**SUMMARY MINUTES**

**OF THE**

**MICROBIOLOGY DEVICES**

**PANEL MEETING**

**OPEN SESSION**

**March 8, 2002**

**Gaithersburg Holiday Inn**

**Gaithersburg, MD**

**Attendees**

**Microbiology Devices Advisory Panel Meeting**

**March 8, 2002**

#####  ***Panel Members***

> Michael L. Wilson, M.D., Chair
>
> Denver Health Medical Center
>
> Kathleen G. Beavis, M.D.
>
> Cook County Hospital
>
> Laura A. Koutsky, Ph.D.
>
> University of Washington
>
> David T. Durack, M.D., Ph.D.
>
> Industry Representative
>
> Becton Dickinson Biosciences
>
> Stanley M. Reynolds
>
> Consumer Representative
>
> Pennsylvania Department of Health

##### ***Panel Consultants***

Donald A. Berry, Ph.D.

M.D. Anderson Cancer Center

George G. Birdsong, M.D.

Grady Memorial Hospital

Juan C. Felix, M.D.

Los Angeles County Women's and Children's Hospital

Janine Janosky, Ph.D.

University of Pittsburgh School of Medicine

Valerie L. Ng, Ph.D., M.D.

San Francisco General Hospital

Kenneth L. Noller, M.D.

Tufts University Medical School/New England Medical Center

Frederick S. Nolte, Ph.D.

Emory University School of Medicine

L. Barth Reller, M.D.

Duke University Medical Center

Carmelita U. Tuazon, M.D.

George Washington University Hospital

Melvin P. Weinstein, M.D.

University of Medicine & Dentistry of New Jersey

###### **Panel Discussants**

Herschel W. Lawson, M.D.

National Center for Disease Control and Prevention

Elizabeth R. Unger, Ph.D., M.D.

Centers for Disease Control and Prevention

##### ***FDA Personnel***

Steven I. Gutman, M.D., M.B.A.

Director, Division of Clinical Laboratory Devices

Office of Device Evaluation

Freddie Poole

Panel Executive Secretary

Thomas E. Simms

Sr. Review Scientist, Virology Branch

Division of Clinical Laboratory Devices

Marina Kondratovich, Ph.D.

Mathematical Statistician,

Office of Surveillance and Biometrics

###  

### OPEN SESSION

### Panel Chair Michael L. Wilson, M.D., called the meeting of the Microbiology Devices Panel to order at 8:37 a.m. and asked the panel members to introduce themselves. Panel Executive Secretary Freddie Poole read the conflict-of-interest statement, noting that a waiver had been granted to Juan Felix, M.D., for his unrelated consultant agreement with a firm having a financial interest in the sponsor and that he could participate fully in panel deliberations. The agency took into consideration matters involving George G. Birdsong, M.D., who had current interests in firms at issue that were unrelated to the agenda and determined that he could participate fully in panel deliberations. Ms. Poole noted that Elizabeth R. Unger, Ph.D., M.D., had reported her employer's unrelated involvement with a firm at issue.

### 

### Dr. Wilson then stated that the panel's charge was to deliberate on a premarket approval supplement to the Digene High Risk HPV DNA test (the Hybrid Capture II test), a nucleic acid hybridization in vitro diagnostic device for the detection of 13 types of high-risk types of human papillomavirus (HPV) in cervical specimens. The device's modified indications are for use as a general population screening test in conjunction with the Papanicolaou (Pap) smear for women age 30 and older, as an aid to determining the absence of high-grade cervical disease or cancer.

### Sponsor Presentation: Digene Corporation

**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.

Panel members asked the Digene representatives for additional
information on their rationale for determining that the changes in
sensitivity and specificity were appropriate for the device. Sponsor
representatives responded that the objective reliability of the HPV
test, coupled with the elimination of the consequences of Pap-test false
positives, makes the decrease in specificity acceptable. Panel members
continued to express concern about the decrease in specificity
associated with the HPV test. **Dr. Lörincz** stated that the sponsor
had discussed the matter with FDA and felt that the decrease was
reasonable.

**Kenneth L. Noller, M.D.**, pointed out that even high grades of CIN
can disappear without treatment and asked whether the sponsors had any
information on the transiency of additional lesions. **Dr. Cox**
responded that anything that improves lesion detection is helpful and
that at this point, there is no way to predict which lesions will
progress.

**Donald A. Berry, Ph.D.,** asked what women believe when they are Pap
negative but HPV positive. **Dr. Killackey** responded that in such
cases, patient education is important. **Dr. Cox** added that patient
education is improving in light of increased media coverage of HPV and
that for most people, HPV infection is transient and has no
consequences. **Dr. Felix** noted that if screening is an important
prevention strategy, a discrepancy existed between the submission and
what the sponsor was proposing with the diagnostic algorithm. **Dr.
Cox** replied that the literature gives reassurance that women testing
negative on both the Pap and the HPV test are at low risk for cancer and
provided additional clarification on the algorithm.

