**SUMMARY MINUTES**

**OF THE**

**OBSTETRICS AND GYNECOLOGY DEVICES**

**ADVISORY PANEL MEETING**

**SIXTY-FOURTH MEETING**

**OPEN SESSION**

**May 21-22, 2001**

**Gaithersburg Holiday Inn**

**Gaithersburg, Maryland**

**Obstetrics and Gynecology Devices Panel**

**May 21-22, 2001**

**Panel Chair**

Jorge D. Blanco, M.D.

Perinatal Associates of Texas

Dallas, TX

\*Machelle Allen, M.D. (Monday only)

Department of Obstetrics and Gynecology

NYU School of Medicine

New York, NY

\*Ralph B. D'Agostino, Ph.D.

Mathematical Statistics Department

Boston University

Boston, MA

\*Michael P. Diamond, M.D. (Tuesday only)

Department of Obstetrics and Gynecology

Hutzel Hospital/Wayne State University School of Medicine

Detroit, MI

\*Gary S. Eglinton, M.D. (Monday only)

Department of Obstetrics and Gynecology

New York Hospital Medical Center of Queens

Flushing, NY

\*Jay D. Iams, M.D. (Monday only)

Department of Obstetrics and Gynecology

Ohio State University

Columbus, OH

\*Temporary Voting Members and Consultants

David F. Katz, Ph.D.

Department of Biomedical Engineering

Duke University

Durham, N.C.

\*Barbara Levy, M.D. (Tuesday only)

Federal Way, WA

Mary Lou Mooney, R.A.C. (Industry Representative)

Clinical, Regulatory, and Quality Affairs

SenoRx, Inc.

Aliso Viejo, CA

\*Michael Neuman, M.D., Ph.D.

Joint Program of Biomedical Engineering

University of Memphis

Memphis, TN

Mary Jo O'Sullivan, M.D.

Department of Obstetrics and Gynecology

University of Miami

Miami, FL

Stanley Reynolds (Consumer Representative)

Department of Health

Commonwealth of Pennsylvania

Lyonville, PA

\*Anne C. Roberts, M.D. (Tuesday only)

Department of Radiology

University of California

LaJolla, CA

Subir Roy, M.D.

Department of Obstetrics and Gynecology

USC School of Medicine

Los Angeles, CA

\*Rebecca A. Schroeder, M.D. (Tuesday only)

Department of Anesthesia

National Naval Medical Center

Bethesda, MA

Nancy C. Sharts-Hopko, Ph.D.

College of Nursing

Villanova University

Villanova, PA

\*Gerald Shirk, M.D. (Tuesday only)

Ob/Gyn Associates

Cedar Rapids, IA

# FDA Representatives

Joyce Whang, Ph.D.

# Panel Executive Secretary

Nancy C. Brogdon

Director, Division of Reproductive, Abdominal, and Radiological Devices

# Colin Pollard

Chief, Obstetrics and Gynecology Devices Branch

Julia Corrado, M.D.

Medical Officer, Obstetrics and Gynecology Devices Branch

Sharon Dillard, M.S.

Office of Surveillance and Biometrics

\* Temporary Voting Members and Consultants

**OPEN SESSION---MAY 21, 2001**

**Panel Chair Jorge D. Blanco** called the Open Session to order at 1:05
p.m., asking panel members to introduce themselves and state their areas
of expertise. **Panel Executive Secretary Joyce Whang, Ph.D.**, noted
that the July 2001 panel meeting had been cancelled and listed a
tentative future panel meeting date of October 15-16, 2001. Dr. Whang
read appointments to temporary voting status for Machelle Allen, M.D.,
Ralph B. D'Agostino, Ph.D., Gary S. Eglinton, M.D., Jay D. Iams, M.D.,
and Michael Neuman, M.D., Ph.D. Dr. Whang also read the conflict of
interest statement. She noted that the FDA had considered declarations
by Michael Neuman, M.D., Ph.D., about his interest in a firm at issue in
matters unrelated to the day's agenda and by Gary S. Eglinton, M.D.,
about an imputed interest through his employers, and had allowed their
full participation.

# Introductory Remarks

**Colin Pollard, Chief of the Obstetrics and Gynecology Devices
Branch,** reviewed Branch activities since January 2001. He stated that
three PMAs had been approved: the Corometrics Fetal Monitor, BEI's
HydroTherm Ablator, and CyroGen's HerOption cryosurgical ablation
device, of which only the last had been brought to panel. The Agency has
also reclassified home uterine monitoring devices from Class III to
Class II with special controls, has issued a guidance document, and is
looking at a device registry.

