March 8, 2002
Gaithersburg Holiday Inn
Microbiology Devices Advisory Panel Meeting
March 8, 2002
L. Wilson, M.D., Chair
Health Medical Center
G. Beavis, M.D.
A. Koutsky, Ph.D.
T. Durack, M.D., Ph.D.
Department of Health
Medicine & Dentistry of New Jersey
for Disease Control and Prevention
Unger, Ph.D., M.D.
Disease Control and Prevention
Steven I. Gutman,
of Clinical Laboratory Devices
Office of Device
Thomas E. Simms
Scientist, Virology Branch
Clinical Laboratory Devices
Surveillance and Biometrics
Charles M. Fleischman, President, Digene Corporation,
began his presentation by stating
that the Hybrid Capture 2 device used in conjunction with the Pap smear provides
better clinical medicine than the Pap alone and that the device is better at
detecting disease than the Pap alone. He
emphasized that they are seeking approval for the device used with the Pap smear
for screening women age 30 and older.
Mark Del Vecchio, Director, Regulatory and Clinical Affairs, Digene
Corporation, introduced the
sponsor’s representatives and provided an overview of the major discussion
points. Mr. Del Vecchio described the current approved claims for the device and
the proposed intended use.
F. Xavier Bosch, Chief, Epidemiology and Cancer Registry, Institut
Catala d’Oncologia, Barcelona, Spain, an investigator for Digene Corp.,
reviewed the scientific literature on the associations between various risk
factors and cancer. He stated that
HPV DNA has been found in virtually all cases of cervical cancer; that the
scientific consensus is that HPV is a necessary, but not sufficient, cause of
cervical cancer; that the absence of HPV means lower risk for cervical cancer;
and that the presence of HPV means increased risk.
Walter Kinney, M.D., Division of Gynecologic Oncology, TPMG
Sacramento, a Consultant to Digene
Corp., presented data from an HMO-based study on clinical utility of combining
cervical cytology and HPV testing. He
noted that because invasive cancer is not an option for an endpoint, CIN2+ was
used as the clinically relevant endpoint instead. Patients who tested negative for HPV received reassurance;
those testing positive received guidance on follow-up testing and compliance.
In his opinion, the study demonstrated that the clinical value of the
test outweighs the perceived negatives of having to educate patients about the
implications of testing positive for HPV. Dr.
Kinney also presented data from other studies, including data from the IARC
study, which pooled data from 10 sites outside the United States.
He concluded by stating that the additional information that high-risk
HPV testing provides is useful to clinicians in many ways and that in settings
in which screening intervals of more than 1 year are recommended, the presence
of high-risk HPV in women age 30 and older helps identify patients who might
benefit from annual Pap smears.
Attila T. Lörincz, Ph.D., Senior Vice President and Chief
Scientific Officer, Digene Corporation discussed the clinical data in support of
the sponsor’s amended PMA. He
described the inclusion criteria for the eight studies selected and stated that
all eight studies were conducted under rigorous protocols.
He described the target condition, which was histologically confirmed
high-grade disease, including cancer. When
data were available; CIN2+ was included in the definition of high-grade disease.
The clinical goal, he stated, is to identify women at increased risk and
to direct appropriate patient management to remove high-grade disease before
cervical cancer develops. Dr. Lörincz
described the specimen-collection devices and provided details on the
Portland/Kaiser study, which he said supports the proposed claim even without
the data from the other studies. He
presented information on HPV detection using cervical lavage methods, the
applicability of the foreign studies to the U.S. population, and other
considerations pointing to the strength of the studies.
Dr. Lörincz then presented comparisons of the sensitivity data from the
eight studies, negative predictive value, and positive predictive value for
CIN2+ and CIN3+ endpoints. After
noting several potential limitations of the studies—namely, issues involving
the collection devices, which are not currently approved for use for HPV—he
stated that in all eight studies, HPV as an adjunct to Pap was a more sensitive
indicator for cervical disease than Pap alone and produced only a minor
reduction in specificity.
Joseph Canner, Biostatistician, Hogan & Hartson LLP,
consultant for Digene Corp.,
presented Digene’s statistical analysis plan, which was developed prior to
data analysis. Because each study was conducted independently under a different
protocol, the decision was made to analyze the studies separately.
The success criteria for each study were developed based on two
assumptions: (1) that the outcome of interest was cervical disease CIN2+ and (2)
that the success criteria were to be applied to the estimates of sensitivity and
specificity uncorrected for verification bias.
Mr. Canner then described the statistical methodology for analyzing the
sensitivity and specificity of the device and presented comparative data from
the eight studies.
Next, Mr. Canner presented
information on verification bias. He
explained that because women are not typically referred to colposcopy, the true
prevalence of false and true negatives is unknown. He described four approaches to dealing with verification
bias and stated that none is entirely ideal.
Finally, he presented data on subsets of patients who tested negative on
both tests and were referred (some randomly) to colposcopy for verification.
On the basis of the results for the more than 1,500 women who received
colposcopy, he stated that the sponsor is confident that verification bias is
minimal. Dr. Canner stated that the
FDA’s statistical review used an overly conservative analysis.
He summarized by saying that although Pap sensitivity is highly variable
in the eight studies, the combined test provides uniformly high sensitivity.
He believes that the data presented constitute valid scientific evidence
that provides reasonable assurance of the safety and effectiveness of the Digene
device as an adjunct to Pap smear in the evaluation of cervical disease risk.
