Objective: To examine the history and suitability of the Food and Drug Administration's (FDA) Risk Evaluation and Mitigation Strategy (REMS) for reducing the safety risks associated with the use of opioid medications, including the risks of abuse and overdose. This article will highlight recent attempts by the FDA to introduce a class wide REMS for new and existing Schedule II long-acting opioid drugs. A critique of these current REMS efforts and recommendations for the future will also be provided.
Design: A literature review and commentary design are utilized to highlight issues surrounding REMS efforts and to explore possible future directions. Expert opinion is offered to potentially guide future efforts in this arena.
Conclusions: The stated goal of the FDA's proposed class wide opioid REMS program is to decrease abuse, misuse, addiction and overdose deaths from opioid medications. While the REMS program may have theoretical capabilities for evaluating and addressing problematic drug use among prescribed patients, it is unlikely to reduce the bulk of prescription drug abuse that occurs with non-patients. Our recommendations provide some ideas on how the REMS program can be improved to achieve the goals set for it by Congress and the FDA.
Key words: REMS, risk management, FDA, opioids, abuse, misuse
The abuse of prescription medications, particularly opioids that are used to treat acute and chronic pain, has increased over the last decade to a level that some have described as "epidemic." (1) At the same time, chronic pain has remained a serious public health concern whose proper treatment with opioids may be hampered by prescribers' fears of inviting excessive and unwarranted regulatory scrutiny. (2) Further, the illicit market for prescription drugs, including controlled substances, (3) is growing rapidly not only in the United States but also throughout the world. (4)
Deaths attributed to the nonmedical use of prescription opioids have increased dramatically over the last decade. (5) In 2007, of the 27,500 fatal unintended drug overdoses in the U.S., 11,500 involved opioid analgesics. (6) As these deaths have increased, so has the public's demand for answers. This has led to congressional hearings, government inquiries, increased regulatory actions, and remedial legislation. (7)
In 2007, reacting to this problem, Congress passed an Amendment to the Food and Drug Act (hereinafter referred to as the FDAAA of 2007 or "the Act") that, among other things, expanded the FDA's authority to require sponsors of drugs with known or suspected risks of abuse and overdose to propose and implement a risk management plan as a condition for initial or continuing marketing approval. Specifically, the Act requires what is called a Risk Evaluation and Mitigation Strategy (REMS) to ensure that the benefits of a new or existing drug outweigh its risks for adverse events. (8) For perhaps the first time in the history of the FDA, the statutory definition of a drug's adverse event was broadened to include abuse and overdose. In effect, the Act expanded the FDA's usual oversight responsibility for drug safety and efficacy to include outcomes that may occur from the nonmedical use of prescribed medications. (9) The Act authorized the Secretary of the Department of Health and Human Services, (10) when warranted, to require that drug sponsors propose a REMS plan as a condition for approving a new drug or for continuing the approval of an existing drug.
The Act requires that a REMS plan must be designed to evaluate and mitigate the risks of a drug's adverse events, which are described as follows:
An adverse event occurring in the course of the use of a drug in professional practice;
An adverse event occurring from an overdose of the drug, whether accidental or intentional;
An adverse event occurring from abuse of the drug;
An adverse event occurring from withdrawal of the drug; and
Any failure of expected pharmacological action of the drug. (11)
When reviewing a drug sponsor's New Drug Application (NDA), the FDA may condition its approval on having an acceptable REMS. In the case of an existing drug for which the FDA determines that a REMS is necessary, the sponsor will have 120 days after notification by the Secretary to submit a proposed REMS for approval. (12)
FDA's Regulatory Function: From RiskMAP to REMS
Since passage of the Pure Food and Drug Act in 1906, the FDA and its predecessor agencies have functioned as the nation's watchdog to ensure the integrity of food and drugs. Over the years, the original Act has been amended many times to upgrade and expand the FDA's responsibility. Today's FDA has a multitude of responsibilities, from approving microwave ovens, medical devices, cosmetics and imported grapes, to assessing the safety and efficacy of sunscreens, dandruff shampoos, and therapeutic drugs. In 2009, Congress enacted legislation that added yet another FDA task for regulating the manufacture, distribution, and marketing of tobacco products. (13)
