### SUMMARY MINUTES

### MEETING OF THE OBSTETRICS AND GYNECOLOGY DEVICES ADVISORY PANEL

**OPEN SESSION**

**May 17, 2005**

**Gaithersburg Holiday Inn**

**Gaithersburg, MD**

**Obstetrics and Gynecology Devices Advisory Panel Meeting**

**May 17, 2005**

**Attendees**

**Chairperson**

Kenneth L. Noller, M.D.

Tufts University Medical School 

Boston, MA

**Voting Members**

Evelyn R. Hayes, Ph.D., R.N., CS-FNP

College of Health and Nursing Sciences

University of Delaware

Newark, DE

Paula J. A. Hillard, M.D.

University of Cincinnati College of Medicine

Cincinnati, OH

Hugh S. Miller, M.D.

Arizona Health Science Center

Tucson, AZ

Jonathon W. Weeks, M.D.

Suburban Hospital

Maternal-Fetal Medicine Center

Louisville, KY

**Consultants**

Marcelle I. Cedars, M.D.

University of California

San Francisco, CA

Ralph B. D'Agostino, Ph.D.

Boston University

Boston, MA

Amir H. Gandjbakhche, Ph.D.

National Institutes of Child Health and Human Development

National Institutes of Health

Bethesda, MD

Melvin V. Gerbie, M.D.

Northwestern University Medical School

Chicago, IL

Yulei Jiang, Ph.D.

University of Chicago

Chicago, IL

Thomas M. Julian, M.D.

University of Wisconsin

Madison, WI

Joseph S. Sanfilippo, M.D.

Magee Women's Hospital

The University of Pittsburgh School of Medicine

Pittsburgh, PA

Russell R. Snyder, M.D.

University of Texas Medical Branch at Galveston

Galveston, TX

**Industry Representative**

Elisabeth George

Phillips Medical Systems

Newton, MA

** **

**Consumer Representative**

Christine Moore

Baltimore, MD

#  

**Executive Secretary**

Michael Bailey, Ph.D.

CDRH

**CALL TO ORDER**

**Panel Chair Kenneth L. Noller, M.D.,** called the meeting to order at
8:34 a.m., to review a PMA for the MediSpectra LUMA™ Cervical Imaging
System (P040028). Panel members introduced themselves. **Panel Executive
Secretary Michael Bailey, Ph.D.,** announced that the next Panel meeting
would be June 23, 2005; meetings for the remainder of the year are
tentatively scheduled for August 15-16 and November 14-15.

**FDA PRESENTATION: Condition of Approval Studies: Recent CDRH Changes**

**Susan Gardner, Ph.D., Director, Office of Surveillance and Biometrics
(OSB),** reported on a major programmatic change in CDRH condition of
approval (CoA) studies, including the move of the Condition of Approval
Studies Program to her office. Her office plays a role in premarket
reviews, conducts signal detection to monitor the postmarket arena,
assumes responsibility for characterizing device risk by reviewing
postmarket data, and interprets medical device reporting regulations.
The legislative authority for their work comes from 21 CFR 814.82(a)
(2).

This shift began a few years ago when CDRH decided to evaluate its CoA
program, initially to look at the quality of the studies required for
condition of approval. They noted that 45 of the 127 PMA studies
approved between 1998 and 2000 had CoA studies. They also realized that
they had no standardized tracking process for this area, and high
turnover among reviewers. There were no results for 22 percent of
studies.

The official move to OSB was January 1, 2005, preceded by a 3-year pilot
program. One of their first steps was to develop an automated tracking
system to help them acknowledge to industry that they have received the
report and conduct any necessary follow-up. The second change added an
epidemiologist to the PMA team to develop the postmarket plan during the
premarket review.

Dr. Gardner said that the changes should provide industry with increased
motivation to carry out the CoA studies. The office will post the status
of these studies on the CDRH website. As well, under Section 522, they
have the ability to mandate postmarket studies; this will allow them to
apply civil penalties to incomplete studies. The Panel will be asked to
provide feedback and advice on better approaches to finish the studies.
Her office will also provide the Panel with an update on the progress of
the CoA study.

**INTRODUCTORY REMARKS**

**Colin Pollard, Chief, Obstetrics and Gynecology Devices Branch,** made
a few introductory remarks to the Panel. He noted that the efforts for
this technology dates back several years; the Panel met several years
ago to draft a guidance document on this technology. The sponsor has
been collaborating with the FDA for a number of years with respect to
this device.

**Panel Secretary Michael Bailey, Ph.D.,** read into the record the
conflict of interest statement. A waiver has been granted to Dr.
Sanfilippo for his consulting interests with a subsidiary of a competing
firm. He was allowed to participate but could not vote in the day's
deliberations. The Agency took into consideration certain matters
regarding Dr. D'Agostino's past personal interests and his current
employer's interest with firms at issue, but in matters not related to
the day's agenda. He was allowed to participate fully in the day's
deliberations. Temporary voting status for the extent of the meeting was
granted to Drs. Cedars, D'Agostino, Gandjbakhche, Gerbie, Jiang, Julian,
and Snyder.

**OPEN PUBLIC HEARING**

Dr. Noller read the open public hearing speaker statement. **Diane
Solomon M.D., National Cancer Institute, NIH, DHHS**, began her
presentation on data from the ASCUS/LSIL Triage Study (ALTS) study. She
noted that the ALTS clinical trial received support in the form of
equipment and supplies at below cost from Digene, Cytek, Tripath, and
National Testing Laboratories.

The study enrolled just over 5,000 women with a community cytology
diagnosis of either atypical squamous cells of undetermined significance
(ASCUS) or low-grade squamous intraepithelial lesions (LSIL). The trial
was a randomized with a 2-year follow-up. The women were divided into
three management arms: immediate colposcopy; human papillomavirus (HPV)
triage; and conservative management.

