Compliance Monitoring and Effective Risk Mitigation Strategy
For those in the health care profession, all eyes are on the U.S. Food and Drug Administration (FDA) as the agency moves forward with plans to develop a standardized Risk Evaluation and Mitigation Strategy (REMS) for long-acting and extended-release opioid analgesics. Once the formal components are revealed, physicians, drug manufacturers, pharmacists, and other vested stakeholders will be held more accountable in promoting the safe use of opioid drugs as part of a chronic pain treatment plan.
However, while the FDA is expected to present several REMS elements for possible adaptation—ranging from patient package inserts to prescriber/patient agreements—physicians will still face the issue of gauging therapy compliance among their patients, namely, a measurable way to evaluate safe use. Compliance monitoring using laboratory screening and confirmation—coupled with the appropriate education—provides tangible value to practitioners aiming to comply with a risk mitigation plan. It can also reduce drug diversion in a practice over time.
Brief History of REMS
Since the medical community’s acceptance of chronic pain as a valid diagnosis in the twentieth century, there have been concerns surrounding its treatment. Chronic pain is often extremely difficult for a physician to verify, yet its effect on a patient’s quality of life can be so debilitating that the prescription of opioid analgesics is often the most efficient way to provide adequate relief. However, as the use of opioids continues to rise, so do occurrences of abuse, serious injury, and even death. In 2008, nonmedical use of pain relievers was listed as one of the drug categories with the largest number of recent initiates among persons aged 12 or older (2.2 million).1 Prescription pain relievers rank second in categories of the most popular drugs of abuse according to the White House Office of National Drug Control Policy2 and opioid analgesics were involved in almost 40% of all poisoning deaths in 2006, up from about 20% in 1999.3
In response to these and similar data, the FDA Amendments Act of 2007, which significantly amended the Federal Food, Drug and Cosmetic Act to increase the FDA’s authority, was signed into law. Under Title IX, Subtitle A, section 901, the agency may now require drug manufacturers to include a REMS as part of a drug application or to comply with one if it decides that a REMS is necessary as new safety information becomes available. For those drugs that do require a REMS, the FDA will determine which components must be included in its safety strategy.4
“Falling under the “Elements to Assure Safe Use” component of REMS, laboratory-based compliance monitoring supports safe-use conditions by upholding the integrity of the testing process.”
To be considered for approval, a REMS submission to the FDA must include two parts: a brief outline of the strategy and supporting documentation containing more detailed information.5 These pieces work together to provide clear reasoning behind the goals of the REMS, selection of REMS elements to achieve those goals, and a concrete timetable for monitoring its success. A REMS may include one or all of the following: medication guide or patient package insert, a communication plan to healthcare providers, and tangible elements to assure safe use on the part of the appropriate stakeholders. The latter can include requirements for those who prescribe, dispense, or use the drug.
Significance of REMS to the Pain Management Community
In a country where the number of deaths involving prescription opioid analgesics increased 160% from 1999 to 20046—a mere five years—and more than half of all drug misuse/abuse emergency department visits in 2006 involved illicit drugs,7 stakeholders are more aware than ever of their responsibility to curb abuse and reduce harm to those who rely on opioids for pain management. However, despite increased exposure from legislation and the media, awareness of the science behind compliance monitoring is sorely lacking among practitioners. Not all opioids work in the same way and patient tolerance can vary widely between drugs—even those within the same class. This means that physicians, pharmacists, and other stakeholders involved in pain management who are not appropriately educated run the risk of making ill-informed decisions that could result in fatality for their patients. At the 2010 American Academy of Pain Medicine annual meeting, a literature review of poisoning deaths involving opioids from 1999 to 2009 revealed that the number of deaths involving meth-adone were disproportionately high, representing less than 5% of all opioid prescriptions but responsible for a third of the deaths. Fundamental misunderstandings about the properties of methadone on the part of physicians when converting patients from other opioids may be to blame.8
The combination of mass prescribing and incomplete education can lead to tragic outcomes but they are preventable. Stringent REMS initiatives, like the FDA’s, and concerted efforts from physicians to maintain a base knowledge of drug profiles can work in tandem to drastically improve patient safety and reduce a physician’s legal liability. Compliance monitoring using laboratory screening and confirmation addresses each of these needs by offering a measurable way to evaluate safe use and providing educational opportunities for physicians and other vested stakeholders.
Compliance Monitoring and Its Impact on REMS
Compliance monitoring is recognized within the pain management profession as an effective means for identifying illicit and non-prescribed drug use, avoiding toxic drug interactions in patients, and evaluating adherence to a prescribed treatment plan. Immunoassay-based techniques—available through point-of-care (POC) devices and routine hospital testing—attempt to achieve these goals by maintaining traditional cut-off levels originally developed for workplace urine drug testing—levels that are typically as high as 300 or 2,000ng/mL for opiates. In stark contrast, compliance monitoring performed by a reference laboratory follows a more rigorous process that relies on state-of-the-art instrumentation usually found only in a laboratory setting. Cut-off levels are significantly reduced to accurately assess patient compliance and can be as low as 50ng/mL for opiates at a few specialty laboratories. Samples that screen positive are confirmed and quantified using mass spectrometry to generate what is essentially a unique “chemical fingerprint” pattern for each drug.