By Alexander J. Varond –
In response to FDA’s increasing reliance on Risk Evaluation and Mitigation Strategies (“REMS”) for the management of risks presented by certain drugs, the US Department of Health and Human Service’s Office of Inspector General (“OIG”) conducted an investigation into FDA’s REMS program. Specifically, it sought to evaluate whether FDA was receiving the information it needed to evaluate the effectiveness of individual REMS programs. OIG recently released its findings in a report entitled “FDA Lacks Comprehensive Data to Determine Whether Risk Evaluation and Mitigation Strategies Improve Drug Safety.” The report makes it clear that, in many instances, FDA has not received adequate feedback about REMS programs. Also, the agency has consistently failed to meet several statutory requirements to timely review sponsor feedback and independently evaluate REMS.
As our readers know, FDA requires REMS for certain drugs to ensure that the benefits from those drugs outweigh their risks. REMS include medication guides, patient package inserts, communications plans, and, for drugs with the most serious risks, elements to assure safe use (“ETASUs”). ETASUs may include restricted distribution plans, physician certification, patient registries, and other similar requirements. REMS are often onerous and require drug sponsors to effectively implement and assess their programs. Sponsors are required to submit assessments at predetermined times (typically 18 months, 3 years, and 7 years after approval of the REMS). Under the Food and Drug Administration Amendments Act of 2007 (“FDAAA”), FDA is then required to review these assessments within 60 days. FDA is also required to assess one REMS with ETASUs each year to evaluate “whether the ETASUs (1) assure safe use of the drug; (2) are unduly burdensome on patient access to the drug; and (3) to the extent practicable minimize the burden on the health care delivery system.”
OIG reviewed “49 sponsors’ REMS assessments and FDA’s reviews of these assessments to determine the extent to which sponsors’ assessments were complete, were submitted to FDA within required timeframes, and indicated that REMS were meeting their goals. [OIG] also determined whether FDA evaluated the ETASUs of one drug in each year of the program, as required by Federal law.”
The study found that nearly half of the 49 sponsor assessments reviewed were incomplete and 10 were not submitted to FDA within the required timeframes. The study also found that FDA review memorandums indicated that only 7 of the 49 REMS met all of their goals and that 21 did not. FDA review memorandums indicated that FDA could not determine whether 17 REMS were meeting their goals, and 4 review memorandums did not contain statements regarding whether the remaining 4 REMS were meeting all of their goals. In addition, FDA’s own review time for sponsor-submitted assessments exceeded the goal of 60 days in all but one instance. Lastly, despite the FDAAA requirement to review one REMS with ETASUs per year, FDA had only conducted one review since the program’s start in 2008.
The OIG report makes several key observations. First, without comprehensive data, FDA “cannot ensure that the public is provided maximum protection from a drug’s known or potential risks.” Second, because only 7 of 49 REMS were found to meet all of their goals and 21 were not, there were “questions about the effectiveness of REMS.” Third, “FDA has limited data to demonstrate that the remaining  REMS with ETASUs [not reviewed by FDA] effectively ensure safe use of drugs or meet statutory requirements to minimize burdens on patients and the health care system.” Fourth, “FDA has not identified reliable methods for evaluating REMS.” And fifth, FDA’s inability to meet its 60-day review clock of sponsor-submitted assessments “may limit sponsors’ ability to implement suggested changes to the REMS before submitting the next assessment.”
Thus, the OIG report calls into question “the overall effectiveness of the REMS program.” OIG concludes its report by offering seven recommendations to FDA:
- Develop and implement a plan to identify, develop, validate, and assess REMS components;
- Identify REMS that are not meeting their goals and take appropriate actions to protect the public health;
- Evaluate the ETASUs of one REMS each year as required by Federal law;
- Identify incomplete sponsor assessments and work with sponsors to obtain missing information;
- Clarify expectations for sponsors’ assessments in FDA assessment plans;
- Seek legislative authority to enforce FDA assessment plans; and
- Ensure that assessment reviews are timely.
FDA responded to OIG’s recommendations and agreed with all but one of the recommendations, choosing to abstain from whether it should seek legislative authority to enforce FDA assessment plans.
As FDA’s reliance on REMS grows, the effectiveness of the program must be carefully measured. FDA must therefore fully collect and review data to judge whether its REMS program overburdens the health care system and modify REMS requirements accordingly. The OIG report emphasizes that FDA’s REMS program should be practical, effective, and tailored.