The ALTS trial results were as follows: no test was completely able to
detect cumulative cervical intraepithelial neoplasma 3 (CIN3);
colposcopically-dervived biopsies were less sensitive that previously
assumed---a finding she said was a surprise; and undetected CIN3 did not
regress, while CIN2 showed significant regression. The ALTS results
demonstrated that colposcopy is a weak link in the screening chain of
events. CIN3 detection was essentially the same in the immediate
colposcopy arm versus the conservative management arm. She contrasted
this with detection levels of CIN2. Undetected CIN2 actually regressed,
and CIN2 detection was 9.9 percent in the immediate colposcopy arm
versus 5.8 percent in the conservative management arm. This demonstrated
that CIN2, as compared to CIN3, is not a precancerous condition but more
likely a mix of high-grade and low-grade disease that looks severe, but
is destined to regress.

**Mark Schiffman, M.D., M.P.H.,** **National Cancer Institute, NIH,
DHHS,** compared data for first and second biopsies taken at colposcopy
in the ALTS trial. The study looked at what a second biopsy added when
done with colposcopic direction and no adjunctive device. They
discovered that the first biopsy did not yield any more significant
information than the second biopsy. However, the severity of the two
biopsies was positively associated (weighted kappa=0.37; 95 percent
confidence interval=0.29-0.45). Therefore, the investigators focused on
looking at the second biopsy and its effect on sensitivity.

Their results show that there is a clear need to improve colposcopic
performance and localization of biopsy sites---this was a major concern.
They realize that any additional biopsies will increase sensitivity to
some degree, but they question what the proper comparison is for any
device. They believe that a proper comparison would not be random
punches of normal epithelium.

The Panel asked for clarification on whether there was any effort to
improve the performance of the pathologies at the initial reading. Dr.
Solomon said they that they did have a pathology quality control group.
This group tended to call more CIN3s than CIN2s, but there was no
significant increase in sensitivity with this group. In answering a
question about procedure, Dr. Schiffman said that colposcopists were
instructed to do the worst site first. A Panel member asked about the
qualifications of the ALTS colposcopists; Dr. Schiffman said that they
were screened by a quality control group and underwent extensive
training.

**SPONSOR PRESENTATION**

**Theresa Wingrove, Ph.D., Senior Director, Regulatory and Clinical,
MediSpectra**, offered a regulatory and clinical history of the LUMA™
Cervical Imaging System (P040028). Their collaboration with the FDA on
this device started in 1998. The FDA issued a nonsignificant risk
determination letter in 2001, and the Pilot Study with 753 patients ran
from May 2001 through February 2002. The first Pivotal Study was held
from August 2002 through September 2003. This study enrolled about 2,300
subjects and was designed as a randomized control trial that compared
LUMA and colposcopy versus colposcopy alone.

The second Pivotal Study ran from July 2003 through October 2003. It was
designed as a multi-center, single-arm study, with more than 700
expected subjects; however, it was terminated early with 227 patients by
the sponsor's Board of Directors for solely financial reasons. Most of
the data was still in the progress of being collected, so those making
the termination decision did not have data from the second study; they
did have the results from the first study. In June 2004, the sponsor
filed the PMA and it was assigned expedited review status.

The current indications state that "LUMA is indicated for use as an
adjunct to colposcopy in identifying high-grade disease (CIN2, CIN3+) in
patients referred to colposcopy with ASCUS or LSIL. LUMA is not intended
to replace colposcopy. A thorough colposcopic evaluation with an
identification or selection of biopsy sites must be performed
independently and prior to the viewing of the LUMA result." The
indication has been changed from the original in two ways: the
adjunctive nature of the product has been stressed, and the indication
has been limited to ASCUS and LSIL subjects.

**J. Thomas Cox, M.D., Director of Gynecology Services, University of
California, Santa Barbara**, spoke on the clinical need for LUMA. He
said that the use of LUMA as an adjunct will increase the sensitivity of
colposcopy and reduce its subjectivity. He differed with the NCI
speakers' analyses of the ALTS data; he believes that colposcopists
always have the option to take additional biopsies, but a device such as
the LUMA will help draw attention to any areas they may have missed.

The ALTS trial concluded that the imperfect sensitivity after
colposcopic referral in all arms of the study is of concern. For the
patients in the ALTS immediate colposcopy arm, 21 percent were found to
have CIN2, 3+; of this number, about one-third were missed at initial
colposcopy, a significant burden of high-grade disease, he said. Many
women probably remain at risk who are receiving routine care. Other
randomized trials have shown similar results. Therefore, 7 percent is
probably the upper limit of possible CIN2 and 3 detection after being
missed at initial colposcopy.

**Ross Flewelling, Ph.D., Chief Technical Officer, MediSpectra**,
provided an overview of the product's technological features. He noted
that the scientific basis for tissue spectroscopy has been established
and well-investigated for decades. There are currently three
FDA-approved optical devices that assess *in vivo* tissue dysplasia in
endoscopy and bronchoscopy.

The LUMA uses three optical measurements: fluorescence excitation,
reflectance white light backscatter, and video imaging. The device's
noncontact probes works at a distance of about 100 mm from the cervix,
outside of the speculum, and takes about 12 seconds to complete a scan.
The scan area has a 25 mm diameter, with 499 points at a 1 mm resolution
in a dense hexagonal path array. There is a disposable cover on the
probe. The LUMA's algorithm is composed of the three optical
measurements, and was established during the 2001 clinical Pilot Study.
This produced pathology-qualified measurements on 1,569 samples that
could be correlated with the device's optical measurements.

**Joan L. Walker, M.D., Section Chief, Gynecologic Oncology, University
of Oklahoma**, worked on ALTS trial from 1995 to 2000 as a clinical
center principal investigator, and has worked with MediSpectra on their
trials of the device. She said that the device has helped her to become
a better colposcopist. She presented a video that covered the basics of
how the LUMA is used as an adjunct to colposcopy. The patient is prepped
for the procedure and the LUMA is calibrated for each individual
patient. The speculum is placed in the vagina and dilute acetic aced
applied to the cervix. A timing device is initiated on the device using
a foot pedal, to make sure the scan is performed both after the acetic
acid has developed any changes in the cervix and before the effect has
disappeared. The probe visualizes the cervix and then performs a scan
that takes approximately 12seconds. The colposcopic examination can
proceed as usual. After identifying colposcopically-indicated biopsy
sites, the LUMA image is reviewed. Blue areas on the LUMA display
indicate additional sites for possible biopsy.

