Washington Editor

GAITHERSBURG, Md. - The Oncologic Drugs Advisory Committee generally agreed that it is reasonable to ask makers of Aranesp and Procrit to conduct placebo-controlled trials to assess possible adverse events.

While the ODAC panel did not take a formal vote on whether to force either firm to initiate safety trials, the consensus leaned toward further studies to rule out thrombotic and cardiovascular events so that patients can use erythropoietin products instead of blood transfusions.

Representatives from Amgen Inc., maker of Aranesp, and Ortho Biotech Products LP, maker of Procrit, did not argue against safety studies. Instead, both firms said they are conducing ongoing trials of their respective products in other indications, so it is possible that safety data could be collected from those studies.

Aranesp (darbepoetin alfa) and Procrit (epoetin alfa) are used for anemia associated with chemotherapy. Procrit is distributed by Ortho Biotech, a Bridgewater, N.J.-based subsidiary of Johnson & Johnson.

Safety concerns associated with EPO drugs surfaced recently after two European trials using similar drugs revealed impaired survival and evidence of possible tumor stimulation. The trials are known as the BEST study and the Henke study, published in The Lancet in October 2003, the FDA said.

In the meeting Tuesday, FDA officials noted that the BEST trial used J&J's European epoetin alfa called Eprex, while the Henke study in head and neck cancer used NeoRecormon, an epoetin beta sold by Basel, Switzerland-based F. Hoffmann-La Roche Ltd. Neither product is sold in the U.S.

"Our issue here is that we would like the companies to definitively address whether there could be adverse events," said Patricia Keegan, director of the FDA's division of therapeutic biological oncology products. "Just because the trials are designed to show superiority doesn't mean they can't show safety, too."

Nevertheless, David Parkinson, vice president of oncology clinical development at Thousand Oaks, Calif.-based Amgen, and Robert DeLap, vice president of global regulatory affairs with J&J, of New Brunswick, N.J., told the panel they do not believe their products cause tumor stimulation.

Parkinson said Amgen and independent investigators are studying Aranesp in several large trials, including a non-small-cell lung cancer (NSCLC) trial in which 213 of 600 patients have been accrued; a neo-adjuvant breast cancer trial that has accrued 400 of 720 patients; an adjuvant breast cancer trial in which 12 of 1,000 patients have been enrolled; a non-Hodgkin's lymphoma trial in which 22 of 600 have been accrued; and a trial in chemotherapy-induced anemia in which all 145 patients have been accrued.

J&J also has ongoing trials in breast cancer, NSCLC and head and neck cancer.

Meanwhile, J&J had commissioned the BEST study (Breast Cancer Erythropoietin Trial, or EPO-INT-76), which demonstrated a detrimental effect on 12-month survival, the FDA said. At the time of the study's interim analysis in April 2002, there were 179 deaths, including 101 in the treated arm and 78 in the placebo arm. The study enrolled 939 patients.

The 351-patient Henke trial consisted of patients with head and neck carcinoma who were to receive radiotherapy. The incidence of vascular disorders (hypertension, hemorrhage, venous thrombosis/pulmonary embolism) was 5 percent in the placebo arm and 11 percent in the epoetin beta arm. The numbers of patients who died from cardiac disorders also differed: five placebo and 10 drug patients, the FDA said.

The FDA said the BEST and Henke studies used treatment strategies (high-target hemoglobin) that are not recommended in labeling for either Epogen/Procrit or Aranesp. The studies were large, multicenter, randomized, placebo-controlled trials designed to assess the impact of supplemental erythropoietin use on survival and tumor outcomes.

Aranesp, a second generation of Amgen's blockbuster Epogen, is licensed in the U.S. for the treatment of anemia in patients with chronic renal failure and patients with non-myeloid malignancies receiving chemotherapy. Aranesp reduces fatigue and the need for transfusions and improves quality of life for patients with grievous illnesses, Amgen said. (See BioWorld Today, Sept. 19, 2001.)

Procrit is approved for a number of indications, including the treatment of anemia in patients with non-myeloid malignancies in which anemia is due to the effect of chemotherapy.

The two anemia products have been in the news in recent years when the Centers for Medicare and Medicaid Services decided the two should be reimbursed in the outpatient hospital setting at the same rate, after siding with J&J and deeming the drugs "functionally equivalent." (See BioWorld Today, Nov. 4, 2002; Dec. 27, 2002; July 7, 2003; Aug. 8, 2003; and Nov. 10, 2003.)