MALLINCKRODT OXIFIRST FETAL OXYGEN SATURATION MONITORING SYSTEM MODEL
N-400 (P990053/S1)

Mr. Pollard introduced the first item on the panel's agenda,
consideration of a supplement to a premarket approval application (PMA)
for Mallinckrodt's OxiFirst Fetal Oxygen Saturation Monitoring System
(P990053/S1). He reviewed the history of the PMA, noting FDA concerns
during its initial review about investigator bias, device accuracy and
safety, and the clinical significance of its results. At the January
2000 meeting, the panel recommended device approval subject to changes
in the indications and labeling, and to postapproval studies. Those
proposed studies include a human factors study, a general use study, and
information acquired through FDA outreach to other public health and
professional groups such as the National Institutes of Health (NIH) and
the American College of Obstetricians and Gynecologists (ACOG). The
panel was asked to look at what sponsors are proposing as a revised
postapproval study plan. The proposed alternative general use study
would include a patient registry, a dystocia study, and a three-arm
randomized controlled trial of 10,000 patients, including a sham
control. With thanks to panel member Jay D. Iams, M.D., for his help,
Mr. Pollard then read the FDA questions for panel discussion.

# Open Public Hearing

**George Macones, Ph.D., University of Pennsylvania,** spoke on behalf
of the **American College of Obstetricians and Gynecologists (ACOG).**
He stated that ACOG is following results on the fetal pulse oximeter
with excitement, but is not ready to embrace or endorse the device for
routine use. Before any such endorsement, ACOG would need to see more
well-designed clinical studies to look at the reason for the puzzling
study results on dystocia-related increase in cesarean sections and on
whether the device has a significant rate of false negative findings.

**Barry Schifrin, M.D. of Glendale, California,** discussed pitfalls in
fetal heart rate monitoring. He stated that part of the problem in
discussion of fetal monitoring lay in the presupposition that monitoring
can be used to analyze the need for acute rescue. The need for rescue,
he said, is driven by analysis of overall patterns rather than a single
value. He analyzed a study of fetal heart rate tracings, suggesting what
could and could not be extrapolated from fetal monitoring and stating
that what is most dangerous and must be prevented is a series of
variable decelerations in heart rates. Dr. Shifrin was also concerned
that the implication of the monitor's goal is the need to decrease the
C-section rate rather than to improve fetal outcome, stating that the
goal of fetal monitoring should be to decrease perinatal mortality, not
just to decrease the C-section rate. Dr. Shifrin warned that an absolute
focus on decreasing the C-section rate would mean an increase in the
length of labor, in duration of second stage labor, in birth weight, and
in the need for skilled medical care during labor.

# Presentation by Mallinckrodt of PMA Supplement P990053/S1

**Simon Thomas, Nellcor Business Unit of Tyco Healthcare's Respirator
Division,** presented the conclusions of the pivotal randomized
controlled trial on which the PMA was initially approved. He noted
particularly findings that addition of fetal oxygen saturation
monitoring improves accuracy of fetal assessment and reduces cesareans
performed for fetal distress but increases cesareans for dystocia. After
listing four possible explanations for the puzzling dystocia findings,
he listed five unanswered questions remaining from the pivotal trial
that led sponsors to conclude additional studies were needed and six
issues the FDA wanted sponsors to address in the three proposed
postapproval studies.

Mr. Thomas stated that sponsors intended to use data from a general use
study, a dystocia study, and an NIH study to answer the FDA's six
issues. He said that the general use study is more than a registry, and
he explained variables, definitions, enrollment criteria, management
protocols, inclusion and exclusion criteria, training, study size,
duration, and analysis plan for the study.

**Richard Porreco, M.D., principal investigator,** discussed the
proposed dystocia study. As background, he summarized findings of the
pivotal randomized controlled trial on dystocia and gave potential
explanations for the increase in cesareans for dystocia. He presented
the conclusions of the trial investigators that inclusion criteria
selected patients who were at increased risk for dystocia and that
improved fetal assessment with the fetal oxygen monitoring device allows
safe continuation of labor that might otherwise be prematurely
interrupted by a cesarean for nonreassuring fetal heart rate syndrome.

Dr. Porreco synopsized the proposed nonrandomized prospective cohort
observational study at five sites to evaluate the incidence and
management of dystocia in 500 patients with nonreassuring fetal heart
rate patterns by fetal heart rate and oxygen saturation monitoring. He
listed variables of interest, purpose, primary objective, secondary
objectives, design, inclusion and exclusion criteria, definitions,
variables, independent review, and analysis plan for the study.

Questions from the panel concerned use of concurrent versus historical
controls and debate over whether the 30 % oxygen saturation cut-off
point had been sufficiently validated. Concerns were also noted over a
possible broadening of the conditions for use and whether use of this
device itself will increase the rate of dystocia.

