UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

MEDICAL DEVICES ADVISORY COMMITTEE

OBSTETRICS AND GYNECOLOGY DEVICES PANEL

68^TH^ MEETING

THURSDAY,

JUNE 3, 2004

The Panel met at 8:30 a.m. in the Whetstone Room of the Gaithersburg
Holiday Inn, Two Montgomery Village Avenue, Gaithersburg, Maryland, Dr.
Kenneth L. Noller, Chair, presiding.

[PRESENT]{.underline}:

KENNETH L. NOLLER, M.D., Panel Chair

SUSAN M. ASCHER, M.D., Temporary Voting Member

ANDREW I. BRILL, M.D., Temporary Voting Member

CAROL L. BROWN, M.D., Member

LAWRENCE A. CRUM, Ph.D., Temporary Voting Member

RALPH B. D\'AGOSTINO, Ph.D., Temporary Voting Member

MICHAEL P. DIAMOND, M.D., Non-Voting Member

EVELYN R. HAYES, Ph.D., Member

PAUL J.A. HILLARD, M.D., Member

GRACE M. JANIK, M.D., Temporary Voting Member

KLEIA R. LUCKNER, J.D., M.S.N., Consumer Representative

HUGH MILLER, M.D., Member

ANNE C. ROBERTS, M.D., Temporary Voting Member

THADDEUS V. SAMULSKI, Ph.D., Temporary Voting Member

STEPHEN B. SOLOMON, M.D., Non-Voting Member

JONATHAN W. WEEKS, M.D., Member

BRANDFORD J. WOOD, M.D., Temporary Voting Member

JOYCE WHANG, Ph.D., Panel Executive Secretary

MICHAEL T. BROWN

[FDA REPRESENTATIVES]{.underline}:

NANCY BROGDON, Director, Div. Of Reproductive,

Abdominal and Radiological Devices

COLIN POLLARD, Chief, Obstetrics and Gynecology

Devices Branch

JULIA A. CORRADO, M.D., Medical Officer

KATHRYN S. DAWS-KOPP

NOEL DEL MUNDO, M.D.

BRUCE A. HERMAN

LOREN A. ZAREMBA, Ph.D.

[SPONSOR REPRESENTATIVES]{.underline}:

ROB NEWMAN, M.S., R.A.C.

BOBBIE S. GOSTOUT, M.D.

GINA K. HESLEY, M.D.

ELIZABETH A. STEWART, M.D.

CLARE M.C. TEMPANY, M.D.

KOBI VORTMAN, Ph.D.

I-N-D-E-X

Introductory Remarks 4

Open Public Hearing 14

Presentation by Sponsor 14

Presentation by FDA 88

Panel Discussion 163

Open Public Hearing 264

Panel Deliberations and Vote 292

Adjourn 363

P R O C E E D I N G S

(8:25:23 a.m.)

DR. NOLLER:  Everyone take their seats, please. We have a very full day
so I want to get started exactly on time. My name is Ken Noller, and
I\'d like to call the meeting to order. This is the Meeting of
Obstetrics and Gynecology Devices Panel. I request that everyone in
attendance please sign in. If you have not done so, please go out and
sign in at the front desk now.

I also note for the record that the voting members present constitute a
quorum as required by 21 CFR Part 14. I\'m going to ask the panel
members to introduce themselves. Let\'s start at this end, please.

MS. MOONEY:  Mary Lou Mooney. I\'m the Vice President of Clinical
Regulatory and Quality for SenoRx, and I\'m the Industry Rep to the
panel.

MS. LUCKNER:  Kleia Luckner, Hospital Administrator, Toledo, Ohio, and I
am the Consumer Rep.

DR. D\'AGOSTINO:  Ralph D\'Agostino from Boston University,
Biostatistician.

DR. BRILL:  Andrew Bill. I am a Professor OB-GYN, University of
Illinois.

DR. HILLARD:  Paula Hillard, Professor of OB-GYN and Pediatrics,
University of Cincinnati.

DR. DIAMOND:  Michael Diamond, Professor OB-GYN, Wayne State University,
Detroit Michigan.

DR. ROBERTS:  Anne Roberts, Professor of Radiology, University of
California - San Diego.

DR. NOLLER:  I\'m Ken Noller, Professor and Chair of Tufts University
OB-GYN.

DR. WHANG:  I\'m Joyce Whang. And I\'m an FDA Reviewer and the Executive
Secretary for this panel.

DR. BAILEY:  I\'m Mike Bailey. I\'m also a Reviewer in the OB-GYN
Devices group, and I\'m an Assistant Executive Secretary.

DR. BROWN:  Hi. Carol Brown, I\'m a Panel Member. I am an Assistant
Professor at Cornell Weill Medical College, OB-GYN and a GYN Oncologist
at Memorial Sloan-Kettering Cancer Center.

DR. CRUM:  I\'m Larry Crum from the University of Washington. I\'m
Director of the Center for Industrial and Medical Ultrasound at the
University of Washington.

DR. JANIK:  Grace Janik, Clinical Professor at the Medical College of
Wisconsin, Reproductive Endocrinologist.

DR. SAMULSKI:  Thad Samulski, Duke University Medical Physics.

DR. HAYES:  Evelyn Hayes, Professor of Nursing, University of Delaware.

DR. ASCHER:  Susan Ascher, Radiologist, Georgetown University Hospital.

DR. WOOD:  Bradford Wood, Interventional Radiologist, National
Institutes of Health.

MS. BROGDON:  I\'m Nancy Brogdon. I\'m not a member of the panel. I\'m
the Director of FDA\'s Division of Reproductive, Abdominal, and
Radiological Devices.

DR. SOLOMON:  Steve Solomon from Department of Radiology, Johns Hopkins.

DR. NOLLER:  Thank you. For the press, the FDA press contact is Colin
Pollard who is sitting here in the front row. I don\'t expect that
we\'ll have any super controversial outbursts today, but we would like
everyone to please be courteous, turn off your cell phones, and if you
have anything to say, wait until you\'re recognized and then come to the
table. For the audience and the panel members I will recognize people
before they speak. Our Executive Secretary has some things to read into
the Minutes.

DR. WHANG:  There will be OB-GYN Devices Panel on July 26^th^ and
27^th^, so the remaining panel meeting date for this year is October
25^th^ to 26^th^.

We are pleased to introduce a new voting member to this panel, Dr. Paula
Hillard of the Department of Obstetrics and Gynecology and the
Department of Pediatrics at the University of Cincinnati, College of
Medicine.

Today we will have eight temporary voting members, Drs. Ascher, Brill,
Crum, D\'Agostino, Janik, Roberts, Samulski and Wood. And I will now
read into the record the appointments to temporary voting status signed
by Daniel Schultz, M.D., the Acting Director for the Center of Devices
and Radiological Health.

\"Pursuant to the authority granted under the Medical Devices Advisory
Committee Charter dated October 27^th^, 1990, and amended August 18^th^,
1999, I appoint the following individuals as voting members of the
Obstetrics and Gynecology Devices Panel for this meeting on June 3^rd^,
2004; Susan M. Ascher, M.D., Andrew I. Brill, M.D., Lawrence A. Crum,
Ph.D., Ralph B. D\'Agostino, Ph.D., Grace M. Janik, M.D., Kenneth E.
Najarean, M.D., Anne C. Roberts, M.D., Thaddeus V. Samulski, Ph.D.,
Bradford J. Wood, 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.\"

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 employer\'s
financial interests. However, the Agency has determined that
participation of certain members and consultants, the need for whose
services outweighs the potential conflict of interest involved is in the
best interest of the government. Therefore, full waivers have been
granted for Dr. Susan Ascher and Anne Roberts, and limited waivers have
been granted for Drs. Michael Diamond and Steven Solomon for their
interest in firms that could potentially be affected by the panel\'s
recommendations.

Dr. Ascher\'s waiver involves a contract to her employer funded for less
than \$100,000 per year with a competing firm. Dr. Roberts\' waiver
involves a stockholding in a competing firm in which the value is
between \$15,001 and \$25,000. Dr. Diamond\'s limited waiver involves a
contract to his institution for the sponsor study in which he had no
involvement in data generation or analysis, and for which total funding
to the institution was less than \$100,000. Dr. Solomon\'s limited
waiver involves a contract to his institution for the sponsor study in
which he had no involvement in data generation or analysis, and for
which funding to the institution is unknown.

The waivers of Dr. Ascher and Dr. Roberts allow them to participate
fully in today\'s deliberations. The limited waivers for Dr. Diamond and
Dr. Solomon allow them to participate in the panel discussions, but
exclude them from voting.

Copies of these waivers may be obtained from the Agency\'s Freedom of
Information Office, Room 12A-15 of the Parklawn Building. We would like
to note for the record that the Agency took into consideration other
matters regarding Drs. Diamond and Solomon. They reported current
interests with firms at issue, but in matters that are not related to
today\'s agenda. The Agency has determined, therefore, that these
individuals may participate fully in the panel\'s deliberations.

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 him or herself from such
involvement and the exclusion will be noted for the record.

With respect to other 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 on.

Transcripts for today\'s meeting are available from Neal R. Gross and
Company of Washington, D.C., at (202) 234-4433, and videos are available
from FDA Live at (301) 984-0001, or FDA Advisory Committee.com at (800)
627-8171.

Any presenters to the panel who have not already done so should provide
FDA with a hard copy of your remarks, including overheads. Michelle
Byrnes will collect these from you at the podium.

DR. NOLLER:  Thank you. First, I\'d like to introduce Colin Pollard,
Chief of Obstetrics and Gynecology Devices Branch of the Food and Drug
Administration.

DR. POLLARD:  Thank you, Dr. Noller, and I just have a few brief
comments to kick off our panel meeting today. I want to welcome all the
panel member, and thank you very much for coming from near and far.

Today you\'ll be looking at a PMA for a high-intensity focused
ultrasound system, really a new surgical modality that uses conventional
MR Imaging for pre-op treatment planning and MR thermal mapping, really
a new feature of MR technology for interactive treatment feedback. And
treatment of uterine fibroids is the very first indication that\'s
coming before this center in a PMA. The technology, obviously, looks
capable of many other clinical applications and the center is currently
working on a plan to optimize our regulatory review approach.

As you\'ll hear later in our presentation, we put together something of
a designer review team for this PMA drawing from all parts of our
center, especially from the technical side, and as we look around the
table here I see several familiar faces, but lot of new faces. And
really, we\'ve put together something of a designer panel, as well, and
so we\'re very much looking for your input.

This PMA, the center granted expedited review to based on unique
features and advantages. The FDA review is still ongoing, but we
consider it quite appropriate at this stage to hear the panel input even
as we continue to work our way through many review issues. And finally,
that we feel this technology pushes the traditional envelope of clinical
management, and if the panel gets to that point, we\'ll be definitely
looking for input regarding training and labeling, and credentialing and
that sort of thing.

So with those initial comments, Dr. Noller, I turn it back to you. Thank
you.

DR. NOLLER:  Thank you. Let me just ask that Drs. Miller and Weeks
introduce themselves, please.

DR. MILLER:  Hugh Miller from Arizona.

DR. NOLLER:  And what do you do, Dr. Miller?

DR. MILLER:  I\'m a Maternal-Fetal Medicine Specialist.

MR. WEEKS:  Jonathan Weeks from Louisville, Kentucky, Maternal-Fetal
Medicine, Norton Health Care.

DR. NOLLER:  Thank you both. First, let me ask before we open the public
hearing, is there anyone present who will be speaking, request speaking
at this session of the public hearing? All right. So if there\'s no one
at this time, I will not read the conflict statement then. We\'ll move
right ahead to the presentation by the sponsor.

I\'d like to introduce Rob Newman from InSightec. The sponsor has been
granted one hour and 15 minutes for their presentations. I ask the panel
members to hold all questions until the end of the presentation.

MR. NEWMAN:  Good morning, Chairman Noller, and thank you very much,
ladies and gentlemen of the panel and the audience. I\'m Rob Newman.
I\'m from InSightec in Dallas, Texas. My trip here has been paid for by
my company. I am a member of the sponsor.

I\'d like to introduce other members of our team today. Dr. Elizabeth
Stewart is an Associate Professor of Gynecology from Harvard Brigham &
Women\'s Hospital. Dr. Clare Tempany is a Professor of Radiology at
Brigham & Women\'s. They are Co-PIs of the study. Dr. Stewart is the
Lead PI for the study.

Also, Kobi Vortman, the President of InSightec is here with us today.
Karin Coyne, Senior Research Scientist from MEDTAP International, who
has helped us with the quality of life work, and some of the
biostatistics. Kathy McDermott from MedTrials, our CRO. We also have a
guest here, Dr. Bobbie Gostout, who is Assistant Professor from the Mayo
Clinic in Rochester, and Dr. Gina Hesley, an Instructor of Radiology,
who are Co-PIs from the Mayo Clinical site.

This is an outline of our discussion today. I\'ll give a brief
introduction. Dr. Stewart will talk about, in general, an overview of
uterine fibroids and their application here. I\'ll give a brief overview
of the device description. If you had a chance to review the video in
the package, I think that will cover some of it, and there was quite a
bit of material in the panel package, so I won\'t go over that in any
great detail.

Dr. Clare Tempany will talk about a review of MR anatomy, and what\'s
commonly seen on MR that may be a little bit more than what some of you
see in a regular clinical practice. She\'ll also discuss the treatment
development process. Dr. Stewart will talk about clinical design trial
results. I\'ll cover some elements of training, in addition to what was
in the panel package, and then Dr. Stewart will summarize.

The indications for use for this device is its for use in pre or
peri-menopausal women with symptomatic fibroids. The fibroids to be
treated must be visible on non-contrast MRI and should enhance on
contrast MR.

Outside the U.S., the system has received CE Mark in Europe in 2002. Its
commercially available in Europe, Israel and Japan. In the U.S., the
only applications are investigational. We have treated approximately 600
women worldwide for uterine fibroids. And I\'d like to introduce Dr.
Stewart, who will introduce the topic.

DR. STEWART:  Mr. Chairman, panel members and guests, my travel expenses
were paid by InSightec today. As Mr. Newman said, I serve as a Clinical
Trial Investigator for the company, and am a Consultant for the company,
but abide by the Harvard Medical School ethical guidelines that limit
consulting when an investigator is involved in clinical research.

I want to start today by talking about the important problem of uterine
fibroids. As everyone in this room probably knows, this is a very
important clinical problem for women. That are very common tumors and
the prevalence rates vary from anywhere from about 20 percent of women
to being affected, to more recent estimates looking at high-risk
populations by ultrasound where the prevalence of clinically detectible
fibroids appears to be in the range of 75 percent.

Most of the discussion regarding uterine fibroids centers around cost
and the costs are substantial for a healthcare system. It\'s estimated
that the cost for hysterectomy alone in the U.S. along per year is in
excess of \$2 billion. This is really the tip of the iceberg because it
doesn\'t even start to take into account other surgical options,
non-surgical options, medical options and various alternative treatments
that women seek to try to control their symptoms.

I think it\'s important to note also that there is information regarding
productivity in women with menorrhagia and so this is probably an
under-estimate for the kind of women that we\'re seeing in our study who
have clinically significant fibroids. The estimation from 2000 was that
lost productivity due to menorrhagia or excessive menstrual flow is in
the range of \$1,600 per woman per year.

I think it\'s important to realize that fibroids are a common source of
morbidity for women. They cause a lot of symptoms that tend to cluster
in several different areas. Menorrhagia or excessive menstrual flow is
an extremely important problem due to fibroids. And for women, this
really limits their ability to carry out their work or their
interactions with their families. There are many women that spend up to
two weeks every month with significant menstrual bleeding, and there are
many women who have such significant menstrual bleeding that they cannot
attend to any other activity for an hour or more without having to stop
to deal with changes in sanitary protection.

Pain and discomfort are significant symptoms related to uterine
fibroids. Many clinically significant fibroids are in the range of a
three, four, five month pregnant uterus, and this gives women
significant symptoms in terms of urinary frequency, urgency bladder
discomfort, pelvic discomfort.

These symptoms have been shown to significantly impair health-related
quality of life, and in several studies there have been demonstrations
that women with uterine fibroids have significantly lower health-related
quality of life than population norms. Uterine fibroids have also been
linked to time away from work and other activities that are important to
the economic system. And the Rand Corporation estimated that medical
therapy may fail to control the symptoms in approximately two-thirds of
women, so we do need better therapies for uterine fibroids.

There are treatment options for uterine fibroids, but I think if you
look at the range of options available for uterine fibroids in contrast
to the woman who has a normal uterus and her options available for
endometrial ablation, the contrast is clear. This panel has approved
many devices for endometrial ablation, and many of those are restricted
to women who have a structurally normal uterus.

Hysterectomy is a good solution for uterine fibroids. It is very
effective in solving the symptoms, but it does have a significant
morbidity associated with it, and a significant time away from work and
family. For many women today to have the six week recovery for a major
surgery is something that they cannot incorporate into their work and
their family.

Myomectomy is an option for women who have a desire to retain their
uterus but want resolution of their fibroid symptoms. Clearly, there are
some women that are amenable to minimally invasive Myomectomies if the
fibroid is in the right position at the serosal or the mucosal surface.
However, again this modality is a surgical modality, and can have
significant recovery associated with it.

Uterine Artery Embolization has been an important option that has been
added in the past decade for women with uterine fibroids. It has
significantly decreased recovery time and fewer complications than
hysterectomy. However, this modality is associated with pain and fever
post-operatively, and there\'s increasing attention to the fact that
there is an age-related impairment of ovarian function and this may be
particularly an issue for certain groups of women.

Thermally ablative therapies have been tried previously for uterine
fibroids. Many people have had experience with either myolysis or
cryomyolsis, and there\'s a small experience with RF-ablation. These
techniques have not really made it into the general gynecologist
armamentarium, probably because of a lack of thermal monitoring.

With these prior therapies, there was no gauging of temperature, and so
you couldn\'t tell had you established a sufficient temperature to
destroy the tissue. If not, you probably decreased your efficacy. Or if
you exceeded the temperature goal, potentially you were injuring normal
tissue and causing problems with adhesions or other follow-up.

Again, we do have drug therapies, but they tend to fall into two broad
categories. Drugs such as oral contraceptives and progestins are widely
used to control fibroid symptoms, but they tend to not be efficacious in
the long-term.

On the other hand, GnRH agonists are very effective, but their side
effects are significant, and their cost is significant, and so these
drugs really haven\'t been great long-term choices for women with
uterine fibroids.

We see that there\'s a spectrum of options available for uterine
fibroids that for women with severe disease or who require a definitive
solution, hysterectomy is still a choice. But many women are sitting
down here with expected management and dealing with significant levels
of symptomatology because they fear the surgical invasiveness of the
other options, or because they cannot, again, take the time and the
recovery that\'s necessary to undergo a very invasive option.

We think MRI guided focused ultrasound surgery will be a very important
option to offer women. It will give them the symptom relief that they
require with significantly less invasiveness than many of the other
options.

There are several unique things that are important to know about MRI
guided focused ultrasound. It is a non-invasive, rather than a minimally
invasive surgery. There is no surgical incision. There is no probe that
goes into the fibroid. It is able to be accomplished as an out-patient
procedure. Again, it serves the uterus and is uterine sparing.

The other important issue is that it is a fibroid-specific therapy.
Unlike something like uterine artery embolization that targets the
entire uterus, the fibroid is specifically targeted so that there is no
impact on the myometrium or the endometrium.

Again, the real time feedback on temperature gives you precise thermal
ablation, and this is very important both for the optimization of safety
and efficacy. Again, you can know that your temperature is getting to a
therapeutic level and causing tissue destruction, and yet remaining in a
safe range. And we have found that this procedure does not preclude or
complicate future treatment options.

I will return the presentation to Mr. Newman, who will talk a little bit
more about the device.

MR. NEWMAN:  Thank you, Dr. Stewart. I\'ll just briefly review some of
the key points of the device itself. As I said, much of this material is
in the panel package, so I won\'t belabor the issues.

MR guided focused ultrasound is really a combination of two things, the
idea of focused ultrasound as a source of thermal energy, and MR to plan
and control the treatment in progress. There\'s two main components; one
is the patient table and the electronics that\'s attached to the MR
system. In the top of the patient table is the transducer, and there\'s
a water bath here. The patient lies on top of that. The energy is
transmitted through the abdominal wall and focuses on a point inside the
body.

Out next to the operator console of the MR is the control console for
the focused ultrasound. Here\'s the regular MR console, and they sit
side-by-side so that you can see your work on both systems during the
treatment. Once the treatment begins, all of the control of the
treatment and all the observation of the patient images is done from the
ExAblate workstation. Next slide, please.

Just a brief history of focused ultrasound. Although this may be one of
the first times that many of you have heard about it, focused ultrasound
is a technology that\'s been around for a long time. There are
publications as early as the 1930s. We didn\'t invent this. We\'re just
kind of the latest people to carry on a long line of research in this.
The Fry Brothers in the 40s and 50s did a lot of work on this looking at
focused ultrasound in the brain and other places in the body.

Lele carried on work looking at several tumors. There\'s also some
carried on with some work using focused ultrasound for acoustic
hemostasis and other applications. In 1993, Hynynen, Cline and others
wrote the first paper on the combination of MR with focused ultrasound
using MR for the thermal imaging. And then 1995 to present is ExAblate,
the development of the device we\'re discussing today.

The transducer, a little of the physics of the transducer. The
transducer lies here. The energy passes through the skin and intervening
tissue to focus at a point. The energy is highly focused. It\'s kind of
like taking a magnifying glass and focusing the sun\'s energy, so you
can put your hand above the magnifying glass, below the magnifying
glass, and it isn\'t until you get right at the point that the energy is
highly concentrated.

The density in the far field, the energy is attenuated and absorbed
along the beam path so while it\'s highly concentrated here, it falls
off with distance in the far field.

The focused ultrasound energy propagates through tissue and skin. It\'s
blocked by air, such as in bowel or the rectum behind the focal point,
and it\'s absorbed by bone, such as the pubic bone or the sacrum in the
far field.

This is just brief picture showing the patient lies on top of it, so
here\'s the transducer underneath. Here\'s the overall beam path for
this entire volume, and in the blue is the focal path for a single
sonication.

The one thing that\'s different about this as a source of thermal energy
is we ablate one small piece at a time, as opposed to a cryoprobe where
you create a large two, or three, or four centimeter lesion in one go,
or RF ablation. We build up the treatment from a series of these
individual sonications that are approximately 25 by 25 by 10
millimeters, so you\'re ablating about a half a cubic centimeter at a
time. A single sonication takes about 20 seconds, and the target is to
raise the tissue in-between 65 and 85 degrees Centigrade. If you raise
tissue above 57 degrees Centigrade for one second, it\'s ablative.

There\'s a rapid fall-off. It\'s a highly focused transducer, so
there\'s a rapid fall-off with distance, so just a very few millimeters
away from the focal spot you\'re back at normal body temperature.
There\'s also a combining effect here because tissue\'s sensitivity to
temperature is very time-dependent, so when you look at one pixel, it\'s
the time temperature, it\'s the product of time and temperature that
dictates whether you\'ve had ablation or reversal heating of that point.
So when do a treatment, the physician draws a region of treatment around
the area to be treated, and then the system tiles it, if you will, with
a series of these jellybeans, so that basically you draw a region of
treatment and the system figures out how many jellybeans are in the jar.
So how many will it take to completely cover this volume, so you can do
a single layer, you can do multiple layers, and here\'s what it looks
like in the horizontal plane, or looking down on it from above.

The treatment is controlled by MR thermometry. You\'re doing MR
continously throughout the treatment, so it isn\'t like you do a single
planning image or a stereotactic plan before. You\'re using MR
continuous throughout the energy delivery, so approximately every three
seconds you\'re acquiring an MR image. The accuracy in vivo in fibroid
tissue is about 3 degrees Centigrade. And what we\'re doing is we\'re
measuring change in temperature with MR. We can\'t measure absolute
temperature, but we measure change relative to body core temperature.

We take the information. We use this to tell us \-- we can see the focal
spot. We can tell where the energy is being delivered in three
dimensions, and we can quantify the temperature to get this
time/temperature information from each pixel.

At the end of each sonication, using this time/temperature information,
we can calculate the volume of tissue that exceeded the dose, and we can
use this information to plan the next sonication.

This is just a quick picture showing during a single sonication we\'re
acquiring an image every three seconds here over a 15 second sonication
in this case, so you can see at 1.7 seconds, you can see the spot start
to show up on the MR image. At the end we take this information,
calculate the volume of tissue that was ablated, and we can draw one of
these time versus temperature histograms here or maps, so we can where
this little red cursor - it\'s hard to see in this slide - but there\'s
a little cursor here, and you can see the time/temperature history out
to 98 seconds.

If we would move that cursor somewhere here in the background away from
the focal point, you\'ll just see some bouncing around, plus or minus a
few degrees of normal body temperature.

We\'ve done extensive thermal modeling in both 2D and 3D looking at a
simulation of energy along the beam path to quantify the absorption of
the energy, and to look at the tissue characteristics. We\'ve done this
to explore boundary conditions, to look at what type of dosimetry would
be appropriate for maximum effectiveness, and to minimize thermal damage
outside the treatment volume. And to really simulate things that we
can\'t really do in vivo to look at kind of worst case scenarios of
energy delivery and absorption that we wouldn\'t be able to do in vivo.

Pre-clinical evaluation was extensive where we looked at transducer
designs, looking at transducer power, verification of ability to control
the focal spot. There\'s a lot of work done in cavitation. Some of you
may be familiar with focused ultrasound in other applications, such as
lithotripsy. In that application, you\'re trying to generate cavitation.
The whole point is to generate a very high energy shockwave to shatter a
stone, such as a kidney stone. In our application, we only want thermal
effects, and we want no cavitational effects, so there\'s a lot of
design in the system and the use, limitations on the use to make sure
that we limit our effects to thermal effects.

There was testing of the biocompatibility and a lot of animal testing in
both \-- for both our system and in the literature. There are several
dozen publications over the last 15 years on the use of thermal imaging
in MR.

Next I\'d like to introduce Dr. Clare Tempany, who will give us an
overview of MR anatomy for treatment planning.

DR. NOLLER:  If I could interrupt for just a second. Our support
personnel, could we have the temperature turned down a little bit,
whoever is doing that.

DR. TEMPANY:  Thank you. Good morning, Mr. Chairman, panel members, and
guests. My name is Clare Tempany. I, too, am a Clinical Trial
Investigator at the Brigham. My trip and accommodations have been paid
for by the company. I work as a consultant like Dr. Stewart for the
company, and work within the Harvard Medical School Guidelines for
Conflict of Interest and Ethics in Research.

What I\'d like to do for you today is two things. I\'d like to introduce
you to the MR imaging anatomy, display of anatomy and pathology that\'s
used in this trial. It\'s used routinely in clinical imaging today, and
then walk you through a typical clinical treatment.

Female pelvic MRI has become a very powerful diagnostic tool, and it\'s
been available now to us in radiology for over 15 years. It exclusively
displays the female pelvic anatomy as you see in these what are called
T2-weighted images for you on this slide. On the left you see a sagittal
view, and on your right is a coronal view. And on the left, you can see
the anatomy of the uterus and cervix displayed with the substructure of
the zonal architecture of the uterus displayed with the layers
delineated for you. And on the right you see the same thing with the
ovary on either side.

Many of you are more familiar perhaps with pelvic ultrasound, and these
are images of patients with fibroids where you can see an enlarged
uterus here in the center, and then you see a slightly different
appearing uterus in the right side here. The texture and tissue
characterization of ultrasound is somewhat limited to either solid or
cystic, where we can see the differences here with the cystic component
on the right.

A little bit of MR anatomy and how we visualize these fibroids before we
determine whether they\'re eligible for treatment or not, selected
images here. Now we\'re going to walk through several planes just to
show you the display of the anatomy, and on the left you can see an
axial view with the patient lying prone. The blue line represents the
sagittal image on your right, and all of the relevant structures will be
labeled, obviously, but you can see a very typical uterine leiomyoma
sitting here in the center. It\'s classically a typical one that has a
very low signal intensity or it\'s black, and it has a very sharp
border. This is what we call a cookie-cutter sharp border which
delineates and differentiates this from say adenomyosis, which will not
have such a sharp border.

The coronal plane here you can now see nicely posteriorally as
delineated up here on the blue line, but way in deep at the back of the
pelvis here and the woman is standing in front of us, you can see the
sacral nerves coming down here posteriorally, coming down along the
lateral aspect of the pelvis to exit through the sacrosciatic notch. And
as we come forward, you can see more anteriorally now. We\'re coming
into the uterus. We see the large fibroid. We can see its relationship
to the bladder. It\'s very easy to understand some of the symptomatology
this patient has experienced when you see images like this with a large
uterine fibroid pressing on the bladder.

Now axial planes in a typical treatment position now with the patient is
lying again prone, and you can see the uterine fibroid sitting here. We
see the anterior skin there, and you can see the direction of the beam
as you will see in a minute. And there\'s the fibroid. These are the
anterior rectus muscles here anteriorally, and posteriorally we see the
fat, the bowel, and the sacral nerves.

We\'ve learned a lot about uterine fibroid or leiomyoma imaging over the
years with MRI, and done many pathological correlation studies, and have
determined that there are many types of fibroids, as you\'ve known in
the clinical world for many years. And these can be seen and
characterized well in MRI. And to just summarize some of them here for
you where you see about five different varieties described.

The top two are probably the typical ones that we would treat in this
trial, or have treated in this trial, and these consist of the classic
leiomyoma which is a fiber muscular stroma. It\'s of low signal in every
imaging sequence we have. In other words, it\'s black, it\'s easy to
see.

A different type is what we call hypercellular, where it\'s also known
as the white fibroid. It appears at high-signal intensity on T2-weighted
images. Those are the ones we\'ve treated.

The other group will represent ones that we wouldn\'t treat, which are
non-enhancing leiomyomas basically, once that have already undergone
spontaneous degeneration or necrosis in vivo, and obviously, of varying
patterns also.

Just to show you some more examples of the range of the types of
appearances of fibroids, here\'s a woman who\'s had very significant
fibroid burden. Everything with an F on it is clearly a fibroid here.
This is a coronal T2-weighted image, as if she\'s standing in front of
us, her urinary bladder in white, and you see how this may appear like a
five-month gravida uterus.

On the right side we see a different patient with multiple fibroids and
an unusual appearing one here posteriorally that\'s already undergone
degeneration. This is a large cystic degenerated leiomyoma, and we know
it\'s degenerated because we have post contrast images here in the
middle that\'s after the injection of intravenous Gadolinium, and it
shows no evidence of enhancement or it stays black with no perfusion;
thus, indicating that it\'s necrotic. So let\'s just move into a
treatment process now.

Much of that imaging will occur prior to the patient\'s being determined
as eligible for the trial, and we have identified, selected the patient
and identified the target treatment, and this is what now happens on the
day. So starting the night before, the patient will receive written
guidelines about the therapy and what to expect during the treatment.
She will review that. She will have prepared the abdominal wall,
removing abdominal hair from the umbilicus down to below the pubic bone.
This is important because we want the skin to be as smooth as possible,
and to not interfere with any coupling or cause decoupling of the
ultrasound beam as it will transmit through the skin.

She remains NPO from midnight because we use intravenous conscious
sedation, and clearly don\'t want to have any problems with food. So we
have the patient then come in the next morning. I meet with the patient.
We review the treatment guidelines with her. We review what sort of
sensations or experiences she may feel during the treatment. We develop
the communication ritual to tell her when we\'re going to do a
sonication, she tells me what she feels, and we sort of discuss all of
that communication issue before we go in the room at all.

I also then consent her for administration of intravenous conscious
sedation per our hospital guidelines. Once that is done, the IV line is
sited, the Foley Catheter is placed. We use a Foley Catheter clearly to
control the bladder during the procedure to make sure that the bladder
stays empty. As you know, when the bladder fills, the uterus moves, and
treating a moving target is clearly difficult, so we use the Foley
Catheter to control that.

At the same time in parallel, the room check is going on. There\'s a
phantom checking of the system occurring, and after all of that is done,
the patient then comes into the room, is positioned on the table in the
coil, her vital signs monitoring devices are placed in position,
obviously her pulse ox, blood pressure cuff, et cetera. The nurse will
remain in the room with her at all times, and both she and the nurse
will have a small little sonic button in their hands which will allow
them to terminate an individual sonication should the patient experience
an unusual severe pain. She has full control of the therapy itself at
the time.

So here\'s just some pictures. You can see this is the MRI magnet, this
is the table, patient sitting getting ready to go into position. She
then turns over and lies prone, positioning the pelvis over the
transducer. The transducer, as you\'ve seen already, is in the table
surrounded by degassed water so she lowers the skin down onto the water
bath basically with a gel pad also in side it, and she makes direct
contact with the skin into the water.

