Rheumatologists are feeling a double dose of effects from the Food and Drug Administration’s (FDA’s) Risk Evaluation and Mitigation Strategy (REMS), which is designed to improve the safety of certain medications.
Rheumatologists must manage the extra patient education required with certain rheumatologic drugs affected by REMS while they also must keep abreast of REMS information related to other drugs that patients may be taken as prescribed by their primary care physician.
The end result of REMS is more detailed patient education but possible confusion from patients and added responsibility for rheumatologists, say a number of sources familiar with REMS.
The use of REMS was enacted as part of the “FDA Amendments Act” in March 2008 in order to manage known or potential serious risks associated with drugs or biological agents, according to the FDA. “A REMS will be required if FDA finds that a REMS is necessary to ensure that the benefits of the drug or biological product outweigh the risks of the product,” according to the FDA Web site.1 A REMS can be required for products not yet formally approved by the FDA or for products already on the market. For example, post-approval studies may reveal serious risks with certain drugs already on the market, according to the FDA. Certain drugs that had risk minimization action plans, or RiskMAPs, are now required to have a REMS.
Six of the 18 new molecular entities approved by the FDA from late March 2008 to the end of December 2008 included a REMS. However, a total of nearly 60 drugs have been issued a REMS since the FDA Amendments Act took effect in March of last year. Of these drugs, a number are used specifically for rheumatologic conditions. These include certolizumab pegol (Cimzia), pregabalin (Lyrica), and etanercept (Enbrel). Tocilizumab (Actemra), for the treatment of moderate to severe rheumatoid arthritis, must have a REMS plan before it will be approved. Roche, which manufactures Actemra, is expected to respond to the FDA’s request for a REMS by the third quarter of this year.
The FDA had to take a closer look at drug safety after the reported risks associated with Vioxx a few years ago, says Alfonso E. Bello, MD, clinical associate professor of medicine at the University of Illinois College of Medicine at Chicago and the Illinois Bone and Joint Institute. “Now, many of our other medications are scrutinized, including nonsteroidal antiinflammatory drugs and biologic agents,” Dr. Bello says.
Drug classes with REMS in effect include corticosteroids, monoclonal antibodies, tumor necrosis factor–a antagonists, and certain vaccines. A variety of opioid products will likely have a REMS associated with them, including morphine, methadone, fentanyl, and oxycodone, according to the FDA.
What’s in a REMS?
On a practical level for patients, physicians, and pharmacists, a REMS for a specific drug includes a medication guide (usually six or eight pages long) and a patient package insert, as well as more detailed safety information about the drug available via the Internet. However, a drug may also be required to have a communication plan, which includes sending letters to healthcare providers and sharing information via professional societies regarding any serious drug risks and protocols to ensure safe use.
Drugs that are deemed necessary to have a REMS before they are approved will have to make the extra research part of the approval process, says Lynn M. Fallon, president of CTI Clinical Trials and Consulting Services in Warminster, Pa. Those manufacturers will want to meet early and often with FDA officials to plan out their REMS, she says.
Penalties range from $250,000 to $1 million per violation when a manufacturer does not submit a requested REMS within 180 days, for a possible total of $10 million for all violations.
Drugs with a REMS must undergo 18-month, three-year, and seven-year assessments, says Fallon. The assessments will take place with information from databases or registries that manufacturers can use to monitor and evaluate safe use of the drug. Some drugs may require more frequent assessments; others may no longer require a REMS after three years if the safety concerns are resolved. However, if the safety concerns continue or a manufacturer is unable to demonstrate that the REMS is effective, they may need to periodically revise, add, or remove information in the REMS.
- Postmarket Drug Safety Information for Patients and Providers: www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/default.htm
- List of Drugs with Approved REMS: www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm
Implications for Patients, Physicians
REMS has the “positive or negative” effect of creating more information for patients on the drugs they are using, Fallon says. “Some patients want all of that information. Other patients want their doctors to tell them what to do.” In specialties such as oncology, for example, patients may feel that the information given to them is too detailed and complicated, and they would rather their physician weigh the risks and make a treatment selection for them.
Fallon anticipates this confusion may be a particularly big challenge for patients who are simultaneously using a number of other medications. Physicians will also feel the effect of the growing number of drugs with a REMS, says Dr. Bello, who represented the ACR at a meeting between the American Medical Association and key FDA stakeholders.
“We understand there should be some control of these medications. The question is how to implement these controls,” he says. For example, there has been talk of requiring special training or certification before physicians could prescribe certain opioids. “Not all physicians want to do that training or have the time to do it,” he says. Consequently, they may not prescribe those drugs to patients who really need them—or, they may refer those patients to other physicians who have that training, thereby taking up extra seats in the waiting room at those physicians’ offices.
REMS and increased restrictions on medications such as opioids could also push physicians to instead prescribe other medications that are not as effective or that are used off-label, say Fallon and Dr. Bello. “It’s like a balloon,” Dr. Bello says. “If you squeeze one side, the other side gets bigger.”
One wrinkle for rheumatologists is how they will manage patients who may use REMS drugs that were prescribed by other physicians. “We inherit patients on these medications, but what do we know about them?” Dr. Bello says.
Better training on medications such as opioids or other drugs that have or will require a REMS is needed in rheumatology—preferably in preexisting CME venues, Dr. Bello says. The ACR and other organizations have done a solid job on this front with biologic agents since the Vioxx controversy, he believes.
Fallon believes that pharmacists will also have to play a stronger role in patient education. “We have to think of a better system,” she says. “It may be a combination of education from the clinic and the pharmacy.”
Vanessa Caceres is a medical writer and editor in Florida.
- Food and Drug Administration. Questions and answers on the federal register notice on drugs and biological products deemed to have risk evaluation and mitigation strategies. Available online at www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFCAct/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/ucm095439.htm. Created March 26, 2008; updated March 27, 2008; accessed July 9, 2009.