FOOD AND DRUG ADMINISTRATION

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

OBSTETRICS AND GYNECOLOGY DEVICES PANEL

Monday,

July 22, 2002

Plaza Ballroom I and II

DoubleTree Hotel

1750 Rockville Pike

Rockville, Maryland

IN ATTENDANCE:

Jorge D. Blanco, M.D., (Chair)

Regional Perinatal Center

Odessa Regional Hospital

Odessa, TX

Carol L. Brown, M.D.

Weill-Cornell Medical College

Memorial Sloan-Kettering Cancer Center

New York, NY

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

Department of Obstetrics and Gynecology

George Washington University Medical Center

Washington, D.C.

Kinley Larntz, Ph.D.

School of Statistics

University of Minnesota

Scottsdale, AZ

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

(Consumer Representative)

Women\'s Ambulatory Health

The Toledo Hospital

Toledo, OH

Mary Lou Mooney, R.A.C.

(Industry Representative)

SenoRx, Inc.

Aliso Viejo, CA

Kenneth L. Noller, M.D.

Department of Obstetrics and Gynecology

Tufts University Medical School

Boston, MA

Mary Jo O\'Sullivan, M.D.

Department of Obstetrics and Gynecology

University of Miami/Jackson Memorial Hospital, Hoetz Center

Miami, FL

Subir Roy, M.D.

Department of Obstetrics and Gynecology

USC School of Medicine

Los Angeles, CA

IN ATTENDANCE:

David B. Seifer, M.D.

Division of Reproductive Endocrinology and Infertility

University of Medicine and Dentistry of New Jersey

New Brunswick, NJ

Nancy C. Sharts-Hopko, Ph.D.

College of Nursing

Villanova University

Villanova, PA

Gerald J. Shirk, M.D.

OB/GYN Associates

Cedar Rapids, IA

[C O N T E N T S]{.underline}

PAGE

Call to Order

Jorge D. Blanco, M.D.

Panel Chair 7

Panel Member Introductions 7

Appointment of Temporary Voting Members

and Conflict of Interest Statement

Joyce M. Whang, Ph.D.

Panel Executive Secretary 9

Introductory Remarks

Colin Pollard

Chief, Obstetrics and Gynecology Devices Branch 12

Medical Device Postmarket Surveillance:

Vacuum-Assisted Delivery Devices

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

Office of Surveillance and Biometrics 14

Barry S. Schifrin, M.D.

Glendale Adventist Medical Center, California 18

Questions and Answers 27

Open Public Hearing

Gabriella Avina, R.N.

Martinez, California 32

Caroline Costello

Division of Reproductive Health

Centers for Disease Control and Prevention 35

[C O N T E N T S]{.underline}

PAGE

Conceptus Essure Micro-Insert System (PO20014)

Presentation by Sponsor Conceptus

Cindy Domecus

Senior Vice President, Clinical Research

and Regulatory Affairs 46, 56, 68

Jay Cooper, M.D.

Principal U.S. Investigator

Founder and Medical Director, Women\'s Health

Research, and Clinical Assistant Professor,

University of Arizona 50

Thomas Wright, M.D.

Study Histopathologist

Associate Professor of Pathology and Director,

Division of OB/GYN Pathology

Columbia University 57

Charles S. Carignan, M.D.

Vice President, Clinical Research

and Medical Affairs 61

Questions and Answers 76

Presentation by FDA

Lisa D. Lawrence, R.N.

Lead Reviewer 105

Julia A. Corrado, M.D.

Medical Officer 110

Gene A. Pennello, Ph.D.

Statistician 126

Questions and Answers 139

[C O N T E N T S]{.underline}

PAGE

Continued Questions and Answers of Sponsor 141

Panel Discussion 144

Simulator Demonstration by Sponsor

Sandy Mayer

Director of Professional Education and

Don Gurskis

Manager of Professional Education 224

Open Public Hearing

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

President

Engender Health 244

Amy Allina

Program Director

National Women\'s Health Network 247

Wayne Shields

President and CEO

Association of Reproductive Health Professionals 253

Panel Deliberations and Vote 263

[P R O C E E D I N G S]{.underline} (8:40 a.m.)

DR. BLANCO: Good morning. I\'d like to go ahead and call the 66th
meeting of the Obstetrics and Gynecology Devices Panel to order this
morning and would like to take care of a little business issues first,
if we could. Just would like to remind everyone that there\'s sign-in
sheets outside the door, if you would please sign in with your name and
your affiliation, so that we have a record of everyone that was here.

I always like to remind, and I\'m reminded to remind the audience, that
we don\'t really want any outbursts from the audience. Please, when
it\'s the time for audience comments, we will recognize you. You can
come to the mike to speak. At the time that you do, please make sure to
state your name, any relationship that you may have with any company
bringing business before this committee, any conflict of interest
disclosure, including any travel per diem or any other relationship with
the company.

At this point, I\'d like for the panel members to introduce themselves
as we go around the table, if we\'ll go ahead and start on this side.

MS. MOONEY: Mary Lou Mooney. I\'m the vice president of clinical,
regulatory, and quality for SenoRx. I\'m the industry representative to
the panel.

MS. LUCKNER: Kleia Luckner, Toledo, Ohio. I\'m the clinical
administrator for women\'s ambulatory, and I\'m the consumer rep.

DR. NOLLER: Ken Noller, Boston, Massachusetts. I\'m an
obstetrician/gynecologist, panel member.

DR. DUBEY: Anil Dubey from George Washington University, embryologist,
new to the panel.

DR. SEIFER: David Seifer, reproductive endocrinologist. I\'m a panel
member. New Brunswick, New Jersey.

DR. WHANG: I\'m Joyce Whang. I\'m the executive secretary of this panel.

DR. BLANCO: I\'m Jorge, George, Blanco. I\'m a perinatologist from
Texas.

DR. BROWN: I\'m Carol Brown. I\'m a gynecological oncologist from New
York City, New York.

DR. SHARTS-HOPKO: I\'m Nancy Sharts-Hopko, professor in women\'s health,
College of Nursing, Villanova University, near Philadelphia.

DR. O\'SULLIVAN: Mary Jo O\'Sullivan, University of Miami, panel member,
OB/GYN.

DR. ROY: Subir Roy, reproductive endocrinologist, University of Southern
California.

DR. LARNTZ: Kinley Larntz. I\'m a professor emeritus of statistics,
University of Minnesota, and I work as an independent statistical
consultant.

DR. SHIRK: Dr. Gerry Shirk. I\'m in clinical practice in Cedar Rapids,
Iowa, and a clinical associate professor at the University of Iowa.

MS. BROGDON: I\'m Nancy Brogdon. I\'m the division director for the
Division of Reproductive, Abdominal, and Radiological Devices, FDA.

DR. BLANCO: Thank you.

The next issue is introducing the FDA press contact, Sharon Snider. If
you would please stand? Is she here?

MS. BROGDON: I don\'t believe she\'s here yet.

DR. BLANCO: Okay. Well, she will be here and she is your press contact.

All right. Let me go ahead and turn over the meeting to Dr. Whang for a
few other items of housekeeping.

DR. WHANG: Good morning.

The next scheduled meeting of this Obstetrics and Gynecology Devices
Panel is for October 21st and 22nd of this year.

Today, we have five temporary voting members, Dr. Anil Dubey, Dr. Kinley
Larntz, Dr. Kenneth Noller, Dr. Subir Roy, and Dr. Gerald Shirk.

\"Pursuant to the authority granted under the Medical Devices Advisory
Committee Charter, dated October 27th, 1990, and amended August 18th,
1999, I appoint the following individuals as voting members of the
Obstetrics and Gynecology Devices Panel for this meeting on July 22nd,
2002: Anil K. Dubey, Ph.D., H.C., Kinley Larntz, Ph.D., Kenneth L.
Noller, M.D., Subir Roy, M.D., Gerald J. Shirk, M.D. For the record,
these people are special government employees and are consultants to
this panel. They have undergone the customary conflict of interest
review and they have reviewed the material to be considered at this
meeting,\" and this is signed by David W. Feigal, Jr., M.D., M.P.H, the
Director of the Center for Devices and Radiological Health.

I will now read the conflict of interest statement for this meeting.
\"The following announcement addresses conflict of interest issues
associated with this meeting and is made a part of the record to
preclude even the appearance of an impropriety.

\"To determine if any conflict existed, the agency reviewed the
submitted agenda and all financial interests reported by the committee
participants. The conflict of interest statutes prohibit special
government employees from participating in matters that could affect
their or their employers\' financial interests. However, the agency has
determined that participation of certain members and consultants and the
need for their services outweighs the potential conflict of interest
involved and is in the best interests of the government.

\"Therefore, a waiver has been granted for Dr. Kinley Larntz for his
interests in a firm that could potentially be affected by the panel\'s
recommendations. The waiver allowing him to participate fully in
today\'s deliberations involves his unrelated consulting services with
the parent of a competing firm. He receives fees that range between
\$10,001 and \$50,000 a year. Copies of this waiver may be obtained from
the agency\'s Freedom of Information Office, Room 12A-15 of the Parklawn
Building.

\"In the event that the discussions involve any other products or firms
not already on the agenda for which an FDA participant has a financial
interest, the participant should excuse his or herself from such
involvement and the exclusion will be noted for the record.

\"With respect to all participants, we ask in the interest of fairness
that all persons making statements or presentations disclose any current
or previous financial involvement with any firm whose products they may
wish to comment upon.\"

Today\'s transcripts are being taken by Friedman & Associates. They\'re
in Rockville, Maryland, at (301) 881-8132, and today\'s meeting is being
videotaped by FDA Live. They\'re in Rockville, Maryland. They can be
reached at (301) 984-0001.

Thank you.

DR. BLANCO: Thank you.

Moving right along, I\'d like to introduce Mr. Colin Pollard, chief of
the Obstetrics and Gynecology Devices Branch, who will make some
introductory statements.

Colin?

MR. POLLARD: Thank you, Dr. Blanco.

I just have a couple of brief comments. So first of all, I just wanted
to welcome all of you to our panel meeting today. I know several of you
had to come from very far and all of you are taking time from very busy
schedules to provide us with important input.

I, first of all, just wanted to announce that we have issued a Level 1
Guidance Document for Adhesion Barrier Devices. This is the culmination
of a panel meeting that we had about two years ago. This guidance
incorporates comments from the industry and clinical community and
represents a joint collaboration with another division in our Office of
Device Evaluation for these kinds of products, and we hope that it will
further provide help to people developing products in this important
area.

I\'d like to next turn to the first agenda item. You may or may not
remember that in May of 1998, FDA issued a Public Health Advisory on
Vacuum-Assisted Deliveries and the devices used for them, essentially
sharing information that came out of our Mandatory Device Reporting
System, and since that and, of course, that advisory itself generated a
lot of interest and activity and comments and concerns about these kinds
of devices, and since that point, our Office of Surveillance and
Biometrics has done continued work in that area and the Office of
Surveillance and Biometrics has taken the initiative to apprise the
panel and apprise us, of course, on the results from that, and this
represents an effort on their part to engage with all of the different
advisory panels to show and to illustrate some of the things the agency
is doing in the area of postmarket following various devices.

This is essentially an informational presentation just to let you know
what\'s going on. I think certainly at Dr. Blanco\'s discretion, he\'ll
entertain a few questions, but essentially it\'s just to let you know
what\'s going on in this area. So with that, I\'d like to introduce
Danica Marinac-Dabic, who will begin the presentation.

Thank you.

DR. BLANCO: All right. Thank you, Colin.

While we\'re waiting for Dr. Dabic, just wanted to remind everyone that
we will try to keep on time. So make sure all the speakers that are
coming, that you do stay on time. We\'d like to be on time.

Welcome.

DR. MARINAC-DABIC: Good morning.

My name is Danica Marinac-Dabic. I work for the Epidemiology Branch of
the Office of Surveillance and Biometrics here at CDRH. Dr. Barry
Schifrin and I would like to thank you for the opportunity to be able to
present this morning an update on the CDRH postmarket activities in the
area of vacuum-assisted delivery devices.

As an introduction to Dr. Schifrin\'s talk, I would like first to give
you a brief background information on the events leading to the 1998
Public Health Advisory as well as an update on the number of the reports
received by the agency in the years following the advisory. After that,
as the main part of today\'s presentation, Dr. Schifrin as the principal
investigator will give you results of the Phase 1 of the FDA-sponsored
study titled \"Adverse Outcomes Associated With Vacuum-Assisted
Deliveries.\"

The number of reports received by the FDA related to vacuum-assisted
delivery devices began to increase in years 1993 and 1994. As you can
see prior to that, on average, we received one report per year. The
total number of reports that the Public Health Advisory was based on is
30, and as you can see, the distribution, the year distribution was
presented in this slide. This is essentially the same number of reports,
the same time period, the same database. It just presents a distribution
of events and serious injuries and you can see there, particularly in
the period from 1994 to 1997, we see the increased number of death
reports associated with vacuum.

Major types of complications reported to us were subgaleal hemorrhage,
cephalhematoma, and intracranial hemorrhage. The information that we
were able to obtain from those adverse event reports were very limited.
In addition to the number of deaths and injuries that were reported and
also the types of complications, we were able to see that all major
vacuum-assisted delivery devices manufacturers were represented as well
as all vacuum types. However, the most critical information was
sometimes missing from those reports and particularly the patterns of
use of vacuum, including number of events or duration of vacuum
application. Also, the clinical environment data were missing, including
the fetal and maternal condition and timing of injuries.

I think it\'s important to put the data that we have received into the
perspective, and I would like to just give this table to you as a
national data that we were able to obtain prior to the Public Health
Advisory that was published in 1997, the National Vital Statistics
Report, reflecting the data from the 1995 and we can see that at that
year, 5.9 percent of total deliveries occurred with the assistance of
the vacuum. One can also notice a dramatic increase in the use of vacuum
from year 1989 when only 3.5 percent of all deliveries was completed
with the assistance of the vacuum extraction.

Of course, there were numerous possible reasons for increased number of
reports and some of them are listed on this slide. First one that I\'d
like to point out is increasing vacuum use, as documented by the
national data, also the second possible reason would be the change in
the reporting requirement, namely the introduction of the User Facility
Reports that overlapped with the year when we began to notice an
increased number of the reports. Also potential underreporting in
previous years was also possible reason as well as the increased
incidence rate of adverse events.

CDRH convened an ad hoc committee of experts to look into this issue and
provide recommendation. On this slide, we have listed some of the
activities that the committee undertook, including the adverse events
reports review, followed by the extensive literature and labeling
review, dialogue with manufacturers, and also dialogue with clinical
users. We performed three user facility investigations at that time and
consulted with professional organizations, including ACOG, American
College of Nurse-Midwives, American Academy of Pediatrics, and finally,
after internal and external review, the Public Health Advisory was
issued on May 21st, 1998, and it was titled \"Need for CAUTION When
Using Vacuum-Assisted Delivery Devices.\"

The purpose of the Public Health Advisory was to advise medical
community that vacuum may cause serious or fatal complications and also
to provide guidance on how to minimize the risk. It provided detailed
recommendations. They were meant for both obstetrical and neonatal
community and stated here that only trained professionals should be
using the vacuum, also to be aware of indications, contraindications and
precautions, always read the instructions, and, what\'s very important,
to alarm the neonatal care community that device was used so they can
look for the specific signs and symptoms for complications, of
complications, and of course report this to the FDA, and these are some
of the post-advisory activities ongoing here at the Center of Devices
and Radiological Health. Of course, the review of the adverse event
reports continues and as Colin Pollard just said, the FDA also sponsored
the study titled \"Adverse Outcomes Associated with Vacuum-Assisted
Delivery Devices.\"

This is just a brief update on the number of reports that we have
received. As you can see in the year following the Public Health
Advisory, 1998, there was a peak of the reports and then the number
declines. The last data that we have ended with the end of month of June
this year. All together, we have received 170 reports, 26 of them were
deaths and 144 of serious injuries. Nationally, we can see the increase
of the vacuum continues. The number for the 1998 is 6 percent of total
deliveries.

With this, I\'d like to turn the podium over to Dr. Schifrin, who will
present the Phase 1 of our joint study. He was the principal
investigator for this. The analysis of the second phase is underway. So
you\'ll be able to see only the results of the first phase today.

Thank you very much.

DR. BLANCO: Thank you very much.

DR. SCHIFRIN: My name is Barry Schifrin. I\'m an obstetrician
perinatologist. I\'m professor of obstetrics and gynecology at Loma
Linda, and I\'m director of the Residency Program at Glendale Adventist
Medical Center in Glendale, California, and I want to thank the FDA for
the opportunity to begin and undertake this study and it was as
informative and to me provided great revelations, notwithstanding the
fact that I had thought I had some familiarity with the subject.

DR. BLANCO: Excuse me, Dr. Schifrin.

Just for the record, any conflict of interest?

DR. SCHIFRIN: No, no. No conflict.

DR. BLANCO: Sorry. Thank you.

DR. SCHIFRIN: No conflict.

The primary focus of the study was to look at the other apparatus and
not only the vacuum apparatus itself but essentially the decisionmaking
apparatus surrounding the use of the vacuum device, and for this
purpose, as suggested by Danica Marinac, we needed to know something
about the condition of the baby, the setting, the circumstances of
labor, and the number of factors about the previous history, about the
physical attributes and presentation of the fetus to be able to make
sense out of the use patterns of the vacuum.

The other issue and perhaps drawback of the advisory was the implicit
notion that all of the adverse outcomes associated with vacuum
deliveries were in fact related to the vacuum itself, and the fact is
that a number of the babies who had ischemic injuries, it is obvious
that those could occur at any time. We could understand that traumatic
injuries related to adverse outcome might certainly be related to the
delivery and this seemingly characteristic hemorrhagic phenomenon called
the subgaleal was almost certainly related to the vacuum itself, and
while it is reasonable, also, to attribute intracranial hemorrhage to
the vacuum and forceps, the fact is, as you\'ll see, the most frequent
kind of neurologic injury associated with the vacuum is hypoxic-ischemic
encephalopathy and not the subgaleal hemorrhage, the intracranial
hemorrhage, or even the traumatic hemorrhage.

The cases, and there were 203, and they derived from malpractice cases,
peer-review, referrals. They come from many sources, hospital sizes, and
they clearly represent the group of patients at increased risk of
adverse outcome. They were attended in the vast majority of them by
board-certified obstetricians and a small group by obstetrical
residents, midwives and others who are multiple providers.

The important emphasis here is that these patients were not selected.
They were selected clearly because they had a vacuum, but it was not the
vacuum necessarily that brought the patient to attention, and we studied
these 203 patients, looking at numerous obstetrical and neonatal factors
related not only to the delivery itself but those factors related to the
process, to the decisionmaking apparatus, and, as we\'ll see just
briefly, in terms of physician behavior.

I will share with you, now that you have copies of all of these data in
the handout, the majority of the patients were nulligravida,
nulliparita. They had no previous vaginal delivery and almost half of
them were high-risk by one of the rather loose definition. You can see
the incidence of the various other problems which would confer risk on
the patient population.

You can see that as part of the actual delivery itself, that forceps
were used in 8 percent, vacuum ‑‑ I\'m sorry ‑‑ forceps, more than one
application of forceps, more than ‑‑ that should be two applications of
the vacuum were applied in 50 percent of them. That is a rather high
number. There were 4 percent of the patients had ruptured uterus and
almost 25 percent of the patients was a shoulder dystocia encountered,
an extraordinary incidence. A normal expected incidence of shoulder
dystocia associated with vacuum might be anywhere from 5 to 10 percent.

The features of labor that the majority of patients were in fact in
spontaneous labor, but a considerable percentage were in fact induced.
More than half had epidural anesthesia and almost 40 percent of them had
a prolonged second stage of labor. The indications by parity, this is
para zero, are those who had no previous vaginal delivery, para 1, those
who had previous delivery whether vaginal or not, and then there\'s all
cases, and I emphasize to you that these numbers add up to more than 100
percent because very many of them, there were multiple \"indications\"
for use of the procedure.

We believe it is a test of the quality of obstetrical care that the
number of emergency panic deliveries that are required is in fact a test
of the quality of obstetrical care that is being delivered. The Hail
Mary pass may be good theater but it is not good football. Emergency
deliveries may certainly be necessary but it\'s hard to relate it to
good obstetrics.

One of the features and rather curious features is that one gets the
notion that many of these deliveries, they are trying to facilitate or
speed up the delivery, and under normal circumstances having the patient
begin pushing before she is fully dilated, before the cervix is fully
out of the way, is probably not a very productive practice. Fundal
pressure. This applies to the use of manual pressure on the uterus to
help to get the baby stationed. This is not in response to the shoulder
dystocia but this simply an attempt to help with the vacuum delivery,
and the number and frequency of these maneuvers speaks for attempts at
intervention.

These two slides in your handout are the same. They just present one as
tabular, one as graphic, and what you see here is the route, the
ultimate route of delivery. It is necessary to remember that all of
these patients had vacuum as almost invariably the first attempt to get
the baby delivered, and you can see that, depending upon which group, in
all cases, only about 60 percent at max of the patients were actually
delivered by the vacuum. I share with you that a normal failure rate is
about 5 percent. That is 5, perhaps 6 to 7, percent, and the
conventional literature suggest that. In this case, it was at least 40
percent or more, depending upon the group.

In terms of the neonatal outcome, you can see that the majority of the
babies had low Apgars, certainly at one minute, a third of them had low
Apgars at five minutes, 25 percent or thereabouts were large, greater
than 4,000, more than almost two-thirds of the babies required admission
to the neonatal intensive care unit, and maybe 4 percent or thereabouts
required extensive resuscitation.

In terms of the neonatal complications, they\'re listed for you here.
The item of interest with regard to the vacuum was the appearance of
more than half had cephalhematoma and more than half required a neonatal
length of stay more than two days.

In terms of the radiologic findings, you can see that about 15 percent
of the population had subgaleal hemorrhage but that the most frequent
injury in this group was the injury associated with ischemic brain
injury. About a little more than a quarter had bleed with or without
some of these co-existed, of course, but far and away, the most common
cause of the injury was ischemic and not obviously traumatic or
hemorrhagic.

In terms of the long-term outcome, there was three stillbirths. There
were 10 neonatal deaths, two later deaths. There were 12 fractures, 20
permanent Erb\'s palsy, which represented about 40 percent of the babies
who had shoulder dystocia, and 126 or 62 percent of the babies had
cerebral palsy, in great measure explained by the providence of the
cases, and this illustrates when the timing, going to use the fetal
monitor in an attempt to time the ischemic event, and you can see that
the vast majority or not the vast majority but certainly about half of
the patients are in fact injured. The babies are injured during the
second stage prior to the application of the vacuum.

I share with you this tracing, and for those of you not familiar with
the tracing, I will try simply to deal with the major points that I\'m
trying to emphasize in this case, and it will illustrate very briefly
how we use the monitor, the fetal monitor, to make the diagnosis of
injury.

If you focus only on the red, you can see that the mother is having
frequent contractions. Those contractions are about a minute and a half
apart. So I think it\'s about 15 minutes across that slide, and the red
arrow represents pushing with contractions, and you can see with each
effort of pushing, there is a deceleration in the heart rate. The
horizontal red line is the baby\'s baseline which it has had for its
entire labor and the first two hours of the second stage in this labor,
and I call your attention now to the green arrow which is what has
happened to the baseline as the baby develops greater and greater
stress, the decelerations become longer. There are periods of time just
before the red vertical arrow where there is no baseline between the
contractions. The baby is obviously deteriorating under these
circumstances and notice that the relentless pushing is maintained
despite the deterioration of the fetal condition.

Here, you see on the left the two arrows associated with pushing and now
for the next four contractions there are no decelerations and you have a
high flat heart rate pattern with no variability. I believe that is the
diagnosis of neurologic injury. At the end of this slide, at the right
edge of this slide, they apply a vacuum which creates the beginning of
that bradycardia. They take the vacuum off and apply the forceps. They
take the forceps off and apply the vacuum. They take the vacuum off,
apply the forceps. They discontinue the forceps. The baby\'s in the
middle of this profound bradycardia. The head is stuck. There is
shoulder dystocia. They try various maneuvers to get the baby delivered.
The baby will eventually have severe neurologic injury, including
subgaleal hemorrhage and Erb\'s palsy. What we believe that this
approach allows you to do is to show that notwithstanding the other
problems, the baby\'s initial at least neurologic injury occurred long
before, reasonably before the application of the vacuum.

The hypotheses for Phase II relate, as might be inferred, that
experience was not protective of injury and, parenthetically, the
largest number of vacuum applications in this study was 16. The longest
duration of application was the better part of an hour. These are
seemingly out of the realm of what experience teaches us, that as I
suggested before, that the urgency of delivery is not an unreasonable
endpoint for evaluating the quality of obstetrical care. The methodology
we will use, as I say, is a control group and we have derived a control
group of almost 200 patients from four California hospitals involving
both private community hospitals, university hospitals, and a large
municipal hospital which is university-affiliated.

The objective is to understand not only the effects of the vacuum itself
but the conduct of the labor in the second stage and to try to answer or
help to answer the notion of how these injuries occur and with the
understanding that it is unlikely to be just a simple problem with the
vacuum.

Thank you very much.

DR. BLANCO: Thank you, Dr. Schifrin.

Does any of the panel members have any questions or comments concerning
the presentation?

DR. O\'SULLIVAN: Barry, considering that this is only the cases that
were reported, in the process of looking, did you have the opportunity
in the control hospitals or in the control cases to look at just vacuums
in general?

DR. SCHIFRIN: Yes, that is what we did. The way you got into the control
group is you had a vacuum delivery.

DR. O\'SULLIVAN: Okay, and the incidence of complications associated
with those?

DR. SCHIFRIN: That will be the subject, but it is quite small, and the
most obvious is that the failure rate in the controls is 5 percent, 6
percent, something like that, and the shoulder ‑‑

DR. O\'SULLIVAN: I\'m sorry. I guess I was not quite listening at that
point.

DR. SCHIFRIN: The shoulder dystocia rate was about 5 percent in those.
So simply the most stunning statistic was the failure rate of about 50
percent of the vacuum. This is everybody. A vacuum is tried and it in
fact failed 50 percent.

Just as a sidelight, there was no simultaneous preparation for Caesarean
section where it was failed. So this creates a scenario where you have
to keep doing it. You have to keep proceeding because having not
anticipated failure, you\'re obliged now to make the best you can under
the circumstances.

DR. LARNTZ: This is Kinley Larntz.

I\'m a newcomer to this panel and just a statistician, but I would have
thought the control group, if you\'re worried about the vacuum, the
effect of the vacuum, you\'d have a control group that would be not
vacuum-assisted.

DR. SCHIFRIN: I\'m sorry?

DR. LARNTZ: You would have a control group that would be not
vacuum-assisted, and I think that would be important to compare if you
were interested in the effect of the vacuum.

DR. SCHIFRIN: We would very much have loved your input at the time we
did this. We made a number of efforts to try to satisfy that issue and
could not come up with a reasonable strategy to do that since the
decisionmaking apparatus does not make that, it seems to me, as
satisfying a comparison as you might think.

We certainly went through it and this went through a large number of
debates about the control group. The only thing I can say is I\'d be
happy ‑‑ there\'s perhaps not enough time to share all of the issues
with you.

DR. NOLLER: Because now an attending must be present when a resident
does deliveries, is it going to be possible in Phase II for you to
determine who actually applied the device and whether it was applied
multiple times, who did it each time?

DR. SCHIFRIN: I share with you two pieces of information. Medical
records are hopelessly inadequate for obtaining that and that may be one
of the ultimate recommendations that will come out of this. The second
issue ‑‑ and I would challenge you all who are clinically involved.
There is an ICD-9 code. I do not remember what it is offhand. There is
an ICD-9 code for a failed vacuum. In no hospital that we have yet
called, and we\'ve called a number of them, including all the hospitals
that have participated in the study, no one has any record of a coded
failed forceps. You can\'t find it in the record.

The last thing I would share with you is the deposition statement of one
of the physicians who was peripherally involved in one of those cases,
and he said simply \"if it was an easy vacuum, I might not even record
it in the delivery note.\" So this approach makes this undertaking,
trying to make sense out of the medical records, challenging to say the
least.

DR. NOLLER: That was really my point. I don\'t think you\'re going to be
able to tell the difference between attending and resident deliveries.
It\'ll all be in one big bundle probably.

DR. SCHIFRIN: The interesting thing, at least, about the control group,
about the study group, is that the vast majority of them are
board-certified obstetricians without a resident anywhere in sight.

DR. BLANCO: Any other comment and questions? I just wanted to ask you.
One of the things that came across in your presentation to me is the
fact that the indications obviously are going to be very important, and
one of the things that a lot of clinicians utilize the vacuum as sort of
what you said, the emergent patient who\'s not quite ready to, you know,
be delivered any other way and so you \"use the vacuum.\"

I wonder. Are you going to be able to separate from your data in that
setting whether it was bad judgment in applying that as opposed to, you
know, the vacuum itself creating the problem? Do you understand where
I\'m getting at?

DR. SCHIFRIN: I understand, and I\'m going to try to answer charily. I
think this is about behavior. I don\'t know how you explain 16
applications of a vacuum under any clinical circumstances. There are
portions of these data that are difficult emotionally to deal with, that
somebody would apply a vacuum 16 times or leave it on for an hour.

You may have seen the \"20/20\" show and this is just hard to deal with,
but ultimately it seems to me that, as I suggested in the presentation,
that we need to decrease the urgency of the deliveries and maybe that is
a test of what we can do, and as I tried to share with you, with the
tracing itself, that the conduct of the second stage, that the
maintenance of the pushing as the baby is deteriorating is something we
need to perhaps rethink and that the whole objective is to make it an
easy vaginal delivery or easy Caesarean section. There\'s nothing in
this study thus far that suggests we should do away with vacuums.

DR. BLANCO: Thank you very much. Thank you, both of you, for a very nice
presentation of the information to the panel.

I would like to go ahead and continue with the rest of the panel
meeting, and before we begin, and we\'ll begin with the open public
hearing, I\'d like to go ahead and remind all of the presenters to
introduce themselves and to describe any potential conflict of interest.
I also would like to remind the presenters, to the panel who have not
already done so, that they should provide the FDA with a hard copy of
their remarks, including overheads. Kathy Daws-Kopp ‑‑ Kathy, would you
please stand? ‑‑ will be available at the podium when you come up to
collect these from you at that time.

Having said that, we\'ll go ahead and begin with the folks who have
signed in and requested time for comments to the panel during the open
public hearing. I just would like to remind the speakers that we
normally have about five minutes for each of your presentations, and
then at the end of the speakers that we know would like to present
before the panel, we\'ll open it up if there\'s anyone else in the
audience who would like to make some brief comments.

The first person that I have on my list is Ms. Gabriella Avina, R.N.,
from Martinez, California, if you would please come forward.

Thank you.

MS. AVINA: Thank you. Good morning. Please keep in mind that it\'s 6:20
in California, and I just got here last night. But thank you very much.
My name is Gabriella Avina, and I appreciate the chance to share my
story today.

I\'d first like to share with you this picture, I know you can\'t see
it, but it\'s of my family, and as you can see, that picture\'s very
full. So we were done with our family planning. I\'d like to ‑‑

DR. BLANCO: I\'m sorry. Would you please, if you have any affiliation
with an organization ‑‑

MS. AVINA: I was just getting to that.

DR. BLANCO: Thank you.

MS. AVINA: My trip today was paid for by Conceptus. I\'m being
reimbursed for my expenses, and my husband and I did purchase shortly
after having the device implanted, we did purchase a small amount of
stock.

Is that all you needed to know?

DR. BLANCO: Thank you. That\'s fine.

MS. AVINA: I am a registered nurse and I have been a nurse for 16 years.
That time has been spent in the maternal/child field of nursing, and in
1991, I received a Master\'s degree with an emphasis on reproductive
health. I\'m married. I have three children, and after the birth of my
second child, we had made the decision to not have any more children.

I researched my options very carefully and at that time made the
decision that I didn\'t want to have surgery because I\'d already had
several surgeries for endometriosis and then I had to have an emergency
colectomy after my second daughter. So we opted to forego for the most
important reason, that I was just too busy to have surgery and go
through the operation and the recovery. So in October of \'98, I had an
IUD placed. Seven months later, I found out I was pregnant with my third
son, my third child, and it was a very complicated pregnancy but he was
born in a healthy delivery in January. So we were faced with the same
decision again, what to do about birth control.

So after some discussion, actually lots of discussion, I convinced my
husband to have a vasectomy, and in March of 2000, he had ‑‑ I\'m going
to spare you his story about his vasectomy because that would ruin the
day for most. He had his sperm analysis in May, and it was virtually
clear. It was negative for sperm, but on the advice of our physician, he
was to return in 60 to 90 days and have a repeated sperm analysis. So he
returned and had a sperm count of 70 million, which was so high that
they assured us that was a lab error and being in the medical field, I
was sure it was a lab error.

So I calmed him by telling him, we\'ll just do another analysis in the
morning and it\'ll be fine, and he did, he repeated it again without
abstinence. It was 36 million, and he was devastated and all I could
think about was what are we going to do now? So I was hoping there was
still some small possibility that that wasn\'t correct. So being that
I\'m employed in a reproductive health center, I took some sperm with me
to work and had our embryologist look at it and she assured me that
those tests were in fact correct.

So it was about that time that I heard about the clinical trials for
Essure and it didn\'t take too much time for me to decide that I had
nothing to lose, really. So in October of 2000, I had the device
implanted, and in January of 2001, I had my hysterosalpingogram, which
documented that I was blocked. It brought about a peace to my life and
to my relationship that I cannot express to you. To have the history
that we had with having children, we needed to find something that we
could go about our life and our marriage with comfort and security.
That\'s what the Essure device did for us.

In closing, I\'d like to say one last thing. In the beginning, I told
you that I\'m a wife and I\'m a mommy and I\'m a nurse, but most
importantly, I am a woman, and I speak for all women today when I ask
for you to allow us to have another contraceptive option because we
deserve it.

Thank you very much.

DR. BLANCO: Thank you.

Our next speaker that I have on the list is Caroline Costello from the
Division of Reproductive Health, Centers for Disease Control.

MS. COSTELLO: Good morning. My name is Caroline Costello, and I work in
the Division of Reproductive Health at the Centers for Disease Control.

I will be here representing the CREST Study Team and my colleagues at
CDC and Bert Peterson at the WHO. I was invited here today to discuss
the sterilization failure method, sterilization failure rates documented
in the largest perspective U.S. study on female tubal sterilization. The
U.S. Collaborative Review of Sterilization is often referred to by the
acronym CREST and was conducted by the CDC and with support from the
National Institutes of Child Health and Human Development.

Between 1978 and 1987, the CREST Study enrolled women scheduled for
tubal sterilization at one of 15 participating medical centers in nine
U.S. cities. A total of 12,138 women were enrolled. Follow-up was
attempted annually by telephone for five years. Women who enrolled
before 1983 or earlier also received an additional follow-up interview
eight to 14 years after the sterilization. A woman\'s follow-up ceased
only if she refused to be interviewed, had died or had aborted a
pregnancy, repeat tubal sterilization, sterilization reversal or
hysterectomy.

For the analysis of pregnancy following tubal sterilization, the CREST
data set was restricted to women who had the same method of tubal
sterilization on each fallopian tube and whose method of tubal occlusion
was laparoscopic unipolar coagulation, bipolar coagulation, silicone
rubber band application, or spring clip application or partial
salpingectomy performed by laparotomy. The final analysis data set
included 10,685 women whose median age at the time of sterilization was
30. Most women were white non-Hispanic or black non-Hispanic and almost
80 percent had a high school degree. Eighty-two percent were currently
married or had previously been married and almost 90 percent had been
pregnant at least twice.

Of this CREST subset, approximately 90 percent of the women were
interviewed at the first year of follow-up, 75 percent of women were
interviewed at the fifth year of follow-up, and 60 percent had the
extended follow-up eight to 14 years after sterilization. During the
annual telephone follow-up interview, women were asked, since your tubal
sterilization, have you had a positive pregnancy test or been told by a
physician that you were pregnant? If a woman responded affirmatively,
the interviewer then completed a separate form which requested detailed
information on the pregnancy. The information requested was the date of
last menstrual period, date of pregnancy diagnosis and gestational age
at diagnosis, date pregnancy ended and the gestational age at
termination. Whenever possible, medical records were obtained for
review. Requested records included results of pregnancy test, ultrasound
exams, et cetera.

All information collected on each pregnancy that was reported during the
CREST follow-up was thoroughly evaluated by the CDC principal
investigator, Bud Peterson, and the project director at the medical site
where the sterilization was performed. The pregnancies were classified
into four groups: true sterilization failures, luteal phase pregnancies,
which refers to pregnancies conceived prior to sterilization but
identified after the procedure, pregnancies that occurred after
reanastomosis or in vitro fertilization, and pregnancies with too little
information to be classified into the previous three categories. A total
of 143 of the pregnancies were classified as true sterilization
failures, 34 were classified as luteal phase pregnancies, and 16
pregnancies occurred after tubal reanastomosis or in vitro
fertilization. Five pregnancies remained unclassified because of
insufficient information.

The life table statistical method was used to calculate the cumulative
probability of pregnancy per thousand sterilizations at each year
following the procedure. The cumulative probability with 95 percent
confidence intervals are plotted in this figure. At one-year post
sterilization, the probability of having a pregnancy following
sterilization was 5.5 per 1,000 procedures. The 95 percent confidence
was 4.1 to 6.9 per 1,000. At each additional year since sterilization,
the cumulative probability of pregnancy increased. By five years since
sterilization, the cumulative probability of pregnancy was 13.1 per
1,000 sterilizations, and by 10 years, the cumulative probability was
18.5 pregnancies per 1,000 sterilizations or approaching 2 percent. This
plot demonstrates the continuing risk for sterilization failure, even
after several years following the procedure.

