Risk Evaluation and Mitigation Strategies: An Update

The good news is that the abuse of illicit drugs in the United States continues to go down. The bad news is that more and more people are beginning to abuse “legal” prescription drugs.In fact, this is a fast-growing trend in the U.S. The National Institutes of Health (NIH) estimates that close to 20 percent of people over the age of 12 in the U.S., or 48 million people, have used prescription drugs for nonmedical purposes. Even more alarming is that the fastest growing demographic of prescription drug abuse is young people aged 15 to 24. The U.S. Department of Health and Human Services (HHS) reports that nearly three million teenagers and young adults(those aged 12 to 25) have become new abusers of prescription drugs. And, prescription drug abuse is rising among the elderly as well. Even though the elderly make up only 13 percent of the population, they account for about one-third of all prescriptions.¹

The abuse of prescription medications is what led to the passage of the Food and Drug Administration Amendments Act (FDAAA), which took effect March 25, 2008. The Act authorized the FDA to require pharmaceutical manufacturers that submit New Drug Applications, as well as those that hold certain drug applications already approved, to submit a proposed Risk Evaluation and Mitigation Strategy (REMS).² As of this writing, there are more than 160 drugs with an FDA-approved REMS.³

But, it has been just three short years since the implementation of the FDAAA. And while the goals behind the program are more than worthy, there remains some question by patients, pharmacists, physicians and manufacturers about whether the current REMS requirements, as well as future requirements under discussion, are doing and will do what was intended.

What Are REMS?

REMS are being mandated to assess adverse risks associated with specific oncologic drugs, biologics and supportive care therapies. Depending upon the severity of the risks, the population likely to be exposed, as well as other factors, a drug may be required to have one or all components of a REMS program: 1) a medication guide or a patient package insert, 2) a communication plan for healthcare providers and 3) elements to assure safe use (ETASU).⁴

A medication guide contains information for patients on how to safely use a drug product. Most of the drugs that have FDA-approved REMS are required only to have this component of the program.

A communication plan involves risk communications to healthcare providers. The plan may include one or all of the following: 1) sending letters to healthcare providers, 2) disseminating educational information about the elements of the REMS to encourage healthcare providers to implement the components that apply to them or to explain certain safety protocols, and 3) disseminating information to healthcare providers through professional societies about any serious risks of the drug and any protocol to assure safe use.⁵

For REMS requiring ETASU, healthcare providers may be required to obtain and dispense the drug through specific distribution channels; possess specific training, education, experience or certifications in order to prescribe the drug; enroll patients in registry programs; and issue mandatory, time-sensitive reports of patient responses to treatment.⁴

What Are the Legal Implications of REMS?

The FDAAA grants FDA the authority to impose penalties on manufacturers that do not comply with REMS requirements. According to the FDAAA penalties section: “A responsible person who violates a REMS requirement is subject to civil monetary penalties of up to $250,000 per violation, not to exceed $1 million in a single proceeding. These penalties increase if the violation continues more than 30 days after FDA notifies the responsible person of the violation. The penalties double for the second 30-day period, and continue to double for subsequent 30-day periods, up to $1 million per period and $10 million per proceeding.”⁶

The FDA also has the authority to use mechanisms to enforce manufacturers to ensure third parties (physicians, pharmacists, distributors) “take reasonable steps” to monitor and evaluate REMS implementation.⁷ However, the FDA does not have any authority to enforce REMS requirements for third parties. But, a third party’s ability to prescribe and dispense certain medications, even some that have been on the market for years, could be contingent upon compliance with REMS requirements. And, those parties that fail to comply with REMS requirements are subject to misbranding violations and civil liability. For example, if a pharmacy fails to dispense a medication guide, that may lead to a misbranding violation. What’s more, if the patient doesn’t receive a medication guide and is injured by the drug, the pharmacy could be held liable in a lawsuit.⁸

Which Drugs Require REMS?

At a time when more and more prescription drug overdoses are being reported, the number of prescriptions for controlled substances is increasing, and more prescription drugs are ending up in the wrong, unintended hands, the number of drugs required to have REMS is increasing. In general, REMS are required for drugs or biologics with significant toxicity levels and/or demonstrable risk factors.⁴ Those that have a potential for abuse, misuse, overdose, addiction or teratogenicity (ability to cause birth defects) are likely to require REMS.And, although the FDA evaluates product on a singular basis, they have been more likely to request a REMS for a product that is within a class of products recognized to have a common risk.⁹ Six classes of drugs have been identified as requiring such a REMS for each medication: long-acting opioids, fluoroquinolone antibiotics, anti-epileptic drugs, tumor necrosis factor (TNF) blocking drugs/inhibitors, botulinum toxins and erythropoiesisstimulating agents.

