Impact of Risk Evaluation and Mitigation Strategies in Oncology
The management of risk in medicine is emerging as a priority topic for numerous stakeholders, including patients, providers (physicians, other prescribers, and pharmacists), specialty pharmacies, industry, and government organizations.
The management of risk in medicine is emergingas a priority topic for numerous stakeholders, includingpatients, pro
viders (physicians, other prescribers,
and pharmacists), specialty pharmacies, industry,and government organizations. The US Food and DrugAdministration (FDA) was given the authority in 2008 underthe FDA Amendments Act to require manufacturers todevelop risk evaluation and mitigation strategies (REMS)both for existing drugs and drugs in development whenit is determined that special action is needed to makecertain that benefits of a drug outweigh its risks.
When used fittingly, REMS can ensure safe use of prescribed drugs, including appropriate selection, monitoring, and education. However, applying REMS to oncology and supportive-care drugs must be done carefully. The risks associated with treating oncology patients must be balanced against concerns about limiting access to lifesaving drugs.
Although some REMS are relatively simple (eg, only require provision of a medication guide), other REMS have numerous components and require actions by prescribers, pharmacists, pharmacies, and patients. Complex REMS must be designed so that they do not impose an inappropriate burden on patients, physicians, pharmacists, and other healthcare providers. In a March 2010 National Comprehensive Cancer Network (NCCN) Trends Survey, opinions of oncology providers and pharmacists were collected on the topic of REMS.1 As noted, REMS may result in significantly more work for prescribers and dispensers of drugs with REMS, making it less likely for a drug with a complex strategy to be used. Results from the NCCN Trends Survey supported this notion, as 60% of respondents agreed that REMS will drive utilization toward drugs without REMS. Risk evaluation and mitigation strategies must not compel providers to use alternative drugs that are not the best treatment option because of the administrative burden of drugs with REMS.
As the new REMS paradigm develops, the practical implications of REMS policies and processes must be carefully considered so that REMS are implemented in a feasible manner. Many providers worry that REMS will interfere with their care of patients. In fact, 55% of the NCCN Trends Survey respondents agreed that REMS will interfere with the provision of care. Ideally, all providers should have the ability to evaluate risk, benefits, and appropriate use of medications, and inform and educate their patients. The majority of providers do not need government oversight to ensure that they are prescribing appropriate medications. Providers must feel they have the autonomy to provide the best care possible for oncology patients.
Within oncology there are drugs, including several supportive-care medications, that currently have associated REMS. Availability of and access to these drugs are essential for patients with serious and life-threatening illnesses. In addition, the proposed class-wide REMS for long-acting and extended-release opioids is particularly relevant to cancer care. Pain is one of the most common symptoms associated with cancer. Pain occurs in approximately one quarter of patients with newly diagnosed malignancies, one third of patients undergoing treatment, and three quarters of patients with advanced disease.2 Unrelieved pain denies patients comfort and greatly affects their activities, motivation, interactions with family and friends, and overall quality of life. Pain management and appropriate access to long-acting and extended-release opioids are vitally important to cancer patients.
An additional example of REMS in oncology is the ESA APPRISE Oncology Program.3 This program was developed because of recent safety concerns about the use of erythropoiesis-stimulating agents (ESAs), including the risk of increased tumor growth, decreased survival, and increased cardiovascular side effects. Healthcare professionals who treat cancer patients and wish to prescribe ESAs must register and maintain active enrollment in the ESA APPRISE Oncology Program; complete a special training module; provide medication guides; discuss the risks, benefits, and FDA-approved uses of ESAs with patients before beginning treatment; and document this discussion. For many advanced-stage cancer patients, the risks that the ESA APPRISE Oncology Program warns of are inconsequential compared with their overall prognosis. In the March 2010 NCCN Trends Survey focusing on REMS, 6% of physicians (all oncologists) reported that they are not registered in the ESA APPRISE Oncology Program and do not plan to register because of the associated administrative burden. Will these types of REMS programs drive physicians away from utilizing appropriate medications due to the increased workload? The application of REMS must balance feasibility for providers and pharmacists with the FDA’s goal of mitigating the risks of a drug.
Oftentimes REMS are for a particular indication or setting only. For example, the ESA APPRISE Oncology Program is only for the indication of low red blood counts in cancer patients who are receiving chemotherapy. In a different situation, ESAs often are used to treat anemia associated with myelodysplastic syndromes (MDS).4 This anemia is a symptom of MDS, not a side effect of treatment. The use of ESAs to treat anemia in MDS patients is considered an off-label use of the drug, which the ESA APPRISE Oncology Program does not address. Physicians who prescribe ESAs for MDS will still be required to hand out medication guides, but will not be subject to the other requirements. Interestingly, a medication guide is considered part of the labeling of a drug and thus cannot contain any information on the off-label use of a drug. Therefore, the MDS patients will not be receiving information appropriate for their disease. It can be easily envisioned how this type of situation could repeat itself time and time again in oncology as more REMS are introduced, due to the high amount of acceptable off-label drug use in oncology.
Risk evaluation and mitigation strategies could create or increase disparities in oncology care for several reasons. As noted earlier, some physicians will choose to not participate and thus not prescribe drugs with REMS requirements. Patients seen by these physicians may not receive optimal care and thus may not have optimal outcomes. The NCCN Trends Survey supports this point, with 53% of respondents agreeing that REMS will create or increase disparities in care. When unwilling or unable to prescribe medications with REMS, oncologists should refer their patients to other providers or specialists who can prescribe these medications. However, they may choose not to do so to avoid losing the patient. In some cases, there may not be an appropriate referring specialist. Both of these situations lead to patients not receiving the most appropriate care. Once again, care and consideration must be taken by the FDA to ensure that REMS do not create disparities in cancer care.
A final consideration regarding the impact of REMS in oncology is the possibility of overwhelming the oncology care system with REMS. Oncologists and pharmacists must be concerned as to what REMS will be placed on other chemotherapy drugs that have risks equal to or greater than those of the oncology/supportive-care medicines that already have REMS in place. Many chemotherapy agents have worse risk profiles than drugs like ESAs, lenalidomide, or thalidomide. Will all chemotherapy drugs have REMS placed upon them, making it virtually impossible for oncologists to practice medicine? Risk is inherent in the treatment of cancer patients, and the acceptability of this risk must be contemplated when considering REMS for oncology drugs.
It must be understood that there is a higher level of acceptable risk when treating a life-threatening disease such as cancer. Care must be taken that REMS programs do not overburden the healthcare system, drive utilization to less effective drugs, or increase or create healthcare disparities for cancer patients. Ultimate consideration must be given to oncology patients and how REMS will affect their care.