The cumulative probabilities of pregnancy per 1,000 procedures are
plotted in this figure. The difference in cumulative probabilities by
method of sterilization indicates the substantial difference in the
sterilization effectiveness by methods. The most effective methods at
preventing pregnancy were unipolar coagulation and postpartum partial
salpingectomy, each with a 10-year cumulative probability of 7.5
pregnancies per 1,000 procedures. The method with the highest cumulative
probability of failure was laparoscopic spring clip application with a
10-year cumulative probability of 36.5 pregnancies per 1,000 procedures
or 3.6 percent.

The cumulative probability of pregnancy by age of sterilization is
plotted here in this figure. The cumulative probability is the
demonstrated difference in the risk of pregnancy by age of
sterilization. Women who were younger at sterilization were more likely
than women older at sterilization to experience the sterilization
failure. The difference in cumulative probability of pregnancy by age
group grew more pronounced as the time since sterilization grew. The
10-year cumulative probability of pregnancy for women aged 18 to 27 was
approximately 33 per 1,000 sterilizations while women who were at 34 to
44 years of age had a 10-year cumulative probability of approximately 6
percent, 6 per 1,000 sterilizations.

Several factors were analyzed in multivariate analysis for their impact
on the relative risk of sterilization failure. Only sterilization
method, age at sterilization, race/ethnicity and study site were
significant predictors of pregnancy following tubal sterilization in the
multivariate analysis. After adjustment for other factors in the model,
interval partial salpingectomy, spring clip application and bipolar
coagulation were significantly more likely than postpartum partial
salpingectomy to result in sterilization failure. After adjustment for
other factors in the model as an age group, women younger than 34 at
sterilization have pregnancy risks that are at least two times greater
than the risk of pregnancy for the group of women 34 and older at
sterilization. Black non-Hispanic women were also at significantly
greater risk for sterilization failure than were the white non-Hispanic
women.

Of the 143 pregnancies that were true sterilization failures, almost 33
percent were ectopic pregnancies, 46 of these pregnancies occurred
within the fallopian tube, the other ectopic was an invariate pregnancy.
The proportion of pregnancies or ectopic varied substantially by
sterilization method. Of the pregnancies following bipolar
sterilization, 65 percent were ectopic compared to 15 percent of
pregnancies following spring clip application. The cumulative
probability and 95 percent confidence interval for ectopic pregnancy per
1,000 sterilization procedures is plotted here for 1, 5 and 10 years
following sterilization. At one-year post-sterilization, the cumulative
probability for ectopic pregnancy was .7 per 1,000 procedures with a 95
percent confidence interval of .2 to 1.2 per 1,000 procedures. Of the
time since sterilization, the cumulative probability of an ectopic
pregnancy increased. By five years, the cumulative probability of
ectopic pregnancy was 4.0 per 1,000 procedures and by 10 years, it was
7.3 per 1,000 procedures. The plot demonstrates the continuing risk of
ectopic pregnancy, even several years following the procedure.

The annual rate of ectopic pregnancy in the fourth through 10 years
after sterilization was no lower than the annual rate of ectopic
pregnancy in the first three years. For the fourth through the 10th
years, the rate was .8 ectopic pregnancies per 1,000 procedures annually
compared to the annual rate of .7 per 1,000 procedures in the first
three years.

Similar factors that influence risk of all types of pregnancies, such as
sterilization method, age at sterilization and race/ethnicity, were
predictors of ectopic pregnancy following sterilization, with the
exception of the additional predictability of having a history of pelvic
inflammatory disease.

From the large CREST Study, it is evident tubal sterilization is a
highly effective method of preventing pregnancy. However, pregnancies
can occur. Because the CREST prolonged study follow-up, the rate of
pregnancies following sterilization was substantially higher than rates
generally reported. The prolonged follow-up also demonstrated that
pregnancies can continue to occur at greater than one to two years after
sterilization. Among women who had pregnancies following sterilization,
the risk of ectopic pregnancy is high. The risk of pregnancy and the
risk of only ectopic pregnancy was similarly associated with
sterilization method, age at sterilization, and race/ethnicity.

In conclusion, all women and especially younger women undergoing tubal
sterilization should be informed that pregnancy can occur following
tubal sterilization and it can occur several years after the
sterilization. Women should also know that if a pregnancy occurs, there
is a high risk that it could be ectopic.

Thank you.

DR. BLANCO: Thank you very much.

At this point, these are all the presenters that we have listed. Is
there anyone in the audience who would like to make some brief remarks
before the panel at this point?

(No response.)

DR. BLANCO: Okay. Having there not been anyone, at this point, we\'ll go
ahead and move on with the agenda. I\'d like to at this time bring back
Mr. Colin Pollard for some initial comments about the next topic that
we\'ll be dealing with.

MR. POLLARD: Thank you, Dr. Blanco, members of the panel, distinguished
audience.

FDA has convened this meeting today to obtain input from you as
independent experts and members of this panel. FDA will use your
recommendation as it moves forward with the review of this PMA
application for the Essure Micro-Insert, a hysteroscopically-delivered
implant for permanent female sterilization.

I\'d like to make several points, as you begin your day on this PMA.
First, as Dr. Whang, your panel executive secretary will go over with
you later today, your recommendation can take one of three forms ‑‑
approvable, approvable with conditions, or not approvable ‑‑ and for the
latter two possibilities, we will expect the panel to provide details on
how to make the PMA approvable.

Secondly, there are three key operative definitions that apply to the
review of PMAs: valid scientific evidence, safety, and effectiveness. I
won\'t go over the definitions with you now. We\'ll do that later. They
are given in your folder and I suggest you take a quick look to refresh
your memory. When we introduce the panel discussion questions in the
afternoon, we\'ll read the definitions out loud.

You have before you today the premarket approval application for a
hysteroscopically-delivered implant that is placed in the fallopian
tubes of women who intend to be permanently sterilized. By way of a
little history, about 10 years ago, starting in the late \'80s, this
panel reviewed three other PMAs which FDA went on to approve for tubal
occlusion devices that are placed laparoscopically. Two of these three
devices were so-called preamendments devices. That is, they were on the
market before enactment of the 1976 Medical Device Amendments. All three
PMAs were for devices that had a great deal of market experience and
were supported by a wide variety of devices from the published
literature, and at each of the three panel meetings for those PMAs, we
were fortunate as we are today to have a representative from the Centers
for Disease Control to discuss what is probably the definitive
longitudinal study of female sterilization, the prospective multicenter
Collaborative Review of Sterilization, the so-called CREST Study. I want
to thank Dr. Costello for giving us a very nice overview of that study.
Results from this study have been useful to help put the safety and
effectiveness of such devices into perspective.

My next to last point is that this PMA before you today represents the
next generation of devices for female sterilization with advancements in
the technology. While this device does not have the extensive clinical
experience of the earlier devices, it is supported by the results from a
series of studies on which the sponsor embarked after substantial
consultation with the agency. This will make some aspects of the review
a little more difficult and we will give you a little bit more
information on that later.

And lastly, I should note that nowadays, FDA does not take every single
PMA we receive before the panel, only first-of-a-kind devices or when
difficult clinical issues are raised. This device is the first
hysteroscopically-delivered sterilization device and that is why we have
brought it before you. This PMA, the results of your deliberations and
ultimately our decision will serve as a model for review of future PMAs
of like devices.

Thank you in advance for your careful attention to the details of the
PMA. We look forward to your discussion.

Any questions?

(No response.)

DR. BLANCO: Thank you, Mr. Pollard.

At this time, I\'d like to go ahead and begin the presentation by the
sponsor, and I\'d like to introduce Cindy Domecus from the Conceptus
Corporation to begin the presentation and introduce the rest of the
speakers.

Welcome back.

MS. DOMECUS: Good morning.

Distinguished panel, FDA and interested public, we are pleased to
present to you today a summary of the PMA for the Essure System. My name
is Cindy Domecus, and I\'m the Senior Vice President of Clinical
Research and Regulatory Affairs at Conceptus.

At the outset of our presentation, we would like to publicly acknowledge
the FDA for all the valuable input we have received from them during
each stage of our clinical evaluations. Our first clinical evaluations
began in 1996 with the earlier design iterations of the device and we
sincerely thank FDA for its guidance during the past six years of
clinical research.

After introducing the other members of our panel presentation team, I
will briefly review the public health issues that motivated Conceptus to
develop an alternative contraceptive option for women. Next, we will
describe the device, its mechanism of action, and we\'ll provide an
overview of the Micro-Insert placement procedure. Following that, I will
provide an overview of the four clinical trials that were conducted in
support of the Essure System PMA. We will then highlight the results
from the prehysterectomy study and pivotal trials. We will conclude our
presentation by addressing each one of the panel discussion questions
today. So that we can stay within the allotted time frame for our
presentation, we respectfully request that you hold questions until the
completion of our presentation.

I would now like to introduce to you the other members of the panel
presentation team. First, Dr. Jay Cooper, who is the principal U.S.
investigator for the pivotal trial. He will speak to you today regarding
the device description and mechanism of action and will also provide an
overview of the Micro-Insert placement procedure.

Dr. Thomas Wright, who is an independent histopathologist for the entire
project, will speak to you today regarding the prehysterectomy study
results.

Dr. Charles Carignan, who is Vice President of Clinical Research and
Regulatory Affairs at Conceptus, will present to you the results from
the pivotal trial.

Conceptus chose to develop Essure because of what we believe to be a
clear need for contraceptive alternatives for women. This need is
evidenced by the high unintended pregnancy rate in the United States.
Based on data from the most recent cycles of the National Survey of
Family Growth, it is estimated that almost half of the pregnancies in
the United States are unintended. It has been suggested in the
literature that the high unintended pregnancy rate is due to
dissatisfaction and imperfect use with reversible methods.

Currently, women must choose between reversible birth control methods
associated with these high unintended pregnancy rates and permanent
methods which require invasion of the abdominal cavity, typically under
general anesthesia. Although permanent methods of birth control are
associated with very high effectiveness rates, they are not without
significant risk. As published by Jamieson, et al., tubal sterilization
performed via laparoscopy is associated with a 1.6 percent major
complication rate. Layde, et al., reported 5.7 percent major
complication rate when tubal sterilization is performed via laparotomy.
Of note, Destefano, et al., reported a fivefold decrease in complication
rates when tubal sterilization is performed with local instead of
general anesthesia. These risks are made more significant by the fact
that tubal sterilization is the most prevalent form of birth control in
the United States. The vast majority of the major complications with the
transabdominal approach are due to incisions, blind insertion of
instruments into the abdomen, and general anesthesia. Conceptus chose to
develop a transcervical approach to tubal sterilization in order to
avoid the risks associated with these characteristics of a
transabdominal approach.

I will now turn the podium over to Dr. Jay Cooper, the principal U.S.
investigator, who will present to you a description of the device, its
mechanism of action, and will provide an overview of the Micro-Insert
placement procedure.

Before Dr. Cooper speaks, however, Colin will pass out to you some
samples of the device. We have it in two forms, the Micro-Insert
provided in a vial and the Micro-Insert contained within its delivery
system provided in a pouch. I\'ll ask that Colin pass those out now, and
we\'ll have a few minutes to handle the device before Dr. Cooper speaks
to you. Just for the record, it\'s more than fine for you to open the
packages and we actually would encourage you to handle the Micro-Insert
itself so you can see its soft flexible nature.

DR. COOPER: As is being done here by Dr. Noller, you can take the
catheter guide assembly system, the plastic tubing, so you can get a
much better idea of the entire system.

Dr. Blanco, shall I proceed?

DR. BLANCO: Yes, please.

DR. COOPER: Thank you. Thank you, Cindy, and thank you to the FDA, the
distinguished panel, for the opportunity to be here this morning and to
speak to you regarding Conceptus\' application for PMA approval.

I have worked with Conceptus as a medical advisor in the refinement and
clinical evaluation of various iterations of the Essure device and have
served as the principal investigator in the North American clinical
trial of the Essure device. As such, I have received compensation which
now represents a financial interest in the company.

As the panel members can now attest, the Essure Micro-Insert is both
soft and flexible. It is four centimeters in length. It is composed of a
narrow inner coil and an outer coil of larger diameter. Laced along the
length of the intercoil is a weave of PET fibers. At full expansion, the
outer coil can achieve a diameter as great as two millimeters. The
leading edge of the device has a ball-tipped swelling which facilitates
the forward advancement and proper placement of the device into the
proximal fallopian tube.

The Essure device is radiopaque and on a simple flat plate x-ray of the
pelvis can be seen to conform in shape to the natural curvature of a
woman\'s fallopian tubes. The Essure System is composed of a handle and
guide wire and coaxial catheter assembly system that allows for
one-handed placement and deployment of the Micro-Insert into the
proximal fallopian tube. The ergonomically designed handle makes use of
a rotatable thumb wheel and gear system which provides for retraction
first of the outer delivery catheter and next withdrawal of the
interrelease catheter, allowing the Micro-Insert to be fully deployed.

Because the outer delivery catheter is only one millimeter in diameter,
it can easily be passed through a five-fringed operating channel of any
commercially available hysteroscope. Using sequential photographs, the
key components of the Essure Micro-Insert and catheter assembly can be
seen. The delivery catheter has several unique properties which aid the
operator in proper device deployment. The catheter is hydrophilic,
allowing it to become slippery and lubricated as it passes through the
saline-filled uterine cavity. The catheter wall thickness provides
appropriate column strength for slow advancement into and through the
tubal lumen. Approximately two centimeters from the leading edge of the
catheter is a black positioning bump. When this positioning bump is seen
by the hysteroscopist to advance to the tubal ostium, the operator is
certain that the underlying Micro-Insert still wound down and
constrained by the release catheter is now properly positioned.

If you would, imagine this line running from this black bump right down
here. To your right represents what\'s happening in the patient\'s
fallopian tube. To your left represents the uterine cavity. So we see
now in this photograph that the delivery catheter has been withdrawn
back into the operating channel of the hysteroscope. The distal portion
of the device can be seen at the tubal ostium still constrained and
wound down. The orange releases catheter has not yet been released.

In the next photograph, the release catheter has been withdrawn, the
device is now free to expand to its maximum diameter. The operator can
see four or five of these microcoils at the uterine cornua, and finally,
in the last image, the guide wire has been separated away from the
device, leaving it free and properly positioned at the utero-tubal
junction and spanning the intramural portion of a fallopian tube.

This schematic illustrates the ability of the Essure device to assume a
greater diameter at the tubal ostium and in the proximal fallopian tube
than it can in the intramural portion of the fallopian tube. The thick
musculature of the uterus prevents the device from assuming its maximum
diameter. It is this unique and dynamic property of the Essure device
that explains its ability to accommodate to variable tubal widths and
also explains its exceptionally high rate of acute and long-term
retention.

There is a threefold explanation for the mechanism of action for the
Essure device. Expansion of the outer coil for acute anchoring,
space-filling and mechanical blockage of the tubal lumen, and finally
tubal occlusion by tissue ingrowth into and around the Micro-Insert from
the tubal mucosa.

Next, I\'d like to show you an animation of the procedure being
performed. The hysteroscope will be placed into the uterus. The left
tubal ostium will be identified. Scope is in place. The guide assembly
catheter system is being passed through the hysteroscope, now it\'s
passed into the fallopian tube to the black positioning bump. A catheter
is withdrawn, the wound-down device will be released as the release
catheter is pulled away. The device now is fully deployed. The guide
wire is disengaged from the device and the device remains in this
position spanning the utero-tubal junction with just a few of the
microcoils seen in the uterus by the hysteroscopist.

Having seen an animation of the device placement procedure, I think it
is easier for us to better appreciate the key steps in device placement
as viewed through the hysteroscope. With the uterus distended with
saline, both tubal ostia are visualized. In this situation, we see the
left tubal ostium in the center of our visual field. In the next image,
we see that the delivery catheter has been advanced into the uterus,
into the fallopian tube, to the position of the black positioning bump.
In the next image, the delivery catheter has been withdrawn away from
the underlying device. The device remains in a wound-down state and the
release catheter can be seen at the periphery of the image.

In the next image, the orange release catheter is no longer in view
because it has been pulled away or released from the device. Now the
device is allowed to spring to life, so to speak, to assume its full
diameter and all that remains in the next image is to disengage the
guide wire from the device. Here, the guide wire is being rotated in a
counterclockwise fashion using the handle, and finally we see the device
at the left tubal ostium fully deployed.

Owing to my experience as the principal investigator in the pivotal
trial and having the opportunity to observe physicians as they began
their experience with the Essure System, it is my view that this
procedure should be seen as the simplest of operative hysteroscopic
procedures. Performed with a hysteroscope similar to that used in
diagnostic evaluations, the Essure procedure is devoid of many of the
risks and concerns associated with advanced operative hysteroscopic
procedures. Cervical dilation is most often not required and if so is
limited to 5.5 millimeters. Physiologic saline is used for distention of
the uterine cavity as opposed to non-physiologic solutions, such as
glycine or sorbitol. The risk of fluid intravestation is minimized as
uterine distension pressures are controlled by gravity feed and there is
no cutting or resection of endometrial tissue. Electrosurgery is not
employed. The procedure is considerably more rapid than is the typical
operative hysteroscopic procedure and intraoperative bleeding is
extremely uncommon.

Thank you for your attention, and I will turn the program back to Cindy.

DR. BLANCO: Thank you.

MS. DOMECUS: Thank you, Dr. Cooper.

I will now introduce the next section of our presentation with an
overview of the four clinical trials that Conceptus conducted in support
of the Essure System PMA.

After two years of clinical testing with the earlier device iterations,
clinical testing of the gamma design began in 1998, with testing in
hysterectomy patients to obtain data on the feasibility of device
placement. Over 40 women were enrolled into this study and the data from
this study supported moving into the next stage of clinical testing. At
the next stage, the Micro-Insert placement was performed in hysterectomy
patients 1 to 30 weeks prior to a planned hysterectomy. This study
yielded the first data on Micro-Insert placement in awake women as well
as the first data on the safety and comfort of the implanted
Micro-Insert. This study also provided histological data to support the
theorized mechanism of action. Over 60 women were enrolled into this
study.

A Phase II study of safety and effectiveness in sterilization candidates
was also conducted. This study provided the first safety and
effectiveness data in the intended patient population and over 200 women
were enrolled into this study. Finally, based on the encouraging results
from the Phase II study, a pivotal trial was initiated in the year 2000
after extensive discussions with the FDA regarding study design. Over
500 women were enrolled into this study. In summary, as you can see,
clinical testing of the current product has involved over 850 women
spanning over a four-year period.

Dr. Wright will now present to you the results from the prehysterectomy
study, followed by Dr. Carignan who will present to you the results from
the pivotal trial.

DR. WRIGHT: Good morning.

Before I describe the results of the prehysterectomy study, I would like
to disclose that I was paid as a consultant by Conceptus to perform the
histopathological analysis of specimens from the prehysterectomy study.
I have no other financial interest in Conceptus.

Next slide.

The prehysterectomy study enrolled women requiring a hysterectomy for a
variety of gynecological reasons. These women underwent placement of the
Micro-Insert 1 to 30 weeks prior to hysterectomy and underwent a
hysterosalpingogram one week prior to undergoing the hysterectomy.
Immediately after the hysterectomy was performed, the cornual regions of
the uterus, together with the fallopian tube, were removed from the
uterus and sent to a central pathology laboratory for specialized
processing. This involved embedding the entire section of tube together
with the device in situ into plastic. The embedded tube and device were
then cut into sections which were ground down to an appropriate
thickness for microscopic assessment using a diamond-grinding wheel.
This allowed us to look at the relationship between the tissue, the
fallopian tube and the device. Histopathological sections were all
evaluated by a single blinded pathologist to wearing time and all
clinical information.

Next. These are the results obtained on the hysterosalpingograms that
were obtained one week prior to the hysterectomy. A total of 51 women
wore the device between 1 and 30 weeks. Most women had devices in place
between 4 and 14 weeks. All 51 women, including the five women who wore
the device for less than four weeks, showed 100 percent occlusion by
hysterosalpingogram.

Next. This microscopic view shows a cross-section of a fallopian tube
with the device in place. It was obtained from the patient who wore the
device for four weeks. Both the intercoil, which you can see here, and
the outer coil are visible. This is a smooth muscle of the tube out in
the periphery. Even after only four weeks of wearing time, the dense
fibrosis, which is seen as a golden brown staining seen there, has
developed between the inner and the outer coils. The normal tubal
architecture is completely disrupted and we have here almost total
occlusion.

The region of loose fibrosis which is immediately adjacent to the inner
coil which you see right here is the area that contains the bulk of the
PET fibers. The apparent space between this area of loose fibrosis and
the denser fibrosis is probably an artifact of the processing and the
methylocrylate bedding and the diamond knife grinding.

Next. This cross-section was obtained from a patient who had the device
present for 13 weeks. Again, you can see both the inner and the outer
coil, and the lumen appears to be almost totally occluded by dense and
by loose fibrosis. In addition, you can see here some smooth muscle
cells which appear to have migrated in from the wall of the tube into
the space between the inner and the outer coil. You can also see here
that the inner coil in this cross-section is occluded by loose fibrous
tissue.

Next. This is a higher magnification of that same section. I\'m showing
this to show the PET fibers present between the inner and the outer
coil. You can see the multinucleated giant cells which are typically
seen in association with the PET fibers together with the fibrosis. This
sort of appearance is very typical of what we see with PET fibers when
they are used in a variety of other devices and vascular grafts in other
body systems, this sort of elicitation of a dense fibrosis together with
an inflammatory infiltrate.

Next. Key histological features observed in the sections were graded in
a blinded fashion. Over time, we observed an increase in the amount of
dense fibrosis which is shown in the yellow line and a reduction in the
amount of acute inflammation which is shown in the white line. Both
chronic inflammation and loose fibrosis appeared relatively stable up to
a 15-week period of looking at these devices.

In conclusion, the prehysterectomy study has shown total tubal occlusion
by hysterosalpingograms in all of the participants at all of the time
points, including even those women who wore the device for less than
four weeks. The histological studies have shown that the tissue response
to the device is predictable and is progressive. It is occlusive in
nature and it produces a dense fibrosis.

Finally, the tissue response is quite localized. Sections from the tubes
taken approximately five millimeters distal to where the device was
showed a normal tubal architecture and there was no evidence that the
reaction to the device extended out to the serosal surfaces of the tube.
So the reaction was confined to the area around the device.

Thank you very much. I would now like to present Chuck Carignan who will
continue with the presentation.

DR. CARIGNAN: Thank you, Dr. Wright. Thank you, members of the panel.

I\'m Dr. Charles Carignan, vice president of clinical research and
medical affairs for Conceptus, and I\'d like to thank you for the
opportunity to share with you the results of our pivotal trial.

The objectives of the pivotal trial were to evaluate the safety and
participants\' tolerance of and recovery from the Essure placement
procedure, the safety and tolerance to the implanted Micro-Inserts,
tubal occlusion by HSG at three months, and the effectiveness in
preventing pregnancy with the primary endpoint being effectiveness at
one year.

Women were followed up at one week and three months following device
placement when they were relying on alternative contraception. She was
then followed up at three, six and 12 months after she began relying on
Essure as her sole method of contraception and Years 2 through 5 are
being conducted under postmarket surveillance. The one-year results are
presented here today.

The average age of the women in the pivotal trial was 32 with an age
range of 21 to 40 and consistent with the study design, nearly
two-thirds of the women were age 33 and younger and one-third were age
34 and older. There were 13 clinical trial sites with eight of the sites
located in the U.S., two in Australia, and three in Europe, and the
majority of women were enrolled in the United States.

This is a summary patient tree of the handouts that you all received.
Five-hundred eighteen women initially underwent hysteroscopy but 11
women were found not to have identifiable tubia ostia. Five-hundred
seven women actually underwent the Essure procedure, with 464 achieving
bilateral placement and two had placement in a unicornuate uterus.
Four-hundred forty-nine women ultimately began relying on Essure, 446
with satisfactory device location and occlusion, and three women began
reliance without undergoing an HSG. Twelve women were noted to have
unsatisfactory device location on the three-month post-device placement
and three women were lost to follow-up after device placement. As of May
24th, we had 408 women completing the one-year follow-up, 14 women who
were lost to follow-up after beginning reliance, and 27 women who were
still awaiting a one-year visit.

Ninety-two percent of women achieved bilateral placement with 88 percent
achieving so on a first procedure and 4 percent of women requiring a
second procedure to achieve bilateral placement. Of the 41 women not
achieving bilateral placement, 23 did not undergo a hysterosalpingogram
after failing placement. However, of the 18 women who did undergo a
follow-up hysterosalpingogram, 15 or 83 percent were found to have
proximal tubal occlusion which would explain their inability to achieve
device placement and only three women who failed placement were found to
have patent tubes.

On the day of device placement, adverse events were noted in only 3
percent of women and all adverse events resolved prior to discharge.
None required major surgery and there were no hospitalizations with the
exception of one woman who was observed overnight due to an adverse
reaction to pain medication she received in the recovery area.

There were Micro-Insert perforations at a rate of 1 percent and there no
symptoms among those experiencing perforation. The majority of women
reported no to mild pain during the procedure, most describing it as
period-type pain. Eighty-two percent of women received a nonsteroidal
antiinflammatory drug prior to the procedure to reduce uterine cramping
and tubal spasm.

When looking at predominant anesthesia and predominant anesthesia is
that which has a higher order of anesthetic effect, you can see that 52
percent of women received local anesthesia alone as a pericervical block
and 41 percent received IV sedation or analgesia. Only one woman in the
pivotal trial received general anesthesia and that was at her request.
With this low level of anesthesia, 88 percent of women rated their
tolerance of the procedure as excellent to good.

The average time to discharge was 45 minutes. There were no immediate
post-procedure events in 58 percent of women and those experiencing an
event, the most frequent were cramping, pain and nausea. As I mentioned,
all were resolved prior to discharge. There was no post-procedural
analgesia required in 75 percent of the women. Of the 329 women who were
employed in the study, 74 percent reported missing less than one day of
work following the day of the procedure and an additional 18 percent
missed one day of work.

At the three-month post-device placement visit, women underwent a
hysterosalpingogram to determine device location and occlusion. They
also had a pelvic exam and office visit to answer questions regarding
comfort and satisfaction. If the woman had satisfactory location and
occlusion, she discontinued alternative contraception and began relying
on Essure. Ninety-seven percent of women were ultimately able to rely on
Essure as their sole method of contraception. Three women or 0.6 percent
were lost to follow-up and 12 women or 2.6 percent experienced an
adverse event that prevented them from relying. Those adverse events
were expulsion, perforation or other unsatisfactory device locations.

Micro-Insert-wearing data was collected at three, six, and 12 months of
reliance. Women were asked about their comfort and satisfaction with
Essure and were asked whether or not they had experienced even a single
episode of unusual pain or bleeding as well as any adverse changes in
health that they experienced.

As can be seen here, at all study visits, comfort with Essure has been
rated very high, with comfort at one year rated as excellent in more
than 90 percent of women. Again, women were asked at each study visit if
they had experienced any unusual pain since the last contact. Pelvic
pain was categorized as dysmenorrhea, dyspareunia, ovulatory pain, or
other pelvic pain. Only 3 percent of women reported such episodes of
pain at more than one study visit and only one woman reported episodes
of pelvic pain at every study visit.

Women were also asked about any episodes of irregular bleeding at each
study visit. Reports were then categorized as irregular menses, spotting
or intermenstrual bleeding or changes in menstrual flow. Few women
reported persistent changes in menstrual flow while some women reported
transient menstrual changes. Of the women with persistent changes, two
women reported persistent intermenstrual bleeding, nine women reported
an increase in menstrual flow, while eight women reported a decrease in
menstrual flow. All of the menstrual function changes and pelvic pain
have to be considered in light of the fact that 48 percent of women
discontinued the use of oral contraceptives after the alternative
contraception period.

Adverse events were defined as any untoward deviation from baseline
health. Daily diaries were maintained by the study participants for six
months. Investigators were also prompted by case report forms at each
study visit on two separate questions, in addition to the questions on
pain and bleeding on the case report forms. It should be noted that
multiple episodes of the same complaint from the same woman are counted
as multiple adverse events. So for example, one woman in the pivotal
trial reported six episodes of low back pain at her three-month
post-device placement visit. That is reflected as six events in the
adverse events by body system table that I will show you next. The
adverse events by body system table reports all events in each category
that were related as possible, probable or definitely related to the
device.

This table shows the number of events reported and the number that you
can see here, the most frequent were low back pain, abdominal pain or
cramps, and dyspareunia. Only eight events were rated as definitely
related to the Essure device. The reports of pain, bleeding and adverse
events are kept in perspective when looking at satisfaction with Essure.
From the three-month post-device placement visit onward, more than 90
percent of women rated their satisfaction with Essure as very satisfied.

There were no reported pregnancies in women relying on Essure in the
pivotal trial. However, it should be noted that there were four
luteal-based pregnancies that occurred prior to device placement but
were diagnosed after device placement. The current estimate of the
first-year effectiveness rate based on the pivotal trial data alone is
100 percent with a 95 percent confidence interval of 99.31 to 100
percent. There were also no reported pregnancies in women relying on
Essure during the Phase II study, with the exception of a woman using an
earlier device iteration, the Beta design, who became pregnant. However,
that design was discontinued in 1998 and is not the subject of this PMA.

Combining the Phase II and pivotal trial one-year follow-up results in a
combined one-year effectiveness rate of 100 percent with a 95 percent
confidence interval of 99.52 to 100 percent.

So in conclusion, in the pivotal trial, Essure was demonstrated to be
highly effective with a very high patient satisfaction, a well-tolerated
placement procedure, a rapid return to work and normal activities. It
was shown to be comfortable and safe without the requirement for general
anesthesia or for incisions.

Thank you.

MS. DOMECUS: Thank you, Dr. Carignan.

I will now conclude our presentation with a few slides to address the
questions put before the panel today for discussion.

Question Number 1 before the panel asks about the effectiveness rate of
Essure in comparison to other methods of female sterilization. Plotted
on this graph are the point estimates and the confidence intervals shown
by the white lines for the failure rates of various methods during the
first year. These rates are based on the CREST Study and published
literature on the Filshie clip since the Filshie clip was not part of
the CREST Study. As you can see, both the unadjusted and age-adjusted
failure rates for Essure compare quite favorably with the other methods
of tubal sterilization.

This graph is the same as the prior graph but presents the second-year
failure rates. It doesn\'t include data on the Filshie clip, however,
since second-year failure rates on the Filshie clip cannot be calculated
based on published literature. As you can see, the point estimate of the
second-year failure rate for Essure is 0 percent. The size of the
confidence intervals is due to the sample size of 149 women completing
the two-year visits. It should be noted, however, that the primary
endpoint for the pivotal trial was the effectiveness rate at one year
and the two-year data is being provided as a supplementary endpoint.

Question Number 2 asked the panel about the age distribution in the
CREST Study as compared to the Essure pivotal trial. This question
compares the age distribution based on three age groups. However, it
should be pointed out that the pivotal trial study design was based on
two age groups, those under the age of 34 and those 34 to 40. As can be
seen, the distribution among these two age groups was quite similar
between the two studies. The pivotal trial was not designed to enroll an
equal percentage of patients to that of the CREST Study in the age group
of 18 to 27 since there was no statistically significant difference in
the failure rates of this age group compared to the next oldest age
group of women age 28 to 33. Also, the CREST Study showed the regret was
highest among this youngest age group. Finally, natural fertility has
been shown to decrease after the age of 34. Therefore, we focused on
only these two age groups. Finally, of note is that the age cap in the
pivotal trial was 40 years of age compared to 44 years of age in the
CREST Study.

Question Number 3 asks about the likelihood of recanalization in the
long-term setting. First, it should be pointed out that there\'s
currently no evidence of long-term failures with Essure. As of the last
update to the PMA, there are 281 women who have successfully relied on
Essure for contraception for 18 months, 149 women who have successfully
relied on Essure for 24 months, and five who have relied on Essure
successfully for 36 months.

In addition to the data on Essure, there\'s a long history with the use
of PET fibers and implant indications, such as cardiac valves, stents,
and grafts. PET fibers consistently produce a durable, dense, fibrotic
response and therefore we believe that the likelihood of recanalization
with Essure is quite low. Importantly, the device was designed to
include a minimum 1.2 centimeter section of the fallopian tube,
including the entire intramural section, which should also decrease any
risk for recanalization.

Finally, as will be discussed on a later slide regarding postmarket
surveillance, both the Phase II and pivotal trials will follow patients
to five years and there\'s already a commitment to provide the FDA with
this data under postmarket surveillance.

Question Number 4 asks the panel about the adequacy of our plan to
require a pelvic x-ray instead of HSG to evaluate Micro-Insert location
and retention. We believe that our plan is adequate for the following
reasons. First, all of the unsatisfactory Micro-Insert locations could
be detected on pelvic x-ray alone. Second, the patency rate observed in
the Essure clinical trials is quite similar to the patency rate
published in the literature when HSGs have been performed subsequent to
tubal sterilization.

Finally, we would like to point out that the performance of the
follow-up HSG is not the standard of care for tubal sterilization and
neither is pelvic x-ray. In that light, we think that our plan is more
than adequate and is actually quite conservative.

Question Number 5 asks about the acceptability of the placement failure
rate. First, as shown previously in Dr. Carignan\'s presentation, it
should be noted that 83 percent of the evaluated placement failures were
attributable to proximal tubal occlusion. While such patients are
reflected in the placement failure rates for Essure, they are not even
identified with the transabdominal approach. Also, when evaluating the
risk of placement failure, one must consider the fact that the placement
procedure is well-tolerated by the vast majority of patients and is
associated with minimal risks.

It is noteworthy that the high placement rates were achieved in both
obese women and in women with a history of prior abdominal or pelvic
surgery. This is of great importance because these very women are often
refused laparoscopic tubal ligation because of increased risk of
intraoperative complications. It is also important to note that
placement failure does not preclude subsequent treatment.

Finally, we believe that offering women a less-invasive approach to
permanent birth control prior to a more-invasive transabdominal
procedure is consistent with common clinical practice in other areas,
such as the performance of angioplasty prior to coronary artery bypass
graft or laparoscopic prior to cholecystectomy.

I will not address Question Number 6 regarding the safety of the
placement procedure since that was already covered by Dr. Carignan\'s
presentation.

Question Number 7 is regarding the adequacy of our proposed training
program which I will briefly review here. First, I would like to point
out that this training program was developed by Conceptus with
significant input and oversight from our Medical Advisory Board. There
are several components to the Essure Training Program.

First, a full-day course with didactic presentation and distribution of
a training manual. This course is given only by trainers approved by the
Conceptus Professional Education Department. Next, training is performed
in a custom-designed Essure placement simulator which, unlike in vivo
training, allows for placement practice in rapid succession. This
simulator was developed to provide a surrogate for the perihysterectomy
model. We have brought the simulator here today and are prepared to
provide demonstration later, if the panel is so interested.

Training in the Essure placement simulator is then followed by
preceptoring of initial cases. We plan to gather placement rate and
adverse event data on all preceptored cases until formal sign-off using
a standardized case report form. We expect preceptoring to average five
cases. Finally, a technical help desk will be manned 24 hours a day
seven days a week to provide ongoing training assistance. This training
program is currently being used in Canada, Europe, Australia, and
Singapore, and the next slide presents the data gathered using this
training approach in the commercial setting.

Looking at the placement rates for the first 10 cases conducted by the
pivotal trial investigators, shown in blue, compared to the first 10
conducted in a commercial setting with this training approach, shown in
orange, we see very similar placement rates. The approximate 4 percent
difference in the rates is likely due to the fact that at the time this
analysis was conducted for submission in the PMA, the average number of
procedures per physician in the commercial setting was less than half of
that in the pivotal trial. We believe that this early data supports the
validity of our proposed training approach and suggests that placement
results seen in the pivotal trial are generalizable to the commercial
setting.

The data from the pivotal trial were analyzed for learning curve using
both placement rates and procedure time as markers. When looking at
placement rates for the investigators that did not participate in the
Phase II trial, placement rates were not significantly impacted after
the first five cases. When looking at procedure times as a marker, we
saw a continuous slight decrease in procedure time with experience. As
another assessment of learning curve, investigators were asked to assess
ease of use. The majority of investigators rated ease of use as simple
or moderately simple. Based on these data, we believe that it is quite
feasible for competency with the procedure to be established after five
cases and the procedure time should continue to decrease with
experience.

Last, I would like to provide an overview of our postmarket surveillance
plans. Both the Phase II and the pivotal trial protocols require women
to be followed for five years. Also, both protocols request that
Micro-Inserts and any surrounding tissue be returned to Conceptus for
histological evaluation should a trial participant undergo future
extrapative surgery of the reproductive organs for any reason. As
mentioned earlier, we also intend to gather placement rate and adverse
event data on all preceptored cases using a standardized case report
form.

Finally, we will have a toll-free number for physicians to call
regarding any adverse events and such events will fall under FDA
regulations which already exist regarding complaint handling and
reporting of certain events to FDA.

In conclusion, we believe that the data gathered to support the Essure
System PMA represent valid scientific evidence in accordance with the
FDA regulations that a reasonable assurance of safety and effectiveness
has been established and that adequate training and postmarket
surveillance plans are in place to support market release. We therefore
respectfully request your recommendation for approval today.

This concludes our presentation. Thank you for your attention. We\'ll be
happy to answer any questions in the remainder of the day. I also wanted
to point out that in addition to a copy of our presentation, we provided
the panel with a letter from Dr. Barbara Levy, who cannot be here today
but wanted to provide comments to the panel.

Thank you.

DR. BLANCO: Thank you very much for that very interesting nice
presentation.

I\'d like to go ahead. We\'re doing great on time. So if any of the
panel members have any questions at this point, let\'s go ahead and
let\'s try, rather than a discussion, since we\'re going to be
discussing this afternoon, let\'s try to keep it to questions of fact,
if you want something clarified, et cetera.

Go ahead. Go ahead, Dr. Brown.