# Presentation by NIH

**Cathy Spong, M.D., Chief of the Pregnancy and Perinatology Branch of
the National Institutes of Health,** presented information on the NICHD
Maternal Fetal Medicine Units (MFMU) Network's randomized trial of fetal
oximetry (the FOX trial), which plans to measure the impact of fetal
oximetry as an adjunct to conventional electronic FHR monitoring on the
overall cesarean delivery rate. Dr. Spong explained the three-arm design
and randomization procedures, inclusion and exclusion criteria,
intrapartum management plans, primary and secondary outcomes,
feasibility, sample size and data management, and oversight. She
discussed whether the FOX trial will provide useful data on the
currently approved indication, noting that of the 10,000 women studied,
at least 2000 will have abnormal fetal heart rate tracings. She added
that the masked arm of more than 3000 women (with electronic fetal
monitoring and blinded oxygen saturation monitoring) will give
significant data on the natural history of fetal oxygen saturation
values and information on the prognostic significance of the 30% cutoff.
Dr. Spong stated that the labor management protocol in the FOX trial
will allow for meaningful interpretation with respect to the management
protocol in the device labeling in that physicians will be instructed to
use the device according to labeling and a computer archive will allow
for measurement of compliance.

Panel questions to Dr. Spong involved the timing of the study and
whether safety data would be available in time to help supplement PMA
data.

# Panel Discussion

#### Study A---NIH Study

1\. Will the proposed NIH study provide useful data, per the panel's
earlier recommendation, on the currently approved indication? If not,
are there patient subsets that can be analyzed?

The sense of the panel was that the NIH study will not provide results
within a timeframe to address the current indication, nor will it
address the concerns expressed by the panel at conditional approval. It
was noted that one useful aspect in the NIH study will be whether use of
the device increases the dystocia rate.

2\. Will the sham arm of the NIH study provide information toward
further understanding of the validity of the 30% FSPO2 cutoff value?

Again, the panel thought the timing of the NIH study would not provide
timely information on this topic. There was disagreement over whether
the 30% cutoff had been sufficiently validated, but there was concern
still that the cutoff has not been tied to clinical meaning. One member
of the panel stated that it is a disservice to create instrumentation
that makes physicians rely on a single number, although he thought that
is what sponsors are doing, based on previously reached agreements and
understandings with the FDA.

3\. Will the labor management protocol employed in the NIH study allow
for meaningful interpretation with respect to the management protocol in
the approved labeling?

The panel agreed that the NIH study will provide such interpretation,
but that it will take time.

*Study B---General Use Study*

4\. Considering the nature of the clinical centers in the NIH study and
dystocia study, should the General Use Study target different types of
hospital settings to optimize the overall information gained?

The panel recommended looking at hospitals with a high C-section rate
and approaching centers formerly in the NIH network with recent data on
C-sections. It was also recommended that sponsors collect data on those
patients who refuse the device.

5\. What would be the appropriate overall timeframe for the conduct of
this study? Is there a need for longer-term tracking?

The panel thought that data should be collected for at least one year or
longer.

6\. Are there any other improvements that can be made in the clinical
protocol?

The panel mentioned a concern about collecting the period of time a baby
remains below the 30% cutoff and the correlation between how long that
period is and the effect. A concern was also noted about whether broader
use of the device under conditions not intended by the labeling would
lead to inappropriate device use.

#### Study C---Dystocia Study

*7. Will this study help elucidate the findings from the pivotal PMA
study that showed more cesarean deliveries for dystocia in the OxiFirst
arm?*

The panel had nothing further to add. They encouraged the NIH study to
follow patients as long as possible, although Dr. Spong stated that
restricted funded would only allow follow-up through discharge. The
panel added that the evidence to date did not provide the basis for a
change in their recommendations.

# Open Public Hearing

**Dr. Shifrin** stated that a preliminary study is underway to look at
the relationship between heart rate and oxygen saturation below the 30%
cutoff. He asked if device use might prove to be unnecessary if study
results show that certain heart rate patterns are related to low oxygen
saturation and to the need for intervention.

# FDA Comments

**Mr. Pollard** observed that the FDA does not typically bring
supplements to the panel and asked if the panel would like to see more
of this kind of issue in the future. Panel members responded they would
if the FDA and sponsors thought the day's discussion was of benefit to
them and that the discussion underscored the need for careful panel
consideration of postapproval study requirements when approval is
granted.

# Sponsor Comments

**Simon Thomas** stated that sponsors had no knowledge of a current
study on heart rates and had found no link between heart rate patterns
and oxygen saturation in post-hoc analysis. He emphasized that the
studies will be performed only on patients meeting the approved
indication for use and that there had been no association shown between
length of time the oxygen saturation remains below 30% and damage to the
baby.

# Panel Vote

It was clarified that there was no need to vote on this topic and that
the panel had given a sufficient sense of its thinking on the proposed
studies. **Panel Chair Dr. Blanco** thanked all presenters, panel
members, and FDA staff for their participation.

