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Use of erythropoiesis-stimulating agents: an ongoing controversy
Due to CMS coverage restrictions and vague FDA labeling, doctors may be forced to practice within two treatment paradigms.
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In 1989, epoetin alfa was approved by the FDA to treat anemia resulting from chronic kidney disease. Epoetin alfa, an erythropoiesis-stimulating agent, raised hemoglobin levels and, more importantly, reduced the risk for blood transfusions and improved quality of life. The agent was later approved to treat patients with anemia resulting from treatment for AIDS and cancer.
Nearly 20 years, many trials and a new formulation later, erythropoiesis-stimulating agents are garnering as much attention as they did when they first became available. The only difference is that the publicity is no longer quite as favorable.
HemOnc Today has spoken with leading experts about the current controversy surrounding off-label use of erythropoiesis-stimulating agents and the FDA’s warnings issued in March 2007, and then in October 2007.
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Photo by Gary Leonard |
ESAs are used to treat anemia in patients with chronic kidney disease or patients receiving chemotherapy. Studies have shown that epoetin alfa and darbepoetin alfa increase hemoglobin levels, reduce the risk for transfusions and improve quality of life when used according to the FDA label.
That is the key point: The drugs have been safe when used according to the FDA label. In trials where the drugs were used in experimental ways, such as pushing a target hemoglobin level higher than 12 g/dL, ESAs have not fared so well.
The results of these off-label trials have had a profound effect on the use of these drugs – including on-label use.
“In some trials, a decrease in survival or an increase in cancer progression has been noted in the patients who received erythropoietin agents,” John Glaspy, MD, a professor of medicine at the University of California-Los Angeles and director of the Jonsson Comprehensive Cancer Center Women’s Cancers Program, said in an interview with HemOnc Today.
“Nobody contests that, nor do they contest that it was only true in off-label studies. People are, understandably, looking for better ways to use the drugs or new populations in which to use the drugs. However, there is not one on-label study that has yielded a negative survival signal or a tumor-progression signal.”
Safety signals
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The original FDA label indicated that maintaining a hemoglobin level of 10 g/dL to 12 g/dL is safe and effective across most patient groups.
Data from randomized clinical trials have demonstrated the benefit of ESAs in treating patients with chemotherapy-induced anemia. These same data have demonstrated a quality-of-life benefit when the drugs are used to achieve a hemoglobin level of 12 g/dL.
In 2003, however, the Breast Cancer Erythropoietin Survival Trial (BEST) (Leyland-Jones et al) was terminated early when data from a safety analysis revealed that overall survival was poorer in patients who received epoetin alfa compared with placebo. In another trial reported in 2003, Henke et al identified a possible connection between ESAs and decreased survival in patients with head and neck cancer.
In both of these trials, the drugs were used off-label and administered in higher doses to target a hemoglobin level higher than the indicated level 12 g/dL.
Patients enrolled in those and similar trials also had a higher incidence of thromboembolic events when they received ESAs. The results of these trials raised concern, and the Oncologic Drugs Advisory Committee met in 2004 to evaluate available data. The committee acknowledged a possible safety concern and said more studies were necessary.
Data from another trial, reported in 2007, suggested a decrease in overall survival in patients with non–small cell lung cancer who received ESAs (Wright et al). Furthermore, data from another study reported in 2007 showed a negative effect on treating patients with cancer who were not receiving chemotherapy (Glaspy et al).
FDA response
The FDA issued a black-box warning for ESAs in March 2007. It also changed the label to indicate that the lowest ESA dose possible should be used to gradually increase a patient’s hemoglobin level and avoid a transfusion.
The FDA panel met again to evaluate safety data and recommended stronger warnings on the label for the specific cancers involved in the previous trials.
“Any time a safety signal is raised, the concern is whether the signal only comes from the area outside of standard use, which is the issue raised by the FDA,” said Jeffrey Crawford, MD, the George Barth Geller professor for research in cancer and chief of medical oncology at Duke University. “The studies have shown a negative effect when hemoglobin levels are pushed above 12 g/dL, but no one really knows why that is.”
What people do know, however, is that a target of 12 g/dL has been safe and within FDA indications for 15 years prior to these experimental studies. The FDA panel has twice determined that 12 g/dL is a reasonable target.
