**SUMMARY MINUTES**

**OF THE**

**OBSTETRICS AND GYNECOLOGY DEVICES PANEL**

**OPEN SESSION**

**July 22, 2002**

**Doubletree Inn**

**Rockville, Maryland**

**OBSTETRICS AND GYNECOLOGY DEVICES PANEL**

**July 22, 2002**

**[PANEL PARTICIPANTS]{.underline}**

Jorge D. Blanco, M.D. Chair

Carol Brown, M.D. Voting Member

Anil K. Dubey, Ph.D., H.C. Voting Member

Kinley Larntz, Ph.D. Voting Member

Kleia R. Luckner, J.D., M.S.N. Consumer Representative

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

Kenneth L. Noller, M.D. Voting Member

Mary Jo O'Sullivan, M.D. Voting Member

Subir Roy, M.D. Voting Member

David B. Seifer, M.D. Voting Member

Nancy C. Sharts-Hopko, Ph.D. Voting Member

Gerald J. Shirk, M.D. Voting Member

**[FOOD AND DRUG ADMINISTRATION PARTICIPANTS]{.underline}**

Joyce Whang, Ph.D. Panel Executive Secretary

Collin Pollard Chief, Obstetrics and Gynecology Devices Branch

Danica Marinac-Dabic, M.D., M.M.Sc. Office of Surveillance and
Biometrics

Julia A. Corrado, M.D. Medical Officer

Lisa D. Lawrence, R.N. Lead Reviewer

Gene A. Pennello, Ph.D. Statistician

**[SPONSOR REPRESENTATIVES]{.underline}**

**Conceptus Essure Micro-Insert System (P020014)**

Charles S. Carignan, M.D.

Vice President, Clinical Research and Medical Affairs

Conceptus, Inc.

Jay Cooper, M.D.

Principal Investigator, U.S. Study Team

Founder and Medical Director, Women's Health Research

Clinical Assistant Professor, University of Arizona

Cindy Domecus

Senior Vice President, Clinical Research and Regulatory Affairs

Conceptus, Inc.

Thomas Wright, M.D.

Study Histopathologist

Associate Professor of Pathology and Director, Division of Ob-Gyn
Pathology

Columbia University

Ashish Khera.

Vice President, Research and Development

Conceptus, Inc.

**OPEN SESSION**

**June 22, 2002**

**CALL TO ORDER AND INTRODUCTORY REMARKS**

**Collin Pollard**

**Chief, Obstetrics and Gynecology Devices Branch**

**Food and Drug Administration**

**Joyce Whang, Ph.D.**

**Executive Secretary, Obstetrics and Gynecology Devices Panel**

**Food and Drug Administration**

Dr. Blanco called the meeting to order at 8:20 a.m. The panel members
briefly introduced themselves in turn. Dr. Whang noted that the next
scheduled meeting of the panel would be held on October 21--22, 2002.
Dr. Whang read appointments to temporary voting status and the conflict
of interest statement.

Dr. Pollard welcomed the panel members and announced the issuance of a
Level 1 guidance document for adhesion barrier devices, which represents
the culmination of a panel meeting held 2 years previously. He expressed
the hope that the document would provide further help to those
developing products in this area.

Dr. Pollard introduced the first agenda item and gave the panel members
some background information. In May 1998, the FDA issued a Public Health
Advisory on vacuum-assisted delivery (VAD) devices. Since that time, the
advisory has generated a great deal of interest and activity. The Office
of Surveillance and Biometrics has continued to work in this area and
has taken the initiative to apprise the panel of the results. The
following presentation, said Dr. Pollard, would be informational in
nature, after which some questions would be entertained as time allowed.

**MEDICAL DEVICE POSTMARKET SURVEILLANCE: VACUUM-ASSISTED DELIVERY
DEVICES**

**Danica Marinac-Dabic, M.D., M.M.Sc.**

**Office of Surveillance and Biometrics**

**Food and Drug Administration**

Dr. Marinac-Dabic thanked the panel for the opportunity to present the
results of the Office of Surveillance and Biometrics's postmarket
surveillance of VAD devices. She reported that beginning in 1993 and
1994, the number of reports received by the FDA related to
vacuum-assisted delivery devices began to increase. There were an
increased number of deaths and the following major types of
complications: subgaleal hemorrhage, cephalohematoma, and intracranial
hemorrhage. All major VAD device manufacturers and all types of devices
were represented in these reports. Missing from the reports was
information on the patterns of use of the devices, the fetal and
maternal conditions, and the timing of the injuries. Possible reasons
for the increased number of reports of VAD-associated adverse events are
an increase in the use of VAD devices, changes in facility reporting,
possible under-reporting in previous years, and an actual increased
incidence rate of adverse events.

Before issuing the advisory, the FDA reviewed the adverse event reports,
the literature on this topic, and the labeling of the devices; engaged
in dialogue with device manufacturers and users; and consulted with
professional organizations. The Advisory was issued on May 21, 1998,
stating the need for caution when using VAD devices. It advised the
medical community that VAD devices may cause serious or fatal
complications and provided guidance on how to minimize this risk.
Post-advisory activities included a review of the adverse event reports
and the launching of an FDA-sponsored study (subsequently presented by
Barry Schifrin, M.D.; see below). Since 1998, the number of deaths and
serious injuries associated with VAD has steadily declined. Meanwhile,
the use of VAD has continued to rise.

**Barry S. Schifrin, M.D.**

**Glendale Adventist Medical Center**

**Glendale, California**

Dr. Schifrin was the Principal Investigator for Phase I of the
FDA-sponsored study, "Adverse Outcomes Associated with Vacuum-Assisted
Deliveries." This study was a case-series review on the use of VAD
devices. Analysis of the results of Phase II, a case-control study, is
currently under way.

A total of 203 cases were enrolled in the study, whose purpose was to
evaluate a decision-making apparatus for the use of VAD devices. The
study included all patients at 37 or more weeks of gestation in which
vacuum extraction was attempted, irrespective of the eventual route of
delivery. Numerous obstetric and neonatal features related to process,
decisions, outcomes, and behavior were evaluated. Of the 203 cases
studied, 106 had more than one application of a vacuum device.

To make sense of the patterns of use of VAD devices, information was
collected on the condition and presentation of the fetus, the setting
and circumstances of labor, and the history and physical attributes of
the mother. Dr. Schifrin noted that, although an implicit notion in the
FDA advisory is that adverse outcomes associated with VAD are in fact
related to the use of VAD devices, in many cases ischemic injuries are
actually not related. Subgaleal and intracranial injuries could be
related to VAD, he said, but the most frequent injury found in the study
was hypoischemia.

The study found that in many deliveries, attempts were made to speed up
delivery and have the mother begin pushing before she was fully dilated.
In many cases, fundal pressure was applied not in response to shoulder
dystocia, but to help with vacuum extraction.

Only about 60% of the deliveries in the study were accomplished with
vacuum extraction. Whereas the usual failure rate of VAD is about 5%, in
these cases it was 40% or more. Most of the neonates had low 1-minute
Apgar scores, and about 138 (70%) were admitted to the neonatal
intensive care unit. Concerning complications, Dr. Schifrin pointed out
that the item of interest was that more than half of these babies had
cephalohematoma. Radiologic examination revealed that 15% had subgaleal
hemorrhage, the most frequent injury associated with ischemic brain
injury.

About half of the babies were injured in the second stage of labor,
before the application of vacuum devices. Fetal heart rate tracings
showed that in many cases relentless pushing was maintained despite
indications of fetal deterioration. Neurologic injuries were indicated
by high nonvariable heart rates. In many cases, forceps and vacuum were
alternated, sometimes in the presence of profound fetal bradycardia.
This scenario, said Dr. Schifrin, was what led to severe neonatal
neurologic injury and Erb's palsy, which occurred before the application
of VAD devices.

