GAITHERSBURG, MdThe Food and Drug Administrations
Oncologic Drugs Advisory Committee (ODAC) has advised Zila, Inc., to
take OraTest (tolonium chloride) back to the clinic for further
testing. But members disagreed whether continuation of an ongoing
clinical trial could provide the data necessary for the group to
recommend approval of the test for detecting oral cancer, or if the
company needs to undertake an entirely new study.
Im not sure that at the end of another 300, 400, or 500
patients, were going to have data that are going to be any
better or any less confusing, said ODAC consultant Stacy
Nerenstone, MD, of the Helen and Harry Gray Cancer Center, Hartford, Conn.
Zila sought approval of OraTest (a ready-to-use kit whose active
ingredient is a patented formulation of a dye commonly called
toluidine blue) as a diagnostic adjunct in patients with oral
lesions suspected or known to be malignant, to help in detection of
all sites of cancer, definition of borders or cancerous lesions, and
selection of sites to be biopsied.
According to the company, the dye in OraTest is taken up
preferentially by cancer cells, which allows identification and
definition of oral carcinomas and carcinomas in situ, often when the
cancers are not found on visual examination.
Although toluidine blue is available for use in detecting oral cancer
in dentists offices, it has been inconvenient for dentists to
mix up the material on their own, Steven Corbin, DDS, chief of staff
to the US Surgeon General, said on behalf of Oral Health America, a
Chicago-based nonprofit organization.
Another speaker, Pier Cipriani, DDS, said that when ordered from a
chemical supply house, toluidine blue arrives as a reagent grade
powder. Preparing the solution stains fingers, clothing, and
countertops, and the resulting liquid has a shelf-life of only 1 to 2
days. In addition, staining results may vary greatly from batch to
batch due to impurities. OraTest uses pure,
pharmaceutical-grade ingredients; is ready to use, premixed, and
flavored; and has a multiyear shelf life, Dr. Cipirani said.
Zila provided the FDA staff with an interim analysis of 16
patientsfrom the first 367 patients enrolled in a trial of
OraTest at 12 centersin whom 17 oral cancers were detected by
the test or by visual examination.
The study was designed to support a screening claim rather than the
narrower adjunct claim that is the subject of the companys new
drug application (NDA). FDA reviewer Ken Kobayashi told ODAC members
that the agency had not recommended that Zila seek approval based on
the interim analysis. He and committee members questioned both the
companys interpretation of the data and how the data were gathered.
The company, for example, listed 10 of 17 oral cancers as identified
solely by OraTest; the FDA review team put the number at five. The
company claimed 100% sensitivity for OraTest and a specificity of
17%; the FDA listed sensitivity at 89% and specificity at 19%.
Among the problems with the study was a protocol violation at the
University of Pittsburgh, which sent patients with suspicious lesions
on to surgery, while enrolling them in the study. Zila Biomedical
president Ralph Green, DDS, said that violation put the initial 131
patients enrolled at the Pittsburgh site off-protocol. We have
discovered it; we have monitored it, and for the rest of the cohort
beyond the 131, they are now back in line, Dr. Green said.
Committee members also expressed concern that the test might produce
a high number of false positives.
Two supportive studies also submitted by Zila were criticized by the
FDA review team as inadequate in design to support the companys application.
Agreement on Value of Test
In spite of the criticisms of the data presented by Zila and flaws in
the studys execution, committee members expressed strong
agreement that a test such as OraTest would have great value in the
diagnosis of oral cancers.
I dont have the sense this is a bad product, and, in
fact, I have the reverse feeling, said Kathy S. Albain, MD,
professor of medicine, Loyola University Medical Center, Maywood,
Ill, who encouraged Zila executives to pursue data on OraTest.
We hope you take our comments as constructive, positive
comments. We hope to hear about OraTest again, she said.
The company said that 673 patients with 25 cancerous lesions have now
been enrolled in the OraTest study. Originally, the protocol called
for the study to end after 54 cancers were identified. Dr. Green said
that following the ODAC meeting, Zila executives and key FDA
personnel met to map a course of action to gain approval of OraTest.
Zila will decide as soon as possible what to do about continuing the