Improving the Food and Drug Administration's Mandate to Ensure Postmarketing Drug Safety

Efforts by the Food and Drug Administration (FDA) to ensure the safety of prescription medicines historically have focused on the requirements for therapies to gain market approval. However, many safety risks are discovered only after a medication reaches the market.¹ During the past decade, reports by the Institute of Medicine² and calls from policy experts have provided momentum to improve the US drug regulation system. One major step in this direction was achieved in 2007 when Congress passed the FDA Amendments Act (FDAAA).³ Although the FDA has frequently sought to avoid a focus on postmarketing regulation by emphasizing that it “does not regulate the practice of medicine,” the FDAAA language suggests increasing involvement of the agency in shaping clinical practice to ensure safe medication use.

A major provision included in the FDAAA was enhanced regulatory authority for the FDA to require drug manufacturers to institute changes in drug distribution or safety monitoring plans based on potential safety risks. Previously, the FDA used a system of Risk Minimization Action Plans (RiskMAPS), which were developed for a limited number of drugs such as clozapine, thalidomide, and isotretinoin. With increased authority, the FDA implemented a new system of Risk Evaluation and Mitigation Strategies (REMS). The goal of the REMS program is to “ensure that the benefits of a drug continue to outweigh certain risks” in the postmarketing period.⁴ In contrast to the previous RiskMAPS, the REMS program also requires manufacturers to design and implement periodic assessments of their programs' effectiveness.⁵ Not all new drugs are accompanied by a REMS, nor are REMS reserved only for drugs that are newly approved for the market. The determination of whether to institute a REMS depends on the overall level of risk that a prescription drug is likely to pose to the public.

REMS may include 1 or more of 3 components. First, REMS may include a Medication Guide, an FDA-approved informational handout communicating safety risks that pharmacies and prescribers are required to distribute with medications posing a serious and significant public health concern. Second, some REMS include a Communication Plan, such as letters to clinicians or professional societies communicating the risks associated with the use of designated therapies. Communication plans may also include the dissemination of information regarding safety protocols such as medical or laboratory monitoring to reduce medication risks. Third, some REMS may include Elements to Assure Safe Use, such as requirements of prescriber or pharmacy certification, dispensing only under certain circumstances, special monitoring, or patient enrollment in a registry.

As of August 2011, REMS were in place for 139 pharmacotherapies.⁵ Of these, 62 included a Medication Guide alone, 58 included a Communication Plan, and 19 included Elements to Assure Safe Use. Nearly half (49%) of REMS combine more than 1 of these approaches. For example, etanercept requires a Medication Guide and a Communication Plan, while vigabatrin also requires Elements to Assure Safe Use (Table).

These risk mitigation strategies are laudable, but there are several reasons for concern. First, nearly half of these strategies have used Medication Guides alone as a tool to improve drug safety. Although some patients may receive, read, and synthesize the information contained in Medication Guides, there are a variety of reasons that many do not, and Medication Guides remain part of a fragmented and disorganized system of consumer medication information that leaves many patients inadequately informed.⁶ The ability of Medication Guides alone to substantially improve the safe use of drugs remains doubtful and unproven, at best.

Second, the FDAAA requires that REMS assessment of program effectiveness be designed and implemented by pharmaceutical manufacturers, and the majority of assessments that have taken place have been patient or clinician surveys.⁷ Carefully developed surveys, designed to avoid common pitfalls such as nonresponse and socially desirable response biases, may provide important information regarding patients' and clinicians' knowledge and risk perception. However, the design and conduct of surveys is a complicated task, and they provide a limited window through which to judge the safety of medication use, the ultimate goal of the REMS program.

Third, and most important, little is known about the effectiveness of the REMS program in achieving its stated goals. More than 3 years have passed since the first REMS were implemented in April 2008, yet there is no comprehensive, publicly available information on the outcomes that have been assessed nor any demonstration of their effectiveness. The limited availability of information regarding the effectiveness of REMS is particularly concerning given evidence of limited support for the program by manufacturers.⁸

A number of strategies to improve the REMS program follow directly from these concerns. Given concerns regarding the effectiveness of Medication Guides in improving safe medication use,⁹ the reliance on them as a central feature of so many of the REMS that have been issued is questionable. To the degree that Medication Guides remain a cornerstone of the program, the agency should consider ways to better standardize and regulate their content and format. In addition, rigorous REMS evaluations must be based on mixed-methods approaches that extend beyond surveys. Information from administrative sources and electronic health records should routinely be used to complement survey-based measures in order to examine the degree to which actual patterns of medication use reflect best practices, narrowly defined, with respect to the specific safety concerns in question. For example, to assess the effectiveness of REMS on reducing the overdose or misuse of narcotic analgesics, electronic health information could be used to examine the impact of REMS for narcotic analgesics (eg, fentanyl and oxycodone) on opioid-related emergency department visits. This is particularly important given the increase in opioid-related deaths in the United States.¹⁰ Similarly, data from administrative claims could be used to monitor the incidence of drug-drug interactions when relevant, such as among users of tetrabenazine (Table).

Moreover, risk management is a dynamic process, and one of its most fundamental principles is the use of measurement to assess the effectiveness of interventions that have been taken and to redesign and retarget risk mitigation strategies accordingly. Despite this, it is not clear how the REMS evaluations that have been performed have incorporated this dynamic element, nor is there publicly available evidence that compares different REMS to identify specific strategies or approaches that may be particularly promising or ineffective. In short, it is not clear how scientific measurement has been used to improve the effectiveness of individual REMS or to redesign and sharpen the program.

During the past few years, the FDA has undergone considerable transformation, including an expanded focus on its role as a public health agency. Greater transparency regarding the challenges of enhancing medication safety has also been evident. Despite this, there has been limited visibility regarding core components of the REMS program—their measurement and success. Efforts to strengthen REMS, and postmarket drug safety more generally, require not only innovative methods of risk communication and mitigation, but also better evaluation of the effectiveness of these methods for improving drug safety and public health.