Dr. Schifrin said that the objective of the study was to understand not
only the use of vacuum devices but also the conduct of labor in which
these devices were applied and the manner in which the injuries
occurred. He said the results indicate that injuries were unlikely to be
related simply to a problem with the vacuum devices.

**Questions from the Panel**

To a question of whether he had the opportunity to evaluate the use of
vacuum devices in general, Dr. Schifrin replied in the affirmative,
noting that the incidence of complications associated with them is quite
small. Referring to the "stunning" result that VAD failed in 50% of
cases, he noted that when there is no simultaneous preparation for
cesarean delivery, as was true in these cases, it becomes necessary to
continue efforts at VAD.

Dr. Schifrin was asked whether, in light of the fact that an attending
physician must be present when a resident performs a delivery, it will
be possible to determine who did the actual application of vacuum in the
Phase II study. He replied that medical records are usually inadequate
for obtaining this information, and that is it possible that the study
may lead to a recommendation to create an ICD-9 code for failed vacuum
delivery. He noted that, although there is an ICD-9 code for failed
forceps delivery, none of the hospitals called thus far had any record
of this code. One physician reported in a deposition that if the
delivery was easily accomplished with vacuum, he may not have recorded
it in the delivery notes.

Dr. Schifrin was asked whether it will be possible in the Phase II study
to differentiate whether problems arose from the vacuum application
itself or simply from bad judgment. Dr. Schifrin referred to an instance
in the Phase I study in which a vacuum device was applied 16 times, a
practice he could not explain under any circumstances. He said that he
believes that the problems studied were due to behavior, not the
devices, and that nothing in the study suggests that VAD should be done
away with.

**OPEN PUBLIC HEARING**

Dr. Blanco opened the public hearing portion of the meeting, during
which presentations were given on the Conceptus Essure Micro-Insert
System (P020014).

**Gabriella Avina, R.N.**

**Martinez, California**

Ms. Avina informed the panel that her financial interest in Conceptus
consists of some stock owned by herself and her husband and of payment
by the company of her travel expenses.

Ms. Avina has been a Registered Nurse for 16 years in the field of
maternal-fetal health. She holds a Master's degree in reproductive
health and is married with three children. Ms. Avina recounted her
experiences when she and her husband decided not to have any more
children. In 1998 she had an intrauterine device placed and became
pregnant 7 months later. After the complicated delivery from that
pregnancy, her husband underwent a vasectomy, only to find after
repeated analyses that his sperm count remained high.

In considering her options for permanent sterilization, Ms. Avina
decided to enroll in a clinical trial for the Essure System. She had the
devices implanted in October 2000, and it was subsequently confirmed
that her fallopian tubes had been successfully occluded. Ms. Avina
reported to the panel that the procedure has brought peace of mind,
comfort, and security in her relationship with her husband. She said
that she spoke for all women in saying that they deserve another
contraceptive option.

**CREST Study**

**Caroline Costello**

**Division of Reproductive Health**

**Centers for Disease Control and Prevention**

Ms. Costello reported on the U.S. Collaborative Review of Sterilization
(CREST) study, which was conducted by the Centers for Disease Control
and Prevention (CDC) with support from the National Institute of Child
Health and Human Development (NICHD). The study was conducted to
determine the pregnancy rate among women who had undergone tubal
sterilization in nine U.S. sites: Baltimore, MD; Buffalo, NY; Chapel
Hill, NC; Honolulu, HI; Houston, TX; Memphis, TN; Sacramento, CA; San
Francisco, CA; and St. Louis, MO. Of the pregnancies reported after the
procedure, 143 were classified as tubal sterilization failures. (The
other pregnancies were classified as luteal phase pregnancies conceived
before the sterilization procedure but not identified until afterward,
as resulting from reanastomosis or in vitro fertilization, or as unknown
status because of insufficient information.) The cumulative probability
of pregnancy increased each year after sterilization and was found to be
highest for procedures in which the spring clip occlusion method was
used and lowest for unipolar coagulation. The pregnancy rate was
greatest in women age 18--27 and lowest in those age 34--44 and in
black, non-Hispanic women. The rate of ectopic pregnancies was 32.9%,
was highest for unipolar coagulation, and increased over time.

The following conclusions were drawn from the study:

• Tubal sterilization is a highly effective method of preventing
pregnancy.

• Pregnancy after sterilization occurs substantially more often than is
generally reported.

• Tubal sterilization failures occur \>1--2 years after sterilization.

• Sterilization method, age, and race-ethnicity can be predictors of
sterilization failures.

• All women undergoing tubal sterilization should be informed that
pregnancy can occur even very many years after sterilization and that if
a pregnancy occurs, there is a high risk that it will be ectopic.

**CONCEPTUS ESSURE MICRO-INSERT SYSTEM (P020014)**

Mr. Pollard opened the sponsor presentation portion of the hearing and
reviewed the panel's function and purpose. The FDA has convened the
panel, he said, to obtain their input as experts and will use their
recommendations as it moves forward in its review of the application for
approval of the Essure implant. He went on to make the following points:

**1.** The panel's recommendation can take one of three forms: 1)
approvable, 2) approvable with conditions, and 3) not approvable. If one
of the last two recommendations is made, the FDA would expect
recommendations from the panel on what would be needed to make the
device approvable.

**2.** Valid scientific evidence, safety, and effectiveness are among
the factors influencing the panel's decision on the premarket approval
(PMA) application for the device, which is intended for implantation in
the fallopian tubes for permanent female sterilization. Tubal occlusion
devices that are placed laparoscopically have been previously developed
and are supported by the published literature. Mr. Pollard said that the
results of the CREST study highlighted by Ms. Costello should prove
useful in putting the issue in perspective.

**3.** The device in question represents the next generation of devices
for permanent sterilization. Although the new device is not supported by
as much clinical experience as are other sterilization methods, it has
been supported by the clinical trials conducted to date.

**4.** This PMA application, the result of the panel's deliberations,
and its decision will serve as a model for the future review of new
devices.

**PRESENTATION FROM SPONSOR**

**Introduction**

**Cindy Domecus**

**Senior Vice President, Clinical Research and Regulatory Affairs**

**Conceptus, Inc.**

Ms. Domecus introduced the panel presentation team and acknowledged the
FDA's input during the clinical research conducted on the Essure system.
She informed the panel that Conceptus chose to develop Essure because of
the need for additional contraceptive choices for women, as evidenced by
the high rate of unintended pregnancies in the United States. The
literature suggests that part of the reason for this high rate is due to
patient dissatisfaction with reversible methods, which leads to
imperfect use and unintended pregnancy. Current methods of permanent
female sterilization, she said, require invasion of the abdominal cavity
through surgery performed under general anesthesia, with its attendant
risks.

Ms. Domecus went on to summarize the risks of tubal ligation via the
transabdominal approach. Although these procedures are highly effective,
they also carry significant risk. The great majority of complications
with the transabdominal approach are related to incisions, blind
insertion of instruments into the abdomen, and general anesthesia. In
contrast, she noted that the transcervical approach avoids all three of
these components.

**Device Description, Mechanism of Action, and Placement Procedure**

**Jay Cooper, M.D.**

**Founder and Medical Director, Women's Health Research**

**Clinical Assistant Professor, University of Arizona**

Dr. Cooper distributed samples of the Essure device to the panel
members. He informed them that he has worked with Conceptus as an
advisor through various iterations of development of the device and
served as the Principal Investigator on the U.S. studies.

Dr. Cooper described the Essure microinsert as a soft, flexible, 4-cm
device composed of an inner and an outer coil. Laced along the inner
coil is a length of polyethylene terephthalate (PET) fibers. Placed in
the uterotubal junction, the device can achieve a diameter of up to 2
mm. The leading edge of the device is ball tipped, which facilitates its
placement into the proximal fallopian tube. The Essure device is
radiopaque and can be seen to conform to the natural shape of the
fallopian tube.

