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 (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, but neither showed a
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.