NOVATRIX LABOR ASSISTER DEVICE: DISCUSSION OF REGULATORY PROCESS ISSUES

Introductory Remarks

Colin Pollard, Chief of the Obstetrics and Gynecology Devices Branch,
explained that the next topic on the agenda, the Novatrix Labor
Assister, was a device that had not developed as sponsors hoped. He and
Panel Chair Dr. Blanco thanked the sponsors for offering to brief the
panel on the regulatory issues involved.

Evelyn Lopez of Novatrix briefly explained the regulatory process and
the protocol. She stated that the company's interaction with the FDA had
gone well.

Howard L. Golub, M.D. of CareStat, defined the clinical problem the
device was intended to address: to help shorten the second stage of
labor for nulliparous women who have elected epidural analgesia. He
described the device, which consisted of a belt designed to detect
contracts and inflate, causing additional external pressure. Dr. Golub
explained the device function, development and testing of the
contraction detection algorithm, and the feasibility study. Possible
safety issues, which included complications from increased intra-uterine
or intra-abdominal pressure, were assessed during the pre-pivotal trial
ascertainment of safety, and methods to address them were found.

Dr. Golub stated that the study was a prospective, multicenter,
randomized clinical trial of active versus sham device with
randomization at the onset of second stage labor. The study hypothesis
was that nulliparous women with uncomplicated pregnancies who elect
epidural analgesia who use the device during the second stage of labor
would have a reduction in the proportion of deliveries that require an
operative delivery, in comparison to the sham group. After explaining
study definitions and study size of 451 patients per group, Dr. Golub
explained clinical management techniques, operation of the device,
randomization procedures, eligibility and exclusion criteria, and
screening.

Results of the clinical trial showed no safety concerns, but overall
results found no statistically significant difference between groups in
operative delivery rate in all sites for all subjects. Trends were
positive in three sites and negative in three sites, and positive in
some subpopulations and negative in others. After examining various
hypotheses, Dr. Golub stated that differences between the sites in
management of the two groups may explain differences in effect size, but
it is not possible to implement a study protocol that would control
these management decision. The subpopulations where the device group had
a lower operative delivery rate than the sham group have some biologic
plausibility, but effect size was only clinically meaningful among
patients with high device use. Therefore, although there is a suggestion
that the device may be effective in certain subpopulations (if
tolerated), it would be impractical to mount a successful PMA study
limited to these subpopulations.

Dr. Golub summarized that there is an important clinical problem for
which the device was a plausible potential solution. The device
functioned as designed and there were no substantial prestudy safety
concerns that should have prevented the study. The protocol was
sufficient to adequately evaluate the safety and effectiveness of the
device. However, the results of the study indicated that while safe, the
device was not effective in the prospectively defined patient
population. In answer to a question from the panel, sponsors added that
there were follow-up studies done on patient satisfaction and device
placement.

Dr. Blanco thanked the presenters and commended the company for a
well-designed study.

Mr. Pollard noted that the 1997 FDA Modernization Act called for an
early collaborative mechanism between the Agency and industry, which
this company had used to mutual advantage. He noted that more sponsors
will continue to do so, and that panel members may have additional
"homework" assignments evaluating such products.

Dr. Blanco thanked the panel and all presenters and adjourned the Open
Session for the day at 4:55 p.m.

OPEN SESSION---MAY 22, 2001

Panel Chair Dr. Jorge Blanco called the Open Session to order at 10:08
a.m. Executive Secretary Joyce Whang introduced three new panel members:
Nancy C. Brogdon, Director of the Division of Reproductive, Abdominal,
and Radiological Devices, Rebecca Schroeder, M.D., of the Department of
Anesthesia at Bethesda Naval Medical Center, and Mary Lou Mooney, of
SenoRx, who is the panel's Industry Representative. She thanked Acting
Consumer Representative Stanley Reynolds, who customarily serves as
Consumer Representative to the Microbiology Devices Panel. After the
remaining members of the panel had introduced themselves and stated
their areas of expertise, Dr. Whang reminded the panel of the tentative
upcoming panel session on October 15-16, 2001, and read the conflict of
interest statement. Waivers had been granted to Nancy C. Sharts-Hopko,
Ph.D., Barbara Levy, M.D., and Michael Diamond, M.D., for their
interests in firms at issue that could potentially be affected by the
panel's deliberations. Matters concerning Ralph B. D'Agostino, Ph.D.,
Anne C. Roberts, M.D., Subir Roy, M.D., Nancy Sharts-Hopko, Ph.D., had
been considered and deemed unrelated, as had past interests of Barbara
Levy, M.D., and Anne C. Roberts, M.D. The full participation of all
these members was permitted.