DR. BROWN: Yes. Do you have any data in both the Phase II and pivotal
trials about the racial and ethnic demographic mix of the patients on
the trials?

MS. DOMECUS: Dr. Carignan is going to pull up that data for you. One
moment.

DR. BLANCO: I might just suggest that if it\'s going to take awhile,
maybe we can set that up and then bring that information back to the
panel before we start the discussion after we\'ve had the other
presentations in the interest of time. Does that seem reasonable? Okay.
So if you all would look that up and see if you can find it, present it
a little later on, we\'ll fit in.

Any other questions? Let\'s go ahead and finish with each individual.
Dr. Brown, did you have anything else?

DR. BROWN: Yes. I also wanted specific numbers or percentages about
patients with a history of prior pelvic surgery and history of pelvic
inflammatory disease that were included in both of the trials.

DR. BLANCO: Okay. We\'ll go ahead and if you all would look those up.

Dr. Shirk?

DR. SHIRK: Cindy, one of the integral parts of this device is obviously
the PET fibers. The panel didn\'t receive any data regarding the action
of PET fibers. Could you guys sort of give us a biological effect?
Obviously it\'s an integral part of equating the fibrotic effect of
this, and I realize it\'s been used in multiple other devices, but again
I\'d like some information about the PET fibers.

DR. BLANCO: Anything else?

MS. DOMECUS: Can I clarify? You want more information about PET fibers?

DR. SHIRK: Yes.

MS. DOMECUS: Or the typical biological response to PET fibers?

DR. SHIRK: Well, the typical biological response.

MS. DOMECUS: Can I have Dr. Wright address that now or do you want to
hold that?

DR. BLANCO: That would be fine. No, go ahead.

MS. DOMECUS: Dr. Wright?

DR. WRIGHT: PET fibers have a long history of being used in a variety of
cardiac grafts and a variety of other prosthesis used in different body
sites.

The response which you see to PET fibers is very well described in the
literature. It consists of an acute and a chronic inflammatory
infiltrate. Many times or typically you will see multinucleanated giant
cells become attracted to the PET fibers. The presence of the
inflammation releases cytokines and chemokines which then induces an
acute followed by a chronic inflammatory infiltrate.

One of the things that determines the exact type of response that you
see with PET, at least in vascular grafts, is the weave of the meshes of
the grafts. If you have a very tight weave, you tend to have less dense
fibrosis going in. If you have a loose weave, such as what we are seeing
here, in the space between the inner and the outer coil, you\'ve got a
lot of inflammatory infiltrate, then you will get a dense fibrosis.

In systems that this event looked at over time, this response appears to
be very durable in that it does not diminish, it remains as it is, and
you maintain a chronic inflammatory infiltrate at the site of the fibers
which is the way it remains as a durable fibrotic response.

Does that answer your question?

DR. SHIRK: Yes. I just wanted some information what the fibers were made
out of and obviously it creates a chronic kind of inflammatory response?

DR. WRIGHT: An acute initially and then a chronic.

DR. SHIRK: During the patient\'s entire lifespan?

DR. WRIGHT: That\'s right, and with vascular grafts, we have long
histories of patients who wear these for very long periods of time,
showing that it does not cause adverse effects.

DR. BLANCO: Thank you.

DR. ROY: Could you just clarify something, though? I think one of the
slides indicated that with chronicity of use, you had more dense
adhesive process and less acute inflammatory process.

Does this mean that these fibers, once they are coated, then are no
longer producing the sort of inflammatory reaction that would be
characterized by the presence of the acute inflammatory cells?

DR. WRIGHT: This study, the prehysterectomy study, was designed to look
at very short time points. Almost all of the patients, except for one,
had their uteruses removed within 16 weeks of placement. So it really is
that period of time where you\'re going from acute to chronic
inflammation.

From vascular graft work, when you look at vascular grafts taken 10
years after they have been in place, you see some acute and chronic
inflammation associated with PET fibers. So it\'s a long-acting
inflammatory response. The absolute amount of the acute response that I
showed you appeared to be diminishing with each passing week. So I
don\'t think it will totally go away. I think what you will see is a
reduction compared to the acute responses at three and four weeks.

DR. ROY: But do the PET fibers themselves undergo some sort of
deterioration or do they consistently persistently remain as a nidus for
stimulating a reaction?

DR. WRIGHT: They remain as a nidus for stimulating reaction.

DR. BLANCO: Thank you.

DR. ROY: So I guess what we\'re all trying to get a sense of is, is
there any pathologic or physiologic process that would suggest that the
property of the PET fiber is subsequently lost or cleared and therefore
that there could be the process of recanalization and hence lack of
effect?

DR. WRIGHT: Right. The dense fibrosis that we\'re seeing here, together
with the smooth muscle ingrowth in these sections, certainly based on
the time lines that we\'ve got which are out to in one patient out to 30
weeks, the rest of them out to 16 weeks, 15 point something, really
shows that this appears to be a progressive response.

Once you replace that space by dense fibrosis together with some smooth
muscles, to me, it\'s difficult to envision how that dense fibrosis
would suddenly disappear and go away. I mean, that\'s not what we see
with inflammatory reactions and repair reactions in other body systems.
I mean, I assume that you would maintain a dense fibrosis. It would
become occluded and unless there was some other force or inciting cause
to cause it to break down or to cause a recanalization, I don\'t see how
this dense fibrosis would become recanalized. It\'s also relatively long
distance. The device is designed specifically to occlude 1.2 sonometer
region which is a relatively long region to undergo recanalization.

DR. ROY: The last concern would be, is there any reason for us to be
wondering whether these giant cells that infiltrate this area or are
produced are in any way precursors for a neoplastic process?

DR. WRIGHT: Right, and I didn\'t answer to that. It\'s the same sort.
The pictures I showed you with giant cells could be from any vascular
graft in the body, and we have a very long history of use of devices
using PET fibers for long-term implants and they have been shown to be
neoplastic.

DR. ROY: But those vascular grafts are typically in much older
individuals and for reasonably shorter periods of time than what we\'re
envisioning here. If we\'re anticipating the use of this as a
sterilization process in women in their twenties who presumably and
hopefully would live to their eighties, so is that differential time
span a concern to someone such as yourself who\'s been involved in these
investigations and processes?

DR. WRIGHT: That is not a concern to me, because I know of no data to
suggest or to implicate PET for producing neoplasms long term, and in
fact many of the implantable devices, such as cardiac valves which have
PET as a dense mass around the valve rings which it\'s there in order to
suture into, are put into quite young, you know, children get cardiac
valves which contain PET.

DR. ROY: Sure. Thank you very much.

DR. BLANCO: Thank you.

DR. SEIFER: I had a question, Dr. Wright, with regard to Dr. Roy\'s
question, the first question about the histopathology that you\'ve
visualized at three months after placement of this and the mechanism by
which it occurs.

Do you look at cross-sections of fallopian tubes after tubal ligation as
well?

DR. WRIGHT: We look at tons of cross-sections of fallopian tubes.

DR. SEIFER: Okay.

DR. WRIGHT: Because it\'s a big GYN practice. We see many things which
we think probably are post-tubal ligation just due to what we see on the
histopathology. However, very rarely do we actually know that these are
from patients who have had tubal ligations.

DR. SEIFER: Can you give us some information with regard to what happens
when you have recanalization after tubal ligation by any of these six
methods that were followed up in the CREST Study and how it might
compare to the kind of pathology that you see after placement of this
Essure device?

DR. WRIGHT: All right. That\'s a really good question, and I actually
have during the course of this study asked a number of GYN pathologists
as I\'ve come into contact with them about what is the pathology of
recanalization of a fallopian tube and have they ever seen a case where
they felt they could definitely say they had seen histopathological
evidence of recanalization, and in fact nobody that I\'ve spoken to,
Chris Crum at the Brigham, people in New York, a variety of people, have
ever seen things which they can tell me were truly recanalization of a
fallopian tube.

Typically, the scenario where this occurs is in the patient who presents
with an ectopic pregnancy, and in that case, the tube has got such
dramatic tubal damage, dilatation, hematosalpinx, all the things which
go along with the ectopic, that you really don\'t see an area which you
are sure has been recanalized in that preexisting tube.

What I can tell you, though, and this I feel very comfortable about, is
that the degree of occlusion and damage which we are seeing with this
device and which you saw in these pictures is order of magnitude greater
than the maximum extent of tubal damage which I see in patients with
ectopic pregnancies. We routinely with an ectopic pregnancy take a
section from the pregnancy to document the presence of the pregnancy and
then for medical and legal reasons, we always take sections from the
non-ectopic portion of the tube in order to document is there follicular
salpingitis? Is there chronic salpingitis, et cetera, for medical-legal
issues?

We never see in those cases this degree of tubal occlusion and this
degree of tubal damage that we\'re getting with this device. So that\'s
all I can say. I have never seen a tube which I am sure has become
recanalized. What I can say is that the extent of damage with this
device is much more than what we see in patients with ectopic
pregnancies.

DR. SEIFER: And just for the record, do we have any understanding of how
recanalization occurs?

DR. WRIGHT: I do not.

DR. BLANCO: Any other questions? Anyone from this side?

DR. SHARTS-HOPKO: Could somebody assure me about your confidence in
tissue compatibility with the steel and the nickel titanium?

MS. DOMECUS: I will have our vice president of research and development,
Ashish Khera, address the biocompatibility testing that\'s been done. Is
that your question?

MR. KHERA: Good morning.

DR. BLANCO: I\'m sorry. First introduce yourself, although you did a
little bit.

MR. KHERA: My name is Ashish Khera. I\'m the vice president of research
and development for Conceptus, Inc.

The materials for the Essure Micro-Insert were chosen for their long
history in use in medical applications. Specifically, nickel titanium
alloy has been used in medical implants for over 30 years. The stainless
steel that\'s on the device has also been used for over 30 years as
medical implant. The testing that was conducted on the devices was
long-term implant testing as required by FDA and ISO guidelines.

DR. BLANCO: Thank you.

MS. DOMECUS: If I can add to that, the panel was not supplied with the
summary of biocompatibility testing that we supplied in the PMA in an
effort to make sure your packages were not unduly long.

Anyway, I wanted to let you know that our biocompatibility test plan was
submitted to FDA early on. We got feedback from the FDA. We\'ve
conducted all of the biocompatibility tests required in the FDA
guidelines. The protocols for the chronic toxin mutagenicity testing
were submitted to the FDA in advance of conducting those tests. Those
results were submitted in the PMA, and it\'s been shown that it\'s not
toxic in the chronic setting and it\'s not mutagenic as well as other
studies in muscle implantation, sensitization, vaginal irritation, et
cetera. The whole battery of tests that\'s required for this category of
implant were conducted and those results were submitted in the PMA.

DR. BLANCO: Thank you.

MS. DOMECUS: Does that answer your question?

DR. BLANCO: Subir?

DR. ROY: Could I ask Dr. Cooper a few questions?

Inasmuch as hysteroscopy could be construed as being a clean
contaminated procedure, there\'s some who would have used prophylactic
antibiotics at the time of performance of this procedure, and I take it
that was a deliberate decision not to be employed?

DR. COOPER: It was my understanding that this was left to the discretion
of the investigator and only one of the investigators in the pivotal
trial made routine use of prophylactic antibiotics.

DR. ROY: Okay. Inasmuch as Dr. Wright described the profound
inflammatory response that does occur with this device, what was done
when perforations were noted?

DR. COOPER: When perforations were noted, the patients were deemed to be
candidates for traditional methods of sterilization. The devices were
retrieved at laparoscopy.

DR. ROY: With I suppose a bit more surgical intervention that
traditionally would occur or did they just slip out?

DR. COOPER: No, the diagnosis of perforation was in most cases made at
the time of device placement. In a small number of cases, perforation
was not noted until the three-month post-procedure x-ray. Retrieval of
the device at laparoscopy was not found to be problematic. In a couple
of the cases, the device was found lying in the omentum but could be
easily removed from the omentum.

DR. ROY: Okay. Because it\'s sort of like the situation with copper IUDs
being perforated. They produce such an inflammatory response, that it is
somewhat problematic, depending on where you ultimately find them,
whether the omentum is able to sequester them or other peritoneal or
intraabdominal contents, such as bowels. So I was just curious to what
extent the inflammatory process, even at a three-month interval, was
sufficiently problematic, and I guess you\'re telling me that it was
not, it was easy to find and remove without resorting to laparotomy, for
example, to do so.

DR. COOPER: Dr. Carignan can speak to this perhaps, but I don\'t recall
any of the patients required laparotomy for device removal.

DR. BLANCO: And let me ask you a follow-up on that. So did I understand
you correctly that in the perforations that you did have, most of them
were not recognized until your follow-up hysterosalpingogram, I guess,
or x-ray for placement three months later, is that correct?

DR. COOPER: Dr. Carignan can speak to this.

MS. DOMECUS: The protocol actually didn\'t ask for a diagnosis of
adverse events that can prevent reliance, such as perforation, until the
three-month time point because conceivably someone on the day zero x-ray
could have had a device that was well located and then on a three-month
follow-up could have had an expelled device. So we actually ask in the
protocol for them not to take action based on the day zero x-ray. The
perforations were noted, though, at the three-month follow-up visit as
well as the day zero x-ray and one physician did take action based on
the day zero perforation.

Dr. Carignan can address maybe in more detail the earlier questions
about device retrieval in those perforated patients who went on to
subsequent tubal ligation.

DR. BLANCO: Okay. Go ahead.

DR. CARIGNAN: So in both the pivotal trial and Phase II, we had nine
women undergo laparoscopic sterilization procedure with five removals
prior to their reliance on the device. In the pivotal trial, there were
four sterilizations performed. Two of them had retrieval of devices and
two did not have retrieval. In the Phase II study, in the prereliance
phase, we also had five women undergo sterilization procedures. Three of
them had retrieval and two did not.

We\'ve had no postreliance women in the pivotal trial undergo any
surgery to remove devices but we have had two women in the Phase II
undergo surgery, both of them with perforations. One of them underwent
just a typical laparoscopic sterilization with a retrieval and the other
woman did undergo a laparotomy to remove a device. So of the retrievals
that we had of 11, only one underwent laparotomy, mainly because it was
the standard of care of the doctor that did the removal. Of the women
whose devices have not been retrieved, we\'ve not had any reports of
unusual pain that can be attributed to the device location.

DR. BLANCO: Let me get a follow up. In perforations, it is typical in a
lot of the devices that other OB/GYNs or at least this OB/GYN is
familiar with, the device is actually moved into placement as opposed to
the way the technique is here where the catheter is moved away.

Is there any fail-safe mechanisms in the way your device is handled that
someone can make the mistake of advancing this process further into the
tube, rather than removing the catheter? Do you understand what I\'m
asking?

DR. CARIGNAN: Yes. The fail safe that\'s built into the design is
related to the black bump at the time of initial positioning. Then
during the training, we stress maintaining that position during the
release of the device.

The other thing that we emphasize during training is if you experience
what we define as a sudden loss of resistance, so that you feel that
you\'re going into the tube, and suddenly you feel like a little, you
know, pop, that you would then recognize that as a potential perforation
and not place the device and that\'s part of the training program that
we emphasize.

DR. BROWN: Specific to the patients, the nine patients you just talked
about, were all of those patients that had the current iteration of the
device, because I thought there was something mentioned about a patient
who had to have cornual resections and that was with a previous
iteration of the device?

DR. CARIGNAN: The one that had the cornual resection was one of our
early Phase II patients and after two years of reliance began having
some pain with menses and she requested to have the device removed. So
she was one of our earlier patients from early 199.

DR. BROWN: But was that ‑‑

DR. CARIGNAN: The current design.

DR. BROWN: That was with the current design?

DR. CARIGNAN: Correct.

DR. BROWN: Why was cornual resection necessary in that case?

DR. CARIGNAN: Because the device spans the utero-tubal junction, the way
to get it out is to do a cornual resection.

DR. BLANCO: A follow-up on that, because I had that as a question. On
the patients that had continual ‑‑ you said a few questions, I forgot
the exact number, had continual symptomatology of cramps and pains and
so forth. What other experience except other than this one case do you
have for someone who has chronic complaint, desires the removal of the
device, in terms of removing the device? Is cornual section the only
option for removal of the device if someone wants it removed? Do you see
what I\'m saying?

In other words, can you go back, do you have any experience going back
with hysteroscope trying to pull the device out or do you have to resect
the corneum?

DR. CARIGNAN: When a device is well positioned across the utero-tubal
junction, because of the extensive fibrosis, it does require a minimal
cornual resection to remove the device. The only time that we ever
actually recommend removal of the device hysteroscopically is if during
the procedure, you recognize that you haven\'t positioned it far enough
into the tube or you inadvertently deploy it into the uterus that you
would then remove it and replace the device. Subsequent to placement, we
do not recommend hysteroscopic removal of a well-positioned device.

DR. NOLLER: Question.

DR. BLANCO: Go ahead.

DR. NOLLER: I have a question regarding the training plan. It wasn\'t
clear to me. In the five cases that are precepted, is there a
requirement that those all be done under local anesthesia?

MS. DOMECUS: Anesthesia is always left up to the choice of the
physician. There\'s no requirement that it be done under local.

DR. NOLLER: Even during the training?

MS. DOMECUS: Correct.

DR. NOLLER: Thank you.

DR. SHIRK: I had some questions for Dr. Cooper.

There\'s not any discussion about preexisting pathology found at the
time of hysteroscopy. As any of us who do hysteroscopy know that we do
find occasionally, you know, pathology in the uterine cavity, and I
would assume that\'s not previously been diagnosed. How many of these
patients had preexisting pathology in the uterine cavity, and how would
you recommend that this be handled?

DR. COOPER: First of all, you may recall that years ago, I had
considerable experience with another hysteroscopic sterilization
technique and as part of that experience, I studied what was the rate of
intercavitary pathology found at the time of an elective sterilization
procedure and was amazed to find that in fact it was a very low
incidence of pathology and rarely did the pathology interfere with the
ability to identify and place the device.

In this case, as Dr. Carignan showed you, I think there were 11 cases of
women undergoing hysteroscopy in whom devices could not be placed
because the tubal ostia could not be identified and that would include
women who had cornual pathology, such as fibroids or polyps, that would
obscure the view of the tubal ostia or perhaps intrauterine adhesions
that had scarred the fallopian tube making them not visible. But as a
general rule, the young woman with no abnormal menstrual complaints is
unlikely to have intracavitary pathology which would preclude the
ability to place the devices.

DR. SHIRK: If you, say, found a small submucosal fibroid, would you
continue to place the device?

DR. COOPER: I would.

DR. BLANCO: Dr. Brown?

DR. BROWN: In the Volume 1 of what we received, there was a statement
made, and I think it\'s also, I believe, on the labeling information
that there is limited to no information about subsequent surgical
procedures, including D&Cs, endometrial biopsies, hysterectomies, in
these patients, and my question was in the follow-up, have you actually
had patients who\'ve had devices placed that have had to have, say, a
D&C for abnormal bleeding, and do you recommend that those patients are
‑‑ I interpret it was implied that at that point. They can no longer
reliably rely on this method of contraception or what do you tell
somebody, say, who needs a D&C for abnormal bleeding, who has had this
device in for two years? Does she need to use something else?

DR. COOPER: Thank you for I think an important question.

We have experience in two of the four women who had luteal phase
pregnancies, chose pregnancy termination. The procedure was accomplished
with a suction D&C. Despite the fact that the devices had not been worn
for the requisite three-month period of time, in neither case were the
devices disrupted with the suction D&C, and women went on to rely on the
Essure devices for long-term contraception.

We also have in the commercial population reports of five women who have
undergone D&C for evaluation of abnormal bleeding with no disruption of
the device, and it has been my experience as a clinician for many years
that the routine evaluation of the woman with abnormal bleeding
generally consists of a papule endometrial biopsy. Even a vigorous and
thorough papule endometrial biopsy probably samples less than four
percent of the endometrial surface. I find it all but impossible to
imagine that the suction that is created with a papule catheter could
dislodge or interrupt a properly placed Essure device, particularly
given its three-month period of time to allow for tissue ingrowth.

DR. BROWN: So what do you tell the patients? So what would the labeling
specifically say about patients who have to have these procedures
subsequently?

DR. COOPER: I would suggest that women who experience abnormal uterine
bleeding who are wearing this device or, for that matter, any woman
experiencing abnormal bleeding undergo a visual evaluation of the
uterine cavity, to include diagnostic hysteroscopy, and I think that
makes good sense, whether a woman is an Essure device-wearer or not.

DR. BROWN: Okay. And then, can you comment about also the mention that
electrocautery should not be used in women who are having, I would
imagine, hysterectomies or other procedures? Is that because of a risk
of burning or sparking or what? Could you comment from the biophysical
‑‑ I mean, how would that happen exactly?

DR. COOPER: Again, the recommendation or the labeling suggests that we
would ‑‑ we don\'t have enough information at this point in time, given
the length of the trial, to speak to this, but we have admonished or
warned physicians to not use electrocautery within a four-centimeter
length from the Essure device, and we do know that at hysteroscopic
endometrial ablation used with rollerball, again in the commercial
population, not in the clinical trial, we know that procedures have been
done and have been done safely which would suggest that the physician
has visual control of the rollerball electrode and is keeping the
electrode a safe distance from the device.

DR. BROWN: What would happen if you touched the electrode to the coils
that are sticking into the ‑‑ I mean, what would physically happen?

DR. COOPER: Let me have Dr. Carignan speak to that.

DR. CARIGNAN: As we showed you earlier, we had quite extensive
prehysterectomy and perihysterectomy studies that were conducted with
the devices in situ. During those procedures, electrocautery was used
very commonly. We did recommend that they stay clear of the device for
the reasons that Dr. Cooper has outlined. In one instance where the
device was touched where that ball would basically be going through, you
could see that there was a little blanching of the tube. So we do
recognize that with our RF-type energies, it is likely to conduct when
it\'s touched.

DR. BLANCO: All right. Let\'s go ahead and start wrapping it up because
it\'s getting time for the break. So if we have a couple of other
questions of fact.

DR. O\'SULLIVAN: I still am having a little bit of trouble understanding
how this device creates adhesions in the fallopian tube, yet when the
device is in the peritoneal cavity, that doesn\'t seem to happen. Is
that what I\'m understanding, and if so, why not?

MS. DOMECUS: I\'ll ask Dr. Wright to come to the podium again since he
did the histological analysis of the devices in both of those
categories.

DR. WRIGHT: In the tube, probably one of the initial inciting events is
the fact that you have this outer coil which expands out and causes, I
assume, trauma to the epithelium and to the plicae extending in from the
tube wall, into the lumen, and that sort of trauma then probably starts
stimulating the entire inflammatory response which then generates the
fibrotic response.

In the two tubes which we have looked at histopathologically, the two
devices which we process which were retrieved from the peritoneal
cavity, both of those showed some inflammatory infiltrate and some
fibrosis immediately around the inner coil which is where the PET fibers
are. So you\'re going to have macrophages and inflammatory cells free in
the peritoneal cavity. They are going to sit there. You\'re going to get
some fibrosis.

What we did not see with those from the sections of them was dense
adhesions and dense fibrosis of bowel or anything or adipose tissue
tightly adherent to the Micro-Inserts. Why we\'re seeing the difference
there, yet compared to what you\'re seeing in the tube, I\'m not sure,
unless it\'s due to the fact that when it\'s in place in the tube,
you\'ve caused damage with the outer coil generating this whole cascade
of events.

DR. O\'SULLIVAN: One last question. What was the longest period of time
one of these was retrieved from the time of perforation to the time it
was retrieved? What was the longest period of time?

DR. WRIGHT: I\'d have to ask Chuck because I was blinded to all the
wearing times and we only unblinded me to the tubes recently. Chuck,
what were the times, the longest time?

DR. CARIGNAN: The longest time that we have with any iteration that used
the PET fibers in a similar configuration was actually a patient with
the beta design who just recently had her devices removed after just
about four years of them being in place, and one of the devices was in
the pouch of Douglas and when the surgeon went in, he was able to just
laparoscopically go in, identify the device and pull it right out.

DR. O\'SULLIVAN: Do you know why? I mean, you\'re still assuming, Dr.
Wright, that this is all related to the fact that it\'s trauma
initially?

DR. WRIGHT: I think it\'s very different when you have a device with PET
fibers sitting in a \"closed cavity\" than when you have that same sort
of device free in the peritoneum.

DR. BLANCO: Let me go ahead because we\'re starting to run a little late
on time, cut it short. You might just want to consider in some of your
biocompatibility data, you probably did some studies of putting the
device inside animal models and looking for adhesions. So maybe you can
look that up and see if you can bring forth any information that might
try to answer that issue on that, and then I think we have one question
over here and actually I have one question afterwards.

Go ahead.

DR. DUBEY: Yes, this goes for Dr. Cooper or Dr. Wright. Can you answer
the question about if the device is extending into uterine cavity, and
from the slide, I see about three to eight expanded coils will be
hanging in the uterine cavity on either side, what will be the tissue
development there, and how much uterine cavity will be compromised? This
is mainly for the patient who may need IVF for the implantation process.
Do you have any idea about that?

DR. COOPER: We have no experience with patients in the clinical trials
who have chosen IVF. Undoubtedly this will happen as the years go by. My
own personal opinion is that the device will not offer a problem for
IVF, and my reason for thinking this is that approximately three or four
millimeters of this device extend into the uterine cavity and can really
only be seen with rather significant distention of the uterine cavity.

As we know, under normal circumstances, the walls of the uterus are all
but touching each other, and I think it\'s unlikely that this small
nidus that may in fact be covered over with fibrosis anyway is likely to
interfere with a pregnancy. That\'s just one man\'s opinion, but we have
no clinical evidence to support or refute that view.

DR. SEIFER: In the material, there was a recommendation for ‑‑ there\'s
18 coils that are visualized in the uterine cavity, and you\'re supposed
to leave the device in place, is that correct?

DR. COOPER: Do you want to speak to this?

MS. DOMECUS: Go ahead.

DR. COOPER: We believe that the ideal-positioned device has three to
eight coils extending from the uterine cavity.

DR. SEIFER: Right.

DR. COOPER: We believe that a device that has as many as 15 or 18 coils
will probably be effective in achieving long-term contraception.
There\'s a difference between an effective device and what we would view
as ideal placement.

DR. SEIFER: Right.

DR. COOPER: What you have to appreciate is that the black positioning
bump has allowed us in our clinical trial to develop a far greater
assuredness that our device is placed at the ideal position, but the
device is four centimeters in length for just that reason, to be certain
that even if it were extending slightly more into the uterine cavity
that it would achieve long-term contraception.

DR. SEIFER: Do you have any idea of what the frequency is of having the
device hang out that amount? In other words, of the 20 investigators,
what sort of incidence occurred that you would have improper placement
of the device but you would leave it in place?

MS. DOMECUS: We can look up the rates of those long trailing lengths in
the trial, but I wanted to clarify the reason that labeling suggests
that you should try to remove a device with a trailing length of 18 or
more coils is because we found in the clinical trials that such devices
are likely to expel and that the labeling instructs that the removal
should occur immediately during the placement and not allow the tissue
ingrowth process to occur.

DR. SEIFER: But do you think the labeling might reflect something
regarding potential adverse effects if it stays in place and it\'s not
properly in place?

MS. DOMECUS: I\'m sorry. The question is?

DR. SEIFER: In other words, if 18 coils are hanging out or less but
it\'s not properly placed, would the response with regard to Dr.
Dubey\'s question ‑‑ I think Dr. Brown\'s question ‑‑ would it change?

MS. DOMECUS: If 18 or more coils are trailing into the uterine cavity,
by definition, it\'s not well placed, and we\'d recommend that such
devices be removed so that the patient doesn\'t undergo a subsequent
expulsion of it.

DR. SEIFER: I don\'t mean to quibble here, but if it\'s not 18, it\'s
16, whatever?

MS. DOMECUS: Right. Then it should be left in place.

DR. SEIFER: And would your concern about difficulty implantation or
scarring of the uterus or any of the sorts of concerns that have been
brought up, would that change your attitude about that?

MS. DOMECUS: I think ‑‑

DR. BLANCO: I\'m going to go ahead and cut that short. If you want to
think about what you want to answer that, we\'ll give you some time
later on, but we\'re running out of time.

I\'d like to ask one question. In the issue of hysterosalpingogram
versus the pelvic x-ray, have you looked at this device with ultrasound
as a method to confirm placement at the end since you can see the uterus
a little bit better with ultrasound than you can with just a plain x-ray
of the pelvis?

DR. CARIGNAN: In our Phase II study, a number of the investigators did
use ultrasound to visualize the device location at three months. We did
not control it to evaluate it against the location as seen on x-ray.
However, with our own internal retrospective review of the x-rays and
the hysterosalpingograms, including the scout film of those
hysterosalpingograms, in the Phase II study, it would show a strong
correlation with what was seen on ultrasound versus the x-ray, but as I
said, we\'ve not controlled for that. All of the investigators, though,
anecdotally reported they can see it well and commercially, there are
people who are obviously very interested in looking at using ultrasound
to identify device location.

DR. BLANCO: Thank you.

We are now running 15 minutes late, for which I apologize to the panel.
We\'ll go ahead and take our break. It\'s now 11:15. We\'ll start
promptly at 11:30 with the rest of the presentation.

Thank you.

(Recess.)

DR. BLANCO: All right. Let\'s go ahead and get started with the
presentation by the FDA, and we\'d like to go ahead and begin with Lisa
Lawrence, the lead reviewer for this particular PMA.

MS. LAWRENCE: Thank you.

Good morning, ladies and gentlemen, distinguished panel members, and
guests. I am Lisa Lawrence, lead reviewer for FDA on this PMA, and I\'m
here to give you a brief overview of the review process that we have
gone through on the Conceptus Essure Micro-Insert.

My presentation will cover a brief overview of the following: device
description, I will highlight the PMA review areas and the review team,
overview of the IDE and PMA review history, and preclinical reviews.
After me, Julia Corrado, our clinical reviewer, will discuss the
clinical studies, and Gene Pennello, our biostatistician, will discuss
the biostatistical aspects of these studies.

The intended use of the Essure Micro-Insert System is for permanent
birth control by occlusion of the fallopian tubes. On the top is the
picture of the Micro-Insert System. On the left is a close-up look at
the distal portion of the delivery catheter which has the Micro-Insert.
On the right is the Micro-Insert as it appears when it is expanded.

Next, I would like to acknowledge the review team. The next two slides
list our review team. As you can see, a number of people have been
involved in the review of the PMA application. Dr. Harvey, Dr. Julia
Corrado, Dr. Pennello, and Dr. Marinac-Dabic are looking at the key
clinical and proof-of-concept studies. Dr. Virmani, Dr. Kammula, and Dr.
Zaremba are looking at the material safety. Continuing with this slide,
Ms. Price, Dr. Whang, and Mr. Kuchinski are looking at the preclinical
concerns. Inspections are being done by Ms. Crowl and Mr.
Murrain-Ellerbe, and Ms. Mendelson is reviewing the professional and
patient labeling.

Next, now I\'d like to briefly review some of the history leading up to
the Conceptus PMA submission. There are four clinical studies that
appear that support this PMA. In 1996, we approved two clinical
feasibility studies, the perihysterectomy study where patients were
scheduled for hysterectomy immediately following the device placement
and a prehysterectomy study where patients were scheduled for a
hysterectomy six to 12 weeks following placement. In 1998, we approved a
multicentered clinical study to test the device in a woman who went off
alternative contraception, the so-called Phase II study. This is still
ongoing and we have a limited amount of two-year data available, and
finally, in 2000, we approved the pivotal study. We will spend a lot of
time today talking about this study which is still also ongoing.

In June of 2000, we had a meeting with Conceptus. Pardon me. I\'d like
to talk a little about the determination/agreement meeting we had with
Conceptus in June of last year. Obviously the pivotal study was already
underway but Conceptus was seeking additional commitment on the part of
FDA for the clinical development plan. During this meeting, FDA and
Conceptus agreed that FDA will file the PMA if the pivotal study had a
minimum of 400 patients with one-year follow-up and these subjects met
formal inclusion/exclusion criteria, adhered to predetermined follow-up
schedule, had met specific age requirements.

It was also agreed that the Phase II study would have 100 subjects with
two years of data and that Bayesian statistics would be used to analyze
the one-year and two-year failure rates. Finally, the mechanism of
action of the device would be supported by data from the prehysterectomy
study.

When Conceptus submitted its PMA, the company requested an expedited
review. In particular, Conceptus noted that in contrast to other devices
for tubal sterilization, typically the laparoscopic length of the Essure
device could be placed without an abdominal incision and without general
anesthesia. We granted the request for the expedited review, citing one
of the four criteria to be used; namely, that this device offer
significant advantages over existing approved alternatives. Expedited
review means that the application takes a higher priority than the due
process. It does not mean the length of review standards.

We are only 90 days into the PMA review process and many of the reviews
are still ongoing. We do not think that this should keep this important
PMA from coming before the panel, but I would like to briefly advise you
of the status of some of the reviews. On the left, I have listed reviews
we\'ve already completed. The animal studies went on to support initial
proof of concept and provide some basis for moving into the clinical
phase. Obviously we\'re well past that phase. Our review gave us some
confidence of proof of concept and potential for effectiveness. Our
review of the MRI compatibility showed that women with implanted Essure
devices can undergo MRI procedures without fear of adverse effects.

On the right are the ongoing reviews. The engineering review covered the
mechanical properties of the device. No issues have surfaced so far. For
chemistry and shelf life, we looked at corrosion of the metals and
continuing functionality following aging. We are also looking at
mutagenicity and device sterilization of the material that could contact
the patient body. For material safety, we found that the appropriate
testing was conducted for this implant device. The sponsor has chosen a
material that has a long history as an implant material.

Our PMA review also includes inspections. We inspect some of the sites
in the clinical trials as well as the data collection analysts sent us.
This bioresearch monitoring review looks at study execution,
recordkeeping and informed consent. We also expect the manufacturing
facilities to ensure compliance with design controls. These inspections
are still ongoing.

I have reviewed a brief device description. The review areas highlighted
the PMA review process, giving you an overview of the IDE and PMA review
history and this concludes my presentation.

Thank you, and next, Julia Corrado will be speaking on the clinical
issues.

DR. BLANCO: Thank you.

DR. CORRADO: Thank you, Lisa.

Good morning, everybody. My name\'s Julia Corrado, and I\'m the medical
officer in the Obstetrics and Gynecology Devices Branch who reviewed
this PMA.

The outline for my talk will be as follows: I\'m going to give an
introduction to the device and a little bit of background in the area of
transcervical sterilization. I will then focus on the safety and
effectiveness of the Essure System, based on the clinical studies, and I
will throughout my talk draw your attention to the discussion questions
that we have provided for the panel.

To remind everyone, the indication for use of the Essure System is
permanent birth control. That is, female sterilization by occlusion of
the fallopian tubes. The principle of operation is that polyethylene
fibers that are wound throughout the inner coil of a double-coil system
elicit a tissue response that results in ingrowth of fiberglass smooth
muscle and inflammatory cells. This process eventually causes complete
occlusion of that portion of the fallopian tube where the Micro-Insert
resides.

As Dr. Cooper alluded earlier in his presentation, the Essure System is
not the first transcervical sterilization device that has seen clinical
use in the United States. There were two investigational stage devices
that saw clinical use in the 1980s and possibly into the 1990s. I want
to make the point that these devices are completely unrelated to the
Essure device and also that they never saw commercial use in this
country, only investigational use. One was a tubal plug and one was a
chemical sclerosing agent.

I\'m not going to say any more about this, except to make the point that
there were sterilization failures following use of these devices. Some
of those failures were related to misreading or misinterpretation of
pelvic x-ray and/or hysterosalpingogram and that this point will come up
later in my presentation when I\'m discussing the Essure device.

As you\'ve heard, there was a perihysterectomy study done at the time of
hysterectomy. There has been a prehysterectomy study where the placement
as well as tolerance to the device and histology was evaluated. The
Phase II and the pivotal studies provided contraceptive efficacy data as
well as long-term safety data and they are still ongoing. I also want to
say that I am not going to discuss the perihysterectomy study at all.
I\'m going to begin with the prehysterectomy study, the objectives of
which were to evaluate device placement, tolerance to the procedure,
relative long-term wear ‑‑ that is, wear out to approximately 14 to 20
weeks ‑‑ and the stability of the device in the fallopian tube once
it\'s placed and occlusion, and the objectives of the study identified
that occlusion might be evaluated as early as 24 hours up to
approximately 12 weeks.

I highlighted tissue response here because that\'s really all I\'m going
to say about it, and in that light, I will just briefly reiterate what
we\'ve already heard from Dr. Wright. The results of this study were as
follows: 53 women actually wore devices. The wear time is as indicated
on this slide, from predominantly between four and 14 weeks.

One of our panel discussion questions had to do with the tissue
response. You have had an opportunity to discuss that at length already,
and I don\'t see any need to spend a long time on this slide, except to
just reiterate that PMNs were common in shorter wear times and in dense
fibrosis set in after approximately four weeks of placement. Also, I\'d
like to emphasize a couple of points that were said earlier, and that is
that there was no evidence of any serosal reaction following placement
and normal fallopian tube architecture was observed approximately five
millimeters distal to the tip of the Micro-Insert.

Now, I\'d like to turn my attention to the Phase II study, the
objectives of which are noted here and virtually identical to the
pivotal study. The company wanted to evaluate long-term safety,
stability, and contraceptive effectiveness. This study and the pivotal
study were prospective multicentered non-randomized studies with planned
five-year follow-up with subjects.

The demographics of the Phase II study is listed here. I\'d like to just
point out that the demographics of this study are different from the
demographics of the pivotal study. Gene Pennello, our biostatistician
who will speak after me, will discuss the differences in the
demographics of these two studies. Suffice it to say that a large
proportion of the Phase II patients were 34 to 45 years old. In the
pivotal study, the age distribution was much younger.

