Although many praised the Food and Drug Administration (FDA) for releasing its long-awaited Risk Evaluation and Mitigation Strategy (REMS) for extended-release (ER) and long-acting (LA) opioid analgesics, there has been some criticism about the program.
A REMS is a risk management plan that goes beyond requirements in the drug prescribing information to manage serious risks associated with a drug. The Food and Drug Administration Amendments Act (FDAAA) of 2007 gave FDA the authority to require companies to develop and implement a REMS when necessary to ensure that the benefits of a drug or biological product outweigh its risks.
In a recent “Viewpoint” article published in the Journal of the American Medical Association (JAMA), Lewis S. Nelson, MD, of New York University School of Medicine and New York City Poison Control Center, and Jeanmarie Perrone, MD, of the Perelman School of Medicine in Philadelphia, Pennsylvania, asserted two problems with drug companies to provide educational materials to doctors on opioids.
Background
The REMS is part of a federal initiative to address the prescription drug abuse, misuse, and overdose epidemic. The REMS introduces new safety measures designed to reduce risks and improve the safe use of ER/LA opioids, while ensuring access to needed medications for patients in pain. FDA is requiring a REMS for ER/LA opioid analgesics because FDA has concluded that there is a disproportionate safety problem associated with these products that must be addressed.
One cause for the opioid problem is that while they used to be prescribed for “severe pain — terrible postoperative pain, terrible preoperative pain of a surgical illness — everything that was related to being close to a hospital and needing a lot of care,” today, opioid analgesics are a “panacea for everything that hurts you.”
A separate REMS for transmucosal immediate-release fentanyl (TIRF) products was announced in December 2011 and was implemented in March 2012. Moreover, the latest FDA's long-acting opioid REMS plan runs contrary to the fentanyl product REMS, which mandates education for prescribers, pharmacies, distributors, and patients, they wrote.
All ER/LA opioid analgesics will be required to have a REMS. The new ER/LA opioid REMS will affect more than 20 companies that manufacture these opioid analgesics. Under the new REMS, companies will be required to make education programs available to prescribers based on an FDA Blueprint. It is expected that companies will meet this obligation by providing educational grants to accredited continuing education (CE) providers to offer training to prescribers at no or nominal cost. These CE activities must cover the content and messages of a blueprint developed by FDA for this purpose.
The REMS also will require companies to make available FDA-approved patient education materials on the safe use of these drugs. The companies will be required to perform periodic assessments of the implementation of the REMS and the success of the program in meeting its goals. The FDA will review these assessments and may require additional elements to achieve the goals of the program.
Debate on Opioid REMS
Dr. Perrone and Dr. Nelson raised concern about the REMS requirement that manufacturers of ER/LA opioids provide educational materials about the appropriate use of these drugs. “The propriety of having the pharmaceutical industry develop unbiased education for prescribers and patients is debatable,” they asserted. This concern is misplaced because the education will be created by independent, accredited, CME providers. Ignoring all of the CME regulations and firewalls that prevent bias or undue influence, the authors are still concerned about the “financial motivations and creative risk/benefit messaging.”
They also maintained that while education was a “crucial element of safety, medication guides and related warnings have generally been ineffective in educating patients about the risks associated with certain medications,” the authors add. This point failed to understand that the central piece of the REMS is education is for doctors prescribing opioids, not patients.
The fentanyl REMS, on the other hand, requires a patient-prescriber agreement that requires patient education.
Karen Drexler, MD, associate professor of psychiatry at Emory University in Atlanta, Georgia, maintained that “A black box warning might have more impact.” Another potential problem identified was the voluntary nature of the REMS for healthcare providers. “An advisory committee expressed concern that a voluntary process would not likely provide sufficient assurance of knowledge dissemination and retention and instead recommended linking certification, through mandatory testing, to renewal of a prescriber’s Drug Enforcement Administration registration,” the authors write. While this argument has some merit, there are several states that require opioid-related education or physicians to maintain their licenses. This argument, however, is problematic, because it is the individual states that must mandate doctors to take pain education, and the goal of FDA’s REMS is for states and CME providers to hopefully incorporate these principles into their state laws, regulations, programs, and requirements.
The authors cite a recent study that showed that 13.4% of 259 practicing family physicians reported that they would no longer prescribe an opioid if they were required to obtain 4 to 8 hours of training and 2 hours of continued medical education every 2 years, although they would be tolerant of lesser requirements (Slevin et al, J Opioid Manag 2011:7;109-115). “Mandatory training is something I'm sure most physicians are not going to be happy about,” Dr. Drexler added.
Dr. Peronne also expressed the need for short-acting opioids REMS that gives warnings about the addictive nature of the drugs even in short-term prescriptions. “For unclear reasons, a REMS for short-acting opioids has not been publicly proposed despite data suggesting that this opioid formulation is widely associated with nonmedical use,” the authors write. While Dr. Drexler agreed that the strength of the REMS is that it addresses a whole category of drugs rather than addressing each individual drug, one of its weaknesses is that “it singles out the [ER/LA] opioids and leaves out other members of the opioid analgesic class.” FDA, however, maintained that it took this approach due to the disproportionate problem with the long-acting opioids.