Dr. Walker discussed the features of the LUMA device pivotal clinical
studies. The two studies totaled 2,526 patients, and were conducted over
15 months at 13 U.S. practice centers, by 52 different colposcopists.
The studies were fully IRB-approved, declared a nonsignificant risk, and
were IDE exempt; the two studies produced similar results. Study
participants were 18 years or older with abnormal Pap smears.
Participants were excluded for pregnancy, heavy menstruation, Pap test
within 7 days but no longer than 6 months, and a biopsy or treatment
conducted since their last Pap test. All colposcopists were required to
have had experience and formal training in colposcopy. The
histopathology slides were reviewed by two pathologists; if they
disagreed a third pathologist was consulted. The patients' results were
categorized as either with CIN2, 3 or not.

**Thomas C. Wright, Jr., M.D., Director of Gynecologic Pathology,
Columbia University, and Consulting Medical Director, MediSpectra**,
presented the results of Pivotal Study I, a dual-arm, randomized study.
Participants were randomized to receive either LUMA and colposcopy
(physicians saw the scan and could take additional biopsies), or
colposcopy only. Patients were referred because of an abnormal Pap test
result including ASCUS, LSIL, or HSIL. The two arms were well balanced,
and there was strong minority representation in the trial. The study
endpoints were true positive (patient had at least one biopsy diagnosis
of CIN2, 3+) and false positive (patients had no evidence of CIN2, 3+ in
all biopsies). The study had two hypotheses: the true positive rate
would be greater for the LUMA +colposcopy group than the colposcopy-only
group; and the false positive rate for the LUMA +colposcopy group would
be no more than 8 percent greater than for the colposcopy-only group.

The difference between the two arms was a 1.9 percent increase in true
positives overall, with a 3.0 percent increase in the ASCUS/LSIL group;
this did not meet statistical significance. They recognize that
examining the ASCUS and LSIL sub-group is a post hoc analysis, but their
reasons for doing so were (1) there was a similar disease prevalence in
each group, and (2) 80 to 85 percent of all colposcopic examinations are
performed for these two cytology reports.. Ultimately, he said, while
the absolute gain in the detection of true positives is 3.0 percent, the
relative gain was 26.5 percent.

For false positive outcomes, there was an overall increase between the
two arms of 3.1 percent (which meets the study hypothesis) and an
increase of 4.0 percent for the combined ASCUS/LSIL group (which does
not meet the original study hypothesis). This was a moderate increase in
false positives. Dr. Wright suggested looking at the mean biopsy rates
to understand further the false positive outcome. This analysis produced
an overall difference between the arms of 0.27 biopsies and a difference
in the ASCUS/LSIL group's two arms of 0.31. He noted that the positive
predictive value went from 10.8 percent for colposcopy only, to 18.1
percent for those biopsies that were also LUMA positive---this is a
significant increase in the positive predictive value of biopsies taken
on the basis of also being LUMA-positive. Because of the appearance of
false negatives, Dr. Wright stressed that the role of LUMA is not to
replace colposcopy but to serve as an adjunct.

Dr. Wright noted that there were no device-related effects in any of the
patients; 4 patients did report cramps, bleeding, and other symptoms
typically associate with colposcopy. He added that they do not see any
age effect for the device; the FDA disagrees with their conclusions. If
they break the age groups into the population's true tertiles (\<23,
23-33, \>33 years), LUMA plus colposcopy has an increased true positive
rate for identifying lesions with CIN2/3+ compared to colposcopy alone
across all three age groups.

**Brent Blumenstein, Ph.D., TriArc Consulting**, discussed the joint
inference testing used on three outcomes for the patients in Pivotal
Study I: true positive, false positive, or no biopsy taken. According to
his analysis, the Cochran-Mantel-Haenszel test (stratified) p-value is
0.011, and the exact test (not stratified) p-value is 0.013; these
results for Pivotal Study I are significant. The joint inference testing
provides evidence that there is significant difference between the two
arms of the study.

**Warner K. Huh, M.D., Gynecologic Oncologist, University of Alabama,
Birmingham**, presented the Pivotal Study II data, a single-arm study in
which each patient served as her own control. A total of 227 patients
were enrolled, and 197 were included in the final analysis. A LUMA scan
was performed on the after acetic acid was applied to the cervix, but
blinded to the investigator. Standard colposcopies were performed with
biopsy commitments. The commitments were annotated on the screen and
locked into place, and could not be changed later. The scan was
unblinded to the investigator who was committed to take biopsies at
LUMA-indicated sites; these sites were also locked into place. Biopsies
were taken and sent to the reference pathologist.

The LUMA true positive rate was defined as the number of subjects with
no positive biopsies recommended by the colposcopic examination
(includes the no biopsy recommended group) that also have at least one
positive incremental LUMA directed biopsy (one or more biopsy positive
results) divided by the total number of subjects in the per-protocol
population. The LUMA false positive rate was defined as the incremental
false positive patients among the "colposcopy no-biopsy" patients, as a
percent of the total population. The study hypothesized that the LUMA
incremental true positive rate would be at least 2 percent for the
overall population (the lower bound of the 95 percent confidence
interval would be at least 2 percent); and that the LUMA incremental
false positive rate would be less than 15 percent for the overall
population (the upper bound of the 95 percent confidence interval would
be 15 percent or less).

The study resulted in a LUMA increment absolute gain of 4.7 percent and
a relative gain of 22.0 percent for the overall population; among the
ASCUS/LSIL population, the numbers were, respectively, 3.6 percent and
25.0 percent. This showed that LUMA identified significantly more CIN2,
3+. The false positive rate increase was moderate, Dr. Huh said, and was
expected given the study design. There were no device-related effects
among the patients. Two patients experienced minor adverse events
commonly seen in those undergoing a standard-of-care colposcopy.

