sponsors had no incentive to improve. FDA, meanwhile, had failed to live up to its statutory requirements to review at least one REMS plan per year, and had also failed to conduct assessment reviews within the 60-day goal period in nearly all cases.

DHHS recommended that FDA seek additional legislative authority for the program, and take steps to shore up its own abilities to conduct timely reviews, clarify expectations to sponsors, work to obtain missing information with the voluntary assistance of the sponsor, and meet its statutory provisions to review at least one REMS per year.

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