**Frederick S. Nolte, Ph.D.,** noted that the HPV test has a single
cutoff point and that no "gray zone" exists around that cutoff. **Dr.
Lörincz** replied that the test is highly reproducible and that false
positives are rare, so no gray zone is necessary. Dr. Nolte asked
whether additional data on quantitative aspects of the test were
available for the eight studies, and Dr. Lörincz replied that the
sponsor could make the data available.

### Panel Discussant

**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.

### FDA Presentation

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.

### Open Public Hearing

**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 routine use.

**Linda Alexander,** Advocates for Women's Health, spoke in support of
the Digene PMA submission, calling HPV screening a "truly primary
prevention activity." In addition, HPV testing offers an opportunity to
help women understand the implications of Pap test results. The HPV
test--Pap smear combination offers an opportunity to improve the status
of women's health care. She urged the panel to recommend approval of the
PMA.

**Wayne C. Shields,** Association of Reproductive Health Professionals,
also spoke in support of the Digene submission. He stated that approval
would allow women to have access to improved technology that can save
lives while avoiding unnecessary procedures.

Ms. Poole then read into the record the presentation of **Phyllis
Greenberger, MSW,** Society of Women's Health Research, along with
letters from **Philip A. Miles, M.D., FACOG, FCAP,** Gyn Path Services,
Inc.; **Keith O. Reeves, M.D.; Elinor Christiansen, M.D.,** American
Medical Women's Association; and **R. Marshall Austin, M.D., Ph.D.,**
Coastal Pathology Laboratories. The presentation and all four letters
supported the approval of the Digene submission.

### 

### Open Committee Discussion

The panel discussed each question in turn.

***Question 1**:* Does the data submitted support use of HPV DNA testing
as a general population screening test in conjunction with Pap smear
considering \[that\] the non-U.S. populations studied showed differences
in cervical cancer prevalence and screening practices versus the U.S.
population; three sites used collection devices with unestablished
performance and one of these an unvalidated matrix; one site defined
positives using any positive results up to 3 years after testing; and
cytology readings and selection of patients for colposcopy were not
standardized across sites?

**Laura A. Koutsky, Ph.D.,** noted that the U.S. population is not
homogenous, so having a variety of studies could be advantageous. She
also commented on the poor standardization of cytology across sites and
observed that because unapproved devices are less sensitive than
approved ones, the studies may be more sensitive than indicated and
performance will only improve.

**Dr. Berry** emphasized that guidance for physicians and women needed
to be developed if the device was approved. The panel had to consider
the practical impact of the device. The issue of verification bias is
important for device specificity, and quantification of the bottom line
is important.

**Dr. Noller** observed that women with a positive Pap test often think
they have cancer and that the physician needs to spend considerable time
reassuring them. An HPV test will only increase anxiety and translate
into increased colposcopy exams. One would have to do many colposcopies
to pick up one case of disease---where does one set the bar? It is
unclear why Pap smears have to take place annually, but it nevertheless
will take a long time to change the interval. **Dr. Felix** concurred
and noted that much of the physician--patient relationship is built on
the annual Pap test visit. Any extension of the interval would have to
involve increased physician and patient education. If managed care
settings change their practices, however, general practice might change
quickly as well.

**Kathleen G. Beavis, M.D.,** said that expanding the interval is
intuitively appealing, but the data do not support it. Implementing
widespread HPV screening could lead to increased colposcopies.

**L. Barth Reller, M.D.,** said that the sponsor's studies fell into the
category of hypothesis-generating studies. That one could increase or
decrease the interval for different populations was plausible but not
proved. **David T. Durack, M.D., Ph.D.,** said that although increasing
the interval could have benefits, the data do not support it; moreover,
expanding the interval is not actually a recommendation of the sponsor.
Extension could have unintended consequences.

**Dr. Wilson** invited a response from Digene to clarify the time
intervals. Dr. Kinney said that the current standards are for 1- to
3-year intervals, and the sponsor is not suggesting extension beyond
those guidelines. **Dr. Cox** noted that clinicians have not taken
advantage of current practice intervals. **Dr. Killackey** said that
women can understand that if they are both Pap and HPV negative, they
are at low risk and can be screened every 3 years.

**Dr. Birdsong** responded that if HPV screening were widely
implemented, colposcopies would increase because many women will have
stress and anxiety and will want to have the procedure to assuage their
worries.