The delivery system consists of a handle with a rotatable thumbwheel and
a guide wire that allows for one-handed deployment. Attached to the
handle is an outer delivery catheter that is 1 mm in diameter and can be
passed through the operating channel of a hysteroscope.

Dr. Cooper presented a series of photographs showing the delivery of the
device and played an animation of the placement steps. He pointed out
that the design of the delivery catheter aids the operator in
deployment, as it is hydrophilic and becomes slippery and lubricated as
it passes through the saline-filled uterine passage. Approximately 2 cm
from the leading edge of the catheter is a black positioning bump that
provides a visual aid to the operator in properly positioning the
microinsert. Once this positioning bump can be seen to have reached the
uterotubal junction, the release catheter is withdrawn and the device is
free to expand to its natural diameter. The guide wire is then separated
from the device, leaving it positioned at the uterotubal junction and
spanning the diameter of the fallopian tube. The musculature of the
uterus prevents the device from achieving its full diameter, thus
accommodating to variable tubal widths and keeping it in place.

The mechanism of action of the Essure microinsert is expansion of the
coils, which results in mechanical blockage, and tubal occlusion, which
occurs through tissue ingrowth. Dr. Cooper said that the Essure
procedure requires no or only minimal (5.5 mm) cervical dilatation and
can be accomplished with the simplest of hysteroscopic procedures,
similar to those used for diagnostic evaluations. The procedure is
devoid of many of the risks and concerns of more advanced hysteroscopic
procedures. Through saline distension of the uterus, the risk of
intravasation is minimized, and no cutting or resection is required.
Electrosurgery is not employed, the procedure is rapid, and
intraoperative bleeding is uncommon.

**Clinical Trials Summary**

**Cindy Domecus**

Ms. Domecus informed the panel that the Essure system underwent 2 years
of clinical testing with earlier versions of the device before clinical
testing of the "gamma" design began in 1998. Forty-six women were
enrolled in the peri-hysterectomy study and 63 in the Pre-Hysterectomy
Study, which yielded data on comfort as well as histological data to
support the theorized mechanism of action of the device. Phase II trials
of safety and effectiveness were conducted with 227 women who were
candidates for sterilization. A pivotal trial of safety and
effectiveness was conducted in 2000 in 518 women. Clinical testing of
the device has involved a total of 854 women over 4 years.

**Pre-Hysterectomy Study**

**Thomas Wright, M.D.**

**Study Histopathologist**

**Associate Professor of Pathology and Director, Division of Ob-Gyn
Pathology**

**Columbia University**

Dr. Wright informed the panel that he is a paid consultant to Conceptus,
Inc. and has no other financial interest in the company.

For the pre-hysterectomy study, the Essure microinsert was placed in
awake women 1--30 weeks before scheduled hysterectomy. A total of 51
women wore the device for 1--30 weeks. Most of the participants had the
device in place for 4--14 weeks.

Hysterosalpingography (HSG) was performed within 1 week of hysterectomy,
and specialized histopathological tissue processing was carried out by a
single histopathologist who was blinded to wearing time and clinical
information. The embedded tube and device were cut into sections and
ground down to allow examination of the relationship between the tissue,
the fallopian tube, and the device. HSG results showed that 100%
occlusion of the tubes occurred in all 51 women, including those wearing
the device for less than 4 weeks.

Dr. Wright showed a photograph of a cross-section of the fallopian tube
in a woman wearing the device for 4 weeks. He pointed out that even
after this relatively short time, dense fibrosis could be seen to have
formed between the inner and outer coils of the device, and the normal
tissue architecture of the tube had been completely disrupted. In a
cross-section from a woman wearing the device for 13 weeks, the lumen
appeared to be totally occluded by fibrosis. Smooth muscle cells could
be seen to have migrated into the spaces between the inner and outer
coils and among the PET fibers within the coils. Dr. Wright said that
this event is typical of what is seen with PET devices used in other
applications.

Histopathological features were graded in a blinded fashion. Over time,
an increase in dense fibrosis and a reduction in acute inflammation was
seen until a stable state of chronic inflammation and loose fibrosis was
achieved.

Summarizing the conclusions of the study, Dr. Wright said that before
hysterectomy, total tubal occlusion occurred in all participants at all
time points, including those wearing the device for less than 4 weeks.
The tissue response with the device was predictable and progressive,
occlusive, and localized to the device, occurring within the normal
tubal architecture 5 mm distal to the device and not extending to the
serosa.

**Pivotal Trial Results**

**Charles S. Carignan, M.D.**

**Vice President, Clinical Research and Medical Affairs**

**Conceptus, Inc.**

Dr. Carignan informed the panel that the objectives of the pivotal trial
were to evaluate the safety of the placement procedure and participants'
tolerance of and recovery from the procedure, the safety and
participants' tolerance of the implanted microinserts, the occurrence of
tubal occlusion at 3 months, and the effectiveness of the Essure device
in preventing pregnancy, using a primary endpoint at 1 year. Women were
followed at 1 week and 3 months after the Essure device was placed,
during which time they relied on alternative forms of contraception.
They were then evaluated after 3, 6, and 12 months of relying solely on
the Essure device for pregnancy prevention.

The trial was conducted among 320 women in eight sites in the United
States, 133 women in two sites in Australia, and 65 women in three sites
in Europe. Adverse events occurred in only 3% of the women, and all of
these events resolved before discharge. None of the women required major
surgery, and the only hospitalization occurred in one woman who was
observed overnight for a reaction to pain medication. Perforation
occurred in only 1% of women, none of whom had any symptoms of
perforation. Most women reported mild to no pain.

The average time to discharge after the procedure was 45 minutes.
Fifty-eight percent of the women had no immediate post-procedure events.
The most frequent events reported were cramping, pain, and nausea.
Seventy-five percent of the women required no post-procedure analgesia,
and 74% reported missing less than 1 day of work.

At 3 months after placement of the device, women underwent HSG to
determine the location of the device and the extent of tubal occlusion.
At this time they also received a pelvic examination and were asked
questions about their comfort and satisfaction. Comfort was rated as
excellent at all the study visits; only 3% of the women reported
episodes of pain at more than one visit. Changes in menstrual function
consisted of irregular menses, spotting or intermittent intermenstrual
bleeding, and changes in menstrual flow. Few of the women reported
persistent changes in menstrual function. All changes in menstrual
function were considered in light of the fact that 48% of the women had
discontinued oral contraceptives.

Adverse events were defined as any untoward deviation from baseline.
Women maintained daily diaries for 6 months. Multiple episodes of the
same event were counted separately. The most common event rated as at
least "possibly" related to the device was back pain, which occurred 43
times. Participant satisfaction with the device was high; from 3 months
after placement and onward, more than 90% reported that they were "very
satisfied" with the device.

No pregnancies were reported among any of the women relying on Essure in
the pivotal trial. The current estimate of the 1-year effectiveness
rate, based on the pivotal trial alone, is 100%, with a 95% confidence
interval of 99.31--100%. No pregnancies were reported among the women in
the Phase II trial. The combined 1-year effectiveness rate is also 100%,
with a 95% confidence interval of 99.52--100%.

The conclusions drawn from the study, said Dr. Carignan, are that the
Essure microinsert system is highly effective, yields high patient
satisfaction with a well-tolerated placement procedure and a rapid
return to work and normal activities, is comfortable and safe, and
requires no general anesthesia or incisions.

**Panel Discussion Questions**

**Cindy Domecus**

Ms. Domecus addressed questions previously posed by the panel regarding
the Essure system. (These questions appear in full in Attachment A.)

