FDA Advisers Urge Tighter Clamps on Erythropoiesis-Stimulating Agents

SILVER SPRING, Md., May 11 -- Although the FDA advised physicians in March to use erythropoiesis-stimulating agents at the lowest possible dose to preclude a transfusion, an advisory committee has urged the agency to develop still stricter standards.

The Oncologic Drugs Advisory Committee voted 15 to 2 to ask the agency for additional restrictions and stronger warnings in product labeling for Aranesp, Procrit, and Epogen. What's more, the advisers voted unanimously to call for new safety studies.

The drugs are approved to treat anemia in patients with chronic kidney failure and in cancer patients whose anemia is caused by chemotherapy. Epogen and Procrit are also approved for patients scheduled for major surgery to reduce potential blood transfusions and for the treatment of anemia for certain HIV patients.

The advisers focused on ESAs for cancer patients receiving chemotherapy. Another meeting will be held in the fall on chronic kidney disease.

While strongly insisting that more safety studies are needed, the panel was uncertain as to what exactly to recommend. The members:

• Voted 12 to 5 that labeling should specifically state that ESAs are not indicated for use in specific tumor types, but left to a future meeting which types, which may include breast cancer, head-and-neck cancer, and non-small-cell lung cancer.
• Voted 15 to 2 that product labeling should define a hemoglobin level in asymptomatic patients at which ESAs should be initiated, but did not specify the level.
• Voted 12 to 5 against the idea that dosing should be titrated to avoid transfusions, generally aiming at a lower hemoglobin level, leaving that thorny question to future panels.
• Voted 16 to 1 to recommend that labeling recommend discontinuation of the ESA following completion of a chemotherapy regimen.
• Agreed that there should be more patient-doctor education on adverse effects of ESAs.
• Generally agreed that a placebo-controlled ESA trial would be a good idea, but difficult to implement.

The FDA warnings in March were issued after it learned of some dangerous side effects, including risk of heart attacks and stroke.

At the committee meeting, the ESA-makers, Amgen and Johnson and Johnson, tried to make the case that ESAs are safe and effective in recommended doses, but the panel was not persuaded by the data.

One panel member called the companies' presentation "sleight of hand," and another, Silvana Martino, an oncologist in Santa Monica, Calif., commented, "The burning question is, does this actually kill people in the doses that you think are reasonable and appropriate? And I haven't seen anything that has an answer. I'd put a stop to all the trials that use higher doses than the recommended doses."

FDA staffers told the panel that of the few studies that were acceptable for analysis, it appears that ESAs actually shorten outcome survival rates and increase tumor production.

Nevertheless, said the FDA's Dr. Richard Padzur, "We're not talking about taking the drug off the market."