A little bit about our conscious sedation and monitoring of the patient
during the procedure. We use standard intravenous conscious sedation
medications at our site. We use Versed and Fentanyl. These are
administered to provide a combination of both analgesia and sedation.
It\'s clearly important that the patient\'s anxiety and any
claustrophobia that she may be experiencing in the magnet be aided by
the administration of these medications. Patients, obviously, may
experience positional pain lying on their stomach in the magnet for the
duration of the procedure. And again, the analgesic effect is useful for
that. And we obviously want to try to reduce any pain from sonication so
we use the Fentanyl.

Typical doses that have been used in the procedures, and these are the
total doses, range from as little as 25 mics of Fentanyl to 250 mics, to
.25 to 5 of Versed. These are both intravenously. We also give patients
an oral non-steroidal anti-inflammatory at the very beginning of the
procedure. Usually, typically 75 milligrams of Voltaren has been used.

The medication then is given as required. Before we start any treatment,
we will give a very small incremental initial dose of Versed and
Fentanyl, and then depending on how the patient is feeling, responding
during the therapy, we will give further doses during the procedure, so
that\'s why the ranges are quite wide here. Some patients require very
little, some patients require a little bit more.

So let\'s just start now with treatment planning. The patient is
positioned on the table, and you can see the transducer. And this is a
good positioning on your left here, as opposed to the one on the right
where the transducer is too high. And you can see this is a very large
field of view image here. The uterus is really too low, and we would
have to angle too steeply to treat that, so we clearly can readjust the
transducer and the patient at this stage before we start going any
further.

We will then take three planes of pelvic MRI images, as you\'ve just
seen, an axial, sagittal, and coronal to again define our target, to
allow me to draw the contour to target volume superimposed on the
fibroid at that point, and those images are coming up in a minute.
We\'ll show you how we do that.

Just to remind you that in the trials, we have protocol treatment
guidelines. Single treatments initially were limited to 120 minutes. The
maximal thermal dose per fibroid was limited to less than 100 CCs, and
you could see treatment for all fibroids, if more than one was treated,
was a total of 150 Ccs.

We have a maximum of four fibroids that could be treated in any one
setting.

The protocol treatment guidelines delineate a little bit further in
detail here for you, and the schema on the right really explains it all
nicely. The large black circle is a fibroid. The smaller one on the
inside the region of treatment, the ROT, is the circle that I would draw
as the sub-volume in the fibroid. We have to work with the guidelines,
obviously, remaining within 15 millimeters of the outer serosal lining,
and 15 millimeters of the endometrial lining. And so this clearly
restricted somewhat the volume of the fibroid that we could actually
treat during the initial safety and efficacy evaluations.

Here are some pictures of the same thing. You can see the treatment
plan. Now the sonication grid has been overlaid and you can see these
jellybeans, as Mr. Newman has already referred to, and you can see them
overlaid here on the images. Before we do anything now, the next thing
to do is to walk through each of these sonications and determine is the
beam path going to be safe, and will it remain within the guidelines. So
we work through this system here where we see the beam path on each and
every one of these. And there are some images now, just to show you how
that\'s done. You can see the passage of the beam going through in green
here, and the focal point is delineated there on the sagittal view, the
axial, and the coronal.

What can be in the way? Well, things that certainly can be in the way
that we can identify relatively easily are things like scars that would
be in the skin from prior surgeries, clearly things that are in the skin
such as scar can cause defocusing of the ultrasound beam as it\'s
passing through, cause local heating of the skin, and something that we
try to avoid at all costs. And so it\'s fairly simple to do this, we
simply identify the scar ahead of time, and then using the roll and tilt
mechanism of the transducer, we can angle around that area.

The same thing with bowel loops. Bowel loops are relatively easy to see
here. You can see them on this T2-weighted image. They\'re the dark
structures up at the top, and you can see again, we can angle either up
and around the bowel loop, or if necessary, just simply not treat that
area, clearly not go anywhere close to the bowel loop. The sonication
can simply be deleted.

Same thing here if we\'re looking at the distal field. We can evaluate
the location of the sciatic nerves, and we can determine whether or not
the beam is going to pass through, and angle and roll, and tilt again to
avoid it.

Okay. So now we\'re ready to go. The first thing we do is the geometric
accuracy, and so this is when a low powered sonication will be
delivered, and the very first set of images will come up as that\'s
being delivered, and this is a cropped down view here of the face map,
and you can see that we\'re determining the accuracy; first of all, the
visibility of the sonication. Can I see it at all? And you can hardly
see it because it\'s covered by the red cross, but underneath that
little red cross is a white dot, and that\'s the first sonication
that\'s being delivered. And the initial assessment is good, now I see
it. Is it in the right place? And so here you can that it\'s off by
about 5 millimeters, so we will readjust all of the anatomical and
adjust the geometric alignment so that the green overlies the red, and
that they are absolutely concurrent.

The next step then is to move into a therapeutic sonication dose, so we
increase the power up to typically 100, 140 watts, and we start the
actual procedure with therapeutic doses being delivered. We compare this
as it\'s going. We modify the treatment parameters as necessary. As
you\'ll see in a minute, we\'re constantly looking at the feedback
mechanisms of the thermal imaging, to determine if we\'ve achieved a
therapeutic dose or not.

Throughout the procedure I\'m in constant communication with the
patient. This is very important because there\'s a one-on-one
communication between myself, the patient, and the nurse in the room,
but I will talk to her, tell her we\'re about to start a sonication at
the beginning of one, and then at the end of that ask her if she\'s
experienced any sensations, and if she has any concerns.

These are some examples now of the typical dose profile. On the left,
you see a sagittal view or a long axis of a sonication, so you see the
jellybean shape. This is a short axis view where you see it on end. And
then these are three incidents of things that could happen, so if you
look at the bottom left, we have a sonication that\'s achieving a
thermal dose that\'s probably too hot. The temperature, you probably
can\'t read that, I\'m sure I can\'t either - it\'s 100 degrees is what
that one has reached, so clearly, that\'s a little too hot. So what we
do in that situation is to back down on the power before we go any
further, so we wouldn\'t continue to treat without changing parameters
once we\'ve seen that.

Similarly, in the opposite direction, the next one demonstrates a
sonication that achieved a 50 degree temperature, and that\'s too cold,
so the first step then would be to increase the power to bring it up to
a therapeutic dose, which we like to see between 60 and 80 degrees.

Calcifications occur in fibroids, as you know, very frequently. They can
be small punctate little pieces of calcium within a fibroid, or you can
have a very more densely, heavily calcified one. The latter patient
doesn\'t usually get into the trial because we can identify that in
imaging, and a dense rim of calcification precludes treatment using this
treatment modality. But small punctate calcifications are impossible to
see ahead of time, and this is what may happen.

The ultrasound beam will be reflected off the sonication, will simply
not achieve any therapeutic dose, so we simply move onto the next
location, delete that sonication, so to speak, and don\'t treat that
specific area. So an overview of the treatment cycle is seen here for
you for an individual sonication. Before anything happens, the MR
scanning starts. Then the sonication is delivered, then a tissue cooling
period occurs, and at all times the images are being acquired, and this
total is about 2 minutes. So this is an extremely interactive treatment.

As you\'ve seen already, the entire beam path is checked prior to
delivery of sonication, irregularities of skin, bowel, and beam path are
evaluated. We have multiple tools available to avoid critical
structures, things that we would not want to have the beam pass through,
and we use each and every image to modify the next sonication, so it\'s
a very iterative process, so we\'re learning from the last sonication
what to do for the next sonication. And we do this with the MR imaging
that\'s continuously occurring during the procedure.

So there are some safety issues, obviously, where motion is a problem,
if patients were to move during the procedure, as I\'ve already said,
heat treating a moving target is not good. So we obviously have
prevented that now by the Foley Catheter placement with the bladder
being controlled. We also obviously coach the patient that she should
not move her pelvis. She\'s lying prone, and if any of you have ever had
an MRI scan, you know that we strap patients in on the table, that
there\'s a coil around it, so it\'s fairly restrictive. There\'s not a
lot of room to maneuver and to move around, so these are things
obviously to our advantage.

We also use the restraint strap which is strapped around the outer
pelvis to hold the patient on the table. The sedation somewhat helps
also, but clearly she can still move if she really so desires. We
monitor this with both sets of images. The real time images being
acquired during the sonication are very easy to see motion, because
it\'s like watching a movie. You\'re sort of seeing a cine loop, so to
speak, so you can see changes if she was to move her skin or her spine.

We also place fiducials at the beginning of the imaging sequences, and
these are the little red marks you see here. And those are monitored
carefully, as well, to ensure that they don\'t change in position over
the procedure.

The outcome assessment while the patient is still on the table,
essentially as we\'re going we\'re developing this blue map in the
center here which represents all of the therapeutic sonications that
have been delivered, and have been therapeutic; in other words, reached
the goal temperature delivery. And so the blue is the area that we will
expect to see the necrosis. And at the end of the procedure, we confirm
this by injecting Gadolinium and evaluating the necrotic tissue. And as
you can see, nicely maps. The blue area here is now seen as the black
area here, which is the non-enhancing or necrotic tissue.

Again, some other images from the end of a treatment. Typical treatments
look like this. They can range from relatively small sub-volumes to
slightly larger volume here, with the areas of necrosis seen in the area
of treatment. And I thank you for your attention, and pass the podium
back to Dr. Stewart, who will continue with the clinical trial design.

DR. STEWART:  Thank you. In moving on to clinical trials in fibroids,
that can be quite a daunting task. As the Duke Evidence-Based Practice
report has shown on, despite the fact of a wealth of clinical experience
with uterine fibroids, this isn\'t a lot of good evidence on which to
base therapy.

We were fortunate in going into our feasibility study having information
from an in vitro model using a rodent model, and using ultrasound guided
high-intensity focused ultrasound that showed treatment with this energy
modality was feasible for uterine fibroids. And we wanted to get several
important things out of our feasibility study.

First of all, we wanted to make sure that this was a safe treatment for
women. We also wanted to confirm our targeting accuracy. As Clare has
discussed, the feedback we get from the MR is important, and we are
depending on the non-enhancing volume representing the tissue that we
have successfully ablated, so we did want to get pathologic confirmation
of this ablation. And this is actually something that hasn\'t been done
with previous therapies, such as myolysis, cryomyolysis, or even uterine
artery embolization. And we wanted to take this information to help
refine our pivotal trial design.

The study design was that it was an open trial for women who were
scheduled for hysterectomy. They were to undergo MRI guided focused
ultrasound three to thirty days in advance of their hysterectomies. In
your panel packet, it appears that there are two distinct studies that
our center and St. Mary\'s in London has described in one area, and then
the other three sites are described in another area. However, because
women were reluctant to go through treatment and hysterectomy,
recruitment in the original cohort suffered, and so as time went on,
these other sites began recruiting patients, as well. And then, in fact,
the Israeli National Health Service made hysterectomy optional for that
group of patients. They felt that it was unethical to require women to
undergo this therapy and then not have the option of opting out of
definitive therapy, so our trial design changed somewhat midstream, but
we followed all of these patients, and reported them together.

We were able to confirm our pathological information, and this is a
diagram from our manuscript. This is the treated fibroid, and this is
the pre-MR imaging that shows Gadolinium going throughout the fibroid
indicating good perfusion. This is the post-treatment Gadolinium MRI
where you see a large area of non-enhancement. And then this is the
hysterectomy specimen. You can see on gross examination that there is a
clear lesion that corresponds to the targeted area. And on microscopic
exam, there appear to be coagulative necrosis corresponding to this
area.

We were also able to confirm that there is a relationship between the
targeted volume, the non-enhancing volume, and the pathologically
correlated area of tissue destruction. In this particular fibroid from
our St. Mary\'s site, you see the thermal dose volume in A, the B is a
little bit bigger, the non-enhanced volume, and the pathologic area
confirmed more closely to this non-perfused volume.

We did find that the non-perfused volume in general over-estimated the
amount of tissue destruction, but we found that in all cases the area of
targeting was confined to the treated fibroid. There was one case where
microscopic evidence of sonication was seen at the serosal border;
however, in retrospect, it appears that that was incorrectly targeted.
This was one of the cases where the bladder filled and the target moved,
and is a reason why we adopted a Foley Catheter with our pivotal trial
treatment.

So we were able to confirm pathologically that the tissue that we
thought we destroyed was destroyed. We also were very pleased with our
results in terms of patient treatment. All but one patient were able to
be treated as an out-patient. There was a single hospitalization
overnight for control of nausea. There was no post embolization
syndrome. There, in fact, was very little pain in women undergoing this
protocol. And most of the patients that we saw were not even taking
over-the-counter medications at the time we saw them within 72-hours of
their treatment.

The one safety issue that we did see in this initial protocol was there,
there was a significant incidence of infection seen post-hysterectomy.
They did not occur between the focused ultrasound and the hysterectomy,
but following the hysterectomy. And we stopped the trial at the time we
saw the first three infections. We reviewed our procedures. At that
time, we did change our protocol to institute prophylactic antibiotics.
And once those were instituted, we didn\'t see further significant
infections. And our pivotal protocol did not have prophylactic
antibiotic use.

We also used the information in the trial to mitigate the adverse events
we saw. We found early on that paying attention to the skin in various
forms was important. Initially, patients were not shaving and there were
small skin burns at the area where there may have been loss of coupling
of the ultrasound to the skin. We also, again, found the importance of
mapping the scars, and incorporating those into treatment planning.
Because scar tissue is very similar to fibroid tissue, some of the
energy would stop at that point and patients would be uncomfortable, and
so we used a lot of the information from this feasibility study to
define the optimal treatment protocol to embark on our pivotal study.

The major issue when embarking on the pivotal study was the selection of
a control group, and there are always issues with picking the perfect
control group. And it\'s especially important, I think, to put this in
the context of the times. At the time that the selection was going on,
it was December, 2001. Although uterine artery embolization today might
appear to be the best alternative, as a control group, this was not
really possible at that time. There were no embolic agents that had
received FDA approval at that time. And with extensive negotiations with
the FDA and the investigators, we looked at the other alternatives. And
we felt that looking at a surgical option would really give us important
safety information. It was important to have a contemporaneously
recruited control group, and not to depend in historical controls.

Again, abdominal myomectomy in many ways appears to be an important
option. The issue for this group of patients was that many of them may
not be symptomatic. They would be pursuing treatment to attain
fertility. They would also tend to be younger than the symptomatic
patients that we were seeing. And with our group, we specifically wanted
to recruit women with a threshold level of symptomatology. Therefore, we
decided that although no control group was perfect, that abdominal
hysterectomy would be the best alternative.

With our knowledge of difficulties in recruitment and our pivotal study,
and also information we were gaining from the experience with uterine
artery embolization trials, at this time many groups were trying to
perform randomized trials between conventional surgical therapies and
uterine artery embolization. And no one succeeded in having sufficient
enrollment, so in that group of patients there were generally case
series or parallel controls. And again, this is the study design that we
settled on.

The hysterectomy group and the focused ultrasound group were enrolled in
parallel. They met the same inclusion and exclusion criteria, and both
received the same six month follow-up. We also chose to separate the
sites TAH and focused ultrasound so that you did not have investigator
bias channeling good prognosis patients into focused ultrasound, and bad
prognosis patients into hysterectomy, so the sites were all separated.
And with our power calculations we found that a 3-2 ratio would give us
the desired number of patient\'s in each arm.

The inclusion criteria included women who were not pursuing future
pregnancy. We felt it was not ethical to treatment women who desired
future fertility until we had information regarding the efficaciousness
of this treatment. They were all pre-menopausal or peri-menopausal
women. They did have both clinical exam and MRI consistent with
fibroids. The fibroids needed to be visible on contrast MR, and feasible
for treatment.

We also chose to have a minimum symptom severity score, so that they had
to score over 40 points on a scale of 100 to be included in this
protocol. The exclusion criteria were fairly obvious. Women who could
not undergo MR were not included. Women with excessive uterine sizes in
excess of 24 weeks, or women that were too heavy to fit in to the MRI
equipment were excluded. We also excluded anyone with an undiagnosed
pelvic mass, or other worrisome pelvic pathology.

The primary hypothesis for our pivotal study was that we would see at
least a 10 point improvement in the uterine fibroid symptom and quality
of life symptom severity score. This is the only validated quality of
life score specific for uterine fibroids. And we felt that in our
treated group, we would have at least 50 percent of our patients
achieving this goal.

We realized that the treatment modality would likely not be as effective
as hysterectomy given the limitations, but we felt that this was an
important landmark in demonstrating the efficacy.

We also evaluated several important secondary hypotheses. We wanted to
look at the significant clinical complications in both arms to compare
safety. We wanted to look at the trajectory of recovery, and also the
costs involved.

For those of you not familiar with the uterine fibroid symptom and
quality of life measure, this again is a disease-specific validated
measure. It was developed specifically for uterine fibroids and it has
two different parts. The symptom severity score, which you\'ll see in
this presentation referred to as the SSS, has eight questions that
relate to the fibroid specific symptoms, pain, bleeding and bulk.

There is also a component to the health-related quality of life which
has six different sub-scales as is common with all quality of life
questionnaires. And this questionnaire was developed from an ethnically
diverse set of focus groups to really get input of fibroid patients, and
what they felt their significant symptoms were.

Also during the validation process, this was correlated with the SF-36,
which is really the standard measurement of quality of life, as well as
a menorrhagia questionnaire indicating its comportance with symptoms of
menstrual blood loss.

For those of you not familiar with the questionnaire, you\'ll see that
the symptom severity score addresses issues such as heavy bleeding
during your menstrual period, passing blood clots. It also looks at bulk
related symptoms, feelings of tightness and pressure, frequency of
urination or nocturia or feeling fatigued. And patients are asked to
rate their symptoms on a five point Likert scale from not at all to a
very great deal.

This is data from the initial validation of this questionnaire that
you\'ll see the two parts are divided here to the symptom severity
score, and these are the sub-scales of the health related quality of
life. One of the first things you\'ll notice is that there\'s an inverse
relationship between them. For symptom severity score, the women in blue
who are women with uterine fibroids, have a higher score, so higher
scores mean higher symptoms. Whereas, with the health-related quality of
life, the normal women tend to have higher scores and impaired related
quality of life is reflected in a lower score.

It\'s also interesting to note the absolute levels of the symptom
severity score. In this study, looking at women with symptomatic
fibroids, the mean score was 44; whereas, the mean score for normal
women was 23 or about a 20 point difference between the two groups.

This clinical difference was the primary reason we selected our 10 point
difference between treatment success and treatment failure; that if 20
points represents the difference between women with fibroids and normal,
getting 50 percent relief of symptoms appears to be an appropriate
clinical end-point.

There were also standard methodologic reasons to choose this. That 10
points is very similar to the standard deviation in the population. The
standard error of the mean and gives a moderate effect size, as well.

We did not depend only on one outcome. We also looked at additional
efficacy measures. We used the SF-36 which gives standard health-related
quality of life. We looked at several measures of disability days, some
assessment of an overall treatment effect, and also patient\'s treatment
satisfaction.

This is a schematic drawing of the pivotal study design that at the
screening visit we perform the MR prior to the treatment, as well as the
symptom screening. A hematocrit ruled out serious anemia, and during the
treatment visit we again got information regarding symptomatology.

We took seriously that this was a new technology, and that there wasn\'t
a lot of experience with follow-up, so we have everyone come back for a
physical exam within a week so that we would not miss important issues
that arose, so patients came back and did have a hematocrit and a
physical exam at that time.

The one month and the three month follow-up were generally by phone, but
then there was a full visit at six months with a physical exam and MR
exam, and again complete testing.

The pivotal study design was originally designed to have outcomes at six
months. However, later we have extended follow-up so that we\'re now
seeing patients who are continuing on at 12 months, 24 months and 36
months. And again, getting information on quality of life, as well as MR
exams at that time.

We wanted to try to capture significant clinical complications, and what
we did at this time was we went to the literature. The paper by Dicker,
et al, arose out of the collaborative study of sterilization. And they
felt it was important at that time to try to define characteristics that
could be used to compare treatment.

We used their criteria, but tried to update it both for the change and
length of stay that has occurred since the 1970s, and also some of the
differences that we would potentially see with this new therapy included
as additions or things like discharged going to a rehabilitation
facility, discharged with either a catheter or a drain, or also various
interventional treatments that may not qualify under their definition of
surgical procedures.

While this would seem to favor picking up complications from
hysterectomy, I think it\'s important to remember that if there had been
inappropriate targeting and significant injury of adjacent structures,
these complications would have been seen and picked up if the treatment
had significant side effects in that way.

So moving onto the results of the trial, as we talked about earlier for
the pivotal trial, there were separate sites for hysterectomy and MRI
guided focused ultrasound. There were three U.S. sites and several
through Europe and Israel. There were also hysterectomy groups and about
half of the enrollment for both arms came from the U.S., and half from
out of the U.S.

There was fairly equal distribution of patients through the sites. There
wasn\'t a primary site that contributed all of the patients. And we
looked at the demographics between the patients undergoing focused
ultrasound, and the patients undergoing hysterectomy. We knew that since
this was not a randomized trial, there were likely to be some
differences. We did find them similar in age, and fairly typical for
women with fibroids. There was a statistically different finding in body
mass index with the women undergoing hysterectomy being somewhat
heavier. And both groups of women had significantly elevated symptom
severity scores.

As you\'ll recall in the validation study, the women with fibroids
typically had scores in the 40s, and both of our groups this mean score
was over 60. And again, there was a difference between these two groups
with women who had elected definitive therapy for hysterectomy having a
somewhat higher score.

There were more black women in the hysterectomy group. Again, probably a
relationship of site selection, but all women in both groups were
pre-menopausal by and large.

There were some differences in co-morbidities. The women undergoing
hysterectomy were more likely to have diabetes and hypertension, and the
women undergoing focused ultrasound were more likely to have thyroid
disease. As you\'ll see later on, we looked at these differences between
the focused ultrasound group and the hysterectomy group to see if these
differences affect the treatment outcome.

We did perform an intention to treat analysis, so that every patient who
received focused ultrasound is included, and so our denominator in the
slide you\'ll see is 109 patients. There were three withdrawals from the
study less than six months, and 11 patients were non-evaluable. We did,
however, do calculations for both evaluable patients and intention to
treat patients, and they were similar.

The characteristics of the fibroid patients were consistent with women
who had symptomatic fibroids. The average uterine volume was
approximately 600 Ccs, but there were clearly a number of women who had
uteruses in the range of 1,000 cubic centimeters or more. The average
total fibroid load, meaning calculating the volume of the fibroids
without the myometrium was in the range of 300 to 400 cubic centimeters.
And patients had an average of two to three fibroids, but as many as 12.
And although one to four fibroids could be treated during this protocol,
in a average most women got one treated.

We excluded from treatment fibroids that were amendable to either
hysteroscopic or laparscopic myomectomy, so although these say
submucosal and subserosal, they were probably more accurately classified
as partially submucosal or partially subserosal with a large intramural
component. And we also looked at differences in location when we
assessed treatment outcome.

So when looking at the treatment parameters again with the intention to
treat patients, the baseline fibroid volume was about 300 Ccs. The
non-perfused volume at the end of treatment was in the range of 68 cubic
centimeters, so we had approximately 24 percent of the fibroid that had
been treated during this protocol. That at six months, there had been a
decrease in size from about 330 to 295. This percentage of shrinkage is
similar to the non-perfused volume. Again, it\'s not a large absolute
number, but it is proportional to the amount targeted for treatment.

Looking at our primary efficacy and the symptom severity score, again we
hypothesized that at least 50 percent of our patients would have a 10
point improvement. We were substantially in excess of that. Over 70
percent of our patients reached this targeted improvement, and this was
statistically significant.

We also found that in fact the symptom severity score at entry was in
the range of 60. By three months there was already clear evidence of a
treatment effect with a mean treatment level going down to 41, and then
some continued improvement between three months and six months. And you
can also see here, this is the criteria we set for entry, so many women
at the three or the six month time point would not have had symptoms
sufficient to qualify for enrollment if they had come at that point in
time to seek treatment.

This is the distribution of changes in symptom severity score, so again
this line indicates the threshold for success, or 10 points or more.
These are the patients who had no improvement, or one to ten points of
improvement, so everyone from here over is a treatment success.

The mean patient improvement, however, was about two and a half times
what we had predicted and the mean treatment improvement was
approximately 24 points. There were, however, some patients who improved
as much as 60 points in symptom severity.

When we turn to look at the health-related quality of life subscales,
these parallel the changes that we saw in symptom severity score.
Because of the inverse relationship these lines go up rather than down,
so again you see a significant change or marked change between baseline
and three months, and then some improvement from three to six months.

We use the SF-36 to be able to compare more accurately the patients
between the focused ultrasound and the hysterectomy arm. What we see
again in the focused ultrasound group is the same pattern of improvement
that already at one month you\'re seeing improvement in some scales,
continued improvement at three months, and stabilization from three to
six months. In contrast, the women who underwent hysterectomy had marked
impairment in some of their functioning at one month, and it took them
three months to six months to get back to where they were and, in fact,
to note improvement following the treatment.

The significant difference is in terms of disability between the two
groups. I think it\'s important to note not only the differences between
the groups, but the absolute level for the focused ultrasound patients.
When looking at the days \-- this is follow-up at one month following
treatment. There were only 1.4 days of missed work on average for the
women in the focused ultrasound group. Whereas, women undergoing
hysterectomy clearly has much more short-term disability with 18 days.
And parallel the days that women with focused ultrasound were kept from
their normal activities averaged about three days. And they again spent
only about a day and a half in bed, so these numbers demonstrate the
significant improvement and short-term recovery seen with this
treatment.

We also looked at resource utilization through six months. Because of
our different sites in different countries we didn\'t bring this down to
dollars, but looked at encounters with the healthcare system. This takes
into account not only all of the scheduled study visits for the MRI
guided focused ultrasound patients, but for those patients that elected
additional therapy, or went on to additional procedures. All of those
resource utilizations are captured.

We found that there was a significantly different length of stay. Only 1
percent of our focused ultrasound patients stayed more than five hours
post treatment. They also had substantially fewer provider encounters,
fewer additional procedures, and fewer diagnostic tests.

We looked at a logistic regression model to see if our baseline
differences affected outcomes, so in the model we included not only the
things that differed between our groups, such as race and BMI, but also
looked at other variables of interest, such as age, country of
treatment, fibroid location, percent non-perfused volume. And the only
predictor of success was baseline symptom severity score. In other
words, the most highly symptomatic patients were the patients that
improved the most.

We also looked at patient satisfaction and asked patients were they
satisfied with their treatment, was it effective in eliminating their
symptoms, and would you recommend this to a friend? And again, over 70
percent of women answered affirmatively to these three questions.

We did continue to follow patients beyond the pivotal study, and
attempted to bring patients in for follow-up between six and twelve
months. Again, we start with our intent to treat population of 109. We
found that 91 patients continued on, 9 patients declined to be included
in the follow-up. They had enrolled for a six month trial, and elected
not to come back, and 9 were withdrawn, which left us with 82 evaluable
patients at 12 months.

We found in following this group that 23 patients had gone on to
alternative therapies, and four patients had elected and were offered
additional focused ultrasound treatments. Both of these groups of
patients are then included as treatment failures in our 12-month
analysis.

So the original study was, indeed, designed for six month follow-up and
we did contact as many patients as we could to come back. Because of the
date that we started to do this, there was some lag, so although it\'s
reported as 12-month follow-up, the actual mean follow-up was
approximately 14 months. The success rates do not look as promising at
this point. If we look at our intent to treat group, there\'s only
approximately a 38 percent success rate. And again, the patients who
declined to come back for us to follow-up or chose alternative
treatments are included here. And if you look at our evaluable patients,
it is slightly higher at 51.

I think what\'s notable is that there were a substantial number of women
who were still improved with the mean treatment being targeted at
approximately 20 percent of their fibroid load. The other thing that is
interesting about the results at 12 months is that we still could see
significant decrements in the treatment parameters as measured by the
symptom severity score, so that at baseline again, we\'re coming in at
about 61 points, and going down to points in the mid to high 30s at six
months and twelve months.

Part of the issue with the twelve month data may be that fibroid
symptoms returned. This is clearly a common problem in the literature,
and is well described for myomectomy. Again, it appears to be an issue
that may be applicable to uterine artery embolization, as well. But
again, many of the studies with uterine artery embolization also have
relatively short-term follow-up. And I think that our original treatment
parameters were aimed at the maximization of safety and, therefore, may
not have optimally targeted the amount of fibroids to get sustained
treatment.

However, there were still significant patient satisfaction with
treatment success at 12 months. Again you see in blue the six month
data, and the twelve month data in yellow, so the patients were still
very happy with the treatment option that they had pursued.

Turning our attention to safety, I think it\'s important, first of all,
to note what we did not see; that many devices that are approved have
significant complications. In many case series, there have been patient
deaths or urgent unintended procedures. There were none of those in this
treatment. There were no bowel injuries. There were no hospitalizations
for pain control or post embolization syndrome. So compared to some
concerns that we had at the beginning, we were very happy that there
were not severe safety issues that we encountered.

Looking at a strict definition of adverse events, we found that 19
percent of patients in the focused ultrasound group had no adverse
events compared with 1 percent in the total abdominal hysterectomy. We
chose for this protocol because of its novel technology to strictly
define adverse events more similar to what you would see in a drug study
than a typical device study. We knew that this was a device that didn\'t
have clear predicates, and we wanted to make sure that we were not
missing adverse events.

However, we found that when we looked at device or procedure-related
serious adverse events, we still did very well with only 2 percent of
MRI guided focused ultrasound patients having serious adverse events
compared to 13 percent in our contemporaneously enrolled group.

We found that the body systems in which adverse events were found to be
similar in most cases. On average, women undergoing focused ultrasound
had about two adverse events versus four for the total abdominal
hysterectomy.

We also wanted to define what we thought prospectively would be device
or treatment-related adverse events. We that non-significant events
might include fever or pain in the treatment area, swelling or firmness
in the treatment area, or minor skin burns. However, we felt that either
skin burns that caused ulceration or any kind of nerve damage should be
termed significant anticipated events, and that we were especially
looking for these events as treatment unfolded.

Again, as we saw in our feasibility study, there was a substantial
decrease in the amount of pain patients had both during this procedure
and post procedure, compared to some alternative therapies.
Interoperatively, the patients reported on average mild discomfort and
mild to moderate pain. And then at post procedure, their levels of both
pain and discomfort were significantly closer to no pain at all than to
mild.

There were patients who had some severe pain during the procedure. And
as Dr. Tempany discussed, we do have the ability to redose pain
medications during the procedure. Only one patient, however, related her
pain as severe post procedure. And again, we found that narcotic use
following the procedure was very rare, and that even over-the-counter
medication use was rare in the days following treatment.

We wanted to look at adverse events again to see if our baseline
differences and the co-morbid conditions or the demographics affected
these outcomes. Clearly, there were some co-morbid conditions in the
hysterectomy group that may have made them more likely to experience
complications. We found, however, that in controlling for this, the odds
ratios still showed that there was significantly increased risk of
dermatologic, gastrointestinal CNS and pain adverse events in the group
undergoing hysterectomy compared to the group undergoing focused
ultrasound.

Again, we wanted to look at the significant clinical complications to
make sure that we captured significant events, and again use the
literature to prospectively define this. We found that the patients
undergoing hysterectomy were more likely to have a significant clinical
complication with about 46 percent of the group in the hysterectomy
group having an adverse event, as opposed to 12 percent in the focused
ultrasound group.

One of the interesting comparisons is looking at fever and antibiotic
use, given that the patients in the focused ultrasound group did not
receive prophylactic antibiotics; whereas, the patients undergoing
hysterectomy traditionally did. And still, the incidents of fever and
antibiotic use started after the prophylactic antibiotics for presumed
infection were lower. The transfusion rate was also low. There were no
unintended surgical procedures, no discharges with appliances. There
were several rehospitalizations, but none requiring interventional
treatment, and no death or life-threatening events.

We also found that there were differences in \-- there were significant
differences in clinical complications. And our most serious adverse
events included device-related adverse events; that we found that there
were several instances of leg pain, which again we had identified as an
anticipated event. There were also some skin burns, although most were
first and second degree burns that resolved easily.

Our most important device-related, and our only device-related SAE
involved a patient who had a treatment where there was injury to the
sacral nerves. I think this is the case that pointed out to us the
importance of having patients talk to us about their pain and
discomfort. And that this patient did not receive pain medication at her
request, and was noted at post treatment time to have weakness and nerve
conduction studies confirmed injury.