**Question 1: Effectiveness of Essure in comparison with other tubal
sterilization methods:** There were no reported pregnancies among women
using the Essure microinsert during the first year of use. This rate is
equal to or lower than that of other female tubal sterilization methods.
As reported in Dr. Corignan's presentation, the combined 1-year
effectiveness rate was 100%, with a 95% confidence interval of
99.52--100%. The second-year effectiveness rate for the Essure device
was also 100%, a rate equal to or lower than those for other
sterilization methods.

**Question 2: Age characteristics in the Essure pivotal study in
comparison with those in the CREST study:** The age range of women in
the CREST study was 18--44 years. The pivotal study design was based on
two age groups: under age 34 and over age 34. Regret was highest among
the youngest age group; the age cap in the pivotal study was 40 rather
than 44, as in the CREST study.

**Question 3: Mechanism of action/recanalization:** There is no evidence
of long-term failure with Essure. Five women have relied on the system
for 36 months with no reported pregnancies. The history of the use of
PET fibers in cardiac valves, stents, and grafts has shown that they
produce a durable dense fibrotic response. The device is designed to
occlude a 1.2-mm section of the fallopian tube. Postmarket surveillance
will be conducted to follow the women who participated in the Phase II
study and the pivotal trial for 2 years.

**Question 4: Pelvic X-ray in lieu of HSG:** Ms. Domecus said that the
plan to require pelvic X-ray instead of HSG to confirm the location of
the microinsert is believed to be adequate because unsatisfactory
locations could be detected on pelvic X-ray alone. The HSG patency rate
with Essure is similar to that with incisional tubal sterilization
published in the literature. Moreover, since follow-up HSG is not the
standard of care for tubal ligation, the proposed plan to use X-ray is
conservative.

**Question 5: Placement failure rate:** Eighty-three of evaluated
failures to properly place the microinsert were attributed to proximal
tubal occlusion that was not identifiable with the transabdominal
approach. The placement procedure was shown in the pivotal trial to be
well tolerated and was associated with minimal risks. High placement
rates were achieved even in obese women and those with a history of
prior abdominal or pelvic surgery. Ms. Domecus pointed out that these
women are often the same ones who are refused laparoscopic surgery
because of their increased risk for complications. She also observed
that offering women a less invasive approach before a more invasive
procedure is consistent with clinical practice in other areas of
medicine.

**Question 6: Safety:** The panel's questions about safety were
addressed by Dr. Corignan in his presentation.

**Question 7: Outline of training program:** The training program will
consist of a full-day course with a didactic presentation and training
manuals, followed by the use of a custom-designed placement simulator
that allows for placement practice in rapid succession. Data will be
collected on preceptored cases until formal sign-off from the training
program. The participants will perform an average of five placements. A
Technical Help Desk will be maintained for post-training assistance. The
proposed training program is already in use in Canada, Europe,
Australia, and Singapore.

Successful placement rates in commercial settings were found to be
equivalent to those in the clinical trials, even though the average
number of procedures per physician in commercial settings was less than
half that in the clinical trials. For this reason, it is believed that
the placement procedure will be generalizable to the commercial setting.
Placement rates were not significantly changed with experience after the
first five cases. Procedure duration decreases slightly with experience.
Ease of use was most often rated by operators as "simple" or "moderately
simple."

**Question 8: Postmarket surveillance:** Patients in the Phase II and
pivotal trials will be followed for 5 years and will be requested to
provide tissue samples and/or the microinserts from future extirpative
surgery of the reproductive organs. Placement and adverse event data
will be collected on all preceptored cases. Labeling of the device will
carry a toll-free number for physicians to call in the case of adverse
events and reportable events to the FDA.

**Conclusion**

Ms. Domecus expressed the sponsor's belief that the data gathered in
trials of the Essure microinsert represent "valid scientific evidence"
in accordance with 21 CFR 860.7. She said that a reasonable assurance of
safety and effectiveness has been established for the device, and
adequate training and postmarket surveillance plans are in place to
support the market release of the device. On the basis of the
information and evidence presented, said Ms. Domecus, Conceptus
respectfully requests approval of the Essure microinsert system.

**QUESTIONS FROM PANEL MEMBERS**

In response to a question concerning the distribution of women according
to race and ethnic background, the sponsor reported having obtained
information for the pivotal but not the Phase II study. The distribution
was as follows in the pivotal study: 5.4% black, 6.4% Latin, 0.4% Asian,
and 0.4% American Indian for all study sites in the United States,
Australia, and Europe. In the United States, the distribution was as
follows: black, 8.8% average, range 2--25%; Latin, 10% average, range
2--32%; and Caucasian, 79% average, range 43--92%.

In response to a question about data on the mechanism of action of and
biological response to PET fibers used in other medical devices, Dr.
Wright said that PET fibers have a long history of use in cardiac grafts
and other body sites. The response to PET fibers is well described in
the literature: cells become attracted to the PET fibers, inducing an
acute or chronic inflammatory infiltrate. Over time, the inflammatory
process diminishes while the dense adhesive process increases. The
literature on the use of PET fibers over a long period shows no
long-term adverse effects. Neither are there any data implicating PET
for producing neoplasms after many years of use (such as cardiac grafts
placed in children).

Ashish Khera, Vice President, Research and Development, Conceptus, Inc.,
indicated that the materials chosen for the Essure device have a long
history of use in medical applications. Ms. Domecus indicated that
biocompatibility test results submitted in accordance with FDA
guidelines in advance of conducting tests show that this material is not
toxic or mutagenic in the chronic setting.

Dr. Cooper was asked about the decision to use prophylactic antibiotics
before the placement procedure. He replied that this was left to the
discretion of the investigators, only one of whom made routine use of
prophylactic antibiotics.

In response to a question about what was done when perforation were
noted, Dr. Cooper said that in those deemed to be candidates for
traditional methods of sterilization, the devices were retrieved at
laparoscopy. He said that in most cases the diagnosis of perforation was
made at the time of placement. In a small number of cases, perforation
was not noted until post-procedure X-ray. Retrieval in those cases was
not problematic; the device was found lying in the omentum and could be
easily removed. Dr. Carignan said that the longest time between
perforation and retrieval was 4 years; in that case, the device was
found in the pouch of Douglas and was removed. Among women whose devices
were not retrieved, there were no reports of unusual pain that could be
attributed to the location of the device.

Dr. Carignan said that a "fail-safe" mechanism consists of using the
black positioning bump to properly locate the device. During training,
he said, it is stressed that the position of the black bump must be
maintained during the release of the device. A sudden loss of resistance
should be recognized as a perforation and is an indication not to place
the device.

Because the device spans the uterotubal junction, said Dr. Carignan, the
method of removal is by cornual resection. Removal of a well-positioned
device, however, is not recommended.

A question was asked about a requirement in the training plan for local
versus general anesthesia in the five precepted placement procedures.
Ms. Domecus said that this decision is left up to the physician.

Dr. Cooper was asked how many patients had preexisting pathology in the
uterine cavity at the time of hysterectomy. He said that a low incidence
of intracavitary pathology was found at the time of elective
sterilization. Rarely did this pathology interfere with the ability to
place the device. Asked whether he would place the device in the
presence of a small amount of pathology, he answered in the affirmative.

A question was asked about the device's labeling information, which
contains little or no information about procedures done subsequent to
placement of the device. Dr. Cooper was asked whether patients
undergoing dilation and curettage (D&C) can still rely on the device or
whether they are advised to use an alternative method of contraception.
Dr. Cooper said that two of four women with luteal-phase pregnancies
chose pregnancy termination via suction D&C. Despite the fact that they
had not worn the device for the requisite 3 months at the time of D&C,
these women relied on the device for long-term contraception afterward.
There were five reports of women in the commercial population undergoing
D&C without disruption of the device. It would be difficult to imagine,
he said, that the suction created by the catheter in a D&C could
dislodge the device, especially after 3 months of tissue ingrowth. Women
with abnormal uterine bleeding, he said, should undergo a visual
examination of the uterine cavity, which is good sense regardless of
whether they have the device.