Dr. Maureen Killackey, Bassett Regional Cancer Program, Cooperstown,
NY, and Associate Clinical Professor of OB/Gyn, Columbia University,
and a guest speaker for Digene Corp., presented a clinical perspective on
the device. She stated that women
and providers need to be educated about the natural history of HPV infection.
The combination of HPV and Pap tests can help reassure women about their
risk, increase follow-up compliance, and identify women who need frequent
screening. The test can also help
clinicians avoid inappropriate colposcopy referrals and unnecessary surgery.
J. Thomas Cox, M.D., Director, Gynecology & Colposcopy Clinic,
University of California Santa Barbara, presented an algorithm for management of
individuals tested by both HPV assays and cytology.
He discussed studies in the literature which demonstrate the subjectivity
and variability in the reading of Pap smears and stated that adjunctive HPV
testing provides clinically meaningful improvement in sensitivity.
He summarized the U.S. cervical screening guidelines, and presented a
diagnostic algorithm for use in the proposed labeling.
He emphasized that the consequence of a false-positive HPV test was more
diligent surveillance, not unnecessary colposcopy.
Jonathan Kahan, Hogan & Hartson, Washington, DC, Legal And
Regulatory Counsel for Digene Corp., summated that the sponsor was seeking
approval for an expanded claim and emphasized that HPV was not a substitute for
the Pap test. He summarized the
points made by the previous speakers: Adjunctive HPV testing provides a
clinically important increase in sensitivity with an acceptable decrease in
specificity and is an objective means of identifying women at increased risk of
high-grade disease. The data
support the sponsor’s claim and proposed labeling, and the recommended
diagnostic algorithm is consistent with current screening guidelines.
Dr. Wilson then invited the Panel to ask questions of the sponsor.
Elizabeth R. Unger, Ph.D., M.D., NCID, Centers for Disease Control
and Prevention, provided an overview of human papillomaviruses.
She described the typology, high- and low-risk variants, and features of
HPV that affect in vitro detection and provided prevalence estimates of HPV-associated
disease in the United States. Data
indicate that the virus sheds below the limit of detection, but the basal
compartment of the epithelium has not been sampled in available studies; no
consensus on the definition of persistent infection exists. Regarding the Digene
device, Dr. Unger noted that the data indicate good interlaboratory comparison;
but the results are not type specific. She
also provided comparative information on HPV PCR assays.
HPV in situ hybridization is
the only method that permits direct visualization of the virus in a morphologic
context, but the results are technique dependent.
Thomas E. Simms, Sr.
Review Scientist, Virology Branch, Division of Clinical Laboratory Devices,
Center for Devices and Radiological Health, presented
FDA’s analysis of the data based on the proposed indication for use and
criteria for screening tests. The
goal of the FDA review, he stated, was to evaluate assay effectiveness in the
population claimed; however, the eight studies relied on by the sponsor were not
originally designed to evaluate Digene’s proposed indication for use and
establish performance characteristics. FDA’s
concerns with the sponsor’s data are that not all the studies included the
full claimed age range; that the study populations were not consistent with the
U.S. population; that one study was a longitudinal study that the sponsor
converted to a cross-sectional study for data analysis purposes; that not all
women with normal Pap smear results proceeded to colposcopy; that patient follow
up was not consistent with U.S. practice; and that study populations were not
stratified for low-risk women. Other
FDA concerns are that unapproved HPV DNA collection devices were used at three
sites; the sites demonstrated differences in cytology readings; and one study
was conducted with a less sensitive version of the Hybrid Capture II device. Mr. Simms reviewed the current approved indications for use
of the Digene device, and then presented data from the studies in support of
FDA’s concerns. Finally, he
summarized FDA’s concerns regarding selection and device bias.
Marina Kondratovich, Ph.D., Mathematical Statistician, Office of
Surveillance and Biometrics, Center for Devices and Radiological Health,
presented FDA’s statistical review. She
reviewed each of the eight studies on which the sponsor relied; for each study,
she stated the sponsor’s estimates of sensitivity and specificity for the
study and provided FDA’s revised estimates.
In FDA’s estimation, the increase in sensitivity was affected by
verification bias; the sponsor’s PMA submission overestimated the increase in
sensitivity and decrease in false negatives.
The China and Baltimore studies did not demonstrate statistically
significant increases in sensitivity when the combination of Pap and HPV tests
was used. In addition, the sponsor did not address other biases, such
as spectrum bias from differential prevalence and device bias.
Mary F. Mitchell, American College of Obstetricians and
Gynecologists (ACOG), presented their recommendations on HPV DNA testing.
ACOG’s view is that HPV DNA testing lacks specificity.
It may be of value in triage of abnormal cervical cytology, but it must
be evaluated prospectively in a clinical trial before it can be recommended for
The Panel Recommended that
Conditions 1, 2, and 3 be completed before FDA approval of the device.
Panel members who voted for
approval with conditions did so because they felt that the sponsor had not
demonstrated safety and effectiveness of the device for the new intended use,
but that the test had value as long as it was used in conjunction with specific
clinical guidelines. Panel members
also indicated that educational materials and postmarket surveillance were
Panel members who voted no felt
that the conditions were unduly burdensome.
I certify that I attended
the meeting of the Microbiology Devices Panel on March 8, 2002, and that this
summary accurately reflects what transpired.
I approve the minutes of this meeting
as recorded in this summary.
Michael L. Wilson, M.D.
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