However, by 12 months she has resumed a high level of physical activity,
and in fact has run a marathon since her treatment. She had significant
symptom improvement, and continues to be a part of our study.

We also put in a number of steps to mitigate the risk of nerve damage.
As Dr. Tempany talked, there are several things that can be done in the
treatment planning and the use of feedback from the patient. Since we
instituted these measures, there\'s been no significant nerve injury,
and the incidence of nerve injury has been minimal. So we also did a
number of simulations that allowed us to look at this issue. And so
again, we had one event since learning from this important case.

Looking at the serious adverse events, again we classified everyone that
was hospitalized as having an adverse event, an SAE, even if it was felt
not to be device or procedure-related; again, sacral nerve injury,
nausea. And then there were four women that went on to additional
therapy, which we felt was really progression of disease and not
device-related.

There is one complication on commercial treatment that resulted in a
patient death. A single patient in one of our outside the U.S. sites had
a pulmonary embolism following commercial treatment. This was
investigated by the local M&M committee, and it was felt that her death
was not related to the procedure. And in fact, in retrospect it turns
out she had several important thrombotic risk factors that had not been
identified.

We do have a continued access protocol, and have continued to treat
patients. It\'s very similar to our pivotal study with mild changes in
the treatment parameters that allow slightly increased treatment time
and treatment volume. And we\'ve been enrolling patients in this
protocol since April of \`03 with 89 patients treated to-date. The
adverse events in this group have been significantly less than in our
pivotal study, and indicate that our mitigation steps have been
successful. And we don\'t have enough of these patients to six months to
comment on efficacy, but the three month efficacy appears similar to the
pivotal study.

So in summary, we only had one device-related SAE, and a low incidence
of adverse events. We confirmed that this treatment can be safely
performed as an out-patient, and have learned from our experience to
design a safer study protocol.

We also found that we met our primary efficacy point with a significant
margin. We had a much lower symptom severity score than we had
predicted, and all of the measures of improvement tend to move together
to show patient improvement.

I\'ll turn the program over to Rob to talk about the training.

MR. NEWMAN:  I\'d just like to speak briefly to amplify on the
information that\'s in the panel packet about the training program. We
believe that this is truly a non-invasive surgical alternative. This is
a scalpel of sorts, a non-invasive one, but it is a scalpel. The
physician controls the delivery of therapy, and the system provides the
ability for real-time interactive control of that looking at the results
from the treatment itself.

The system works only a 1.5T MRI system. We believe that this is
necessary. It\'s the current state-of-the-art for pelvic imaging for
assessment of anatomy and pathology. And it also gives us the image
quality that we need for accurate temperature measurements. These
symptoms have a high level of service, and are in wide use throughout
the medical community.

This system will only be used under the direct supervision of trained
physicians. This is not something that would be used by anybody else. We
believe that the gynecology and radiologic expertise is required, and
the nursing requirements for these kinds of treatments are similar to
what is currently being used in hospitals for regular interventional
radiological interventional control, so there\'s nothing unique about
that part of the treatment.

The training for all installations will include the entire team,
doctors, the MR technologists and nursing. It\'s divided into two
phases. One is the system operation, the technology side of it. The
other part will be the clinical issues, which will be covered by
preceptorships at clinical sites involving topics of patient selection,
treatment planning, anesthesia, adverse event management and those kinds
of things.

First, treatments will be supervised. And on our system, every
sonication on our system is recorded and kept in a file, so we have a
log of every treatment we\'ve ever done. This allow us both to review
prior treatments if you had an adverse event, or if you\'ve had
something interesting. It also builds us a continuously growing teaching
file that we can use for future sites.

Just a brief overview, the kinds of things would be what you expect we
would cover in the classroom part of it on system components, and the
physiology, device, protocol development, and we would follow this up
with training after the procedures have begun at a specific site.

InSightec has a continued commitment to studying MR guided focused
ultrasound. We think that this is \-- there\'s an ongoing process here,
a lot we can learn. As we\'ve described before, we have the continued
access protocol is in progress. We\'ve treated 89 of 250 patients, and
we intend to complete that 250 patients and collect three-year follow-up
data on them to look at \-- to gather more data on safety and efficacy
of the system. And will provide us a lot of information on improvements
in treatment planning, and ways to make it more effective. And we also
have additional studies ongoing outside the United States, and will
include the analysis of that in our development of future features.

DR. STEWART:  So in summary, I think we\'ve demonstrated to you that the
device that we\'re presenting has a low risk of serious adverse events.
We were very careful to try to capture all events that occurred, and to
report as completely as we could to make sure that this novel technology
did not have any unintended side effects that we were missing.

One of the important issues with this technology is that it is
fibroid-specific. And I think that that has benefits beyond what we\'ve
demonstrated today. The risk of complications is significantly lower
than hysterectomy. And I think if we had chosen other control groups, we
would have probably been able to demonstrate significant differences
with other treatment modalities.

We\'ve had a very low incidence of device-related events. And because
this technique employs conscious sedation rather than anesthesia, there
is also a decreased risk of anesthesia-related events.

We have seen a clinically significant improvement in these patients.
Patients are very vocal about voicing their improvement with this
treatment, and we have been able to capture that by a number of
different modalities. We designed our study and well-exceeded both our
primary and our secondary end-points. And to be able to gain this kind
of improvement without surgical incision, without major disability I
think is a major step forward. The fact that these procedures can be
performed as out-patients is important, as is the fact that it preserves
the uterus.

Many women, I think, with fibroids tend to live with their symptoms
rather than go through some of the treatment options. Some women have
significant disability that they put up with day in and day out because
of their concerns regarding invasive therapies. And I think MRI guided
focused ultrasound surgery gives us an important new choice, and an
important choice to help reduce the symptoms of uterine fibroids for
women. Thank you.

DR. NOLLER:  Thank you. We very much appreciate the sponsor staying
within their time limit.

Our next presentation will be by the FDA. By the clock we are using up
here, it is now 10:13. We will take a break until 10:30 by this clock,
for 17 minutes, and then the FDA will make their presentation.

(Whereupon, the proceedings in the above-entitled matter went off the
record at 10:07:53 a.m. and went back on the record at 10:26:03 a.m.)

DR. NOLLER:  Okay. We\'ll reconvene now, please. And again, I\'ll ask
the panel to hold its questions until after the FDA presentation. At
that time we will I think have about 30 minutes to formulate and ask
some questions. I\'d like to introduce Kathryn Daws-Kopp, who will lead
us through the FDA presentation.

MS. DAWS-KOPP:  Good morning, ladies and gentlemen, distinguished panel
members and guests. I\'m Kathy Daws-Kopp, the Lead Reviewer for FDA on
this PMA. My presentation will give a brief overview \--

DR. NOLLER:  Excuse me. Turn to the sound up. We can\'t hear her.

MS. DAWS-KOPP:  Okay. Good morning. I\'m Kathy Daws-Kopp, the Lead
Reviewer for FDA on this PMA. My presentation will give a brief overview
of FDA\'s review process on this PMA to orient you for the remainder of
the FDA presentations.

You may notice as we go through our presentation that you\'ll be hearing
some of the same things that the company said. Our intention is to focus
on the issues we felt were important in our review of the file.

I\'ll start off by describing the history of regulatory interactions
with the company, and I\'ll describe components of the device from a
regulatory perspective. I\'ll provide a list of the PMA review team, and
briefly discuss what we did in reviewing the PMAs, and I\'ll follow that
with a list of some major issues that are still ongoing with this
review, some of which are part of the panel discussion questions.

I\'ll close with an agenda of the remaining FDA topics and presenters.

This is a brief overview of the history of FDA review on this device.
The sponsor first came to FDA with a feasibility study in 2000. That
file was reviewed by another branch in FDA, the General Surgery Devices
Branch, who consulted with us on the file.

In late 2001, our branch took over review and the sponsor came to us to
discuss a pivotal study. The study was given conditional approval in
March of 2002, followed by full approval in May. We worked with the
company on the protocol, and the study includes as you\'ve heard both
U.S. and foreign sites.

In 2003, when they had completed enrollment of the pivotal trial, the
sponsor requested permission to conduct a continued access study which
allows the company to continue to enroll patients while they\'re working
on preparation of a PMA, and while the PMA review is ongoing.

For a number of reasons, the proposed protocol for the continued access
study differ somewhat from the pivotal study. The continued access study
was given conditional approval in June of 2003, and full approval in
August. We received the PMA submission on January 27^th^, 2004, and I\'d
just like to note that that file received expedited review status.

The ExAblate system is made up of the following basic components;
patient table, operator workstation, software, equipment cabinet. The
patient table is a standard MR table that has been modified to house the
ultrasound transducer and associated equipment, and was already
described by the company.

It should be noted that the MR system is a commercially available GE
device, the Signa 1.5T MRI system is not commercially approved for
thermography at the site. Software in the ExAblate device uses MR
information from the GE device for mapping and targeting, as well as
these new thermography functions.

This is the indication for use the company has already presented, but
we\'d like to go over this again. ExAblate is intended for use in pre
and peri-menopausal women with symptomatic uterine fibroids. Patients
must have a uterine size of less than 24 weeks, and be family complete.
The fibroid or fibroids to be treated must be visible on non-contrast MR
and should enhance on contrast MR imaging.

This is a list of the review team. As you can see, a number of people
have been involved in the review of this PMA application in the areas of
clinical, statistical, epidemiology, MRI, ultrasound software,
bioresearch monitoring, patient labeling, human factors, and
manufacture.

This slide lists the things that we look at during our review. For
software and hardware we look at safety and effectiveness. Examples of
safety issues for software and hardware include electric shock, EMI
shielding, and unintended burns. Examples of effectiveness are adequate
targeting and thermal dose delivery.

We specifically look at requirements in testing. We check to see that
the device is designed to do what the sponsor or manufacturer says it
will do. And we look to see that they do tests that check to see that it
works the way it\'s supposed to.

For bioresearch monitoring, we look at study execution, including
recordkeeping and informed consent administration, as examples. For
manufacturing, we look at compliance with design controls both included
in inspection. Bioresearch monitoring inspects clinical sites, as well
as any records related to the conduct of the trial at the sponsor\'s
facility. Manufacturing connects an inspection at the manufacturing
facilities.

Bioresearch monitoring inspection is common for clinical trials, but is
not required. A pre-approval manufacturing inspection is required. Drs.
Corrado and Del Mundo will address clinical and statistical reviews
during their presentations.

This is a list of our current major ongoing issues. This is not a
comprehensive list of all issues. We are still discussing the thermal
accuracy of the system with the company. Dr. Loren Zaremba will discuss
this further in his presentation. We\'re still discussing adverse events
that occurred, and appropriate medications to employ in response to
these events. This will be discussed further by Dr. Noel Del Mundo. We
will also discuss how the treatment in control groups differed, which
Dr. Corrado will be discussing in her talk.

A pre-approval inspection is required, as I mentioned. FDA is working to
get this inspection completed in a timely manner. Review of the labeling
for a device is an integral part of the scientific review; however, we
do not complete our review of labeling until we have finished the rest
of our review of the file. These last two items, inspection and labeling
will not be discussed further by other presenters today.

The rest of FDA\'s presentation will proceed as follows. Dr. Corrado
will provide a summary of the clinical study and results. Dr. Zaremba
will discuss the MR thermal mapping review. Bruce Herman will discuss
the ultrasound-related review concerns, and Dr. Del Mundo will close
FDA\'s presentation with a safety analysis discussion that will cover
what we have considered most significant adverse events. Thank you for
your time and attention, and I will now turn the floor over to Dr.
Corrado.

DR. CORRADO:  Thanks a lot, Kathy. Good morning, everybody. I\'m Julia
Corrado, and I\'m a member of the review team.

You have all already heard about the clinical trials of ExAblate from
Dr. Stewart and Dr. Tempany, and I am going to be covering some of the
same material, but I\'m going to try to give an FDA perspective on that
material. And I will try very hard to avoid unnecessary redundancy.

I\'m going to be starting with a brief description of the feasibility
study. I will then describe in more detail the pivotal clinical study,
and the aspects of that study as you see here. And finally, I will give
a very, very brief synopsis of the continued access study.

I\'d just like to say who the \-- normally we don\'t spend much time
talking about the feasibility study at panel meetings, but this one was
especially important because it signaled to us a couple of aspects of
this treatment that we really wanted to scrutinize closely when it came
to the pivotal study.

This feasibility study was prospective. It was non-randomized. It was
conducted at two centers, and I\'ll just digress for a second. Dr.
Stewart described five centers. There was an IDE pivotal study that was
conducted under FDA approval, and that was conducted at a center in the
U.S. and one in Britain. And I\'m speaking just about that feasibility
study in my next couple of slides.

It was a pre-hysterectomy study. The women who volunteered were
scheduled for hysterectomy, but they agreed to undergo the ExAblate
procedure approximately a month prior to hysterectomy. And we approved
the study for 15 subjects and 13 subjects received treatment.

The objectives were already described by Dr. Stewart. There were, in
general, two types of tissue effect that are noted from ExAblate. I
won\'t speak about them further, but there is a thermal coagulative
necrosis and then there is an ischemic necrosis. The difference is that
the thermal coagulative necrosis is caused by direct heating, and the
ischemic necrosis results from lack of blood flow to surrounding tissue
following heating.

In the summary of the feasibility study, the pathologist from Brigham &
Women\'s described the tissue effect as follows; that the volume of
necrosis was sometimes larger than the treated area. That\'s a very
important point that I\'m going to be emphasizing. The treatment effect
consists of bland and highly uniform coagulative-type necrosis with
relatively sharp outline, scattered interstitial hemorrhage, and
variable amounts of acute inflammation consisting mostly of neutrophils.

The next point also should be noted, and that is that the only
abnormality noted in the myometrium outside of the fibroid, this was
beyond the fibroid capsule, was microscopic coagulative necrosis
extending one to two millimeters beyond the fibroid. This is the only
case where we saw this effect, that there was a treatment effective
beyond the fibroid capsule. But nevertheless, we thought it was
important, as I\'ll describe further.

The purpose of the next slide is to illustrate something I just hinted
at, and that is that the volume of effected tissue is different from the
thermal dose volume; that is, the volume that was actually targeted. And
there are two volumes that we can talk about from the feasibility study.
One is the non-profuse volume immediately following treatment. This is
on, I believe, T1-weighted images with Gadolinium enhanced MRI. But also
from this population, most of these women underwent hysterectomy so we
also have volumes from hysterectomy specimens. And what I\'d like you to
notice here is that there is a consistent \-- the non-profuse volume and
the volume from histology are consistently greater than the thermal dose
volume, which led us to feel that we wanted to be cautious in how the
pivotal clinical study was conducted because we did not want to get
injuries resulting from tissue necrosis beyond the targeted area.

As always, as we would expect during any kind of a clinical study of an
investigational device, problems were encountered during treatment. For
example, several patients received what was described as sub-optimal
treatment due to excessive fat layers within the beam path. And in one
case, the portion of the fibroid that the clinician wanted to treat was
too close to intestine, and that limited treatment in that case. In
three cases, patients did not receive treatment due to tissue aberration
and scar in the beam path that caused the patient to experience pain.

FDA, of course, always looks closely at adverse events and clinical
trials, and we saw the following. But before I go into these adverse
events, let me just note that despite that enhanced volume effect that I
have described, we did not see any evidence of thermal injury to tissue
adjacent to the uterine serosa, and this is one of the types of adverse
events that we always watch very closely in devices that treat uterine
pathology, so we did not see any such adverse events.

What we did see was bleeding post ExAblate, two first degree skin burns,
a couple of cases of nausea and vomiting, and some post-hysterectomy
adverse events that we would not be able to argue were related to the
treatment. They were probably related to the hysterectomy.

As Dr. Stewart mentioned, there is also feasibility data from outside of
the United States. And interestingly, in this study although 56 patients
received the ExAblate treatment, only four of those patients elected to
undergo hysterectomy, and that was as of 14-month follow-up. So there is
relatively less hysterectomy data from this feasibility study
population.

The next couple of slides I\'m not going to spend much time on, but I
would just like to say that they demonstrate a trend, at least, towards
non-profuse volume being greater than the thermal dose volume, although
it was not uniform as it was in the smaller feasibility study conducted
at Brigham & Women\'s and at St. Mary\'s in London.

In the feasibility studies that were conducted in Israel, again this was
not conducted under FDA IDE regulation. However, there was one adverse
event that in hindsight we probably under-appreciated at the time, and
that was a case of sciatica post treatment. This patient had symptoms as
of three weeks following her treatment, which at that time were
described as improving, and at that time she was referred to a
neurologist. I\'m going to at least allude to this adverse event later
in my discussion.

Dr. Stewart described the IDE pivotal study of ExAblate, and I\'m not
going to repeat what she said, nor will I repeat the primary and
secondary hypotheses, with the exception that I want to note that the
secondary hypothesis here, which was in valuation of the trajectory of
recovery in the two treatment groups. The sponsor has already described
this. I am not going to talk about that any further.

Now FDA worked with the sponsor on the pivotal study design, and we
really perseverated on what we consider to be potential for adverse
events with this device. We were nervous about the potential for tissue
necrosis of non-targeted tissue; in particular beyond the uterus of the
necrosis of tissue up adjacent to the uterus, so we worked with the
sponsor to establish a very conservative treatment planning program. And
the list of items that contributed to this was already discussed by Dr.
Stewart. But, for example, we felt that because this is a very new type
of technology combining MRI thermography and focused ultrasound, and
because we have seen this volume effect that was greater than the
targeted volume, we felt that it would be prudent to begin here with
limiting the volume of tissue that could be targeted both within
individual fibroids and within the entire uterus.

I also want to add an important point here. Our concern at the time that
we were reviewing this IDE for the pivotal study was in what I would
call near-term thermal damage. We were not, at the time, sensitive to
the fact, or that we might get treatment effects in the far field. That
is beyond the area of focus, so that\'s going to be important later in
my talk, and critical when you hear from Dr. Del Mundo later this
morning; that we did not appreciate the potential for effect in the far
field.

Very generally, I\'d like to just reiterate a little bit about the
baseline demographics between the two populations. There was no
difference in age, essentially. The body mass index was higher in the
hysterectomy group. There was a significant difference with respect to
race, and with respect to other chronic disease, there were some
differences between the ExAblate arm and the control arm. And
specifically, women in the control arm had significantly greater
prevalence of diabetes mellitus, hypertension, and anemia.

I just want to make a couple of simple points with respect to this
slide. First is that you\'ve heard about the symptom severity score of
the uterine fibroid symptom quality of life questionnaire. It was the
subset of that questionnaire, the symptom severity score that formed the
basis for the primary endpoint in the study and the definition of
success of the study.

There were, however, two scores that were taken prior to treatment.
There was a screening score to determine whether or not a patient was
eligible for the study. And then there was a score that\'s called the
baseline score. That\'s in maroon color on this slide. And that baseline
score formed the comparison for the six-month evaluation, so the
screening score was only relevant to get into the study. After that, it
was the baseline score that was relevant to the study success. But we
thought that it would be interesting for you to see that even before
treatment, there were subtle differences in the scores that were derived
from that questionnaire.

And what this slide simply shows is the distribution. Right in the very
middle of the X axis you see the word \"unchanged\", and right above
that \"zero.\" And what this means is the 23 subjects had no change in
score between that screening questionnaire and the baseline
questionnaire. Beyond that, there is a very roughly equivalent
distribution on either side of zero, but nevertheless, you can get the
feeling for actual numbers of subjects whose scores changed by a
particular range of points prior to treatment. Again, this is all prior
to treatment. And we think that this will give you a feel for the
stability of the scoring instrument.

Okay. Now I would like to change gears a little bit and talk about study
success. And I just want to mention that there are two ways to look at
study success. Intent to treat has a very strict definition.
Essentially, it is all patients enrolled and treated, and all of these
patients must be represented in calculating the percentage success.

Evaluable is a different way of looking at it. The rules for an
evaluable analysis are not, frankly, as tight as they are for intent to
treat, but what evaluable permits one to do is to not be penalized by
counting subjects as failures who one can argue really shouldn\'t
strictly be viewed as failures. But, nevertheless, from the most strict
definition standpoint, intent to treat, the percent success was 70.6.
Remember that the primary hypothesis was that greater than 50 percent
would improve by a score of 10 points or better at six months. And the
70.6 is well within the 95 percent confidence interval. It\'s well above
50 percent.

And this slide again indicates that for those subjects who achieved
success, you can get a feeling for how many of them met that primary
endpoint and by how many points. And what this also shows you is that
there were some subjects whose scores were considered unchanged, and
then some whose scores were considered worse. And just because often we
are interested in well, what happened with those failures, I\'m just
going to try to give you a quick rundown for the population at six
months for whose scores worsened and whose were unchanged.

Among patients who were considered to have worsened scores were two
treatment failures. These subjects underwent hysterectomy. Two patients
withdrew, and subsequently one had hysterectomy. One withdrew. She had
an aborted treatment, but nevertheless, she had a worsened score. One
subject was lost to follow-up, and had no six month quality of life
data. Seven women in this category completed treatment, and they had
actual worse scores following treatment at six months.

Unchanged is a little bit different the way we look at that. We asked
the sponsor to consider seven patients to have had zero change who were
treated with protocol deviations, because we felt that the success rate
for \-- we feel that the success rate for any study ought to reflect
patients who are treated according to the strict rules so that we can
write meaningful labeling, so the clinicians can understand what they
might expect. And that it would be inappropriate to have the results
reflect women who were treated outside the bounds of that treatment
protocol, so that explains seven of the subjects with unchanged scores.
Two had no six-month data, and one actually had no score change.

And I should have mentioned, we have a patient tree in your day-of
folders, and it might help you if you\'re interested in looking at those
numbers more closely in understanding what patients from the original
intent-to-treat populations fell into which categories.

Now I\'d like to just talk about patient satisfaction. You\'ve heard
from the sponsor about overall grouping of patient satisfaction and the
ExAblate group in general had high levels of satisfaction. What I wanted
to do here was just give you a slightly different perspective, and in
the interest of doing that, here you can see satisfied being broken down
into three different categories, very moderately in some. And similarly,
patients who describe themselves as dissatisfied, what level of
dissatisfaction did they experience. And for very satisfied, the point
here is that the hysterectomy subjects at six months were significantly
more apt to say they were very satisfied, compared to the ExAblate
group, which is probably not surprising because the hysterectomy
subjects did receive definitive treatment for their fibroids. But
nevertheless, we think that it\'s important to keep perspective when
you\'re thinking in terms of patient satisfaction. There are degrees of
satisfaction, and they did differ between the two groups.

Now at 12 months, you\'ve heard that both the intent-to-treat and the
evaluable success rates dropped. I should preface this by mentioning
that when the study was designed, FDA had a different understanding
regarding the length of follow-up than the sponsor had. And it was a
misunderstanding. We expected three years of follow-up. The sponsor
believed that they were expected to follow the patients through six
months, so in all honesty, we informed them very late in the pivotal
study that they would be required to follow-up these patients for up to
three years. And it created some difficulty for them in terms of
tracking down patients, and asking patients if they would continue to
participate in the study, so I think it\'s only fair to mention that.
And that helps to put some perspective on the next slide where I talk
about some of the women who were not successes at 12 months, in part
from an intent-to-treat analysis. If they declined to participate,
they\'re considered failures; withdraw or lost to follow-up,
non-evaluables.

Significantly, though, we think it\'s important to note that 23 women
did have alternative treatment as of 12 months, and many of these women
had hysterectomy by 12 months. Four of them had a second ExAblate
treatment.

You\'ve already seen Dr. Stewart\'s slide that covers this material.
There are a couple of things that I just want to highlight. One is that
the percentage of non-perfused volume of 23.6, that was the average
percent of non-perfused volume that is immediately following the
treatment. And then at six months, the volume of the treated fibroids
was measured, and the percent shrinkage of the treated fibroids was 15.3
percent.

In looking at these numbers and thinking about them, it\'s worthwhile
again to think about the fact that the treatment guidelines for the
ExAblate procedure only permitted the sponsor to treat up to 33 percent
of any individual fibroid, and only up to 100 Ccs in any one fibroid up
to 150 Ccs for an entire uterus, so I think that part of what we\'re
seeing there reflects the conditions of the treatment.

You all have in your folder a list of discussion questions that you\'ll
be talking about after lunch, and I want to bring to your attention
Discussion Question 1 now, because it relates to some of the things
I\'ve been talking about. And it asks you how you view the symptom
severity scale of the UFS-QOL as the instrument that was used to measure
the primary endpoint in the study, or that was used to determine study
success.

I\'d also like to draw your attention now to Discussion Question 2, just
to kind of plant the seed that this afternoon you\'re going to be
talking about essentially whether the study demonstrated the
effectiveness of the procedure. And in making that assessment during
that discussion, FDA would request the panel would consider the results
from the symptom severity score. And also, couple that with the clinical
results of actual volume reduction in making your decisions.

I\'m going to change speeds once again now, and briefly talk about
safety-related aspects of the procedure. But I want to preface this by
saying I am going to ask you to focus at the end of my discussion on two
types of adverse events, and they were skin burns and nerve injuries.

As Dr. Stewart described, we worked with the sponsor prospectively
before they started the pivotal study to identify what we thought would
be a legitimate list of adverse events or complications against which to
compare the two study populations. And the result of that comparison,
not very surprisingly, showed that there were relatively fewer of the
significant clinical complications in the ExAblate group compared to
abdominal hysterectomy patients.

There were some other adverse events that are possibly more relevant to
the ExAblate procedure, and those are pain and discomfort, in
particular, during the procedure, menorrhagia post procedure, urinary
symptoms, nausea and vomiting. And then the last two, skin burns and
nerve injury that we do believe are unique. We believe that these are
unique to this procedure, to ExAblate.

And I just want to conclude my discussion of the safety evaluation in
the pivotal study by pointing out that in Discussion Question 6, you\'re
going to be looking at the relative safety of two procedures, ExAblate
compared to total abdominal hysterectomy. We just want you to include in
your deliberation, or at least address the differences between the study
arm and the hysterectomy arm at baseline, because there were some
differences, and provide your input to FDA with respect to how
comparable these two groups are, and what types of conclusions we might
be able to reach or not reach regarding relative safety of ExAblate
versus total abdominal hysterectomy.

Now as you\'re aware, the sponsor has permission to continue to treat
patients with the device, although the pivotal clinical study is over.
And of the aims of this, in addition to allowing continued access, was
to modify the treatment planning in addition to improving long-term
follow-up. But we wanted to essentially liberalize the parameters for
treatment, and you can see that the sponsor is now allowed to treat up
to 50 percent of an individual fibroid volume, as long as it\'s not a
sub-serosal fibroid. And the 15 millimeter margin, in retrospect,
didn\'t make much sense with respect to the endometrium, so that has
been eliminated. In addition, the sponsor may perform one additional
treatment session. And as you see, increased maximum duration of the
treatment.

As of March, 89 patients had been treated. The baseline demographics are
similar to the pivotal study, but there are three months safety data
available on only 53 to 54 subjects, so it is these subjects who have
been followed up for at least three months who are going to be discussed
by Dr. Del Mundo.

The preliminary efficacy data are good, 79 percent reported 10 point
improvement in their symptom severity score.

In the continued access study to-date, there have been two instances of
sonication-induced leg pain, and the significance of these events,
whether or not they are nerve injuries, will be described by Dr. Del
Mundo.

In conclusion, I have attempted to give you an overview of the
effectiveness of the device as seen in the pivotal clinical study, and
to a limited degree discuss the safety profile of ExAblate as FDA
understands it at this time. I have indicated to you that two types of
adverse events appear to be unique to ExAblate, and that is skin burn
and nerve injury. And as you recall, there was a nerve injury even in
the feasibility population, but at the time, that was a case of
sciatica. At the time, we did not appreciate how it might be related to
this device.

Before Dr. Del Mundo presents a detailed FDA analysis of those injuries,
Loren Zaremba and Bruce Herman are going to discuss for you the physics
of MRI thermography and focused ultrasound, and the results of some
modeling, and how modeling can help us understand the potential for
heating of tissue in the far field using ExAblate. Thank you very much.

DR. ZAREMBA:  Good morning. My name is Loren Zaremba. I\'m an MR
reviewer in the Radiology Branch, Office of Device Evaluation. This
morning I will be discussing the role of thermal mapping in the focused
ultrasound of uterine fibroids using the ExAblate 2000. I will discuss
the advantages and limitations of MR thermal mapping, and the safety and
reliability concerns with respect to the use of MR thermal mapping for
this intended use.

MR thermal mapping provides three major functions in the ExAblate 2000.
First, it allows adjustment of the ultrasound focus location. This is
done by obtaining an image of the temperature distribution produced by a
low power sonication. Second, it provides a measurement of the
temperature distribution during the treatment procedure. Third, it
provides feedback which enables the user to adjust the power following a
sonication if the temperature was too high or too low.

Temperature measurements are necessary with any type of therapy which
uses heating. Previous devices, such as those approved for hypothermia
have used temperature probes. The ExAblate uses a new approach, MR
thermal mapping, which has the advantages that it does not require
surgical implantation. It can be integrated with the MRI system, which
is used to visualize the uterine fibroids, and it provides a temperature
over the full MRI field of view, not just a few points.

Also, unlike temperature probes, it does not cause heating at the probe
tissue interface which can lead to an overestimate of the temperature
with those types of probes if they are not corrected.

The limitations of MR thermal mapping are, first, it does not measure
the actual temperature, but change in temperature. Second, it cannot
make measurements in bone or fat. Third, a very small amount of motion
by the patient during the three seconds required for MR thermal mapping
can spoil the measurement. Four, MRI thermal mapping has lower time and
spatial resolution than temperature probes. And five, calibration can
present some difficulties.

I want to direct your attention to the Discussion Question 3, has the
sponsor demonstrated the MR thermal mapping provides adequate
interoperative feedback during treatment regimen to ensure safe and
reliable dosing to the intended fibroid?

With regard to safety, we have these considerations; can temperature
measurements be made in all regions of interest? Are they sufficiently
accurate? Can they be made in time to allow adjustments? And with
respect to reliability, how frequently does thermal mapping fail? If it
fails, is adequate backup provided?

With regard to the first safety factor, the ability to measure
temperature in all regions of interest, the critical data showed that
the ExAblate is capable of measuring temperature in the principal region
of interest, the uterine fibroid, and in most surrounding tissues.
However, it cannot measure temperature in the sacral nerves due to the
fat surrounding these nerves ,and also near the bone tissue interface
where heating can be intensified due to the very high ultrasound
absorption by the bone.

In a later presentation, Dr. Del Mundo will discuss the adverse events
during the clinical trial that may be related to nerve heating. Since MR
thermal mapping cannot provide the answer, we must rely on thermal
modeling to estimate nerve and bone heating. The next speaker, Bruce
Herman, will discuss the modeling and results that have been done by FDA
with respect to nerve and bone heating.

Accuracy is relevant to the evaluation of the ExAblate 2000 because if
an incorrect reading of temperature is given to the user, they could
adjust the power level higher, which could result in injury, or lower,
which could result in inadequate treatment. MR thermal mapping measures
the temperature change not temperature. The ExAblate assumes that a
sufficient time has elapsed following a sonication that the temperature
has returned to a baseline of 37 degrees Centigrade. The company
recommends that the user wait 90 seconds before initiating the next
sonication to allow the temperature to return to baseline. However, this
can be adjusted by the user.

If an adequate cool-down time is not selected, the heating induced by
the previous sonication will add to that induced by the current
sonication, but this will not be shown by the thermal map. This is of
particular concern with regard to the sacral nerves because modeling
shows that the return to baseline may take longer in the nerve region as
will be discussed in the next talk.

A second issue relating to accuracy is temporal or time resolution. This
is just the amount of time it takes to make the measurement compared to
the heating period. The ExAblate requires a little over 3 seconds to
obtain a thermal map. The fibroid can be heated very rapidly, and
temperature can rise 10 degrees in the time needed to obtain a thermal
map. And the MR thermal mapping, the result is the average temperature
rise during measurement peak rather than the peak. For all measurements
but the final one prior to the termination of the sonication, the
ExAblate assigns the temperature to the midpoint of the measurement
interval, which partially corrects for this. However, this is not done
for the final sonication.

The third issue relating to accuracy is spatial resolution. In MRI, this
is determined by pixel size, which is about 1 millimeter by 2
millimeters for the normal ExAblate field of view. Focused ultrasound
produces very high temperature gradients, which means the temperature
falls off very rapidly with distance from the focus. Thermal mapping
averages the temperature over a pixel, and that could result in an
under-estimate of the maximum temperature for a small focal spot, or an
under-estimate of the size of the region ablated by sonication. However,
for the large group of spot sizes normally used in treatment of uterine
fibroids, this is not a serious concern.

