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

Abstract

EFFORTS BY THEFOOD ANDDRUGADMINISTRATION(FDA) to ensure the safety of prescription medicines historicallyhave focusedon the requirements for therapies to gain market approval. However, many safety risks are discovered only after a medication reaches the market. During the past decade, reports by the Institute of Medicine and calls frompolicyexpertshaveprovidedmomentumtoimprove the US drug regulation system. One major step in this direction was achieved in 2007 when Congress passed the FDA AmendmentsAct(FDAAA). AlthoughtheFDAhasfrequently sought toavoida focusonpostmarketingregulationbyemphasizing that it “does not regulate the practice of medicine,” the FDAAAlanguagesuggestsincreasinginvolvementoftheagency in shaping clinical practice to ensure safe medication use. AmajorprovisionincludedintheFDAAAwasenhancedregulatory authority for the FDA to require drug manufacturers to institutechangesindrugdistributionorsafetymonitoringplans basedonpotential safety risks.Previously, theFDAusedasystemofRiskMinimizationActionPlans(RiskMAPS),whichwere developedfora limitednumberofdrugssuchasclozapine, thalidomide, and isotretinoin.With increasedauthority, theFDA 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. In contrast to the previous RiskMAPS, the REMS program also requires manufacturers todesignand implementperiodicassessmentsof theirprograms’ effectiveness. Not all new drugs are accompanied by a REMS,norareREMSreservedonly fordrugs thatarenewlyapproved for the market. The determination of whether to instituteaREMSdependsontheoverall levelof risk thataprescription 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. Of these,62 includedaMedicationGuidealone,58 includedaCommunicationPlan,and19 includedElements to AssureSafeUse.Nearlyhalf(49%)ofREMScombinemorethan 1of theseapproaches.Forexample,etanerceptrequiresaMedicationGuideandaCommunicationPlan,whilevigabatrinalso 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 drugsafety.Althoughsomepatientsmayreceive, read,andsynthesize the informationcontained inMedicationGuides, there areavarietyofreasonsthatmanydonot,andMedicationGuides remain part of a fragmented and disorganized system of consumermedication information that leavesmanypatients inadequately informed. 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. 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