NEWS

FDA Panel Scrutinizes Safety of Anti-Anemia Drugs

Judith Randal

Commercials on American television that feature cancer patients made anemic—and therefore miserably tired—by chemotherapy and whose energy is restored by the drug Procrit are hard to escape. Given by injection, this drug is a genetically engineered version of erythropoietin, the human hormone—often referred to as EPO or epoetin—that corrects anemia by stimulating the production of red blood cells that ferry oxygen to the body's tissues.

Procrit is made by Amgen and marketed by Johnson & Johnson subsidiary Ortho Biotech Products. It reduces the number of transfusions that cancer patients may need without, it was believed, posing a risk that it will make their tumors recur or progress. The same goes for Amgen's Aranesp, which is Procrit's only competitor in the United States and is also a genetically engineered version of erythropoietin given by injection. (It is chemically similar to Procrit but has been molecularly altered to be longer acting.) Such is the demand for both drugs that their annual sales run to billions of dollars.

Safety Concerns

The U.S. Food and Drug Administration (FDA) now has safety concerns about them. The reason is that in Europe—where the approved versions of genetically engineered erythropoietin include Aranesp, Hoffman-LaRoche's NeoRecorman, and Johnson & Johnson's Eprex—the last two drugs fared poorly in two large randomized multicenter trials that were conducted in cancer patients on chemotherapy. (See News, Dec. 17, 2003, Vol. 95, No. 24, p. 1820.)

More specifically, in both of these trials, disease-free survival and overall survival were shorter in the group of patients treated with erythropoietin than in the comparison group of patients given a placebo. In these trials, as well as in some others done in Europe, there were also more cardiovascular complications—particularly thromboses (blood clots)—in the erythropoietin-treated group.

At the May meeting of the FDA's Oncologic Drugs Advisory Committee held in Gaithersburg, Md., representatives of Johnson & Johnson and of Amgen said that, after reviewing the preclinical and clinical data on their own erythropoietin drugs, they found no evidence that the use of Procrit or Aranesp adversely affected patient survival.

They further argued that EPO drugs and their oxygen-boosting effects were probably not to blame for how the trials of NeoRecorman and Eprex had turned out. Instead, they speculated that the patients in these trials who got EPO treatment fared worse than those who did not because they had likely had a higher rate of preexisting cardiovascular disease.

Also likely to have figured in those results, according to some industry speakers at the meeting, was that the erythropoietin doses in these trials were larger than those the FDA has approved for Procrit and Aranesp. As Bruce Cheson, M.D., of Georgetown University, acting chair of the advisory panel, later explained: "The European studies not only used erythropoietin formulations that are not available in this country but also sought to normalize the treated patients' hematocrits (blood hemoglobin levels), which is not standard practice (for supportive cancer care) here."

Possibility of Progression

The FDA, however, is not ready to rule out the possibility that Procrit and Aranesp can contribute to cancer recurrence or progression—even when prescribed at the doses their U.S. labeling recommends. Among the reasons cited in the agency's briefing document on the topic is the fact that many types of malignant cells have receptors for erythropoietin. Although it is not known whether erythropoietin that binds to receptors on these cells can fuel cancer growth, there is considerable laboratory evidence that the risk may be real, according to the briefing document.

"The FDA considers all these products (to be) members of the same product class.... Thus, these evolving safety concerns [from the European studies] are assumed to apply to all [erythropoietin] products unless adequate and well-controlled trials demonstrate otherwise," Harvey Luksenburg, M.D., a medical reviewer at the FDA, said at the May meeting.

Johnson & Johnson and Amgen have started or are planning trials that may fill this bill. These trials were originally designed to determine whether anemia-fighting drugs can make cancers more susceptible to radiotherapy and chemotherapy by delivering more oxygen to tumors. But both companies told the meeting of their willingness to make certain modifications in the studies that should also provide better answers as to whether the drugs may worsen a patient's prognosis.

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The FDA panel did not discuss whether advertisements or promotional materials for the drugs should be revised in light of the current uncertainties about their safety. An FDA spokes-person said that the agency is working with the drug's sponsors, Amgen and Johnson & Johnson, on possible labeling changes for them. She could not, however, say what these changes could entail or when they might take effect.

Meanwhile, the question was also put to McGill University's Brian Leyland-Jones, M.D., who was the principal investigator on an erythropoietin trial of metastatic breast cancer patients. His understanding is that there will be labeling changes in the United States, but not until European regulatory authorities decide what, if any, such changes should be made for the EPO products that are sold there.


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