The last issue relating to accuracy is calibration. In the case of MR
thermal mapping, calibration enables us to translate the observed change
in proton resonant frequency with temperature into the temperature
change. In the ExAblate, the calibration factor relating the frequency
change to temperature change is assumed to 0.009 parts per million per
degree C, independent of the amount of temperature rise, tissue type, or
thermally induced changes in tissue.

A calibration for MR thermal mapping involves comparing the mapping
results with an independent temperature measurement method, such as a
thermal couple probe. Ideally, the calibration for the MR thermal
mapping used in the ExAblate should be done for uterine fibroids in
human subjects in order to derive some indication of the variations
between fibroids, subjects, and other conditions of treatment.

We have an in vitro study using tissue samples heated by a water bath,
which indicates a variation of 3 degrees. And we have an in vivo
calibration in rabbit muscle which indicates a variation of 10 degrees.

One of the purposes of MR thermal mapping is to provide feedback to
allow adjustment of the power following a sonication. However, there is
a delay in feedback from the thermal mapping. The temperature versus
time graph in the thermal ridges for a sonication are not displayed
until the sonication is complete. Consequently, a correction cannot be
made until the next sonication.

Among our reliability concerns is the fact that a very small amount of
patient motion can result in a loss of a thermal map. The temperature
measurement cannot be repeated because this would mean resonicating the
same spot.

The failure rate for thermal mapping appears to be quite low. InSightec
estimates it is only about 4 percent, and since the treatment consists
of a large number of sonications, this may not be a concern. The user is
instructed to check the fiducial markers to determine if movement was
sufficient to affect the treatment.

Another reliability concern is the availability of an alternate means of
assessing its effects over the treatment; i.e., a backup method. If the
thermal maps are lost, the so-called magnitude images may not be
adversely affected. Magnitude images display signal strength and are not
as sensitive to motion as thermal images. However, the magnitude images
may be of limited usefulness in displaying the effects of the sonication
on fibroid tissue. The final confirmation of the effect of the treatment
is contrast enhanced image obtained after the treatment.

In summary, MR thermal mapping provides significant advantages over
other available technologies in that it is non-invasive, can be
integrated into MRI system use to visualize the pathology, provides a
thermal map over the full MRI field of view, and does not interact with
ultrasound. The major limitation is that it cannot measure temperature
in bone or fat, which prevents estimation of the heating of the bone and
sacral nerves in the far field. The limitations associated with
sensitivity to motion and lower temporal and spatial resolution are not
serious. And the calibration of the method can probably be improved with
additional studies.

I would now like to turn the discussion over to Bruce Herman, who will
describe the thermal modeling that has been done.

MR. HERMAN:  Hello. My name is Bruce Herman. I\'m a Physicist with the
Office of Science and Engineering Laboratories within CDRH. I\'ll be
discussing the thermal effects distal to the focus using the ExAblate as
regards possible adverse thermal effects. My presentation will not be an
exhaustive discussion of every concept that might affect the thermal
modeling, but I hope to give a relevant background and orientation.

I will be discussing the concept of thermal dose, some factors affecting
the temperature rise of the sacral nerve, and the bone, and the
so-called far field of the ultrasound beam. I\'ll be talking about the
limitations of the knowledge regarding tissue characteristics, which are
relevant to modeling the temperature rise in these structures. I\'ll
give a couple of temperature rise simulations, and I\'ll talk about the
limitations of these models.

As Dr. Zaremba mentioned, it\'s important because magnetic resonance
thermal imaging can not determine the temperature rise near bone or in
fat which might typically surround nerves, which means that theory,
i.e., modeling, plus, of course, clinical trial results are very
important to assess the safety.

In most biological systems for temperature rises \-- with temperatures
above 43 degrees, which corresponds to a 6 degree temperature rise
assuming the baseline temperature of 37 in the body, each temperature
rise of 1 degree C requires housing the exposure time to achieve the
same level of effect. If the temperature is a varying function of time
and T-43 is the time necessary to achieve an effect at 43 degrees CI, a
6 degree temperature rise, and the time necessary to achieve an effect
for a time varying temperature is given by this integral equation. It\'s
not just the peak temperature that\'s relevant, but the temperature and
the time over which a particular organ sees that temperature, which is
relevant to assess the propensity for any type of damage due to an organ
or structure.

This gives a report of thermal dose thresholds for cell damage for
certain tissue types. We receive for muscle, fat, and fibroid, typically
42 degrees C. The time necessary to see an effect is 14,400 seconds,
which corresponds to 240 minutes. At 51 degrees C, though, the time
required drops to 56 seconds, 53, 14, 55 degrees Celsius, to 3.5.

With more sensitive structures, such as nerve, colon, or intestine,
reported times for effects at 42 degrees C have been between 1,500 and
3,600 seconds. This corresponds to a time of 10 seconds at 51, 2.4
seconds at 53, .6 at 55. Rule of thumb might be for these more sensitive
structures, as you get into the lower 50s, you might begin to see some
type of damage.

Of course, for all these structures when you get to be above 65 degrees
C, the damage occurs almost instantaneously, and you get pretty much
ablation almost instantaneously, as has been mentioned in previous
presentations.

This slides shows - and it\'s not drawn to scale - shows the ultrasound
transducer focusing the beams with very high intensity within the region
of treatment within the fibroid. The beam distal to the focus then
spreads out, and the intensity is lowered both due to the spreading-out
of the beam, and due to absorption in the intervening layers.

In the far field of the beam, you might have a structure such as sacral
nerve surrounded by fat, and it might be near a bone. You can think of
the absorption in let\'s say the sacral nerve as a combination of two
types of phenomena; one, direct absorption in the nerve and in the fat
surrounding the nerve. And if it\'s near the bone, then since the bone
is such a highly absorbing material, as we\'ll see, it then will conduct
heat to the sacral nerve after absorbing a lot of the ultrasound energy.

As the nerve gets closer to the bone, this phenomena might become
prominent, predominant. And as, of course, it gets further away from the
bone but closer to the focus with higher intensities, the direct
absorption might be the predominant mechanism of temperature rise.

The temperature is a function of, of course, the local intensity, the
absorption of ultrasound by the structures, the incidence of the
ultrasound beam on the bone. I mention this because if an ultrasound
beam is normally incident on the bone, most of the energy is absorbed by
the bone. But if it\'s offset or comes at an angle greater than about 30
degrees to normal, most of the energy is actually reflected and not
absorbed, so the bone heating would not be a strong factor.

Of course, the beam restructures size, as we\'ll see is important. The
thermal characteristics of the tissue, such as thermal conductivity,
heat capacity are important, and the geometry, the size, how close one
structure is to another. I want to emphasize, basically it\'s a
complicated phenomena, multi-parametric phenomenon.

This slide shows the range of reported tissue absorption value. As you
can see, for various tissues, there\'s a wide range of reported values.
This is important because for a lot of structures, the direct
absorption, the temperature rise due to direct absorption is
approximately linear with the absorption value, how much of this energy
it absorbs.

Now these red diamonds are the values used by InSightec in their
modeling. Now they are commonly accepted values for tissue absorption,
do cluster around the red diamonds. But I wanted to emphasize that these
values, which will be used in modeling you\'ll see, come with very large
error bars.

We talked about that the size of a structure might be critical in
determining the temperature rise. This shows, for one, soft tissue
absorption model, that for the stated incident intensity, the
temperature rise after 20 seconds is a strong function of the dimensions
of the structure, for something on the order of 1 millimeter, .1
centimeters, the temperature rolls over very quickly. And after 20
seconds, the rise is not very great. Whereas, for a large structure,
such as the 3 centimeter structure, the temperature stays linear up to
20 seconds, and you get a much higher temperature rise. We use 20
seconds because that is the sonication time used by the ExAblate.

This is a simulation which was actually done by InSightec which shows
the temperature rise at a sacral nerve 3 millimeters from the bone, and
surrounded on all sides by 3 millimeters of fat. It utilizes a
focus-to-bone distance of 40 millimeters, which again, InSightec showed
a slide that showed this is the current protocol for use, to keep the
bone at least 40 millimeters away from the focus, and it uses a power of
250 acoustic watts. This is the maximum power that this transducer can
put out, so this is a worst, worst case.

The red curve shows the temperature right at the sacral nerve without
the bone and so gives an indication of the direct absorption, the
temperature rise due to direct absorption of energy, and the blue line
shows the temperature rise with both contributions, the bone and the
direct effect. As you can see, the temperature rise for this case get
into the mid-50s or the low 50s. But again, I want to mention that if we
assume a higher absorption than was used, this red curve could be quite
a bit higher than was assumed in this model.

This next, again an InSightec model, shows the same situation, but here
the protocol demanded focused temperature is equal to 85 degrees. Again,
the protocols currently demand that the temperature at the ablation
focus should be no greater than 85 degrees. And, of course, this would
consequently lower the total power needed. And this gives the
temperature rise again at that same sacral nerve with and without bone.

As you see, the temperature rises are lower. It goes from 37 to 41
without bone, and goes to about 44 with. But again, I want to emphasize
that the if the absorption values used are higher, these temperatures
will go up. If the sacral nerve is closer to the focus, let\'s say it
may be 13 millimeters away instead of 3 millimeters away, this bone
contribution will be less, but the contribution due to direct absorption
could be as much as 75 percent higher. Again, emphasize the complexity
of the situation.

Actually, I do want to mention the fact that we see that we have a 20
second sonication time and then a 90 second cool down time. And this
model shows that even after the 90 second cool down time in the far
field, there\'s still a significant temperature rise, which may mean
that if there is any overlap of two consecutive sonications on the bone
or on the structure, you might get some addition of temperature to the
second sonication from the first.

This is a model done by CDRH. This shows a temperature rise at the bone
tissue interface again for 85 degrees for the focus, and a focal bone
distance of 40 millimeters. It assumes no fat between the focus and the
bone, so the maximum energy hits the bone. Again, this has arised at the
bone tissue interface. As you can see, we have two consecutive pulses,
20 seconds on, 90 seconds cool down. Temperature rises can be very high,
so if by chance a nerve structure is right at the bone, it can
experience quite high temperatures due to bone heating. Again, a
significant temperature rise after the 90 seconds, so you might have a
partial additive effect if there\'s an overlap.

Again, I want to emphasize these last three slides assume normal
incidence of the ultrasound beam on the bone, meaning maximal energy
absorption by the bone. The current protocols used by ExAblate try to
maximize the angle of the beam on the bone to avoid this absorption by
the bone. And, of course, these temperature rises would go down
consequently if the beam did come in at an angle of 30 degrees or more
from the normal.

Okay. The factors that may cause temperature rises higher than those
models by CDRH or InSightec could be higher absorption values than
assumed, larger structures than assumed, structures closer to bone or
focus, possible inaccuracy of the temperature map at the focus. If it
reads low than a higher intensity to cause 85 degrees to the focus might
be used and is necessary, which would increase the intensity in the far
field. Incorrect thermal conductivity or heat capacity, and possible
overlap of consecutive sonications.

Now in conclusion, the modeling using generally accepted values for
tissues parameters, together with the discussed protocol caveats,
predict reasonably that thermal events of adverse effects in the far
field should be very rare. But given the range of imported and possible
actual variability of tissue values, the individual range of structure
geometries, the accuracy of MR, et cetera, this modeling in and of
itself does not allow adverse thermal effects to be totally ruled out,
which of course means that clinical results take on added importance in
assessing the accuracy of the modeling and the actual risk benefit. And
I gather that the clinical situation is consistent with these
conclusions.

As regards this, Dr. Del Mundo will shortly present specific adverse
effects that have occurred during use of the ExAblate, and will discuss
how we and InSightec have used this modeling to try to understand and
prevent such events. Again, as regards this also, you will be presented
with a discussion question for this afternoon. Basically the question
is, do the results from the thermal modeling and our understanding of
the underlying physics allow sufficient information to understand the
etiology of the injuries that occurred in the study and, of course, to
mitigate their occurrence? Dr. Del Mundo will now give his presentation.

DR. DEL MUNDO:  Thank you, Bruce, and good morning. I\'m Noel Del Mundo,
Medical Officer in the OB-GYN Devices Branch. I will be presenting the
safety analysis of sonication-related adverse events that occurred
during the pivotal trial.

I will focus on the description of the types and severity of skin burns
and nerve injuries that occurred during the pivotal trial. I will
provide the analysis of possible causes of the sonication-related
adverse events, and I will then go through the list of possible
mitigations to prevent each type of adverse event, and I will provide
the preliminary safety results from the continued access study in which
the mitigations were implemented.

Of the adverse events that Dr. Corrado had previously summarized for
you, the most notable sonication-related adverse events were skin burns
and nerve injuries. IN all, there were five first or second degree skin
burns during the pivotal trial. Improper acoustic coupling between the
skin and the gel pad can result in undesired heating of the skin. In
other words, any areas between the skin and the transducer that allows
for increased reflection of the ultrasound energy can cause heating of
the skin and possible skin burn. Examples are air bubbles present in the
skin folds and around the hair, oil between the skin and the transducer.

In all the cases of first and second degree skin burns, all patients had
hair in the sonication pathway. And also, early in the pivotal trial the
patient moved and decoupled from the acoustic gel, resulting in a first
degree skin burn.

The steps in the training manual to reduce the risk of skin burns want
the patient to shave the hair from the lower abdomen to two centimeters
below the pubic synthesis. The abdominal is cleaned with alcohol to
remove oil on the skin, and patient movement is limited with a table
strap. And lastly, the MR planning images are examined for air bubbles
at the skin-gel interface and for skin folds.

These steps were re-emphasized to the investigators during the pivotal
trial and prior to the continued access study. Preliminary results on 54
patients treated in the continued access study suggests that the
mitigations and retraining have reduced the incidents of skin burns as
no cases of skin burns have been reported.

I\'d like now to focus on the nerve injuries. These injuries have been
the subject of extensive review by FDA and InSightec. In all, there were
five cases of sonication-related nerve injuries during the pivotal
trial, and the patient\'s symptoms lasted anywhere from two days to
twelve months.

In addition to the five nerve injury cases, there were three cases of
what we\'re calling nerve stimulation. These cases differ from the nerve
injury cases in that the leg pain did not extend beyond the day of
treatment, but we think that in the continuum of unintended heating of
the nerve by unfocused ultrasound, these cases represent the mild form
of heating of the sacral and sciatic nerve in the far field of
treatment. This is a point that I\'ll get back to in subsequent slides.

Now getting back to the five cases of nerve injuries, InSightec analyzed
these cases and found that common to all five cases were the following.
Lower extremity pain was acutely felt by the patient during the
treatment. The distribution of pain is consistent with either sacral of
sciatic nerve injury. There was rapid onset of pain during the last
three to five seconds of sonication, and the sacral nerve or sciatic
nerve bundle was identified in the far field of the ultrasound beam.

There appears to be varying degrees of peripheral nerve injuries related
to sonication. A mild effect is nerve stimulation resulting in leg pain
which resolves the day of treatment. The next degree of effect is nerve
injury resulting in the interruption of nerve function without anatomic
discontinuity axon. This injury can take days to weeks to recover.

The most severe form of sonication-related nerve injury we have seen in
the pivotal trial resulted in the interruption of the axon, requiring
regrowth of the axon. This injury can take months to recover and
considered permanent if symptoms persist for greater than two years.

This worst case was that of Patient 919, which occurred near the end of
the pivotal trial. The patient complained of leg pain at the completion
of the sonication treatment, and developed left lower extremity
weakness. She had difficulty walking and climbing stairs. She had
numbness and tingling from her left calf to the dorsum of her left foot.

She was evaluated by a neurologist at six months, and physical
examination revealed that nerve injury consistent with neuropraxia had
resolved. However, minor deficits present at six months due to axonal
loss would recover over a much longer time point as the axon has to
regenerate from the pelvis all the way to the target muscle.

Evaluation at 11 months by the same neurologist showed that the patient
had almost fully recovered, except that she was unable to flex her left
toe. She had otherwise returned to her baseline level of activity.

Now because of the symptomatology and because of the location of the
sacral nerve bundle in the far field of the beam, it\'s believed that
this patient sustained injury to the sacral nerve bundle located in
close proximity to the sacrum. This axial MR image of the pelvis is to
show the proximity of the anatomic structures of concern. This is not an
image taken from an actual treatment of Patient 919.

To orient the audience, the patient is laying face down, and at the
bottom of the screen is the abdomen, and at the top of the screen is the
patient\'s back. The structures of particular interest to us are the
sacrum pointed to in a dark blue arrow, and the sacral nerve, 4
centimeters away from the treatment volume pointed to by the red arrow,
and the treatment volume represented by the rectangle, pointed to by the
orange arrow.

As was mentioned by Dr. Zaremba, since MR thermography cannot provide
temperature measurements at the bone or at the interface between the
nerve and the bone, the company has provided temperature modeling to
help explain how nerve injury could have occurred in Patient 919. This
temperature graph is slightly different format from that that was
presented earlier by Bruce Herman. This graph shows the temperature as a
function of distance from the transducer. The temperature graph depicted
assumes that the angle of sonication is perpendicular to the sacrum, and
the baseline temperature is at 37 degrees Celsius.

When the focused ultrasound causes temperature to rise to 85 degrees
Celsius at the treatment focus in the fibroid, unfocused energy in the
far field causes the temperature to rise at the nerve to 42 degrees
Celsius, and 55 degrees Celsius at the sacrum.

Following the caveats previously mentioned by Bruce Herman, if the peak
temperature at the treatment focus is higher than 85 degrees Celsius,
the temperature at the nerve and bone will be higher proportionately.
Conversely, if the incidence angle is turned away from the perpendicular
to the sacrum, the amount of absorbed energy to the bone will be less,
decreasing the rise in temperature at the bone. And also, the
temperature at the nerve will increase if the nerve is closer to the
bone.

The previous graph had assumed that the baseline temperature was at 37
degrees Celsius throughout the beam path. Now this temperature modeling
is of the nerve tissue 4 centimeters from the treatment focus. The red
line shows that if the nerve is in close proximity to the bone, the
temperature will be at 39 degrees Celsius at 90 seconds after completion
of the treatment.

The blue line, on the other hand, shows that if the bone is in close
proximity to the nerve, the temperature will be 42 degrees Celsius 90
seconds after the completion of the treatment.

Now if the length of cooling time is not extended beyond the nominal 90
seconds, the cumulative effect of this small difference in temperature
can be significant after a series of sonications.

Bruce had previously shown this temperature graph of the nerve in very
close proximity to the bone. It illustrates the concern for adequate
cooling time between sonications that I had mentioned in the previous
slide. From a practical clinical standpoint, as the user becomes more
efficient at targeting and sonicating a focus in a fibroid, the nominal
90 seconds of cooling time becomes insufficient to allow the sacral and
sciatic nerve to return to baseline temperature before subsequent
treatment is initiated; thus, increasing the risk for nerve heating and
injury.

From the temperature modeling, the possible steps to prevent heating of
the sacral and sciatic nerve are to alter the incidence angle of the
beam to decrease the amount of absorbed energy at the bone, establish a
minimum distance from the treatment focus to the sacrum, lower the peak
temperature at the treatment focus, and possibly increase the cooling
time between sonications to allow the bone and nerve temperature to
return to baseline before subsequent treatment.

Of these, the company has implemented in the training module, a change
in incidence angle away from perpendicular when the sacrum is 4
centimeters away from the treatment focus, and to maintain a minimum
distance of 4 centimeters when the sacrum is in the far field of the
beam.

Now working with the company, we recently compiled the incidence angle
and distance data to see if the current mitigations if implemented in
the treatment of the five patients with the nerve injury would have
prevented the nerve injury. From this chart we can see that the most
severe case could have been prevented, but clearly, two cases meet the
requirement greater than 4 centimeter distance, and greater than 30
degrees change in the incidence angle.

The question is, are additional steps such as lowering the peak
temperature at the treatment focus and increasing the cooling time
warranted to decrease the risk of nerve injury?

Now we can also look at the preliminary results of the continued access
study to see if the mitigations are working, and so far there has been
one case of a patient with symptoms consistent with nerve stimulation,
and one case of nerve injury that resolved two days post treatment.
It\'s reported that this patient experienced warmth down the right leg
during two to three sonications, and that one day post treatment she
felt her right foot hitting the ground harder than the left, and she had
stumbled once.

Now in conclusion, it appears that the skin burns have been limited by
additional training, but nerve injuries have not been eliminated by
currently implemented mitigation methods. And while we believe that the
risk of nerve injury will not be completely eliminated, are additional
mitigations warranted?

The attachment to the discussion questions provides a listing of the
mitigations implemented in the pivotal and continued access studies. In
the discussions of Question 5, please also comment on whether or not
additional mitigations are warranted to prevent unintended heating of
the sacral and sciatic nerves. This completes the FDA presentation, and
I turn it back to you, Dr. Noller.

DR. NOLLER:  Thank you very much. Once again, thank you for staying
within the time allowed. We have a few minutes now before lunch time,
and during this short period of time, what I would like to do is to ask
the panel if they have any questions that they would like to perhaps
pose to either the FDA or the sponsor this afternoon. We won\'t discuss
them now, but if we present the questions now, it will give them a
chance to think them over, and develop some answers.

I\'m going to take the Chair\'s prerogative and ask my questions first
so I get them all in. First of all, I\'m curious - and this is a
question for the sponsor - I wonder if you have an explanation for the
variability between the dose volume and the non-perfused tissue volume.
You stated it was not blood-flow dependent. From the charts we saw that
the FDA presented it wasn\'t consistent either. If it were always 1.5
times the volume or 2.3 times the volume, you could make calculation,
but it varied all over the place. And if you could try to explain that
to me.

Secondly, in the material we received, and this goes along with safety
and education, I didn\'t see any teaching about conscious sedation. You
might have thought that\'s not necessary because hospitals have rules,
but this is an out-patient procedure that could be done in a
free-standing place where that wouldn\'t be required, so are you going
to include that?

And last, is there any sort of lockout feature that prevents providing
pulses closer together than every 90 seconds as you now have them set
up? If somebody is in a hurry, they have to get to their golf game,
could they do pulses every 15 seconds and cause damage, or do you have a
lockout feature. Yes, sir. Dr. D\'Agostino.

DR. D\'AGOSTINO:  I have a few questions which may have been covered but
I missed them. The first one is the symptom severity scale. We talked
about validation. Is there a literature that I\'ve not been able to find
that talks about a change of 10 points as being some high level of
clinically meaningful change?

My second question is that I\'m struck by the control group, that I
would have thought the adverse events that the hysterectomy group was
going to be observing would be somewhat different than what this new
treatment is. And you may have said it, but what was the actual logic? I
heard a lot of negatives on why you had to get a control group, and you
ended up picking hysterectomy, but I don\'t hear any positives on how
you could really make these sort of safety comparisons, especially on
the issues that are relevant to the ExAblate.

And then my third question is that the symptom severity scale in the
baseline versus the screening seemed to have on the data that was
presented, that you almost had like 20 percent or so of the subjects
changing by a score greater than 10. And I\'m concerned when you get to
the year, you have about 40 subjects who are positive, meaning greater
than 10; where if you just took repeated measures you may have had
something like a change of 10 out of those 20 just by chance alone. And
so I\'m concerned about how I\'m supposed to interpret the 12 month
results given the variability in the scale, and also the fact that you
only designed a six month follow-up, and how is the panel supposed to
respond to that? Thank you.

DR. NOLLER:  We\'ll go to Dr. Brown and then Dr. Crum, then Dr. Miller.

DR. BROWN:  My questions are really all for the sponsor. I have a
question about and a concern - we talked a lot about the risk to the
sacral plexus and sacral nerves. And from my knowledge of anatomy and
review of the materials, it seems to me that the colon and rectum are
going to often be included, if not almost always included in the post
focus point beam. And I wanted to get a little more detailed information
about exposure of the colonic mucosa serosa to the post focus beam
energy and the effects that may be have seen in the patients in terms of
GI symptoms. And also, there was some discussion about air stopping the
beam. Was there any consideration given to patients having an empty
rectum at the time, and is that being looked at in the ongoing study?

Second question is what provisions were taken and will be recommended,
particularly in the training, to ensure that the abnormalities were
being looked at in MRI are actually fibroids and not some other entities
such as a sarcoma or adenomyosis?

Third question is, who are the intended potential practitioners? Is this
intended to be used only by radiologists? Is it intended to be used by
practicing OB-GYN physicians. And again, I didn\'t really glean that
from any of the materials.

Another question for me is one of my more important questions. What are
the implications of the fact that only 11 percent of your treatment
group in the pivotal study were African American women, only 1 percent
Latino, 3 percent Asian, no Native American or Native Hawaiian women.
What are the implications of this to the generalizability of your
results in the population in the United States? As we all know, the
group who would probably most benefit from this treatment and have the
highest incidence of symptomatic fibroids are African American women, so
could you comment on that? That\'s about it.

DR. NOLLER:  Dr. Crum.

DR. CRUM:  This is for the sponsor. In your panel package, a statement
was made, \"The ability to predict the ablated tissue volume as a result
of a given sonication is the central factor upon which the entire
treatment plan is based\", so this issue of predicted thermal dose area
versus non-profuse volume I think is the central issue there.

And it seems to me that the fault is in the thermal dose prediction in
the model, and I would like to ask because I couldn\'t determine it from
our package, in the thermal model do you consider temperature dependent
attenuation, because the attenuation can go up by a factor of 50 to 75
percent during a temperature elevation, frequency dependent attenuation,
because if you have a water path in front, you get non-linear effects,
which means you get higher frequencies. And those are \-- those
attenuations are frequency dependent.

No perfusion I could see in the model. No long linear effects, as I
mentioned earlier, and no cavitation. That\'s a difficult issue, but
cavitation-related heating is, of course, in the recent literature a
very important factor, so I\'d like the sponsor to address that.

The second thing following on the point of cavitation is there is some
statements, page 35 I think, that says that the threshold for cavitation
is approximately 1,300 watts per centimeter squared, D-rated. The
intensity would be on the order of 800, so that\'s significantly below
the threshold for cavitation, but on the other hand, that data from
Hynynen was based upon pulsed cavitation, pulsed acoustic protocol. And
it also was done at a fixed temperature. The temperature at 85 degrees,
the threshold for cavitation is significantly less, of course, than
1,300 watts per centimeter squared.

I know you have a cavitation detection system that was never mentioned,
and I\'d like to see how that works, and if it works. Thank you.

DR. NOLLER:  Dr. Miller.

DR. MILLER:  Yes. My questions are also directed to the sponsor. I\'m
interested to know in the primary pivotal study why a non-randomized
design was chosen. And I again I may have missed it, but I don\'t see
enough address of the differential in the study populations since it
wasn\'t randomized. And the specific issues that I\'m interested in are
these populations differed, as we\'ve already heard, by race. I don\'t
find any report of the number of fibroids in the TAH group, or the
volume assessments of those fibroids, and how they compared.

Also, in terms of the calculation of disability, there\'s a lot of
analysis relative to the differential in calculated disability, but if
you consider that 33 percent of the focused ultrasound group needed to
be retreated, some of whom were then treated by hysterectomy and other
modalities, there doesn\'t seem to be any aggregate calculated
disability that would include complete treatment, particularly when
you\'re looking at outcomes over a six and twelve month period.

In terms of the health-related quality of life scale, and this again
gets back to the differential in the populations, if I read this right,
there was a significant prevalence of underlying depression in the TAH
group, which wasn\'t reflected in the focused ultrasound group. And
there were some other differential characteristics, like anemia and
hypertension, what medications were they taking for their hypertension?
Again, these all speak to the fact that these populations were very
different. And since you\'re basing your efficacy on this 10 point
scale, what analysis can be deployed to understand the comparison?

And the final thing that I want to ask you about is what post hoc
analysis was done to better understand the treatment failures in the
focused ultrasound group? Clearly, it\'s a significant population.
Obviously, I would think that you\'d want this to be a modality that
would be effective for the long term. Can we have any better
understanding of what patient population is this better designed for,
and maybe that would inform the exclusion criteria in the future. Thank
you.

DR. NOLLER:  We have about eight more minutes and five people. Dr.
Hillard, you were first, then Dr. Brill and Dr. Solomon, Dr. Diamond.

DR. HILLARD:  Questions for the sponsor, questions about the patient
death. Was an autopsy performed on that patient? What were the findings,
particularly the findings in the pelvis for this patient? And given that
she did clearly have additional risk factors, are there any screening
issues that could be recommended. If you had known she had Factor V
Leiden, could or should this have been an exclusion for treatment?

In follow-up of the questions about who is the intended practitioner, if
this is a radiologist, what recommendations would be given for
communication between the gynecologist and the radiologist in terms of
both follow-up, and also in terms of immediate potential for
complications, the potential for acute bowel injury or intra pelvic
hemorrhage, so these need to be addressed in the planned training and
recommendations.

DR. NOLLER:  Dr. Brill.

DR. BRILL:  Yes, I have a number of questions. First query regarding
inclusion or exclusion and the follow-up. For what reason FSH was not
followed in the patients after therapy? And I wondered if there\'s any
stratified data regarding the effect of this and oral contraceptives
which appears to be acceptable in the protocol in the patients after
treatment.

In regards to the myoma treatment itself, if I\'m reading the materials
correctly there were a number of myomas of 2.3 per patient, and a mean
number of treated 1.3. So the question is what method was used to choose
which fibroids were to be treated, number one. Number two, what was used
to rule out the fact that they may be degenerated already, and why were
non-perfusion volumes not applied before the institution of the
protocol?

And third, Dr. Stewart, you mentioned that those amenable to
hysteroscopic or laparascopic myomectomy would not necessarily have been
treated, and I\'d like to know more details about that statement
regarding the pivotal trial.

And last, regarding the non-perfused volume - we heard a number of
references to the point that in fact the NPV appears to under-estimate
the histology. Well, if that\'s the case, if we take the statistics that
were presented with a non-perfused volume of average of 68.7 Ccs and a
percent of the myomas treated 23.6 percent, then how at six months do we
have a 14 percent shrinkage, and thereafter, a 9.4 percent shrinkage
from the intent-to-treat, if indeed the area was greater than treated
versus less.

DR. NOLLER:  Dr. Solomon.

DR. SOLOMON:  In the material presented to us, the test arm inclusion
criteria include MR accessible fibroids, but there isn\'t a discussion
as to how many patients were rejected because of interrupted \--
intestines in the pathway of the beam or calcifications in the fibroid,
so that there are a number of patients that were obviously excluded, and
we don\'t have a good sense of that in the materials.

Secondly, the beam pathway can be affected by interactions or interfaces
between different tissues. And the beam then can be in a different \--
the focus can then be in a different place from where the predicted
focus would be, and that\'s part of the calibration procedure early in
the program here. The question is how often is the sub-lethal dose
different from the actual focus, and how far do you have to move it,
because that may be something that comes up in other parts as you move
the focus around, that you could be endangering other tissue.

And the third question is, we have in here the use of MR thermometry in
order to mitigate the risk of unnecessary heating of critical
structures, but it appears that in the case of the skin and the nerves
that MR thermometry safeguard was unable to succeed, and so maybe
further discussion there would be helpful. Thank you.

DR. NOLLER:  Dr. Diamond.

DR. DIAMOND:  I had a number of questions actually about the logistics
of how the study was conducted. First of all, you said that the decision
was made to use a 3-2 ratio for randomizing patients or assigning
patients in the treated arm or in the control arm, but why was that \--
what were the demographics that were utilized to come up with that power
calculation, and the idea to use that ratio?

The evaluation of the perfused area, like Dr. Brill, I wondered was that
done before the study. It\'s my understanding it was. What percent was
not perfused at that point, or were they all totally perfused if they
were going to be included in the study. Was the \-- obviously, the
practitioners, the radiologists were making that assumption in the
decision at the time of the study, but was that the actual data that was
utilized for the calculations that we see here, or was the ultimate data
that we\'ve seen here generated from a central review of perfused and
non-perfused areas. If it was not, how was that standardized between
different investigators. And did the individuals doing it, if it was
central site, did they know whether it was initially procedure,
immediately post procedure, or at later time points, because without a
control group which has those sorts of measurements, I think there\'s a
potential for bias knowing that it\'s potentially treated; and,
therefore, subconsciously thinking maybe it should be either larger or
smaller, whichever that could potentially go.

You\'ve given us the change in fibroid volume and perfusion volume. You
didn\'t give us the uterine volume changes though, and I\'d be very
interested to know that, typically since you\'re treating just 1.2
fibroids in these patients.