Dr. Wright finished the sponsor's presentation by stressing that the two
studies were designed to measure only the adjunctive benefit of using
LUMA with colposcopy. There were no device related events. There was
remarkable consistency in the outcomes of both studies, including
roughly the same relative gain. In addition, the 3 percent absolute gain
produced in Pivotal Study I was nearly significant, and the results were
statistically significant in the second study. If joint inference
testing is used in the first study, there is statistical significance.
In the second study, for the ASCUS/LSIL group and the overall
population, they meet the statistical hypotheses for true positives, but
not for false positives; he suggested that this may have been due to the
instructions given to clinicians to take a biopsy whenever possible.
This resulted in one additional biopsy per patient. He stressed that the
LUMA device identifies the patients who need additional biopsies at the
time of the examination, which the sponsor hopes will lower the rate of
loss-to-follow-up of women with true cancer precursors who are missed by
colposcopy.

**PANEL QUESTIONS FOR THE SPONSOR**

The Panel asked for clarification on several points made by the sponsor.
A Panel member asked how the "eligible" number of patients was
calculated for the second study. Dr. Wingrove answered that there were
193 subjects after exclusions; 152 subjects were found not to have CIN2,
3+ after colposcopy, referred to as "eligible." A member suggested that
another way to interpret the data from Pivotal Study I is that, the
study is negative because the true positive failed. The joint analysis
study doesn't clarify this issue because it was done post hoc. The
second study results look better, but only if arbitrary redefinitions
are made post hoc. Dr. Wright suggested putting the study results into a
more clinical perspective. The sponsors clarified a number of points:
LUMA does not identify atypical vessels; if there was an exceptionally
large cervix the central transformation zone would still be captured;
LUMA produces a static image; and doing a Pap immediately before using
the LUMA may produce excessive blood and could limit the area in which
the device is effective.

**FDA PRESENTATION**

**Joyce M. Whang, Ph.D, Office of Device Evaluation**, provided an
overview of the devices' FDA review and a brief regulatory history. In
August 2000, the FDA determined that the LUMA™ Cervical Imaging System
would be regulated as a Class III device under the premarket approval
process. In February 2001, the FDA decided that the use of this device
in clinical studies would be a nonsignificant risk; therefore, the
clinical studies did not require regulatory approval from the FDA via
the IDE process. There was no agreement letter for the first Pivotal
Study, but there was one issued in February 2003 that described the
single-arm Pivotal Study II. The PMA received expedited review in June
2004.

Dr. Whang described the device's three main components: the console and
accessories, the illumination probe; and the disposable probe cover. She
covered what was involved in four of the six major review areas for the
device. For the electro-optics, all review concerns have been adequately
addressed. The FDA looked at algorithm development, especially the
changes made to the algorithms between Pivotal Studies I and II. The FDA
concluded that the use of the revised algorithm would not have reduced
the improvement of true positives as seen with the LUMA in the first
study, although it may have made the increase in false positives in the
first study slightly larger. For bioresearch monitoring the FDA reported
no outstanding concerns. For manufacturing, the sponsor has been found
to have an acceptable program.

**Julia A. Carey-Corrado, M.D., Office of Device Evaluation**, reviewed
the devices' indication for use, highlighting three aspects: the device
is to be used as an adjunct to colposcopy; ASCUS includes ASC-US and
ASC-H; and the indication for use reflects the FDA's "always/never
rule." This rule, or approach, states that the clinician must always
identify colposcopically-directed biopsy sites prior to viewing the LUMA
image, and the clinician should never eliminate a
colposcopically-directed biopsy after viewing the LUMA image.

She compared the two studies' designs, treatment groups, primary
endpoints, sample sizes, and presence of agreement letter. She noted
that the "always/never approach" was not followed in Pivotal Study I but
was followed in Pivotal Study II. The denominators in the first study
were the total number of subjects, as opposed to the total number of
diseased subjects; she noted that the study designs made it impossible
to know the true disease status of the subjects. As well, neither study
was designed to determine the sensitivity of LUMA to detect CIN2, 3+ in
patients who have the disease.

Dr. Carey-Corrado looked at subject accountability in the first study to
show how many patients were lost from each study arm, and made the point
that patients were excluded prior to and after randomization. The
primary reasons for exclusion were device malfunction and no majority
pathology diagnosis. For the first study, the only hypothesis met was
the false positive endpoint for all subjects. The hypothesis was not met
for the ASCUS/LSIL group. The LUMA false negative rate was 23 percent,
compared with the colposcopy false negative rate of 15; this shows that
the LUMA device did not identify some of the CIN2+ lesions that the
colposcopist saw, and, similarly, the colposcopist did not see all of
the lesions detected by LUMA.

Pivotal Study II followed the "always/never" approach. The FDA agreed
with the sponsor's design choice for the second study. The FDA wanted to
see what benefit LUMA contributed after colposcopy. The study design did
require additional biopsies based on the LUMA overlay if it indicated
any suspicion of CIN2, 3+; there was some room, however, for individual
clinician discretion. The study hypotheses required an incremental true
positive rate of at least 2 percent, and an incremental false positive
rate of \<15 percent.

For the second study, the only hypothesis that was met was the true
positive endpoint for all subjects. Neither hypothesis was met for the
ASCUS/LSIL group.

**Gene Pennello, Ph.D., Office of Surveillance and Biometrics**,
discussed additional analyses performed on the clinical trial data. He
looked at how diagnostic endpoints are typically evaluated, compared
with how they were analyzed in the two studies. He emphasized that it is
clinically more important to detect more CIN2, 3+ subjects than CIN2, 3+
biopsies, which is why the primary endpoints are at the subject level.
He also noted that nothing is known about the accuracy of the tests for
those patients who tested negative, because there was no follow-up.

In addressing the design limitations of the two pivotal studies, he
noted that the colposcopist in the first study was not blinded to which
arm the subject was randomized. They knew, for example, when LUMA was
used; this could have introduced bias because they may have been relying
ultimately on the LUMA. In the second study, the subject was her own
control; if the initial colposcopy was undercalled, there could have
been bias in favor of finding an effect with the LUMA device.