In the Phase II study, 18 women were treated with the beta version of
the device that was eventually discontinued. 227 women were treated with
the gamma version of the device in a total of 233 procedures. The
results for the gamma device are as follows. We\'ve been very interested
in bilateral placement rates at first attempt. That is, on the first
trip to the operating room, what percent of the patients came out of the
operating room with devices successfully placed in both tubes. In the
Phase II study at first attempt, that percentage was 86 percent. Of
those women, at three-month post-device placement, hysterosalpingogram,
97 percent had bilateral occlusion and so the point I\'d like to make
with this slide is that successful bilateral placement does not
necessarily equal successful bilateral occlusion, although the bilateral
occlusion rates weren\'t very high.

Briefly, I wanted to mention an aspect of the Phase II study experience
with that earlier, now discontinued, beta device. The bilateral
placement rates for one thing were lower than for the gamma device and
the company may be in a better position than I am to talk about this
contributing to their development of the gamma device, but I would like
to say that there was one pregnancy with the beta device in a woman who
was relying on that device for contraception. Regarding that pregnancy,
the following things can be said. The optimal nature of device placement
was questionable from what I\'ve been able to glean from that case. That
is, there were somewhat conflicting results on x-ray and, I believe,
pelvic ultrasound, although the company may want to address this.
Nevertheless, there was not a clearcut satisfactory device placement in
that case.

However, the woman, the patient, in that case did rely on the device for
contraception and at approximately 23 months post-reliance, she was
diagnosed with an intrauterine pregnancy. She carried that pregnancy to
term. It was uncomplicated, except that at full term, she developed
preeclampsia and she underwent delivery by repeat Caesarean section at
approximately 38 weeks.

Around nine months after she delivered, she began to experience groin
and thigh pain and this got to the point where she believed that it
might be due to the device and she requested removal. Therefore, she had
surgical removal of this device, following which all of her symptoms had
resolved. As the sponsor mentioned this patient in their presentation,
one of the devices was in the pouch of Douglas. The other device was in
the desired position in the utero-tubal junction on the left, in the
left fallopian tube.

Regarding effectiveness for the Phase II study, as of the database
freeze in late May of this year, 194 subjects had relied on the device
for 12 months, and there are no pregnancies in that group. Neither are
there any pregnancies in the women in the Phase II study have now gone
out to 24 months.

Regarding the gamma device in the Phase II study, I\'d just like to
summarize some adverse events. There was six perforations in a total of
233 procedures. Two women had vaso-vagal reactions, either in the OR or
in the recovery room. Ninety-three percent had the procedure performed
under local anesthesia or IV sedation. Only 4 percent had general
anesthesia. One-hundred fifty-three out of 233 in responding to a
question regarding intraoperative pain reported that they did experience
intraoperative pain. However, 63 percent of that 153 stated that the
pain was less than or equal to what they expected during the procedure
and 26 percent responded that it was greater than what they expected
during the procedure.

Within one week of the procedure, 81 percent of these subjects reported
some bleeding which might have constituted spotting, 1.7 percent
reported fever. However, in all cases, the fever had responded within 12
hours, had resolved within 12 hours. There was one expulsion diagnosed
at three months post-procedure. Acceptability was good to excellent as
reported at one week. That was for a rate of 90 percent, and at 3 to 24
months post-procedure, 88 to 94 percent of the subjects reported
excellent tolerance.

I\'d like to now turn to the discussion of the pivotal study and as you
can see, the objectives and the design were virtually the same as the
Phase II study. Question 2 had to do with demographics of the pivotal
study population. As I pointed out earlier, the demographics of the
Phase II study were somewhat different from the pivotal trial. In the
Phase II study, the women were older, basically 70 percent of them were
older than 34, and in this study, the distribution was approximately 60
percent were younger than 33, and I also would like to say in fairness
to the sponsor that their study design did not break out the
demographics into three groups. FDA wanted to look at it as we
understood that the demographics in the CREST Study had been considered.

Question 5 had to do with bilateral placements. 446 out of 507 patients
in the pivotal study who underwent an attempt using the device had
successful bilateral placement on that first trip to the operating room.
Of the women who did not have successful bilateral placement in the
first attempt, some of them after HSGs demonstrating tubal patency, went
back for a second attempt and that brought the total number, the total
percentage of women who ultimately had bilateral placement up to 92
percent.

Of women who got bilateral placement, the 464 that is who got bilateral
placement, 452 are relying on the device for contraception. Twelve women
were lost from the relying group because at three months, there were
perforations diagnosed. There were unsatisfactory device locations and
expulsions.

Question 1 had to do with the effectiveness, and I\'d like to say here
that as of our database freeze in late May, there were data in on 408 of
the 452 in the population of women relying on the device. As of that
date, we were expecting data for 27 women and there were patients who
were lost to follow-up. These numbers have changed somewhat, based on
data received on patients who have had their follow-up since May 24th.
There continue to be no pregnancies, and I should also mention that we
expect all of the 12-month data from the pivotal study to be received
prior to the end of the 180-day review period for the PMA.

Regarding pivotal study, I\'d like to just highlight that within 24
hours of the procedure, the following adverse events were observed: one
perforation was diagnosed within 24 hours, there were two cases of
hypervolemia, and three women experienced vago-vasal responses. At three
months post-procedure, there were some additional perforations that were
diagnosed on hysterosalpingogram. Also, there were some device
expulsions diagnosed on HSG.

The next group of adverse events described at three months were
intramenstrual bleeding, irregular menses, heavier menses, and lighter
menses, and what I\'d like to say about this table is although these
data are in the PMA, they might in some cases represent one episode or a
single incident of one of these events. So they don\'t imply a recurrent
or persistent adverse event. In that light, I\'d just like to look at
the following table. I\'d like to spend a minute or so going through
this table. On the top row, we\'ve identified the number of patients who
filled out questionnaires at baseline, at three months, at 12 months,
and then that last column represents a category that consists of women
who reported this particular adverse event at all four of the follow-up
visits that occurred after device placement. So persistent means she
complained of this problem at all of the visits. So if we look at
irregular bleeding and look at the baseline percentages and then at
three and 12 months and persistent, you get a perspective on how often
these happen from the persistent column. Similarly, with intramenstrual
bleeding, that three-month number is 24 percent. That seems very high
compared to baseline, but as it turns out, perhaps only one of these
cases was actually a patient who persistently reported this problem, and
with that, I\'d just like to in all fairness note that there were women
who noted lighter bleeding, who reported lighter bleeding after the
device placement procedure than before.

Pelvic pain. I\'d like to just go through a similar analysis. You can
see the baseline rate of this complaint, and we\'ve broken down pelvic
pain into dysmenorrhea, dyspareunia, ovulatory pain, or other, and other
means none of the above three. If you look at this table, it would
suggest that, gee, dysmenorrhea which occurred in 35 percent of the
women was occurring at baseline really improved after the device
placement and that is not necessarily the case, but nevertheless these
are women who reported significant complaints following device
placement. Nevertheless, the numbers who are considered under the
persisting category are either zero or very, very small.

The last row that is entitled \"Other\" I\'d like to draw your attention
to because this is going to be a question that we ask ourselves when
we\'re looking at the labeling for the device, and that is whether or
not there is some pelvic pain that women experience after placement of
the device that is not dysmenorrhea, it\'s not dyspareunia, it\'s not
ovulatory pain, and the question being is there any kind of discomfort,
residual discomfort following placement of the device? Again, the
three-month and 12-month data would make us wonder, yet when we ask who
experienced this complaint persistently at all four visits, it\'s very
low.

As the sponsor mentioned, there were four pregnancies during the pivotal
study. However, these pregnancies were not among women who were relying
on the device for contraception. As a matter of fact, early first
trimester sonogram confirmed that conception occurred prior to
Micro-Insert placement, although these pregnancies had not been picked
up on the pregnancy test that was required within 24 hours of the
procedure. Three of these women chose not to continue the pregnancy and
one had spontaneous AB and all four of these women are in the population
of women relying on the device, and they did not have any further Essure
procedure following the initial placement.

Earlier this morning, the panel discussed the issue of device removal. I
think that that is very important. In the event that a woman would like
to have the device removed, the procedure, as a generalization, cannot
be performed hysteroscopically. There have been no requests for device
removal among women and in the pivotal study, it was left as an option
to remove the device at pelviscopy in women who were undergoing a
pelviscopic approach to sterilization.

I should mention that in the Phase II study, one woman underwent surgery
to have the device removed because of a complaint of pain. In the
pivotal study, there were four attempts to remove devices that had
perforated. All of these attempts took place during pelviscopy, the
purpose of which was to undergo an alternative form of sterilization.
Two devices were successfully retrieved at pelviscopy and two were not.
The women who continued to have those devices in their peritoneal
cavities are apparently without complaint.

Patient comfort has been very good, as you see from this table. PDP in
that middle column stands for post-device placement. So those statistics
were gleaned from questionnaires filled out at three months after the
device was placed. In the next column, PAC stands for post-alternative
contraception, and although post-alternative contraception was 15 months
post-device placement for many patients, nevertheless because some women
required repeat HSGs, that one-year post-alternative contraception is
not necessarily 15 months following device placement, and if you
calculate the percentages that fall into the very good and excellent
category, we\'re in the mid-90th percentile for both groups at three
months post-device placement and at a year post-alternative
contraception and the percentages of women reporting poor comfort are
extremely low, as you see.

Patient satisfaction. I\'m not going to go through that same analysis.
The story is basically the same. Very high rates of somewhat to very
satisfied and very low rates of very dissatisfied.

Question 7 has to do with the training program. Basically, the training
program the sponsor\'s proposing for commercial use involves didactic
materials, experience and practice with the hysteroscopic simulator, and
preceptoring of initial cases. I\'d like to point out that when we
consider the question of are we going to get the same types of bilateral
placement rates, for example, in commercial use as we had in the pivotal
trial, that a lot of the investigators in the pivotal trial had prior
experience with the device. So our question was is it going to be enough
to get didactics, to get simulator training, and preceptoring? It might
be a small point, but nevertheless those perihysterectomy cases did
provide some of the investigators with actual OR experience placing the
device prior to going into the Phase II and the pivotal studies.

The three-month work-up is another issue, and here, I\'d just like to
recall for you all that when I was talking about those earlier
transcervical sterilization investigational trials, that there were
pregnancies among women who were told on the basis of pelvic x-ray or on
HSG that they could rely on the device for contraception who
subsequently became pregnant, and also in the Phase II and the pivotal
study for this device, the women did get HSG at three-month
post-placement. So we think that it\'s important to get the panel\'s
input on whether or not a pelvic x-ray is going to be satisfactory in
lieu of HSG.

Now, I\'d like to also point out that this would only be the case if
pelvic x-ray indicated that device location was satisfactory. If there
was questionable or suspicious or unsatisfactory device location on
pelvic x-ray, that patient would not be told that she could rely on the
device and she would go on to further evaluation.

One of our issues also has to do with postmarket surveillance, and we
were very fortunate this morning to have a presentation by Dr. Costello
about the findings of the CREST Study, and I\'d just like to highlight a
couple of the lessons that were learned and that was the cumulative rate
of sterilization failure continues to increase beyond two years, that
there were ectopic pregnancies as we all know in women who have
sterilization failure, that the device and patient age seemed to have a
bearing on sterilization failures, and very importantly, that the
duration of follow-up is one of the things that makes that CREST Study
such a landmark study, that, you know, they followed up approximately
10,000 women well past two years, many of whom were followed out to 10
years, and in that light, we want to more or less capitalize on lessons
learned in that study and ask the question: how far out should you
follow a patient population following a sterilization procedure to learn
about things like sterilization failure and the rate of ectopic, and how
many women do you need to follow out, and also what are the lessons
learned from CREST in terms of minimizing loss to follow-up?

In summary, I have hoped to present for you a summary of FDA\'s review
of the effectiveness and the safety of the Essure Micro-Insert System
and also provide for the panel a feel for patient acceptability, and
I\'ve tried to tie some aspects of our review into specific discussion
topics that we\'ve identified for the panel.

At this time, I would welcome any questions the panel might have, and if
there are none, I would like to turn the podium over to Gene Pennello,
our biostatistician.

Are there any questions?

DR. BLANCO: Dr. O\'Sullivan?

DR. O\'SULLIVAN: You said there were several cases of what is listed in
the data that we have of luteal phase pregnancies that occurred prior to
insertion of the device.

DR. CORRADO: Right. That\'s correct.

DR. O\'SULLIVAN: The device was supposedly inserted between the seventh
and the 14th day.

DR. CORRADO: These were luteal phase insertions. Actually, they might
have even been late luteal phase insertions.

DR. BLANCO: Thank you.

DR. CORRADO: At this time, Dr. Pennello will present the biostatistical
review.

DR. PENNELLO: Thank you, Julia.

Good morning, panel members. My name is Gene Pennello, and I work at the
Division of Biostatistics at CDRH, and I provided a statistical review
for this Conceptus Essure System, and I\'d like to summarize that review
for you today.

Just to give you an outline, I\'d like to talk a little bit about this
study design in the pivotal and Phase II studies, give you some facts
about the patient population, review the patient tree that is available
in your handout or in your panel packet, and then I\'ll give you an
accounting of the patients and then go to talking about the
effectiveness analysis and mention some adverse event results that I
think are notable and summarize.

First, the study design. I\'m only going to consider in this
presentation the pivotal and Phase II studies. In the pivotal study,
there were 20 investigators at 13 sites and to date, there\'s data
available out to one-year follow-up post alternative contraception. In
the Phase II study, there were five investigators at five sites, and
there\'s data available at two years, and I want to mention up front now
that in the effectiveness analysis was a Bayesian analysis which I\'m
going to explain a little bit about later. Bayesian analysis is useful
for combining prior information with clinical data and the Bayesian
analysis was used to combine the Phase II data with the pivotal study
data using the Phase II data as prior information into the pivotal
study.

The two studies were conducted worldwide and here\'s a breakdown of
investigators and sites. I\'d like to mention that in the Phase II study
investigators, all five of them participated in the pivotal study, so
they had the benefit of the experience in the Phase II study going into
the pivotal study. There was also one investigator not in the Phase II
study that participated in the perihysterectomy studies and so that
investigator had the benefit of that experience, and I bring that up as
information related to Question 7 on training.

Now, here\'s some variables that give you an idea of the patient
population and also some protocol requirements. First, the protocol
requirements require that the women had to have had at least one live
birth and once they\'re enrolled in this study and got the
Micro-Inserts, that they needed to have four to eight coital acts per
cycle during the study. The median age was 32 with a range of 21 to 40
years of age in the pivotal study, and the median gravidity was three
and the median parity was two with the ranges given here.

I\'d like to make a comparison with the CREST Study of the pivotal and
Phase II studies in terms of the age distribution. As has already been
mentioned in the protocol, it was required that the pivotal study be
age-matched to the CREST Study in terms of women aged over 33 years of
age and that was met. As you can see, the percentage was 36 percent in
the pivotal study and it was 32 percent when you consider all methods
studied in the CREST Study. So it was more or less matched to the CREST
Study for that age group.

Nevertheless, I wanted to break it out a little further into three
different groups that were looked at in the CREST Study, and if you do
that, you can see that for women younger than 28 years of age, the
percentage in the pivotal study is only 17 percent which is about half
of that in the CREST Study for all methods used. So there are fewer
younger women, and also that the Phase II study was not matched at all
to the CREST Study in terms of these distributions of age in that there
were 70 percent that were over age 33.

Now to give you a brief patient tree, and this is for the pivotal study,
there were 650 enrolled initially and then due to voluntary withdrawals
and subsequent findings of inclusion/exclusion criteria violations, the
intent-to-treat population was only 518 and at the operating table,
there were 11 in which it was decided not to attempt placement and so
the evaluable group is only 507. The loss to follow-up was 17, three
during the three-month post-device placement time period and 14
following that up to one-year post alternative contraception.

The bilateral placement was achieved in 464 women, 446 on the first
attempt. There was a total of 24 additional second attempts at achieving
bilateral placement and 18 were successful. Among the women that got
bilateral placement, the 464, 456 underwent the hysterosalpingogram at
three months post-device placement, so nearly all of them got an HSG. To
give you some of the HSG results, there was satisfactory device location
and tubal occlusion that was confirmed among 421 of the women out of the
456 that had the HSG, 19 had unsatisfactory device location and most of
those were expulsions.

I should mention here that among the 13 expulsions, nine agreed to
undergo a second attempt at placement and all nine achieved satisfactory
device location after their second attempt. There was satisfactory
device location among 16 women who were observed to have patency in the
tubes and so for these women, they had to undergo second or third HSGs
to see if there was really tubal occlusion further on and for all 16,
there was at the second or third HSG.

There were 449 total women that were able to rely on the Micro-Inserts
for bilateral contraception, excluding the three that were lost to
follow-up, during the three months post-device placement, and 420 of
those were able to rely after the first attempt at placement and the
first HSG. There were nine others that were able to rely after the
second attempt at placement. There were 16 others that needed additional
HSGs to confirm occlusion and three are relying on the device without
HSG confirmation of occlusion and satisfactory device location.

The bilateral placement rate at first attempt is then 88 percent, if you
consider the device evaluation group as a denominator, and the bilateral
placement rate when you consider all attempts is 92 percent. The
bilateral reliance rate when you\'re using the number of women that went
to HSG, it\'s 92 percent initially and 98 percent ultimately when you
consider second attempts and additional HSGs. I\'d like to mention that
the denominators here are still being evaluated as far as what is the
proper denominator to use to report these rates in the labeling.

I\'d like to go to the effectiveness analysis which was a Bayesian
analysis, based on the 449 women that were relying on the device for
bilateral contraception. Bayesian statistics, to give you an idea, is a
scientifically valid way of combining previous information with current
data and it\'s been used at CDRH for other kinds of devices. There\'s
been other devices that have been approved in which the primary analysis
was Bayesian. So this is not the first time, and the way it works is you
think about the possible values for the parameter of interest and
here,we\'re thinking about the one-year cumulative probability of
pregnancy as a primary endpoint or cumulative rate of pregnancy and
we\'re thinking about the possible values for that and you assign prior
probabilities to those possible values. So you would assign a
probability for a 1 percent or a 2 percent rate, and these are assigned
according to some prior information, such as the Phase II data, and then
you update these prior probabilities to posterior probabilities after
observing clinical data, like you would in the pivotal study, and you
make your emphasis based on the posterior distribution.

Here are the results from the Bayesian analyses by the sponsor. As was
mentioned, there\'s 408 patients at one year of follow-up in the pivotal
study, although the analysis considered all women-months and considered
other women that had women-months accumulated but at less than one year
of follow-up. There were no pregnancies and so the estimate is zero, and
the 95 percent interval, which is called an HPD interval, is between 0
and .69 percent. If you consider the Phase II data only, again there
were no pregnancies and the results are as follows: 0 percent is the
estimate and there\'s the interval estimate there.

If you combine the Phase II and pivotal studies, where you think of the
pivotal study as prior information going in the pivotal, Phase II data
as prior information going into the pivotal study, you get these
results, and the interval estimate is the upper bound is lower. It\'s
only .48 percent here compared to .69 when you consider the pivotal
study data only. You can also look at the second year of follow-up and
look at the cumulative probability of obtaining pregnancy in the second
year using the Phase II data where you had two-year follow-up and you
get these results here.

If you\'ll bear with me, I\'d like to show you the posterior
distribution just to give you an idea of this Bayesian analysis. The
posterior distribution gives you the range of all the probabilities that
are assigned to each of the possible values for the one-year rate and so
the X axis gives you possible values for the one-year rate and the Y
axis is the posterior probabilities assigned to those rates, and you can
see that at zero, you\'ve got the most likely value that has the highest
posterior probability and so that\'s why that\'s the estimate, although
you could also consider the averaging over all the possible values
according to their posterior probabilities to come up with a mean rate
as an estimate and when you do that, that\'s this line here and that\'s
actually above zero. That\'s .23 percent. This is based on only the
pivotal data and now if you combine that with the Phase II data, you can
see that the posterior distribution is being pulled more towards zero
and so that\'s why your upper bound on your interval estimate is lower.

Here are some notes on this. The analysis is based on women-months, not
just the 408 that made it out to one year follow-up, and the results are
comparable to those like what you would normally see in the life table
method approach, a product of Kaplan-Meier survival analysis approach.
The problem with the life table methods is that with zero pregnancies,
there\'s no standard error on the estimate and so there\'s no way to
compute a confidence interval. The Bayesian estimate will give you an
interval, a confidence interval-like estimate without having to have any
pregnancies.

There was an assumption that the monthly rate of pregnancy was assumed
constant over each of the 12 months of follow-up in that one-year rate
and that the monthly rate was used to compute the yearly rate of
pregnancy. The Bayesian estimate of zero is the most likely value
according to the posterior distribution, I already mentioned that, and
this interval estimate that I gave you in the table is called the
highest posterior density interval and it\'s generally regarded as the
most valid Bayesian interval and it\'s analogous to a 95 percent
confidence interval in a non-Bayesian analysis.

There was additional effectiveness analysis in which some of the
women-months were censored due to not enough coital acts per cycle
and/or also due to reduced fertility of the partner due to alternative
contraception or surgical techniques, but when you remove these
women-months, it really didn\'t make any difference to the results.

What I think might be more important in terms of labeling is that the
analysis that I\'ve just presented that were given by the sponsor
didn\'t have any kind of age adjustment. You need an age adjustment in
that the Phase II study data were not age-matched to the CREST Study in
terms of this greater than 33 years of age category, and so if you were
going to combine the Phase II data with the pivotal study data, you
really ought to have some kind of age adjustment so that you could
account for these much older women in the Phase II study.

Even though the protocol only considered age matching to the over 33
years of age category, I\'m going to look at all three of these groups
and age adjust with my own analysis and I\'m considering two age
adjustments where I consider the age distribution in the pivotal study
and age adjusted at distribution or I consider the age distribution in
the CREST Study and adjust to that distribution, and I used the method
of direct standardization which is a common method in epidemiology to
make these age adjustments, and I use that to compare multiple
populations that might have different age distributions.

So the first line in this table is no age adjustment which I\'ve already
given you and the upper bound on the interval estimate is .48 percent,
but when you adjust to the age distribution in the pivotal study, you
get a slightly larger upper bound of .51 percent and if you age adjust
to the CREST Study, you get an even larger but still very small upper
bound of .67 percent which I think is reassuring.

We asked the company, since there was 27 women that hadn\'t been
followed out to one year yet, we asked the company what is the chance of
these women getting pregnant in the remaining women-months, and you can
use in Bayesian statistics, you can use what\'s called a predictive
analysis, predictive probabilities to make this calculation for you, and
if you use all the women-months that have been observed so far, the
probability of no pregnancies among these 27 women is about 99 percent,
the probability of one is about 1 percent, and there\'s virtually no
probability of two or more pregnancies.

We also asked them to only consider the women-months experience in terms
of months 11 and 12 of follow-up because among the 27 women, the
women-months that were missing were mostly months 11 and 12. So if you
only consider those, the probability is 95 percent of no pregnancy and
about 4 percent for one pregnancy, and this is not considering the Phase
II data. So if you add that into this analysis, the probability of no
pregnancies will most likely be even higher.

You could also do a hypothetical analysis. Suppose there was one
pregnancy among the 27 women, then what happens to the results? Here,
the current analysis is given in the first line and I\'ve given you the
mean one-year cumulative pregnancy rate and instead of the 0 percent,
the median rate is .23 percent as I showed you earlier and it about
doubles to .44 percent if you consider one pregnancy in the remaining
women-months for the 27 women not followed out to one year, but both the
estimate and the interval estimates are still pretty low.

There was a learning curve analysis that was done by the sponsor as they
mentioned. Here are some results. They considered the number of
procedures that each of the investigators had done and to see whether
that had an effect on hysteroscope time and placement rate. The
hysteroscope time decreased with increasing procedure number from about
18.4 minutes in procedures 1 through 5 to 10.3 minutes after you\'ve had
more than 20 procedures. However, there didn\'t seem to be any effect on
placement rate in terms of how many procedures you had done.

I also would mention that among the 14 expulsions, four occurred in the
first few procedures by investigators, and I\'m just mentioning that as
part of disclosure. I don\'t know how to interpret that. It may not be
statistically significant but it did occur.

Here are some adverse event results that I think are notable for your
consideration. The rate of adverse events initially preventing reliance
was significantly higher at one site than at other sites and that rate
was 17 percent, and in the P value, non-Bayesian analysis, is less than
.05. So that\'s why it\'s statistically significant. The expulsion rate
varied significantly by site. The reasons for this are still being
investigated. There were some women that experienced sharp pain or
sudden or severe cramping that was thought to be related to the device
and it was borderline association between unsuccessful bilateral
placement and pain on average since the procedure with a P value of
about .08. The rate of return to regular menses was 5.9 percent. That\'s
about three and a half times that at baseline, and by recurrence, I mean
that a woman who\'s reported irregular menses at at least two of the for
follow-up times, and the rate of recurrent intramenstrual bleeding was
8.7 percent. That was about 3.8 times that at baseline.

To summarize, the bilateral reliance rate was 92 percent initially and
what I mean by that if you consider only the women that got bilateral
placement and that went to get a hysterosalpingogram that you saw, that
they had satisfactory device location and occlusion. Now, the rate would
be lower if you included all the women in the device evaluation group or
in the intent-to-treat group. The cumulative one-year pregnancy rate was
0 percent. The 95 percent interval varies by whether you add in the
Phase II data or make an age adjustment, but the upper limit on the
interval estimate is still pretty low in any of the analyses that I
presented here, and as was mentioned previously, the patient
satisfaction was high.

Some issues that relate to training is that sites varied in adverse
events preventing reliance and there was a learning curve effect in
hysteroscope time.

So that concludes my presentation. Thank you very much.

DR. BLANCO: Thank you.

Any questions of fact from the panel?

DR. SEIFER: Yes.

DR. BLANCO: Go ahead.

DR. SEIFER: Could you elaborate a little bit on this sites varied and
adverse effects preventing reliance?

DR. PENNELLO: Well, I\'m not a clinician. I look at variation by site
because, of course, that could relate to a training issue. The
significant variation was due to adverse events that initially prevented
reliance, not ultimately preventing reliance. So in some cases, I
believe some of the women were able to get by ‑‑

DR. SEIFER: So by reliance, you mean bilateral placement?

DR. PENNELLO: Yes.

DR. SEIFER: Is that what you mean?

DR. PENNELLO: I mean bilateral placement.

DR. SEIFER: Is the one site, is that in the U.S. or outside the U.S.?

DR. PENNELLO: It was outside the U.S. It was in Europe.

DR. BLANCO: Any other questions?

(No response.)

DR. BLANCO: All right. If we don\'t have any questions, let\'s go ahead
and take a recess for lunch. It\'s now 12:35. Let\'s begin promptly at
1:20.

(Whereupon, at 12:35 p.m., the meeting was recessed for lunch, to
reconvene at 1:20 p.m.)

[AFTERNOON SESSION]{.underline} (1:31 p.m.)

DR. BLANCO: All right. If we could settle down, please, so we could go
ahead and get started.

I think that if we look at our agenda, we\'re going to begin the panel
discussion, but before we do that, we had some questions for the
company, and I believe they\'re ready with some of the answers to some
of the questions that we had. So let\'s begin with that and we\'ll read
the definitions and all that as soon as they finish with the questions.

Ms. Domecus?

MS. DOMECUS: Dr. Carignan can address all the questions raised earlier
by the panel.

DR. BLANCO: Well, bring him on.

(Laughter.)

DR. CARIGNAN: Is it okay if I sit here?

DR. BLANCO: Oh, please. Thank you.

DR. CARIGNAN: Thank you. It\'s a little bit easier to spread out this
way.

The first question that I\'ll respond to was the one that Dr. Brown
raised regarding the distribution in the study of women according to
race and ethnic background and also with prior abdominal surgery. We
have this information for the pivotal trial. For the Phase II study, we
did not collect race information specifically. In the pivotal trial for
the entire study cohort, we had 5.4 percent black women, 6.4 percent
Latin and then .4 Asian, .4 American Indian, .8 percent of mixed race,
.4 percent other, and the remaining women were Caucasian. That was for
study sites in the U.S., Australia, and Europe.

If you look at the racial distribution just within the U.S. study
cohort, which is a little bit more particular for these classifications,
black women accounted for 8.8 percent, with a range of 2 to 25 percent
of patients, depending on U.S. study site, Latin women were 10 percent,
with a range of 2 to 32 percent of participants, depending on study
site, and Caucasian women were 79 percent, with a range of 43 percent to
92 percent, depending on study site. So there was quite a bit of
variation by study site.

If you look at prior abdominal surgery, in the pivotal trial, 19 percent
of women had had prior abdominal or pelvic surgery, and if you look at
obesity as greater than or equal to of body mass index of 30, 26 percent
of women would have been considered obese. First question.

The next question related to the animal studies and the issue that was
being discussed about the toxic reaction of the device potentially if it
were in the peritoneal cavity. Just to review all of the
biocompatibility studies that we did of the implant, we did
cytotoxicity, sensitization, genotoxicity, an implantation study,
subchronic toxicity study that I\'ll speak about, a mutagenicity study
that was an in vivo mutagenicity study, an irritation study and an acute
systemic toxicity. So we had quite a range looking at the components of
the implant.

Specifically, the subchronic toxicity study was conducted as a 26-week
study in 20 rabbits. The rabbits had two Essure devices placed in one
side of the perivertebral muscle and they had two control rods placed in
the other perivertebral muscle. When the implant sites were excised, we
had them embedded in the methylocrylate similar to the process that we
do for the intertubal devices, so that we can again see the relationship
of surrounding tissues to the actual device, and they were then
evaluated to look at local toxicity. We also looked at end organs for
systemic toxicity, and there was no evidence of either systemic toxicity
or local irritancy noted with the Essure devices when placed into the
perivertebral muscles as well and again within the fibers, we did see
what was the expected reaction to PET fibers.

The other issue that was raised related to long trailing lengths, and in
the pivotal trial, we had nine women in whom one of the devices was
rated to be greater than or equal to 18 millimeters by the investigator
assessment. Of those, three resulted in expulsions and six have been
reliant, and as we pointed out in the data before, we have no persistent
pain with the exception of one woman and that woman did not have one of
these long trailing lengths, and there\'s no difference in these women
who have a longer trailing length with women who had different trailing
lengths.

Thank you. I think that was all.

DR. BLANCO: Those were the big ones. Thank you.

Any quick comments or questions from the panel?

(No response.)

DR. BLANCO: If not, we\'ll go ahead and proceed with the panel
deliberation portion. All right. What we need to do at this point is we
need to go over so that it\'s on the record and also refreshed
everyone\'s memory of some of the definitions and the issues that will
be discussing, and essentially the first thing would be the definitions
of safety, effectiveness and valid scientific evidence, and we\'ll go
ahead and I will just read you. The panel has these handouts in their
packet.

The definition of safety. \"There is reasonable assurance that a device
is safe when it can be determined, based upon valid scientific evidence,
that the probable benefits to health from use of the device for its
intended uses and conditions of use when accompanied by adequate
directions and warnings against unsafe use outweigh any probable risk.\"

The definition of effectiveness is \"There is reasonable assurance that
a device is effective when it can be determined, based upon valid
scientific evidence, that in a significant portion of the target
population, the use of the device for its intended uses and conditions
of use, when accompanied by adequate directions for use and warnings
against unsafe use, will provide clinically significant results.\"

The definition of valid scientific evidence is \"Valid scientific
evidence is evidence from well-controlled investigations, partially
controlled studies, studies and objective trials without matched
controls, well-documented case histories conducted by qualified experts,
and reports of significant human experience with a marketed device from
which it can be fairly and responsibly be concluded by qualified
expertises that there is reasonable assurance of the safety and
effectiveness of a device under its condition of use. Isolated case
reports, random experience, reports lacking sufficient details to permit
scientific evaluation and unsubstantiated opinions are not regarded as
valid scientific evidence to show safety or effectiveness.\"

The next thing, and you should have all this in your packet, is the
discussion questions, and what we have found to be useful in the past,
rather than reading all of the discussion questions at one time, is to
go ahead and deal with discussion questions and discussions by the panel
at the same time so that we can deal with it as we read it. If we run
over a little bit on time, we\'ll, I\'m sure, use some of the voting
option panel deliberation time. So it should be okay.

So let\'s go ahead and take a look at the first discussion question that
we have presented before us which deals with effectiveness, and I\'ll go
ahead and read this. \"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?\" I\'ll let you look at the table there yourselves
as well as the comments on the table.

Unless someone objects, what I\'d like to do at this point, if I could,
is have Dr. Costello, who presented the information on the CREST Study,
review for us a little bit about some of the data from the CREST Study
looking at number of pregnancies, number of patients in terms of their
success rate and also look at from the viewpoint of this device and
other methods.

Is Dr. Costello back? Thank you for agreeing to do this, by the way.

MS. COSTELLO: No problem.

All right. If you will, while I\'m going over the different methods and
their failure rates, if you\'ll look back at the handout that I used for
this morning\'s presentation, the Slide Number 6 has the cumulative
probability of pregnancies by year since sterilization for all the
different methods, and what you\'ll see ‑‑ not on that graph ‑‑ is the
overall cumulative probability of pregnancy at one year following
sterilization was 5.5 per thousand procedures or about .6 percent by one
year.

If you look at them by method, you\'ll see that spring clip application
was actually the highest risk for pregnancy at one year following
sterilization and only one other method was actually statistically
significantly more at risk for pregnancy than the reference group
postpartum partial salpingectomy and this other method was silicone
rubber band application.

Does that answer your question?

DR. BLANCO: Yes.

MS. COSTELLO: What other questions do you have?

DR. BLANCO: Well, let\'s bring you back if we have it because it deals
with this, if you wouldn\'t mind. I think unless someone wants a
clarification, we\'ll go ahead and start the panel deliberations.

MS. COSTELLO: Okay.

DR. BLANCO: Thank you.

MS. COSTELLO: You\'re very welcome.

DR. BLANCO: Okay. Does anybody have any comment on this question they\'d
like to begin? Please, sir.

DR. LARNTZ: This is Kinley Larntz. I\'m the statistician.

If you look at the number of pregnancies column, you\'ll see all zeroes.
Statistically, you can\'t do better than that.

(Laughter.)

DR. LARNTZ: And with respect to is this adequate information, you have
to look at the sample size and the upper bounds of the Bayesian
intervals, and by the way, the Bayesian analysis is highly appropriate
and very useful for combining the two data sets, and so if you look at
the combined data set, which is what I\'d look at, is you have
assurance, good assurance, that the rate at one year is less than half a
percent. That\'s what you have. Good assurance is less than half a
percent.

Is that good enough? Well, that\'s beyond my statistical expertise, but
it certainly looks consistent with the rates that we saw in the figures.

DR. BLANCO: Thank you.

I guess implied, and I\'ll throw this out since we\'re not getting a lot
of other discussion, but I\'ll throw this out, to some extent implied, I
think, in this question is also the issue that\'s also brought up in
Question 8, the post-approval study, and that has to do with the length
of time that we have of the data in terms of efficacy, especially in
light of data from the CREST Study showing that the rate increases with
time, and so I guess I\'d like someone, if they are interested in, I
know someone is, to talk a little bit about the one-year data and what
they think of that.

David, I think you wanted to address that issue, didn\'t you?

DR. SEIFER: Well, I think the point\'s well taken that at one year and
with the Phase II trial at two years, there are no pregnancies. It\'s
hard to do better than that. But what we\'ve seen this morning, the
presentation from the CDC, sort of highlighting why the CREST Study\'s
such a landmark study and was used as a benchmark for this presentation,
the fact that when we look at this Slide Number 6 that was just pointed
out to us, if someone might want to comment on not only does the failure
rate increase with time but it seems to accelerate in the latter portion
of the years that are followed here between, say, five years and 10
years, and because of that, I wish there was some kind of remark that
somebody could make regarding the likelihood that the success rate with
this particular device isn\'t going to accelerate, its failure rate
isn\'t going to accelerate with time, because here\'s six other methods,
all producing tubal ligation, failure rate is supposedly due to
recanalization of which it seems we have very limited understanding of
why that occurs, and with age being such an important factor here
because the younger women are the greater the change they\'re going to
have recanalization, the greater change that they\'re going to be
recanalated, if you will, at a younger age when they\'re still fertile
and still able to conceive.

So I wish I had a better understanding of how this method is going to
hold up over the course of time and with this five-year follow-up, I
wonder if it begs the question of is that long enough because here you
have data which is well illustrated by each of the six methods and you
can see that it increases between five and 10 years.

DR. BLANCO: Any comments from anyone else?

DR. O\'SULLIVAN: Well, I think what we can say, based upon the
information that they did give us and based upon what Kinley said, that
the pregnancy rate, the highest possible pregnancy rate at the end of
one year, if I got your terminology correct, would be .5 percent.

DR. LARNTZ: At most.

DR. BLANCO: Please speak into the microphone.

DR. O\'SULLIVAN: He did. He said .5 percent at most, and if I look at
the CDC CREST Study that Dr. Costello mentioned, the pregnancy rate at
the end of one year was .6 percent. So, they could be basically
equivalent and that\'s all we have. We have nothing beyond that for this
particular study, and I don\'t think that they can give us anything more
than that, other than what they\'ve already said, which is that the
occlusion is one and a half centimeters because of the device. They\'re
assuming that it\'s a one and a half centimeters.

DR. BLANCO: Go ahead.

DR. BROWN: Just one other possibility might be, I don\'t know if what
Dr. O\'Sullivan is saying, this may be that in the postmarket follow-up,
would they consider extending that follow-up period to be longer for the
patients that are already on it, since you see this bump. It almost
seems like starting at six to seven years, it starts to accelerate
again. So you know, could we consider maybe having longer follow-up on
those patients?

