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FDA panel votes to restrict erythropoiesis-stimulating agents
CMS will also limit coverage of the agents; the decisions are a reaction to data suggesting harm.
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The FDA Oncology Drugs Advisory Committee voted 15-2 to recommend the FDA place more restrictions on erythropoiesis-stimulating agents in light of recent study data that show increased adverse effects are associated with higher-than-normal doses of the drug.
The committee recommended disease-specific restrictions based on recent study results that showed adverse effects in patients with breast cancer, head and neck cancer and non-small cell lung cancer. The committee, however, did not specifically state which cancers should be subject to the restrictions. The committee also voted unanimously that more studies are needed before any definitive restrictions can be made.
"Just because the studies that raised concerns about erythropoiesis-stimulating agents enrolled patients with breast cancer, head and neck cancer and lung cancer does not mean that there is anything special about those diseases," David Steensma, MD, associate professor of oncology at the Mayo Clinic in Rochester, Minn., said in an interview. Steensma has also written several articles about erythropoiesis-stimulating agents.
"Patients with some types of cancer might do worse with erythropoiesis-stimulating agents, but we just don't know. Banning the use of epoetin and darbepoetin in specific cancers is a knee-jerk reaction that doesn't seem appropriate in view of the limitations of current evidence," Steensma said.
Data from recent studies have shown that erythropoiesis-stimulating agents were related to decreased overall survival when used at higher doses to treat patients with anemia not related to chemotherapy. This prompted calls from Congress to halt marketing of these products until the FDA determined an appropriate action.
In March, the FDA requested that black box warnings be placed on packaging for epoetin alfa (Procrit, Johnson & Johnson; Epogen, Amgen) and darbepoetin alfa (Aranesp, Amgen). The warnings advise of possible severe consequences resulting from off-label use. The request was based on reports that erythropoiesis-stimulating agents cause increases in blood clots, tumor growth and significantly higher mortality rates.
Appropriate doses
The advisory committee also voted 16-1 that anemia therapy should end when chemotherapy is finished and voted 11-6 against lowering the ceiling hemoglobin level at which anemia should be corrected; it remains at 12 g/dL.
"We are seeing that there are issues when the dose is pushed beyond what is recommended," S. Gail Eckhardt, MD, acting committee chair of the advisory panel and director of the division of medical oncology at the University of Colorado Health Sciences Center, said at the meeting. "The problem is that these safety signals are at doses that are off-label. Are there messages that need to be incorporated into the current utilization of the agent to maximize safety until we can conduct appropriate studies at appropriate doses?"
The FDA will render a final decision and may or may not follow the recommendations of the advisory committee.
"The burning question here is whether these drugs actually kill people in the doses that we think are reasonable and appropriate," committee member Silvana Martino, DO, director of the breast cancer program at the Angeles Clinic and Research Institute in Santa Monica, Calif. "I don't see anything that has approached an answer to this question, and I would actually put a stop to all of the trials that are using higher doses than allowed. They are going to continue to confuse us and waste patient resources."
Because of recent reports, it is entirely appropriate for an FDA advisory panel to review safety issues regarding erythropoiesis-stimulating agents, according to Jeffrey Crawford, MD, the George Barth Geller Professor for Research in Cancer and chief of medical oncology at Duke University. Crawford, who has written several articles about erythropoiesis-stimulating agents, spoke at the committee meeting on behalf of the sponsors.
"I'm not sure their conclusions quite match my look at the data," Crawford told Hem/Onc Today after the panel meeting. "The safety signals that did occur were outside the standard indications for the drugs. I'm not quite sure why the panel felt the need to further restrict usage."
CMS may limit coverage
Just days after the advisory committee meeting, the Centers for Medicare and Medicaid Services announced a proposed decision to limit coverage of erythropoiesis-stimulating agents for its beneficiaries with certain cancers and related neoplastic conditions.
The proposed national coverage decision was in response to the black box warning of erythropoiesis-stimulating agents issued by the FDA.
"We pay close attention to the FDA black box warnings because the safety of our Medicare beneficiaries is paramount," CMS Acting Administrator Leslie V. Norwalk, said in a press release. "We have carefully examined the evidence surrounding these labeling changes and have issued this proposed decision to protect our beneficiaries."
The CMS proposes that treatment with erythropoiesis-stimulating agents is reasonable and necessary only under specified conditions for the treatment of anemia in certain cancers. In addition, the CMS will continue to review its monitoring policy for the use of the agents in patients with renal disease. The public comment period for this proposed decision is open until June 13.
"Because there is a preponderance of emerging data for erythropoiesis-stimulating agent use in the oncology setting, we have narrowed the focus of the national coverage analysis to erythropoiesis-stimulating agent use in cancer and related neoplastic conditions," Barry M. Straube, MD, chief medical officer for the CMS, said in a press release.
Open-label studies from the 1990s have shown erythropoietin agents are beneficial in treating chemotherapy-induced anemia in patients with cancer, providing the only alternative to red blood cell transfusions. Randomized clinical trials have also shown erythropoietin agents improve both overall survival and quality of life when used to achieve an optimum hemoglobin level of 12 g/dL.