Within the FDA, the Center for Drug Evaluation and Research (CDER) has responsibility for making sure that safe and effective drugs are available to improve the public health. CDER regulates over-the-counter and prescription drugs, including biological therapeutics, as well as branded and generic drugs. CDER's authority covers more than just medicines and includes, for example, fluoride toothpaste, antiperspirants, medicated shampoos and other consumer products for which healthcare claims are made. (14)
Until passage of the Act, the FDA's role in addressing the abuse of prescription drugs was limited mainly to offering scheduling recommendations (15) for controlled substances and to requiring cautions and warnings of abuse potential in the labeling of certain drugs. For several years before passage of the Act, pressure had been building in the Congress for the agency to increase its role in curbing prescription drug abuse. (16)
The impetus for having the FDA play a larger role in reducing prescription drug abuse began with the 1995 introduction of an extended-release form of oxycodone called OxyContin[R] (Purdue Pharma LP, Stamford, CT). By the end of the decade, this drug had been identified by authorities as having caused a unusually high number of accidental overdose deaths. (17) By 2001, the New York Times had devoted an entire cover story in its weekly magazine section to what was described as an epidemic of OxyContin abuse sweeping Appalachia where, the article stated, it was known as "hillbilly heroin." The article pointed to alarming signs that this epidemic was about to spread beyond Appalachia, to metropolitan centers along the East Coast from Boston to Miami. (18)
In December 2003, the Government Accountability Office (GAO) published a report on OxyContin abuse that, among other things, recommended that the FDA develop a plan to encourage drug manufacturers to adopt strategies to prevent the abuse and diversion of their products. (19) Within six months of the GAO report, the FDA issued three lengthy Guidance for Industry documents that described in draft form a new and voluntary risk management program called RiskMAP (Risk Minimization Action Plan). (20) These reports were reissued as "final" in March 2005. Although the RiskMAP program applied to all drugs with known or potential safety risks, the risks associated with C-II opiates were specifically highlighted:
Opiate drug products have important benefits in alleviating pain, but are associated with significant risk of overdose, abuse, and addiction. The Agency recommends that sponsors of Schedule II controlled substances, including Schedule II extended release or high concentration opiate drug products, consider developing RiskMAPs for these products. (21) In the RiskMAP program, the FDA recommended, among other things, the use of tools and techniques for the signal detection of safety risks, including the risks of overdose, abuse, and addiction. Some sponsors voluntarily employed sophisticated and expensive product surveillance programs to comply with the FDA's recommendations. Many sponsors followed the lead of Purdue Pharma and its FDA-approved RiskMAP for OxyContin. The Purdue Pharma RiskMAP established the "Researched Abuse, Diversion and Addiction-Related Surveillance" (RADARSTM) program to track the misuse of OxyContin, the drug that initially triggered much of the public's concern about prescription drug abuse. The RADARS program was designed to track the abuse of all opioids, with particular emphasis on OxyContin[R]. (22) As in the ease of Purdue Pharma's RADARS RiskMAP, the FDA appeared to leave most of the practical elements of its voluntary RiskMAP program to drug sponsors and their consultants. (23)
Within several years, the RiskMAP program lost most of its significance as sponsors discovered that reducing the risks of prescription drug abuse through postmarket signal detection and product surveillance was a task better suited for regulatory officials. (24) Keeping track of drug diversion and abuse is one thing; doing something about it is quite another and can expose sponsors to considerable legal liability--a concern not shared by public regulatory agencies with statutory authority to perform these tasks. The FDA's RiskMAP program lacked the force of law to compel companies to act, or to protect them thereafter from liability for so acting.
The Birth of REMS
Although the RiskMAP program was not abandoned, some of the program's major deficiencies were corrected by passage of the FDAAA of 2007. This Act, among other things, provided the FDA with the power to require all NDAs, not just NDAs for opioids, to have an approved REMS if having one was deemed necessary by the FDA to ensure that the benefits of the new drug outweigh its risks. (25)
The Act requires that after the FDA determines that a REMS is necessary, it should be designed and proposed by the...