GAITHERSBURG, Md--Faced with significant differences between FDA staff and company-associated scientists in the analysis of data from two clinical studies, the FDA's Oncology Drugs Advisory Committee (ODAC) declined to vote either way on whether to recommend approval of Pharmacia & Upjohn's Remisar (bropirimine tablets) for the treatment of patients with BCG-refractory or BCG-intolerant urinary bladder carcinoma in situ (CIS).
GAITHERSBURG, Md--Faced with significant differences between FDAstaff and company-associated scientists in the analysis of datafrom two clinical studies, the FDA's Oncology Drugs Advisory Committee(ODAC) declined to vote either way on whether to recommend approvalof Pharmacia & Upjohn's Remisar (bropirimine tablets) forthe treatment of patients with BCG-refractory or BCG-intoleranturinary bladder carcinoma in situ (CIS).
The panel instead advised the FDA and the sponsoring company tosee if they could satisfactorily resolve the discrepancies betweentheir interpretations of the pooled data from the nonran-domizedstudies involving a total of 105 patients.
The sponsor claims 25 patients (24%) responded completely; another30% had no response. FDA evaluators, however, put the number ofcomplete responders at nine.
Bladder CIS often responds well to intravesical BCG (TICE BCG,TheraCys). However, about 30% of patients with diffuse CIS arerefractory to this treatment or cannot tolerate it. Urologistsgenerally consider these people candidates for immediate cystectomybecause they are at high risk of developing invasive and metastaticcancer.
The FDA panel members unanimously agreed that a drug producinga long-lasting, complete remission in a sizable number of CISpatients would provide a "meaningful clinical benefit."They disagreed with Pharmacia & Upjohn, however, that thecompany had proved that Remisar was that drug.
In its safety evaluation, the sponsor included participants froma third Remisar bladder CIS trial. No increase in urinary eventsoccurred, but increases in some cardiovascular episodes were seenamong the 134 patients in the analysis.
These included tachycardia (15/11%), palpitations (13/10%), flushing(8/6%), hypertension (5/4%), and myocardial infarction (5/4%).While 4 of the 134 died (3%), only 1 death appeared possibly attributableto the drug.
The studies show the drug is effective, has a "good safetyprofile," and offers "a practical alternative to radicalcystectomy and urinary diversion," said Langdon L. Miller,MD, Pharmacia & Upjohn's vice president for US oncology development.
However, the FDA's Robert M. White, MD, disagreed. Of the company'sreported 25 complete responders with a median duration of responseof 210 days, FDA evaluators accepted only 9 as complete respondersand put the median duration response at 157 days, he told thepanel.
Among the reasons for rejecting 16 of the 25, "some of theresponders did not have documented CIS at baseline," he said,and some "did not have a positive urine cytology at baseline."
The FDA team also found that two responders did not have urinecytology and biopsies on the same day, and several patients "hadinadequate follow-up." Dr. White cited, as an example, apatient who did not receive six follow-up biopsies as requiredby the trial protocol.
He also noted that although it is difficult to assess side effectsin nonran-domized trials, 23% of the participants dropped outdue to toxicity.
"The conclusion is that there is a lack of substantial evidenceof safety and efficacy of bropirimine in BCG-refractory and BCG-intolerantbladder CIS," Dr. White said.
Robert Temple, MD, the FDA's associate director for medical policy,told ODAC that the agency had no objection to the fundamentaldesign of the Remisar studies presented by the company.
After listening to the company's response, ODAC members decidedto make no recommendation on the drug's approval and urged thetwo groups to reassess their interpretations of the data. Pharmacia& Upjohn later issued a statement saying that it "willcarefully consider and discuss the committee's concerns with theFDA."