It\'s also very curious to me that with the small percent change that
you saw in the fibroid volume, that you saw the benefit that you did
see. That\'s one of the reasons why I want to have the total uterine
volume changes, but do you have any idea why such a small change in what
I\'m assuming will be total uterine volume would have the beneficial
effects that you did identify?

Other logistic issues, you mentioned the thermography is measuring
temperature change, and have you done the standardized temperature of
the patient or temperature of the room? Have any studies been done in
other animals that have uteruses like humans, like primates, with
thermistors to see whether the ultrasound treatments \-- what sort of
temperature changes are seen there, and how well that is picked up with
all the modeling that\'s been shared with us, whether that correlates or
does not.

It appears to me that, at least as I\'ve read the documents, that some
of the patients that were in initially treated ended up being found out
that have adenomyomas and, therefore, were excluded from the analysis,
although they had already been treated. Since that\'s likely to happen
in clinical practice, as well, the practitioners were not able to
differentiate initially, I\'m not sure that\'s the right thing to do.
Similarly, I\'m not sure that it\'s necessarily appropriate to exclude
those patients who are outside the window when they had their
follow-ups, and would like to see data as to how that might affect
uterine volume changes in those individuals.

The question came up is if you have multiple fibroids, which one was
treated. I\'d also like to know where within the fibroid was treated,
and how that was decided, and whether that has any impact? Perhaps was
it closer to the uterine surface, the middle, or what location.

And then the question \--

DR. NOLLER:  Last question.

DR. SOLOMON:  Last question. Another way to assess the effect of the
sonication might be functional MRI looking at blood flow changes, and
has that been done?

DR. NOLLER:  Thank you. One quick question.

MR. WEEKS:  If I may, three really brief questions.

DR. NOLLER:  Ten seconds each.

MR. WEEKS:  First, the difference between the thermal dose area and the
non-prefused area, have you looked at the relationship between that
variance and BMI?

As far as your questionnaires for symptoms as a tool, two questions. Was
the timing of the questionnaire, the taking of the information any way
related to where the patient was in her menstrual cycle? And third, has
there been any data on the particular tool with regard to placebo
effect? So for example, has the same tool been used in medical studies
where there\'s been a prospective randomized placebo control trial, and
what is the magnitude of placebo effect? That\'s it.

DR. NOLLER:  All right. Obviously, we don\'t expect you to respond to
all of those. We\'d be here for all week. And we will not be asking you
to respond to all of them, but those are the sorts of questions we have
that may come up in our discussions of our nine questions. But if you
could prepare short one or two sentence answers to some of those, and
some of them won\'t be asked, I\'m sure, because the questions won\'t
directly affect that.

We will meet back here at exactly 1:00. For the panel members, there\'s
a place in the back of the restaurant for panel members only, and I have
a message here I don\'t understand. Why don\'t we do those as we come
back in our open panel discussion, doing that, because I think a lot of
people have more questions. One o\'clock, it\'s now 12:01.

(Whereupon, the proceedings in the above-entitled matter went off the
record at 12:01:35 p.m. and went back on the record at 12:59:47 p.m.)

DR. NOLLER:  During intermission we worked out a couple of things here.
I know there are other panel members that had questions. We\'ll try to
get to everything today. We certainly don\'t want to cut discussion
short, but I think what we\'ll do for the next little bit, we have now
panel discussion from 1 to 2:45. We\'re going to ask the sponsor to
respond to the questions that they had in general categories. And they
said they can do that in about 10 minutes. At that point, we will start
our discussion of the nine questions. And the work we have to do this
afternoon is to develop some answers to those nine questions, and
develop an overall opinion concerning the approvability.

The open public hearing from 3 to 3:30, we know that there will be at
least one person to speak then, so I ask the panel to watch the time and
the length of comments, questions, et cetera, but we will go until
we\'re done. We hope that go until we\'re done is 4:30. Is the sponsor
prepared to respond?

DR. STEWART:  Thank you, Dr. Noller and panel. What we tried to do is
get some of the areas of maximum overlap in terms of questions. And
while we\'ll be here to answer all questions. Our beepers and cell
phones are locked away in the suitcases, so if we missed your question
on the first round, we\'ll clearly go back to it. But it appeared to be
a cluster of questions around the primary efficacy endpoint, and why the
symptom severity score was an appropriate measure, was the 10 points the
appropriate measure, was there too much variability inherent in this
measure. And I think we chose this as a primary efficacy endpoint
because symptomatology is really the primary complaint for women with
fibroids. And that this is significantly impairing their lives.

We chose the only fibroid-specific validated measure. Again, it\'s a
shame that the field is so far behind in measuring disease impact for
women, and it wasn\'t until the last several years that there was,
indeed, a validated study. And so the symptom severity score of the
UFS-QOL is really the appropriate measure for this disease.

Several people raised the issue of why 10 points, and if we can go back
to one of the slides that was in my presentation this morning, I know we
had a lot of different things over the morning, but the 10 points was
defined at the outset of the study for two very different reasons. First
of all, we believed that it meant that there was clinically significant
improvement, that if we can get the graph up eventually, if you\'ll
recall, when they were validating this questionnaire, the women with
fibroids had mean scores about 40, and women without fibroids in the
normal population had mean scores in the 20s. So 20 points separated
significantly effected individuals from non-effected individuals.

And just like with other treatments for fibroids, such as GNRH Agonist,
if you get a 50 percent volume reduction or a 50 percent reduction in
bleeding, this is generally clinically significant. So for that, reason
we chose 10 points.

Here we go. Do we have the pointer again? So it\'s the two bars on the
left, the symptomatology and the fibroid bars are in blue with a mean of
44. And the normal women were at 23. And, in fact, what we found from
our data was not that 10 points separated our groups, but a mean of 23.8
points separated our group. So again, if we look at the differences that
would bring the fibroid patients really down into the normal range.

So if we had set our criteria for success instead of at 10 points where
we got 70 percent of patients to respond, and we had hypothesized that
there would be 50 percent of patients, even if we move that up to 15, we
had 70 \-- we would have 50 percent of our patients having improvement.
And we found, again, a 40 percent reduction in symptoms which again from
our previous experience with drugs such as GNRH Agonist or Mifepristone
generally does translate into symptomatic improvement.

We also chose this cut-off for several methodologic reasons, and if we
can go back to the word slide in terms of statistical methodology that
10 points was very close to the standard deviation of the population
very near to the standard there or the mean, and it correlated with a
moderate effect size.

The other issue that had been raised by several individuals was that
there was a variation between the screening that we obtained on this
questionnaire at the screening visit, versus the baseline at the
treatment visit. And we went back to look at those issues to assess what
the differences were.

It turns out that the treatment day assessment of symptom severity and
the follow-up ones are very consistent. It was really the screening day
that showed variation. And in trying to understand that difference we
looked at several things. We looked at difference to menstrual period
and the menstrual cycle. Cyclicity didn\'t seem to make any difference.

What we found out was that there were some centers that were not
administering it in the standard format. As you may know, quality of
life questionnaires really do depend on you using the same instrument in
the same way. And some of the recruitment centers, especially ones that
had patients coming in from long distances would sometimes use fax
copies or phone interviews to try to assess symptomatology.

So we then were able to look at that. We also found that there really
wasn\'t any difference in which measure we looked at. Both the median
and the mode of the differences were zero, and if we assessed values
between screening and six months versus baseline and six months, we got
the same difference. So I think although it is a concern, it doesn\'t
affect the results, and this has proved to be a dynamic measure.

There was also question about whether this could represent a placebo
effect. And although any self-reporting measure is vulnerable to a
placebo effect, the first thing is that we do have clear documentation
that we had an effect. We have the radiographic imaging. We see the
differences in blood flow, and everyone did, indeed, have an MR image
prior to treatment that showed that there was enhancement. That was one
of the inclusion criteria.

We also know that size is not the only criteria for efficacy. The
questions were raised about why we didn\'t get more size reduction, and
I think the UAE experience has told us that size reduction doesn\'t
necessarily correlate with symptom reduction. And there are many changes
that may be going on in the consistency or the density, having a lead
ball sitting on your bladder may be very different from having a cotton
ball sitting on your bladder and the size reduction doesn\'t have to
factor in.

Finally, although there may have been some placebo effect at three
months, that at six months I think we were seeing a real effect. We got
some patients who would maybe see symptomatology relief at three months,
and by six months it was pretty clear to any of us that spoke to the
patients that they clearly knew they were using less tampons or getting
up less at night to urinate, or they weren\'t, and I think that goes in
general timing with the known information about placebo effects.

And finally, we had multiple parameters that were consistent. We didn\'t
just rely on the symptom severity score. We had SF-36 monitoring to
prove that we were getting concordance in our study sample. We also had
health-related quality of life and overall treatment effect, as well. Is
that my 10 minutes?

DR. NOLLER:  It is.

DR. STEWART:  Okay. Is there any questions?

DR. NOLLER:  Thank you.

DR. STEWART:  Okay.

MR. NEWMAN:  If there\'s any of the questions that were asked earlier
that need to be covered before the deliberation, we\'d be glad to cover
those.

DR. NOLLER:  We may ask you back up to the podium as we go along here,
you and/or the FDA. Okay. That was 10 minutes. Is the company okay with
that? That\'s what you asked for, that\'s what you got. Are you \--

MR. NEWMAN:  We said we believed in 10 minutes we could cover the main
topics that had been covered by several people. Of course, that left
many other questions unanswered, the physics questions and some of the
other more specific things, and we\'d like to cover those before we get
to the deliberation and vote.

DR. NOLLER:  Okay. That sounds good. What I\'m going to do now for the
panel is to read you three definitions. The definitions of safety,
effectiveness, and valid scientific evidence. These are the measures
that we are supposed to use in making our decisions today.

Safety, the definition reads: \"There is a 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.\"

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.\"

And then finally, the definition for valid scientific evidence: \"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 fairly and responsibly be concluded by
qualified experts that there is reasonable assurance of the safety and
effectiveness of the device under its conditions 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.\"

MS. BROGDON:  Dr. Noller, I\'m sorry to interrupt.

DR. NOLLER:  Yes, ma\'am.

MS. BROGDON:  I just have a procedural question. The panel laid out a
number of questions for which you\'d like answers from the firm. I\'m
just not clear on when you intend the firm to be able to answer those
questions.

DR. NOLLER:  I think those that were not answered will come up as we go
through these questions, and we will give the sponsor time as we go
through the questions.

MS. BROGDON:  Okay. Thank you.

DR. NOLLER:  And certainly before we do our voting. The first group of
discussion questions are six, and they deal with safety and
effectiveness. And the first is the primary effectiveness endpoint for
the pivotal study is the symptom severity scale derived from the uterine
fibroid symptom and health-related quality of life questionnaire.
Success was defined as a 10 point improvement in the symptom severity
scale of the UFS-QOL instrument in at least 50 percent of ExAblate
patients at six months. Is the 10 point improvement at six months a
clinically meaningful measure of success?

As we go through these, I will ask our primary reviewers, Dr. Diamond
and Dr. Roberts, to start the discussion of each one of these points.
Dr. Diamond.

DR. DIAMOND:  At this point, I guess I remain unconvinced that a 10
point drop here was a clinically significant difference. It seems like
this group of patients is a very select group of patients with uterine
fibroids. We were told that they were not amenable to hysteroscopic
treatment. They were not amenable to laparascopic treatment because
those patients would have been treated in those fashions.

Furthermore, the average hematocrit of these patients I think was about
37 to start with, and so there are a group of patients who have fibroids
but are not overly or imminently symptomatic, at least as the data has
been presented to us. If you had included some patients who have greater
symptoms, greater amount of bleeding, then the original score in the
fibroid group might have been more than 40, and the differences going
back to a normal patient population may have been 30 or 40, which would
have, as the company has presented to us, would have influenced what
they were seeing as a clinically significant difference because they
were looking at standard deviation or standard error, or half the
distance from where the treatment group was to the control patients in
the validation study which described the use of this instrument.

And I guess the last component I\'d want to make about that comment is,
as I read the manuscript which was presented to us in our packet, that
manuscript describes a difference between patients with fibroids and
patients without fibroids, as to what you would expect to see on the
scores, and that data was presented to us. But that manuscript does not
talk about at all any sort of changes, or what is a clinically
significant change for that instrument. So while it\'s been validated,
differences for patients with fibroids as opposed to without, I\'m not
convinced that it\'s been validated for changes of symptoms for patients
who are having treatments for fibroids.

DR. NOLLER:  I\'ll say just as an side, I understand that at the open
public hearing we will be getting some more information about the
instrument that was used from a public member who \-- from a person in
the audience who will speak. Would you like to respond, sir?

MR. NEWMAN:  Chairman Noller, can we respond to that question?

DR. NOLLER:  Yes.

MR. NEWMAN:  That was one of the questions, we didn\'t cover that in our
10 minutes.

DR. STEWART:  I think that it is clear that the patients that we saw
were significantly symptomatic, that if you look at again our symptom
severity score, we were well in excess of what was defined as a mean
level of symptoms for women in the validation study. We were looking at
a mean of 40, and our patients in the MRI guided focused ultrasound
group had a mean of 61, which was very similar to the mean of 69, I
believe, in our hysterectomy group. So although they may not have had
significant anemia, they did, indeed, have significant fibroid symptoms.

They also had a significant uterine volume, that the mean uterine volume
was 600 cubic centimeters, and with the standard deviation there were
patients in this population that had well over 1,000 cubic centimeters,
so I would agree that they didn\'t overlap the patients for whom we
would perform a hysteroscopic myomectomy or a laparascopic myomectomy,
but they clearly were the patients who would currently undergo an
abdominal myomectomy, a hysterectomy, or in many institutions a uterine
artery embolization.

DR. NOLLER:  Thank you. Dr. Roberts.

DR. ROBERTS:  Well I had some of the same concerns because when I \-- to
some degree I think have been answered, but when I went through the
paper looking at the quality of life measurements, and I went through
other papers that talked about looking at quality of life, I couldn\'t
find anywhere that 10 points meant anything, so you\'ve somewhat
answered my question in terms of whether or not that\'s a realistic
goal. I don\'t think we really have a good answer for it.

I was impressed, though, when I looked at that, that in comparison to
the group where there was in the validation study where the patients
with uterine fibroids certainly had a \-- the patients in this group had
a much more of a severity index than those patients, so they obviously
were quite symptomatic.

The one thing that I was little bit - a little bit off the subject of
this - but one of the things I was a little bit confused about in terms
of the study was, I didn\'t find anything anywhere that indicated what
were the primary symptoms of these patients. In other words, were most
of them coming in with bleeding, were most of them coming in with both
symptoms? When you look at the anemia levels, unless they\'re doing
pretty well on keeping up on their iron levels or something, and being
able to keep up with their blood less, you would have to say that maybe
most of them were bulk symptoms. But I think that\'s very important
because when you look at some of the patients that then go on to have
hysterectomies or drop out of the study, you get the impression that
many of these are for bleeding problems. And maybe I missed it, but I
just couldn\'t find it in there to indicate what it was that these
patients were coming in with.

DR. NOLLER:  Let\'s hold off just a second, get other comments, and then
we\'ll ask you. Any other panel discussion on this number one? Yes, Dr.
Hillard.

DR. HILLARD:  Just in thinking about whether 10 points is clinically
meaningful or not, one could just mathematically come up with a
situation in a patient who is maximally symptomatic, so answering five
at the far extreme of the scale for all of the symptoms, and could with
only half of those symptoms drop down to having symptoms a great deal.
And that would be a drop of over 10 points, so if you ask me if that\'s
a clinically significant improvement, she still has symptoms a great
deal of the time for many of her symptoms, so I think that
mathematically I have \-- in theory that would not qualify as a success.
And so, therefore, I wonder about having some sort of an absolute value
in addition to a magnitude of decline.

DR. NOLLER:  Dr. D\'Agostino.

DR. D\'AGOSTINO:  I was just going to say in terms of when I\'m involved
with these type of scales, the validation with the change, you\'d like
to see the group move to some other clinically relevant group. And
they\'re moving to 40, which is sort of what the original comparison
group was with the normal, so it\'s hard to figure out I think what the
10 means, and even where they moved into.

I do also think that if they got very extreme individuals, it tends to
be on the scales, the ones that are extreme tend to change the most. And
I don\'t remember the way the comment is, but I don\'t know what\'s
driving the scale, and what the 60 to 40 actually means in terms of the
clinical symptoms, and is that really clinically exciting? And I think
we\'re missing that by just putting everything into a number like 10.

DR. NOLLER:  Dr. Brown.

DR. BROWN:  Another question that I hadn\'t asked was, which I didn\'t
find, was what were the percentage of the patients that hysterectomies
that had a 10 point change? Because to me, that would give me some
perspective to gauge again, so we say that 100 percent of the patients
that had hysterectomies had a 10 point change, that would mean one
thing. If you said 30 percent of them had a 10 point change, that would
mean another thing, so I thought that bit of information would be
helpful, and I wasn\'t able to find that anywhere. I don\'t know if that
could be addressed.

MS. MOONEY:  If I understood the 10 points correctly, I think in looking
at the validation or the comparison between fibroid patients and normal
patients, the scales we looked at earlier, it was a 40 to 20 drop, so
the 10 points there represented a 50 percent change. And I think, if
I\'m reading this correctly, from the six month data, it looks like
baseline for the intent to treat patients was 61 as was just mentioned,
and dropped to 34. So I think in terms of that 50 percent improvement
for this patient cohort, it seems fairly similar to that 40 to 20. So I
think the 10 points was not so much an absolute number. It was chosen,
if I\'m understanding correctly, but it represented a 50 percent change
from fibroid patient to normal patient.

DR. NOLLER:  Dr. Janik.

DR. JANIK:  I think six months is very short. We need to really look out
a little bit farther to see if there\'s a risk gain that\'s beneficial.
To take any risk for a six month temporary improvement is similar to
medical management, so we have to go beyond that, and also correlate
with how many people go on to have hysterectomy. It\'s too short.

DR. NOLLER:  Yes, Dr. Solomon.

DR. SOLOMON:  One of the things I\'m having trouble with on the scale is
the meaning of all of this in absence of what I think the ideal control
would be, which would be to separate a placebo effect. In this study, we
wave all these fancy machines and we tell the patient things went great,
and they go home, fill out a survey. And then you say well, how did you
do, and they want to please. And we don\'t have a control here where
maybe \-- in any study I\'ve seen, this is the best one because you can
do a sham operation without having to put the patient through a big
incision. There\'s no real downside than taking up some time. They can
sit on the machine, the lights flicker and they say hey, you got the
treatment, and then they get the survey later. I think something like
that would give meaning to a 10 point change alone.

DR. NOLLER:  Dr. D\'Agostino.

DR. D\'AGOSTINO:  I was going to follow up on the 12-month follow-up.
They ran into trouble because there weren\'t evidently designing a
12-month study, but the 12 months certainly makes the comparison or the
numbers look a lot less exciting. They\'re down to less than their 50
percent changing over by a 10 point scale. And they also were in a
situation where they have a lot of individuals moving to another
procedure, and getting the hysterectomy, and I did ask that as one of
the questions. And I really, if possible, to try to get a response from
the sponsor on that, because I don\'t see how we \-- personally how I
move out of the dilemma that I\'m very unimpressed by the 12 month data.

DR. NOLLER:  I\'m going to call on Dr. Miller, and then I\'m going to
ask the sponsor to respond to some of these items that have come up. Dr.
Miller.

DR. MILLER:  Well, interpreting the success or the meaning of the value
of that 10 point drop, I mean I think we have to understand it in terms
of the real attrition of this population. So if 12 months is a
meaningful endpoint, at that point we only are dealing with 44 patients
that we have data for. We\'ve lost over 60 percent of our sample, and I
think that makes the question of bias, and who stayed in, and whether
people who actually felt better about their treatment; in other words,
were maybe less symptomatic to begin with, were more satisfied to begin
with, and were still in the study. So that 10 point as a reference point
is material in terms of who stays in the study when you have an
attrition rate that\'s that high.

DR. NOLLER:  In fairness to the sponsor, too, let me remind people what
we said earlier, that originally there was some misunderstanding, I
guess, in the length of follow-up, so they didn\'t recruit these people
to be followed for a year, so they had to go back and find some of them,
and so there was some additional loss that normally we wouldn\'t expect.

Everyone who comes to the microphone from now on, even though you\'ve
spoken before, please give your name as we\'re recording this, so they
have the name. So does the sponsor want to respond to some of these
issues?

DR. STEWART:  I\'m Ebbie Stewart, and it sounds like there\'s still
concern about the 10 point threshold. That clearly at the outset of the
study, it was a hypothesis that this was an important difference. I
think there are good methodologic and clinical reasons to suppose that
this is an important endpoint, but I think, in fact, we saw
substantially better improvement than that. We found 24 points on
average, and many patients improved 30 or 40 points on this scale.

I think we also got objective endpoints in terms of by a reduction in
terms of comparability to the treated endpoint, and outcomes on SF-36. I
think also some of the concerns addressed the control group, and I would
love to be able to tell you we could perform a randomized study. I think
at the outset of this, there wasn\'t any way that we could feasibly
perform a randomized study that we didn\'t have a minimally invasive
treatment that had FDA approval. We had, ourselves, the experience of
randomized, or trying to get people to trade-off between this minimally
invasive procedure and an open procedure, and had seen what had happened
with the attempts to do the same thing for uterine artery embolization.
So we, therefore, chose the most comparable group we could find, and I
think that the women in our study were indeed women who would have
qualified for hysterectomy in any institution.

We weren\'t able to blind people to this treatment modality, and I think
that we have established that we did get significant efficacy with these
patients, that there are very significant clinical improvements that we
have seen.

There\'s other investigators here that may be able to give their input
since you\'ve heard a lot from me. I\'ll introduce you to one of our
other investigators.

DR. NOLLER:  Please limit to about a minute.

DR. GOSTOUT:  Okay. In one minute. I\'m Bobbie Gostout, and I\'m from
Mayo Clinic, and I\'m a consultant for InSightec, but I do operate under
the guidelines of Mayo Foundation, and under the guidelines of IRB at
Mayo Foundation. And I should state just to be clear that my travel and
accommodations here were provided by InSightec.

A couple of things to just briefly wrap up. Some people are saying well,
maybe if the patient\'s initial symptom scores were higher, we could say
more about what this means, and I\'d just like to point out that I
believe we really are presenting to you a spectrum of patients with a
range of symptoms of human fibroids that require treatment, which I
think makes it, if anything, the best study that we could be presenting
to you, rather than saying we only took patients that were at the
maximum on every symptom possibility.

I\'m hearing questions saying well, what is the clinical significance of
this reduction on this symptom severity scale? I think it\'s important
to consider a couple of slides that we presented before when we looked
at patient satisfaction, and documented that at six months the
patient\'s satisfaction in terms of saying that it was effective is, I
believe, 72 percent. And at 12 months, we\'re looking at 79 percent. So
the patients are telling us that the difference that they\'re measuring
on this objective score means something to them. And in my mind, that
validates the clinical significance of this. They\'re telling us that
\-- we asked them to put it in numbers and make it objective, but
they\'re telling us saying I call this treatment effective. And, in
fact, American College of OB-GYN\'s recommendations are that you treat
uterine fibroids when they\'re a bother to the patient. And the patients
are telling us that we effected the change that she came requesting.

If we go to a randomized clinical trial, I would tell you that at least
one-third of the patients that I see that have entered into this trial,
it would probably be an ethical question whether or not I could do a
sham procedure for her, and in fact do nothing for her symptoms, because
really, in fact, we are dealing with a number of patients that had the
severe type of bleeding that makes me concerned about fainting episodes,
that makes me concerned about them driving or even caring for their
children when they\'re having their period, so we have a significant
number of patients that were highly symptomatic, and I would be
concerned about just randomizing them to no effective treatment.

DR. NOLLER:  Thank you. I\'m going to go on to the second question,
because it also deals with effectiveness. The intent-to-treat success
rate at six months was 70.9 percent as indicated in the table below, and
you all have that table.

The ITT success rate at 12 months was 40.4 percent. The success rate
dropped in part due to patient lost to follow-up between 6 and 12
months. By 12 months, approximately 20 percent of the ExAblate subjects
had undergone alternative treatment for their fibroids. Secondary
endpoints included fibroid volume changes at 6 months. On average, the
treated fibroid volumes decreased by 16 percent. The question: Did the
patient reported outcome data from the quality of life instrument at 6
and 12 months, when coupled with the clinical result of actual volume
reduction of reduced fibroids support the effectiveness of the ExAblate
for the treatment of uterine fibroids? Panel discussion. Yes, Dr.
Diamond.

DR. DIAMOND:  In order to put into perspective for me the 16 percent
drop in fibroid volume, it would be very helpful for me to know some of
the things I asked for before the break, which was when happened to
total uterine volume before and after? So was the 16 percent consistent
with what happened to total uterine volume going down, did it go in the
opposite direction of total uterine volume? How were the readings done?
Was it done by a blind reviewer centrally, or controlled for potential
bias as to when it was being done; again, some of the logistics of how
the study was actually conducted to get a better feeling for whether the
16 percent is \-- how real that data is.

DR. NOLLER:  Dr. Wood.

DR. WOOD:  I\'d like to make a point of clarification on the 16 percent,
and it relates to thermal ablation therapies are often staged in cancer.
And in this case, followed with volumes, and it points to the \-- it\'s
maybe not representing what you think it is. And if you think about a
tumor, or in this case a fibroid, changing characteristic, becoming
soft, that\'s not represented volume, and overall your thermal lesion,
your effective devascularized coagulative necrosis area is also
represented in this fibroid volume, as I understand it. So it\'s not
necessarily a very pertinent measure.

DR. DIAMOND:  Well, it\'s what we\'re presented with, and it\'s one of
the markers that the sponsor has put forward as a marker of efficacy.

DR. WOOD:  I understand that. I just want to clarify for the panel that
this number is not necessarily indicative of \-- you\'re not talking
about a fibroid that is just shrinking 16 percent. The characteristics
are shrinking and changing potentially, and they\'re not representative
of that number.

DR. DIAMOND:  That\'s true, but I don\'t know of any information that
suggests that the characteristics of the fibroid, whether it spongy or
whether it\'s hard, where that\'s been documented to show that that was
associated with different symptoms by the patients. I think that\'s
relevant.

DR. WOOD:  Speaking from cancer therapies, we can treat a tumor, have it
remain the same size. We can partly treat a tumor and get symptomatic
relief that\'s long-lasting and not have he volumes change whatsoever in
the measurement, so that\'s why the cyst criteria don\'t really apply to
thermal ablative therapies in cancer, for example. I know this is off
the subject, but the same sort of paradigm here may not fit. It\'s just
a point of clarification.

DR. NOLLER:  Other comments from the panel. Dr. Roberts.

DR. ROBERTS:  Well, the only thing that I would say is that certainly
\-- my experience has with uterine artery embolization that even though
you may not get a huge decrease in the size of the fibroid, the patients
will tell you that there\'s something different about the fibroid, even
if it\'s more or less the same size. But I do think it\'s \-- I think
that there is some confusion, certainly in my mind, and maybe the
sponsor would be willing to look at this, or to give us some information
about that; and that is, how does the change in the fibroid volume \--
do you have any documentation about the uterine volume at the same time?

DR. NOLLER:  Let me ask the sponsor here to answer that. Do you have
data on the total uterine volume? And then the other question was were
the volumes and results blinded as to whether it was treatment or not?

DR. TEMPANY:  Yes. I\'m happy to respond to that. I\'m Clare Tempany.
The uterine volume was measured at baseline, but it was never measured
again after that in the follow-up examinations.

DR. DIAMOND:  Don\'t you have that? I mean, you\'ve got the images.

DR. TEMPANY:  Yes, but I don\'t have that data to present to you now.

DR. NOLLER:  Let\'s let them finish the \--

DR. TEMPANY:  We have the total fibroid volume, and we have those
numbers that we\'ve shown you already. And to go back to your other
questions, Dr. Diamond, about the measurements, and whether they were
done by single readers at single sites, or whether they were done at a
core lab. They were, in fact, all done at the core lab with standardized
interpretation and measurements ahead of time by a single person.

DR. BAILEY:  And was that reviewer blinded to whether it was a pre, or a
six month, or a twelve month evaluation?

DR. TEMPANY:  No, I believe they knew which examination it was. They
knew it was baseline, they knew it was six months. And then the other
questions you had asked, just to clarify those to make sure that
measurement of the perfusion areas, everybody had a totally perfused
fibroid to enter study, so all of the non-perfused \--

DR. NOLLER:  Yes, you said that before. You said that in the 10 minutes.

DR. TEMPANY:  Okay. Sorry. And just to concur with what Dr. Wood was
saying also, I mean, I think a lot of us now believe in imaging.
Certainly, that size and volume are very imperfect measures of any
treatment effect. Certainly, in the cancer world, it\'s not being
regarded any more as really being the most accurate measure of effective
drugs, and this is where I think we\'re going to learn a lot more. And
somebody asked about FMRI and perfusion imaging, and these are certainly
neutrals that we\'re definitely going to apply. They\'re certainly not
standardized today, and certainly not something we could have used in
this trial. But to look at the consistency of the fibroid, and its
perfusion, those are indices that I think we\'re going to learn an awful
lot more about softening and reduction in pressure in the capsule which
we think is probably occurring in this treatment.

MR. NEWMAN:  I\'d just like to add a little bit more to that. This is
Rob Newman. Your question about was the reader blinded. The treatment
effect is very obvious, and it would be \-- you see a very large \--
there\'s just an example from an image we showed you before. When you
get a very large non-perfused volume in the middle of a well-perfused
fibroid, it\'s going to be very easy to tell without any dates on the
image to tell which is the pre-treatment and which is the post-treatment
images.

DR. NOLLER:  Other panel discussion regarding question 2.

DR. MILLER:  It would have been very worthwhile to have the data
stratified regarding the location of the fibroids. I mean, even if we
acknowledge that size may or may not have a significance, I think
there\'s reason to believe that location does affect at least the
symptom severity scale, assuming that most of it represents menstrual
bleeding aberration, and some of it represents pressure aberration; that
indeed those myomata that were deeper set or impact the cavity, or in
fact may be within a cavity in part, may or may not relate to the
reduction of your scale. Do you have any information about that?

DR. STEWART:  This is Elizabeth Stewart. We do have some information
about location influencing symptoms. That was one of the things we
looked at in our logistic regression model, and we found that fibroid
location did not effect outcome.

With regards to the question about whether we primarily got improvement
in bleeding symptoms or bulk symptoms, that the way that the symptom
severity score is designed, it actually has questions that cover bulk.
It isn\'t separately validated to be able to say we improved on bleeding
versus we improved on bulk. However, we did look at the data because
some of the questions clearly relate to more bleeding-related questions,
and some related to bulk. And there didn\'t seem to be a difference. We
got benefit in both.

DR. NOLLER:  Yes, Dr. Roberts.

DR. ROBERTS:  One of the questions that I had that was not clear to me
from this was oftentimes it seems as if, if you have a, for example, a
submucosal fibroid and you\'ve got someone with bleeding, it\'s probably
that submucosal fibroid that\'s causing it. Even if they\'ve got other
fibroids that are subserosal, they\'re not causing the bleeding. It\'s
the submucosal one that is. My question is, if you had someone, let\'s
say, that was bleeding, and had multiple fibroids, could you target the
fibroid that you felt was causing the symptoms, whether it was bulk
symptoms or whether it was bleeding symptoms?

DR. STEWART:  Absolutely.

DR. ROBERTS:  You could.

DR. STEWART:  Absolutely, and in fact \--

DR. ROBERTS:  And you\'re saying that it didn\'t make any difference,
you could treat the one that you would say was probably causing the
symptoms, and it didn\'t make any difference, didn\'t help at all?

DR. STEWART:  No. What I\'m saying is that we saw patients who had
benefits in bleeding, and we had patients who had benefit in bulk
symptoms. But we did absolutely tailor the treatment to the patient
symptomatology.

Now clearly in some patients where there\'s only a single fibroid,
there\'s no decision making to be done. It\'s intuitively obvious if
there\'s one fibroid and you treat it. However, the second level of
assessment in terms of determining which fibroid to treat in women that
have multiple fibroids, is are there any that are unsafe to treat. And
so going back to the issues about is it too close to the spine, does it
meet our treatment parameters? We have to assess that. But barring an
exclusion for that, then we did have the patient symptomatology at
baseline and could then choose to have \-- for example, if the patient
had bladder frequency, and she had one fibroid that was clearly in the
lower uterine segment, and another that was up on the fundus and fairly
subserosal, we could choose to treat the one nearest the bladder as a
primary goal. And so we did tailor our treatment to the patients
presenting symptomatology.