He examined the joint analysis and the age effect in Pivotal Study I.
The dual hypothesis was not met for all subjects or for the ASCUS/LSIL
group; however, it is unclear whether the true positive difference is
significant and whether the false positive difference is no more than 8
percent. Dr. Pennello said that there may be an age-related device
effect. The FDA used Bayesian analysis shows that the device may be
finding more disease in younger age groups.

In Pivotal Study II, there were two changes made in the protocol
analysis: the target value for the ASCUS/LSIL group changed from 2 to
1.5 percent; and the denominator was reduced from all subjects to all
subjects minus the true positive subjects already detected by initial
colposcopy. For the first change, the dual hypotheses were not met for
the ASCUS/LSIL group. For the second change, the analysis is invalid
unless the hypotheses for the true positives and the false positives are
both changed; this change does not coincide with sponsor's agreement to
use the full denominator.

Dr. Pennello briefly presented issues of concern that appeared in both
studies: biopsy frequency, subgroup testing; site and colposcopist
variability; and a per biopsy positive predictive value. Ultimately,
neither study met both the true positive and false positive hypotheses
in any of the populations. Combining data from both studies is
problematic because the two designs are so different. The age effect
that seems to appear in the first study does not appear in the second
study, but this may be an artifact of the size difference between the
two studies. He also noted that one could get a LUMA false negative rate
of 23 percent based on colposcopy used as a reference for detecting
CIN2, 3+ subjects, based on the Pivotal Study I results.

**PANEL QUESTIONS FOR FDA**

The Panel asked the FDA for some clarification about LUMA's algorithm.
**Brandon Gallas, Ph.D., Office of Science and Engineering
Laboratories**, said that there are many components to the algorithm,
and it can be very difficult to track one item in a coherent manner.
Because of this, they cannot look to the algorithm to make judgments
about the device's effectiveness; they must rely on the clinical study
to make that call.

**PANEL QUESTIONS FOR SPONSOR**

The Panel asked the sponsor to speak on the LUMA device's sub-par
ability to detect HSIL lesions, and whether the preponderance of
academic medical sites limited the type of colposcopic experience in the
study to highly experienced clinicians. Dr. Huh said that, according to
the literature and their interpretations from the trial, HSIL lesions
are typically more obvious. Therefore, the sponsor did not expect to
improve detection in these cases substantially. Dr. Wright said that
there were a wide range of colposcopists at the sites, but they saw no
significant variability depending on colposcopists. He suggested that
there may be less impact from the LUMA as the colposcopists' skill
increases.

Panel members expressed concern about the early termination of the
second study. The sponsors stressed that Pivotal Study II was cancelled
for strictly financial reasons, and not because of any findings from
that study.

**PANEL QUESTIONS FOR SPONSOR AND FDA**

Panel members asked the sponsor about the lack of LUMA benefit with
high-grade lesions, and whether the benefit is based on the prevalence
of the disease in the population. Dr. Wright said that the prevalence of
disease in patients with HSIL is different than those with ASCUS and
LSIL. Colposcopists may perform differently because of the expectation
of whether a high grade lesion is present; this may explain why the LUMA
did not have as much of an effect as expected in HSIL in the first
study.

There was also a question about older patients in the studies. Dr.
Walker said that colposcopy is acknowledged to be more difficult in
older women; in fact, the LUMA will not perform in older women because
the transformation zone recedes into the canal of the cervix, making
lesions after an abnormal Pap more difficult to find.

A Panel member asked about the longevity of the fiber optic system in
the device. Dr. Flewelling said that the sponsor has done life testing
on the fibers with a result of more than 10,000 shots, and that the
fibers last for the lifetime of the product, more than 5 years. There is
required yearly maintenance where the system is tested against
standards. In addition, at run time, the device goes through a series of
statistical tests to calibrate the system and verify that it is
performing within normal operational parameters.

The Panel raised an additional question about patient age, noting that
the study did not include patients under 18 years. Dr. Wright said that
the sponsor is asking for labeling that includes only those age groups
studied, so those under 18 would be excluded from intended us. Panel
members were concerned that the disease was somewhat more prominent in
younger women, and that the sponsor would be excluding younger women
from device use. The sponsor noted that the indications for use
currently do not have an age cut-off; if the Panel had a recommendation
for language including younger patients the sponsor would abide by that.
They expect the device to perform the same in women across all
reproductive ages.

The Panel asked the sponsors how clinicians unfamiliar with the trial
will be trained on the device. Dr. Wright said that the first part of
the training program will be conducted on-site, during installation; the
second training will consist of hands-on, interactive methods to show
clinicians how to interpret the displays. He noted that the trial's
investigators were able to learn to use the device very quickly.

In response to a Panel member's question about data for patients under
age 18, Dr. Wright said that they had very few 15- and 16-year-old
patients; therefore, they had no analysis specifically done for patients
under age 18.

**FDA QUESTIONS AND PANEL DISCUSSION**

**1. The two co-primary effectiveness endpoints of Pivotal Study I (PS
I) pertained to true positive (TP) and false positive (FP) rates.
Individual subjects were TP, FP, or negative as follows.**

-   **TP subject: one or more biopsies taken, at least one was CIN 2/3+
    positive**

-   **FP subject: one or more biopsies taken, none was CIN 2/3+
    positive**

-   **Negative subject: no biopsies taken**

**TP and FP rates were calculated by dividing the numbers of TP and FP
subjects by the total numbers of subjects.**

**a. For the original study population (i.e. all per protocol subjects),
the FP endpoint was met, but the difference of TP rates was not
statistically significant. Please discuss the strength of these findings
relative to the proposed indication, i.e. as an adjunct to colposcopy
for use in patients referred with ASCUS or LSIL cervical cytology
results after a thorough colposcopic evaluation with identification or
selection of biopsy sites.**

**b. The original population in the clinical trials was women referred
for colposcopy because of an abnormal Pap smear result (first-time
ASC-US/-H, repeat ASCUS/- H, LSIL, HSIL, or squamous cell cervical
cancer). The proposed indication is for a portion of this population,
the ASCUS/LSIL Pap referrals. Please discuss the clinical significance
of this proposed population.**

**c. For the ASCUS/LSIL sub-population, neither the TP nor the FP
endpoint was met in PS I. Please discuss the significance of these
findings. Note that the analysis for this sub-population was not
pre-specified.**

There was general agreement that one of the critical aspects of Question
1a was that the difference in true positive rates was not statistically
significant. Other members expressed difficulty with the sponsor's shift
from the original population to the subpopulation, and lack of adherence
to the original protocol. Members raised the issue of colposcopists
receiving large numbers of false positives using the LUMA adjunctively
without a corresponding significant increase in the number of true
positives. Even though the increase was not statistically significant,
one member said that it would still be an absolute increase in the
number of women whose lives could possibly be saved. Another member
pointed out that this would not be the last chance to pick up a
patient's disease; colposcopy is a secondary testing tool, and there
would, at least, be repeat cervical cytologies because the patients were
referred originally for an abnormal Pap. The LUMA would be a third level
of testing. For Questions 1b and c, Panel members discussed whether
screening fewer younger women with LUMA would further reduce the
significance levels.