Introductory Remarks

Colin Pollard, Chief of the Obstetrics and Gynecology Devices Branch,
introduced the first topic, a discussion of room air and gas emboli
during hysteroscopy. He stated that after reports of eight episodes
involving emboli during hysteroscopy, Ethicon had voluntarily withdrawn
its Versapoint device last fall and had returned it to the market in
late January only after making changes to the labeling. The panel charge
was to discuss this issue to help FDA focus on important aspects of the
problem. Mr. Pollard listed several caveats: that the problem involved
issues of terminology, that the focus of the discussion was on operative
rather than diagnostic hysteroscopy, that multiple device systems were
involved, and that FDA's Mandatory Device Reporting System has
limitations that must be understood.

Presentation by Ethicon

Richard Isenberg, M.D., Director of Medical Affairs at Ethicon,
described the sequence of events, noting that Ethicon was the sole
distributor for the Gynecare Versapoint Bipolar Electrosurgery System,
which had been on the market since 1996. The device is a hysteroscopic
surgical technology that operates in normal saline distention medium and
enables diagnosis and treatment of benign intrauterine pathology. It was
voluntarily withdrawn in September 2000 after Gynecare received seven
reports of suspected air/gas embolism during operative hysteroscopy
using the Versapoint device. No patients died or suffered permanent
sequelae.

Dr. Isenberg listed the actions Gynecare took after withdrawal to
investigate, including a meeting of international scientists and
advisors to evaluate the cases. This panel concluded that four cases
were most likely caused by air embolization and three may have resulted
from embolization of electrosurgically created gases. The panel of
experts agreed that the true incidence of embolism is unknown, that it
is inappropriate to conclude that the incidence of gas embolism is
higher with the Versapoint than with any other hysteroscopic
electrosurgical device, and that monopolar and bipolar devices likely
have similar risks of embolism. Various risk factors associated with air
embolism were listed, and the international panel recommended that the
rate and composition of the gases generated during both monopolar and
bipolar electrosurgery should be investigated and warnings incorporated
into instructions for use.

Dr. Isenberg described a gas production study that demonstrated that
rates of gas production by Versapoint electrodes are comparable to those
of commonly employed monopolar devices and that there is no significant
difference between the volume of gas produced by monopolar and bipolar
technologies. As a result of theses investigations, no changes were made
to the Versapoint device components, but warnings were added to the
instructions for use before the device was returned to the market.

Malcolm G. Munro, M.D., of the UCLA School of Medicine, presented
recommendations of the scientific panel regarding hysteroscopy. He
explained the various types of hysteroscopic electrosurgical systems and
listed the recommendations of the panel regarding patient selection,
patient preparation, facility preparation, physician preparation (both
surgeon and anesthesiologist), team preparation, and intraoperative
considerations and precautions. Dr. Munro summarized the conclusions of
the panel that hysteroscopy remains a safe procedure, that air embolism
is rare, potentially catastrophic, and associated with any procedure
involving the endometrial cavity, that gas embolism arising from the
products of electrosurgical vaporization occurs with unknown frequency
but seems rarely if ever associated with permanent sequelae, and that in
vitro evidence suggests there are no clinically significant differences
between unipolar and bipolar systems in the volume or composition of
electrosurgically generated gases.

# Presentation by FDA

**Julia Corrado, M.D., Medical Officer in the Obstetrics and Gynecology
Devices** **Branch,** summarized the FDA staff response to the reported
instances of room air and gas embolization. After hearing of the problem
in early November 2000, the Agency convened a working group that
reviewed the company reports and the recommendations of their expert
advisory panel. The FDA looked at the company's bench testing results
and worked with the company to make more prominent the risks of room air
emboli in the product labeling. Dr. Corrado recognized in particular
panel member Rebecca A. Schroeder, M.D., and the role of
anesthesiologists in addressing this issue, and she thanked Jay Houser
of Karl Storz for offering to make a presentation and Isaac Chang of the
FDA Office of Science and Technology for his cooperation.

Dr. Corrado discussed physiologic, iatrogenic, and equipment-related
risk factors for pulmonary embolism. She listed signs of intraoperative
pulmonary embolism and techniques for intraoperative management
techniques. Dr. Corrado also reviewed the recommendations of the expert
scientific panel regarding considerations and precautions prior to and
after commencing operative hysteroscopy and the panel's conclusions. She
discussed unipolar, bipolar, and hybrid systems and their methods of
vaporization and distension media. After briefly reviewing the eight
embolic events involving the Versapoint system, she listed labeling
revisions the company had made.

Dr. Corrado stated that the FDA's role is to assess the risk of room air
and gas embolism during unipolar and bipolar hysteroscopy, to respond
commensurate with risk, and to decrease that risk through research,
labeling, and clinician awareness, as well as to improve event reporting
and analysis.