The FDAAA mandates that the FDA consider certain elements to determine which drugs need REMS. This includes considerations in initial drug product approval, estimated patient population size, seriousness of disease or condition, expected benefit of the drug, expected or actual duration of treatment, seriousness of any known or potential adverse events, whether the drug is a new molecular entity, considerations after drug product approval, availability of new safety information, and new evidence that REMS requirements are needed to ensure that the benefits of a drug outweigh its risks. Among those 160-plus drugs with FDA-approved REMS are some “deemed drugs” that in the past were the subject of risk minimization action plans, known as RiskMAPs, that have now been “grandfathered” in as REMS-approved.

While the FDA has not been granted authority to require a class-wide REMS program, there is debate about whether one should be established. At issue is whether one REMS for an entire class of drugs versus a single REMS for each product in the class will still provide the same safeguards, despite the fact that many of the REMS in a drug class are redundant. At the center of this debate are extended release opioid analgesics, which contain fentanyl, hydromorphone, oxycodone, oxymorphone, methadone or morphine. In 2009, the FDA asked for comments about the proposed class-wide REMS for extended-release opioids, and after more than 2,000 responses, it had extended the comment period until October 2010. An FDA advisory meeting will be held this spring to make a final ruling, which could serve as a precedent for other classwide REMS.⁸

REMS Problems and Possible Solutions

Many in the healthcare industry believe there are problems with the current REMS process, but most do think it’s necessary, and they do offer some possible solutions. The main concerns are what it takes to get a drug through the regulatory process, patient access to a drug, the time and financial investment required, and the effect on product sales.

The complexity in creating a REMS program can place a potential burden on the healthcare system, especially if a class-wide REMS system is established. For instance, Gerard Maher, chief operating officer of REMS Group, Princeton, N.J., a research-based consultancy and training institute that helps clients develop REMS for their products, believes “it would overwhelm the healthcare delivery system if each manufacturer in a drug class had their own REMS.” At issue is how fairly the burden of developing, implementing, managing and assessing a REMS program can be distributed among each manufacturer in a drug class. For instance, smaller branded and generic organizations may not have the financial resources to develop and implement a REMS. That, then, may keep some important drugs or cheaper drugs off the market. 10 Marc Boutin, executive vice president and chief operating officer of the National Health Council, agrees: “The reality is we are still not getting new treatments to market as quickly as the patient community would like or need.”¹¹

Some of the more complicated strategies of REMS programs have made it more difficult for physicians to prescribe drugs off-label, which occurs more than 100 million times a year, with at least 20 percent of all prescriptions written off-label. According to Gregory Conko, a senior fellow at the Competitive Enterprises Institute, Washington, D.C., and Henry Miller, a physician and fellow at Stanford University’s HooverInstitute and a former FDA official, “The term ‘elements to assure safe use’ sounds benign enough, but regulators’ demands can be so drastically restrictive as to constitute a new, distinct and limited, or conditional, class of approvals — one that makes off-label prescribing much more cumbersome and difficult.”¹²

Kathryn Keller, PharmD, CPE, who is on the board of directors at the American Chronic Pain Association, believes that the stricter the program is, the more burdensome it may be to prescribe. “For at least one of the newly approved, rapid-onset opioids, the fentanyl buccal film, the REMS has presented a significant impediment to access due to its complex requirements and limited sources,” she says. However, that may be due to unfamiliarity with the process. “If you look at some of the established REMS programs for non-opioids, with multiplestep programs requiring a patient registry and input of laboratory test results, for example, there was an initial drop in the use of the drug, followed by a return to usual usage as clinicians and patients became familiar with the requirements and understood their purpose,” Keller adds.¹¹

Patient access also may be affected by the financial and time investment required to execute the additional safe use features of the programs. Gerald Aronoff, MD, DABPM, FAADEP, medical director of Carolina Pain Associates, Charlotte, N.C., says that physicians have only a certain amount of time each visit in which they must write prescriptions and evaluate patients, so they’re likely to opt for prescriptions that don’t include a rigorous REMS program. He suggests better access to and development of databases of patient prescription information, as well as further research into developing abuse-deterrent opioid drugs.¹¹

Maher says he also is worried about “the potential effect on product sales. REMS is adding greater uncertainty to the drug approval process and is also an issue any time safety information is released on a marketed product.”¹¹

What Now?

Something has to be done to combat the illicit use of legal prescription drugs. The question is: Are REMS working? Many of the concerns raised have to do with complex REMS requirements, meaning all three elements of a REMS program must be in place for the product to be prescribed. But, most FDA-approved REMS drugs require only one of those elements, the medication guide.

The need for a REMS program is clearly warranted, and in the end, the program needs to be a result of a shared solution. Which is why the FDA is working with all parties involved to find a manageable solution.