DR. BLANCO: I think there are several points that we\'re discussing or
that need to be looked at. I think Number 1 is the issue which maybe
bothers David a little bit, if I\'m reading things into what he\'s
saying, but is Number 1, is one-year and some two-year data sufficient
to be able to allow the device to be marketed, and there, you have to
weigh the short number of years that we have versus to some extent the
fact that this permanent method has some benefits in terms of ease and
safety and other issues. Okay. So that, that\'s one issue that maybe we
should address, and then as a second issue is, if that is sufficient
information to say, well, we need to go out and gather more to know for
sure and that we can better counsel our patients that are going to have
this, knowing what the information is for the first couple of years,
then what needs to be done and that may be more appropriately Question
8, but maybe we can do it here as well. What needs to be done and for
how long and what\'s the need?

So maybe we can try to break that up. Does that seem reasonable?

MS. LUCKNER: I think it does. Speaking as a consumer rep here, I think
when you use the word \"permanent sterilization\" and we are showing a
one-year level of great compliance and great doing the job it\'s
supposed to do, I don\'t see how you can call this permanent. I don\'t
think there\'s a woman in the audience or here on the panel who would
like to buy into that system for just one year. It\'s a little risky if
you are going for permanent sterilization.

DR. BLANCO: Well, but let me not let you off the hook so easy. So then,
do you think that more data needs to be gathered in terms of length of
time of efficacy before you would want to see the device approved?

MS. LUCKNER: Or very, very careful labeling that the permanent implies
one year or restrictive labeling so that people understand. The woman
who elects it with her gynecologist understands that his confidence is
based on the data that states X and Y.

DR. BLANCO: Gerry?

DR. SHIRK: Dr. Shirk. I guess I\'d sort of take some of the other view
in that we do have some limited data over a two-year follow-up that they
presented that basically showed similar prolonged success rate and in
fact the curves were, as the FDA showed, were going towards closer to
zero, you know, as far as their confidence rates and what our
statisticians decide how significant that is, but this device is also
different than the other means of sterilization in that this device has
built within it a chronic irritant that basically causes continued
scarring and stuff like that. So it\'s not like, you know, you\'ve got a
healing process that goes on and then over time, how does the body
repair that? This is an agent that has got built inside it with the PET
fibers that basically continues to cause irritation and may prevent, you
know, recanalization over time.

DR. BLANCO: Go ahead, Nancy.

DR. SHARTS-HOPKO: I would disagree with doing anything with the word
\"permanent\" because you want women to clearly understand that they\'re
going down a one-way street, even though we know some of them will
change their mind later on.

I also think that it\'s probably not reasonable to expect longer than
five-year follow-up by the company. That\'s not been standard for any
product in this category, but I see that as a labeling issue. We have
data for two years, and for all other devices in this category, here\'s
what it looks like at five to 10 years. That\'s how I would see that.

DR. BLANCO: So you would see it not as a need for more data now. Some
postmarket need for longer data, but as a very specific labeling, which
is what you what you brought up as well, in terms of what is known about
the device at this point, and with obviously the proviso that as more
data appears, then that labeling can be resubmitted to be changed.

DR. SHARTS-HOPKO: And we know that many parties in World Health
Organization and elsewhere are going to be interested in the long-term
results with this. We know that data will be gathered.

DR. BLANCO: Anyone else? Any other comments or statements? Awfully quiet
panel.

Subir, I want to just call on you. What do you think of the one-year and
two-year? If you don\'t speak, I start asking people to speak. So let\'s
hear from you.

DR. ROY: As I think we\'ve heard, zero pregnancies is pretty great, and
the likelihood that that error is not going to be significantly
different than .5 which certainly is as good if not better than any
other available method, so I don\'t know that we\'re being asked is this
as compared to other methods better, the same or worse. We\'re just
asking is it effective and by the parameters we have available to us,
this evidence, it is effective.

So I would in the affirmative say that it is effective on the basis of
the available information we have for one and two years of use. What
will happen subsequently, I sort of suspect, as Gerry suggested, that it
will continue to be effective because of the unique features in its
design, but time will tell us whether that is in fact true or not. But I
don\'t think we\'re being asked to necessarily say is it going to remain
the same or somehow between eight and 10 years start drifting up. On the
basis of these other methods, those as Gerry pointed out are different
and permit a different healing of smaller segments of separation.

DR. BLANCO: Thank you.

Dr. Noller?

DR. NOLLER: I think it\'s important for us to compare the one-year data
versus one-year data, and it looks like it\'s as good as or better than
all the other techniques for those women who had bilateral placement.
Now that\'s coming up in other questions, but if we look in the
intent-to-treat, it\'s not nearly as good as laparoscopic where the
failure rate, inability to get something you think are the tubes, is
less than 1 percent. Here, it\'s 8 to 12 or depending on what numerator
and denominator you look at, maybe 14 percent, but among those that had
them placed at one year and at two years, it\'s as good as the other
methods, probably better, looks like.

DR. BLANCO: David, you want to make any other comments on this?

DR. SEIFER: I wonder what it would look like if we had concurrent
controls doing the tubal sterilization with the same people, same
investigators. Probably the pregnancy rate would be close to zero as
well.

DR. BLANCO: Well, I don\'t think that this device is necessarily to be
marketed to beat other devices or whatever. I think it\'s basically this
is the information, and it\'s an option and it has these other benefits
and these drawbacks, and it\'s just part of the labeling and counseling
of patients, you know. I don\'t know how necessarily ‑‑ you know, there
are various methods obviously being used by different people in
different settings and it just adds one more. So I don\'t know that it
has to necessarily beat every method.

DR. SEIFER: It adds one more option with one-year follow-up, two-years
follow-up.

DR. BLANCO: Go ahead.

DR. LARNTZ: I mean, I would have to say, what I\'m saying, I may get
thrown out of the statistical society, but, I mean, if we\'ve got to
concur in the control, I don\'t think we\'d have any different
information because zero is still zero and how much better could it have
done if we\'d had a concurrent control? I don\'t think it would have
changed our thoughts about this at all. So I think, I don\'t disagree
that we don\'t know what\'s going to happen in the future. That\'s one
of the nice things about the future. If we knew, then maybe we wouldn\'t
like it so much, but in fact I think the fact is that for the data that
we have for the one, and I\'ll have to say, I think it\'s relatively
limited two-year data. I don\'t want to oversell the two-year data, but
the two-year data is as good as it can be, given the limited nature of
it, and with the plan I think that\'s in place to follow patients and
I\'ll argue later that I don\'t want to throw any patients out for the
follow-up, by the way, I want to follow everybody, just to let people
know where I\'m going to stand on that because these are small numbers
of patients for small rates, we hope are small rates of future
pregnancies.

DR. BLANCO: All right. I think we\'ve probably done that one in, unless
someone wants to throw in anything else.

(No response.)

DR. BLANCO: If not, we\'ll go ahead and move to Question 2. Question 2
is, \"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 are given below. Are these age characteristics
appropriate for a study of this type?\" Again, I\'ll let you look at the
boxes of data yourselves.

Anybody want to address the issue? I mean, obviously there\'s some
difference in terms of the percentages in looking at the age range, 21
to 27 and 18 to 27, 17 percent versus 33. Is there concerns over that by
anyone on the panel? Most people say no. I think the point of this
question is the issue of women who have it at a much younger age group
are going to have this device implanted for many more years, and they
may be more fertile than the older women. So is the data applicable, and
I guess what I\'m getting from everybody in the panel is that it is.

DR. NOLLER: The other thing about younger patients is that a bigger
percentage of them either regret or want reversal. So that\'s the other
fact.

DR. BLANCO: Yes, and I think it is interesting to point out when you
bring reversal, that if you need a corneal resection to remove this,
reversal isn\'t going to be much of an option in most patients. I think
that\'s probably safe.

DR. NOLLER: It certainly would require a C-section then if the woman did
get pregnant.

DR. BLANCO: And reanas most of the tube. It\'d be a lot more complicated
than lots of other options.

DR. SHIRK: Well, I guess my answer to that would be that very rarely do
we do reversals now anyhow. In vitro fertilization has gotten to the
point where it\'s statistically better than trying to reverse. So I
think it\'s sort of a mute point. I think the big question would be
basically are these patients a candidate for in vitro fertilization
which would be more on safety issue thing than the issue of
reversibility.

DR. BLANCO: All right. I guess the other issue just to bring up would
be, do you think that there are any different results if they had
included younger patients with potential higher rates of fertility?
Let\'s try to hit all the different points of the answer.

DR. SEIFER: Only if we\'re going to follow them out some significant
period of time. You\'re not going to see much of anything within 12
months. I think time is the issue here.

DR. BLANCO: Okay.

DR. ROY: Just a different side of the points that were just raised. I
don\'t think everyone has IVF as a viable option if they change their
mind. I work at a county institution and I would be somewhat fearful
that people might downplay the permanence of this procedure and by ease
of use use it in individuals who have every right to change their mind
and then they\'re over a barrel. So I think counseling is going to be
very crucial in many settings.

DR. BLANCO: Well, take the opposite side of that. I mean, I\'m sorry, I
didn\'t mean to interrupt, but take the other side of that. So would you
recommend some form of labeling because of the information that\'s been
presented in terms of fibrosis, continued inflammation, not something
easily ‑‑ you know, would you recommend any labeling over and beyond a
typical permanent ‑‑ forgive me ‑‑ method? Other permanent methods of
sterilization concerning reversal of this particular method, maybe
especially in younger women? I mean, do you feel that strongly about it?

DR. ROY: I do, and I agree that some assurance must be placed that
because of the ease of use, out-patient and the perception of saving
health care dollars, which are very precious, to accomplish a goal that
we don\'t sort of sweep under the table the importance of the permanence
of it and if one changes their mind.

I mean, the most frequently performed procedure in practically every
infertility service I know of at at least a municipal center is tubal
reanastomosis. I mean, we do that every week and these are women who
were counseled and were told that tubal sterilization is permanent, yet
they change their mind. Now, if we\'re putting these in and having to do
cornual resections and trying to reimplant fallopian tubes, I mean, you
know, that\'s an all together different kettle of fish and the
likelihood of them being successful is markedly diminished over
conventional tubal sterilization.

DR. BLANCO: Dr. Brown?

DR. BROWN: It already says in your discussion, I was just looking at the
labeling, and I would argue that both the physician and the patient
labeling be made stronger. For example, the patient labeling actually
says something about if you want to have IVF in the future, I would like
to see some type of statement saying something like because of the
unique mechanism of action of this device. You know, emphasizing more
that it\'s not known to be reversible. Just make that really stronger so
that the patient hears that.

Also, for the physician, it might be a good idea maybe to include some
data about age and rates of changing your mind and maybe some
suggestion, the same kind of thing, that because of the unique mechanism
‑‑ well, it\'s believed to be the mechanism of action ‑‑ you should
highly select patients who may be older and more sure about not wanting
any future fertility. To me, that\'s my concern about them not having
more young people, is that this might be a device that really needs to
be geared towards women who are older and therefore more sure about
their decision.

MS. LUCKNER: I just want to add that remember we taught patients that
having a tubal ligation was permanent sterilization, tieing the tubes.
There is a genre of understanding out there about these kind of surgical
procedures that have something to do with the tubes, that if you put it
in, you can take it out. So even though labeling is going to be a part
of it, I think there\'s much more of a burden on a physician to explain
because they\'ve heard their mothers and others talk about it. You can
untie it, and we spend hours teaching patients before they go for tubal,
remember what it means. Just because you tie and untie a shoe, there\'s
a lot of very not well-informed women making decisions about
sterilization and then being surprised that it\'s not what they think it
is.

DR. BLANCO: Gerry?

DR. SHIRK: Well, I guess I\'m going to bring up an issue I brought up
when I first asked the question, was basically it\'s not a question of
reversibility, but it\'s a question of whether these patients really are
even candidates for in vitro fertilization. I think we have to ask
ourselves what these little metal devices coming out of the fallopian
tubes, what statistical problems are we going to run into with
pregnancies if the patient does get pregnant? We\'ve obviously got three
pregnancies that went to term in their study from luteal phase, things
that really showed no problems, but I don\'t think we have any data to
the panel that would suggest that we have any way of guessing as to what
kind of obstetrical complications would be created by having these
devices in the uterine cavity.

DR. BLANCO: So the flavor that I\'m getting from the panel is that
there\'s not much of a concern in terms of the results of the data but
much more concerns again in terms of labeling and selection of patients
with a potential for the younger patients to want reversal later on and
this being much more difficult to accomplish with this particular
device. Is that kind of how people feel?

Okay. We\'ll be back to that.

Okay. Anything else on this particular question?

(No response.)

DR. BLANCO: Let\'s move on to Number 3. \"The PMA presents results from
a prehysterectomy \'proof of concept\' study with with 52 patients 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?\"

Any comments to start off the discussion? Anybody?

DR. SEIFER: Dr. Wright\'s opinion this morning may have changed by this
afternoon, but it seems that there was very limited information or
understanding about that very topic.

DR. BLANCO: Dr. Brown?

DR. BROWN: I don\'t know. I would kind of take the opposite tack. I
mean, although again you can\'t know what\'s going to happen in 10
years, it seemed to me that we\'re talking about something that is a
unique mechanism of action compared to all these things that were in the
CREST Study in the sense that you have these two coils in between which
is this substance that has been shown in other implants long-term to
have this long-term fibrotic reaction. So I thought the answers to this
would be it indicates that it\'s a fairly unique mechanism of action
that, although we don\'t have the proof of it, is probably less likely
to have recanalization, I mean, if you look at what you\'re saying about
the data with valvular grafts and heart valves and that kind of thing.

DR. SEIFER: Well, I\'d like to ask Dr. Wright, what other tissues most
similar to tubal epithelium that would give us some analogous
comparison?

DR. BLANCO: Dr. Wright, just introduce yourself for the record.

DR. WRIGHT: Tom Wright from Columbia University, a GYN pathologist.

One of the issues with this, and I hope I was clear in my earlier
presentation this morning, is, is that, PET fibers have been used in a
variety of implants which are predominantly vascular grafts and settings
different than what we see with the fallopian tube because in the
fallopian tube, you have an epithelial line structure in which you\'re
placing this into, and I know of no analogous situation where a device
containing PET has been used to actually occlude an epithelial line
structure.

Having said that, though, what we see histopathologically is an ingrowth
of dense fibrosis together with some smooth muscle growing into this,
which is very typical of the histopathological responses that we see
with PET at a variety of different body sites. That is a very long
segment. It\'s 1.2 sonometers which is the region in which we\'re
placing this device in. So if you say is there an analogous situation
where someone has tried to occlude an epithelial line structure using a
PET device and looked at it 10 years later, the answer to that is I have
never heard of that application.

DR. SEIFER: How about more than three months?

DR. WRIGHT: We have not looked at these long-term tubes. The whole
purpose of the prehysterectomy study was specifically to look at
mechanism of action and how does occlusion take place. That study was
not designed to look at recanalization. I mean, it\'s a different study
design. It wasn\'t designed to do that.

DR. BLANCO: All right. Thank you.

DR. WRIGHT: Thank you.

DR. BLANCO: I think, and I can\'t read the mind necessarily of everybody
that wrote this study or wrote these questions, but I wonder, again it
seems to me to hark back to the issue of the one-year, possibly
two-year, length of data and then saying, well, this is a mechanism
probably more recanalized, so we can believe that the failure rates
won\'t go up further down the line as well as the issue of the
permanence and the difficulty of trying to change things if somebody
changes their mind, and I don\'t know if that\'s what they were looking
at but I think we kind of addressed that. So unless there\'s another
different angle, I don\'t know that we need to keep talking about this
one. Anybody else want to say anything?

(No response.)

DR. BLANCO: Well, let\'s move on. Doing great.

Number 4. \"In the three months following device placement, the patient
is instructed to stay on alternate contraception to allow for sufficient
tissue ingrowth to produce tubal occlusion.

\"In the pivotal study, a hysterosalpingogram confirming correct device
placement and tubal occlusion was needed before the patient stopped
alternative contraception. The pivotal study showed that the rate of
bilateral occlusion was 96 percent of the number of correctly placed
devices.

\"The sponsor is proposing that in commercial use, alternate
contraception can be stopped three months post-placement if a pelvic
x-ray, not a hysterosalpingogram, 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?\"

I guess I\'m going to start this one off because one of the things that
I saw from their data was that there actually were 16 patients out of
the 456 that had the device placed correctly but the hysterosalpingogram
showed the tube to be still patent and therefore ‑‑ and please correct
me if my numbers are wrong, but I think I wrote that down, but were
still patent and they therefore continued to use a different method of
contraception and then had a second hysterosalpingogram.

So I think this is an issue because 16 out of the 456, if my math works
out correctly and it may not be, is 4 percent. So there was what I think
is a sizeable number of patients that had it in place. So even if the
x-ray shows is to be in place, they still could have ways for those
little sperm to get past that thing. Okay. You were going to make a
comment, please.

DR. LARNTZ: No, my comment was it\'s a concern if you change the way the
device is used from the way the device is studied. That\'s simple
procedure, and the 4 percent, admittedly if you went out further, I
think you\'d go out another three months, if 15 of those are taken care
of but it looks like another one took nine months, if I understand the
timing, I may not understand it perfectly, it seems like if we\'re
getting rates down at under half a percent with ‑‑ this is going to
raise the risk considerably for an additional period of time and I would
worry about that.

DR. BLANCO: Well, the problem is you don\'t know how many of those 16
would have gotten pregnant or might not have gotten pregnant, but we
don\'t have that data to really know whether this would have caused a
higher rate. I think that\'s what you\'re saying. So this is of concern
to me on here.

Any other comments? Dr. O\'Sullivan?

DR. O\'SULLIVAN: To do the x-ray alone once again reinforces what you
said, but wouldn\'t it be a lot cheaper to do a sonogram and even a
hysterosonogram?

DR. BLANCO: That would be a lot cheaper and probably easier and less
trauma to the patient.

DR. O\'SULLIVAN: And more reliable.

DR. BLANCO: Any other comments?

DR. ROY: Could I just get clarification? Those 16 who had non-occluded
tubes, were they continued on contraception until such time as they did
demonstrate occlusion?

DR. BLANCO: Ms. Domecus, could you come answer that, please?

MS. DOMECUS: Yes. They all continued on alternative contraception for an
additional three months and all were found to be occluded at that time.

DR. BLANCO: Dr. Brown?

DR. BROWN: Could I just ask, because I had that same thought as Dr.
O\'Sullivan, and I know you mentioned that in commercial uses, people
were using ultrasound, but has there been any standardization, even
though it was not in the study, in terms of how ultrasounds can be
interpreted to show that there\'s occlusion and so on in the commercial
uses that might be able to be provided to the people using this device?

DR. BLANCO: Do you understand the question, and we\'ll give you a little
leeway, because I think we\'re going to want to hear a little bit about
your experience, at least I would like to hear a little bit about your
experience with ultrasound for placement of this device. I think it\'d
be worthwhile for the panel to hear about that, although I will rein you
in if you talk too long.

DR. CARIGNAN: Okay. The issue, just to clarify, it\'s not the issue of
placement with ultrasound but follow-up at three months with ultrasound,
correct?

DR. BROWN: Well, that was my question.

DR. CARIGNAN: Yes. As I mentioned in the Phase II study, we initially
were looking at ultrasound as the modality to check device location at
three months as well as the women were undergoing hysterosalpingogram in
terms of the occlusion. When we looked retrospectively at those x-rays,
we could then see that the ultrasound correlated well to the device
locations. As you all know, the ultrasound image is going to be somewhat
different to train to than a pelvic x-ray would be, where you can
clearly see here\'s the device.

We decided not to continue with that in the pivotal trial, just to go
with the one study, thinking that if we could just demonstrate a
consistency with device location and occlusion, then that would be the
endpoint and that\'s what we tried to do with that, but of the
investigators who did perform the ultrasound, all felt that they could
visualize the devices with ultrasound. Again, we weren\'t looking at the
level of precision that we thought we could see otherwise, and I\'d just
like to point out that that\'s different than what we see with the prior
iteration as was mentioned before which is difficult to see on
ultrasound. This device was much easier to see ultrasonographically.

DR. SEIFER: But even if you could confirm adequate placement, would you
be able to confirm occlusion on an ultrasound?

DR. CARIGNAN: As was mentioned, it is possible to do tests of occlusion
via ultrasound if it\'s scaled up. That probably is not as widespread
currently as just basic ultrasound looking at device location. You can
see an echogenic device in the area of the uterus and the cornua. It is
easier than trying to see flow through the tubes at this point in time.

I would like to mention, if I could, just regarding the patencies, I
could clarify. We did have 15 women who proceeded to become occluded at
between the three-month and the subsequent HSG and the remaining
patient, the 16th, actually had an equivocal HSG at three months where
it really couldn\'t be ascertained by the investigator whether or not
what was seen was actually venous or lymphatic filling for flow through
the tube, it was that minuscule, and that there\'s no pooling contrast
noted on the HSG films. They were reviewed by myself and an independent
radiologist. Neither of us could conclude that it in fact was patent. To
us, it appeared occluded. So we do think that all 16 were occluded by
the sixth-month HSG.

The other thing of note is that there was one investigator who was doing
the HSGs himself, rather than having the radiologist do it, and his
technique one might describe as a bit aggressive for this procedure, and
in fact was probably recanalizing past the device at that time point
because of the amount of pressure and the duration of time that he was
actually distending the uterus because he was using as an endpoint
basically the woman saying that hurts too much, stop, and so at that
point, he was probably opening the tube as it\'s used in other
applications with HSG.

DR. BLANCO: Yes, but let me interrupt you for a minute. But I don\'t
think, see, that\'s the real issue. I think the real issue is you got a
great result because everybody went in and you knew ahead of time that
everybody was occluded, okay, and that\'s great, but now you\'re asking
the panel to say that it\'s okay not to have that check for occlusion.

I think most people will likely buy the ultrasound or x-ray for
placement, but you don\'t have that occlusion, and now what we don\'t
know is how many of those 16 would have gotten pregnant had they not
been using some other form of contraception, and therefore would your
results have been the same?

I don\'t know if our statistician could do it very quickly, but, I mean,
how many pregnancies would you have had to have had in order to make
your results not look anywhere near as good as they do?

So the issue I don\'t think is whether the device works and it occludes.
I don\'t see that as an issue at all. The issue is we\'ve had data
presented that says nobody gets pregnant on this, but everybody got
checked to make sure they were occluded. Now, the question is, nobody\'s
going to get checked to make sure they\'re occluded. Is the pregnancy
rate going to be the same and that\'s a little more difficult to
believe, let\'s put it that way, at this point.

All right. Thank you. That was just a statement, not a question for you.

MS. MOONEY: Dr. Blanco?

DR. BLANCO: Yes, ma\'am?

MS. MOONEY: One thing I think we should look at in the packet which I
think is relevant to this discussion is the literature that the sponsor
references regarding patency rate versus pregnancy rate, and in our
panel packet, they did make mention of the fact that for tubal ligation
patients at a three-month time point, there was a similar patency rate
and obviously after we\'ve seen the CREST data, that does not
automatically translate to a pregnancy rate. So I think we have to
factor that in, also, as we think about this.

DR. BLANCO: Right. No, I\'m not saying that that invalidates it or
whatever. I\'m just saying the issue is not the HSG, just that there\'s
a change in technique from the study to clinical use with a potential
for changing success rates, and I have a problem with that, and I think
other panel members do, too.

MS. MOONEY: They may be trying also to standardize the post-procedure
techniques to other types of ‑‑ for example, I don\'t think HSG is
standard for other sterilization methods.

DR. BLANCO: No, I don\'t either.

MS. MOONEY: So I think they may be looking at trying to standardize
that, too.

DR. BLANCO: No, I know, and I understand that, but I guess I keep going
back that it\'s not standard, you know. When you do a laparoscopic tubal
ligation, you don\'t go do an HSG, but the data for what the failure
rate is isn\'t limited only to the patient that had the HSG and showed
the occlusion. It\'s to everybody, so it\'s comers, and I just wish in a
way ‑‑ I mean, I wish that we had that data to know if it does make a
difference or not.

Am I stressing this too much? You guys agree with this or somebody want
to take me on? Go ahead.

DR. SHIRK: My question would be basically with an x-ray and you\'ve got
no outline of the uterine cavity or uterus itself because it\'s not
going to show up soft tissue, I mean, how can you absolutely be sure
that they\'re placed correctly? I mean, ultrasound obviously is going to
give you at least the outline of the uterus itself, so you know that
you\'re in the proximity. So obviously an HSG gives you an idea of the
uterine cavity, so you know where the uterine cavity is. So I just have
a hard time visualizing that you\'d see two, you know, sterilization
objects in a flat plate and say yes, they\'re placed correctly. Who can
really make that statement?

DR. BLANCO: Well, the thing, though, with that is that ‑‑ I\'m trying to
look for the data, but my recollection is that there were only three,
and please, if the company can put the number ‑‑ there were only three
patients where there wasn\'t the combination of incorrect placement and
recanalization.

Maybe I\'m wrong. Do you all know in how many patients you did the
hysterosalpingogram and found incorrect placement? How large a number of
patients was that? It was in your data. I just didn\'t write it down.

Do you see what I\'m saying, Gerry? But it wasn\'t a big number to begin
with. So I think it\'s more whether there\'s occlusion or not occlusion
becomes the issue.

DR. CARIGNAN: To that point, there were 19 women.

DR. BLANCO: Just say your name, please.

DR. CARIGNAN: Dr. Charles Carignan.

There were a total of 19 women who had on HSG an unsatisfactory device
location. However, the expulsions were identified just on the flat plate
portion of it. So if the number was small, then we look at what was
actually diagnosed by the HSG.

DR. BLANCO: So let me make sure that ‑‑ wait. Don\'t go away. Let me
make sure that you\'re saying there were 19 women that on
hysterosalpingogram you identified incorrect placement?

DR. CARIGNAN: That\'s true.

DR. BLANCO: Okay. Now, of those 19, did I misread the slide or you also
had concomitant lack of occlusion or was that a separate group? You also
had another 16 women?

DR. CARIGNAN: Yes.

DR. BLANCO: We have proper placement but ‑‑

DR. CARIGNAN: Right.

DR. BLANCO: Okay. Thank you.

DR. SEIFER: Do you happen to know the age of those 19 women?

DR. BLANCO: Repeat your question, David. I\'m sorry.

DR. SEIFER: Well, if we\'re concerned about pregnancy rate after failure
placement or incorrect placement, I wonder if those are younger women or
older women.

DR. BLANCO: Yes. I\'m not sure they\'re going to be able to pull that
data out that quickly for those particular patients.

Dr. Brown?

DR. BROWN: Just sort of to the second ‑‑ and I don\'t know if this is
what was being brought up, but besides the issue that you brought up, to
me is the issue, and maybe I\'m wrong and you all can correct me, but to
my knowledge, the standard reading of a flat plate for uterine anatomy
is not a standard thing that most radiologists know how to do, whereas
in an institution that has a busy OB/GYN practice, they probably do know
how to read a hysterosalpingogram. So my concern is that you\'re asking
radiologists, and again correct me, I didn\'t see any training for
radiologists in here about reading these flat plates.

I mean, it\'s one thing if, yes, you have normal uterine anatomy and
antiverted uterus and tubes are both hanging off the side to tell
symmetry, but what if the woman has a retroverted uterus? What if it\'s
distorted by, you know, subcerval fibroid? Are you relying a lot on a
radiologist who may have never read a flat plate for placement of these
devices before, which obviously won\'t have, so that the issue which is
if I prepared the correct interpretation of the pelvic x-ray I also
think is of concern in addition to ‑‑ because hysterosalpingogram is
something that is a standard radiologic test that radiologists have been
trained to read whereas this is different.

DR. BLANCO: Dr. Noller?

DR. NOLLER: We\'re confusing a couple of numbers here. The 19 bad
placements, something like 14 of them were in the uterus and those are
not the same people that had patent tubes, correct? If you saw the
device in the uterus just sitting there, it was out of the tube, you
didn\'t go ahead and do an HSG and look for occlusion, is that correct?
So they\'re different people? I\'m leading to a point, based on your
answer here.

MS. DOMECUS: They are somewhat different categories, but everyone had an
HSG done. That was how the expulsions ‑‑

DR. NOLLER: Even the expulsions.

MS. DOMECUS: Right. They all had the pelvic x-ray and HSG done at
three-month visit.

DR. NOLLER: So were the expulsions included in those 12 women that were
patent or 15 women?

DR. BLANCO: It\'s 16.

MS. DOMECUS: Yes.

DR. LARNTZ: The 16 had satisfactory device location and then were
patent.

MS. DOMECUS: Correct.

DR. NOLLER: Right. See, those are little different. See, I would love to
say let\'s just do an x-ray. It\'s less trauma to the woman. But you
didn\'t do that study. If we say yes, it\'s okay just to do pelvic
x-ray, it\'s kind of on no data because that isn\'t the study you did. I
wish you would have done it, but you didn\'t.

DR. BLANCO: Well, let\'s follow up on that. So what would you like to
see in terms of data to satisfy you that they can switch over either
from a hysterosalpingogram to a flat plate or from a hysterosalpingogram
to an ultrasound with or without liquid assistance to see if there\'s
recanalization? Do you understand my question?

DR. NOLLER: I certainly do.

Well, it would require a group of women that had the device placed and
you\'d check them in three months with flat plate and those that show
good placement, you\'d take off whatever the other contraceptive method
they\'re using is and those that had bad placement, of course, then you
have to replace or something, but that wasn\'t done.

It would require really another study, I think. I don\'t think there\'s
any way to use the flat plate since you went ahead and did HSGs and you
didn\'t remove the contraceptive, additional contraceptive, method from
those you found were wrong or tubes were opened by HSG. So we\'re mixing
apples and oranges. That study wasn\'t done.

DR. BLANCO: Well, Ken, let\'s pin it down even more because what I\'m
saying is which issue ‑‑ Dr. Brown\'s concern is one thing, and then
there are two issues to address. One is the patency issue, and the other
one is the correct placement issue, right? You would agree with that?

DR. NOLLER: What I would love to know is among those women who on flat
plate had normal placement, if you follow them for a couple of years,
how many get pregnant, if any?

DR. BLANCO: Well, by inference then, I guess the question I\'m asking is
let\'s say that the patency wasn\'t an issue. It was just placement. Do
you think that going from the study they did of the hysterosalpingogram
to a flat plate, that would be comfortable enough for you to know that
you had correct placement or would you want that study and then we can
deal with the patency issue?

DR. NOLLER: Actually, because of the anatomy of the tubes and because of
the length of the device, I think you could be fairly sure on a flat
plate that it was correctly positioned. It would be nice to know if
ultrasound were better. We don\'t know that either, but there might be,
I should say, some way short of HSG of determining whether it\'s okay
and they can stop their birth control pills, but we don\'t know that.
Right now, we only know that with HSG and if they\'re patent, you keep
following them and it\'s okay, but we don\'t know about flat plate.

MS. LUCKNER: But if we\'re trying to find out which modality is best to
use to confirm the either placement or patency at three months, we\'ve
discussed three, but you\'re only now talking about only two collecting
data on. You have the flat plate with some restriction about who can
read them with the skill and that has to be built into the study, and
then you\'ve used ultrasound, and which one gives from patient
acceptance, cost and accessibility, which one is the most reasonable one
to collect data for that will be used in general practice? I mean,
we\'re now talking about lots of ladies getting this done with their
gynecologist. Which modality at three months is most representative of
what will be in general practice?

DR. BLANCO: Gerry?

DR. SHIRK: I think the question is pretty straightforward. Most
gynecologists do ultrasound in their office, so ultrasound\'s going to
be the modality that you\'re going to choose. It\'s also simple to do on
ultrasonic hysterosalpingogram just by putting fluid in the uterine
cavity and then putting some carbon dioxide gas in behind it. I mean,
you can watch the bubbles go through the tubes, if they\'re going
through the tubes. So I mean, it\'s not standard. That\'s not standard.

That\'s sort of an investigational process right now of looking at tubes
ultrasonically, but it\'s certainly possible to do that. It certainly
would be easier to get gas through a small hole than it is to get fluid
through a small hole, but I still think ultrasound is probably the most
reasonable modality.

DR. ROY: Well, the study was done with HSG. I mean, what\'s the price
you\'re going to pay? You got the convenience of an out-patient
procedure. You have the inconvenience of three months of contraception
and an HSG. Well, until we have other venues, we shouldn\'t just assume
that other things are going to work. A flat plate will only give you at
best location, not patency, and ultrasound with or without CO2 bubbling
through and all of that could be investigated in the meanwhile. Maybe
downstream, they\'d have more data and they say, well, you can do
something less invasive, but at the present time, the only facts we have
are these facts.

DR. BLANCO: Dr. Dubey, did you want to say something?

DR. DUBEY: No.

DR. BLANCO: Well, I\'ll throw something else out just because I think
trying to look at some guidance for them. The other possibility is just
that you don\'t need any tests, okay, and then you look at raw pregnancy
rates at that point without any tests and then you\'re able to talk
about that and see how effective it is without any kind of tests. Would
you agree with that or would you guys ‑‑ I mean, we don\'t do other
tests for other methods of sterilization, but we know that the have a
failure rate and we know without checking they have a failure rate. I
don\'t do tubals anymore very often, but when I did them, I put them on
birth control for awhile until I knew they weren\'t going to recanalize.

DR. BROWN: But when other devices were approved that had to be approved,
were the criteria that you had to have a test? For example, when the
clips were approved or whatever, were any of these devices approved
through this process, were they approved based on studies that did use
an HSG or were they based on studies that just, as you said, provided
the raw data?

DR. BLANCO: Well, I don\'t know that. I guess what I was saying, I was
just trying to give options because the company\'s listening and FDA,
and I\'m just saying, I mean, and obviously I\'m the only one that
thinks that, but I mean, if they hadn\'t done anything, if they\'d just
put the devices in and then just looked at raw pregnancy numbers and it
turns out to be very, very low or low enough, you know, then do you
really need anything else? No. I mean, the question here is because they
did do the other things and we make sure it was occluded and properly
placed and so therefore that\'s going to affect the rate. But maybe I\'m
just offbase here.

DR. LARNTZ: No, it\'s not. This is Larntz.

Obviously if they had not done any tests and they\'d gotten zeroes,
we\'d all be sitting pretty and not having to worry about it, but they
did have a confirmatory test at three months and then if it didn\'t work
out continued, and from the company\'s point of view, if I were advising
them, I would say do everything you can to make sure you do get the
thing through in the sense of have these confirmatory tests because what
if they had gotten two or three pregnancies in their thing? We wouldn\'t
be sitting here talking the same way.

DR. BLANCO: Okay. Any other comments?

(No response.)

DR. BLANCO: I think we probably beat that one pretty good.

Let\'s move on then. Number 5. \"There was a 12 percent 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?\"

Gerry, why don\'t we start with you? You do a lot of hysteroscopy. What
do you think?

DR. SHIRK: Well, I mean, certainly there are lots of reasons why you may
not be able to visualize a fallopian tube. One of the things is
obviously the question of just basically tubal plugs. We see
infertility, you see a lot of just plugs where the tubes aren\'t really
occluded, where there\'s just a plug in the tube, and so and so the big
question in these patients, and I\'m not sure whether the company\'s
answered it or not, is how do you deal with these patients where you can
get unilateral placement?

I mean, are they then supposed to be subject to other means of
sterilization if they want it? If you go back and do a
hysterosalpingogram and it shows bilateral occlusion of the tubes, then
do you assume that these patients are basically then sterile? Certainly
a good portion of those are just going to have tubal plugs. You can\'t
really say that the procedure is then a success, that these patients can
use it as a contraceptive device. So I think the big question is
direction there.

My other question was basically again the question of you get in there
and find existing intrauterine pathology, is it appropriate then to
place the tubal plugs or that first ‑‑ treating that intrauterine
pathology, and the intrauterine pathology may have ‑‑ it may preclude
putting the tubes in or putting the plugs in.

DR. BLANCO: Dr. Noller?

DR. NOLLER: This is one of the two areas I have real problems with.

First of all, I don\'t see in any of the labeling, particularly to the
consumer, where it says you have one chance in eight that we can\'t do
this. The people doing this also, I know some of the names. I don\'t
know all of them. The names I know are expert hysteroscopists. When
35,000 gynecologists who do a little bit of hysteroscopy have this
available who are not experts, I can\'t believe that the failure to
implant rate will be anywhere near as low as 12 percent. It\'s going to
be higher.

Also, none of the \"non\" except for some REIs and occasionally
generals, none of the 35,000 practicing OB/GYNs have any experience
doing hysteroscopy on an awake patient. They do them all with the
patient asleep. I don\'t think that is going to change. I think they\'re
going to do these asleep. I suspect, based on my experience being a
department chair with 50 and 25 members, knowing the hysteroscopic
skills, that what\'s going to happen is the patient\'s going to be put
to sleep, we\'ll try it, see if we can get in from below, and if we
can\'t, then we\'ll do a laparoscopy. That\'s what the patient\'s going
to be told. All along here, there are problems, and it all revolves
around the fact that at the very best, the failure rate to get these in
is 12 percent, and I suspect that it could easily be 20 percent among
people that don\'t do this very often. So even with the 12 percent rate,
if women are told that up front, unless there\'s some fallback plan,
like laparoscopy at the same time, I don\'t know why they would accept
this.

DR. SEIFER: Twelve percent is probably a conservative estimate. There
were 20 investigators but five of these investigators had more than 50
percent of the cases. So there\'s an obvious learning curve, and in the
best of hands, that probably brought down the overall failure rate.

DR. SHIRK: My argument would be that this procedure\'s probably in the
office equivalent to a diagnostic hysteroscopy, and I\'ve done thousands
of them in the office and have yet to have a major complication. I mean,
it\'s an extremely safe procedure and a lot of the interuterine
pathology I look at before I do an operative hysteroscopy, I do a
diagnostic hysteroscopy in the office.

DR. NOLLER: May I respond?

DR. BLANCO: Well, let him finish.