The reason for the recommendation against using electrocautery in women
wearing the microinserts, said Dr. Cooper, is due to insufficient
information on its effects. Physicians are warned not to use
electrocautery within 4 cm of the device. In one case where the
electrode touched the tip of a device, some blanching of the tube was
seen.

Dr. Wright was asked how the microinsert creates adhesions in the
fallopian tube but not in the uterine cavity. He said that in the tube,
the outer coil of the device expands outward and causes localized trauma
to the epithelium. This trauma stimulates an inflammatory response.
Retrieved devices have shown some fibrosis immediately surrounding the
inner coil containing the PET fibers. No dense adhesions or adipose
tissue was seen in the tissue tied to the microinserts. Dr. Wright said
that it is believed that the answer to the question lies in this cascade
of events generated by the outer coil when the device is in place.

Although there is no experience in patients wearing the device who
undergo in vitro fertilization (IVF), said Dr. Cooper, his personal
opinion is that these patients will not have a problem with this
procedure. It is unlikely that the small area affected by the device,
which is covered over with dense fibrosis, would interfere with
pregnancy.

Dr. Cooper said that it is recommended that the device be removed if
15--18 coils are seen to be extending into the uterine cavity after
placement. He said that the reason for this recommendation is that in
these cases it has been shown that the device is likely to be expelled.

A question was raised as to whether ultrasound had been looked at as a
way of confirming placement. Dr. Carignan said that in the Phase II
studies, some investigators used ultrasound for this purpose but that
this was not controlled for.

**PRESENTATION FROM FDA**

**Lisa Lawrence, R.N.**

**Lead Reviewer, CDRH/ODE/DRARD**

Ms. Lawrence, lead reviewer for the Essure PMA, updated the panel on the
status of the FDA review process for the device. She described the
Essure device, highlighted the PMA review areas, and provided an
overview of the IDE and PMA review history and the preclinical reviews.

In June 2001, FDA held a Determination/Agreement meeting with Conceptus,
which sought an additional commitment from the agency as the pivotal
study was underway. It was agreed that the FDA would file the PMA for
the device, if there were at least 400 subjects in the pivotal study
with 1-year follow-up, and at least 100 subjects in the Phase II study
with 2 years of data. Bayesian statistics would be used to analyze the
1- and 2-year failure rates. The mechanism of action would be supported
by histology data from 30 patients in the pre-hysterectomy study.
Expedited review was requested on April 22, 2002, and granted on May 22,
2002, when it was determined that the device offers a significant
advantage over existing approved alternatives. Preclinical reviews have
been completed for animal studies and MRI compatibility studies. Reviews
are ongoing for engineering, chemistry, and device sterilization of the
material that will contact the patient. Appropriate testing was
conducted on material safety. Inspections on bioresearch monitoring and
manufacturing are also underway.

**Julia Corrado, M.D.**

**Medical Officer, CDRH/ODE/DRARD**

Dr. Corrado gave a historical overview of transcervical sterilization
devices and reviewed the principle of operation of the device, its
indications for use, and clinical studies on the Essure system.

Two investigational devices developed in the 1980s were completely
unrelated to the Essure device and never saw any commercial use in the
United States. Sterilization failures following the use of these devices
were due to misreading of pelvic X-ray and/or HSG.

The clinical studies of Essure consisted of a peri-hysterectomy study to
evaluate the feasibility of placement; a pre-hysterectomy study to
evaluate placement, tolerance to inserts, and histology; and Phase II
and pivotal studies for safety and contraceptive efficacy.

The objectives of the pre-hysterectomy study were to evaluate placement,
tolerance to the placement procedure and relative long-term wear (14--20
weeks), stability of placement, and occlusion at 24 hours to 12 weeks
and beyond. A total of 53 women wore the device from less than 4 weeks
to more than 14 weeks; two were lost to follow-up. Tissue response to
the device showed predominantly macrophages and lymphocytes,
polymorphonuclear leukocytes at shorter wear times, and
foreign-body-type giant cells at longer wear times. Dense fibrosis was
present after 4 weeks. No serosal fibrosis or adhesions were seen, and
the tubal architecture was normal 5 mm distal to the microinsert.

The Phase II study was conducted to determine the long-term safety of
the procedure, the long-term stability of the microinserts, and the
contraceptive effectiveness of the device. The study had a prospective,
multi-center, nonrandomized design with a planned 5-year follow-up.
Participants ranged in age from less than 28 to 45 years; the largest
proportion of women were 34--45 years of age.

Eighteen women were treated with the beta device, a discontinued version
for which placement rates were lower than for the gamma device. A total
of 227 women were treated with the gamma device in a total of 233
procedures. At 3 months after placement, 97% of the women had bilateral
occlusion of the fallopian tubes. Dr. Corrado noted that successful
bilateral *placement* did not necessarily result in successful bilateral
*occlusion*, although occlusion rates were high with successful
placement.

No pregnancies occurred in 194 subjects at 12 months, and none occurred
in 149 subjects at 24 months. The number of adverse events was small;
there were six perforations and 153 instances of intraoperative pain out
of the 233 procedures. Adverse events within 1 week of the procedure
consisted of 188 reports of bleeding and fever that resolved within 12
hours in four subjects. One instance of expulsion occurred at 3 months
post-procedure. Acceptability of the procedure was rated "good" to
"excellent" by 90% of the subjects at 1 week, and 88--94% reported
"excellent" tolerance at 3--24 months.

The pivotal study was a prospective, multi-center, nonrandomized,
noncontrolled trial with a planned 5-year follow-up. The ages of the
women in the study ranged from less than 28 to 40 years old; the largest
proportion was 28--33 years. Of the 507 patients receiving the device,
bilateral placement was achieved on the first attempt in 446. Bilateral
placement was achieved in 18 women on the second attempt. Of these 464
patients, 452 are relying on Essure for contraception. No pregnancies
had occurred at 12 months post-procedure in 408 of these women. Adverse
events within 24 hours of the procedure consisted of one perforation,
two cases of hypervolemia, and three cases of vasovagal response.
Adverse events at 3 months were similarly small in number, consisting of
four perforations and 14 expulsions. Intermenstrual bleeding occurred in
112 subjects, irregular menses in 49, heavier menses in 90, and lighter
menses in 57. Only 12 patients had adverse events that prevented
reliance on the Essure device.

Four luteal-phase pregnancies occurred before device placement and were
not identified on the pregnancy test given before the procedure. Three
of these women chose pregnancy termination and had no problems with the
procedures.

Dr. Corrado noted that the device cannot be removed hysteroscopically.
There were no requests for removal of the device among women in the
pivotal study. Four attempts to retrieve the devices were made during
alternative sterilization procedures performed after perforation was
diagnosed on HSG at 3 months; two of these retrieval attempts were
successful.

Patient comfort with the device was rated as "excellent" by 82% of women
3 months after placement and by 91% at 1 year after placement. Patient
satisfaction was also high; 92% were "very satisfied" at 3 months and
95% at 1 year after the placement procedure.

Dr. Corrado noted that the clinical studies used HSG for placement
confirmation, whereas Conceptus proposes the use of X-ray in lieu of HSG
if device location is satisfactory. She asked the panel members for
their input on this issue.

Dr. Corrado noted that the CREST study showed that the cumulative rate
of sterilization failure continues to increase beyond 2 years. Ectopic
pregnancies are more common in women with sterilization failure; the
type of device and the age of the woman seem to have a bearing on the
failure rate. She noted that the duration of follow-up in the CREST
study makes it a landmark one; many women were followed out to 10 years.
She said that this raises the question of how many women to follow and
for how long.

**Gene Pennello, Ph.D.**

**Division of Biostatistics, CDRH**

Dr. Pennello reviewed the study design of the Phase II and pivotal
studies, described the patient population, presented a patient tree, and
presented results of the effectiveness analysis and adverse events.