**2. Please comment on the observed age-related device performance seen
in PS I, i.e. the increase in the TP rate was observed primarily among
patients in the \<21 age group across all Pap strata. What are the
clinical implications of this finding?**

Panel members discussed the implications of the observed age differences
in the first study. A Panel member said that the literature documents
indicated that lesions in younger patients are more likely to regress;
therefore, picking up more lesions is not necessarily a good thing in
this age group. Studies are needed in patients under 18 years old. The
Panel discussed the possibility, as well, of recommending upper and
lower age limits for the device, although Panel members agreed that most
clinicians with access to this instrument, who believe it would help a
patient, would most likely use it regardless of the patient's age.
Members agreed that there may be potential problems in older patients.
Another member expressed concern that clinicians may come to rely on the
LUMA too heavily.

**3. a. In Pivotal Study II (PS II), for the original study population,
the TP endpoint was met, but the FP endpoint was not met, i.e. there was
95% confidence that the LUMA increment of TP exceeds 2%, but there was
not 95% confidence that the LUMA increment of FP would be less than 15%.
Please discuss the strength of these findings relative to the proposed
indication, i.e. as an adjunct to colposcopy for use in patients
referred with ASCUS or LSIL cervical cytology results after a**

**thorough colposcopic evaluation with identification or selection of
biopsy sites.**

**b. For the ASCUS/LSIL sub-population, neither the TP nor the FP
endpoint was met in PS II. Please discuss the significance of these
findings. Note that the analysis for this sub-population was not
pre-specified.**

With regards to Question 3a, there was discussion among Panel members
that the sponsor arbitrarily chose the 2 percent increment. Dr. Noller
noted that the 2 percent and 15 percent were agreed upon by the FDA with
the sponsor prior to the initiation of the trial. There were also
concerns about why the sponsor changed the sample size but not the
margin.

For Question 3b, most Panel members agreed that the ASCUS/LSIL
sub-population was the correct population to look at from a clinical
point of view, if another diagnostic tool is to be added.

**4. The Sponsor has proposed two changes to the analysis of TP rate for
PS II compared to the original protocol:**

**i. changing the success criterion based on observed prevalence, and
assigning success criteria to each Pap substrata,**

**ii. changing the denominator for calculating TP rate.**

**As indicated below, with these changes, the study meets the revised TP
requirements for both the overall population and the ASCUS/LSIL
sub-population. For analogous changes to the FP rate analysis, the study
does not meet the revised FP requirements for either the overall or the
ASCUS/LSIL populations. Please discuss the significance of these
results.**

Panel members discussed the sponsor's justification for switching to a
1.5 percent increment and changing the denominator. The greatest concern
was that much of this was done post hoc, and that the change was
arbitrary. There is no true way of judging the significance of these
changes. One member said that colposcopists are trained to select the
most abnormal area(s); however, with the LUMA device there may be a
tendency to perform additional biopsies based on the LUMA without regard
for the colposcopic image and impression.

**5. Based on the results of PS I, LUMA's false negative (FN) rate can
be estimated to be 23% when colposcopy is used as the gold standard to
determine true disease status, i.e. of all CIN 2/3+ patients found by
colposcopy, 23% were not be found by LUMA. In PS II, 22% of the TP
biopsies identified by colposcopy were not identified by LUMA.**

**These false negative rates underscore the importance of the
"Always-Never" rule. Does the panel believe that this risk of false
negatives is adequately mitigated by the indication statement (for use
only after a thorough colposcopic evaluation with identification or
selection of biopsy sites)?**

Panel members discussed whether the increase in false negatives was
worth the extra biopsies. One member said that this shows that LUMA is
truly a complementary tool. Others said that if the test was really
complementary and all of the lesions that were previously missed were
picked up, there would be no question as to LUMA's value. However, the
statistical significance is simply not present, and even when the
interval is changed to 1.5 percent the data are not very encouraging.

A Panel member asked the rest of the Panel to consider the final numbers
for who will be affected by this device. Roughly 900,000 women are
screened with CIN2, 3+. About 10,000 women will get cervical cancer each
year, and about one-half of those have never been screened with any
method. Of the 5,000 who have ever been screened, about 2,000 will
survive. Of these, another 5 to 10 percent have adenocarcenomas or very
aggressive, untreatable lesions. Assuming the use of LUMA increases the
pick-up by between 2 and 5 percent, there would be between 25 and 100
lives saved by the entire process. This raises the question whether
900,000 patients should be tested to save 25 lives.

Other Panel members continued to express concern that clinicians will
come to rely too heavily on the LUMA rather than being diligent in their
colposcopies. Colposcopy skills could decline overall, of concern
because LUMA misses about 22 percent of the lesions. With respect to the
"always/never" rule, Panel members agreed that the device should be used
only as an adjunct as noted in the indications. Panel members discussed
the high skill level of the LUMA study's colposcopists; some expressed
concern that the trial used high-level experts, which is not
representative of the real-world use of the product.

**6. Are there any safety concerns associated with use of this device?**

Panel members agreed that the device does not pose any electrocution or
infection hazard to patients. However, some Panel members were worried
that using the LUMA might make clinicians less apt to do appropriate
cytology screening. A Panel member asked if a Pap test is inappropriate
just prior to using the LUMA. The sponsor said that conducting a Pap
immediately before the LUMA scan can result in bleeding. The LUMA can be
used only if blood is able to be cleared off the cervix with acetic
acid.

