WASHINGTON--Citing inadequate data to prove efficacy, ODAC (Oncologic
Drugs Advisory Committee) voted unanimously against recommending that
the FDA approve the new drug application for Anthra
Pharmaceuticals valrubicin (Valstar).
The drug, an intravesically administered anthracycline, was tested
(as AD32) in 90 patients in two phase II nonran-domized trials for
the treatment of refractory carcinoma in situ (CIS) of the urinary bladder.
"Valrubicins safety is not in question," said ODAC
consultant George Sledge, MD, professor of medicine and pathology,
Indiana Cancer Pavilion, Indianapolis. "However, efficacy of the
drug has not been demonstrated in these trials."
Part of Anthras argument for approval of Valstar was based on
the lack of any approved drug treatment options for CIS of the
urinary bladder once a patient has failed several courses of BCG therapy.
"Once BCG treatment fails," said H. Barton Grossman, MD, of
M.D. Anderson Cancer Center, speaking on behalf of Anthra,
"salvage strategies must be considered." Further BCG
treatment pro-duces more risk than benefits, he said, and
radiotherapy "doesnt work." Mito-mycin (Mutamycin)
shows only a 7% complete response rate, and interferon produces low,
nondurable responses. Radical cystectomy entails 30% morbidity and
poor quality of life, and may be refused by some patients. "BCG
is the prime treatment," Dr. Grossman said, "and
BCG-refractory cancer is the primary problem. An alternative is needed."
The ODAC panels objections involved two efficacy issues: (1)
Did complete response correlate with patient benefit in this
nonrandomized trial? (2) Did the treatment actually change the
patients disease or can the observed benefits be ascribed
simply to patient heterogeneity?
The company cited complete response rates of 44% at 3 months, 21% at
6 months, 14% at 12 months, and 12% at 15 months. However, the FDA
felt that only 7 of the 20 complete responses claimed by the company
were verifiable because these were the only patients with documented
multifocal disease at baseline.
Some panel members argued that, in any case, complete response was
not an appropriate endpoint in this trial.
Time to cystectomy was delayed in responders (median, 23 months vs
8.3 months in nonre-sponders). However, "a significant
proportion of patients who failed did not go on to cystectomy,"
said panelist Howard I. Scher, MD, of Memorial Sloan-Kettering Cancer
Center. Only 37 of 60 patients who failed on Valstar therapy went on
"Is a complete response in fact a clinical benefit?" Dr.
Sledge asked. "Does this benefit improve the time to
cystectomy?" And, he continued, is a delay in cystectomy a real
benefit or simply due to a different natural history of the disease
between responders and nonre-sponders? "I am concerned that this
indicates selection bias in a nonrandomized trial," he said.
Robert Temple, MD, of the FDA, called this "a classic phase II
vs phase III problem. You can document efficacy, but can you conclude
there is sufficient benefit without a concurrent control group?"
Some panel members suggested that further data from Anthra might help
support the companys efficacy claims.