For the pivotal study, Bayesian statistics were used to analyze the
first-year effectiveness rate. Phase II data were used as prior
information. All five investigators in the Phase II study participated
in the pivotal study as well. One pivotal study investigator who was not
in the Phase II study participated in the peri- and pre-hysterectomy
studies.

Protocol requirements in the pivotal study required participants to have
had at least one live birth and to have four to eight coital acts per
month. A total of 650 patients were initially enrolled in the pivotal
study, of whom 518 eventually made up the intent-to-treat population.
Bilateral placement was achieved in 464 women. Placement was successful
after one attempt in 446 and after two attempts in 18 women. HSG was
used to confirm satisfactory location. A total of 449 women were able to
rely solely on the device for contraception.

Dr. Pennello described the use of Bayesian analysis as a scientifically
valid way of combining previous information with current data. This
method was used in the first-year effectiveness analysis, which includes
all woman-months, including those from women followed for less than 1
year. Some women were censored from the study because of an insufficient
number of coital acts for two consecutive cycles or because of reduced
fertility of their partners.

In reference to Questions 1 and 2 from the panel, Dr. Pennello informed
the panel that the Bayesian analysis combining data from the pivotal and
Phase II studies did not adjust for the older ages in the Phase II
study. Age adjustment is important, he noted, for labeling the device
appropriately. He explained that the FDA approach to age adjustment is
to adjust the first-year rate to the age distribution in either the
pivotal or the CREST study, using the method of direct standardization.
This method is commonly used in epidemiology to compare rates from
multiple populations.

Dr. Pennello presented the sponsor's analysis of missing data. At the
time of PMA submission, 27 women have been followed for less than 1 year
post-alternate contraception. The Bayesian predictive probability of
pregnancies is 98.90% for no pregnancies, 1.09% for one pregnancy, and
0.00% for two pregnancies.

Referring to Question 7 regarding the learning curve analysis for the
placement procedure, Dr. Pennello presented hysteroscope times and
first-attempt placement rates by procedure sequence for investigators
with more than 20 procedures. The first five procedures required an
average of 18.4 minutes hysteroscope time with placement rate ranged
from 87.0%; for more than 20 procedures, the average time was 10.3
minutes, and the placement rate was 89.3%.

Notable results from the adverse events analysis included the
observation that the rate of adverse events that initially prevented
reliance on the device was significantly higher at one site (17%) than
at other sites (0--3.5%). The expulsion rate also varied significantly
by site, ranging from 0--13.5%. Seven women experienced sharp pain and
three had sudden or severe cramping that was thought to be related to
the placement of the device. There was a borderline association between
unsuccessful bilateral placement and pain on average since the
procedure. The rate of recurrent regular menses (5.9%) was 3.5 times
that at baseline (1.7%), and the rate of recurrent intermenstrual
bleeding (8.7%) was 3.8 times that at baseline (2.3%).

In summary, Dr. Pennello noted that the initial bilateral reliance rate
was 92%, the first-year pregnancy rate was 0%, and patient satisfaction
with the device was high. He acknowledged the issues of variation among
sites in adverse events that prevented reliance and the effect of
learning curve on hysteroscope time.

**PANEL DISCUSSION**

The panel discussed Questions 1 through 8 (Attachment A) in light of the
information presented by the morning's speakers.

**Question 1: Effectiveness of Essure in comparison with other tubal
sterilization methods:** Questions were raised concerning the adequacy
of the time period on which effectiveness data for the device were
based, particularly in light of results from the CREST study showing
that sterilization failure rates not only increase but seem to
accelerate over time. Dr. Blanco pointed out that the device will not be
marketed as being more effective than other sterilization methods but
will be presented to the consumer as having benefits and drawbacks, like
other methods. Dr. Larntz noted that the number of pregnancies, zero,
was as low as it could be, and that Bayesian analysis is highly
appropriate for combining the data from the 2 clinical studies. Ms.
Luckner suggested that the labeling for the patient should include the
information that the device is called a "permanent" method based on only
1 year of data. It was agreed that this is a labeling issue and that the
labeling can change as new information becomes available.

**Question 2: Age characteristics in the Essure pivotal study in
comparison with those in the CREST study:** The panel discussed whether
the data on effectiveness and safety are equally applicable to younger
women, who will have the device in place for many more years than older
women and who may be more fertile. The panel expressed concern that the
procedure is not reversible, and patients must understand that the
device should be regarded as a permanent contraceptive method. It was
suggested that the labeling for the device include a statement for the
physician about the importance of selection and counseling of patients.

**Question 3: Mechanism of action/recanalization:** The panel agreed
that there is limited information on or understanding of the precise
mechanism of action of the device. PET fibers have been used
predominantly in vascular grafts, which are different from the fallopian
tube. The members did not know of an analogous situation in which PET
has been used to occlude an epithelium-lined structure. In regard to
recanalization, it was observed that the purpose of the pre-hysterectomy
study was to look at the device's mechanism of action, not at how
recanalization takes place. The panel agreed that the unique mechanism
of action makes it less likely for recanalization to occur.

**Question 4: Pelvic X-ray in lieu of HSG:** Concern was raised over the
possibility of doing the procedure differently in the commercial setting
compared to the clinical studies. Of specific concern was the use of
X-ray instead of HSG for device location and confirmation of tubal
occlusion. The possibility of using ultrasound for this purpose was
discussed. Dr. Blanco pointed out to the sponsor representatives that
the occlusion results were high because HSG was used for confirmation of
device location and tubal occlusion, but in the commercial setting
pelvic X-ray will be recommended for this purpose instead. He said it
may be unrealistic to expect the same results in the commercial setting
when a different method is used.

Several panel members said that they would like to see data justifying
the switch from HSG to flat plate X-ray for confirmation. This would
require a group of women with the device in place to be checked at 3
months with pelvic X-ray. It was pointed out that because alternative
contraception was not discontinued in women whose tubes were found to be
patent, there is no way of knowing what the pregnancy rate might have
been in those women if they had relied solely on the microinsert for
contraception, especially since it is possible to confirm only device
location, not tubal occlusion, with X-ray.

**Question 5: Placement failure rate:** Dr. Shirk asked how to manage
patients in whom only unilateral placement can be achieved. Dr. Noller
said that among gynecologists who perform only a small number of
hysteroscopic procedures, the placement failure is likely to be higher
than in the clinical studies. He also noted that gynecologists generally
do not perform hysteroscopy on awake patients, but rather use general
anesthesia. He said that women need to be told about a contingency plan
in which laparoscopy will be done if placement cannot be achieved via
hysteroscopy.

Dr. Blanco pointed out that, to some extent, almost all studies of all
devices are done by those with a particular interest in the procedure.
He noted that the sponsor has presented an educational plan to train
anyone who will be performing the placement procedure. This is a
labeling issue, he suggested, in which appropriate counseling and
notification of the patient must be done until more clinical experience
can be gathered, at which time the labeling can be changed to reflect
the data obtained from larger numbers. The panel agreed that direction
to the physician should be built into the labeling concerning how to
deal with failed and unilateral placement. Physicians should be told
what to discuss with the patient in terms of what will happen if the
device is determined to be properly positioned in only one tube.

**Question 6: Safety:** The panel discussed whether the safety profile
is acceptable, particularly in terms of the risk of hypervolemia. Dr.
Shirk said that saline infusion is fairly safe, especially since the
procedure should be done with a small hysteroscope in the range of 5 mm
and it is nearly impossible, even in 30 minutes, to infuse much more
than 2--3 liters through an instrument of this size. The panel agreed
that the labeling should emphasize a cutoff of 1,500 ml of infused
saline to be used during the placement procedure.