**Dr. Beavis** said that a longitudinal study could demonstrate that the
interval could be increased, but the sponsor's studies are snapshots;
the question cannot be answered in a single-time study. In response,
**Drs. Cox** and **Canner** provided clarification on the study design.
**Dr. Kinney** added that the data gave no indication that the sponsor's
conclusions are wrong; the Portland study alone is large enough. **Dr.
Lörincz** stated that data from the Portland study provided an
impressive demonstration of the long-term protective effects of the
device's proposed use. Panel members asked various questions for
clarification on the study's methodology, which the sponsor
representative answered.

***Question 2:*** \[Are\] Digene's criteria of decreasing false negative
rate more than 25% and not decreasing specificity (true negative rate)
by more than 10% acceptable to measure the benefit of adding high-risk
HPV testing to the normal Pap smear?

**Dr. Berry** stated that the criteria were not acceptable; one had to
consider the implications of the test and its consequences. Sensitivity
and specificity are not the only or most relevant characteristics to
address. **Dr. Koutsky** noted that positive and negative predictive
values vary for different populations, depending on prevalence, and
asked what other characteristics could serve as criteria. **Dr. Berry**
noted that sensitivity and specificity only address relative, not
absolute, risk and benefit.

**Dr. Felix** said that clinical aspects of sensitivity do not add to
its positive predictive value because positive predictive value does not
take into account the future risk of disease in HPV positive women. A
25% improvement is reasonable. He would test the hypothesis that
sensitivity is higher with the HPV test than without. **Dr. Birdsong**
said that the device could serve as an adjunct to cancer screening; the
negative predictive value is so good that a 25% increase is reasonable.
He had concerns about the decrease in specificity.

The panel members expressed additional concerns over the impact of false
positive and false negative readings and the test's positive predictive
value. **Dr. Beavis** reminded the panel that the test detects HPV, not
the presence of cancer.

***Question 3**:* If the panel finds the new indication for use as a
general population screening test acceptable, how might the device be
labeled and what recommendations should be made for its use, given the
different populations and conditions used to derive the data and the
nonpoolable nature of the data?

**Dr. Felix** said that the most important issue involves the
consequences of testing positive for HPV---the labeling needs to include
guidance for the user. **Dr. Nolte** noted that the labeling goes in the
package insert and would be a fairly inefficient way to educate the
medical community.

**Dr. Reller** said that the data are insufficient to provide guidance
on clinical practice. Until such data are available, nothing that would
change the guidelines should be put into the labeling.

**Open Public Hearing**

No comments were made.

**Industry Response**

In response to a comment by **Dr. Nolte**, **Dr. Kinney** provided
background on ACOG's recommendations concerning HPV testing. He added
that the need for provider education is important but is not a reason to
not approve the PMA. **Dr. Cox** said that a prospective clinical study
with an endpoint of cancer was not feasible. The issue of unnecessary
colposcopies can be handled through education; a greater concern is the
3,000 to 4,000 women who have had screening yet have cancer. Approval of
the adjunctive application has public health implications. **Dr.
Lörincz** stated that the sponsor's data support the proposed claim for
adjunctive use for women age 30 and older. The test is robust, and all
studies showed the same trends of improvement. Clinical benefits are
that it permits the objective classification of women into low- and
high-risk groups. The proposed algorithm will become part of the
labeling upon FDA approval. The studies show a remarkable level of
congruence, and the decrease in specificity is minor.

**Final Recommendations and Vote**

Ms. Poole read the voting options for premarket approval applications
and noted that

**Drs. Beavis** and **Koutsky** were voting members of the panel. She
then read a statement signed by the Center Director, David Feigel, M.D.,
appointing to temporary voting status, **Drs. Berry, Felix, Nolte,
Reller, Birdsong**, and **Janosky**.

The panel voted 6-2 to approve the device with the following four
conditions:

1.  The sponsor should provide specific recommendations for how to use
    the test in clinical management (including how to interpret results
    near the cutoff).

2.  The sponsor must demonstrate that the recommendations will have a
    positive impact on clinical outcomes. These conditions could be
    satisfied by evidence based on data derived from longitudinal
    studies.

3.  The sponsor must develop educational materials to accompany the
    tests both for laboratory users and clinicians.

4.  Postmarketing surveillance must be conducted to assess the impact of
    the device performance on clinical outcomes.

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 important.

Panel members who voted no felt that the conditions were unduly
burdensome.

### 

### Adjournment

### Dr. Wilson thanked the panel, the speakers, and the FDA for their participation and adjourned the session at 4:24 p.m. 

> I certify that I attended the meeting of the Microbiology Devices
> Panel on March 8, 2002, and that this summary accurately reflects what
> transpired.
>
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> Freddie Poole
>
> Panel Executive Secretary

I approve the minutes of this meeting

as recorded in this summary.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Michael L. Wilson, M.D.

Panel Chair

Summary minutes prepared by

Caroline Polk

Polk Editorial Services

1112 Lamont Street, NW

Washington, DC 20010

\(202\) 265-8271

Edited by: Freddie M. Poole