BETHESDA, MdThe Oncologic Drugs Advisory Committee (ODAC) declined to vote on whether to recommend that the Food and Drug Administration approve Eloxatin (oxaliplatin, Sanofi Pharmaceuticals) for the first-line treatment of patients with advanced colorectal cancer in combination with fluorouracil(Drug information on fluorouracil) (5-FU)-based chemotherapy.
The panel passed up a formal vote after it decided unanimously that a key study presented by the company failed to demonstrate persuasively a survival advantage for Eloxatin.
The company submitted two phase III trials conducted in Europe, two second-line trials, and four monotherapy trials in support of its application. The FDA, however, only accepted the two multinational, randomized phase III trials (420 and 200 patients, respectively) for review.
Both studies compared 5FU/leucovorin to 5FU/leucovorin plus Eloxatin and made overall survival a secondary endpoint. ODAC has long regarded survival as the fundamental basis for recommending approval of drugs for the first-line treatment of colorectal cancer.
The FDA medical review team concluded that both randomized trials showed an increased response rate and progression-free survival with the addition of oxaliplatin(Drug information on oxaliplatin), but neither showed a survival advantage.
In material provided to the advisory committee, the FDA argued that the addition of Eloxatin to 5-FU/leucovorin in the pivotal study presented by Sanofi did not demonstrate a survival advantage employing the log rank test specified in the protocol as the planned method for analysis.
The company provided an alternative adjusted analysis that it contended demonstrated a survival advantage for the combination of Eloxatin and 5-FU/leucovorin. The principal adjustment in the alternative analysis was for baseline alkaline phosphatase.
ODAC members did not accept the companys alternative analysis. One panel member, Richard M. Simon, DSc, chief of the National Cancer Institutes Biometric Research Branch, said that the analysis violated many of the basic principles of statistical practice.