**Sharon Dillard, M.S., of the FDA Office of Surveillance and
Biometrics,** gave an overview of FDA's Medical Device Reporting Program
and reports associated with embolytic events during operative
hysteroscopy. Mandatory adverse event reporting for manufacturers
involves cases of death, serious injuries, and malfunctions; user
facilities must report deaths and serious injuries. There is also a
voluntary reporting program available to healthcare professionals and
consumers called "MedWatch." Ms. Dillard discussed strengths and
limitations of the FDA's adverse event reporting system, emphasizing
that it cannot be used to reliably determine incidence or prevalence of
a given product problem or to differentiate between good or bad firms or
products.

Ms. Dillard stated that an MDR search from 1996 to the present found no
MDR reports associated with unipolar electrode use. One report was
received in association with the hybrid device, since withdrawn. Eight
reports were submitted in association with the Versapoint device from
July 1999 to April 2001. She looked at questions raised by the reporting
pattern and asked whether FDA needs to do more at this time, given the
company's response. In conclusion, Ms. Dillard listed postmarket
initiatives available to the FDA in addition to MDR.

# OPEN PUBLIC HEARING

**Jay Houser, of Karl Storz Endoscopy,** discussed electrocautery
procedures of the uterus, listing possible complications of operative
hysteroscopy. He compared monopolar and bipolar energy resectoscopes and
their method of operation. Mr. Houser reviewed the history of uterine
surgery and the findings of the MGH pilot study in 1999. He concluded
that there is a need to understand the difference in the reported
incidence of gas/air embolism between monopolar and bipolar systems,
including the incidence and significance of the formation of bubbles and
the risk that might be associated with each under varying intrauterine
pressures. He also asked whether the study should be extended to urology
resectoscopes.

**Andrew Brill, of the University of Illinois and a Gynecare
consultant,** observed that there are various factors affecting the
development of air/gas emboli. He stated that bubble formation is an
observational event but one that has no clinical sequelae. He thought
this problem an amalgam of clinical issues and observational concerns.

# Panel Discussion of FDA Questions

1\. What are the underlying conditions that lead to the formation of
room air and gas emboli during operative hysteroscopy with RF unipolar
and/or bipolar electrosurgery?

\--How common are room air and/or gas emboli during operative
hysteroscopy using RF ablation techniques?

> \--Are the risks essentially the same, whether using bipolar or
> monopolar modes?
>
> \--Are there other studies that should be done to understand this
> risk?

The panel stated their impression that clinically significant events of
this sort in operative hysteroscopy are very common, although impossible
to quantify precisely. The sense of the panel was that there is always
some amount of air embolism in hysteroscopy, and that there is no easy
way to quantify gas embolism except to note when it is happening.
Serious problems arise when the amount is significant enough for a
pulmonary obstruction or atrial/ventricular defect to shunt the gas
within the heart or an embolus to the brain. Fortunately these are rare,
but almost all patients undergoing these procedures have some amount of
gas going into their systems.

The panel could not answer whether the risks are essentially the same
for unipolar and bipolar systems, saying that this will take ongoing MDR
and MedWatch surveillance.

The panel advised that studies should be done using transesophageal
echocardiograms, esophageal Doppler, and end tidal CO 2 and nitrogen
monitoring. Patients with ASD/VSD and intracardiac shunts should be
excluded from the studies. A marketing issue for companies should be to
study how much gas is produced and goes into the patient. The focus of
studies should be on keeping the patient safe, not design.

The panel recommended that the FDA should send out an alert to stress
labeling improvements such as the risk of sucking air into the venous
system in certain positions and the need to exercise care in the
procedure, to educate all members of the operating team, and to report
MDRs.

2\. How can we improve our communication of risk, as well as recommended
practices for reducing risk?

Again, the panel stressed the importance of issuing an FDA alert and the
need for better education on reporting of adverse events.

3\. How can we improve reporting of events such as air/gas emboli? Are
there additional communication means that would facilitate MDR
reporting?

The panel suggested that relevant professional societies should develop
and post a website with a template for the information to be collected.
They stressed that this is a human factors rather than a technical
problem and urged training for residents and other medical
professionals.

4\. Are there additional measures that can be taken by FDA, NIH, and
relevant professional societies that will add to the understanding of
the risks of air and gas emboli during operative hysteroscopy?

The panel stated that basic research is up to NIH. Endoscopic
laboratories should be used to educate residents and clinicians. Cases
of intraoperative emboli should be published so others can learn from
them. Also, information on the reporting process should be included as
part of the alert for physicians.

**Comments from the Public**

There were no additional requests to address the panel.

**Comments from the FDA**

**Mr. Pollard** thanked the panel and suggested a possible homework
assignment for some members on the reporting template. **Dr. Blanco**
thanked all presenters and panel members.

