FDA Advisory Board Wants to See Further Analyses of Ethyol Trials

ROCKVILLE, Md--The FDA's Oncologic Drugs Advisory Committee hasdeclined to recommend Ethyol (amifostine injection, U.S. Bioscience,Inc.) for approval at this time. The drug is being consideredas a cytoprotective agent against both the acute and cumulativehematologic and renal toxicities associated with alkylating agentssuch as cyclophosphamide (Cytoxan, Neo-sar) and platinum agentssuch as cisplatin (Platinol) in patients with ovarian cancer.

Although there was general agreement among the committee membersthat amifostine does indeed have a biologic effect, they foundthat the data submitted did not make clear whether that effectis sufficient for approval.

Robert L. Capizzi, MD, U.S. Bioscience executive president, saidthat the company has since had a constructive meeting with theFDA, resulting in an FDA proposal that the company submit an amendmentto its NDA for Ethyol based on analyses of the existing clinicaldata. The company intends to submit this amendment and anticipatesreturning to the committee by mid-year 1995.

He added that the recent recommendation for approval of the drugin Europe and the anticipated commercial sale in the United Kingdomshould provide opportunities to demonstrate Ethyol's clinicalbenefit for cancer patients.

A U.S. Bioscience representative said that the treatment for ovariancancer patients has improved somewhat over the past several yearsbut at a great cost in toxicity.

In its presentation of Ethyol trials in patients with advancedovarian cancer and melanoma being treated with alkylating andplatinum agents, the company claimed that pretreatment with Ethyolled to a significant decrease in hematologic, renal, neurologic,and otologic drug toxicity, without reducing the antitumor effectsof chemotherapy.

U.S. Bioscience representatives also said that use of Ethyol decreasedthe incidence of infections associated with neutropenic fevers,resulting in fewer days of hospitalization and fewer days on antibioticsin the ovarian cancer trials.

In addition, the drug was said to confer cytoprotection on normalmarrow, which could have important clinical significance for patientswith advanced breast cancer undergoing high-dose chemotherapy/autologousbone marrow transplantation.

In response to questions by the committee members, U.S. Biosciencerepresentatives acknowledged that, although it is too soon totell, it is unlikely that Ethyol will result in increased survival.

Drug Appears Safe

John Glick, MD, of the University of Pennsylvania, a principalamifostine investigator, discussed the safety of Ethyol as seenin his multicenter clinical trial of 242 ovarian cancer patients(consisting of an original cohort of 121 patients and a new cohortof 121 additional patients).

The principal side effects, Dr. Glick said, were nausea and vomitingand hypotension. Both were present only on the day of treatmentand were transient in nature. There were no cases of anaphylaxisand no deaths.

Problems arose at the meeting because of the FDA requirement ofat least two confirmatory studies. Thus, the committee consideredthe two cohorts in the clinical trials as two separate studies.

Robert J. DeLap, MD, the FDA evaluator, said that the company'sprimary efficacy hypothesis, which was demonstrated in the firstcohort of patients, was not confirmed in the new cohort of 121additional patients. Eight of 55 evaluable patients in the amifostinegroup in this new patient cohort experienced neutropenia-associatedevents versus 11 of 62 patients in the control group, he said.

Dr. DeLap did acknowledge, however, the existence of some beneficialeffects of the agent on cumulative bone marrow suppression, renaltoxicity of treatment (although renal toxicity was generally mildin this patient cohort), and neurotoxicity and ototoxicity. Inaddition, Dr. DeLap said that the drug may not be absolutely selective;that is, it does not necessarily act only on normal tissue, butmight also be protective of the cancer.

He also said that the study's primary endpoint was not well definedand urged the company to provide more data that would confirmefficacy, especially in relation to neutropenia-associated events.