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
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
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
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
Effectiveness
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?
|
|
number patients |
number pregnancies |
Bayesian estimate of pregnancy rate, 95% confidence interval1 |
|
Primary
Endpoint: pregnancy at 1 year PAC
(post-alternate contraception) |
|||
|
Pivotal Trial |
408 |
02 |
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 Trial4 |
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.
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?
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
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:
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?
7. For
the pivotal study, the training program for investigators included:
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
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