ROCKVILLE, Md--TICE BCG vaccine (Organon Teknika Corp.) has won the
backing of the Food and Drug Administration's Oncologic Drugs Advisory
Committee (ODAC) as a prophylaxis against recurrent papillary carcinoma
of the urinary bladder.
TICE BCG is one of the three most commonly used forms of the vaccine
in the United States. Long known as a tuberculosis vaccine, it has been
licensed since 1990 for use against carcinoma in situ of the urinary bladder
and is marketed in 25 countries for that purpose. Organon Teknika has sought
since 1992 to win its approval for use in preventing recurrent superficial
The FDA twice sent the company letters of nonapproval, in August 1994,
and May 1996, and sought additional supporting information before sending
the product licensing application for the new use to ODAC for review.
"I think there is a significant number of urologists who are using
the 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 with
mitomycin C--one carried out at Nijmegen University in The Netherlands
and the other by the Southwest Oncology Group (SWOG 8795).
Researchers chose mitomycin C as a control because of its "good
toxicity profile and its effectiveness against carcinoma in situ,"
said urologist Donald Lamm, MD, of the University of West Virginia, who
provided 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 rate
of 36%; malaise at a rate of 14%; and fever at a rate of 3.6%. Eighteen
percent of patients receiving TICE BCG and 30% of control patients had
"TICE BCG is not innocuous," Dr. Lamm said. "It can cause
life-threatening, even fatal side effects. But none of those effects occurred
in the 511 patients treated in these two studies."
Dr. Lamm argued that the benefits outweighed the risk. "BCG significantly
reduced the incidence of tumor recurrence and prolonged time to recurrence
compared to mitomycin C," he said. "The trends with regard to
progression and mortality, as expected, favored BCG. BCG may significantly
reduce 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 for
the two letters of nonapproval sent earlier to the sponsor. The FDA reviewers
found that in the Nijmegen Study, 44% of the TICE BCG patients suffered
a recurrence versus 29% of those in the mitomycin C arm. "The trend
was 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 recurred
versus 57% receiving the control drug, FDA reviewer Richard Steffen, MD,
told the panel. Unlike the Nijmegen study results, this finding was statistically
significant, Dr. Steffen added.
The FDA did note, however, that 47% of the participants in the SWOG
study had TaG1 lesions. The FDA generally requires that superficial bladder
cancer studies include no more than 20% of patients with TaG1 lesions.
"A subset analysis of patients without TaG1 tumors demonstrated that
50% of the patients on the TICE BCG arm recurred and 63% of the patients
on 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 regarding
TICE BCG, ODAC members agreed unanimously that the Nijmegen study did not
provide evidence that TICE played an active role in preventing the recurrence
of Ta/T1 tumors. Ten of its members, however, agreed that the SWOG study
did provide this evidence.
The panel voted 10 to 0, with one abstention, to recommend that the
FDA approve TICE BCG for prophylactic use against recurrent papillary carcinoma
of the bladder.
The abstention came from retired US Army Colonel James Schultz, ODAC's
patient advocate for bladder cancer issues. The meeting marked the first
time a patient representative had the power to vote on an issue referred
to the committee by the FDA.