DR. NOLLER:  Thank you, Dr. Stewart.

DR. ROBERTS:  Can I just \--

DR. NOLLER:  Yes.

DR. ROBERTS:  Just a follow-up. And were you successful in all of these
patients in treating the fibroid that you felt was the most likely one
to cause their symptoms, or were there patients where the fibroid that
you would have wanted to treat, you couldn\'t treat because of its
positioning?

DR. STEWART:  I don\'t believe there were any cases where we couldn\'t.
I can defer this to Clare. I think in almost all cases we were able to
target the primary fibroid that we thought was symptomatically most
important. And in some cases, we were able to target more than one in
terms of the limitations that we sometimes went into treatment saying
we\'d like ideally to treat two fibroids. And in some of those cases, we
could treat two, and in others we could only treat one. And I don\'t
know whether you would like to amplify.

DR. TEMPANY:  Yes. This is Clare Tempany again. No, I mean, absolutely.
It\'s very rare that we weren\'t able to treat a fibroid that we had
identified on baseline imaging. This one case that I remember that the
bowel literally had fallen all the way down between the fibroids and the
anterior abdominal wall so we didn\'t treat her, but very rare.

DR. NOLLER:  Dr. Weeks.

DR. WEEKS:  Jonathan Weeks. In your evaluable patients in the pivotal
study, as I recall, you had 20 some patients that went on to receive
other treatment, hysterectomy or other treatments. I think perhaps there
was a link there that ties into what Dr. Diamond was getting at. If many
of these patients had multiple fibroids, and over the course of six
months or a year you may have effectively treated one or two of the
fibroids, but one would expect that there would be growth in some of the
other fibroids. I think it would interesting to look at those images and
get volume information on the entire uterus for that reason.

And I also wondered if you got pathological information from those
treatment failures so that you could look at the extent of thermal
injury and the original fibroid sizes.

DR. STEWART:  Ebbie Stewart again. We have obtained tissue in as many
cases as we can from patients who underwent surgery, and we have at the
minimum gotten operative notes and pathology reports on everybody that
has gone on to have additional surgery.

We haven\'t been able to find any evidence that there was more extensive
thermal damage than was recorded at the time of the treatment, and there
was no case where there were found to be significant pelvic adhesions or
injury that suggested that there was damage to the serosal surface. And
clearly, we want to take those specimens and study them further from
here on out.

I think also the fact that women went on to a different treatment, we
have classified them as failures, and I think that\'s the right thing to
do for them. But many of them actually did have some significant
decrease in their symptoms from treatment, but then when they had a
recurrence of their symptoms felt that they wanted to go on to more
definitive treatment.

I think the constraints that we had in this protocol really maximized
safety, to make certain that we didn\'t get to the serosal surface, the
endometrial surface. We didn\'t ablate large volumes of tissue, but I
think that did limit our efficacy. And as we move forward, I think to
get maintenance and longstanding relief, we may either need to be more
aggressive in our treatment, or to choose different treatment
candidates. I think that the efficacy that we saw was very impressive
given the constraints that we worked under for the protocol.

DR. NOLLER:  Thank you. I want to remind the panel that this isn\'t a
question and answer between the sponsor and us. We are discussing among
ourselves. There just happen to be 60 people out there that are
listening in on our private discussion here, so let\'s try to discuss
and help each other out with answers. For example, as we had going
there, and then we\'ll turn to the sponsor if there are things we really
don\'t know that we need to know, but let\'s try to discuss some of
these among ourselves.

Were there other things about Question 2 that you want to discuss before
we move on to the next one?

DR. BRILL:  Well, I would just like to add that just as Dr. Stewart has
said, that our ability to evaluate these patients is relatively
primitive because of our lack of instruments. I think we\'re even more
primitive in our ability to explain why women do or do not bleed with
uterine fibroids, and even beyond that, it\'s incredibly presumptuous to
assume that a patient with abnormal bleeding and fibroids necessarily is
bleeding from those fibroids, and doesn\'t have a coincident
coagulopathy, and doesn\'t have some sort of coincident dysfunction at
the endometrial level which we haven\'t been able to identify.

With that said, what I\'m hearing in part is when you have a technique
that is a selective myomectomy technique, and unto that I think there\'s
some presumption, because clearly I do not which fibroid to selectively
destroy having multiple fibroids. We do know from the uterine artery
embolization data that the response in the context of diminished
abnormal uterine bleeding is not necessarily related to the location of
the myoma whatsoever, so I think that we\'re all sort of treading water
here, and walking on thin ice when it comes to really knowing what we
are or aren\'t doing, and deciding in a defining way which fibroid
we\'re going to treat.

DR. NOLLER:  Yes.

DR. ASCHER:  I have, maybe it\'s a naive question and I apologize. Does
not knowing the ultimate durability really change whether something is
effective even in the short term? And maybe someone in the panel or
elsewhere can address it. I\'m trying to get a handle on effectiveness.

DR. NOLLER:  Things can be effective for an hour, a day, a week, a
month, a year, for life.

DR. ASCHER:  Okay. That will certainly impact on some of the discussion.

DR. NOLLER:  I don\'t think we are going to consider approving something
that works for an hour or a day, but 10 days - where does it end?

DR. ASCHER:  Something like GnRH analog as a temporizing method. I mean,
there is some precedent for temporizing.

DR. NOLLER:  Particularly in the peri-menopausal. Did you have a
comment, Dr. Wood?

DR. WOOD:  I was just going to reiterate what I said before, that I
think the imaging out parameters as a surrogate marker of efficacy are
unreliable, and we should rely on them more for safety issues here. And
the bottom line is we don\'t have a perfect questionnaire mechanism,
quality of life mechanism, but they used the best one that\'s out there.

DR. NOLLER:  Other comments before we move on?

DR. BROWN:  So my answer to 2 would be that the volume does not seem to
contribute at all, because it doesn\'t seem \-- to me, the volume
changes were not impressive. And secondly, we don\'t know that that
means anything, but there were consistent changes in the questionnaire
that although the amount of effect was not as great at 12 months, there
still was some persistent effect.

DR. WOOD:  As an aside, the time course and volume changes are similar
to palliative thermal ablation with needle-based techniques for soft
tissue tumors and cancer, and the periation can happen. Again, maybe if
\-- I don\'t know the mechanism, nobody does, maybe decreased
interstitial pressures within the tumor can have an effect without
actually getting rid of the whole cancer, just as an aside again.

DR. NOLLER:  Should we move on to the third question? Here I think we
will need the sponsor to respond to some of the physics questions we
asked before. The third question is, has the sponsor demonstrated the MR
thermal mapping provides adequate intraoperative feedback during the
treatment regimen, sufficient to ensure safe and reliable dosing to the
intended fibroid tissue? Drs. Diamond and Roberts, any comments about
that?

DR. MILLER:  Dr. Noller, where are you reading these questions?

DR. NOLLER:  It\'s in your packet. The left-hand pocket. You may have
received a previous version. It\'s a couple of weeks old. It looks like
this. Okay. Yes, Dr. Crum.

DR. CRUM:  This follows up some of my earlier statements, and I\'d sort
of like to make a comment because we\'re sort of discussing this amongst
ourselves rather than asking the sponsor and so forth.

DR. NOLLER:  But we will ask them.

DR. CRUM:  So it seems to me that the monitor, MR temperature monitor
assumes that you get a temperature elevation. It\'s not an absolute
measure, it\'s temperature elevation. And it also makes the assumption
that after the treatment, we start in a sense de novo again at exactly
the same temperature that you started last time; that is, at 37. And
when you destroy the vascularity of that region, you also shut down the
perfusion. And so the perfusion is not a major factor in carrying the
heat away, but nonetheless, if it\'s adjacent to a treated region, the
heat has to go somewhere. So to assume that you\'re going to come back
to the initial conditions ab initio in each case, I think is a
questionable assumption.

The temperature increase that does occur in this model assumes some very
simplistic conditions, no non-linearity, no temperature dependent
attenuation, so forth and so on, so it\'s not surprising to me that the
prediction of the thermal dose differs from the non-perfused volume.
This is complicated stuff. I mean, doing modeling inside biological
tissue and these sorts of conditions are difficult to do.

But the endpoint of this is that after you do this treatment, you can go
back in and get a non-perfused volume that\'s correlated pretty closely;
that is a factor of like 2 or some number different from the computed
thermal dose. So even though there might not be a one-to-one prediction,
there is a correlation. And similarly, empirically one can get the
non-perfused volume, which I think is certainly what induces the
biological effect and the successful treatment, so I think that there
are some inefficiencies and inaccuracies perhaps in the thermal model,
but to answer the question, does this provide a reliable doing, with
some modification, yes. I think that that\'s true, and I would invite
you to comment on it.

DR. NOLLER:  Dr. Diamond.

DR. DIAMOND:  I have a question. Do you understand from the way the
machine works whether a second sonication would be adjacent to the first
one, or would it be some place far distant, because if it\'s next to it,
you\'re going to have a potentially greater thermal effect than if it\'s
at a big distance on the other side of the fibroid.

DR. CRUM:  I don\'t know how they do that. I know that in other
situations involving HIFU applications, focused ultrasound, people tend
to go here, then there, and then back and forth, rather than do the
adjacent one, so it\'s a question now for the sponsor to answer; do you
do adjacent ones, or do you do \--

DR. NOLLER:  Let\'s hold up just \-- did you have something to say, Dr.
Wood, and then we\'ll go to the sponsor.

DR. WOOD:  I was just going to say there\'s a spiral mechanism out
there, as well, which takes advantage of that very effect and changes
the modeling completely, and the effect. And one more question - maybe
you guys could answer while we\'re here - adjusting the calibration in
the beginning offset the test zone. That test zone, is it just done
once? And if not, do we have any information on how tissue
tissue-to-tissue interfaces in interactions between your transducer and
the fibroid can affect future inhomogeneities in your treatment zone?
And would it be more effective to have more than one test zone done?

DR. NOLLER:  Would you address those questions, please?

DR. TEMPANY:  Yes, I\'d be happy to. This is Clare Tempany again. To
answer your question about how we do the sonications, you can do it
either way. You can either go one, two, three, four, five and across.
More commonly, we will go from one part to the other. There is a time
penalty with that because you\'re moving the transducer. But certainly,
we receive the return to temperature baseline on the graph, so you\'ll
see it return to baseline temperature. If it doesn\'t return to baseline
temperature in the 90 seconds, clearly the easy thing to do is to move
to a completely different location and go to the opposite side of the
fibroid, and then take that even two or three sonications later before
you get back there.

And yes, we\'re continually verifying the location of the sonication
because you have the coordinates. So even if there is beam attenuation,
you will see whether it\'s off, and everything is registered both in
short axis and long axis. We can choose to do it in sagittal or coronal
plane. Does that answer?

DR. NOLLER:  Thank you. Other discussion on this topic?

DR. BRILL:  I\'d like to just to ask the technical expertise of the
panel, is there any concern that there\'s monitoring of the differential
between core temperature and realized temperature versus absolute
instantaneous temperature monitoring as it was presented this morning? I
believe it was stated that it was a differential between core
temperature, was it not?

DR. NOLLER:  Dr. Crum.

DR. CRUM:  I think the question was appropriately answered. If you have
a monitor that it drops back down to the background, they want it to
drop back to the initial condition. And I presume that the initial
condition was 37, so if it drops back to that initial condition and they
do not fire the second shot until you\'ve dropped back to the initial
condition, that you\'re back ab initio again, you\'re back where you
started. So I don\'t see that the core temperature is going to come up
very much, maybe 1 degree or so, but I don\'t see that being a problem
myself.

DR. DIAMOND:  I\'d like to ask also again, the FDA presentation, they
had two physics presentations, each of which seemed to be suggesting
that there are lots of potential where measurements and assumptions
could lead to big temperature elevations greater than might have been
expected and leading to tissue injury, but yet both ended up concluding
that the likelihood of injury was actually rare, and having given us
that presentation. What is your interpretation of that from what was
presented? Is that going to be an exceedingly rare occurrence, or are
the scenarios that we\'re describing as potential concerns, are they
things that are perhaps more frequent?

DR. CRUM:  I mean, I have lots of concerns, but for example, there was
no treatment of what happens if there is bowel gas. I didn\'t hear a
discussion of that. I\'m sure they have thought about that, but if you
have bowel gas, then you have other effects that are non-thermal,
cavitation. And the literature is full of descriptions if you have bowel
gas and you have either Lithotriptor or other kinds of even diagnostic
ultrasound pulses, you can get damage to the tissue in the bowel from
the result that you\'re trying to drive a pressure release interface.
That was not discussed. Maybe the sponsors could discuss that.

The other thing is that non-linear effects and changes in the various
tissue layers, as Dr. Wood was mentioning, will cause focusing in
different regions that you would anticipate. And, of course, they argue
that they do the sublethal measurement each time, and then they correct.
If they do that every time, then that corrects for that error. And so I
think that the FDA\'s analysis is that there is some areas that should
be watched, and I presume that those directions will be given to the
sponsor, and they will address those.

MR. WEEKS:  This is a question, and I have no idea what the answer is;
but the coupling gel itself, is there any reason to believe that there
can be a variation in say that quality assurance and the density of that
material, and as it\'s mass produced or whatever, can there be enough
variation that that changes the thermal injury or damage in any way?

DR. CRUM:  What happens with that is that \-- and I think that\'s been
addressed also, is if it\'s not adequately coupled to the patient, and
if you move around and you introduce a bubble or a void of some sort,
then you have a potential problem because then you\'re going to get a
skin burn or something.

MR. WEEKS:  I\'m concerned with like the density or say the density of
the material itself, so assuming it\'s got good skin contact \--

DR. CRUM:  It\'s typically acoustically transparent, so there\'s very
little attenuation in that material, and so there should be no effect on
that material from the ultrasound because it\'s essentially acoustically
transparent. When we have an interface with gas, then you can have a
problem, but not if you have adequate coupling.

DR. NOLLER:  Dr. Samulski, did you have \--

DR. SAMULSKI:  I agree with this off-the shelf kind of interface that
you use when you use ultrasound in a clinic for diagnostics, and this
application as well. I think the sponsors must have tons of data testing
animals and stuff like that, and could give you an idea of what the
outcome was.

DR. NOLLER:  Why don\'t we stop at this point and see if the sponsors
have any comments regarding this discussion that\'s been going on for a
few minutes.

DR. VORTMAN:  Kobi Vortman, employee from InSightec, paid by InSightec.
I\'ll try to address first the cavitation. Cavitation was a major issue
in the design of the system. We had a real time integrated detector that
continuously during the sonication is receiving the signal and looking
for any clue for cavitation, which right now is between half of the
frequency and then several minutes. In our training or in our
instructions for use, the spectrum appears. You can see it here.

On the left side you see a different spectrum without the cavitation.
Okay. And on the right side here, you could see what happens when the
detector detects cavitation. You\'ll see a wide spectrum white noise,
and the user is instructed to immediately switch off the system in this
case, and move to some other place.

And as Dr. Crum said before, cavitation pressure could change as a
result of temperature and so on, so this is a major tool. I would add to
this that in addition to the cavitation at that point, we have a
reflection detection continuously. So if the signal received by the
system is detecting any air bubble or air surface, the system will
detect it, and again the user is instructed to switch off. Okay. So
that\'s, I believe, in response to \-- here you could see the reflection
detector. And what we do, in addition to measuring reflection, we are
measuring it on the scale, AP coordinate, so you will be able to
allocate it to the area which generated the reflection. So if it be
internally, the bandwidth would be 76 or 102. At the interface between
the transducer and the skin line, it would be 50, so you would be able
to allocate the reflection to whatever place.

DR. CRUM:  May I just ask you if that\'s a passive cavitation detector
or an active cavitation detector?

DR. VORTMAN:  It\'s a passive.

DR. CRUM:  Passive, and what\'s the bandwidth?

DR. VORTMAN:  The bandwidth is between 20 kilohertz and about three and
a half megahertz, while we\'re working at 1.1.

DR. CRUM:  So you\'re just looking at the subharmonic, are you not?

DR. VORTMAN:  Correct.

DR. CRUM:  And you realize the subharmonic means stable cavitation,
which means that if you had this kind of intensity, you would get
inertial cavitation rather than stable cavitation.

DR. VORTMAN:  Of course.

DR. CRUM:  Why wouldn\'t you be looking in a bandwidth up around 10
megahertz or something like that?

DR. VORTMAN:  Okay. What we have said before, we are using continuously
thermometry of the whole field of view, so if you will have any
non-linear effect, like CW cavitation, we\'ll be able to see non-linear
effects through heating, and detect it immediately, so we are using
both. We are using both passive detector and thermometry to monitor
those non-linear second and certain harmonic effects.

DR. CRUM:  Do you ever think that maybe the reason the thermal model is
not working is that you\'re getting submicroscopic cavitation, and
that\'s coupling through the bubbles through increased heating?

DR. VORTMAN:  This is an issue that we addressed extensively. The
predictor in our system, both in our accumulated experience, is
over-predicting the dose. Okay. So we didn\'t see effects like this at
the levels that we are working. However, it could have been, and as
I\'ve said, it will have something like this. This should translate to
either moving down, shifting down the focus immediately, if the focus
were generating, or at some point in the way overheating. So we are
training our user to watch for this.

DR. CRUM:  So when you did histology, did you ever see cases where you
had non-cigar-shaped lesion in some areas that were not treated because
of the non-symmetric shape of the lesion indicative of some kind of
inhomogenetic effect?

DR. VORTMAN:  WE\'ve seen it in animal work. Since we\'ve driven the
system into a very high intensity and we have seen in this case.

DR. CRUM:  What about the hysterectomies?

DR. VORTMAN:  Didn\'t see it there. We\'ve seen \-- scoped minimum
number of cavitations that were switched off.

DR. NOLLER:  While you\'re there, let me just ask you one question. You
said that the operator is instructed to turn off the machine, but
there\'s no automatic shutdown, or is there?

DR. VORTMAN:  Correct.

DR. NOLLER:  Thank you. Okay. Yes. Another point?

MR. NEWMAN:  If I could just finish answering the question too about the
acoustic gel. The acoustic gel, we buy it from Parker Laboratories.
It\'s a general manufacturer of it, and it\'s a one-time use. Parker
pours it for us in a specific shape. It has an expiration date. We use
it for a single patient treatment, and then it\'s discarded. So we\'ve
done the biocompatibility testing and all that kind of stuff. Parker has
done that already. And if there was an issue with a problem with the
density or the acoustic properties of it, you\'d see it through the
reflection monitoring when you did the testing of the treatment before
the patient is put on the table. We set the system up and we put a
phantom patient, if you will, on top of a tissue specific phantom on the
acoustic coupling gel, and do a quick in-room check before the patient
is put on the table, that we would detect a problem like you had
suggested.

DR. NOLLER:  Thank you. Let\'s move on to question 4. A number of
adverse effects specific to ultrasound treatment occurred during the
clinical trial, including nerve injury, leg pain, and skin injury.
Question: Do the results from the thermal modeling and our understanding
of the underlying physics provide sufficient information to understand
the etiology of the injuries that occurred in the study?

I\'ll respond. I think the presentations did a very good job of
explaining how the people got the injuries, I thought. It\'s a different
question whether or not there are adequate ways to prevent them, but I
thought the explanation made sense. Any comments? Dr. Diamond.

DR. DIAMOND:  I thought for the skin injuries, that was well-explained,
and I don\'t have any questions. For the nerve injuries, some data was
presented to us about incidence angle and estimated distance form the
focus to the sacrum. Other things I guess I would have liked to have
seen what was what known about the number of pulses, sonication pulses
that went to the area where the nerves were in those patients. What
happened to the temperature thresholds, and we\'re shown example of how
if it\'s a little bit too high, the next sonication they lowered the
energy. What do we know about the patient actually got injured? Did they
have higher energy that was transmitted?

DR. NOLLER:  It would be particularly interesting in that one page they
had months to resolve that.

DR. DIAMOND:  Yes, the 9019, yes.

DR. NOLLER:  Other questions? Yes.

DR. CRUM:  I\'d like to ask either Dr. Herman or the InSightec people if
you\'ve examined the side lobes, because when you show these pictures,
you assume a nice conical shape input for the focus wave, a nice conical
on the outside. What happens, of course, with acoustic propagation is
you get what we call side lobes, which means that it doesn\'t follow
that nice conical thing. So if you had side lobes, you would get hot
spots outside that area. If you had a hot spot on the nerve in which you
didn\'t think you were illuminating you could get some damage. So I
don\'t know whether Dr. Herman has modeled that or whether InSightec
people have modeled that, but I\'d just like to ask that question.

DR. NOLLER:  Do you have a response? Please.

DR. VORTMAN:  Again, Kobi Vortman. Yes, we have extensively modeled side
lobes. The design of the transducer is such that normally you don\'t
have any side lobes. The distance between elements and the number of
elements is such that you don\'t have any deviation from a closely
spherical surface. In addition to this, we have in system tissue
aberration correction that is used \-- I\'m now probably getting into
too much detail but I\'ll say the following. We are using the MR image
in segmenting between muscle and fat, and this could be downloaded to
the bin former to correct for tissue aberrations, speed of sound and so
on, so the bin former takes this in and refocuses the focus.

The third point is you have real-time feedback on the focal shape in any
second hot spots from the thermal image. So that is the reason we\'ve
addressed it.

DR. NOLLER:  What about the answer to Dr. Diamond\'s question? I\'d like
both the sponsor and FDA to respond to that, if possible, about
particularly looking at those patients that had injuries, if you learned
anything from those.

DR. ROBERTS:  Could I also just ask maybe a part of that, is that
you\'ve set up a 4 centimeter distance. My question is did any of the
patients who have nerve injury, in fact, be within what you would say
now is within 4 centimeters, or were there ones where everyone outside
of that 4 centimeter area and still had a problem? So I guess my
question is, do we really know that 4 centimeters really means anything,
or is that a theoretical construct?

DR. VORTMAN:  Again, Kobi Vortman. What is done, we\'ve looked at energy
intensity. The factor that generates the heating is energy intensive
heat, and it\'s a multi-parametric problem. It\'s not only what is the
energy intensity, it is what are the incidence angle of the beam
impinging on the bone? If this will be above 38 degrees, you will have
no heating at all. So we assumed that the combination of 4 centimeters
that is keeping the energy intensity at a reasonable level, and
non-perpendicular bin would build this into a safe environment, or
envelope.

Have we seen cases in which even more than 4 centimeters and we had some
leg pain? The answer is yes. And many of those cases that I\'ve looked
at, the bin was perpendicular, so you need to use both. One wouldn\'t do
the job.

DR. NOLLER:  Did FDA have any comments about that?

MR. HERMAN:  I think we would agree with that.

DR. NOLLER:  Give your name, please.

MR. HERMAN:  My name is Bruce Herman. We would agree with that
assessment with the caveat that while searching for non-normality and
the 4 centimeters are definitely steps that would markedly mitigate the
possibility of adverse effects to the sacral nerve or something, it
wouldn\'t \-- considering what I think I know about the possible
variation of physical structure, wouldn\'t absolutely rule out the
possibility. But again, go a long way to minimize the possibility of
those effects.

DR. NOLLER:  That helps us too with the next question.

MR. HERMAN:  It\'s not an absolute demarcation as you mentioned, below 4
centimeters you can get damage even with normality and beyond. You
can\'t. But putting both together gives, I think, a broad range of
physiology and tissue characteristics. Looking at it with a fairly
conservative eye, a reasonably good possibility of having only very rare
occurrences of, let\'s say, sacral nerve damage.

DR. NOLLER:  Thank you.

DR. DIAMOND:  Dr. Noller.

DR. NOLLER:  Yes.

DR. DIAMOND:  I find both those answers actually sort of unsettling,
because the data that was presented to us by Dr. Del Mundo, three out of
the five patients who actually had nerve injury had incidence angles of
30 degrees or more, and distances of 4 centimeters or greater. I\'m
uncomfortable, which is why I was asking are there other parameters,
such as thermography or other ways that you\'ve looked at those patients
where you could shed more light on that information to us, and give us a
greater degree of comfort for the future above and beyond just these two
criteria.

DR. STEWART:  Ebbie Stewart again. I think the clinical input is also
important here. This is where the patient having conscious sedation and
being able to respond to discomfort, that the patients who do have
heating of their nerve typically do feel sacral pain, buttock pain, and
are able to terminate the sonication. In that case, there can be
reassessment of the treatment plan, and moving of sonication points. I
think the index case where there was a significant nerve injury, first
of all, caused us to focus in more carefully on what was going on in the
far field. And I think a lot of our mitigation steps have brought that
to bear. But I think the other thing it\'s made us very cognizant of is
the fact that interacting with the patient and responding to discomfort
that she presents is important, as well, because oftentimes when the
patient is having right buttock pain and you\'re sonicating near the
right serosal surface of the fibroid, that\'s an indication that you are
potentially getting some nerve heating, and that you should move before
anything more happens. That I think nerve injury certainly can take
place at the time of hysterectomy, as well. There are well reported
cases where the retractor or the positioning caused this to bear. But we
do have feedback, and now we have over 600 cases where we haven\'t seen
a significant nerve energy.

DR. BRILL:  Do you have a number of instances where patients complained
of heat but didn\'t have any deficit thereafter?

DR. STEWART:  Absolutely. And, in fact, that\'s been one of the major
things that we focused in on in the continued access protocol. The study
sheets for the continued access protocol actually ask you are there
sonications where the patient has pain? And then you record the
sonication number, you record the pain, you record the intensity of the
pain, and so we have been very cognizant of what\'s going on and
interacting with the patient.

DR. BRILL:  Do you have those numbers?

DR. STEWART:  Which numbers?

DR. BRILL:  Do we know reported instances where there were not deficits
thereafter, how many?

DR. STEWART:  Probably, Clare, maybe you have a better sense than I do.
I think a lot of patients will report pain during sonication, that
certainly there is back pain from positioning, as well. But most of the
pain they have is fairly mild to moderate, and it\'s pretty rare to have
severe pain during sonication.

DR. NOLLER:  The question is do you have numbers of patients?

DR. TEMPANY:  No, we don\'t have numbers but almost every patient will
feel a sensation at some point during the procedure related to a
sonication, be that something in the skin, cramping in the uterus or
something in their back. And that\'s why I constantly am asking them
before we hit the sonication button telling her we\'re about to do one,
and then afterwards how do you feel about that? And then if there\'s any
sensation I move to a different place like I just described, to the
other side of the fibroid to allow that area to completely cool down,
and then try to come back again. This is constant feedback.

DR. NOLLER:  Dr. Roberts.

DR. ROBERTS:  I\'m a little bit confused though because you say that all
of these patients have positional pain, whatever. Is there something
very specific about this complaint of pain that makes you feel that this
is going to be a nerve problem? I mean, is there something that the
patient describes that you then say uh-oh, I better move to some place
else? Or do you just say well \-- what I\'m thinking about is I\'m
trying to think ahead. Okay. Now you\'re going to have instructions for
use, and how are you going to explain to your users and to the patient,
you need to tell me when you feel like this, because that means I need
to move what I\'m doing, as opposed to well, my back is getting sore and
so you give her some more drugs.

DR. TEMPANY:  Oh, absolutely. I mean, we give her guidelines ahead of
time, and I explain the sensations that I expect potentially during a
sonication, ranging all the way through from near field to far field.
And when it\'s related to nerve stimulation, they are going to feel an
electric sensation going down their back.

DR. ROBERTS:  Okay. So it\'s a specific type of feeling that they\'re
going to have.

DR. TEMPANY:  Yes.

DR. ROBERTS:  It\'s not with a dull ache in their back. It\'s going to
be electric shock.

DR. TEMPANY:  Yes. And it\'s absolutely temporally related to the
sonication.

DR. ROBERTS:  Okay.

DR. TEMPANY:  Where if it\'s positional, it\'s going to be there no
matter what we\'re doing.

DR. NOLLER:  Dr. Crum.

DR. CRUM:  Larry Crum. I just wanted to point out in some unpublished
data, there is a company in the Seattle area that\'s doing catheter
wound sealing with ultrasound HIFU. And, of course, near the femoral
artery there are several nerves, and they actually use this as an
indication of when they\'re targeted. They say do you feel the pain, and
when they do, then they move. So nerves are very sensitive to this rapid
thermal increase.

DR. TEMPANY:  Yes. And the patients can give you instant feedback.

DR. BRILL:  Is there anyone on the panel who at least can help me
understand whether the pain is coming from a thermally perceived event
on nerve? Is it something that\'s physical? And if it\'s thermal, then
how good is our modeling for temperature change during this process? I
guess I\'m still confused.

DR. NOLLER:  Dr. Wood.

DR. WOOD:  Brad Wood. I think the modelers are confused as well as the
physiologists because we don\'t know. I think the assumption is that
nerves are more sensitive in normal tissue to damage, and there\'s a
spectrum of damage. And we\'re seeing that in some of these adverse
events.

There\'s actually \-- you can do thermal neurolysis where we target the
nerve with a certain temperature and burn the nerve on purpose for
therapeutic pain relief, and there\'s a method there for pulsed radio
frequency where we use a 42 degree level, and apply milliseconds of
pulsed energy through a needle, measure the temperature at the spot
where we\'re delivering, and 42 degrees is therapeutic there. The pain
fibers are more sensitive in a nerve than normal fibers to heat effects,
and there may be some other effects going on there that may change the
conduction specific to that frequency, which is different than this. But
there\'s a number of issues here that are complex, and I think looking
at the thermal modeling of the nerve damage, for example, you know, the
number of assumptions there. I think we\'re kind of dancing around the
issue.

I don\'t think we have a true handle. I mean, certainly mitigating steps
are helping to decrease the risk and have helped, but I don\'t think we
have a true handle of the \-- from a scientific point of view what is
actually going on in there when it\'s dependent on conduction from bone
back to the sacral nerve, and that conduction is affected by convective
heat loss of nearby vessels, and the properties of the tissue nearby,
and those tissue properties change as the heat goes up, so I think it\'s
all \-- I don\'t think we know really from a modeling point of view, or
scientific point of view, except that the nerves are more sensitive.

Another issue that comes up when we treat therapeutically, not
neurolysis, or not treating nerves for pain. In this case again,
treating cancer near nerves for pain. Treating cancer near nerves for
pain in order to get rid of the cancer with thermal ablation
needle-based, we will do it with conscious sedation. We\'ll keep that
sedation very light during the whole procedure, and there is a typical
\-- we\'ll train the patient beforehand extensively. If you feel this
symptom related to whatever nerves were near, and we know what those
nerves are going to feel like depending on the innervation, if you know
that symptom and if that develops, let us know right away. And we keep
them light, and it\'s a painful procedure for the patient because we
don\'t give them the sedation that they need. It\'s a conscious
sedation. It\'s not a deep sedation, so it\'s a very challenging thing,
and I would ask you all how are you going to ensure that users and
physicians are going to be able to titrate this fine balance between
sedation and feedback, which is imminently related to the safety for
nerve damage. It\'s a hard thing to do. Is there any level of
consciousness issues?

DR. NOLLER:  Can I ask you to hold? Let\'s do that as part of the next
one, because I think that\'s an important question, but I think it fits
better with Question 5, than Question 4.

DR. MILLER:  Can I ask something about Question 4? I\'m just wondering
from our panel if there\'s any sense that the extent of nerve injury is
understood in the brief proximity of follow-up. In other words, is there
any reason to believe physiologically that there might be nerve injury
that hasn\'t been perceived yet, because it\'s going to take longer.

DR. NOLLER:  Three years, four years, five years.

DR. MILLER:  Right. Clearly, these nerves are getting energy of one kind
of another.

DR. NOLLER:  Anybody on the panel a neurologist?

DR. ROBERTS:  My personal feeling is that if you get nerve injury,
you\'re going to find it out quickly. Unless you have a lot of scarring
or something in the area that later on develops some kind of nerve
problem - I mean, I suppose that\'s possible - but I suspect that with
this kind of things it\'s going to be presumably a thermal injury, and
it\'s going to occur at the time that \-- or right around the time that
you start this whole process, or do this whole process.

DR. NOLLER:  Dr. Crum.

DR. CRUM:  I have a Ph.D. student who\'s trying to develop a HIFU system
to treat chronic pain, and so what we\'ve done is done various levels of
intensity and looked at the histology of the damage to the nerve system
on animal models. It\'s a pretty complicated thing. We don\'t understand
it yet, but I think this follows Dr. Wood\'s comment. I don\'t think
you\'re going to find out in a human, and it\'s a very complicated thing
even in an animal model, so I don\'t have anything to add other than it
is much more sensitive. The nerve is more sensitive to the thermal
effect than other tissue. And there are various degrees of damage. You
can damage the myelin sheath, for example, and cut down some pain. But
again, that doesn\'t totally disrupt the axon conduction.