**7. Do the planned and unplanned analyses of PS I and PS II demonstrate
the safety and effectiveness of this device for the ASCUS/LSIL
population, i.e.**

**a. Do the probable benefits to health from use of the device outweigh
any probable risks?**

**b. Will use of the device provide clinically significant results?**

For Question 7a, Panel members discussed their concerns about overly
aggressive treatment management. One of the groups most highly
identified by LUMA was young women with CIN2, 3+ lesions, which may
increase the number of loop electrosurgical excision procedures (LEEPs)
they receive. This may lead to more procedures that potentially increase
chance of pre-term deliveries. Additional data on younger women who have
high-grade lesions should be collected. This is an area that the Panel
can address in their suggestions to the FDA and the sponsor. A member
stressed the fact that it will be hard for clinicians who have LUMA in
their office to not use it in a patient who is outside the proscribed
age parameters.

Panel members said that they had already covered Question 7b when they
looked at how many deaths may be prevented using the LUMA device. One
member stressed that there are no statistically significant results in
the study, so the Panel may be looking at numbers that have no
scientific validity.

**8. Does the panel have any comments on the labeling and instructions
for use provided by the sponsor?**

Panel members offered a number of suggestions, primarily related to
patients' age. A couple of members said that a lower age limit of 18
would complement the cytological evaluation recommendations. Other
members also raised the issue of women evaluated between 18 and 21, and
expressed concern that increased identification of lesions may lead to
more treatment and that treatment may impact future fertility and
pregnancy. The Panel noted that pregnancy must be clearly stated as an
exclusion criterion. Another Panel member suggested that the labeling
specifically state that it is not appropriate for older patients. Other
members expressed the belief that age recommendations should not be
made, as there is no strong evidence of age differences in the study.
Inclusion and exclusion criteria for a study are typically different
than for clinical use; the indications are more stringent in this study
than they might be in clinical use. A final comment was made about what
could happen if the label forbids use in patients of a certain age. The
cost would probably not be reimbursed for those patients; this is an
example of how the labeling could affect medical practice.

**9. Does the panel have any concerns about the training needed to use
this device safely and effectively?**

Panel members generally agreed that the device appears to be easy to
use, especially if the clinician is already a colposcopist. Others said
that the device looks straightforward but there remained concerns about
bias and the undermining of clinical skills. One member asked the
sponsor why the device could not be used as a colposcope; the sponsor
responded that the resolution is not sufficient to examine atypical
vessels.

**10. Does the panel have concerns about any issues that should be
addressed in a postapproval study?**

A Panel member asked if there could be changes made to the study, such
as design changes, after the premarket approval. The FDA responded that
the sponsor would have to submit a PMA supplement describing changes and
validation to support the changes.

**PANEL DISCUSSION**

The FDA had a few questions and comments for the Panel. Dr. Pennello
told the Panel that the FDA was hearing some support for excluding
younger women from the device indications; however, he wanted to point
out that much of the effectiveness from the device is in the younger age
group in the first study. If that age group is removed, much of the
device's effectiveness may be removed.

A Panel discussion about risk/benefit from the device ensued. Members
noted that this device may be setting up young women for more invasive
procedures and complicated pregnancies. A Panel member asked if it would
be possible to sort out the different CIN levels in the studies. The
sponsor responded that the CIN2, 3+ figures are only in aggregate.

The FDA asked whether there had been enough discussion about the use of
colors in the LUMA display. A Panel member noted that the colors were
actually on a continuum from yellow to blue, and asked how study
colposcopists handled a biopsy instruction if there was no precisely
blue spot. Dr. Wright said that colposcopists were told to biopsy a blue
site, and a yellow site if clinically indicated.

**OPEN PUBLIC SESSION**

**Mark Spitzer, M.D., Professor of Clinical Obstetrics and Gynecology,
Weill Medical College**, presented during this session. The primary
reason he supports the use of a device such as the LUMA is that this it
should help novice colposcopists with limited clinical experience
improve their skills and identify significant disease. Most studies
suggest that clinicians need between 50 and 150 colposcopies to gain the
best experience in this procedure, but trainees and residents don't feel
adequately skilled in colposcopy because they are receiving limited
clinical experience.

Dr. Schiffman spoke during the Open Public Session on his own behalf,
not on behalf of the NIH. He urged the Panel not to recommend approval
of the device because the device failed to meet the requirements set
forth in the letter of agreement, and could force additional biopsies.

**FINAL FDA COMMENTS**

The FDA had no final comments.

**FINAL SPONSOR COMMENTS**

**Ronald Alvarez, M.D., Professor of Gynecologic Oncology, University of
Alabama, Birmingham**, stressed that the LUMA is intended strictly an
adjunct to colposcopy, not a replacement for colposcopy. There needs to
be improved methods of responding to abnormal Pap smears. Colposcopy
remains the "gold standard" for evaluating these patients. The LUMA
device advances the performance of colposcopy by improving the detection
of CIN2, 3+ by 25 percent when used with colposcopy. Relying on patient
follow-up to address deficiencies in colposcopy is challenging. The
sponsor has demonstrated that the device is safe and easy to use, and
especially valuable in the ASCUS and LSIL populations.

Dr. Wingrove spoke, noting that the two studies have consistently
resulted in the same findings. She said that the sponsor would welcome
further recommendations so that they may address the Panel's concerns.

**PANEL DELIBERATIONS AND VOTE**

Dr. Bailey read the instructions to the Panel on the voting procedures,
the official definitions of safety and effectiveness, and the voting
options. Dr. Noller asked whether there was a motion to recommend
approval, approval with conditions, or not approvable; he added that
this motion would be specifically for ASCUS and LSIL indications. Dr.
Cedars put forth a motion not to approve the device. Dr. Snyder seconded
the motion.