DR. SHIRK: So I mean, you know, I think you\'re looking at it from the
standpoint that this has the same hazard as doing a hysteroscopy asleep.
I mean, none of us would not do an endometrial biopsy in the office. We
wouldn\'t even blink about doing an endometrial biopsy in the office and
diagnostic hysteroscopy is basically on about the same level, once you
get comfortable and get over a learning curve, to basically do an
endometrial biopsy. So I don\'t see this nearly as a hazardous procedure
to the patient that a major operative procedure would be.

DR. NOLLER: I absolutely agree that office hysteroscopy is possible,
good, safe, but the fact is that virtually no practicing OB/GYNs have an
office hysteroscope. When they do them, they do them in the OR with the
patient asleep. I think it would be great if they were doing them in the
office but they don\'t and your skills and those you\'ve done are way
beyond the usual practicing gynecologist.

DR. BLANCO: I guess at this point, I\'d like to remind the panel,
though, that to some extent, almost all studies of almost all devices
are always done by people who have an interest in the particular
methodology being performed. This is true for fetal heart rate
monitoring or any other type of monitoring or whatever. So that, I
don\'t think that it\'s a question that we say, well, it\'s 12 percent
and when it gets in the hands of everybody else, it\'s going to be
horrible and whatever. I don\'t think that that\'s fair to the company
or fair to what we need to look at.

I mean, basically, we can try to impact on that by requiring appropriate
labeling and appropriate disclosure and I think the company has
presented an educational plan to try to ensure that there is some
education of the physicians who are going to be doing this with a
reasonable amount of experience, and I think that you can break this
question as FDA did in two parts. One is the overall just failure rate
to put the device in. The other one is the issue of the experience of
the investigator.

I think their data does show that after about five insertions, you may
shorten the time of the hysteroscopy but you don\'t really improve the
failure rate, if you will, if I read that data correctly, and you know,
the difference between 14 and 10 minutes on a hysteroscopy, I mean, we
sometimes waste five minutes doing other things that aren\'t anywhere
near as important with the patient in that setting.

So I\'m not as concerned about that. I think if everybody has to be an
expert before they use something, before something\'s approved,
nothing\'s ever going to be approved. So I think the issue is labeling
and appropriate counseling and notification for the patient of what\'s
going on until more experience is gathered and as experience is
gathered, then that labeling can be changed to reflect what the actual
numbers are with larger numbers, Number 1, and then Number 2, an
educational program requirement for physicians that are going to be
inserting this device to ensure that they have the appropriate training
to at least attempt to be as close to the lowest failure rate possible.

Yes, sir?

DR. NOLLER: I absolutely agree with that. I guess where I started with
my point was that I think that we have things on labeling later, but it
just doesn\'t say now that there\'s a 1 in 8 chance that this won\'t
work, and I think women deserve to be told that up front in big letters
in a box, you know, this isn\'t perfect, and we may find with experience
that it\'s a whole worse or might be even better with time, but that
isn\'t in their labeling currently nor is the general anesthesia
problem.

DR. BLANCO: Go ahead, David.

DR. SEIFER: The training program, it was proposed to have five cases of
proctored surveillance, and I think it was Dr. Pennello from FDA. He had
a slide. I think it was Slide 23. I don\'t know if he\'s still here, but
it showed the timing of the procedure being cut in half from, I think it
was ‑‑

DR. BLANCO: Eighteen to 14, and 14 to 10.

DR. SEIFER: Yes. Based on the number of cases that were done, and I
think there\'s a pretty good argument that this five cases be extended
to something more meaningful than five because again we\'re trying to
improve the chances of this being effective, and at five cases, it
hardly seems that it\'s going to be useful, it\'s going to have its most
beneficial effect. The patient\'s going to be under twice as long and
everything that correlates with time under anesthesia, even if it\'s IV
sedation or local, amount of volume will increase in terms of the media
exposure and risk to the patient.

DR. BLANCO: Anybody want to comment on that? I\'ll make commentary.
Well, go ahead.

DR. SHIRK: Well, I think the answer is that basically what they said, if
you have a person who\'s an experienced hysteroscopist that within five
cases you can teach this individual to place these adequately and that
their learning curve will be fairly rapid, and I would agree that
that\'s probably true.

The big question you have is what about the person who has limited
hysteroscopic abilities and you\'re trying to teach them essentially two
things, hysteroscopy and also placing these devices in the tubal ostia,
and so the big issue with the training process is basically what
criteria should there be before somebody\'s allowed to come into a
training session or should there be two different levels of training,
those people who have very limited hysteroscopic experience and those
people who are adequate hysteroscopists, because I think the question
about the technical ability to do this rides more on the person\'s
ability to do hysteroscopy, rather than their ability really to place
the tubes.

DR. BLANCO: I think the thing is, and this is something we wrestle with
in this committee all the time in terms of devices, and it has to do
with once things are approved, then they\'re out in the market and
physicians can use them in ways other than the intended way, but that\'s
still not, you know, something that we can fix or are going to fix in
this committee.

I think we need to come up with a reasonable educational program with a
reasonable number of interaction of education so that the average
physician who should be getting into this will know how to do it and the
ones that shouldn\'t shouldn\'t. That doesn\'t mean they won\'t, but
that\'s, I think, the most that we can ask, you know, when we approve
something, and I guess to me, failure rates are more important than the
decrease of time for hysteroscopy from 18 to 10 something minutes, and
so with five failure rate didn\'t seem to change. So I guess I\'d be
satisfied with five proctored events at this point and maybe that\'s
wrong but we\'ll see.

Anybody else? Rebuttal? Go ahead.

MS. MOONEY: Yes, Dr. Blanco. I was going to bring up that same statistic
you just mentioned.

I think Dr. Pennello\'s slide showed a trend towards decreasing time
with experience but I think his placement rate analysis for different
experience didn\'t show a difference and maybe that is partially
explained by the sponsor\'s evaluation of the reasons for failure which
seemed to be a majority of those related to proximal tubal occlusions.
So it may have been more anatomical limitation as opposed to an actual
level of experience of the operators. So that may help explain Dr.
Pennello\'s data that didn\'t show a difference in success rates over
experience level.

DR. BLANCO: And I guess the thing is if you\'re really going to go for
that and go for the 10 minutes, and I don\'t have the slide in front of
me and I don\'t remember that, but it became a significant number.

PARTICIPANT: Twenty.

DR. BLANCO: Thank you. You had to get over 20, you know, before you
reduced the time from 18 to 10 and that\'s a lot to ask, I think, to be
proctored. Maybe that\'s just my bias.

Anybody else? Gerry?

DR. SHIRK: I think it\'s always a problem when you try to put numbers on
a credentialing game. You know what I mean? I mean, some people are
going to in five have it completely, some people in 60 are not going to
be able to accomplish it very well. So I think it\'s difficult.

DR. BLANCO: Well put.

DR. SHIRK: So I think five is adequate.

DR. BLANCO: Anybody else? Any comments? Anything else on this particular
question?

DR. NOLLER: We didn\'t really answer the question.

DR. BLANCO: Oh, well, we often don\'t do that.

(Laughter.)

DR. BLANCO: Do you want to go ahead?

DR. NOLLER: I don\'t know the answer to is the failure rate acceptable?

DR. BLANCO: Well, I think there are two issues and you brought them up
and I think you brought up a very good issue. I think, one, I mean,
it\'s always the labeling and counseling. Clearly that needs to be
strengthened, the actual numbers that are known need to be told to the
physicians and to the patients. But I think your other issue is actually
a very good suggestion and that\'s the issue of a fallback plan. If you
do face that situation whether that should be, you know, a repeated
attempt at introduction, depending on what the reason was for the
failure, or whether that\'s at that same time and place to go into a
different methodology. I think that\'s a good suggestion that maybe
needs to be considered as a possibility in there.

DR. SHIRK: I guess that was a question I initially brought up when you
asked me the question, was basically that tubal occlusion thing, and
there\'s no direction from the company as to which way, how to handle
that. Certainly you could say, well, just go straight to other means. If
you get one in, a unilateral one in, and you can\'t but there\'s a lot
of those patients that have tubal plugs. If you go back and do a
hysterosalpingogram, you\'re going to blow the plug which they found out
and were able to go back and replace the second tube, you know, the
second device. So it\'s two procedures, but again you\'re not doing it
under general anesthetic. I mean, you\'re basically saving a lot of cash
and also you\'re obviously protecting the patient from a general
anesthetic and some other risks. So I think that I\'d like to see at
least some type of direction built into the physician labeling as to how
to deal with this, you know, from the company.

DR. BLANCO: Well, I wonder if you want to be that specific, though. I
wonder if it might not be better just to say that you should have a
discussion with your patient of what\'s going to happen if you are
unable to insert, you know, the devices bilaterally as to what your next
move is because if it is utilized in a non-general anesthesia-type
setting, I mean, you may not necessarily be in a situation where
they\'re going to go do a laparoscopy at that point nor do you
necessarily need to. As you pointed out, there may be other reasons to
try it later.

I think the issue more is that the point of what happens if we don\'t
succeed which does happen at this rate needs to be brought up, discussed
and some plan that is appropriate to that particular patient and to that
particular physician should be made.

Dr. Noller, you brought this up. You think that\'s fair enough or would
you be more specific?

DR. NOLLER: No, I think that\'s fair enough.

DR. BLANCO: All right. Anything else?

(No response.)

DR. BLANCO: All right. Well, let\'s move on.

Safety, Number 6. \"The authors of the CREST Study 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?\"

Dr. Brown?

DR. BROWN: Well, in reading through in detail the adverse events, even
though I think tubal perforation, I guess that was one of the more
frequent adverse events, I just think it\'s interesting that in terms of
the sequelae of that seem to be nothing or very little, and I guess
that\'s probably not surprising when you actually look at the diameter
of this device, and the fact that if you are perforating, you\'re
perforating with something that is so tiny and its non-reactive effects
if it does get extruded into the peritoneal cavity, but what I thought
was more concerning was reading, I guess, the two cases of hypervolemia
and maybe that\'s because I come from a city where a patient actually
died from this, was very well-publicized case. So I was just interested
in terms of the labeling.

Reading those two cases, it\'s almost like the data we looked at with
the vacuum. Why would you put a vacuum on 16 times, and I guess I might
say why would you infuse, you know, whatever it was, several liters of
fluid in? I mean, I would never do that, but given that that is a
potential risk, maybe there should be something in the labeling just in
terms of the life-threatening nature to the patient. That\'s the one
thing to me that seems to have a potential to be really the biggest risk
to patient safety. So maybe there should be a little more emphasis in
the labeling that even though that\'s a rare complication just to
re-emphasize you have to monitor the ins and outs, you know, kind of
thing in the labeling so the physicians keep that in mind.

DR. SEIFER: I agree with Dr. Brown, and I would go one step further and
there is some discrepancy about the amount of time that was delineated
in this calling it not successful. I think in one piece there, it said
after 10 minutes and one tube but 30 minutes total. So if we could have
a consistent message about it\'s 20 minutes for total procedure or 30
minutes for total procedure and perhaps some discussion about Is and Os
input and output deficits, if the deficit exceeds 1,500 ccs of normal
saline, and then for those who do hysteroscopy in what I read in terms
of the temperature of the saline media, it\'s that I think it said to
have it at body temperature and I know that there are other methods or
other approaches to that. You could have it at room temperature and
perhaps lower your chances of intravasation.

So I agree with Dr. Brown. I think that in the labeling, it would be
helpful to have some guidelines as to how to reduce the risk of fluid
overload because that probably is the most serious complication.

DR. SHIRK: Well, I guess I could speak to this since I\'ve got two or
three papers in the literature about fluid overload.

I mean, first of all, saline is fairly safe as we learned with when we
did laser ablation and some of the newer devices were used and obviously
it\'s not innocuous because you can drown somebody with it as I proved,
but probably the half-lethal dose is three liters for the average
patient. It\'s not as onerous as nonelectrolytic type of solution that
obviously plays havoc with the internal electrolyte balance. Your
average anesthesiologist is going to run in two liters during most
surgeries. So you know, I think that obviously especially in settings
maybe put a three-liter limit on the amount of fluid used. There are
devices that, basically pump systems, that do monitor fluids for you. So
I mean, you can set alarms and stuff like that to achieve that if
you\'re doing it in a hospital setting.

The other thing is that these procedures probably should be done with
small hysteroscopes that basically are in the range of five millimeter
scopes. Having done a bunch of studies with how you put fluid through
scopes and how much fluid you can put through a scope, it\'s damn near
impossible even in 30 minutes to put, you know, much more than two or
three liters through a five millimeter scope. I mean, you just cannot do
it. There\'s a constriction problem as far as getting fluid through even
under pressure. So just the amount of fluid you can use is an issue, and
you shouldn\'t be dilating the cervix. You\'re not cutting into the
uterine cavity. So you should have a fairly minimal chance of getting
hypervolemia. I think it should be put in as a labeling thing, as a
warning and maybe suggest that cut-out point of three liters for maximum
fluid use, but I don\'t see it as an onerous problem as it would be with
significant operative hysteroscopy.

DR. BLANCO: Do you want to say anything?

DR. SEIFER: Yes. I don\'t know if anyone wants to comment on the two
cases that are in here with five and seven liters of fluid and how much
time it took.

DR. BLANCO: Well, I was actually going to ask the company. I didn\'t see
it, maybe I just didn\'t read it. Do you have any concept of how much
fluid was actually infused not in those two particular cases but in most
of the routine cases? It\'s okay to say no. Okay. Do you have it offhand
that you know?

DR. CARIGNAN: Charles Carignan, Conceptus.

Typically, most procedures were done with between 500 and 1,000 ccs,
many more on the lower end of that scale, and actually in our training,
we emphasize a cut-off of 1500 ccs.

DR. BLANCO: Is that in your labeling?

PARTICIPANT: No.

DR. BLANCO: I was just asking if you\'re aware of not.

MS. DOMECUS: Give me a few minutes to look through all the pages of the
labeling to see if it\'s in there or if it\'s just in the training
program.

DR. BLANCO: Okay. Well, I just wondered whether it was already in there.
I mean, it appears that the panel\'s going to make some suggestion of
some limit. I just wondered whether you had it in there or not.

MS. DOMECUS: It\'s already our plan.

DR. BLANCO: All right. You addressed the two biggest issues. Actually,
the hypervolemia issue and the fluid. What about these other things they
talk about, vaso-vagal responses, discomfort, bleeding and spotting?
Those are pretty minor symptomatology. So other than labeling and
appropriate counseling of the patient, I don\'t think it\'s that big of
a deal, but what about the tubal perforation issue? Is there something
that concerns the panel? Is there any way that that can be minimized?
Anything anybody wants to talk about that?

Dr. O\'Sullivan?

DR. O\'SULLIVAN: Yes, a couple of things I think about that. Number 1, I
think that by putting the little black knob on, they tried to at least
limit the amount of times that that would happen. That\'s Number 1.

Number 2, many of these perforations were recognized at the time they
occurred just by the feel that they had when they did them. The third
thing is they were relatively asymptomatic. There didn\'t seem to be any
bleeding associated with them, and I think if you compare that ‑‑ I
mean, part of our question says in conjunction with safety and
acceptability of female sterilization procedures in general is the way I
was reading that. If you compare it to some of the complications of the
general, I don\'t think that it\'s any worse than anything general and
maybe somewhat better.

DR. BLANCO: Okay. Go ahead.

DR. SHIRK: I want to introduce a couple things that aren\'t on the list
that I consider possible safety issues. Okay? One would be treatment of
future uterine disease. Obviously they made the comment that you can\'t
use electrosurgical devices in the uterine cavity after these things are
placed. Certainly a percentage of these women in the future are going to
develop interuterine pathology that can be treated by intrascopic means,
both submucosal fibroids and large endometrial polyps.

My question would be does this mean that we no longer can treat these
modalities with minimally invasive surgery and have to go to
hysterectomy to treat them? So that\'s one of my concerns.

The other concern was basically with endometrial ablation. We have a
thing called post-ablation syndrome, where after tubal ligation and then
you do an ablation, it occludes the tube and you get sort of a small
hydrosalpinx.

My question would be by occluding both ends of the tubes, if you have a
preexisting tubal disease with distal occlusion, are you going to create
a symptomatic hydrosalpinx with this thing by occluding both ends of the
tubes where there\'s no egress point for the serus fluids? So are we
going to create some problems with this procedure as far as creating
problems with pelvic pain and hydrosalpinx by placing these devices?

These are obviously out of the scope of the present study, but certainly
if we\'re looking at possible issues down the line, those two issues at
least pop into my mind as possible issues.

DR. BLANCO: Okay.

DR. SHARTS-HOPKO: A concern that I have, also not on the list, is
related to the question I raised earlier today about sensitivity to
metals. I am a person with an extreme sensitivity to metals other than
14k gold, which is a great problem.

(Laughter.)

DR. BLANCO: You sure it\'s not 18?

DR. SHARTS-HOPKO: Eighteen is better.

So I don\'t know what happens to people with metal sensitivity when you
implant metals in them.

DR. BLANCO: The other issue, you know, and I wondered about that. I was
going to ask because the other issue is pelvic inflammatory disease or
salpingitis. I also would wonder if your rate of perforation in those
cases might be higher just because the tube\'s been scarred already. I
don\'t know exactly, other than in ithnikinidosa, how much scarring you
get in this area, but it might cause for harder placement and might
cause for higher rate of perforation if you have prior history of
salpingitis and that may be something, another reason to consider
whether those are good patients to do this on.

Anybody from this side? Dr. Noller?

DR. NOLLER: Well, having seen lots and lots of complications of
laparoscopy in supposedly simple cases, based on the data that we\'re
presented and the theoretical complications and even with my assumption
that these are all going to be done under general, I still think this is
probably considerably safer than laparoscopic tubal sterilization.

DR. BLANCO: Any other comments on this particular question?

(No response.)

DR. BLANCO: Let us move on to the next question.

Labeling and Training. Number 7. \"For the pivotal study, the training
program for investigators included: didactic materials, practice on a
hysteroscopic simulator, device placement in perihysterectomy patients,
interpretation of device placement by hysteroscopy, HSG, and pelvic
x-ray, and proctoring of initial device placements in sterilization
patients by experienced personnel.

\"The sponsor is proposing to delete the requirement for placement in
perihysterectomy patients and to train investigators using 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?\"

Anybody want to make any comments on this one? We\'ve sort of addressed
some of these issues but go ahead.

MS. LUCKNER: I think there should be some recognition of prior skills
because I\'ve heard the panelists and having known in university
settings the level of skill of a variety of people, some of the problems
we had in the earlier fetal monitoring studies and when that came into
general practice was the level of people skilled when they were
inserting the scalp electrodes and handling some of the instruments.

So I\'m wondering rather than changing the five, I\'d rather see better
counsel from the company as far as what the candidate prerequisites as
you have in some academic requirements, you have prerequisites. I think
there are some prerequisites for this skill, and if they don\'t come
with those, then those have to be accomplished first before you go into
this as almost a Level 2 ultrasound versus a Level 1.

DR. BLANCO: What would you think of ‑‑ because I was thinking of saying
something in the labeling for the use. It should be used by physicians
who already have training in hysteroscopic procedures, I guess.

DR. SEIFER: Operative hysteroscopy.

DR. BLANCO: I\'m sorry.

DR. SEIFER: Operative hysteroscopy as opposed to diagnostic
hysteroscopy. I know Dr. Shirk wants to say something about it.

DR. SHIRK: Well, I was just saying I think it\'s appropriate to do this.
A better parallel to what went on was what went on when we did
laparoscopic colectomy and you had surgeons that had no laparoscopic
skills and created a horrendous amount of complications with that. So
they jumped into this. I mean, I\'d hate to see gynecologists being
forced into doing, you know, this for competition reasons and then
basically trying to do it with minimal hysteroscopic skills. I think
it\'s safer obviously if we follow our usual learning curves and
basically learn how to use the piece of equipment that we\'re using and
then progress to an operating procedure.

DR. BLANCO: Well, it sounds like everybody agrees that you have to have
some hysteroscopic skills, but you brought up about the difference
between diagnostic and surgical hysteroscopic skills, and I\'m not sure
if every hospital staff differentiates that or not and whether you want
one or the other.

DR. SEIFER: Well, just for the sake of argument, operative hysteroscopy
would imply that someone has operative privileges, goes in the OR, does
hysteroscopy. Others, diagnostic as opposed ‑‑ some people have it in
their office. Most don\'t. So I don\'t know if that would be strong
enough.

DR. BLANCO: All right. Dr. Noller?

DR. NOLLER: I have another point to make, if you want to finish this.

DR. BLANCO: Yes, then let\'s keep talking with this. Anybody else wants
to address that issue?

DR. BROWN: The point is that, I mean, you can\'t have hospital
credentialing be a criteria because one of the potential advantages of
this is that even though many people may do it under general anesthesia,
there are many people who do hysteroscopy in the office which is not
going to be monitored by any hospital credentialing process.

So I would think you\'d have to say something like basic diagnostic
hysteroscopic, and from what we\'re hearing this is analogous not to an
operative hysteroscopy where you\'re resecting fibroids, but to
diagnostic hysteroscopy. That\'s the diameter of it.

DR. SEIFER: It also begs the question Dr. Shirk brought up about if you
find concomitant pathology, you know, what do you do? Not that we\'ve
answered that question, but it also implies a certain level of
proficiency at hysteroscopy.

DR. BLANCO: Subir, what do you think?

DR. ROY: The other factor I would be interested in is this hysteroscopic
model.

DR. BLANCO: Well, before we go on to that, let\'s finish with them. What
criteria? Obviously everybody agrees that some hysteroscopic experience
should be a prerequisite to utilizing this procedure, and I guess the
question is ‑‑ I don\'t know. Dr. O\'Sullivan, were you going to address
that issue? I know you were going to say something. I mean, where should
we go with it? Do we say diagnostic or operative or just make it
general? I mean, do we want to give any guidance?

DR. O\'SULLIVAN: Well, the only one you can control is operative. You
can\'t control diagnostic. I mean, operative is easily controllable.
Diagnostic is not controllable at all. I don\'t know what goes on out in
the communities, but if there are people out there who do diagnostic
laparoscopies or think that\'s what they\'re doing and probably I
suspect if they\'re doing that, they\'re doing a little bit more, and it
may be dangerous in their hands. So the only thing you have control over
is operative.

DR. BLANCO: Anyone else?

DR. O\'SULLIVAN: And this is an operative procedure in a sense. You are
guiding something that you ordinarily would never do.

DR. SEIFER: You\'re inserting an intervention here.

DR. O\'SULLIVAN: Yes.

DR. BLANCO: All right. Anything else on that? If not, let\'s do Dr.
Noller first because he was first.

DR. NOLLER: This is the opportunity to get these done under local
anesthesia. I think that sounds wonderful. I don\'t think they\'ll be
done that way unless as part of the training, if you have to do five
procedures or 10 or 100, whatever the number is, let\'s just say five,
you have to do five procedures, you say five procedures under local
anesthesia and/or IV sedation, period. So if you do five under general
anesthesia, they don\'t count. You have to do five more under local and
that would be one way to try to \"force\" more of these into the local
anesthesia which would certainly be better for women.

DR. BLANCO: Any comments on that? Gerry?

DR. SHIRK: I would agree that that\'s probably appropriate. I disagree
that these\'ll be done under general anesthesia simply because
competition in the marketplace by people who can do it in their offices
are going to obviously push the rest of the OB/GYN population into doing
it in their office, to creating an office situation to do this in or at
least do it in a surgicenter basis under a local anesthetic, but I would
agree that, you know, suggesting that the preceptorship under local or
IV sedation is not inappropriate.

DR. BLANCO: Go ahead.

MS. LUCKNER: The other thing to keep in mind is there is a shortage with
anesthesiologists and many in community hospitals are having trouble
covering their surgical procedures and closing ORs because of not having
enough anesthesia. So if we consider this procedure is good for women
and we want to make it available to them, and local anesthesia is better
for the patient, the woman, then we really should push very hard for
that piece and not push a procedure that might have general anesthesia
requirements.

DR. BLANCO: Well, you know, I always like to be the devil\'s advocate,
but I guess my question with this is we\'re kind of sort of pushing the
company to making public policy as to how physicians utilize this
particular device which somewhat limits maybe who\'s going to use it and
may actually limit the women who are able to use it. It may be that
somebody starts doing it under general and eventually learns enough
skills to be able to do it under local. So I\'m not real crazy about
putting that requirement. I mean, maybe we can recommend or encourage
that this procedure be tried under local, but I\'d hate to make it a
requirement per se.

DR. SEIFER: But one of the reasons why this has come up for expedited
review is because it doesn\'t require general anesthesia and perhaps
local or IV sedation, but I would bolster the argument that we should be
trying to encourage a non-general anesthetic.

DR. BLANCO: I have no problem encouraging. I have a problem with
requiring.

Dr. Noller?

DR. NOLLER: The only reason I really brought this up at all is because
the information in the draft patient pamphlets and the insert and some
of the comments that the company has provided suggest of course this
will be done under local and I think that we disagree on how many will
be done that way but certainly some will be under general, and I think
we ought to push any way we can to get these done under local. I see the
training issue as being an easy way to do it. The person can do five
under local with the preceptor and then never do another one. There\'d
be no control then, but I think if they learned to do them under local
and, gee, this works, I guess you can do it under local, I\'ve never
done it before, it works, I think they\'re more likely to do them.

DR. BLANCO: Well, it seems like I\'m severely outvoted.

DR. NOLLER: I don\'t know. There are an awful lot of quiet people.

DR. BLANCO: Anything else on the local anesthesia? If not, there are
several other points in this question that we probably ought to address.
Anything else on the anesthesia?

(No response.)

DR. BLANCO: What about the training, the number, the issue of
perihysterectomy patients versus the hysteroscopic model and this level
of training, number of initial procedures? Anybody want to tackle any of
those?

DR. O\'SULLIVAN: I think you can take out perihysteroscopy.

DR. BLANCO: You can take it out?

DR. O\'SULLIVAN: Take it out.

PARTICIPANT: Yes.

DR. ROY: But if you\'re going to take it out, that\'s where I was going
with the hysteroscopic model. There are some that are just completely
non-realistic being hard plastic where everything just slips right in so
easily that you think it\'s a piece of cake. I mean, you have to have a
realistic model and it can be done. There are lots of skinlike materials
available.

DR. BLANCO: Well, let me interrupt you for a second. At the pleasure of
the committee, we could see the hysteroscopic model. It has not been
presented to FDA before this point. So that\'s why it hasn\'t been
brought up. But the nice thing of being on this committee is that once
we\'re here, if we all want to do something, we usually can get away
with it, or at least I try to look at it that way. They may not.

If the committee would like to see the model, what we can do is we are
getting close to break time. We can ask the company to bring their model
forth and do that and look at the model in the beginning when we regroup
after the short break. So it\'s at the pleasure of the committee.

DR. O\'SULLIVAN: I vote for that.

DR. BLANCO: Do I hear support for that? Hear, hear. Anybody strongly
opposed to it? Okay. Then why don\'t we plan during the break if you
guys would bring in the model and we will take a look at it shortly
after we reconvene from the break.

All right. Leaving the question of the hysteroscopic model out, now that
we\'ve taken care of that, what about all the other issues? Any of the
other issues that anybody wanted to address? I think we\'ve sort of
addressed the hysteroscopy and level of knowledge. We\'ve talked about
the hysterosalpingogram and pelvic x-ray and ultrasound added to that
before. We talked about the proctoring and we sort of came on five, but
is there ‑‑ go ahead.

DR. NOLLER: I think if we really want a lot of people to begin doing
this, to require more than five for proctoring is almost impossible.
Five is going to be hard enough for people to hit. Also, if you aren\'t
good after five, you may never be.

DR. BLANCO: All right. Anything else that we want? I think that pretty
much does that question.

DR. BROWN: I just have a question. Is it standard in terms of this kind
of thing that you\'re potentially saying that the company forever after
is going to be responsible for doing this training for every person of
the 35,000 OB/GYNS, and I have some questions about the implications of
that for graduate medical education, et cetera.

I mean, is there some time frame on this? Because obviously if this
turned out to be as great as it\'s supposed to be and became such a
common procedure, you know, 15 years from now, is Conceptus still going
to be teaching OB/GYN residents? I mean, I hate to bring that up, but is
there some way ‑‑

DR. BLANCO: Well, I\'m sure they\'re going to be eager to sell their
devices to these people.

DR. BROWN: Right, right.

DR. BLANCO: So I think they\'ll probably be interested in training them.
You still have to train the folks somehow.

DR. O\'SULLIVAN: But they\'ll eventually get trained through residency
training programs.

DR. BROWN: Right.

DR. O\'SULLIVAN: I think it will come through that, and this is another
way that it can be done because if these devices are something that the
company can buy, there are devices that could be bought by residency
training programs not just for this either. I think that\'s important,
and as we get more and more into credentialing for procedures that have
to be learned after training, you know, we\'re going to have to become a
little bit innovative in how we do this kind of credentialing.

DR. BROWN: So I guess my question specifically is once Conceptus, say,
has credentialed me, will I then be allowed to teach my residents how to
do this so that when they graduate from OB/GYN residency, they don\'t
have to be credentialed by Conceptus? I\'m just wondering mechanically
is that how this works.

DR. BLANCO: It\'s up to us.

DR. BROWN: I know.

DR. BLANCO: I mean, not to have it happen but to make the recommendation
that we\'d like to see.

DR. BROWN: I would make the recommendation for that, that you allow, you
know, somebody who knows how to do it to then teach it themselves as
opposed to having to be a company-specified person to teach 35,000
people.

DR. BLANCO: But I think at the beginning, you want the company to do
that and then in educational systems, you may want to open it up a
little bit more.

Anybody have any major objection to that?

(No response.)

DR. BLANCO: All right. Good. We\'re a little early, but rather than go
to the next question, why don\'t we just ‑‑ I\'m sorry?

MS. LUCKNER: If we notice the label, we did not really discuss labeling.

DR. BLANCO: Well, we\'ve done a lot of discussion on labeling. Bring it
up.

MS. LUCKNER: No, I\'m just saying as I look at the question, we did a
very nice job on the second part, training.

DR. BLANCO: Okay.

MS. LUCKNER: So I\'m not sure, and I\'m not sure when we will be
discussing that explicitly under the heading of labeling.

DR. BLANCO: Let\'s do it right now. What kinds of labeling are you
concerned about that you\'d like to look at?

MS. LUCKNER: I think we got two. One is that is going to be
consumer-driven and one that is available for physicians so that they in
the guidance and counseling to what patients are good candidates for
this procedure and which ones are not.

The other thing that I don\'t see anything about is the post-long-term
follow-up requirements for this procedure. Not being a clinician or a
gynecologist, I don\'t know whether that\'s a standard kind of a thing,
but I know we do long-term follow-up on birth control pills and we do
certain things about that and that often is in the warnings and
instruction pamphlet that we received. So should there not be something
about long-term management of this device? This is a device.

DR. BLANCO: Let\'s get it clear, because I was going to say, well, the
next question has to do with that but it really doesn\'t, not what you
just said, not management. It has to do with following for longer years
to find what the success rate of the device is over a long period of
time. So what you\'re saying is labeling for management of these
patients after they\'ve had the device in place. Okay.

MS. LUCKNER: Exactly.

DR. BLANCO: Okay. Things like Gerry brought up about the inability to
use electrocautery inside the uterus.

MS. LUCKNER: Right. Given the mobile population that we have, the burden
goes on the patient to be aware that she has this device in her and what
she needs to communicate with her next provider. I mean, HMOs come and
go like alphabet soup. So when the patient\'s going to have to change
their provider based on what their insurance coverage is, I want more
emphasis that the patient understands her responsibility in
communicating this to the next set of people who take care of her.

DR. BLANCO: Now, we know that there\'s an MRI compatibility and that\'s
not a problem. That data was looked at. Electrocautery is a problem. I
think this was what you brought up about metal allergy or metal
sensitivity. What are some of the other things that we would like to see
the patient cautioned about and make sure that they\'re aware of it for
their future health care? What are some other things that we can think
of?

DR. ROY: Well, Dr. Noller pointed out that one in eight won\'t be able
to have the device placed. They should at least be aware that it might
take a little more effort to try to reduce that number or else not use
it at all.

DR. BLANCO: Okay. Anything else that we can come up with?

DR. NOLLER: In the IUD package inserts, there\'s a couple of pages
about, you know, if you miss your period and stuff, make sure you get a
pregnancy test because you might have an ectopic. Should that be
inserted in here? Personally, I\'m not sure whether it should or not,
but it isn\'t and that would be something we could think about.

DR. BLANCO: Well, I think until we have more years of data, you know, at
least theoretically, you could argue that without the years of data, you
don\'t know if this will have a lower rate of ectopic pregnancy when it
does fail and eventually there will be the zero will turn to one at some
point if enough of these ‑‑ well, maybe not, maybe not, maybe never will
be, but potentially could be. So yes, I think that that would be another
issue that the patient needs to be cautioned about and concerned about.

DR. O\'SULLIVAN: I think the patients are being given like a little
wallet-sized card typically of what a cardiac pacemaker is getting, and
on that card should also be listed these factors and people with
pacemakers are usually pretty good about bringing up their little card
and actually patients given the right information, if you gave patients
cards with all of their clinical information on it and they could carry
these around, they would be the first ones to present them to the
physician who probably will say no, I don\'t need that.

(Laughter.)

DR. O\'SULLIVAN: I have one other question.

DR. BLANCO: All right. Well, let\'s make it general then. We included
some but let\'s not exclude other possibilities. They can get together
and figure out where there are some other things that the patient needs
to know about for their next 40 years or 60 years of their life or
whatever. So we\'ll leave it broad.

All right. Go ahead, Dr. O\'Sullivan.

DR. O\'SULLIVAN: Now, my one question, don\'t everybody laugh, what
happens when you go through the airport? Did you guys think about that?
Will this turn those machines off? How is she going to get away with
that one? She\'s going to need the card.

MS. DOMECUS: We\'ve had no reports of airport security issues.

(Laughter.)

DR. O\'SULLIVAN: The problem is, you may not know.

DR. BLANCO: That was Ms. Domecus. Okay. All right. Have we addressed
that issue then?

DR. O\'SULLIVAN: Yes. Thank you.

DR. BLANCO: Thank you.

All right. Why don\'t we go ahead? It\'s 3:25. Let\'s take a break, a
15-minute break. So we will reconvene at 3:40. We will look at the
hysteroscopic model and do the last question, and then we\'ll do the
voting.

(Recess.)

DR. BLANCO: Let\'s go ahead and get started.

We\'re going to go ahead and begin the last part with a little bit of
presentation about the hysteroscopic model that will be used for
training with this device and then finish the question and then do the
next question.

Ms. Domecus?

MS. DOMECUS: We have two of the simulator kits right here to show the
external and internal anatomies and we have different versions of the
internal anatomy. They\'re in separate pouches. We have two of these.
We\'ll start them at both ends of the table and pass them around so you
can touch these things, and then at the same time, we\'ll be having two
people from our Professional Education Department walk you through
visually the placement in the simulator.

Let me introduce those people to you now. First is Sandy Mayer, who\'s
the director of professional education at Conceptus, and Don Gurskis,
who\'s one of the managers in the Professional Education Department. Don
will actually operate the simulator for you and Sandy will walk you
through the procedure.

DR. BLANCO: Thank you.

MS. MAYER: Thank you for the opportunity to show this simulation to you.
As the models are going around, you will see that they are made up of
both internal and external components and if you take the pink plastic
out of the wrapper, you\'re able to open it and see that you can put in
different uterine linings to give the physician the opportunity to
practice on different types of anatomy that they will encounter in their
patients, from simple tubes to lateral tubes to tortuous tubes to
blocked tubes, and the physician will have the experience of doing that
during the total training period.

So while you\'re doing that, I\'m going to direct your attention to Don
at the monitor and the public can look at the hysteroscopic view on the
screen but the panel, you can actually see what is going on if you look
at the screen. So Don is going to start the demonstration using the
exact instrumentation that a physician would use in the procedure, in
the like procedure with patients.

The procedure begins with the introduction of the hysteroscope with
fluid so that you have distention of the uterus which is the same as you
would have with the distention during the procedure. The first thing
that Don does is that he looks for the visible ostium, identifies both
the ostium. When he determines which ostium is the most difficult, he
will determine that that is the one that he will do first and put that
ostium in the center of his field of vision for visualization throughout
the whole procedure.

At that time, he will put the split introducer into the working channel
of the hysteroscope, maintaining distention, and when it is in, he will
pull the stylus out and insert the catheter into the split introducer in
the working channel of the hysteroscope. You will see that he continues
to feed it down the working channel of the hysteroscope and when it is
halfway in, he pulls out the split introducer, continues to feed the
catheter down the working channel, maintaining visualization, until the
device is in the uterine cavity, at which time, he guides it into the
fallopian tube, inserting it slowly until the black positioning bump is
at the entrance to the ostium. At that point, the physician will
stabilize the handle of the device against the handle of the
hysteroscope, and once he has determined that the black bump is at the
ostium, he will then retract the delivery catheter one click every
second until it is retracted exposing the device.

Once he hits a hard stop, you see in the picture the release catheter
and the notch which give you two points of visualization for device
location. When the physician is pleased with the placement, he then
presses a button that releases the release catheter and the device
deployment when he pulls back on the device catheter with the thumb
wheel, and you see device deployment. The outer coils then expand. The
physician waits 10 seconds, counts to 10, to allow full expansion of the
outer coil. Once the outer coil is fully expanded, you begin rotating
the handle counterclockwise 10 full turns to disengage the delivery
catheter from the device. Once the disengagement has happened, you
gently pull the delivery catheter out of the uterine cavity.

At this point, the physician will use the hysteroscope to go in and view
the number of coils trailing into the uterus with ideal placement three
to eight coils, and in this case, we have one, two, three, four, five,
six, seven coils. We have seven coils exposed in the uterine lining. At
this point in the training, the doctor then would turn and do the second
tube and throughout the training course, they would be able to use the
various anatomies that you see here, so they get practice in all types
of anatomies that they will find with live patients, and again Don is
doing this with the exact instruments that the doctor will use in the
procedure to get them physically comfortable with everything that is
going on in the procedure, and we feel that this simulation is the
surrogate for the procedure in the perihysterectomy population.