DR. NOLLER:  Dr. Wood.

DR. WOOD:  I agree totally, but I can\'t imagine seeing any subacute or
chronic effects from thermal induced damage to a nerve. You get what you
get, and you\'re not going to see anything down the road. I think the
six to twelve month follow-up we have here is perfectly adequate to
assess those issues.

DR. NOLLER:  Let\'s move on to Question 5. And for this the chart
that\'s attached is important. Adverse effects, noted potential risks
related to the use of the device prompted the development of active
mitigations as identified in the attached chart. Are these mitigations
sufficient to ensure safe use of the device? Given the effectiveness
achieved, do the benefits outweigh the risk for this device? Let\'s
discuss this a bit, and then we\'ll ask the sponsor to also discuss it.

DR. BRILL:  I think it was alluded to this morning. At least for me,
I\'m still confused as to how the 15 millimeter, 5 millimeter, 33
percent formula was established. My sense was that it was to minimize
the chance that there would be a thermal margin that would affect
something vital.

DR. NOLLER:  And some of that has been changed now in the continued
access protocol.

DR. BRILL:  So I guess I need to understand some objective explanation
that substantiates these parameters.

DR. NOLLER:  FDA, were those distances chosen based on literature and
sort of a best guess? Okay. The distances that were in the original
protocol, 15 millimeters from serosa and endometrium, 30 percent volume.
Were those based on best guess of safety? This should be safe. Was that
the idea behind those numbers?

DR. DEL MUNDO:  Basically, it boils down to a check on what we felt to
be safe from the pre-hysterectomy studies. As Dr. Corrado had mentioned,
there was one occasion where an area of what appeared to be an area
affected by sonication outside the capsule of the fibroid was noted, and
that along with increased volume that we saw that was greater than the
treatment, those all factored into our decision and the company\'s
decision for those particular margins and volumes.

DR. NOLLER:  Thank you. Yes.

DR. ASCHER:  What was the thinking to disregard any concern about the
endometrial requirement was dropped for the continued access study? Did
they do hysteroscopic looks? Was there any incidence of adhesions caused
if you had a sonication that crossed the endometrial canal and just a
little \-- I don\'t understand why that was \--

DR. NOLLER:  I was wondering the same thing. You knew what I was
thinking. My thinking was kind of who cares, but maybe there\'s more to
it than that.

DR. ASCHER:  You know, I can see that these women maybe aren\'t going to
get pregnant because that was a contraindication, but if you caused a
significant adhesion if they\'re peri-menopausal and still having
menses, an adhesion could be \--

DR. NOLLER:  To the endometria or \--

DR. ASCHER:  Yes. So I didn\'t know, did anybody look hysteroscopically
and see that there was no problem, or if crossing the endometrium had no
clinical sequelae?

DR. NOLLER:  Dr. Crum.

DR. CRUM:  I don\'t want to address that issue. I want to talk about
another issue, so if you want to follow-up on her comment.

DR. NOLLER:  Any more thoughts about that? Dr. Stewart.

DR. STEWART:  Ebbie Stewart. We haven\'t seen any endometrial damage
throughout the protocol. We haven\'t had any patients who underwent
procedures who were documented to have adhesions. We also haven\'t seen
what has been seen with some uterine artery embolization patients, and
that\'s the fibroid being expelled vaginally, so I think maybe \-- I
can\'t speak for the FDA on why that was an original constraint, but we
certainly haven\'t seen any endometrial problems. Now certainly, our
patients were chosen because they weren\'t interested in future
fertility, so there could be some issues there for the future.

DR. NOLLER:  Dr. Crum.

DR. CRUM:  This enhanced volume effect, I think is very important, so
there\'s two hypotheses that sort of contribute to how cysts form or its
consequence. One is that it\'s ischemic, and that makes a lot of sense.
That sort of effect shows up in Lithotripsy a lot, and I think that\'s
probably right. If that\'s true, then because the fibroid, as I
understand it, usually comes from a central blood supply, so if you have
enhanced volume effect, you proably would only damage the fibroid, and
you wouldn\'t go somewhere else if it\'s basically coming from that
central blood supply.

On the other hand, I\'m not really impressed with some of your thermal
modeling, and it could be it\'s a thermal modeling effect, and that
you\'re not correctly addressing the thermal modeling. That is to say
that the volume that you calculate in terms of thermal dose is much less
than what you actually get, and if that\'s true, now you do have to
worry about damage to the endometrium and other areas.

DR. STEWART:  Ebbie Stewart again. Certainly, there is a possibility
that the extension of treatment is via an ischemic effect. Certainly, in
the pathology that we examined, we tended to see more coagulative
necrosis, rather than ischemic necrosis. But we also had a relatively
limited number of samples and a short sampling interval.

There is also another explanation from the fibroid literature, and that
comes from some experiments where in trying to assess the feasibility of
gene therapy for fibroids, Greg Christman at the University of Michigan
has shown that you get a substantial bystander effect, that if you kill
one cell, you get substantially more cells that are killed. And his
hypothesis is because gap junctions are frequent in fibroids, that if
you generate tissue death, then apoptotic mediators may be able to be
spread through the fibroid. And so I think everything that we\'ve seen
does suggest that the extension of damage is to the treated fibroid. The
one case where there was damage at the serosal surface was incorrect
targeting and was not an extension of the injury passed that border.

DR. CRUM:  Just follow that up, can I follow that up with a question?
Larry Crum. Forgive this comment, but I mean, if it\'s ischemic, why
don\'t you just go in and treat the major vessel supplying your fibroid?

DR. STEWART:  That\'s one \--

DR. CRUM:  You can see it with ultrasound, you know.

DR. STEWART:  Yes, that\'s one strategy we have contemplated for the
future. I think the vessels don\'t really come from the center of the
fibroid, they come from the periphery, so that gets to our margin
errors. But one of the things we would like to do in the future is to be
able to compare interstitial treatment to peripheral treatment to kind
of address that question.

DR. NOLLER:  Let\'s focus a bit on these mitigations. That\'s what the
question is about. We have four risks in the table, and the mitigation
in the pivotal study, and then the continued access study. Are there
things there that people are uncomfortable about? We\'ve already talked
about the unintended heating of bone and nerve for some length, the skin
burns. It appeared to me that with careful attention to the skin,
they\'ve been able to mitigate that problem. Adjacent anatomy we were
just talking about a bit. Other comments about any of those four?

DR. BRILL:  Well, just for my own clarification, on one hand there\'s 4
centimeters between treatment focus and the sacral nerves, which I
believe is a function of heat transfer, and that would be the issue. Now
we have a minimum of 15 millimeters to the outside of the uterus, which
has bowel on the surface. Now we\'ve kind of visited this issue on a
previous panel before, and is there any cause for concern that on one
hand we\'re seeing the 40 millimeters between the maximum temperature
and the sacral nerves, and yet we turn it down to 15 for maybe a piece
of bowel that\'s on the surface of the uterus.

DR. NOLLER:  Any comments?

DR. WOOD:  Speaking from other thermal techniques, 15 is plenty. We can
\-- with care and experience, you can get very close to bowel, a little
risky, obviously, but you can get closer than 15 millimeters and a liver
with bowel touching it. Perfused organ, different issues, more prone to
convective heat loss, but not as sharp of a margin as focused ultrasound
between heated and unheated. So assuming no secondary side lobing or
tissue-tissue secondary burns, which it sounds like they are not, it\'s
probably adequate.

DR. MILLER:  My question relative to the unintended heating of adjacent
anatomy has to do with the patient movement. I mean, I know that the
patient is situated and they\'re sedated, but they\'re also in that tube
for a while, and there\'s lots of sonications. If they have an itch or
they get a scratch while they\'re being sonicated, aren\'t you going to
be heating unintended tissue?

DR. TEMPANY:  Certainly, we don\'t want the patient to move. We have a
nurse who hopefully can scratch their nose for them. But seriously, we
can see motion. And certainly in the feasibility trial where we didn\'t
empty the bladder, we did see motion. And when you see significant
motion, a millimeter or two, you stop the treatment, and you actually
replan all over again, so that\'s what we actually did several times I
can tell you, much to my frustration at times because it was restarting
all over again. You replan and you draw the circles again, and then you
replot your sonication so if there\'s significant you can definitely do
that.

DR. WOOD:  Another sort of side point - Brad Wood. The fiducials, is
there a least common \-- is it dummied up enough so that the end user
has to use fiducials? And if so, do they have to use a number of them,
not just one?

DR. TEMPANY:  Yes, remember the drawing \--

DR. WOOD:  But that\'s a requisite.

DR. TEMPANY:  Yes. That\'s a step in the prep process.

DR. NOLLER:  Dr. Hayes.

DR. HAYES:  I was wondering, is the nurse the one that monitoring this
conscious sedation such that they will be able to tell you of
discomfort, but yet be quiet enough? Who\'s monitoring the conscious
sedation?

DR. TEMPANY:  Myself and the nurse, the doctor performing the procedure
and the nurse. The nurse is actually in the room right beside the
patient, so she\'s closer and can maybe hear her slightly better
sometimes. But between both of us, we\'re both \-- we have monitors as
far as the pulse, blood pressure both inside and outside the room, but I
think you\'re asking about discomfort. So discomfort would be reported
either directly from the patient to me, or the patient to the nurse.

DR. HAYES:  And I understand there were three stop sonication buttons.

DR. TEMPANY:  There are, yes.

DR. HAYES:  You, the patient, and the nurse.

DR. TEMPANY:  Yes.

DR. HAYES:  And I wonder \-- I didn\'t hear too much discussion about
indeed when they were used, and if, in fact, how they correlated with
any of these adverse effects.

DR. TEMPANY:  Right. Good question. They\'re used, and usually when it
was used, it was when the patient was experiencing severe sciatic nerve
pain, so she would stop it off. That\'s the most common time it
occurred.

DR. NOLLER:  Thank you. Dr. Diamond and Dr. Brill.

DR. DIAMOND:  As far as potential other mitigating factors that could be
taken, beepers go off, and phones ring, and I could see someone be
distracted and glance away when someone is moving or when something else
is happening. Maybe some of these can be built as failsafes into the
machine. The MRI picks up motion, then it shuts off during the
sonication, or if picks up some of the cavitations, if I understood that
correctly, that it would automatically shut off, rather than relying on
an end user who could be distracted momentarily.

DR. NOLLER:  Dr. Brill.

DR. BRILL:  Just another reflection now, picking up what Dr. Wood said
previously about the neurolysis. It\'s my understanding in the FDA
presentation this morning, that at least with the thermal modeling, with
a 90 second cool down that there are two curves that are generated. The
lower curve, which is the best case scenario, there was a variation of
39 to 42 degrees. And you just said that for neurolysis you go to 42
degrees.

DR. WOOD:  This potentially is a different mechanism. That pulsed radio
frequency, 500 kilohertz.

DR. BRILL:  So if that\'s the case, she \--

DR. WOOD:  That may not be thermally mediated. That could be mediated by
impairment of the electric neuro conduction potentially \-- so that may
be a different mechanism.

DR. BRILL:  So I\'m bringing that up as a point, as perhaps the 90
second interval may be something that\'s worth looking at in the context
of a larger window of safety, if indeed the nerves are more sensitive
than realized to thermal effects.

DR. NOLLER:  We have six minutes before our break, but let\'s start on
Number 6. Total abdominal hysterectomy was selected as a control group
in this study in order to allow for comparison of rates of recovery and
serious adverse events between ExAblate and what has been seen
historically as the standard of care for uterine fibroids. However, this
was not a randomized study, and ExAblate patients differed significantly
from TAH patients and BMI, really prevalence, not incidence of diabetes
mellitus, hypertension, anemia, and other chronic conditions. Are the
results of this study sufficient to demonstrate clinically meaningful
comparisons regarding the safety of the ExAblate procedure compared to
total abdominal hysterectomy?

I\'d just like to mention there, it says standard of care for uterine
fibroids is hysterectomy. That\'s certainly not true. The standard of
care is observation, but in patients with severe symptoms, TAH has been
a rather common procedure used. But the question is, do we think that
this is a meaningful comparison.

Now again to \-- we need to remember that the study was designed in
conjunction with the FDA, so the sponsor did what was decided. But do we
think that what was done gives us a feeling that this is a procedure
that gave meaningful clinical results? Yes, Dr. Brown.

DR. BROWN:  In my opinion it was \-- short answer, no. I don\'t \-- to
me in evaluating this, comparing it to hysterectomy, that doesn\'t \-- I
don\'t really quite get the clinical relevance of it. It\'s like
comparing \-- you know, you\'re doing something that you know is
completely different and has a whole different set of complications,
that there\'s no way you would see, but I don\'t know that that\'s
really germane to looking at the safety of this particular \--

DR. NOLLER:  Really efficacy we\'re on now.

DR. BROWN:  Or the efficacy, but this is clinically meaningful
comparison regarding the safety of ExAblate compared \-- is that
supposed to be efficacy, that word? It says, \"Are results of the study
sufficient to demonstrate clinically meaningful comparison regarding the
safety of ExAblate\"?

DR. NOLLER:  Yes, that does say safety, doesn\'t it.

DR. BROWN:  So to me, the answer to that is no. I don\'t know why you
would be shocked if \--

DR. NOLLER:  The ExAblate, it had certainly fewer complication than TAH,
but you\'d expect that for anything, except maybe radical hysterectomy.

DR. BROWN:  No, but I mean it\'s a general anesthetic. I mean, it\'s
totally different.

DR. D\'AGOSTINO:  I mean, even the fact that they had the patients at
different locations as opposed to the same location, I mean not only I
think was suggesting a randomized controlled trial against a sham
operation, but I mean, we do these things in cancer. We do it in
cardiovascular. We get individuals who could have qualified for a
particular procedure, and we ask them if they\'d be willing to try some
new procedure, and you possibly could have randomized the two different
procedures. But even in that, if you didn\'t want to go through a
randomization same location, trying to do a propensity score adjustment
is just \-- I mean, it\'s wishful thinking when you only have something
like 73 subjects.

DR. NOLLER:  I guess the thing that appealed to me about the different
sites, even though normally I wouldn\'t think it\'s a good model, is
that if it weren\'t randomized, if it were at the same site, I would
think you\'d have a terrible uncontrolled \--

DR. D\'AGOSTINO:  Exactly, then you might. But then you might be able to
do some kind of a propensity score adjustment because you have sort of a
similar group of subjects. You don\'t really know what you have here.

The other thing that\'s bothering me is the time on this here. Again,
granted they\'re thinking of six months, but the FDA is saying we want
to follow these individuals for three years, or we want you to follow
them for three years. By the end of the year, the study has fallen
apart. I mean, you have 23 people switching or taking an alternative
treatment. You have four who have taken a second focused ultrasound, and
you have 11 who had less than 10. So if you forget the efficacy, if you
wanted to talk about safety, what is the safety, after six months or
after 12 months? You\'d have different safety comparison if you start
saying what happens to these individuals by the end of 12 months,
because a number of them now are taking alternative procedures, and
unfortunately being blessed with all of the curses of the more serious
procedure. I really don\'t know what we can make of this, personally.

DR. NOLLER:  And it was pointed out before the days of lost work and so
forth for those that had to have a hysterectomy, and were not added in.
Mike.

DR. DIAMOND:  Unfortunately, I think the control group as it is is
worthless in a word. But a couple of people have made the comment that
we should not have considered the sham group here, and I think that\'s a
real viable option. I can envision a study where patients would get on
the machine, everything would be going through. You either would or
would not turn the machine on to sonicate, and patients wouldn\'t be
told what was done or not. And obviously, this would all be in the
consent form. They know they\'d have a 50 percent chance or whatever it
is of being assigned to that arm, and they could be promised that if
they\'re in that arm, and then they decide they have to go for further
therapy, that at that point they could be treated like that. There would
be some patients that wouldn\'t participate, but I think there would be
many that would.

And with all due respect, the comment that it\'s not ethical to
randomize patients into it, now we have a situation we\'re being forced
to see whether we\'re going to recommend or not this device. And we may
have end with patients going in in the future with a device that\'s
approved and being used, without truly being demonstrated to be
efficacious. And unfortunately, it gets even worse because there are
other situations which have been looked at for pelvic pain in women,
both for uterine fibroids and adhesions where placebo controlled studies
have shown that at three and six months follow-up, the placebo treated
group, again the patients weren\'t told whether they were treated or not
had benefits on severity of symptoms scale. And so without a comparison
arm to assess the primary endpoint here, I don\'t know what we\'re left
with.

DR. NOLLER:  Dr. Weeks.

DR. WEEKS:  I would agree with Dr. Diamond in terms of study design. And
especially if it were a pre-hysterectomy type trial, where everyone
ultimately will get a hysterectomy say six months later. As far as
safety, comparing this to TAH, I agree with Dr. Brown, I think is not
really appropriate and helpful. Given the constraints that the sponsor
had, my feeling is two key factors here. First, some misunderstanding
about the length of follow-up, and I think we have to acknowledge that
that probably impacted their result. And the fact that at the time,
there weren\'t as many procedures for uterine embolization, for example,
et cetera. So my feeling is I think safety has been diligently
monitored, and they put into place some mechanisms for limiting the
risk, so I almost see it as two separate questions. Have they
demonstrated an adequate or reasonable degree of safety? Perhaps yes. It
is appropriate to compare TAH? I think the answer is no.

DR. NOLLER:  Do you have a comment?

MS. MOONEY:  I think I recall Dr. Stewart saying that of the patients
that were enrolled in the trial, they all based upon their
symptomatology would have been candidates for hysterectomy procedure, so
I think that from a clinical standpoint and from a patient standpoint it
is valid to say that a patient was facing a choice clinically between
hysterectomy and something less invasive. And I think one of the things
we should not lose sight of is, I think we\'re wrestling with the fact
that it feels like apples and oranges because we\'re comparing a
surgical procedure to something that\'s totally non-invasive.

I think we should be careful not to penalize the device, so to speak,
because it is non-invasive versus surgery. I think the patient\'s actual
clinical choice here was between those two modalities, again in the time
frame when the study was set up, and perhaps Dr. Stewart would like to
comment on some of the \-- elaborate a little bit more on the discussion
that took place relative to sham versus separate \--

DR. NOLLER:  Give us just a second. I think that\'s an important point,
what Dr. Diamond said. Certainly, there are multiple, multiple trials
that have shown long lasting good results in pelvic pain, and this could
be bleeding or pelvic pain as symptoms, but from sham operations or
placebo drugs, or whatever. It\'s tough to know what the real effect of
this is, particularly since 30, 33 percent of those left in the study
could have had something else done by 12 months, so it\'s difficult.
Yes.

DR. JANIK:  I also agree. I think a sham operation would clear a lot of
these questions, both on the validation study and statistically probably
it wouldn\'t take many patients to answer the question. It could be a
small number.

DR. D\'AGOSTINO:  What I was saying is I don\'t even think you need to
do a sham operation. You could have done the idea that these are all
going to ultimately go to hysterectomy, and do randomization at the
beginning, hysterectomy or not, and then later on go to hysterectomy.
There are a number of designs that could have been done. If you think
the sham procedure is ethically valid, then that\'s even better
procedure. I just don\'t buy at all the idea that you can\'t do a
randomized trial.

DR. JANIK:  I think in this subset you could find patients that are
symptomatic, that they often wait years before they get intervention. So
if you get the right subgroup of people who are symptomatic enough, but
on the fence enough to do something intermediate, I think it could be
done.

DR. BRILL:  I\'d like to add that there really is no correlate, because
we have a procedure which is this selective myomectomy, or selective
myolysis, or selected myoma destruction procedure, and is this an
abdominal myomectomy where you take one myoma out and leave the rest
behind or take the one out that you prefer? Is this a myolysis where you
coagulate one and leave the others behind? I\'m saying to find a
correlate with what\'s being done in the study is impossible, because
there is nothing that we\'re doing on this level.

DR. NOLLER:  Let\'s \-- do you have one more comment? Then we\'ll ask
sponsor for a response and then we\'ll break. Yes.

MS. MOONEY:  Just one last comment. I think that in terms of the patient
satisfaction scores, I believe they even had 12 months. Those were
somewhere upwards of three quarters of the patients treated with the
device still had some form of positive feedback or assessment.

DR. D\'AGOSTINO:  It was less than 50 percent. It was 44.

MS. MOONEY:  On the patient satisfaction scores?

DR. STEWART:  Yes.

DR. NOLLER:  Dr. Stewart.

DR. STEWART:  Yes, Ebbie Stewart. We concede that there is no perfect
study design, especially in this field, but we do feel we\'ve presented
the optimal study that was feasible at the time. And I think if we look
at the history of fibroid therapies and where we\'ve gone in the past,
that this is a superior study design to that of many of the procedures
that have been introduced.

The Duke Evidence-Based Practice Report talks about various surgical
therapies, and really comments that there is no evidence that there\'s
efficacy beyond 12 months for myomectomy or other minimally invasive
surgical procedures. Uterine artery embolization is the clearest
parallel procedure. And to date, there are no published studies of
either randomized trials involving uterine artery embolization and
another technique, or even significant parallel controls, that the
studies that led to FDA approval of embolic agents for uterine artery
embolization were based on generally six months of data in a single
study pair, so the fact that we did do a contemporaneously assigned
control group to look for safety issues, we clearly didn\'t expect
hysterectomy to be the proper control for efficacy, but to provide some
mechanism of safety. And I think the data that we\'ve shown you today do
show clearly that women undergoing MR guided focused ultrasound surgery
have fewer safety complications than women undergoing hysterectomy at
the same time.

And regarding the possibility of randomizing women pre-hysterectomy,
that\'s in many ways as close as we can get to our feasibility study. In
fact, we didn\'t want to allow anybody the option of going on to focused
ultrasound without being able to confirm that they were going to
hysterectomy. And even that study design wasn\'t able to be carried out.
I think a sham study would also be facing the same difficulties, and we
realize that there are limitations in the study design, but I think we
did learn very important things, and have proven the safety of the
procedure. And I think that we do have significant efficacy, and like
some newer therapies that are being seen in medical treatments, there
are potentially groups of better responders and groups of worst
responders, but I think we\'ve seen a subgroup of patients who do get
consistent long term results.

DR. NOLLER:  We will now \-- did you have one comment?

MR. NEWMAN:  I\'d just like to say that these issues of an appropriate
control arm, comparisons for safety, comparisons for efficacy,
randomization, sham treatments were all things that were discussed a
great deal with FDA during the design of the study and things we
wrestled with at great length. And that\'s how we came to the
negotiation of the design of the study. And we believe within the
limitations that we were able to develop starting in December of 2001,
that we made the point that the focused ultrasound as a treatment is
safe. We :acknowledge the limitations when we\'re comparing it to TAH,
and we believe that the efficacy measurements that are available to
prove that it\'s an efficacious treatment for uterine fibroid.

DR. NOLLER:  Thank you. We will take a break now until 5 minutes after
3, when we\'ll have an open public hearing.

(Whereupon, the proceedings in the above-entitled matter went off the
record at 2:54:45 p.m. and went back on the record at 3:06:30 p.m.)

DR. NOLLER:  We\'ll now move on to the \-- we\'ll interrupt our
discussion of the nine questions and have the open public hearing. I
need to read a statement to start the hearing.

Both the Food and Drug Administration and the public believe in a
transparent process for information gathering and decision making. To
ensure such transparency at the open public hearing session of the
advisory committee meeting, FDA believes that it\'s important to
understand the context of an individual\'s presentation. For this
reason, FDA encourages you, the open public hearing speaker, at the
beginning of your written or oral statement, to advise the committee of
any financial relationship that you may have with the sponsor, its
product, and if known it\'s direct competitors. For example, this
financial information may include the sponsor\'s payment of your travel,
lodging or other expenses in connection with your attendance at the
meeting.

Likewise, FDA encourages you at the beginning of your statement to
advise the committee if you do not have any such financial
relationships. If you choose not to address this issue of financial
relationships at the beginning of your statement, it will not preclude
you from speaking.

If there are people in attendance who would like to speak, I would ask
them to come forward, state their name and any statement they wish to
make concerning these financial arrangements, and then begin their
presentation.

DR. SPIES:  Thank you for allowing me to speak. I\'m Jim Spies and I\'m
from Georgetown. And I\'m here \-- let me refer to my next slide.

DR. NOLLER:  We can\'t hear you. I\'m sorry.

DR. SPIES:  Oh, I\'m sorry. I\'m here representing the Society of
Interventional Radiology, which has an interest in the subject of
minimum invasive treatments for fibroids, and specifically uterine
embolization. I have been a consultant in the past and have spoken with
this panel before in evaluations of both Biosphere Medical Products and
Boston Scientific, and as many of you in the panel might know, I have a
significant interest in uterine embolization which I think is probably a
competing technology. But certainly my primary goal here today, I hope,
is to discuss some of the issues related to the questionnaire.

I was the principal author in developing this questionnaire along with
MEDTAP International. Karin Coyne is here today, and we collaborated on
this, and did this based out of Georgetown and it was developed here in
Washington, D.C., so I think I may be able to address some of the
questions that the panel has had regarding this.

There\'s no question that uterine sparing therapies are a new paradigm
for treatment of fibroids, and I would actually agree that hysterectomy
is not a very good comparison because it\'s rapidly going out of favor
among many gynecologists as an optimal treatment, although obviously
still very commonly done.

We\'ve learned with embolization, one of the reasons that we developed
the questionnaire was because there were no valid ways to measure
outcome from this. And really, it is symptom driven, and I applaud the
company, the sponsor for using this questionnaire because they
recognized early on that what really matters are patients better. And,
of course, the Society does welcome new therapies for fibroids and
minimally invasive therapies, and we\'re in clear support of comparative
evaluation of this therapy, for example, studies of embolization versus
this technology.

The change in uterine and fibroid volume are key points in this, and
we\'ve alluded to this before. The volume doesn\'t really matter. It
does not make very much difference. And we\'ve done some studies, and
I\'ll show you some data regarding that.

Symptoms need measurement by a validated question. That\'s why that was
developed. The imaging outcome really is a better predictor of
recurrence. You have to completely infarct the fibroids on contrast
enhanced MRI or they\'ll regrow.

So talking a little bit about the questionnaire, this questionnaire was
developed with a grant from the research arm of the society of
interventional radiology with the specific intent of assessing the
effectiveness of embolization and other therapies. And we had hoped that
it would become sort of lingua franca, something that everyone would use
so we\'d be able to talk about scores and have some meaningful
comparison, because really there was no way to do that previously. And
I\'m again pleased that the sponsor has chosen to use this. There are
some other uses out there which I\'ll mention that are ongoing which
should help us to be able to put into context the issue of what does a
change of 10 points mean, or 20 points, or whatever.

There is no question that the symptom and quality of life situation
changes over time within a women even without therapy, and so there\'s
always going to be some degree of fluctuation. This particular
instrument has a very high test/retest reliability. You\'ve already seen
these so I\'m just going to skip through.

Basically, this can discriminate between normal patients and abnormal
patients or those with fibroids, so you can see the bright green bars
are the normal patients, and the other green bars are the abnormal
patients. And this is from the original validation.

Similarly, if you were to look at a patient and say how severe are your
symptoms - so if you take a patient with fibroids and say are your
symptoms mild, moderate, severe, on a 10 point scale and group them,
this instrument can distinguish between various levels of symptoms
related to fibroids. I should also mention that the original validation
of this include patients that have minimal or no symptoms for fibroids.
They just have confirmed fibroids by a gynecologic examination, and they
were recruited in a gynecologist\'s office and in our own practice with
uterine embolization. So they had known fibroids but not necessarily
significant symptoms, so that\'s why the scoring you see in the original
validation was in the range of about 44 because there were some people
that had relatively minor symptoms.

And I would agree with the sponsor when they say that a score in the mid
60s is significant symptoms. If you look at the scale and you go in the
mid point, which is the somewhat answer to eight questions, you\'re
going to get a score of 50. You go up from there and you get a score of
75, so in the mid 60s is moderate to significant symptoms.

This is being currently used in a number of longitudinal research
programs. The largest is sponsored by CIRREF, our organization, and
it\'s done in conjunction with DCRI which is the FIBBROID Registry,
which has 3,000 women in it. We\'ve just completed a daily collection
and one-year follow-up, and that\'s going to be assessed fairly soon,
probably in the next few months. We\'re looking for short term outcomes,
as well.

Also, it\'s been used in a study of a pharmaceutical company looking at
the efficacy of selective progesterone receptor modules in a life study.
And then my own use most recently, and I\'m just going to show a little
bit of data to give you a flavor of the changes you might see in a
randomized comparison of two different embolic materials for uterine
embolization. And that\'s the only data that I have here today that I
can actually show you that\'s raw data, and part of it is going to be
published. It\'s been accepted for publication, will be published in
about two months.

The key questions for you, and you\'ve been asking them, is what is the
normal score for the two scales. And by the two scales I mean the
symptom scale, and then there is the total quality of life scale. And
the white represents a typical abnormal squares for patients undergoing
therapy, and we talked a little bit about that. And one represents a
clinically meaningful change in scores. And I don\'t have all the
answers, but I\'d just like to give you a little bit of data.

For those that are following this in the handout that I passed out, I
apologize the way this is formatted, these numbers don\'t come out very
well, but if you look at this and you say well, if you took the normals,
and unfortunately the screen is off a little bit, but if you take the
normals which is the first row - this is from the original validation,
the symptom score mean was 22.5. The quality of life score was 86.

Now in a perfect world, in one we would have zero score, no symptoms
whatsoever, and they would have a perfect quality of life. But most
quality of life studies have shown, particularly with gynecologic
symptoms, that most women do have some gynecologic symptoms. They
usually fluctuate with their cycle, bloating, pressure, discomfort, a
variety of different things that are normal physiologic events.

If you took the fibroid patients from that original scoring, you got a
score of 44. The quality of life score was 62, so they had a diminished
quality of life based on the increased amount of symptoms they\'re
having associated with their scores.

Then in this most recent study that I\'ve done in which we\'re taking
patients that have significant fibroids that are going to undergo
uterine embolization, our mean score for that group of 100 patients was
53.7 with a total quality of life score of 52. So again, they are
somewhat more symptomatic. Now that\'s to compare to the sponsor study
where they\'re in the mid 60s at baseline, so their patients, if
anything, were slightly more symptomatic than this.

This again is that study that I\'ve just alluded to that we completed at
Georgetown, and we looked at 100 patients and randomized 50 to two
different embolic materials, three months and 12 months. We have not
completed the 12 month grid, although it is already is statistically
significant. But I\'m not presenting that because I don\'t have all the
numbers.

For the three numbers, and again I think this is a misprint. It should
be 53.7, but the symptom score, I just alluded to this, was in the 50s,
standard deviation of 22. Three months later after uterine embolization
the score was 21. Now with the sponsor study it was in the mid 30s. They
started higher, they ended higher, and that\'s one of the questions, is
a score that\'s 35 or 37 adequate improvement? And I don\'t have the
answer. It certainly is moderate improvement, but this symptom score is
normal. If you go back to the original validation, 22 is a symptom score
the patients had. This is normalized.

The quality of life score was a day long which is more or less in the
same range as the normal score, so just to give you some feeling of what
another therapy can actually do. Unfortunately, this doesn\'t project on
this particular computer.

What I would say about this is that on all the scales, there are six
step scales, and the total quality of life scale, and all the symptoms
score, all of them were statistically significantly improved with this
comparative study that we did.

Now the other thing I\'d just like to concentrate on is to talk a little
bit about \-- this is using the criteria of the sponsor. I took that
same set of 100 patients, and I said how many of those patients meet the
criteria that leads to 10 point improved symptoms score, and you can see
that the proportion improved just in pure portion, the 78 out of 94 that
we had the complete questionnaire on, 83 percent. There\'s was about 70
percent, so again we\'re seeing similar kinds of results.

If we go from an intent-to-treat basis, look at the entire sample, it\'s
84 percent without complete data. HRQOL scores again are similar.
They\'re about 83 percent or so. It\'s a similar number, although we
don\'t again have complete data, so I can\'t give the intention-to-treat
that one year. So in general, embolization works. This is a way that you
can measure. Now this obviously would have been different if we put 15
or 20, and really what has to happen with a large data set is you have
to do some modeling, and sort of look appropriate cutoffs.

The other thing I\'d just like to take a couple of minutes to talk about
is the imaging outcome because it\'s very germane to this. Focused
ultrasound at this time is not actively trying to infarct the entire
fibroid, and it\'s reasonable for safety considerations, et cetera. And
I recognize that they were very limited in what they\'re allowed to do
under this protocol. And in fact, it\'s entirely possible that the
symptom score would have improved significantly more had they been
allowed to do more complete therapy, so I don\'t think you can look
exactly at the results with their hands tied behind their back and make
a complete judgment.