The central debate
In 2003, however, preliminary results of the Breast Cancer Erythropoietin Survival Trial (BEST), a large clinical trial of patients with metastatic breast cancer, caused concern. In this trial, the patients were treated with epoetin alfa to reach a hemoglobin level well above the optimal level of 12 g/dL.
The BEST trial, reported in the Journal of Clinical Oncology (2005;23:5960-5972), was terminated prematurely when a safety analysis found that the overall survival in patients assigned epoetin alfa was poorer compared with that in patients assigned placebo. This outcome prompted additional investigations of the drug's safety.
In another study reported in the Journal of Clinical Oncology (2006;24:4708-4713), researchers identified a possible connection between erythropoiesis-stimulating agents and decreased survival in patients with head and neck cancer receiving chemotherapy. Earlier this year, yet another trial reported in the Journal of Clinical Oncology (2007;25:1027-1032) suggested a connection with decreased overall survival in patients with non-small cell lung cancer.
The various tumor types analyzed in these three studies are the basis of the advisory panel's recommendation for disease-specific restrictions on erythropoiesis-stimulating agents.
Adverse outcomes of investigational uses of the erythropoiesis-stimulating agents are having an effect on the use of the agents for its indication. Physicians are urged to remember that the drugs do have benefit when used in the manner for which it is intended.
"These warnings should not be construed as to throw the baby out with the bath water," Harry Jacob, MD, chief medical editor for Hem/Onc Today, said in an interview. "The drug is proven safe to target a hemoglobin level of 12 g/dL, which is the standard of care. There is also no question that the drug, when used as indicated, improves the quality of life in catastrophically ill patients. There may be some unwarranted side effects, but I believe these are minimal in terms of what the patients are going through otherwise."
In an editorial in the Journal of Clinical Oncology, Crawford wrote that although recent studies have suggested erythropoiesis-stimulating agents have negative effects, data from any one trial should be put into a larger context. In the case of these drugs, Crawford wrote that there have also been several other larger randomized trials that indicate no association with decreased survival.
Other considerations
Speaking on behalf of the American Society of Hematology in the public hearing portion of the FDA advisory panel meeting, Samuel Silver, MD, PhD, director of the University Cancer Center Network at the University of Michigan and section editor of the Policy, Patient and Practice Issues section of Hem/Onc Today, said that erythropoiesis-stimulating agents lessen the need for transfusions and thus alleviate the strain on the nation's blood supply.
"Of paramount importance to ASH is to ensure the highest degree of patient safety and protect not only against overuse but also the underuse and misuse, as well," Silver said. "The impact on the blood supply also needs to be taken into account. ASH is currently updating its evidence-based practice guidelines for the use of erythropoiesis-stimulating agents and firmly believes that high-quality clinical trials are needed to demonstrate the effect on patients with hematologic diseases."
Silver said ASH has made the following recommendations:
- Erythropoiesis-stimulating agents should continue to be used for treatment of anemic patients with hematologic malignancies who are not undergoing chemotherapy, but phase-3 studies should be initiated to address this usage.
- Erythropoiesis-stimulating agents may be used as a treatment option for patients with chemotherapy-associated anemia and should be continued for treatment 90 days post-chemotherapy.
- Erythropoiesis-stimulating agents may be used as an appropriate treatment option for patients with anemia from chronic inflammation; patients with non-cancer related conditions are distinct from patients being treated for the anemia from cancer.
- Erythropoiesis-stimulating agents should be started in appropriate clinical settings, at or below a hemoglobin level of 10 g/dL, and the target should be 12 g/dL at most.
Silver also said that with patients with hematologic malignancies not on chemotherapy, there is evidence to support the use of ESAs in patients with anemia associated with low-risk myelodysplasia with a blast count less than 5%. Studies from the Nordic Group, the Italian Cooperative Group and a recent pooled analysis from the Cleveland Clinic have demonstrated the effectiveness of ESAs to decrease the need for transfusions.
Another issue to consider is the differences between patients. Jacob said that every patient is different, and this is not a decision meant to be made on the basis of a group.
"We have to respect the uniqueness of patients, rather than try to put everybody in the same box," Jacob said. "There are some very active people who will complain that they are no longer able to be active when anemic and therefore will try any rational treatment. Then there are others who have had chronic problems all of their life and are not as concerned about cancer treatment side effects. Advisory boards make decisions based on a group, not individual patients. This is an unavoidable shortcoming that will undoubtedly diminish quality of life for many patients."
Steensma said that there is a role for erythropoiesis-stimulating agents in preventing transfusions among people receiving cancer treatment. He said that the recommendations will lead some physicians to be more conservative about using the agents. Crawford also said that attempting to avoid blood transfusions is important.
Erythropoiesis-stimulating agents, however, are the only known alternative to transfusions, and a solution to the controversy is still far away.
"This is a complicated area, and it will continue to evolve," Crawford said. "The guidelines will continue to be updated, and physicians should stay tuned and watch for the changes." – by Emily Shafer
For more information:
- 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.
- Henke M, Mattern D, Pepe M, et al. Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J Clin Oncol. 2006;24:4708-4713.
- 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.
- Crawford, J. Erythropoietin: High profile, high scrutiny. J Clin Oncol. 2007;25:1021-1023.