I\'ll be glad to answer any questions. This concludes this part of the
demonstration.

DR. BLANCO: Thank you very much.

Any questions? Yes? Go ahead.

DR. SEIFER: Could you just review for us what zero ‑‑ is that a 0-, 12-
or 30-degree scope?

MR. GURSKIS: This is a 25-degree scope.

DR. SEIFER: Is that what you\'re recommending that we place it in with?

MR. GURSKIS: This can be done up with a variety of different angle
scopes. The minimum requirement is that it\'s a five-frame scope so for
the working channel, the scopes of the device can pass through. There\'s
no requirement on an angle of the hysteroscope.

DR. SEIFER: This model is extremely clean in the sense that it\'s smooth
and flat, and is there any recommendation for preparing the uteri with
any kind of pharmacologic medication or is that unnecessary because of
when they\'re going to be inserted?

DR. BLANCO: Please identify yourself.

DR. COOPER: Dr. Jay Cooper.

The recommendation is that the procedure be done whenever possible
during the early proliferative phase of the cycle when the endometrium
is likely to be thin and not having a situation where you would have a
lot of intrauterine debris.

I have personal experience performing the procedure at any time in a
woman\'s cycle, but there\'s no doubt that the hysteroscopist routinely
find that the early proliferative phase of the cycle is the ideal time
to do this procedure.

DR. BLANCO: Go ahead.

DR. BROWN: And so for each tube, you have this whole device for each?

DR. COOPER: Yes.

DR. BROWN: Okay. So one procedure would take two of these holes?

DR. COOPER: It\'s a single-use disposable.

DR. SHIRK: Hey, Jay?

DR. COOPER: Yes?

DR. SHIRK: Is there different lengths of these? Because like obviously
some of the flexible hysteroscopes are a lot longer than the rigid
hysteroscopes.

DR. COOPER: At the present time, there\'s only one length and that
length will accommodate to virtually any rigid hysteroscope on the
market. At the present time, the recommendation is that a rigid
hysteroscope is to be used, and to be perfectly frank with you, that\'s
I think because the great majority of hysteroscopy is done with rigid
hysteroscopy. The time may come that we\'ll find that a flexible
hysteroscope might in fact be a better tool for placement, but at the
present time, rigid hysteroscopy is the standard, so to speak.

DR. SHIRK: Yes. Well, I mean, with a flexible, you obviously get a zero
degree situation and it\'s coming straight off of your end.

DR. COOPER: You\'re preaching to the choir. You know that.

DR. BLANCO: This is a little more subtlety probably than what our
recommendation\'s going to be.

Any other questions? Anything on the procedure or the model?

(No response.)

DR. BLANCO: All right. Thank you very much. I appreciate that the
company did that and many thanks to the individual who put it in who
I\'m sure was perspiring.

(Laughter.)

DR. BLANCO: All right. Let\'s go ahead and move on.

Were there any other questions? Any other comments on labeling and
training, Question Number 7? Go ahead, Gerry.

DR. SHIRK: I had one, I guess. We\'ve talked about the question of in
vitro fertilization after this. Do we want to put anything in the
labeling about pregnancy after this and the fact that we don\'t know
anything about this, and how should we approach these patients as far as
in vitro fertilization? I mean, I think it\'s a big question because I
don\'t think we have any way of answering it, but I don\'t know. You
obviously don\'t want to do a study to answer the question. It\'s just a
question I\'ve got. How do we approach this thing? Because, you know, I
really don\'t know if we should put some special labeling in there that
if you get pregnant with this device in, that you may have severe
complications of pregnancy.

DR. BLANCO: Well, but we don\'t really know that.

DR. SHIRK: We don\'t know that.

DR. BLANCO: I think that ‑‑

DR. SHIRK: We don\'t know that it doesn\'t.

DR. BLANCO: I said may. You know, a lot of what we\'re doing really has
been for answering the question that has a lot to do with labeling, and
I think the nice thing about being on the committee is that we can put
forth to the FDA and the company the idea that they somehow need to
address this issue, especially when we talk about the younger folks that
may be in their late twenties that, you know, may have this procedure,
or mid-twenties, that there needs to be some issue addressed to the fact
about regret and about any other pregnancy in the future and that little
information is known about what\'s going to happen.

I mean, we don\'t know. You know, the reality is what\'s left in there
is pretty small. We\'ve had a fair number of pregnancies with IUDs, and
oftentimes they don\'t create that much problems once the string\'s out
and away from the cervix, which is not a problem here.

So I think we can just make the recommendation that that issue needs to
be addressed in labeling. Is that all right with everybody? Let them
work it out.

DR. SHIRK: I guess the question is, an IUD obviously is an accident. I
mean, you don\'t get pregnant with an IUD in place on purpose. Okay? But
this would be on purpose with an IUD in place.

DR. SHARTS-HOPKO: You mean the in vitro part?

DR. SHIRK: Yes, IVF. I mean, the only way you\'re going to get pregnant
is if this thing remains zero as far as number of failures is basically
a deliberate rod around the obstruction. So to me, it\'s different
between ‑‑ I mean, basically a pregnancy with an IUD in it is an
accepted risk of having the IUD in, when you\'re deliberately doing this
to go around the obstruction.

DR. BLANCO: No, but that just also brings up the issue that ideally,
with appropriate counseling, we know it\'s going to happen. You know, it
shouldn\'t happen.

All right. Anything else? Nancy, did you want to say something?

DR. SHARTS-HOPKO: Well, no. That was my point, that you don\'t want
anything in the labeling that gets women to think that this is not a
permanent contraceptive strategy.

DR. SHIRK: I understand, but I mean, I think that makes it permanent.

DR. SHARTS-HOPKO: Yes.

DR. SHIRK: I mean, that means that even if you decide to change your
mind down the line, that we don\'t recommend that you do IVF, and that
also comes across the people doing IVF. If you do IVF and you get a
complication of pregnancy, then you\'re at risk legally for that
complication.

DR. BLANCO: Now, somehow I think the company\'s probably going to have a
big interest in how they word that one. So I think we can probably leave
it at just that something needs to be addressed about that. How\'s that?

All right. Let\'s move on to the next question. Post-Approval Studies.
Number 8. \"An important finding from the longitudinal CREST Study 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 postmarketing 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?\"

Who would like to tackle that one, first of all? Not overwhelming.

DR. SHARTS-HOPKO: I\'ll comment.

I think five years is a reasonable expectation for the company. There
was something that caught my eye, and I forget which of these five
volumes it was in, but you all anticipated getting maybe a private
investigator to track down your drop-outs, and I thought that was a
little zealous.

(Laughter.)

DR. BLANCO: All right. Dr. Brown?

DR. LARNTZ: I don\'t.

(Laughter.)

DR. BROWN: I would actually take the opposite tack and say that based on
the data that we now have about the CREST Study, that if they\'re going
to be doing the follow-up for five years, I would like to see it done
for longer so that you\'d be able to more definitively say you don\'t
see this acceleration that seems to start with all the other methods at
five years and go up, so maybe extend it to seven years.

DR. BLANCO: On that remark, I\'d like to ask Dr. Costello to come up and
do two things. One is we\'ve mentioned this acceleration issue several
times, and I\'d like to comment on that because I think what she\'s
going to tell us is that there is no acceleration issue, Number 1, and
then Number 2, why don\'t you, while you\'re up there, please address
the issue of were there any strategies that were used in the CREST Study
that helped in the maintaining follow-up of these patients that you
could suggest that might be things that the company could do?

Thank you, Dr. Costello.

MS. COSTELLO: Okay. You\'re welcome.

First, I\'d like to have you look again at Slide 6 and what you see is
cumulative probabilities of pregnancy following sterilization. At year
1, that cumulative probability is a certain height but at year 2 that
impedes the probability at year 1, year 2. So it\'s throughout the
years. So it\'s not that it\'s accelerating. It\'s that that probability
is going to increase with each year because it includes the years
beforehand.

So the use of the term \"accelerating\" is actually really making me
quite uncomfortable because that\'s not really what we found. Actually,
when we look to the ectopic pregnancy analysis, the annual rate of
pregnancies in the fourth through 10th years was actually at the same as
the annual rate of pregnancies in the first three years. So their actual
annual rate of pregnancies is not actually accelerating.

DR. BLANCO: So what you\'re saying, for somebody simple like me, what
you\'re saying is that the rate is 1 percent year 1, it\'s 1 percent
year 2, 1 percent year 3, 1 percent year 4, 1 percent year 5, but now
you\'re at 5 percent?

MS. COSTELLO: Exactly.

DR. BLANCO: Because you\'ve got each year cumulative, right?

MS. COSTELLO: Exactly.

DR. BLANCO: So it\'s not accelerating, it\'s additive?

MS. COSTELLO: Exactly.

DR. BLANCO: Thank you.

DR. SEIFER: And just to clarify that, on Slide 6, when the slope
increases, all that means is ‑‑

MS. COSTELLO: That means that by year 10, then the probability of having
a pregnancy by year 10 includes the probability of having pregnancy at 1
through years 9 up until year 10.

DR. BLANCO: Were there any method for which you saw an increasing
percentage of pregnancies subsequent years beyond the first 1, 2, 3, 4,
or 5 years? Do you understand my question?

MS. COSTELLO: Well, if you look at the graph, it looks like possibly
bipolar is the only one that seems to be increasing at a greater rate,
but I would say that if you looked at that with the confidence
intervals, it wouldn\'t appear so.

DR. LARNTZ: If I might just make a comment. The way I look at this to
see if it\'s accelerating is I put a pencil or something at zero zero
and then see if it deviates from a straight line, if it\'s going up from
that. Most of them don\'t. Actually, most of them actually curve off a
bit, so they\'re actually, if anything, decelerating. But it\'s an
approximate way to do that. Just take your pencil at zero zero and see,
and I think with the noise, I\'m sure there isn\'t an acceleration.

DR. BLANCO: Thank you.

MS. COSTELLO: Yes, exactly. With the noise, it may seem like bipolar is
the one that might be the one that has the rate that continues the same
rate each year, whereas the others may possibly seem to flatten off.

Your question about follow-up. The CREST Study filled out for each
patient, they filled out a patient locator form at sterilization and
then at annual follow-up, the CDC investigators sent a list of patients
to the study site who were due for their annual telephone follow-up
interview. So then, the nurses who have been trained at each study site
attempted to call each patient about their annual interview and they\'ve
tried three times at different times of the day, and if they didn\'t
respond, then they were still tried for the next follow-up interview.

DR. BLANCO: Okay. Any questions? Yes, Dr. Noller?

DR. NOLLER: I have another comment.

MS. COSTELLO: Anything specific?

(No response.)

DR. BLANCO: All right. Thank you very much.

DR. NOLLER: As far as the follow-up, there are a number of books and
articles that have been written about increasing follow-up, and I think
probably the best thing is just to talk to people that have done it. The
CREST Study. We have a study that started in 1974 and we still have
about 84 percent of the women, several thousand women, in it. You know,
there are ways you do this, and it\'s well written up. In the United
States right now, it\'s hard to lose anybody if you really, really try
and you don\'t have to use detectives.

DR. BLANCO: Any comments? Dr. Brown, I\'d like to ask you since you
brought it up, but it sounds, if the rate had pretty much stayed the
same in most of these other methodologies, it sounds like five years may
be sufficient to really figure out whether it\'s changes or it\'s the
same.

DR. LARNTZ: Well, certainly, if there\'s any kind of increase, we\'ll
probably see it in five years.

DR. BLANCO: All right. So, the question is is five years adequate?
Sounds like everybody thinks it is, and then Dr. Noller mentioned there
are ways of minimizing loss to follow-up that would be recommended. So
the last one here is are there any other elements that need to be
mentioned or included in a post-approval study?

David?

DR. SEIFER: I just wanted to beg the last question.

DR. BLANCO: Go backtrack.

DR. SEIFER: If in five years, the failure rate looks greater than anyone
expected, could then there be some kind of contingency plan to follow
that for another X amount of time?

DR. BLANCO: We could recommend it, yes.

DR. SEIFER: So depending on the performance of the product.

DR. BLANCO: Yes, sir?

DR. LARNTZ: Are we saying if the product\'s really good, we want to
penalize them to have them follow more?

DR. ROY: No, I think he meant if it was worse.

DR. LARNTZ: No, I thought he said if it was ‑‑ do I understand it? I\'m
asking if I understood that right. If it\'s really low, it\'s doing
really well?

DR. SEIFER: No, no, no. If the people are getting pregnant using this
product.

DR. LARNTZ: Oh, if they are?

DR. SEIFER: Yes.

DR. LARNTZ: Then you know there\'s a problem at five years.

DR. SEIFER: But then what do you do?

DR. LARNTZ: That\'s the information you\'ll have and that can be brought
back. The FDA will have that information. They can give a report, do
whatever they need to do with that information. Maybe they should tell
me what they do, but what I would do is once you have that information,
then you have to take action on that available information and decide
based on if the rates are poor, then obviously someone needs to write a
paper about it and it needs to be publicized, that kind of thing. I
don\'t think you\'d want to necessarily follow them more based on that.
I think you\'ve probably got the information you need.

So I did misunderstand you. I\'m sorry.

DR. ROY: The private investigators would find each of us, bring us back
here, and ask us why we approved this.

(Laughter.)

DR. BLANCO: Okay. I think we better get to voting pretty soon here.

Dr. Noller?

DR. NOLLER: Other elements of post-approval study needed. It would
certainly be nice to know in actual practice what the failure to insert
both devices at the first sitting would be. I don\'t know if that should
be studied, you know, later as a retrospective study or if it should be
part of the company\'s responsibility.

DR. BLANCO: I\'m sorry. Let me interrupt you. The way it\'s written now
and the way I think their proposal for the post-approval study is,
they\'re going to follow the folks who already have it inserted. So what
you\'re suggesting is that they need to gather further data on some of
the ‑‑ I mean, I\'m just clarifying. I don\'t disagree with it, but that
they need to gather further data on the failure rates, especially maybe
when it opens up to not so famous or whatever hysteroscopists. Is that
what you\'re suggesting?

DR. NOLLER: I guess since the failure rate is so high, 12 percent, say,
8 percent, among experts, you know, if it\'s 20 or 25 or 30, who knows
what it is, but let\'s just say it\'s 30 percent, I think we\'d probably
all agree it\'s probably not something that everybody should use. I
doubt it will be, but I wonder if there shouldn\'t be some sort of
surveillance of that.

DR. BLANCO: I think that\'s a good recommendation. I think it might even
help them if the failure rate stays low in terms of their labeling and
what it says.

MS. MOONEY: That may already be addressed, Dr. Blanco, in terms of the
complaint reporting that ‑‑

DR. NOLLER: Think so?

MS. MOONEY: Well, I think that in that case, the physician would
probably be looking to have that device replaced or some sort of credit.
So in my experience, those particular complaints, you do get pretty good
reporting back from the sponsor.

DR. BLANCO: Well, I hate to put too much onus on the company, but I
think that this is probably a big enough issue, that one is, that they
need to look at that. I mean, maybe they don\'t need to look at it
forever, you know. Some reasonable number to get a better gauge and
also, like I say, it could improve and they may want to change their
labeling or whatever.

So I think they need to not just rely on complaint reporting because a
lot of docs will just say oh, I don\'t want to use it, and they\'ll not
use it any more, and you may never get those reports. I think they need
to make some effort to figure out with broader use what the failure rate
is at initial insertion, but I could be convinced otherwise if somebody
disagrees.

Dr. Brown?

DR. BROWN: Just one other thing that they might want to consider. I
don\'t know if it would be necessarily a study but to keep some type of
registry of users in terms of some of these other factors that were
pointed out may be prognostic in terms of failure rate, such as age and
ethnicity. You have that breakdown, but as it comes into use in the
general population, since we know that black women are basically, I
guess, four times more likely, three times more likely to have failure
with these other methods, it would be good if you could collect that
data as it\'s happening so that it could be available.

DR. BLANCO: Any other suggestions for things that they should look at?

(No response.)

DR. BLANCO: Well, that ends the questions. If any of the panel members
have anything else they want to bring up at this point with great
urgency?

(No response.)

DR. BLANCO: No? Then we go to the final comments and what we do here is
we open it up again to the audience and the FDA, then the sponsor, to
make some final comments. This is not an interactive session or time for
questions and answers, basically just a small amount of time to make a
final statement.

Dr. Costello, are you comfortable with the statements that you\'ve made?

MS. COSTELLO: Sure.

DR. BLANCO: You\'re okay? Do you want to make some other comments? Yes?

MS. COSTELLO: No, everything I said is fine.

DR. BLANCO: Okay. Dr. Costello is happy with her comments. So we\'ll go
ahead and go with the next one.

The next one that I have that has registered to speak before us is Dr.
Amy Pollack, president of Engender Health. Please remember to introduce
yourself and any conflict of interest.

DR. POLLACK: Hi. My name is Amy Pollack. I don\'t have any conflict of
interest here, and I\'m speaking to you as an obstetrician-gynecologist.
I have a specialization in public health, and I\'m the President of
Engender Health and Engender Health is a not-for-profit organization
working in the U.S. for the last 60 years and internationally for the
last 30 in the field of family planning and reproductive health. We are
most widely known for our experience and work with female and male
sterilization in service delivery which is why I\'m talking to you.

Bilateral tubal sterilization as provided today in the U.S. is
considered both safe and highly effective. We all know this from years
of clinical experience using different methods to access the tubes and
then different methods to occlude them. Approximately half of the
700,000 female sterilizations performed annually in this country are
provided as interval laparoscopic procedures. Those estimated 350,000
women choose for a variety of reasons to undergo a procedure that
carries with it an estimated risk that the procedure will lead to
unintended abdominal surgery of almost 1 percent. That risk is not
statistically related to the method of tubal occlusion. You probably
heard about that this morning, but it is related to the necessity to
enter the abdomen and to access the peritoneal cavity. This
transgression alone represents the invasive nature of the currently
available permanent sterilization methods.

In addition, female sterilization using both laparoscopic and minilap
procedures are most often provided using local anesthesia in many other
countries around the world. They are almost exclusively performed in the
U.S. using short-acting general anesthesia. Data from the CREST Study
cites the use of general anesthesia as a predictor of complications in
women undergoing interval tubal sterilization.

Although there are many reasons to argue boldly for the development of
and access to transcervical methods of sterilization, I would like to
emphasize the two attendant risks described briefly above. Despite these
risks, hundreds of thousands of U.S. women each year choose permanent
sterilization. Many of those women might choose highly-effective
temporary methods, such as hormonal implants or IUDs, if they were more
readily available. But many of these women recognize the side effects of
all of the temporary methods as significant and as a disadvantage over
permanent sterilization.

The recognizable risks of surgical sterilization and the side effects of
the available temporary methods mandate the need for a transcervical
option. After all, research to develop a safe and effective
transcervical sterilization method has been ongoing for over 30 years.
If we have now and I understand that there remain a few ifs here, a
transcervical method that is well tested and is highly effective and
safe to provide, one that can be provided without trespassing in the
peritoneal cavity and that does not require general anesthesia, women in
the U.S. should have access to that method.

In addition to that, I would like to urge the developers of Essure to be
rigorous in their postmarketing surveillance, given some of the
questions being explored here today, and to pursue simpler methods of
placement of the device with the intent to market this device more
widely on a global scale in places where permanent contraception is
desperately needed by millions of women living in very low resource
settings.

Thank you.

DR. BLANCO: Thank you.

The next speaker that I have that requested time is Amy Allina, program
director, National Women\'s Health Network.

MS. ALLINA: Hi. Thank you.

I am Amy Allina, and I\'m the program director of the National Women\'s
Health Network, which is a non-profit organization that advocates for
national policies that protect and promote women\'s health and also
provides evidence-based independent information to empower women in
health care decisionmaking. We don\'t accept any financial support from
pharmaceutical or medical device companies, and we\'re supported by a
national membership of about 8,000 individuals around the country and
300 organizations. So I have no financial conflict of interest.

We\'ve reviewed the information provided to the FDA regarding the Essure
device and are here today to provide some comments on the questions
before the committee, particularly as they relate to women\'s need for
and ability to use this method of sterilization safely, effectively, and
with long-term satisfaction, and I\'m very happy that the committee\'s
already addressed a number of the points that are in my comments. I
think your discussion\'s been really interesting and very good today. So
thank you for that.

Conceptus has provided a lot of detail about women\'s need for an
expanded array of contraceptive choices and Dr. Pollack also spoke about
it. I won\'t repeat their arguments, except to say that the network
agrees that existing options aren\'t adequate to meet women\'s
reproductive health needs and that expanding the number of safe and
effective contraceptive methods available would be a significant advance
for women\'s health, helping to reduce unintended pregnancy and increase
women\'s control over child-bearing and as a consequence other aspects
of their health status as well.

That said, this is a new device and as you\'ve discussed, there is not a
lot of data available on its use. It\'s been tested in a few women and
not for very long. We recognize the difficulty in doing clinical trials
in this area and we have supported contraceptive approvals based on
trials of this size and length and the focus of our comments today is on
what women need to know to make an informed choice for Essure and
especially on the question of how to convey to women the limits of our
knowledge in light of the small number of women who have used it and the
short time of the trial.

The network believes that the use of a written consent procedure for
long-acting or permanent methods of contraception improves the
likelihood that women and their clinicians will engage in the full
discussion necessary to achieve informed choice, and we\'ve asked the
FDA to mandate written consent for long-acting contraceptive methods in
the past. In this case, the method in question is an alternative to a
surgical procedure which requires written consent and we urge the FDA to
mandate the use of a written consent procedure for Essure with the
consent language to be approved by the agency and include similar topics
and information to those proposed in the patient information booklet.

Providing patient information booklets can also be useful for helping
women to understand the risks, benefits and consequences of their
contraceptive choices, and we reviewed the proposed booklet, the
language, and we have a few additions and amendments to suggest, some of
which you\'ve touched on, but we wanted to start by complimenting
Conceptus on including language about women\'s right to be informed
about other options and to change their minds about using Essure at any
time without being required to provide explanation or reason. We were
also pleased to see the acknowledgement in the patient booklet that
Essure is a newer procedure and it hasn\'t been studied in as many women
or for as long as other contraceptive options.

Our first and primary concern, I think, as you all have also focused a
lot of your discussion, is on how to provide women with an accurate
understanding of what\'s known about the effectiveness of Essure. The
statement that\'s currently included in the brochure in the Key
Considerations Section, \"if the Essure procedure is completed
successfully, the one-year effectiveness rate is greater than 99.8
percent,\" fails to provide women with an adequate basis for
understanding the limits of what\'s known and for comparing the device
to other options where there is longer-term data.

Because of the small amount of data on Essure, it\'s difficult to
compare its effectiveness to other methods that have been in use for
many years, and we would like to see language included which explains
something along the lines of, you know, while in a study of about 400
women, no one got pregnant in the first year. The study may have been
too small to discover reliable effectiveness rate and to give some
information about how effectiveness changes over time as seen, for
example, in the CREST Study.

The patient information should also include a statement as you all have
mentioned about the fact that some women who attempt to have Essure
Inserts placed won\'t be able to use this method of sterilization, it
might include a statement to the effect that in the trial, X percent of
women who elected to use Essure underwent attempted placement but were
not able to use the method, so that women know that going in before they
decide to go through any procedure.

In the Warning Section of the Safety Summary, Conceptus has proposed
language concerning the unknown risks that may be associated with
intrauterine therapies that use electrical energy and also the
possibility that any intrauterine procedure could pose unknown risks and
could interfere with Essure\'s effectiveness in preventing pregnancy,
and we think these warnings should be explained in greater detail. The
language should include information about the conditions which might
make these procedures necessary, so that women have some understanding
of what they really are agreeing to and those include endometriosis,
fibroids, dysfunctional uterine bleeding, and the patient booklet should
inform women that these conditions are not uncommon in women in their
thirties and forties. This is also something that might be studied
post-approval, what happens when those procedures are done in women
using the device.

The Warning Section also includes language about the possibility that
Essure may pose risks for women who choose to undergo in vitro
fertilization and you all discussed this earlier. We do believe that
this has the potential to be confusing regarding the reversibility of
the device, but we also agree that it\'s something women need to know
since some women will change their minds and we wanted to suggest that
there might be language to the effect, repeating what appears in other
places in the booklet about the reversibility in that section about IVF,
so that it would say something like the Essure procedure should be
considered irreversible and you should only choose it if you\'re sure
you don\'t want to have children in the future. If you change your mind
in future years, which is not something that\'s in the IVF section right
now, that it doesn\'t say if you change your mind, but to say if you
change your mind in future years and decide to attempt to become
pregnant using in vitro fertilization, you should know that the effects
of Essure on the success of IVF in achieving pregnancy, the effects on
your health, the health of your baby and the continuation of your
pregnancy are all unknown.

The only other thing I wanted to mention was just on the question of the
HSG versus pelvic x-ray or some other test. We recognize some of the
reasons the pelvic x-ray might be preferable for women, for clinicians
and also for the sponsor, but we don\'t have enough information about
whether or reliably confirm the position of the device in tubal
occlusion, and until studies have shown that pelvic x-ray is a reliable
measure of these questions, we believe that an HSG should be required
and also that the patient information booklet should explain that this
test is necessary to determine whether the Essure procedure has been
successful and that the booklet needs to include a description of
what\'s involved in an HSG and what that experience is like for women. I
don\'t believe there\'s anything like that in there now since the
sponsor wasn\'t suggesting that the HSG be required.

So my conclusion is just to say that in light of the need for expanded
contraceptive choice and the desirability of making sterilization a
safer choice for women, we support approval of the Essure device and we
believe that if it\'s appropriately incorporated into the array of
contraceptive options that are offered to women and adequately studied
post-approval, it has the potential to advance women\'s health.

Thank you.

DR. BLANCO: Thank you very much for your comments, and I apologize for
mispronouncing your name.

MS. ALLINA: That\'s okay.

DR. BLANCO: I still apologize.

All right. The last person that we have on the list that would like to
speak before us is Wayne Shields, president and CEO, Association of
Reproductive Health Professionals.

MR. SHIELDS: Hi, and thanks for the chance to talk to you this
afternoon. I really appreciate it. Again, the name is Wayne Shields, and
I\'m president and CEO of the Association of Reproductive Health
Professionals. ARHP ‑‑

DR. BLANCO: I\'m sorry. Before you start, make sure that you say
something about conflict of interest.

MR. SHIELDS: Yes, I\'m about to do that.

DR. BLANCO: All right.

MR. SHIELDS: We receive support from our individual members and we
receive foundation grants. We also receive support from restricted
educational grants from companies, and we have in the past received that
kind of support from Conceptus. So I wanted to be sure you knew that.

I represent about 2,400 health care providers and those include not just
physicians but nurse-practitioners, nurse-midwives, and physician
assistants, all the advanced practice clinicians, some educators and
scientists, but they\'re all directly involved in the practice of
women\'s health and reproductive health. I also represent a larger
constituency of 15 to 20,000 primary care physicians and advanced
practice clinicians who regularly participate in our educational
programs that we develop. Our members work in both the public health
sector and in private practice. So they\'re really basically in all
types of environments.

ARHP\'s mission is education and we\'ve been educating health care
providers and the public on reproductive health issues since 1963. So
it\'s almost our 40th year. We work closely with other organizations. My
friends and colleagues, Amy Allina and Amy Pollack, are in the room.
We\'ve worked with their organizations and many others. All of the
acronyms that you can possibly imagine in Washington, D.C., we\'ve
worked with them at some point.

The reason I\'m here is that although ARHP has addressed many
reproductive health topics through our accredited education programs
over the years, much of our focus has been on contraception and I\'m
sure you can imagine why, particularly with health care providers in
need of this kind of information. ARHP places a very strong emphasis on
provider education, provider training and particularly on patient
counseling. Those are what we see to be the most important, I\'m sure
you do, too, the most important ingredients of safe and effective
contraceptive health care, and we also view communication between the
health care providers and the patients as key and an essential part of
better health care.

Also because every woman\'s and man\'s needs are unique, ARHP supports
the availability of as many safe and effective contraceptive options as
possible, and we believe this is critical for the good health care of
women and men in the United States, and it\'s key to a healthy
functional health care system here in the U.S.

Many women prefer, of course, reversible methods of birth control
because they want the option of having children at a later time, and it
is a huge counseling issue. It\'s an important one. Others have
preferences for things that are more \"natural,\" but in the U.S.,
there\'s just the option right now of one type of sterilization option,
and women who choose sterilization do choose tubal ligation, but I\'m
here to say that we\'re very pleased that women have the potential to
have access to a new, safe, effective sterilization option in the U.S.
We think this is a very positive development, and at our organization,
we\'re particularly pleased at the care that the manufacturer,
Conceptus, has taken to thoroughly study this new method and I know
we\'ve talked about that today, but also to carefully focus on provider
training and education about the insertion. You witnessed that earlier.
Our impression is that they have done a very good job thinking about
this at length and believe me, we\'ve talked to other organizations and
companies who haven\'t had this type of depth of thought, and it\'s
definitely appreciated by our members and by our board.

The other part that\'s important to us at ARHP is that Conceptus seems
to have recognized the critical importance of patient counseling in
making decisions about permanent sterilization, and of course, to Amy
Allina\'s statement about including information about IVF in the
labeling. Women do change their minds, and it\'s critical that women do
have information about what it is they\'re about to decide in an adult
conversation with their health care provider, and to us, this is
critical, and I\'m sure it is to you all as well.

I was very pleased and surprised, as was our board, to find that
Conceptus had thought about this in length and that their interest in
patient counseling matches that of ARHP. So we\'re very pleased about
that, and I\'m very convinced at this point, which is I think a good
thing and it\'s not that common, about this company\'s commitment to
very thorough appropriate training and also to patient counseling and
that\'s key, and I\'m glad to see that and I wanted to share that with
you, and thank you for allowing me to comment.

DR. BLANCO: Thank you very much.

I thank all the audience for your participation.

Now, is there anyone else in the audience who hasn\'t signed in that
would like to make a comment?

(No response.)

DR. BLANCO: Next is the FDA, a member of the FDA, for some final
comments at this point. No comments from the FDA at this point?

MS. BROGDON: No. We have no comments.

DR. BLANCO: No comments. That\'s very politically correct.

All right. Then it\'s the company\'s opportunity to come forth and make
some comments at this point.

MS. DOMECUS: Thank you for the opportunity to provide a few comments on
the discussion that ensued since our presentation. I just wanted to
address a few points mostly for clarification.

First, of course, I\'d like to address the issue of x-ray in lieu of
HSG. I wanted to provide a couple of clarifications. Dr. Brown, I think
you had a question about why our training program didn\'t provide
interpretation of x-rays to the radiologists, and I wanted to clarify
that our plan was to train the gynecologists who perform the procedure
in the appropriate interpretation of x-rays and that we were not
recommending that the radiologists do that interpretation.

Second, I just wanted to clarify that the x-ray at three months was
being suggested as a first step and that if there were any suspicious
findings noted on x-ray, that then those subset of patients would
undergo an HSG. If there was clearly unsatisfactory device location,
those patients would not undergo an HSG but would be told to use
alternative contraceptive methods. So some patients would undergo an HSG
if the x-ray showed suspicious findings.

I think I heard in the discussion today but I just wanted to reiterate
that all of the unsatisfactory device locations that we found in the
trials could be detected on pelvic x-ray alone. It seemed to me, though,
that the discussion centered around the 4 percent patency rate, and so I
wanted to highlight a point which I believe the industry representative
made that I think is of critical importance, and I wanted to just read
two sentences here from the PMA just to address this point.

Bruce, et al., reported a patency rate of 16.7 percent in a study of 54
tubal ligation patients followed for an average of 4.5 years and cited
literature references for a total of over 1,000 patients followed for
three months where the average patency rate was 3.2 percent. It should
be noted that the pregnancy rates in these studies do not equal the
patency rates noted. Therefore, it has been reported in the literature,
and I quote, \"Although there may be failure of absolute physical
occlusion of the tubes, this cannot be directly equated with failure of
sterilization.\"

I would like to tie that comment to the histology data that was
presented earlier where Dr. Wright showed that not only was the tissue
response occlusive in nature but that also there was consistent loss of
normal tubal architecture in all specimens evaluated, and I also would
like to remind you of his comments about the amount of tubal occlusion
and damage that he\'s seen in our histology specimens as compared to
that seen in specimens from ectopic pregnancies.

I wanted to provide a couple of clarification points on training. I just
wanted to clarify that the preceptoring for five cases is what we expect
to be the average. It\'s not a minimum, that we will not sign people off
until they have demonstrated competency. So I just want to be clear, we
expect it to be an average of five based on our pivotal trial data, but
it\'s not a minimum of five.

I also wanted to clarify the comments about training and local versus
general anesthesia, and I\'m reading from our labeling. We actually
recommend that local anesthesia be used. What we say is local anesthesia
is the preferred method for implantation of the Micro-Inserts. So we
actually recommend that in the labeling.

I also think there\'s a lot of discussion around the concern about how
generalizable the placement success rates were in the pivotal trial to
the general population, and I just wanted to remind the panel about the
data that we do have in that regard, that we\'re not without data to
speak to that. I presented a slide earlier this morning that showed the
baseline, just an average of four procedures per physician with our
commercial training program to date, that we\'re already having success
rates that are very close to those in the pivotal trial. So we do have
data to speak to how generalizable this might be.

I\'d also like to remind the panel of the figure we presented earlier
this morning, that when looking at placement failures that were
evaluated by HSG, that 83 percent of them were found to have proximal
tubal occlusion. So placement failure isn\'t just a factor of physician
experience or learning curve, it\'s also an anatomy issue.

There\'s also some comments or suggestions to have an implant card or
patient ID card, and I just want to clarify that that\'s already been
proposed in the PMA. We did so in the clinical trial as well and the
back of the card carried some statements about not having data on the
future procedures, such as IVF, intrauterine procedures, et cetera, and
so we are proposing to do that in the commercial setting as well.

Dr. Shirk, you also raised some issues about unilateral placement and
what we would suggest in that regard. In the protocol, we allowed
patients the opportunity to come back for a second placement procedure
after first undergoing a follow-up HSG since the likelihood of PTO was
probably increased in the patients who had placement failure, and many
patients did elect to undergo a second placement procedure and were
successful, and so we\'d be happy to include our protocol
recommendations in the labeling as well regarding patients that achieved
unilateral placement at first visit.

There was also some discussion about the label containing cautions about
lack of data on IVF, and I just wanted to clarify that both the
physician and the patient labeling do have that language and the
physicians labeling has it in the Warnings Section and the patient
labeling discusses it under the section on Procedures that we don\'t
have safety and effectiveness data, and contrary to the prior speaker, I
wanted to point out that these bullet points in both the physician and
patient labeling, that bullet point is right next to the bullet point on
reversibility and how we don\'t have any data on the success of the
reversibility.

I also want to comment about the postmarket surveillance and the
five-year follow-up, and there seemed to be some concern that we might
have decreases in pregnancy rates and if so how would that be known and
how would that be communicated, and I just wanted to clarify that, you
know, once we have the next year failure rates established, we will be
submitting that to the FDA and certainly if there is any change, we
would be required to update our labeling. We wouldn\'t wait till five
years to then let patients know that there was a change in the failure
rate.

I think that was all the clarification comments that I had.

DR. BLANCO: Thank you very much.

All right. Now we come to the voting on panel recommendation options and
I\'m going to go ahead and read the options for premarket approval
applications.

\"The Medical Device Amendments to the Federal Food, Drug and Cosmetic
Act (the Act), as amended by the Safe Medical Devices Act of 1990,
allows the Food and Drug Administration to obtain a recommendation from
an expert advisory panel on designated medical device premarket approval
application (PMAs) that are filed with the agency. The PMA must stand on
its own merits and your recommendation must be supported by safety and
effectiveness data in the application or by applicable publicly
available information. Safety is defined in the Act as reasonable
assurance, based on valid scientific evidence, that the probable
benefits to health (under conditions on intended use) outweigh any
probable risks. Effectiveness is defined as reasonable assurance that,
in a significant portion of the population, the use of the device for
its intended uses and conditions of use (when labeled) will provide
clinically significant results.

\"Your recommendation options for the vote are as follows:

\"Approval, if there are no conditions attached.

\"Approvable with conditions. The panel may recommend that the PMA be
found approvable subject to specified conditions, such as physician or
patient education, labeling changes, or a further analysis of existing
data. Prior to voting, all of the conditions should be discussed by the
panel.

\"Not approvable. The panel may recommend that the PMA is not approvable
if the data do not provide a reasonable assurance that the device is
safe or if a reasonable assurance has not been given that the device is
effective, under the conditions of use prescribed, recommended, or
suggested in the proposed labeling.

\"Following the voting, the chair will ask each panel member to present
a brief statement outlining the reasons for their vote,\" and I would
just add that the vote is vocal and individual by person as we go
around.

Just from prior experience, I\'d like to suggest that we basically see
if anyone is interested in providing a motion for approval or not
approval and then depending on how those go, we\'ll see the approval
with condition. So at this time, I will entertain a motion, if anyone
would like to make it, of approval with no conditions.

Dr. Shirk would like to make the motion. Is there a second to that
motion?

DR. SHARTS-HOPKO: Second.

DR. BLANCO: Second to that motion.

Is there any discussion at this point? I\'d like to open up the
discussion. We put a lot of conditions already that we discussed. So
I\'m not sure that we can add those or that they will be there. If we
approve it without conditions, it\'s done, and they don\'t have to
change a thing. Okay? So I\'m not sure that that\'s ‑‑ that wasn\'t what
I was searching for really.

(Laughter.)