**Question 7: Outline of training program:** The panel expressed the
wish for more assurance from the sponsor as to the level of operator
skill that will be achieved in the training program, particularly with
regard to the operator's ability to perform the procedure using local
rather than general anesthesia, which carries greater risks. Dr. Noller
noted that the information in the patient inserts, as well as some of
the comments made by the sponsor representatives, imply that the
procedure will be done with local rather than general anesthesia. He
said that it would be important to ensure in the training program that
the procedure will be done with local anesthesia in the practice
setting. The panel agreed that some hysteroscopic skill should be a
requirement for this procedure.

Also discussed was the question of long-term follow-up and management,
specifically with regard to the avoidance of electrocautery in patients
wearing the microinserts. Given the mobility of the population, the
burden is on the patient to ensure that subsequent physicians are
informed of the presence of the device.

**Question 8: Postmarket surveillance:** The question was raised as to
whether 5 years is an adequate length of time for postmarketing
follow-up. Dr. Brown said that, given the data from the CREST study, she
would like to see a longer time to determine whether the device will
show the accelerated failure rate seen with other sterilization methods.
To clarify this issue, Ms. Costello reviewed the slide from her
presentation showing the cumulative probability of pregnancy after
sterilization. She said that the rate of annual pregnancies in 4--10
years was the same as that in 1--3 years after sterilization, which is a
cumulative and additive, not an accelerated, effect.

**Additional Comments from Panel**

Dr. Blanco asked the panel members whether they had any further issues
or questions to be mentioned or included. It was observed that it would
be desirable to know what the failure rate of the device is in actual
practice. Although women with the device will be followed, it was
suggested that data be included on the placement failure rate in actual
clinical practice. It was also suggested that a registry of users be
maintained to track age and ethnicity and to collect failure rates as
they occur.

The panel agreed that the issue of placement in younger women (e.g.,
mid-20s) needs to be addressed in regard to future desired pregnancies
and the feasibility of IVF. It is important that nothing in the labeling
implies that the procedure is anything other than permanent.

**Simulator Demonstration**

The placement simulator that will be used in the training program was
demonstrated to the panelists, with the view through the hysteroscope
projected on a screen. The simulator includes different types of models
of the uterus to simulate the different types that would be encountered
in clinical practice.

**OPEN PUBLIC HEARING**

**Amy Pollack, M.D., M.P.H.**

**President, Engender Health**

Dr. Pollack informed the panel that she is an obstetrician-gynecologist
in the field of public health. Engender Health is a nonprofit
organization that provides family planning and reproductive health
services in the United States to women and men.

Dr. Pollack noted that clinical experience shows bilateral tubal
sterilization to be safe and effective. About half of the 700,000 female
sterilization procedures performed annually in the United States are
interval laparoscopic procedures. About 250,000 women choose procedures
that involve abdominal surgery with its attendant risks, which are not
statistically related to the method of tubal occlusion but to the
necessity of entering the abdominal cavity.

Female sterilization, said Dr. Pollack, is most often performed using
local rather than general anesthesia, both in the United States and in
other countries. In the United States, these procedures are done almost
exclusively with short-acting agents because of the risks associated
with general anesthesia. She emphasized to the panel the attendant risks
of these procedures, despite which hundreds of thousands of women choose
permanent sterilization. Dr. Pollack said that women choose permanent
sterilization because they recognize the risks of temporary, reversible
contraceptive methods. The side effects of these methods, she said,
mandate the need for a transcervical option. She said that if there is a
transcervical method of permanent sterilization that has been well
tested, is shown to be highly effective and noninvasive, and does not
require general anesthesia, then American women should have access to
it.

In closing, Dr. Pollack said that, given the questions raised today, the
developers of the device under consideration must be rigorous in their
postmarketing surveillance. This option, she said, is one that is
desperately needed particularly by low-income women living in areas of
limited resources.

**Amy Allina**

**Program Director, National Women's Health Network**

Ms. Allina informed the panel that the National Women's Health Network
advocates for policies that promote women's health and evidence-based
health care and practices. She suggested the following additions to the
proposed patient information booklet to be distributed to patients using
the Essure device:

• Information about how the effectiveness of the device may change over
time and how the effectiveness of the device was tested, including the
number of women and the number who became pregnant

• The statement that some women will not be able to have the device
successfully placed and some of the conditions that may preclude
placement, such as uterine polyps and endometriosis

• In the warnings section, greater detail on the unknown risks of
uterine procedures using electrical energy

• Language about IVF and the reversibility of the procedure in
accordance with the panel's prior discussion in this area

• That the effects on pregnancy and the fetus are unknown

• The statement that X-rays to confirm device placement and tubal
occlusion may be preferable to HSG, but there is not enough information
to determine this at present

In closing, Ms. Allina said that, in light of the need for expanded
contraceptive choices and for increasing the safety of permanent
sterilization, her organization supports the approval of the Essure
system, which has the potential to advance women's health.

**Wayne Shields**

**President and CEO, Association of Reproductive Health Professionals**

Mr. Shields told the panel that the Association of Reproductive Health
Professionals (ARHP) represents about 2,400 health care providers who
are directly involved in the practice of women's health and reproductive
health. He said that ARHP places a strong emphasis on education,
provider training, and patient counseling as the most important
components of safe and effective contraceptive health care. ARHP
supports the availability of as many safe and effective contraceptive
options as possible and is pleased at the potential for the new option
that Essure represents. Mr. Shields thanked the panel for the
opportunity to comment and expressed his hope that the application would
be favorably considered.

**Additional Comments from Cindy Domecus**

Ms. Domecus thanked the panel for the opportunity to clarify a few
points raised during their discussion.

First, in the matter of using HSG versus X-ray for confirmation of
device location and tubal occlusion, Ms. Domecus said that X-ray would
be recommended as a first step, with suspicious findings proceeding to
HSG. All unsatisfactory locations of the device, she said, could be
detected by X-ray alone. Concerning the determination of patency, she
said that the tubal patency rate does not equal the pregnancy rate in
tubal ligations, and that therefore failure of occlusion is not
equivalent to failure of sterilization. She pointed out that with the
Essure device, the tissue response was occlusive in nature and that
changes in the tubal architecture was also seen.

Second, in the matter of training, Ms. Domecus informed the panel that
five procedures is expected to be the average, not the minimum. Trainees
will not be signed off until they have demonstrated competency in the
placement technique. In regard to concerns about the generalizability of
placement success, Ms. Domecus said that using an average of four
procedures per physician, success rates are achieved that are very close
to those in the trials. Among the placement failures evaluated by HSG,
83% were due to proximal tubal occlusion.

Third, the suggestion of tracking patients who wear the device has been
considered, said Ms. Domecus. A card or ID to be carried by the patient
is proposed in the PMA.

Fourth, concerning unilateral placement of a device, Ms. Domecus said
that in the study protocol patients were allowed to return after HSG for
another attempt at bilateral placement. Many patients opted to do this
and were successful. The protocol, she said, will include this
recommendation for unilateral placement at the first visit.

Fifth, Ms. Domecus told the panel that language about the safety and
effectiveness of the device is present in the patient information
brochure, as is the lack of data on reversibility. Language to this
effect is included in the patient insert and the physician guide.

Finally, Ms. Domecus assured the panel that labeling information would
be updated as soon as new data warranted a change, rather than waiting
for 5 years until the end of the postmarket surveillance study.

**PANEL DELIBERATIONS AND VOTE**

Dr. Blanco read aloud to the panel the options for premarket approval
applications. A motion was made and seconded to approve the Essure
device without conditions. The motion failed with one vote for, seven
votes against, and one abstention.

Dr. Blanco asked for a motion to not approve the Essure device. No
motion was made.

A motion was made and seconded for approval of the Essure device with
the following conditions:

**1.** HSG for confirmation of device location and tubal occlusion will
be required after placement of the device, as was performed in the
original study. The FDA would be amenable to evaluating further data on
alternative methodologies for correct device placement and tubal
patency.