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The concerns are not unique to oncology. In November 2006, data from reported studies showed that patients with chronic kidney disease experienced more cardiovascular events when their hemoglobin levels were pushed higher than 12 g/dL. In other research, the drugs had no effect on quality of life among this patient group and increased risk for death and cardiovascular events.
A joint FDA advisory panel voted not to impose additional restrictions on ESA administration to patients with chronic kidney disease. The Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee recommended that the maximum target hemoglobin level for these patients remain 12 g/dL.
In November 2007, the FDA changed the label again to include stronger cancer-specific safety warnings. The label specified that ESAs should not be used in patients with cancer who are not receiving chemotherapy. The label also states that there are no data that show a risk when the drugs are used to target a hemoglobin level less than 12 g/dL.
CMS restrictions
In the meantime, the CMS has established a National Coverage Decision pertaining to the use of ESAs. Soon after the FDA meeting in May 2007, the CMS announced that they were restricting reimbursement for ESAs.
Originally, the CMS proposed restricting reimbursement for ESAs to chemotherapy-associated anemia for patients with a starting hemoglobin level of 9 g/dL or lower. The proposed maintenance hemoglobin level was 10 g/dL or lower. Reimbursement would not cover ESAs for patients with anemia due to myelodysplastic syndromes.
Various professional organizations including ASCO and ASH argued against these restrictions, worried mostly about increased transfusion risks and their patients’ quality of life. In response, when the final National Coverage Decision was implemented in August 2007, the initiation hemoglobin level required for reimbursement was increased to 10 g/dL or lower and coverage restrictions for MDS were delegated to local carriers. The maintenance hemoglobin level of 10 g/dL, however, remained unchanged.
“The CMS has had these drugs on their radar for a long time,” David Steensma, MD, associate professor of oncology at the Mayo Clinic in Rochester, Minn., said in an interview. “They wanted to decrease the use of this expensive drug to save money. They have taken the opportunity with these legitimate safety concerns to revise how physicians can use the drugs for Medicare beneficiaries, but they have gone too far in the other direction.”
Many physicians fear that if this National Coverage Decision is not overturned, they will be forced to practice with two treatment paradigms: one for Medicare beneficiaries and one for everyone else. The result will be an increased number of transfusions for Medicare beneficiaries who are receiving chemotherapy, a group of people who need the drugs the most, according to Glaspy.
“The CMS is taking away the doctor’s ability to make treatment judgments for individual patients and putting this judgment in the hands of policymakers, many of whom are not even oncologists,” Glaspy said. “We make judgments every day about medications that are much more dangerous than ESAs. Taking the doctor and the patient out of the decision-making process raises a lot of concern.”
ESA initiation
Although the FDA has clearly identified a maintenance hemoglobin level of 10 g/dL to 12 g/dL, it has not clearly stated an ideal point at which to initiate ESA treatment. Although the label did not specify a starting point, the most common clinical practice was to initiate ESA treatment when a patient’s hemoglobin level had fallen to 10 g/dL regardless of symptoms.
Physicians also initiated treatment if the hemoglobin level fell below 11 g/dL and the patient had severe symptoms of anemia or the hemoglobin level had decreased drastically in a short period of time. The FDA label allows for this practice; CMS, however, will not reimburse for it.
“There will be some irate patients and patient representatives who say that we are defying the FDA,” David Henry, MD, clinical professor of medicine at the University of Pennsylvania School of Medicine, told HemOnc Today. “We are not defying the FDA; CMS is defying the FDA.”
According to Henry, transfusion rates are a function of when ESA therapy begins. If treatment is started after a hemoglobin level goes below 10 g/dL, the rate of transfusions will increase, which defeats the purpose of ESAs.
Not consistent with practice
“To keep transfusions at a minimum, you really have to initiate the ESA at a hemoglobin level no less than 10 g/dL and maintain between 10 g/dL and 12 g/dL,” Crawford said. “The CMS decision is not consistent with clinical practice, or with good clinical care, or with understanding how the biology of these drugs work.”
Patients do not respond to ESA treatment for at least four to six weeks, Glaspy said, which is why timing is crucial when initiating treatment. After receiving an ESA, patients continue to receive chemotherapy. Thus, the hemoglobin level continues to fall and often reaches transfusion level before ESAs take effect.
Many argue that the FDA’s vague stance on initiation points has not been helpful. Although there are data on transfusion risks associated with different hemoglobin levels, the FDA has not responded to that data in its labeling.