DR. BLANCO: But I\'m not sure that that\'s where we want to go. Let me
just put it that way. If we want all these labeling changes and we want
the issues that we have all discussed, then we need to add those as
conditions. Okay?

Any other discussion anyone else would like to say anything?

(No response.)

DR. BLANCO: Then I\'ll ask the voting members to vote on the motion on
the floor. We\'ll start with you, Dr. Shirk, over in that area.

DR. SHIRK: I guess at this point, I think the company\'s aware and
responsible and I guess I would vote for approval.

DR. BLANCO: Okay.

DR. LARNTZ: No on the motion.

DR. BLANCO: Dr. Roy?

DR. ROY: No on the motion.

DR. BLANCO: Dr. O\'Sullivan?

DR. O\'SULLIVAN: I abstain.

DR. BLANCO: Dr. Sharts-Hopko?

DR. SHARTS-HOPKO: Despite seconding it, no to the motion.

DR. BLANCO: Thank you.

DR. BROWN: No on the motion.

DR. BLANCO: Dr. Brown.

The chairman doesn\'t get to vote, unless there\'s a tie. So we\'ll keep
going to the right.

DR. SEIFER: No on the motion.

DR. DUBEY: No on the motion.

DR. NOLLER: No on the motion.

DR. BLANCO: The results are one yes, seven nos, one abstention. The
motion does not pass.

I may be getting into trouble again, but this time, I\'ll ask to see if
anybody wants to make a motion for not approving the PMA flat out.

(No response.)

DR. BLANCO: Okay. No motion.

Then I will at this point entertain a motion for approval with
conditions and then we can begin listing conditions.

Dr. Noller?

DR. NOLLER: I move that it\'s approvable with conditions.

DR. BLANCO: Any second?

PARTICIPANT: Second.

DR. BLANCO: I hear a second.

Now, what we need to do at this point is we need to go through the
conditions, get a vote of general consensus at least on each of the
conditions, an actual vote if there\'s controversy and then we will vote
on the entire thing again. Okay? So anybody care to lead off with some
of the conditions we\'d like to place, and if you can, can you do them
in order of the questions, if you can, or if not, whatever order. Sorry.

Go ahead. Dr. Brown?

DR. BROWN: One condition would be that HSG be required as it was done in
the pivotal study as opposed to substituting the plain x-ray.

DR. BLANCO: So you would like the study to be done ‑‑

DR. BROWN: The commercial use to reflect the conditions of the study.

DR. BLANCO: Okay. Do you want to make any suggestion that if the company
provides data, it should be brought to use something else, if effective
should be brought forth and reconsidered?

DR. BROWN: Yes, absolutely.

DR. BLANCO: Okay. Any comments on that condition? Anybody else wants to
amend it or add anything else to it?

DR. SHIRK: My question would be, would ultrasonic HSG be as good as
regular radiographic x-ray?

DR. BLANCO: Well, we don\'t know that. So I don\'t think we can
recommend that.

DR. SHIRK: Okay.

DR. BLANCO: I think that would not go over. I think that the best that
we can do is that at the present time, they replicate their study for
commercial use and that they be encouraged to gather further data on
optional ways of doing it and bring that data forth to be able to change
that recommendation. Is that fair enough?

Is there general agreement on that statement or should we take a hard
vote? General agreement? Everybody shake their head. Yes, there seems to
be general agreement. So we\'ll move on. Okay?

Any other recommendation? Dr. Brown, since you started, we\'ll just go
with you.

PARTICIPANT: The hypervolemia.

DR. BROWN: Oh, the qualifications of the training, that the company
provide some basic qualifications to include a statement about general
hysteroscopic proficiency.

DR. BLANCO: I think, remember, when we were talking about it, we said
knowledgeable hysteroscopists in the discussion, and maybe we need to
bring it up again and see if we need a hard vote on it, was the issue of
diagnostic versus operative hysteroscopists.

Dr. Noller, I think you brought up something about that, and Dr. Shirk,
you guys want to address that? Which way do you want to see it?

DR. SHIRK: I think just a general statement is fine. I don\'t see that
we need to differentiate between diagnostic or operative.

DR. NOLLER: I agree.

DR. BLANCO: You agree? All right. Anyone else disagree? Anybody else
wants any stronger language or recommendation?

(No response.)

DR. BLANCO: Then as I have it now, it is recommended that the company in
their training program put something to the effect that one needs to be
a knowledgeable hysteroscopist in order to be able to utilize this
device. Is that acceptable to most people? I\'m sorry. Did someone have
a hand up? No? Okay.

All right. Any other conditions?

DR. NOLLER: I have one.

DR. BLANCO: Please. Go ahead.

DR. NOLLER: I would like to see the labeling for both the physician
package insert and the consumer prominently include the fact that
approximately 10 percent of first placements, first-time placements are
unsuccessful.

DR. BLANCO: Any comments on that? Everybody\'s in agreement with that?
Why don\'t we tackle other labeling issues, if we could, while we\'re at
it? Anybody want to bring up any other labeling issues?

DR. BROWN: That there be stronger ‑‑ I\'m sorry.

DR. BLANCO: No, go ahead. Go ahead, Dr. Brown.

DR. BROWN: That there be a stronger statement in the physician labeling
about the age of the patient and the correlation between young age and
patients changing their mind and just emphasizing that the physician
needs to be aware in their selection of patients, they should be highly
selective of patients who are sure about their decision and in the
patient labeling maybe even stronger language about the irreversibility
of ‑‑ emphasizing more that there is no known way to reverse this
procedure. I think that is a true statement.

DR. BLANCO: Okay. Anybody else want to refine it, add anything to it,
something along those lines?

(No response.)

DR. BLANCO: All right. Go ahead.

DR. SEIFER: For the physician labeling specifying a consistent time
before they consider to stop the procedure.

DR. BLANCO: I\'m sorry. Wait a minute. Let me clarify.

DR. SEIFER: Whether it be 20 minutes, 30 minutes in terms of the
duration of the first attempt. Also, some specifics with regard to
perhaps the fluid deficit. Somebody from Conceptus said 1,500. That\'s
what they\'re teaching their classes with. I know there\'s disagreement
about that amount, but I think it should be specified.

DR. BLANCO: Okay. Specify the amount. You want to make the amount 1,500
milliliters?

DR. SEIFER: That\'s what they\'re teaching. I\'d prefer it, yes.

DR. BLANCO: Okay. Anybody have a problem with that?

DR. ROY: But I don\'t think that\'s fluid deficit. That\'s total fluid
use.

DR. SEIFER: Yes.

DR. BLANCO: Well, I think Dr. Shirk had mentioned earlier three liters.
So if the company was 1.5 liters, that sounds to me like ‑‑

DR. SHIRK: That\'s if you look at a drug and what dose\'s limiting
factor is half-lethal dose and so, I mean, three liters of fluid is not
going to drown somebody.

DR. BLANCO: So 1.5 is less likely to ‑‑

DR. SHIRK: One point five is well within the safety range.

DR. BLANCO: Anybody else? Yes, sir?

DR. DUBEY: Yes. The success of this device, when it puts on the label
like 99.8 percent, should be defined with number of patients tested for
limited number.

DR. BLANCO: And I think it should be clarified, 99.8 percent, I think,
is ‑‑

DR. DUBEY: Based on like 400 cases, 500 cases.

DR. BLANCO: Yes, I\'m not sure what I would put in there, but something
that\'s more applicable to patients and that maybe does have that number
in there in terms of the success rate of the procedure.

All right. Any other comments on labeling?

DR. SHARTS-HOPKO: Caution with metal sensitivities.

DR. BLANCO: Metal sensitivities. Actually, let\'s broaden that. Metal
sensitivities and the electrocautery issue and there was one third one.
What was the third one that we discussed?

DR. ROY: Pregnancy IVF.

DR. BLANCO: Right. Thank you.

Okay. So something to address the issue of metal sensitivity and no
longer use of electrocautery and subsequent pregnancy.

DR. O\'SULLIVAN: I might add that every effort should be made, in fact
it probably would be better to put it on the product labeling, that
these should be done only in the proliferative phase, ideally in the
first 10 days.

DR. BLANCO: Okay. Everybody agrees with that?

PARTICIPANT: Yes.

DR. BLANCO: Okay. Go ahead.

DR. SEIFER: Is there a way to put in the labeling something that will
help with the follow-up of these patients so that Conceptus has an
easier time keeping tabs on these patients for the five years that
they\'ve agreed to follow them? In other words, motivate the consumer
who\'s getting this product with regard to the importance of
participating in the follow-up with this company?

DR. BLANCO: What did you want to say?

DR. SEIFER: An incentive is always good. Disincentive is probably less.

DR. LARNTZ: I mean, these patients who are being followed for five years
are already implanted.

DR. BLANCO: Right. They\'re going to follow the ones that are already in
there.

DR. LARNTZ: That are already implanted already.

PARTICIPANT: (Inaudible.)

DR. LARNTZ: Right. So I don\'t think that applies.

MS. LUCKNER: You can shape patient expectation by putting in the patient
information brochure how helpful it will be for their own women\'s
health to notify their provider of certain conditions and that you\'d
like it for about five years.

The only other thing I haven\'t heard discussed is the issue of informed
consent. One of the last speakers talked about consent. There is a
difference between informed consent and consent. Are we going to make a
comment about that?

DR. BLANCO: Well, I had it written down, and actually it never even
occurred to me, and I\'m glad the speaker brought it up. It never even
occurred to me that it wouldn\'t be written consent for this. I mean,
maybe I\'m making a big deal about that, but to me, it just seemed that
was kind of like a given.

MS. LUCKNER: But written consent does not imply informed consent.

DR. BLANCO: Well, what would you like to be sure that it is informed
consent?

MS. LUCKNER: Use the word informed consent.

DR. BLANCO: Okay.

MS. LUCKNER: Governed by many places by statute.

DR. BLANCO: What about written? Do you agree with that?

MS. LUCKNER: Yes, definitely.

DR. BLANCO: I hear some yeses. Okay.

DR. BROWN: I\'m sorry. I have a question about that. So are we saying
that the company must provide a standardized written consent as part of
the package or are you saying ‑‑ because obviously patients who undergo
this are going to need to undergo, unless it\'s in a private office and
you don\'t have to do that, but you would be cited if you performed the
procedure without informed consent, but certainly if it\'s done in a
hospital setting, the physician who\'s doing it will have to have
written and documented that I had informed consent.

I thought the speaker was specifically referring to some type of
standardized language and something that is provided by the company
that ‑‑

DR. BLANCO: Well, I think that\'s what you\'re saying because what
consent you\'re going to get, if you take them in the hospital, is going
to be an OR consent. I\'d like to hear from the industry representative,
but I don\'t think it would be a major onus on the company to produce
what represents an informed consent. They\'ve already done a lot of that
in the PMA that\'s submitted, I think a lot of the information, and then
just have that available for the physicians to use on their patients. I
don\'t think we want to make the onus that it\'s the company\'s
responsibility to make sure every physician uses it. Lord knows we
can\'t get physicians to do anything. So I wouldn\'t go that far, but at
least they can provide it so that if the physician doesn\'t use it,
it\'s really the physician who\'s at fault for not doing the appropriate
thing.

DR. BROWN: Could I just make one suggestion? It\'s part of what I was
going to finish saying. I mean, many studies have shown that the value
of written informed consent is very, very low, and we were talking about
women\'s preconceptions and miscommunications. So I was going to suggest
that maybe the company, as long as they\'re doing this, might want to go
ahead and make a video or some type of other mode that you could use to
inform the patients, besides just the written word, a CD-ROM that the
person could put in their office and show to the patients before they
have the procedure. Something like that might be very helpful as another
type of means of getting across the informed consent.

MS. MOONEY: Yes, Dr. Blanco, I agree. I think it\'s reasonable to ask
the company to recommend a language for informed consent and then people
will apply that and modify that as fits their practice and that it would
be the onus of the physician to ensure that that\'s done.

DR. BLANCO: Now, what about educational materials? That\'s what you\'re
really saying, Subir, whatever. How do people feel about that? What do
they think?

DR. ROY: Well, you\'re going to have, I suppose, a patient
information ‑‑

DR. BLANCO: Booklet?

DR. ROY: ‑‑ booklet. I think the video is very good, and then you have
also a written informed consent that repeats it for the third time, and
then it should be an informed consent, informed written consent. So I
think all three are certainly suitable. How else are you going to convey
a lot of this information that we\'ve been talking about?

The other thing I\'d do is once they get it in, I\'d give them a card
that contains this information as well, so that if they were to have a
surgical procedure or something like that, they could pull it out and
explain it to the appropriate clinicians.

DR. BLANCO: Yes?

MS. BROGDON: Dr. Blanco, I think it\'s fine that the committee has
recommendations to the sponsor for wording for informed consent written
documents. However, it would be impossible for FDA, I think, to
institute that as a requirement on this or another sponsor. It\'s almost
impossible for us to require this because we can\'t enforce it. So you
can make whatever suggestions you wish as a suggestion, we just can\'t
require it.

DR. BLANCO: Well, I don\'t think the requirement was that every patient
have it because just like I said, that\'s really more the physician. The
only suggestion of requirement was that the company provide it for the
physicians to utilize with their patients. I don\'t think ‑‑

MS. BROGDON: Yes.

DR. BLANCO: That was the point I was making, was addressing. I think we
can put the onus on them that everybody has it. They just provide the
materials.

MS. BROGDON: That\'s fine.

DR. BLANCO: Then it\'s up to the physicians to utilize it. Okay?

All right. Everybody\'s in agreement what we\'ve said so far? All right.
Any other problems? Any other suggestions that we want to make? Let me
go back to one. We talked about recommended length and limit of 1,500
milliliters. I also had a size of scope as a small scope that was
brought up during the discussion. Do we want to address that or just
leave it up to the person? I think I would leave it up to the person
because you may need different scopes for different people. It was
brought up.

DR. SHIRK: The problem with that would be a lot of hospitals, if it\'s
done in the hospital setting, already have scopes of greater diameter
that would force, if we put a limit on size, it would force them into
buying new equipment.

DR. BLANCO: So throw that out. Everybody okay with that? Okay. Yes?

DR. NOLLER: I just reviewed the patient information labeling to make
sure, but there\'s no mention of what to do if you think you might be
pregnant, if you miss a period, because if that happens, the risk of
ectopic pregnancy is probably high. I think it should be mentioned in
there.

DR. BLANCO: All right. So if miss a period instructions, recommended
procedures if you miss a period.

DR. NOLLER: Talk to your doctor, get a pregnancy test, that sort of
thing.

DR. BLANCO: Okay. All right. The other one that I have written down is
fallback plan if you run into the failure rate. Okay. Does anybody want
to make it more specific than that or is that general enough? They\'ve
heard everything we\'ve said. Okay. So fallback plan.

DR. O\'SULLIVAN: You\'re going to ask the company to require that?

DR. BLANCO: No, we\'re just going to make it in the labeling. We\'re
talking about labeling right now that they suggest. I think the way we
worded it was when we discussed it was that the company should make a
suggestion that if there is this failure rate and in case there\'s a
failure, you should have discussion with your physician as to what
you\'re going to do if he or she\'s unable to insert the devices
bilaterally. Is that fair enough? Okay. I just like to shorten things.
Fallback plan.

Anything else that anybody wants to add?

DR. SEIFER: There was a question about if there was tubal pathology
before putting this device in, if ‑‑

DR. BLANCO: We didn\'t address that a lot other than mention it.

DR. SEIFER: Yes.

DR. BLANCO: We didn\'t discuss that a lot, whether there might be a
higher rate of perforation, pain with small hydrosalpinx, something like
that.

DR. SEIFER: Or formation of a cyst, hydrosalpinx, after placing that
because of distal and proximal obstruction.

DR. SHIRK: I think it could be in the informed consent as a possibility,
but I don\'t know how we would predetermine that a patient\'s got, you
know, distal tubal disease.

DR. BLANCO: Well, I\'d hate to drop back into a major discussion, but
you could make it an exclusion criteria where if they\'ve had a history
of pelvic inflammatory disease, not necessarily recommending that. I\'m
just saying it would have to be something very broad at that point.

The pleasure of the panel? Do we want to address it, say anything about
it?

DR. O\'SULLIVAN: There\'s another issue regarding pelvic inflammatory
disease. First of all, in the study, they did require that the patient
subsequently deliver if she had a history of pelvic inflammatory
disease, but I think the other issue is pelvic inflammatory disease is
very subtle and quiet and you don\'t know anything about it, such as
associated, let\'s say, with chlamydia, and that\'s not going to help
you. It\'s not going to get you off the hook. I mean, you might want to
make that a requirement, but it\'s got to be understood that you may not
have had a history of it but still have.

DR. BLANCO: So what would you recommend? How should we address the issue
of PID? We didn\'t really talk about it a lot. That\'s a good point.

DR. SHIRK: I just think if they wanted to put it in informed consent, it
would be fine, but I think it would be difficult to put it in the
labeling for the physician. I mean, I don\'t know how you determine
that. I mean, 65 percent of women that have endometriosis have been
diagnosed as having PID at least once. I mean, that\'s a disease that
has nothing to do with pelvic infection. I mean, I don\'t think our
criteria for PID are good enough. I mean, in the best hands, you\'re
only going to be right on a diagnosis of PID at 60 percent of the time.
That\'s already documented.

So I think it\'s a difficult issue to tackle. I think that it might be
part of the informed consent that if you have previous tubal disease, it
may create complications, surgical complications, in the future, but I
don\'t know that it should be in the labeling per se.

DR. BLANCO: Well, what about should we recommend that the company look
at that issue? They\'re going to be looking at their patients, but we
also had mentioned some things that they might want to look at in a
post-approval study. I mean, do they need to look at that and have some
better idea of what this device is going to do in people with PID or
even just as they ‑‑ you can look at it the other way around. If they
get patients who develop significant infections after insertion of the
device to try to ascertain whether they might have a history of
salpingitis before or some evidence of it that might have been the
reason why this happened?

DR. SHIRK: And then are we going to recommend that they have a
post-approval databank for all patients having the procedure done?

DR. BLANCO: Well, no.

DR. SHIRK: I mean, that\'s what you\'re suggesting.

DR. BLANCO: No, no. We talked about a registry. I think Dr. Brown
mentioned a registry of complications, looking at those. That\'s all
that I was bringing up, not keeping track of every single patient that
ever has it put on.

DR. NOLLER: Question.

DR. BLANCO: Yes, go ahead.

DR. NOLLER: For insertion of IUDs, you\'re supposed to have a negative
chlamydia and GC test before you insert it. I just quickly looked
through here. I didn\'t remember it and I didn\'t find it just now. If
it isn\'t in there, I would think that wouldn\'t be a bad idea. We
didn\'t discuss it before. I\'m sorry.

PARTICIPANT: It is in their study.

DR. NOLLER: It was in their study but in their recommendations for use
training, I didn\'t see it. Is it in there? Does anybody remember? It
just seems a reasonable thing to do. It says no recent or current pelvic
infection and in their studies, they said they did lab tests, but I
don\'t see it for a routine recommendation in there.

DR. ROY: But the culture or PCR for chlamydia could be negative, but
they could have had prior ‑‑

DR. NOLLER: Correct.

DR. ROY: ‑‑ exposure with a high titer and unless you did something
else, you might not know that the distal oviduct was closed.

DR. NOLLER: It\'s two separate issues, yes.

DR. BLANCO: Yes. One issue is where there\'s some baseline or some
history of salpingitis, and I think the impression I was getting from
most people is probably other than recommending that they realize this
and if they start getting patients with infection, reports of patients
with infection, that they need to take a look to see whether it may be
that this device is inflaming, you know, some old infection, but that\'s
one issue.

The other issue is the issue of do you want to ‑‑ Gerry, when you\'re
going to do a hysteroscopy diagnostic with therapeutic on someone for
whatever, do you get a GC and chlamydia culture before you do it on the
patients?

DR. SHIRK: Not routinely, no.

DR. BLANCO: What do you think? What\'s your sense of the countrywide
utilization of that?

DR. SHIRK: I don\'t think it\'s routine for hysteroscopy.

DR. BROWN: Or for endometrial biopsy.

DR. SHIRK: Or endometrial biopsy. I mean, I just don\'t see it. I mean,
obviously if you\'re putting in a device, I suppose, like an IUD,
that\'s a new indwelling device, then it\'s obviously important.

DR. BLANCO: Well, so is this, though.

DR. SHIRK: So I have no problem culturing them or recommending that they
do that. I think that\'s reasonable. The hysteroscopic procedure itself,
I don\'t see it as an issue.

DR. SEIFER: I think it\'s probably regional. I mean, some parts of the
country, I think when you do an initial work-up, you\'re doing cultures
on patients.

DR. BLANCO: Dr. Noller, what do you think?

DR. NOLLER: I really don\'t know. We don\'t have data to make a rational
decision. It is an implanted device. It\'s different from a diagnostic
procedure that has a beginning and an end quickly. This will be there
for years, but I don\'t know if it\'s a risk or not.

DR. BLANCO: What do you think?

DR. SEIFER: I think a culture\'s relatively cheap to do and it\'s
usually done before you can do a hysteroscopy anyway because it\'s part
of your initial work-up of the patient. So particularly with the new
device, such as this, I would support doing it.

MS. MOONEY: Dr. Blanco, maybe since we\'re on the fence on this, one
option would be in the labeling to say \"recommend\" rather than
\"require.\" It calls the clinician\'s attention to that, but you give
some option based upon that individual patient\'s situation.

DR. BLANCO: Yes, and I think the other thing is that it also depends on
the individual. I mean, I think if I were still back in Houston at LBJ
with an inner-city population, I\'d probably want some cultures or DNA
for those. I think in Iowa, maybe you don\'t need to do it so much.
Those cornfed girls up there.

(Laughter.)

DR. SHIRK: I mean, obviously it\'s a patient population.

DR. BLANCO: Dr. Brown?

DR. BROWN: I would just point out that the current labeling does say
contraindications pretty clearly, active or recent pelvic infection and
untreated acute cervicitis. I mean, I think it\'s a matter of semantics
if you wanted to add on to that cultures, but in the physician training
module, they clearly say negative pap smear, negative GC and chlamydia.
I don\'t personally think it\'s necessary to add anything else, but I
think it\'s pretty clear, what\'s already in here, that\'s how to handle
it.

DR. BLANCO: Happy with that?

PARTICIPANT: Yes.

DR. BLANCO: We\'ll forget that.

All right. The only one that I have written down is the five minimum,
the proctored, as part of the training. Anybody want to address that? I
think everybody kind of liked five, I think, except for you. Okay. So
we\'ll put the five. Anybody against that?

DR. BROWN: I\'m kind of against it, because I think, you know, if
somebody is already a very accomplished hysteroscopist, it\'s probably
going to frankly take them about two seconds to do this and they may not
need to have five proctored, and as they said, it may take more than
five in some people. So I would rather leave it loose, frankly, and then
also for the future in terms of medical education. So I think it\'s
better to leave it open.

DR. BLANCO: All right. You still have faith in your fellow physicians.
It\'s nice to see that.

(Laughter.)

DR. BLANCO: All right. How do we want to do this? It sounds like
there\'s enough difference of opinion here, I\'d like to take a vote on
suggesting either a minimum of five or an average of five which is how
they placed it.

DR. NOLLER: Point of order, point of information. Once this is out
there, if you get privileges to do this or if you have a private office,
you\'re going to do them, you know, you\'re able to do it with zero
proctored insertions. So you know, whatever we put as the recommendation
that in fact people maybe to get credentialed to do it in their hospital
have to have five, if it says five, but there will be an awful lot of
people doing them with zero.

DR. BLANCO: Well, all we can do is have faith in the fellow physicians.

MS. BROGDON: Dr. Blanco, I don\'t know if anyone asked the firm if they
have plans to not ship the device unless people are signed off. You
might want to find out what their proposal is.

DR. BLANCO: Would you all care to answer that? Don\'t put the five
because they said not, they said an average of five. So let\'s say, are
you planning on shipping the equipment before you have some knowledge
that this person has had some experience with the device, whatever that
experience turns out to be?

MS. DOMECUS: We won\'t ship devices to physicians who haven\'t completed
the training program, unless there is a preceptor going with those
devices.

DR. BLANCO: Okay. So then it does become important to say average or
minimum.

Okay. Any more discussion to an average or minimum? All right. Well, I
think we better take a vote on this one. Which way would you like to see
it? Subir, which way do you want it, and we\'ll vote that up or down,
and it\'s my fault.

DR. ROY: Until the physician has demonstrated competency.

DR. BLANCO: Okay. Anyone want to second that?

DR. BROWN: Second.

DR. BLANCO: Okay. Second. Any further discussion? Okay. Let\'s start out
over on this end.

DR. NOLLER: Aye.

DR. DUBEY: Yes.

DR. SEIFER: I vote no.

DR. BROWN: Yes.

DR. SHARTS-HOPKO: No.

DR. O\'SULLIVAN: Abstain.

DR. ROY: Yes.

DR. LARNTZ: Yes.

DR. SHIRK: Yes.

DR. BLANCO: Please do say it into the microphone. This is for posterity.
I mean, that\'s okay this time but for the future.

DR. SHIRK: Yes.

DR. BLANCO: Six yeses, two nos, one abstention. So the recommendation
will be as worded by Dr. Roy and I won\'t try to repeat it but it\'s in
the record. Okay?

All right. Okay. Anything else that we need to include as a condition or
that we would like to include as a condition? Anyone else? Going once,
going twice. Okay. This is what I was looking at, you know. We agreed
with the five-year postmarket analysis of the patients that are
currently enrolled, and Dr. Noller, I think it was you that brought it
up but if not, that\'s okay, I\'ll take care of it.

Any further assessment of the failure rate for placement? Do we want,
once it\'s out in the general marketplace, and this is what I was
talking about, a registry of failures to try to understand the rate a
little bit better once it gets out into the community? Anybody want to
address that?

DR. ROY: Well, don\'t you have to have a registry of users before you
can have a registry of failures? I mean, you could have the other, but
it\'s sort of worthless.

DR. BLANCO: You wouldn\'t have any denominator. Anybody, how strongly do
you want to look at this?

DR. O\'SULLIVAN: Well, they\'re going to have a registry of users. I
mean, that\'s going to be easy enough for them because they\'re the ones
that ship them out. They know they can\'t go out without a proctor.
Okay. So they\'re going to have a registry of users.

DR. BLANCO: Okay.

DR. O\'SULLIVAN: And then, I think that the next issue is follow-up from
the user, if he has difficulties getting them in what they were.

DR. BLANCO: Because basically what you\'re saying is that when they ship
them out, when they have a preceptored user, so that they\'re shipping
regular numbers of these, that they get some sort of report back from
their user in terms of how many failures they had. That\'s probably not
that difficult.

DR. O\'SULLIVAN: And it\'s easy enough because then they don\'t ship out
again until they get it back from them.

DR. BLANCO: Power.

DR. O\'SULLIVAN: Yes.

MS. MOONEY: Dr. Blanco, I think maybe the recommendation I would make
would be to communicate to the sponsor and for the record that we want
to have some way of assessing the failure rate, but I think it may be
most prudent to let them work that out with the FDA as far as the actual
method.

DR. NOLLER: Yes. I agree with that.

DR. BLANCO: Very nice. Thank you.

Is that all right with everybody? All right.

MS. BROGDON: Dr. Blanco?

DR. BLANCO: Yes, ma\'am?

MS. BROGDON: I think we would like probably a clearer recommendation on
whether the panel is recommending that there be a new postapproval study
as opposed to continued follow-up of the subjects for five years.

DR. BLANCO: All right. Well, the panel will correct me if I\'m wrong,
but I ‑‑ no. The panel would like the continuation of the five years of
the currently enrolled patients.

MS. BROGDON: Right. We understand that.

DR. BLANCO: Okay. The panel would also like a better concept of failure
of insertion rates once this procedure gets out in the general
population, not as a study necessarily but just so that appropriate
consent and appropriate information may be given to the patient. You
know, I don\'t know what is a good failure rate for this procedure, but
if it is done locally and if it\'s straightforward and with low risk, I
mean, you may be happy to say okay, I\'ll go do this and fails 20
percent of the time, 30 percent, maybe it will only fail 5, but I\'m
willing to do it because I\'ve just got to go to the doctor\'s office
and then that\'s it. I get it done, and if I don\'t, I get it done
another time.

So I think what Dr. Noller was asking was a better understanding of once
it gets out in non-expert hysteroscopist hands, what will be the failure
of insertion rate? Am I saying that correctly?

DR. ROY: Absolutely. Thank you.

DR. BLANCO: Okay. Does that clarify it for you? It still doesn\'t look
like it does it for you. Okay.

MS. BROGDON: Let me just ask our postmarket surveillance people. We\'ll
work with what you\'ve already given us. Thank you.

DR. BLANCO: You always do a wonderful job with that.

DR. LARNTZ: Could I comment?

DR. BLANCO: Please.

DR. LARNTZ: I mean, we\'re asking a question that requires ‑‑ I mean, if
you do the study right, it could be quite burdensome, and I would argue
that it might be easy to do a small observational study with a few
physicians to get a notion of this and maybe that\'s all that would be
satisfactory. I don\'t think we want to mandate getting precise
information on this. I think that\'s actually very difficult to do, very
difficult to do right. It would require another study to get this
information and to the extent that it probably could be contained in
labeling, it probably would take another study to do, and I think that
would be ‑‑ I\'m the statistician. I should be arguing for more data,
but in fact, I think if you don\'t collect the data well, it\'s not
worth too much.

DR. BLANCO: Right.

DR. LARNTZ: And so we\'ve got to be very careful of if we ask for this,
I think we\'re asking for it informally, I think the company understands
that, and I think that may be okay, but it\'s difficult to have any
enforcement on that.

DR. BLANCO: It may be that it may be a better way to approach it as you
said, to take some sample of new users and try to get an idea, I think,
but I think there is some feeling and maybe, you know, there is some
feeling on the panel that we would like some feedback and possible
changes in labeling eventually in terms of failure rates once it gets
out in more widespread use and without putting much of an onus
necessarily on the company to redo, you know, another study.

MS. BROGDON: We can ask the sponsor to make a proposal to the agency
later.

DR. O\'SULLIVAN: Jorge, I think this becomes important for a lot of
reasons. There are always new devices that get out on the market for one
reason or another, and in the world of technology, this is increasing
more and more, and the point is that all of these things have associated
with them costs and who\'s paying the cost while the patient is the one
who is not getting what needs to be gotten or the information is not
coming across that this device is not as successful across the board of
insertion as it has been, for example?

I mean, there are all kinds of reasons why this can happen, and I think
it\'s very, very important in today\'s world of technology and as things
get released to be much more rigid. I\'m not saying rigid rigid but at
least get information for the first four or five years that you\'ve got
these devices out there and you\'re working with them so that you know
that they\'re okay and not wait 25 years to say hello, we\'ve got to
bring this back in.

DR. BLANCO: Okay. I think I\'m going to go ahead. Go ahead, Ms. Domecus.
I\'m going to go ahead and take the chairman\'s prerogative and let you
speak.

MS. DOMECUS: Thank you.

I just wanted to clarify that the company already has a plan to gather
placement rate and adverse event data on all preceptored cases. So we
already have this plan in place.

DR. BLANCO: Thank you.

DR. ROY: But how widespread will your preceptored cases be? I mean, what
numbers are we talking about? All?

MS. DOMECUS: That\'s what we\'ve said. I mean, I imagine at some point,
if after a certain period of time, it was a well-established consistent
placement rate, we\'d go back to the FDA and ask to not do it anymore,
but right now, the plan is on all preceptored cases. We have a great
interest, too, in making sure that the placement rates are high. We have
no interest in anything else.

DR. O\'SULLIVAN: I think that fulfills the need.

DR. LARNTZ: That certainly is adequate and then some, but be very
careful to make sure that you\'re very consistent in collecting those
data. It\'s not easy to get all. It might be better to take a sample and
get good information on a sample, but I appreciate what you\'re saying.

DR. BLANCO: Have we given enough guidance?

MS. BROGDON: Yes.

DR. BLANCO: Great. All right. Any other items? Anything else that we
would like to add?

All right. Let me just refresh everybody\'s memory of what we\'re going
to vote on and then we can have a vote. Basically, as I\'ve written it
down and please correct me if I\'m wrong, we have a motion on the floor
to vote for approval with conditions. The conditions that were included
was the hysterosalpingogram at this point be required as was performed
in the original study but the committee recommends that the FDA be
amenable to having the company bring forth further data on alternative
methodologies to look at correct placement and patency to approach
changing this particular recommendation.

Number 2. Training, to include knowledgeable hysteroscopists as a
prerequisite for beginning to do these. In labeling, we include that we
need to clarify the failure rate and place that and the word that was
used was \"prominently,\" that some labeling needs to address ‑‑ and
I\'m going to paraphrase these ‑‑ the issue of the young age and
potential sequelae, that an issue be noted in the labeling, and these
are all labeling issues, about metal sensitivity, electrocautery, and
pregnancy subsequent to this procedure, that we have an issue or
inclusion about a recommended length for the procedure to the physician
and a limit of 1,500 milliliters of saline for use in the patient, again
the success rate, that 99.8 percent should be clarified or at least
maybe not clarified but something to the effect of the numbers or
something that patients can understand with the number of patients that
this has been performed in.

A recommendation that the procedure be performed at the proliferative
phase of the cycle, that an educational written informed consent be
obtained, and the company make an example to be provided to the
physicians utilizing this device.

Some recommendations included in the patient pamphlet concerning what to
do if you miss a period, a \"fallback\" plan which just ‑‑ what are you
going to do if you are one of those where they\'re unable to insert this
in both tubal ostia, definitely recommend the training as previously
stated, and then that the continuation of the observation of the current
patients for a total of five years and then a better assessment as has
been discussed of the failure of insertion rates for patient counseling
and patient labeling.

Did I state those to the satisfaction of the committee? Okay. If there
is no other discussion, then let\'s go ahead and begin with a vote, and
you\'re voting for approval with the prestated conditions. Let\'s go
ahead and start with Dr. Noller.

DR. NOLLER: I vote aye.

DR. DUBEY: I vote aye.

DR. SEIFER: Aye.

DR. BROWN: Yes.

DR. SHARTS-HOPKO: Yes.

DR. O\'SULLIVAN: I\'m abstaining.

DR. ROY: Yes.

DR. LARNTZ: Yes.

DR. SHIRK: Yes.

DR. BLANCO: The motion passes with a vote of eight yes, zero nos, and
one abstention.

As is the custom, we\'d like to go around the table and just have a
brief mention of why you voted the way you did. Let\'s begin on this
side. Dr. Shirk?

DR. SHIRK: Well, I think this device is as safe as any other devices on
the market. Certainly transcervical sterilization is ideal. I think it
may represent a significant improvement in women\'s health care and so I
felt that we should approve the device. I commend Conceptus on their
PMA.

DR. BLANCO: Thank you.

DR. LARNTZ: I voted yes because the device clearly met and the studies
presented, data presented, clearly met the criteria of safety and
effectiveness that are required for approval.

DR. BLANCO: Thank you.

DR. ROY: This device clearly meets those requirements for safety and
effectiveness, but I am cognizant of the issues that we\'ve discussed,
particularly the use in younger individuals who may not fully appreciate
the permanence of the procedure, and I think we\'ve belabored that point
sufficiently, that that should be conveyed to anyone who might use it at
that age.

DR. BLANCO: Thank you.

DR. O\'SULLIVAN: I abstained for religious reasons.

DR. BLANCO: Thank you.

DR. SHARTS-HOPKO: I voted yes because I believe this offers women a less
risky, more accessible procedure for permanent sterilization, and I
think Conceptus was very thorough in the materials, the large quantity
of materials which you provided.

DR. BLANCO: Thank you.

DR. BROWN: I voted yes because I think the device clearly met the
criteria for safety and effectiveness as well as the favorable
risk-benefit ratio, particularly since it offers the option of
sterilization without general anesthesia which is not basically
currently available.

DR. BLANCO: Thank you.

DR. SEIFER: I voted yes because I thought many of the concerns that were
voiced during the discussion were addressed in the final vote.

DR. BLANCO: Thank you.

DR. DUBEY: I voted yes the results are very clear. I\'m very impressed
with the sponsor\'s data and all the discussion we had in panel to
address all borderline issues, and I voted yes for that reasons.

DR. BLANCO: Thank you.

DR. NOLLER: I voted to approve the motion because I feel the company
showed that the method is clearly safe and effective and that it has a
great chance of improving health care for women in the United States.

DR. BLANCO: Thank you.

I always allow the non-voting members, if they\'d like to make a comment
at this point, of what they think, be happy to listen.

MS. LUCKNER: I think this is a great addition to female contraception,
and I commend the company. I think our deliberations are not just for
today but for tomorrow, and I hope the company proceeds posthaste
putting them in place.

DR. BLANCO: And no comment.

I always reserve the right for the last set of comments. I\'d like to
compliment the company on what I think is one of the best presentations
of a PMA that I\'ve seen in eight years here and their data. Thank you
very much. It made for a very enjoyable day instead of a very difficult
day as we\'ve had a few here in other times.

I also would like to commend the audience for their participation and
welcome their comments. Some of them were very good and actually things
that we had not thought of and were very good suggestions. We appreciate
that, and as always, I\'d like to commend everyone at FDA for all of
their hard work and wonderful presentations and wonderful participation,
and I think you guys do a great job.

So thank you.

With that, unless anyone else would like to make some ‑‑ well, if you\'d
like to make some comments, otherwise we\'re going to close it up
because we\'re 25 minutes late, and I don\'t like to be late.

MS. BROGDON: I would just like to thank the panel for your
deliberations.

Thank you.

DR. BLANCO: So I\'d like to thank the panel, too. It was a great
deliberation. Please leave all your paperwork here and they\'ll get it
taken care of with the confidential issues.

Thank you very much. Thank you for your attention. Good night.

(Whereupon, at 5:25 p.m., the meeting was recessed, to reconvene in
closed session at 8:00 a.m. on Tuesday, July 23, 2002.)