October 01, 1998 BETHESDA, Md--Three months after refusing to give its blessing to Valstar (valrubicin), the Oncologic Drugs Advisory Committee (ODAC) reheard Anthra Pharmaceuticals new drug application and recommended that the FDA approve the new anthracycline for use in a limited population of patients with carcinoma in situ (CIS) of the urinary bladder.
The panel gave its backing to Valstar for intravesical use in patients who are refractory to BCG immunotherapy and who have a medical contraindication to cystectomy. It refused to endorse the drugs use in BCG-refractory patients who are candidates for cystectomy but who refuse to undergo the surgery. During its presentation, the company had argued that after BCG failure, people who refuse cystectomy and those who cannot undergo the surgery have no effective drug treatment.
Last June, Anthra presented ODAC with combined data from two nonran-domized, open-label phase II studies that involved a total of 90 patients. The trials were identical except for the study sites. Patients were treated with 800 mg of Valstar weekly for 6 weeks in each study.
Anthra claimed complete responses in 19 patients. The FDA staff accepted only 7 of these in its analysis, which the company and its consultants challenged.
ODAC members in June generally found Valstars toxicity acceptable but questioned whether the trial data supported the benefit claimed, because a number of people who didnt respond also did not go on to cystectomy, with no apparent difference in outcome. Several suggested that Anthra might have additional information that would make its case more persuasive.
New Analyses
At the September ODAC meeting, both the company and FDA presented new analyses of the combined studies, A9301 (35 patients) and A9302 (55 patients), that included additional data supplied by Anthra. The company again listed 19 complete responders; the FDA classified 9 patients as complete responders and 7 more as potential complete responders, for a response rate of 18%.
In the FDA analysis, three patients were listed as "potential CR" because they had single lesions with negative or inadequate baseline cytologies. Another four patients were considered potential complete responders because they had only one follow-up biopsy documenting complete response instead of the two sequential biopsies designated by the protocol.
Barton Grossman, MD, deputy chairman of urology, M.D. Anderson Cancer Center, said that Anthra asked him to do an independent analysis of the two trials to determine if patient benefit was observed. "After careful review of these data, I can honestly answer that question in the affirmative," he told the panel. "These patients are a highly refractory population. . . . A very conservative definition of complete response was employed."
Anthra also contended that the 19 complete responders derived clinical benefit from Valstar. It cited a longer time to cystectomy in complete responders than in nonresponders. Also, the time to disease recurrence after treatment with Valstar was longer for complete responders than nonresponders, approximately 18 months vs 6 months, a significant difference in favor of the Valstar group, Dr. Grossman said.
The FDA generally agreed. "These data demonstrate that intravesical treatment with Valstar produces durable complete responses and delays time to cystectomy in patients with BCG-refractory CIS of the urinary bladder," it told the committee in a written document.
Committee members spent considerable time debating whether it was wise to encourage people who fail BCG treatment to avoid cystectomy. Speaking for the company, Paul Lange, MD, of the University of Washington, maintained that, "there is a value in many patients in trying to delay or avoid cystectomy."
Michael Droller, MD, of Mt. Sinai Medical Center, New York, also presenting for Anthra, said: "I think the issues are, Do we have an agent that has efficacy; can we apply that agent in a patient population that is not at risk for immediate progression of disease and in whom drug failure can be cured by cystectomy; and does the use of the agent identify a group of patients who can then be urged to undergo cystectomy at some point?"
In the end, the committee decided the study data failed to support the wisdom of using Valstar as an alternative to cystectomy in patients medically able to undergo the procedure but who refuse to do so. It voted 9-to-2 with one abstention to approve Valstar only for those patients in whom cystectomy is medically contraindicated.
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