Response from the ACCME
Dr. Murray Kopelow, Chief Executive of the Accreditation Council for Continuing Medical Education (ACCME), respectfully responded to this editorial by noting that the opinions on CME “should be based on the best available information.” He asserted how accredited CME “providers are required to meet rigorous standards designed to ensure actual—not ostensible— independence. Providers must comply with the ACCME’s Standards for Commercial Support when offering any accredited activities, including those related to the REMS for long-acting and extended-release opioid analgesics.
He explained how these Standards “require CME providers to design activities that are independent, free from commercial bias, and based on valid content. Providers must ensure that all content- related decisions are made free of the control of commercial interests. The ACCME believes that CME can receive commercial support from industry without receiving any advice or guidance, either nuanced or direct, on the content of the activity or on who should deliver that content.”
Kopelow also recognized how accredited CME providers “have more than 20 years of experience managing the boundary issues created by commercial support,” and the Standards “have become a national model” for numerous other health professional groups.
He also reiterated how FDA’s ER/LA REMS requires opioid manufacturers to offer accredited continuing education (CE) grants to produce education based on the blue print, and “explicitly state[s] that manufacturers are prohibited from having any input or influence over educational design or curriculum.” Further, he points out how the blueprint says that “accrediting bodies and CE providers will ensure that the CE activities developed under this REMS will be in compliance with the standards for CE of the Accreditation Council for Continuing Medical Education (ACCME) or another CE accrediting body.”
Martin Grabois, MD, and Lynn R. Webster, MD, the president and president-elect of the American Academy of Pain Medicine, respectively, also responded to the Viewpoint. They recognized that while there is a potential for bias in industry funded CME, the current system includes only two sources for funding: government and industry.
However, we are completely unaware of any kind of funding from the government to provide CME whatsoever. If any such funding exists, it is likely extremely limited and probably has significant restrictions and administrative burdens. In fact, we noted last year that the Department of Defense had to close its CME office.
Nevertheless, Grabois and Webster are correct in recognizing that the authors “did not advocate for pragmatic solutions.” Instead, they went for the low-hanging fruit of critizing industry support, when as Grabois and Webster correctly note, it is “the best idea to come forward because for now it is the only idea to come forward.” Given the issues America faces funding numerous aspects of health care reform, and the complete absence of any mention of continuing education in the Affordable Care Act, it is highly likely that no funding for government for CME, or specific to opioids will ever emerge.
Congress and FDA have negotiated for 25 years now regarding user fees to help expedite the drug approval process, and every five years included new requirements and added regulations to ensure safety. This process of industry-funded agencies has largely succeeded, and perhaps the only true way to get more education is establishing in the next User Fee negotiations a more formal CME funding process.
Problems for Psychiatrists
Dr. Drexler noted that while the REMS is for all prescribers, for psychiatrists, it presents “additional challenges.” For example, “one of the directions to prescribers is to make sure that you do a thorough history and physical examination and that you really understand the source of the pain and individualize the treatment before you prescribe any of these [ER/LA] opioids.” But most psychiatrists don’t have an examination room in theirr office suite, and it may have been years perhaps since they have done a thorough physical examination, Drexler said. She noted that frequently, patients ask psychiatrists to write prescriptions for opioids if they are having pain and haven't been able to see their internist or pain medicine specialist. These are the cases where psychiatrists must be “especially cautious” to prescribe opioids without all the information they need.
The other caution for psychiatrists, said Dr. Drexler, is to be aware of what other medications patients are taking. “We do prescribe sedative hypnotics that can combine with opioids [and that can] lead to overdose deaths. Adequately screening as best we can for high-risk alcohol use is also important because alcohol can combine with opioids and sedative hypnotics and lead to overdose deaths.”
Dr. Perrone and Dr. Nelson also believe now is an ideal time to “inventory the evidence” for the efficacy and risks associated with opioid drugs for chronic non-cancer pain and moderate pain and to revise existing labeling to reflect the current clinical science and risk-benefit profile.
It will also be important to “minimize the burden on physicians and the health care system by implementing a REMS that does not compromise patient care,” write Dr. Perrone and Dr. Nelson. “For example, physicians may avoid prescribing a drug if they are unwilling or unsure of how to meet the REMS requirements. This may result in increased prescribing of drugs that are not part of a REMS,” they add.
Despite these concerns, the authors were “optimistic that the [REMS] is the first of several steps needed to enhance safe prescribing of these powerful drugs.”
A better option, Nelson and Perrone wrote, would be to tie opioid education to certification via mandatory testing for renewal of a physician's DEA registration.
Although Nelson and Perrone assailed the FDA's recent action, they also cautioned that if the REMS is too restrictive, it may lead prescribers to choose other drugs not part of a REMS — such as short-acting opioids like Vicodin, a hydrocodone combination product.
The best option is to see how this first REMS works out before we go on a giant hunt to find alternatives to a program not yet tried.