The Panel discussed the motion. Dr. Cedars made the motion because she
doesn't believe there is enough scientific evidence to support the
device's claims of efficacy and because of the concerns for the youngest
population in which there appeared to be the greatest benefit. Dr.
Snyder said he was excited about the technology, and, while he did not
want to stifle ongoing research, he said that it is not in the public's
best interest to approve a device without statistical support. Dr.
D'Agostino said that he was worried about approving the device with so
few data and lack of statistical significance.

Dr. Noller asked the three non-voting members of the Panel to make brief
statements. Ms. Moore, the Consumer Representative said that if the
device is to be used as adjunct, it could serve as another beneficial
tool in the diagnostic process. She said that she would like to see it
approved with conditions. The Industry member, Ms. George, said that she
agreed with Ms. Moore. She would choose approval with
conditions---specifically after conducting more analysis of the data.
Dr. Sanfilippo said that the clinical applications and the clinical
importance are absolutely paramount when looking at the LUMA. He said
that he would like to see some additional data because he believes that
this is a device with clinical applications at all age ranges;
unfortunately, he added, he did not see that in the current data.

The panel voted 9-2 (no abstentions) to recommend to the FDA that the
PMA for the MediSpectra LUMA™ Cervical Imaging System (P040028) is not
approvable. The following Panel members voted for the motion: Drs.
Hayes, Snyder, D'Agostino, Julian, Weeks, Cedars, Hillard, Miller, and
Jiang. The following Panel members voted against the motion: Drs.
Gandjbakhche and Gerbie.

Dr. Noller asked each Panel member to explain their vote.

Dr. Gerbie said that the technology has shown enough promise to get into
the public arena for further development, and that the positive aspects
should be highlighted rather that the statistical analysis.

Dr. Jiang said that the device's ability to pick up additional lesions
was appealing, but that he was concerned about the possibility of
additional biopsies and over-treatment, as well as the impact on younger
patients.

Dr. Gandjbakhche said that he wanted to approve with conditions of
additional data analysis and more information about the device's
algorithm.

Dr. Miller said that he was not persuaded that the technology would
provide significant benefits above what a skilled colposcopist could
accomplish. He also noted concerns, including over-treatment,
over-diagnosis, as well as the possible "dumbing down" of a skill set
that needs improvement among many clinicians.

Dr. Hillard said that the device had potential, but she was concerned
that the results did not meet the preset conditions for statistical
significance. An increase in false positives could lead to
over-treatments that may harm women.

Dr. Cedars said that the results of the studies did not pass the burden
of proof.

Dr. Weeks said that he was not convinced by the sponsor's statistical
analyses.

Dr. Julian stated that the sponsor had not rigorously met the criteria
for endpoint success.

Dr. D'Agostino said that in addition to the concerns he had about the
statistics, he was worried about the clinical issues; for example, he
wanted a better sense of what happened to the individuals classified as
false positives.

Dr. Snyder said that he would have liked to recommend that the device be
kept in the hands of clinical researchers; when something like this is
FDA-approved, he said, patients will hear about it and demand it that
their physicians use it.

Dr. Hayes said that the device did not meet the definition of safety and
effectiveness, and there could be a high probability of over-treatment
and inappropriate treatment with this device.

Dr. Noller next asked Panel members to identify what was needed to help
the sponsor and the FDA make the device approvable.

Ms. Moore asked for better data on the use of the device among senior
citizens and adolescents.

Ms. George wanted additional focus on training and labeling. She said
that the device limitations are not clearly stated on the labeling.

Dr. Sanfilippo said that he would like to see studies for patients under
18 years old; the device in the hands of residents and attending doctors
who may need some colposcopic education and training; head-to-head
comparisons between the device and colposcopies; certain labeling
restrictions; and statistical significance in the study.

Dr. Gerbie stressed that he sees great potential with this device. He
believes that a new trial would be difficult, primarily because he
believes the current trial is satisfactory; however, he acknowledged
that a 4.5 percent improvement is relatively small.

Dr. Jiang said he would like to see reduced numbers of false positives,
and better analysis on the age factor.

Dr. Gandjbakhche said that he saw no need for additional clinical
trials, but he would appreciate more information about the algorithm.

Dr. Miller asked that the sponsor enhance that which distinguishes the
LUMA assessment from the colposcopic assessment; this would ideally
increase the true positives and lower the false positives. There should
be better analysis about what happened in the cases where the LUMA
identified a lesion that didn't exist. He added that aggregating CIN2
and CIN 3 diluted the value of data; these should be separated.

Dr. Hillard asked for additional data, such as the age of patients'
first intercourse. She would also like to see CIN2 and CIN3 data
separated and analyzed by age.

Dr. Cedars said that there are more studies that should be done, but any
new study should be based on new criteria. New screening guidelines
should be used, and the sponsors should set and meet hard statistical
guidelines. She noted that even changing the algorithm, the study must
be redone because there will not be biopsies for those spots.

Dr. Weeks said he would like to see the second study completed. He
suspects that the results would be very compelling. He also supports
separating CIN2 and 3. As well, the teaching material should be expanded
to address the issue of avoiding multiple LEEPS in young women.

Dr. Julian said that the sponsors should demonstrate that LUMA improves
outcomes in nonexpert colposcopists.

Dr. D'Agostino urged the sponsors to separate CIN2 and 3. He said that
the next study should be designed on a tighter population where the LUMA
would make a larger contribution.

Dr. Snyder said that he would like some changes in the algorithm, if
possible.

Dr. Hayes suggested another study that operationalizes many of the
previous suggestions.

**ADJOURNMENT**

Dr. Noller thanked the Panel members and adjourned the meeting at 4:31
p.m.

> I certify that I attended this meeting of the Obstetrics and
> Gynecology Devices Advisory Panel Meeting on May 17, 2005, and that
> these minutes accurately reflect what transpired.
>
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> Michael Bailey, Ph.D.
>
> Executive Secretary

I approve the minutes of this meeting

as recorded in this summary.

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

Kenneth L. Noller, M.D.

Chairperson

> *Summary prepared by*
>
> Susan C. Sanderson
>
> 5932 Lee Highway
>
> Arlington, VA 22207
>
> \(703\) 237-3696
>
> astrobuddy@mindspring.com