**UTERINE FIBROID EMBOLIZATION (UFE)**

**Panel Executive Secretary Joyce Whang** introduced arriving panel
member **Anne C. Roberts, M.D.**

**Introductory Remarks**

**Colin Pollard, Chief, Obstetrics and Gynecology Devices** **Branch,**
gave an overview of the regulatory status of uterine fibroid
embolization (UFE), which was reviewed at the October 4, 1999 panel
meeting. At that meeting, the panel heard a presentation from the
Society for Cardiovascular and Interventional Radiology (SCVIR) that
updated the panel on their establishment of a patient registry, on
standards for reporting data, and on UFE in the United States. As UFE
has continued to grow in use, there have been more study proposals and
more published literature. The polyvinyl alcohol particles used in UFE
are a Class III device on track for reclassification to Class II. There
are currently two FDA approved clinical trials underway to study
artificial agents for UFE, and an FDA guidance document is under
development to look at what is needed in clinical studies and 510(k)
submissions. The FDA discussion questions were designed to elicit panel
feedback on the contents of that guidance.

**Presentation by Society for Cardiovascular and Interventional
Radiology**

**James Spies, M.D., of Georgetown University,** gave an overview of
uterine artery embolization (UAE) for leiomyomata, providing background,
technique and slides from case histories. He presented findings from
nine peer-reviewed published series that showed promising improvements
in symptoms at follow-up ranging from five to 29 months. He also
presented findings from a Georgetown study on 200 patients with a
minimum follow-up of 12 months that showed an improvement in most
symptoms. He summarized periprocedural complications and stated that
results of a regression analysis found very few predictors of success.

Dr. Spies also gave SCVIR's response to the FDA's discussion questions.
On inclusion and exclusion criteria, Dr. Spies looked at the difficult
issues involved in studying women on hormone therapy and concluded that
eliminating patients on hormones may prevent complete assessment of
safety of UAE, in particular thrombotic complications. The FDA could ask
for statistical comparison of users versus nonusers as a part of the
submission. Simple hyperplasia patients should be excluded until treated
and cured; those with endometrial polyps should be eliminated. On
design, he suggested that patients should represent their own controls
and each study should set an appropriate level of symptom change
measured by validated means. Randomization is not feasible for most
studies, so a parallel prospective cohort design of UAE versus other
therapy could be used. On follow-up, he recommended six months for
premarket surveillance and two years for postmarket surveillance, which
could be done through the FIBROID Registry. Retreatments should be
considered failures. Labeling should focus on future fertility, and each
patient should be assessed to determine which therapy is most likely to
preserve the uterus in a functional state. UAE should not be used as an
infertility treatment. He concluded that the comparative studies
currently approved by the FDA are a major step forward in assessment of
this therapy. Other efforts such as the FIBROID Registry and the
adoption of uniform validated measures for assessing outcome are
critical, as are physician education and training standards.

**Malcolm Munro, M.D., University of North Carolina,** discussed the
FIBROID Registry and SCVIR standards activities. He presented UAE survey
results and looked at growth of UAE in the United States. SCVIR
activities on UAE have included activities on training standards,
research initiatives, physician education, public information, and
payment advocacy. Training standards for physicians, radiation safety,
and reporting have been developed. Research initiatives include a RAND
health multidisciplinary expert panel meeting and five research grants.
The FIBROID registry is an ongoing effort, and Dr. Munro described its
organization, goals, design, study procedures, inclusion criteria, data,
follow-up, and outcomes. He concluded that the registry will provide
long-term data on the use of UAE for treatment of fibroids with a
24-month follow-up for 450 patients and 12-month follow-up for 1350
patients. Dr. Munro stated that it is difficult to conduct randomized
controlled trials comparing surgical to nonsurgical treatment, but the
registry will provide answers to key questions.

**Open Public Hearing**

**Vicky Hufnagel, of No More UAE** spoke against uterine artery
embolization, stating that the general destruction of normal uterine
tissue as a result of UAE has

not been given significant status in the evaluation of this procedure.
She also stated that women are not being fully informed about the
procedure, its risks, its results, and alternative treatments. Ms.
Hufnagel expressed her concerns about radiation exposure to the female
for a non-life threatening condition and the long-term affects of
radiation on the ovaries, as well as toxic exposure from polyvinyl
particles. She stated that there has been lack of adequate disclosure of
complications and lack of follow-up care.

**Nora Coffey, of HERS,** stated that UAE is now performed in those
lacking a risk to life and those lacking symptoms. The numbers of
adverse events have increased, although the reports of adverse effects
have not yet been published in journals. She asked the FDA to exercise
its authority to require vendors and physicians to curb advertising and
publicity that suggests the results are in and are positive, saying the
sequelae will be learned on women's bodies. She asked for full written
disclosure in clinical trials, with an opportunity to ask questions in
writing and receive a written response. Adverse events should be
reported in triplicate to the doctor, to the FDA, and to the patient.
Women should also be told of all alternative treatments.