“We have a responsibility to minimize transfusion risks in patients with cancer,” Glaspy said. “For all drugs, we can only deal with the data we have available. We need more studies, but in the meantime, we should not cut back on on-label use as a reaction to off-label data.”
In a recent study, Charu et al analyzed immediate vs. delayed intervention with darbepoetin alfa for chemotherapy-induced anemia. According to the data, patients who received the drug before a hemoglobin level fell below 10 g/dL had fewer transfusion requirements and were more likely to achieve and maintain the target hemoglobin level than were patients who received the drug after the hemoglobin level fell below 10 g/dL.
Transfusion risks
Before ESAs became available, patients were treated with transfusions to correct anemia. ESAs became available during the HIV crisis in the late 1980s, at which point people were realizing the danger associated with transfusions, Steensma said.
If the National Coverage Decision remains unchanged, a large increase in the number of transfusions given will likely result.
“It’s unlikely that CMS will ease its restrictions, at least not until they see how the use of these agents play out under the new rules,” John Adamson, MD, clinical professor of medicine in the division of hematology/oncology at the University of California-San Diego, said in an interview. “If there were a marked increase in transfusion requirements, that will be the tipping point that leads to a medical revolution as far as the CMS rules are concerned.”
Infection risks
Although transfusions are much safer than they were 20 years ago, there are still safety and infection risks. More transfusions will also negatively affect the nation’s blood supply.
Transfusions are also much more time-consuming than erythropoietin treatment: A transfusion can take four to six hours, whereas an ESA shot takes just seconds, Steensma said.
“With transfusions, I can keep my patients at a level where they are not symptomatic,” Steensma said. “But we just don’t have the extra units of blood to do that. Hospitals are already cancelling elective surgeries periodically because there is not enough blood in the blood bank. When patients in emergency departments can’t receive blood after accidents because the blood went to a patient who could have been treated with an ESA, then the CMS policy will be revisited.”
The future of ESAs
“If you asked anybody a year ago, nobody would have foreseen the situation that we are in now,” Crawford said.
What is known? The data show that maintaining a hemoglobin level between 10 g/dL and 12 g/dL is safe, and the FDA agrees. The CMS does not.
“The biggest mystery is why the CMS is saying this,” Henry said. “How are we all looking at the same data and coming to different conclusions?”
The FDA has said that trials should be designed to prospectively test the on-label use of the drugs in specific single disease states. Most of the original trials for ESAs were done to show that they reduce transfusion requirements, improve hemoglobin levels and improve quality of life. Thus, these studies were done in patients with a range of different cancers and did not test for survival.
The National Coverage Decision has been brought to the congressional level, and both the Senate and the House have introduced resolutions that force the CMS to reconsider the decision. ASH and ASCO have updated their guidelines on the usage of ESAs and have been communicating with Congress on the issue (Rizzo et al).
“We all know there are safety concerns, but the controversial question is, what do we do about it?” Glaspy said. “If everyone has been totally honest with us, this is being driven completely by a desire for patient safety and not by concern of the drug cost. If there is concern about the cost of the drugs, we should start speaking about it. We cannot deal with concerns that are not spoken.” – by Emily Shafer
Are restrictions on ESA use justified?
For more information:
- Charu V, Saidman B, Ben-Jacob A, et al. A randomized, open-label, multicenter trial of immediate versus delayed intervention with darbepoetin alfa for chemotherapy-induced anemia. Oncologist. 2007;12:1253-1263.
- Glaspy J, Smith R, Aapro M, et al. Results from a phase-3, randomized double-blind, placebo-controlled study of darbepoetin alfa for the treatment of anemia in patients not receiving chemotherapy or radiotherapy. #LB-3. Presented at: American Association for Cancer Research Annual Meeting 2007; April 14-18, 2007; Los Angeles.
- Henke M, Laszig R, Rübe C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomized, double-blind placebo-controlled trial. Lancet. 2003;362:1255-1260.
- Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-Line chemotherapy: a survival study. J Clin Oncol. 2005;23:5960-5972.
- Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update. Blood. 2008;111:25-41.
- Wright JR, Ung YC, Julian JA, et al. Randomized, double-Blind, placebo-controlled trial of erythropoietin in non–small cell lung cancer with disease-related anemia. J Clin Oncol. 2007;25:1027-1032.