New BCG Bladder Cancer Indication Gets Panel Nod

ROCKVILLE, Md--TICE BCG vaccine (Organon Teknika Corp.) has won thebacking of the Food and Drug Administration's Oncologic Drugs AdvisoryCommittee (ODAC) as a prophylaxis against recurrent papillary carcinomaof the urinary bladder.

TICE BCG is one of the three most commonly used forms of the vaccinein the United States. Long known as a tuberculosis vaccine, it has beenlicensed since 1990 for use against carcinoma in situ of the urinary bladderand is marketed in 25 countries for that purpose. Organon Teknika has soughtsince 1992 to win its approval for use in preventing recurrent superficialpapillary cancer.

The FDA twice sent the company letters of nonapproval, in August 1994,and May 1996, and sought additional supporting information before sendingthe product licensing application for the new use to ODAC for review.

"I think there is a significant number of urologists who are usingthe drug off-label for this purpose," ODAC consultant Robert R. DiLoreto,MD, of Warren, Mich, noted during the proceedings.

The company presented data from two studies that compared TICE BCG withmitomycin C--one carried out at Nijmegen University in The Netherlandsand the other by the Southwest Oncology Group (SWOG 8795).

Researchers chose mitomycin C as a control because of its "goodtoxicity profile and its effectiveness against carcinoma in situ,"said urologist Donald Lamm, MD, of the University of West Virginia, whoprovided an overview of the studies on behalf of the sponsor.

Not unexpectedly, "BCG resulted in significantly more side effects,"Dr. Lamm noted. Fifty-two percent of the TICE BCG patients suffered dysuria;25%, malaise; and 17%, fever. Mitomycin C patients had dysuria at a rateof 36%; malaise at a rate of 14%; and fever at a rate of 3.6%. Eighteenpercent of patients receiving TICE BCG and 30% of control patients hadno symptoms.

"TICE BCG is not innocuous," Dr. Lamm said. "It can causelife-threatening, even fatal side effects. But none of those effects occurredin the 511 patients treated in these two studies."

Dr. Lamm argued that the benefits outweighed the risk. "BCG significantlyreduced the incidence of tumor recurrence and prolonged time to recurrencecompared to mitomycin C," he said. "The trends with regard toprogression and mortality, as expected, favored BCG. BCG may significantlyreduce the risk of grade 3 occurrence, and so we would anticipate that,with further, broader experience, this would translate into saving lives."

An FDA analysis of the two studies shed some light on the reasons forthe two letters of nonapproval sent earlier to the sponsor. The FDA reviewersfound that in the Nijmegen Study, 44% of the TICE BCG patients suffereda recurrence versus 29% of those in the mitomycin C arm. "The trendwas distinctly against TICE BCG and almost reached statistical significance,"the agency told the ODAC members.

In the SWOG study, 46% of those getting the BCG vaccine died or recurredversus 57% receiving the control drug, FDA reviewer Richard Steffen, MD,told the panel. Unlike the Nijmegen study results, this finding was statisticallysignificant, Dr. Steffen added.

The FDA did note, however, that 47% of the participants in the SWOGstudy had TaG1 lesions. The FDA generally requires that superficial bladdercancer studies include no more than 20% of patients with TaG1 lesions."A subset analysis of patients without TaG1 tumors demonstrated that50% of the patients on the TICE BCG arm recurred and 63% of the patientson the mitomycin C arm recurred," the agency said in a written statement.

The ODAC Vote

In addressing a series of questions posed by the FDA staff regardingTICE BCG, ODAC members agreed unanimously that the Nijmegen study did notprovide evidence that TICE played an active role in preventing the recurrenceof Ta/T1 tumors. Ten of its members, however, agreed that the SWOG studydid provide this evidence.

The panel voted 10 to 0, with one abstention, to recommend that theFDA approve TICE BCG for prophylactic use against recurrent papillary carcinomaof the bladder.

The abstention came from retired US Army Colonel James Schultz, ODAC'spatient advocate for bladder cancer issues. The meeting marked the firsttime a patient representative had the power to vote on an issue referredto the committee by the FDA.