**Susan Booker** spoke as an individual and a health advocate, saying
that this surgery will be known as barbaric in 20 years. She asked for
complete follow-up on UAEs immediately.

**Panel Discussion**

1\. *Are the inclusion and exclusion criteria appropriate? Should
hormone therapy (hormonal contraception) be an exclusion criterion for
UAE studies? If patients on hormone therapy are included, should their
data be pooled with data from patients not on any hormones, or should
they be a subset? Should simple endometrial hyperplasia be considered a
premalignant condition?*

The panel discussed extensively whether hormonal contraception should be
an exclusion criterion, with the majority urging that patients on
hormonal contraception be included. These data should be not pooled but
stratified and should be stratified not only for those on or off
hormonal contraception, but also for those on standard birth control
versus high- dose birth control for bleeding. The majority of the panel
agreed that pregnancy should be an exclusion criterion until more
information is available and that women should not be required to have
regular menstrual cycles to be included. Patients on dialysis should not
be excluded, although those with borderline renal function should be.
Uncorrectable coagulopathy and allergy to IV contrast media should be
exclusion criteria. Simple endometrial hyperplasia should be considered
a premalignant condition and excluded.

> *2. As the primary study endpoint, FDA-approved studies currently use
> either a quality of life (QOL) instrument validated for uterine
> fibroids or a validated uterine bleeding scoring instrument coupled
> with a QOL instrument. Secondary endpoints include adverse events,
> fibroid and uterine size, time to return to normal activities, and
> comparisons to controls. Patients are serving as their own controls,
> with secondary comparisons to patients in nonrandomized arms. Please
> comment on the interpretation of these studies.*

The panel thought the primary and secondary endpoints appropriate. They
urged that quality of life questionnaires be done early in the studies
and that concurrent controls be used rather than historical controls.
The panel also stated that radiation exposure estimation should be done
in a subgroup of patients, with accounts kept of radiation time and the
number of images because of concerns about radiation exposure to the
ovaries in young women---whether this would generate cancer, premature
menopause, or damage the ovaries. Sponsors should stratify the data to
see if the procedure fails more often in uteri over a certain size
because this would be important information for patient awareness.

3.  *FDA currently asks for a six-month follow-up (premarket) with an
    additional six- month follow-up (postmarket) for a total of a
    one-year follow-up. Is this an appropriate follow-up regime?*

The panel thought this an appropriate regime, although they suggested
continuing the registry for five years. While they thought six months
sufficient for safety, they also suggested giving sponsors an option of
a six-month or 12-month follow-up to provide a bigger delta.

> 4\. *Should there be specific study requirements regarding
> retreatment? How should the clinical study design account for this?
> Should these subjects be handled as primary treatment failures? Can
> these data provide additional information on the success of UFE
> retreatment?*

The panel consensus was that retreatments are failures and should be
counted as such, although retreatment should be given. Data should be
collected and followed for data on demographics, size, location, and so
forth. Those with large ovarian arteries should be warned about the
possibility of retreatment in the informed consent.

4.  *What are the key elements that should be covered in the
    professional labeling of embolyzing agents that are cleared for UFE?
    How should labeling handle the issue of women who desire a future
    pregnancy? Should bleeding results be stratified by use and nonuse
    of hormonal contraception?*

The panel agreed that pregnancy and recurrence rate must both be
discussed in the labeling, but it must be clearly stated that there is a
lack of data and that results are unknown. The informed consent document
needs to present clearly the possibility of increased morbidity. Panel
members agreed with public presenters about the need for a well-crafted,
written informed consent document that would list possible alternative
treatments and all data obtained on results to date.

**Panel Chair Dr. Blanco** thanked the panel and all presenters.

**Public Remarks**

**Dr. Vicky Hufnagel** stated that she resented the dismissal of
negative comments and legitimate concerns about UAE other than to
ridicule them. She thought the panel did not listen and respond in an
appropriate way to her concerns.

**FDA Remarks**

**Nancy C. Brogdon, Director of the Division of Reproductive, Abdominal,
and radiological Devices,** thanked the panel on behalf of FDA for their
preparation and input.

**Panel Chair Dr. Blanco** adjourned the Open Session at 4:46 p.m.

I certify that I attended the Open Session of the Obstetrics and
Gynecology Devices Advisory Panel Meeting on May 21-22, 2001, and that
this summary accurately reflects what transpired.

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

Joyce Whang, Ph.D.

Panel Executive Secretary

I approve the minutes of this meeting as recorded in this summary.

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

Jorge D. Blanco, M.D.

Panel Chair

Summary minutes prepared by

Aileen M. Moodie

9821 Hollow Glen Pl.

Silver Spring, MD 20910

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