**2.** The training program for placement of the Essure device shall
include knowledge of hysteroscopy as a prerequisite to performing the
placement procedure.

**3.** Changes in the labeling shall include the following:

• Clarified and more prominent information on the placement failure rate

• Information about the correlation between patient age and changing her
mind; emphasis in patient labeling about irreversibility of procedure

• Warnings about metal allergy, electrocautery, and pregnancy occurring
while the device is in place

• The recommended maximum duration of the placement procedure and limit
of 1,500 ml of saline

• Clarification of the 99.8% success rate, including the numbers of
patents

• A recommendation that the placement procedure be performed during the
proliferative phase

• An example of educational written informed consent to provide to
physicians

• Recommendations on what patients should do in the event of a missed
period; risk of ectopic pregnancy

• Information on a contingency plan in the event that one or both
devices cannot be satisfactorily placed

• Training requirements as stated previously (item 2)

• Continuation of observation of current patients for 5 years

• Better assessment of failed insertion rates for patient counseling and
labeling

The motion to approve the Essure system with these conditions was
carried by a vote of eight in favor, none against, and one abstention.

**ADJOURNMENT**

Dr. Blanco complimented the presenters on what he called the best
presentation he had seen in 8 years of serving on the panel. He also
commended the audience for their participation and comments and the FDA
staff for their hard work.

The meeting was adjourned at 5:25 p.m.

######### [Attachment A: Discussion Questions]{.underline}

[Effectiveness]{.underline}

1.  The results for the single-arm clinical trials featuring bilateral
    placement of the current (gamma) version of the Essure Micro‑insert
    are provided below. How does the effectiveness of the Essure
    Micro-insert compare to other available methods for female tubal
    sterilization?

+--------------------------+-------+----------+----------------------+
|                          | n     | number   | Bayesian estimate of |
|                          | umber | pre      | pregnancy rate,      |
|                          | pat   | gnancies |                      |
|                          | ients |          | 95% confidence       |
|                          |       |          | interval^1^          |
+--------------------------+-------+----------+----------------------+
| Primary Endpoint:        |       |          |                      |
| pregnancy at 1 year PAC  |       |          |                      |
| (post-alternate          |       |          |                      |
| contraception)           |       |          |                      |
+--------------------------+-------+----------+----------------------+
| Pivotal Trial            | 408   | 0^2^     | 0% (0, 0.69%)        |
+--------------------------+-------+----------+----------------------+
| Phase II Trial           | 194   | 0        | 0% (0, 1.53%)        |
+--------------------------+-------+----------+----------------------+
| Combined                 | 602   | 0        | 0% (0, 0.48%)^3^     |
+--------------------------+-------+----------+----------------------+
| Secondary Endpoint:      |       |          |                      |
| pregnancy at 2 year PAC  |       |          |                      |
+--------------------------+-------+----------+----------------------+
| Phase II Trial^4^        | 149   | 0        | 0% (0, 1.65%)        |
+--------------------------+-------+----------+----------------------+

> *^1^ The Bayesian estimate given is the posterior mode (analogous to
> the maximum likelihood estimate in a non-Bayesian statistical
> analysis); confidence interval is Bayesian higher posterior density
> (HPD) interval (analogous to a 95% confidence interval in a
> non-Bayesian analysis)*
>
> *^2^ 4 luteal phase pregnancies*
>
> *^3^ does not adjust for the older age distribution in the Phase II
> study*
>
> *^4^ 1 pregnancy with discontinued ("beta") version of device*

2.  The ages of the women in the pivotal study trial ranged from 21 to
    40, with median age 32. The age distributions in the Pivotal Trial
    and in the CREST study (Peterson et al., *Am J Obstet Gynecol* 1996;
    174:1161-70) are given below. Are these age characteristics
    appropriate for a study of this type?

  -------------- ----------------- ------- --------------- ----------------
  Pivotal Trial                            CREST study     

  age range      \% of population          age range       \% of population

  21-27          17%                       18-27           33%

  28-33          47%                       28-33           35%

  34-40          36%                       34-44           32%
  -------------- ----------------- ------- --------------- ----------------

3.  The PMA presents results from a pre-hysterectomy \'proof of
    concept\' study (n=52) where fallopian tube specimens were examined
    histologically 24 hours to 14-plus weeks following device placement.

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a.  What do the results of this study indicate about the mechanism of
    action of the Essure device?

b.  Can results from this study shed any light on the likelihood of
    tubal recanalization in a long-term setting?

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4.  In the three months following device placement, the patient is
    instructed to stay on alternate contraception to allow for
    sufficient tissue in-growth to produce tubal occlusion.

> In the Pivotal Study, an HSG confirming correct device placement and
> tubal occlusion was needed before the patient stopped alternate
> contraception. The Pivotal Study showed that the rate of bilateral
> occlusion was 96% of the number of correctly placed devices.
>
> The Sponsor is proposing that in commercial use, alternate
> contraception can be stopped 3-months post-placement if a *pelvic
> x-ray* (i.e. not an HSG) confirms position of the device.
>
> In view of the potential for placement to overrepresent occlusion, as
> well as the potential for incorrect interpretation of pelvic x-ray, is
> the sponsor's proposal adequate?

5.  There was a 12% failure rate of bilateral placement on the first
    attempt.

    a.  Do the failure rates experienced by the investigators in this
        study provide an adequate indication of the failure rate that
        might occur when this device is in wider use?

    b.  Is this failure rate acceptable?

[Safety]{.underline}

6.  The authors of the CREST study (Peterson et al., *Am J Obstet
    Gynecol* 1996; 174:1161-70) noted that sterilization "failure
    rates...should not be considered in isolation but rather in
    conjunction with safety and acceptability of the \[female
    sterilization\] procedures evaluated." The following are known risks
    of the Essure System placement:

-   Tubal perforation

-   Hypervolemia (due to high volumes of distention fluid over a short
    time)

-   Vaso-vagal response

-   Discomfort

-   Bleeding/spotting

> Potential risks, not observed in the study, include sterilization
> failure, ectopic pregnancy and infection.
>
> Given the advantages of the Essure System procedure (e.g. less
> anesthesia; avoidance of abdominal incision; patient satisfaction and
> comfort), is the safety profile of this device acceptable?

## Labeling & Training

7.  For the pivotal study, the training program for investigators
    included:

-   Didactic materials

-   Practice on a hysteroscopic simulator

-   Device placement in peri-hysterectomy patients

-   Interpretation of device placement by hysteroscopy, HSG and pelvic
    x-ray

-   Proctoring of initial device placements in sterilization patients by
    experienced personnel

> The sponsor is proposing to delete the requirement for placement in
> peri-hysterectomy patients, and to train investigators using a
> hysteroscopic model. The proposed Physician Training Program also
> includes proctoring of an unspecified number of "initial procedures"
> by a Conceptus-designated preceptor. Is this Training Program
> adequate?

[Post-approval Studies]{.underline}

8.  An important finding from the longitudinal CREST study (Peterson et
    al., *Am J Obstet Gynecol* 1996; 174:1161-70) was that the risk of
    sterilization failure persists for years after the procedure (and
    varies by method of tubal occlusion and patient age).

> At present, only one- and two-year contraceptive efficacy data are
> available for the Essure System. Conceptus does plan to follow all
> Phase II and Pivotal Study subjects out to five years post-device
> placement.
>
> Is five-years an adequate time-frame for post-marketing follow-up for
> this device? Does the panel have recommendations about how to minimize
> loss-to-follow-up? Are other elements of a post-approval study needed?

I certify that I attended the Open Session of the Obstetrics and
Gynecology Devices Advisory Panel Meeting on July 22, 2002, 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

Deborah J. Shuman

9100 Providence Avenue

Silver Spring, MD 20901

301-589-9366