What we\'ve learned though from embolization sort of by a hard lesson is
that you have to completely infarct the fibroids to have good long-term
outcome. Short-term outcome, you can injure them, infarct half of them
or a third of them, you\'d probably do pretty well. But long-term,
you\'ve got more of a problem. Failures and early recurrences relate to
the regrowth of uninfarcted large or key fibroids. Late recurrence is
generally due to the growth of small incompletely infarcted fibroids at
the original treatment or new fibroids, and that\'s with embolization.
But it probably applies to this therapy, radio frequency ablation or any
others.

So the key things to long-term outcome is not the volume reduction. And
there\'s a reference there - we showed in a group of 200 patients that
it doesn\'t matter how much it shrinks. You\'re likely to have pressure
or other symptoms go away, it is the same. What matters is you have to
completely infarct the fibroids, and particularly long-term. And we just
published this paper about two months ago by Dr. Pelage, myself, and a
group at Georgetown looking at that particular issue.

I just want to give you two examples. I don\'t have a pointer, I
apologize. If you look at a series of sagittal images here, the first
one is a non-contrast image. If it were contrast, most of the uterus
would be white. All the fibroids subsequently are all black. They\'re
rounded. They\'re getting progressively smaller, and you can see that
three years out they\'re all completely infarcted and they continue to
shrink. There was no symptom recurrence in this patient. This is one of
the patients from the study I just showed you. We had 20 patients with
three-year imaging follow-up, 17 of them look more or less like this.
Three of them look more like this.

This is a patient, you can see in the pre-image, the first at the top
left, large fibroid that is completely vascularized. At three months,
you can see that almost all of this fibroid is completely infarcted, but
there are little ridges there that are prefused. And if you then go to a
year and two years, which is the first at the left on the bottom, three
years and four years, you can see that that fibroid is progressively
regrowing. That\'s despite the fact that this fibroid is smaller at the
end than it was at the beginning. The uterus is much smaller than it was
at the beginning, so size doesn\'t matter. What matters is this is
vascularized. This patient\'s symptoms came back between two and two and
a half years. She\'s now been retreated actually a little over four
years after her procedure. And if I had a pointer I would show you just
in the last image there is \-- that is a new fibroid. We\'ve now shown
with this and other studies that you can develop new fibroids after
uterine embolization, which is not very surprising. Of course, that
would be with ultrasound ablation, as well.

So I would bring to the table some moderate concerns regarding labeling
in this particular device or others which you\'re looking at a uterine
sparing therapy. The FDA by nature, and these studies have been mostly
focused on short-term efficacy and safety. I have participated in
studies for embolization which are the same way looking at three month,
six month, one-year data, but the early recurrence is going to be high
if you don\'t completely infarct the fibroid.

Now that brings up the question what really is efficacy. Is efficacy six
months, is it a year, is it two years. Many treatments have good
short-term benefit, and clearly uterine embolization is among them. It
is important, I think, to consider the two to five year effect.

We generally now are moving in the direction of uterine embolization
because if you\'re not better for a year, it\'s a failed procedure. If
you\'re going to have something \-- we\'re looking at the reaction of at
least a year of benefit, and frankly, it would be much better to have it
go much longer.

I would just conclude by saying that first, I think that the evaluation
of high frequency ultrasound does benefit form the use of this
questionnaire. I applaud the company because they took on that
questionnaire at a time when we didn\'t have a lot of data, and they are
correct, there is not a lot of data out there yet. It\'s in the
pipeline. It\'s going to be published in terms of the treatment effect
that you can detect with the instrument.

The results need to be considered in the context of the therapies that
we\'re using some measure. So in other words, you\'re going to say
what\'s better, embolization or whatever. You can\'t take the numbers
and directly compare them, but certainly it does provide you the basis
of doing comparative studies. And then I would again emphasize the
issues related to contrast enhanced MRI. And thank you for your
attention. I appreciate it.

DR. NOLLER:  Thank you. We have another presentation that will be read
by Ms. Luckner, our consumer representative.

MS. LUCKNER:  \"To the members of the FDA Acceptance of Gynecological
Devices Panel Committee, my name is Carla Dionne, and I am the Executive
Director of the National Uterine Fibroid Foundation. We are located in
Colorado Springs, Colorado, and represent the only national non-profit
patient education and advocacy group specifically representing women
with fibroids in the United States. Thank you for the opportunity to
submit my testimony today on a subject of a tremendous importance to the
health and welfare of women with uterine fibroids.

Although I cannot attend today\'s meeting, would like to present a few
issues for the panel to consider when making recommendations for
potential approval of the InSightec ExAblate 2000 for the treatment of
uterine fibroids.

Based on the limited information made publicly available June 2^nd^,
2004 regarding this study, the following areas are of great concern.
Safety and efficacy.

Typically, the clinical trial recruitment of a motivated patient
population can minimize loss to follow-up, and provide more extensive
information. This particular group of women who underwent focused
ultrasound treatment for symptomatic fibroids should have been an
incredibly low risk group for loss to follow-up. It is, therefore, quite
surprising to see a nearly 30 percent loss rate within six months, a
loss rate of 60 percent at 12 months, and an additional 20 percent of
the final group not lost to follow-up who went on to a secondary
alternative procedure.

The FDA has previously indicated that loss to follow-up of 15 percent or
more make the determination of safety and efficacy difficult to assess.
And as such, the maximum calculated as acceptable is generally 15
percent. It would seem loss to follow-up rates of 30 percent at six
months, and 60 percent at 12 months would completely negate the results
of this study in terms of truly determining safety and effectiveness.

Under the circumstances, and in consideration of the desperate attempts
women make to avoid surgical intervention, it is extremely questionable
as to why so many women would be lost to follow-up so soon after
treatment. It is critical for the clinical investigators involved in
this study to provide more information about follow-up for these
women.\"

There are pages more, Mr. Chairman. Do you want \--

DR. NOLLER:  Are there any other points that are \--

MS. LUCKNER:  Let me just pull one point out, and then I will suggest
the several other points go on to labeling and training, and I can read
them at that time. And then go on for post-market study.

DR. NOLLER:  Thank you.

MS. LUCKNER:  But let me just read one other piece. \"In terms of
efficacy, the 14 percent volume reduction at six months is
disappointing, at best. Further, the decline in average percentage of
fibroid shrinkage at 12 months as 9.4 is abysmal. Based on the data
submitted regarding loss to follow-up, subsequent alternative
procedures, potential for increased risk and subsequent procedures, and
the overall decline in the average volume reduction, the cost benefit
analysis must truly be questionable here.

Is this an appropriate treatment for women with systematic uterine
fibroids? Will women desperate to avoid surgical intervention by any
means possible truly understand the potential risks involved with
undergoing this procedure\"?

DR. NOLLER:  Thank you.

MS. LUCKNER:  Thank you.

DR. NOLLER:  I\'m sorry. We can\'t read it later. Are there any other
points that are important or pertinent?

MS. LUCKNER:  I\'m trying to be objective.

DR. NOLLER:  Yes.

MS. LUCKNER:  I think the labeling and training. There\'s a discussion
of the exclusionary consideration, and I think that that will be picked
up by the panel as I \-- I just received this now, so I think that will
be picked up by the panel. There are two different lists of what should
be excluded. There\'s discussion about what training requirements are.

DR. NOLLER:  Well, I have been instructed to ask you to read the whole
thing.

MS. LUCKNER:  I\'d be delighted to. Let me go back and figure out where
I left off.

\"In addition, in an additional review of the initial phases of the
study where women underwent hysterectomy after HIFUS, there were
seemingly inordinate number of patients who developed post operative
hematomas requiring surgical drainage.

IN addition, due to incisional bleeding, one patient required ligation
of a single uterine artery. During the current study under review, if
HIFUS is non-durable for a great many women, what are the subsequent
surgical risks? Has surgical or embolization risks increase due to the
treatment with HIFUS? If so, at what ratio, and what would the severity
of that potential risk truly be? Would undergoing HIFUS become a
contraindication to myomectomy or embolization?

From the Agency of Healthcare Research and Quality, AHRQ, based on the
1997 healthcare cost utilization project, state in-patient database for
19 states and post operative hemorrhages or hematoma rate was 1.61 per
thousand population at risk. There are other references on the same
topic.

DR. NOLLER:  Thank you.

MS. LUCKNER:  It would seem that hysterectomy after the HIFUS group had
an incident ratio significantly higher than the norm per the average.
However, given the small number of women studied who subsequently
underwent hysterectomy, only a larger study of women undergoing
subsequent surgical treatment would potentially offer more conclusive
information on this issue.

Given this, an incredibly critical question remains unanswered. If HIFUS
does not prove to be durable long-term, greater than one year for women,
has undergoing the treatment compromised the potential for subsequently
undergoing a more durable treatment safely, such as hysterectomy or
myomectomy, or even embolization?\"

I\'m reading about labeling now?

DR. NOLLER:  Please.

MS. LUCKNER:  Okay. Labeling and training. \"One, exclusionary
considerations. Patient exclusionary criteria appears to be absent from
public review, but it is absolutely essential to the very offering of
this to women with fibroids. The following exclusionary items should be
reviewed for potential dissemination to the medical community treating
women with fibroids, and to the general public of women with uterine
fibroids who may be considering this treatment option for symptomatic
fibroids.

One, pediculated submucosa or subserosa fibroids. Fibroids smaller than
4 cms or larger than 10 cms, presence of more than three to four
fibroids, presence of abdominal pelvic scars of keloids from prior
treatment, fibroids located too close to the bladder, bowel or bone
within 4 centimeters, Hematocrit level less than 25 percent, excessive
fat and/or muscle in the abdomen, presence of adenomyosis, desired
fertility positive pregnancy test.

In addition, the following exclusionary items related to ultrasound
contrast and MRI should be reviewed for dissemination; contrast
allergies, impaired renal function, claustrophobia, minus 15 percent of
the population has \-- give or take 15 percent of the population has
claustrophobia severe enough not to tolerate the enclosure of an MRI,
presence of any metallic substance or implanted material such as heart
pacemaker, surgical clips from prior surgery sometimes applied during
C-section or myomectomy to the uterine artery or by a tubal ligation,
insulin pumps, cochlear implants, jewelry.

Presence of abdominal pelvic tattoos. Depending on the location, they
may contain enough trace elements of metal so as to interfere with the
clarity of the MRI. Weight girth of no greater than 350 pounds table
limit, but abdominal girth limit might place this at no greater than 250
to 300 pounds depending on the individual.\"

The next category is called training. What are the potential plans for
radiology and gynecological training and certification for the InSightec
Albate 2000? Given exclusionary factors and what appears to be a
learning curve based on the trials to date on selecting appropriate
patients and using this equipment in the treatment of symptomatic
uterine fibroids. It is of tremendous concern that an appropriate
training and certification plan be firmly in place prior to additional
installation and use of this equipment.\"

Post market study, and it\'s only another page. \"Given the poor showing
of data presented for this clinical trial, in consideration of FDA
approval of the InSightec Ablate 2000, this device has simply failed to
provide enough post treatment patient information on its safety and
efficacy in the treatment of women with symptomatic uterine fibroids. In
short, the InSightec ExAblate 2000 should not receive FDA approval at
this time based on the data presented, and with the continued
outstanding concerns over patient safety and efficacy.

It would be the recommendation of the National Uterine Fibroid
Foundation that this device continue to be followed pre-market for an
additional year prior to subsequent review by the FDA. However, given
the loss to follow-up rate currently identified, will there be any
patients remaining from the pivotal study one year from now who are not
also lost to follow-up? Will there be any additional effort to report on
what exactly occurred to those patients lost to follow-up? Did they
ultimately undergo an alternative procedure?

Furthermore, if the average percent of fibroid shrinkage declines any
further, will there be a single patient left who is clinically versus
technically successively treated with HIFUS?

It would be our further recommendation that the members of this panel
consider the absolute need for the design of a new study protocol with
an increased awareness of the potential for loss to follow-up,
exclusionary factors, and the risk to subsequent procedures required for
the potential clinical treatment failure of HIFUS. Preferably this study
would not be a comparative study to a hysterectomy, but rather
comparative to other uterine sparing treatments, and matching for
appropriate patient controls.

The Cardiovascular and Interventional Radiology Research and Educational
Foundation and the Society of Interventional Radiology, in cooperation
with Duke Clinical Research Institute have established the uterine
artery embolization fibroid registry for outcome data. The purpose of
the fibroid registry is to specifically assess the durability, impact on
fertility, and the quality of life, and to obtain data which would allow
researchers to compare UAE to other fibroid therapies.

Due to the number of patients undergoing the non-surgical uterine
sparing treatment of uterine fibroid embolization, there is an abundance
of collected data for this treatment modality. This would distinctly set
UFE apart from hysterectomy as a much more appropriate study group for
comparison to HIFUS than hysterectomy, and it would be our
recommendation that this be reviewed for consideration. Respectfully
submitted, Carla Dionne, Executive Director, National Uterine Fibroid
Foundation, Colorado Springs, Colorado.\"

DR. NOLLER:  Thank you for reading that. We\'ve now used all of the time
for the open public hearing. For panel members, what we will do is to go
through the last three questions. At the end of that time, I\'m going to
ask the panel if there are other questions that you\'d like to pose to
the sponsor that you did not get a chance to ask previously.

Then we will allow the sponsor to sort of sum up and present answers to
questions that haven\'t been asked before or address points that
haven\'t been made. And then we will go into the recommendation phase,
the voting phase. So let\'s go to Question 7, labeling and training.

Does the panel have any comments on the labeling provided by the
sponsor? Does the panel have specific recommendations related to the
proposed indications, contraindications, warnings, precautions, adverse
events, clinical study?

I\'m going to instruct the panel that we aren\'t looking for
wordsmithing things here, we\'re looking for major concerns, things that
were omitted or introduced that are clearly incorrect. I would also like
to ask the sponsor to specifically address the question that\'s asked,
not to do a summing up or get off on other related issues. So number 7,
indications, contraindications, warnings, precautions, adverse events,
and clinical study. Any comment? Yes, sir.

DR. SOLOMON:  I think the prescribing information should include more
detail as far as who you are excluding, meaning patients that have dense
calcifications or patients who have intestines in th way, or there
should be more warnings here as to clarifying who you need to screen
for. It may be more difficult to get patients who have fibroids that are
lower than those that are more at the fundus, so I think more detail as
to who they should include should be included.

DR. NOLLER:  I\'d like to make one comment there. I had sort of
mentioned this before, but in the patient brochure and some other parts
of the labeling, there are several times that the standard of care is
mentioned. It\'s hysterectomy. As I said before, that absolutely is not.
The standard of care is observation. For patients with serious
complications of fibroids, then you might consider doing more. And I
would probably avoid using the term \"standard of care\", since it
really doesn\'t mean much except in a courtroom, but be more specific
about the labeling.

DR. JANIK:  I agree that we need to have more clarification on
indications, and indications would be number of fibroids, optimal
location of the fibroids, in addition to exclusions that were mentioned,
so it\'s not real clear who would be best qualified for this.

DR. NOLLER:  Dr. Brown.

DR. BROWN:  Two comments. I would think that given the data we heard
today that the issue of nerve injury should be included and labeling
under potential adverse events that says back or leg pain. I think
that\'s a very different thing than saying nerve injury.

And I also, relevant to my other question that did not get addressed
about the diversity, lack of diversity in the study population, there\'s
specific mention in the labeling that the device \-- the study results
did not show any decreased effectiveness in patients based on race, age,
menstrual status, BMI, or fibroid type. And I just really question
whether there was really enough power in the study to talk about
differences in any of those factors. I don\'t think that\'s really a
valid statement, so I would suggest that that \-- I don\'t know if that
\-- because it didn\'t seem to me this study had the power to say that
those things were not factors.

DR. NOLLER:  Dr. Roberts.

DR. ROBERTS:  Well, when I read over these instructions for use, quite
frankly I think it needs a lot of work by the agency and the sponsor. I
mean, I think that somewhere in here it\'s going to have to be clear
what this study looked at, and what it didn\'t look at. And I think
there\'s a lot of things, one of the things is I think it\'s going to be
important to put in here what at least the pivotal study was or, in
fact, what the expanded study was, so that even if you go to the
expanded study, that the limitation of sonication was 180 minutes, that
there was a 15 millimeter margin to the serosal surface, that the
treatment volume was up to 50 percent if that\'s what you\'re going to
go for, that maybe you could do more than one treatment, but it wasn\'t
done any more than one treatment, if there was total treatment to a
volume maximum of 150 Ccs. I mean, I think somewhere in here that\'s
going to have to be spelled out because presumably that\'s going to be
the only place that at least it\'s written down some place.

And I think the other thing that really is important sort of goes to
what was said before, which is it\'s kind of lost in here that it really
needs to be 4 centimeters away from the sacrum and the importance of
making sure that it\'s away from the sacral nerve plexus. It really
needs to be standing out in here.

And I think the other thing that somebody is going to have to kind of
look at and try and figure it out is that given the numbers that we saw
that the non-perfused volume was more than - essentially at least in the
study - was more than twice the region of treatment, and that the
question is going to be how do you counsel physicians about what
they\'re going to do? So if they go more than that, what does that mean?
We don\'t know, but somehow that\'s going to have to get in there.

DR. NOLLER:  Dr. Wood.

DR. WOOD:  It would be nice to see a section on the importance of the
light sedation or something besides just the words \"conscious
sedation\", the importance of constant feedback from the patients, that
it hasn\'t been used with general anesthesia or deep sedation, and that
could pose increased risk.

DR. NOLLER:  Dr. Diamond.

DR. DIAMOND:  A couple of things, in the essential prescribing
information under training, it states that \"Training in ExAblate is
provided by InSightec.\" I think that probably ought to be stronger,
really along the lines of what Mr. Newman presented to us during his
presentation of what would be required as part of the training process,
and who would be involved in it, as a prerequisite for utilizing it.

In the brochure for the patient, it currently states that this process
will be repeated to treat your entire fibroid, and that\'s not what is
intended at least at this point, so that needs to be modified. And then
at the end of that, I think it needs to be provided \-- it needs to be
real clear that this may not provide patient benefit in selected
patients, so they may not see a benefit. And if they are going to see an
improvement, what kind of improvement should they expect and over what
time is it likely to be present for.

DR. NOLLER:  Others? Yes.

MS. LUCKNER:  There\'s no mention of the scar issue or the size of the
patients that may not be eligible for this. And that big issue has been
discussed several times by the panel.

DR. NOLLER:  Others?

DR. WOOD:  There\'s one line about scaring or surgical clips in the
individualization of treatment section. But it raises a question that we
didn\'t address. Were patients with previous C-sections stratified in
any way according to complications?

DR. NOLLER:  Dr. Roberts.

DR. ROBERTS:  The only thing I was going to say is in terms of the
patient manual. In the long-term effects or risks it says \"back or leg
pain or weakness.\" I think it probably ought to be a little stronger
than that, and basically say it\'s nerve damage, because that\'s what
we\'re really talking about. I mean, if they just think well, their leg
is going to hurt, that doesn\'t really \-- I don\'t think it really
answers what might be potentially anyway, a serious problem.

DR. NOLLER:  And if you read the labeling on aspirin or anything it\'s
your head may fall off, your arms may fall off. It goes on, and on, and
on. Yes, Dr. Brown.

DR. BROWN:  Just one other comment about the patient manual. I think (a)
it\'s way too detailed. It\'s at extremely high reading level, and I
also would take exception to the table where you\'re comparing
alternatives, because for example, it says that hormone therapy is only
effective for six to twelve months. Well, we\'ve just heard that this is
only effective for six to twelve months, so that just needs to be
completely reworked, and looking at what are the important messages
you\'re trying to get to the patient, try to make them understand what
the procedure is, what the risks are, and what the potential benefits
are. I\'m not sure how important it is in your document to compare other
treatments. That\'s really the job of their physician who\'s counseling
them about what choice to make.

DR. NOLLER:  Others? If not, we\'ll move on to Question 8. For that
point, is there any sponsor \-- we didn\'t really ask any specific
question. Number 8, FDA and the sponsor agreed upon procedural
requirements during the pivotal trial, and in the continued access study
to mitigate safety-related concerns that are shown in the attached
table. Is the ExAblate training system sufficient to ensure that the
proposed mitigations are followed? Discussion?

DR. ASCHER:  I have a comment.

DR. NOLLER:  Yes.

DR. ASCHER:  Given mitigation and all the stuff we\'ve learned today, I
wonder how the sponsor came up with the training recommendations. At
least my reading of it, it\'s one session. Potentially you phantom and
then potentially you might see a patient being done, and then they\'ll
come to your institution for five times. I guess what is the learning
curve, and do they have any information on the learning curve with doing
this procedure?

DR. NOLLER:  We\'ll ask them in a minute. Yes.

DR. SOLOMON:  This is amazing technology, but it\'s very complicated,
and very few people have been trained in the physics of ultrasound,
physics of MRI, the interactions of tissue and the physiology. It\'s
very cutting edge, and I think the training, especially for safety
purposes, is absolutely critical because there can be a lot of damage
that\'s done. I have no doubt that we\'re seeing very good safety
results in this continuing study that they are having that there
haven\'t been skin burns, for instance. And that\'s terrific and it
comes from experience of the women and men who are performing the
procedure. But I think it\'s very important that there\'s a lot of
training, and that there\'s a lot of follow-up in several cases in the
beginning so that people are prepared to do this appropriately and
safely.

DR. NOLLER:  Other comments? Yes.

DR. HAYES:  I was going to say, we need to include the training for the
role of the nurse specifically.

DR. NOLLER:  Yes.

DR. HAYES:  And also in follow-up to someone else\'s comment, what was
magical about the number five times from the physician?

DR. NOLLER:  Could we hear from the sponsor about the learning curve? Do
you have data to support one session followed by up to five at a site,
and then being proficient in doing it?

DR. TEMPANY:  I\'d like to speak to that in two parts, and I think if
you talk about the training that we have designed, and how we ourselves
in the trial \--

DR. NOLLER:  Please. We have read the training, so don\'t repeat what we
already have, please, but new information we\'d be happy to hear.

DR. TEMPANY:  Well, you\'ve asked about why five, and I think five or
ten treatments could be observed at a treatment site, and then the
simulations - one of the key things that I think is going to be very
helpful here is that we have the ability to play the treatments that
have already occurred, and show those to trainees, to people who are
going to be learning how to do the procedure, so they can see individual
sonications and direct it, and how to change or angle the tilt. So
there\'s a lot that can be learned ahead of time before you actually are
involved in doing primary treatment yourself through either virtual or
simulated learning techniques. Those are things that I think that are
tools that we have at our disposal for many facilities. Certainly, in
the Boston area, we have a simulation center which trains people on how
to manage codes, for example, in a radiology suite or an operating room.
And we have video playback of how you responded under pressure, so we
can obviously learn a lot from these simulation tools. I think this
particular device and the way that it records everything that occurs
lends itself very nicely to that type of training.

Going back to our experience and how we learned this procedure, and how
the 600 patients across the world have been treated by different people
in different sites, I think there is a relatively fast learning curve.
Certainly, radiology imaging is an important part at the beginning of
it. It\'s not necessary to learn all of the MR physics, nor is it
necessary to be proficient in ultrasound physics. There are certain
basic principles that can be taught in the beginning. Interpretation of
the images, all of the imaging modalities that I have been involved in
in my career, I think MRI is one that\'s relatively easy for people to
learn, because if you know anatomy, you know MR imaging. You can see
things so incredibly clearly. It\'s not like learning ultrasound, which
I still have struggles with. So from that perspective, I think the
learning curve is relatively quick, and certainly the experience that
we\'ve had with the safety problems, such as the skin burn or the nerve
are very easy to train and teach people about. And I think with the
mitigating factors that we put into place, I think it will be relatively
easy.

It might be useful to hear from another radiologist who learned a lot
from a prior experience and his use at the first site, as well, so I\'d
introduce Dr. Hesley.

DR. NOLLER:  Please limit it to answering the question that was asked.

DR. HESLEY:  Okay. I\'m Gina Hesley. I\'m from the Department of
Radiology at the Mayo Clinic. My travel and accommodations are paid for
by InSightec, but I operate under the Mayo Clinic Foundation guidelines
and institutional review board there.

Our site did join, after significant experience was obtained by other
institutions. We benefitted significantly from the training. We had,
first of all, classroom training, followed by that we went and actually
did a mock setup with a phantom where all of us, our technologist, a
nurse, study coordinators, radiologists, and the gynecologists were
invited, as well, to participate in the setup of a patient and do
phantom experiments. After that, the company did come for a limited
number of treatments to help us in our learning curve of how these
treatments operate, some things that we might encounter.

As far as skin burns, we never encountered any skin burns. We joined a
study after those kind of features were identified, and so from the very
beginning we were shaving all our patients. We were making sure that we
cleaned them off with alcohol no matter what the circumstances may be.
As far as also movement, we secure our patients down similar to what Dr.
Tempany does. And I would also say from our experience with the nerve
injury, we as well benefitted from that. We joined later on. We already
knew some of the things to be aware of by that time.

DR. NOLLER:  Okay. Thank you. Are we ready for Question 9? This deals
with post market study. Under current FDA guidance patients from the
pivotal study are scheduled to be followed for a total of three years
after the procedure, one year pre-market, and two years post market, and
up to 250 patients to be enrolled in the continued access setting are
scheduled to be followed for a total of three years after the procedure.

Two questions. Is there a need for additional post approval studies or
other post market measures? Number two - If so, what is the purpose of
such studies, and what are the key elements of the study design?
Discussion. Dr. Diamond.

DR. DIAMOND:  I would think it would be very important to gain
additional knowledge about whether the improvements that they have seen
could be increased by treating larger portions of the fibroids or by
more of the fibroids, so that hopefully patients could get better and
longer lasting benefit. And if we go with what Dr. Spies told us earlier
about having to get complete infarction of the fibroid, with the amount
of treatment now it\'s probably not very likely to happen in those
situations, so I think that would be a valuable study to conduct.

DR. NOLLER:  Other comments. Dr. Brown.

DR. BROWN:  I would just emphasize again my point about the lack of
diversity in your studies that going forward I would like to see a post
market study that specifically recruited the population that has a very
high incidence of disease, and to make sure that there are no unexpected
findings in a population. For example, maybe different or different
ethnicities have higher percentage of calcified fibroids or things like
that, so I think that should be a key component of any post market
study.

DR. NOLLER:  Dr. Roberts.

DR. ROBERTS:  Well, I think it\'s important that the patients that have
already been enrolled in the study be followed, but I think we have to
be really careful about expanding what the sponsor has to do in terms of
enrolling new patients, and following these patients for three years.
Now that\'s an enormous amount of work and expense, and quite frankly,
I\'m not sure that it\'s appropriate to have the sponsor do that. I
think that that\'s a study that needs to be done. I think there is going
to be presumably people out there that can make a good career out of
doing those kinds of studies, and I would certainly encourage them to be
done. But I think we really do have to be careful about putting an
enormous burden on the sponsors. We\'re already asking them to follow
the patients that have been enrolled in the pivotal study. They\'re
already being asked to follow the patients that are being enrolled in
the continued access study for three years. I think that\'s important. I
think it needs to be done, but I wouldn\'t agree with asking them to do
a whole other study on other patients.

DR. NOLLER:  Dr. Brill.

DR. BRILL:  Well, since this our time for a wish list, this is also
directed at the FDA itself. One of the problems with these quality of
life instruments is that most of these things are surrogate
measurements, and there\'s no question that the symptom severity score
is mostly menstrual in nature, but there are some pressure and physical
phenomena integrated into that score.

Why objectification and menstrual blood loss was not included in the
study, I don\'t know. But surely we can add this to whatever is
forthcoming. It\'s going to objectify some of this information and take
it out of the realm of the discrepancies that occur with quality of life
instruments. And I would highly suggest we consider that.

DR. NOLLER:  Others?

DR. MILLER:  I think at some point, and I\'m not sure exactly where to
do this, because this is a uterine-sparing procedure, and because it\'s
being done in a reproductive age population, the issue of potential
pregnancy following the use of this technology is going to come up, and
there needs to be some provision for how that\'s done. If it\'s done by
registry or some other way, but if this technology is going to be
successful, it\'s going to be considered as an adjunct to enhanced
fertility for those people who have large fibroids and want to conserve
their uterus.

DR. NOLLER:  Yes.

DR. WEEKS:  Jonathan Weeks. I\'d like to see some of the sponsor\'s date
on uterine volumes. You\'ve got stored images on uterine volumes in
patients over time. Again because in many cases you\'re selecting a
fibroid to treat, or two of a number of fibroids to treat, and I think
there may be a correlation between total uterine volume and how well a
patient does. If they\'ve got several more fibroids that couldn\'t be
treated because of the 150 CC, let\'s say limitation, then those
patients may be more likely to fail in the other procedures down the
road.

DR. NOLLER:  I guess we didn\'t ask any specific questions there. So now
what I would like to ask the panel is, are there questions that you have
that have not been asked of the sponsor either before lunch or as we
went through the questions? Seeing none, I will ask the sponsor to
close.

DR. STEWART:  Thank you very much, Mr. Chairman. This is Elizabeth
Stewart. I know it\'s been a complicated technology to try to grasp all
the subtleties, and I appreciate everyone\'s perseverance. I\'d like to
go back, first of all, and just look at the efficacy data since there
were questions raised about dropouts. I think that Dr. Spies information
gave us much more context to put our primary efficacy endpoint in, and
did describe an endpoint.

In the letter it was raised that there as loss to follow-up along the
six month study. There was actually no loss to follow-up. We had 109
patients, and we know exactly where each of them went during the six
month trial. And it seems like from the discussion that the concern has
not been with the efficacy that was demonstrated at six months, but
instead the efficacy at 12 months. Can we go on to the next slide.

It\'s a complicated slide and I know that it\'s somewhat confusing. But
again, we started with 109 patients. We had 91 who continued. There were
9 patients who we did contact and talk to, but declined to come in for
official 12 month follow-up. However, if any of these patients had
alternative treatments they did end up here, so if they did report to us
they had a hysterectomy, a myomectomy, a uterine artery embolization,
that information was captured. So it was really only 9 patients who we
didn\'t have follow-up on. The 9 patients that were non-evaluable, we
did again have information on, but may not have fallen exactly on the
window of evaluation.

And in fact, if we look at the patients going to alternative therapies,
I don\'t think we can characterize this as falling apart. We did have 23
patients going on to alternative therapy out of 109, but as the uterine
artery embolization data suggests, these are all women who very well
could have gone on to hysterectomy, and so in essence, we\'ve had around
75 to 80 percent of people who have not elected to go on to therapy. And
can you just go to the next slide. No, one more, please.

Again, looking at the symptom severity score, again we see that we start
at a marked level of symptomatology. We come down substantially, and I
think it\'s important to note at this 12 month time, this represents 61
patients for whom we had actual values, and all of the rest of the 109
had zeroes added into it. So I think that this under-represents the
symptomatology or the symptom improvement that we\'re seeing.

Three other questions I think that have been directed regarding the
clinical issues are patient diversity, and we recognize that that is
important issue. In fact, in Boston we specifically tried to recruit
minority women through various publications that cater to the minority
community. I think we were hampered in this effort by certain sites that
had no minority representation in their demographic area, and I think
that\'s an important part for moving forward.

We have talked about the intended practitioners tangentially, and I
think that it is important to recognize that there is a lot of input
that needs to go into this in terms of radiographic decision making,
gynecologic decision making. And that\'s why we view this technology as
a true partnership. And that at this point in time of its evolution, it
absolutely requires a radiologist and gynecologist to be working
together.

I think what we see for the distant future is that there will be
specific individuals doing this kind of therapy, just like every
gynecologist on the staff is not doing hysteroscopic surgery, and every
radiologist is not doing interventional procedures. And we may move to a
model very much like high risk ultrasound where people can come through
an MFM background, or they can come through a radiology background and
meet the same needs.

I think your point about potential pregnancy is very important. In fact,
right now the company is sponsoring a trial outside the U.S. to look at
women who want future fertility and following them, and we have
extensively discussed a registry for U.S. cases when and if we get to
that point.

I\'d like to turn things over to Clare Tempany at this point so she can
address a couple of the issues related to the more technical aspects of
the procedure.

DR. TEMPANY:  Thank you. There were two other sets of questions really
relating both to bowel gas and structures in the distal field. And I
think that a lot of the simulations and modeling have shown you that the
bowel gas issue really reflects the ultrasound wave, that there\'s been
no evidence of damage to anybody, none of the patients have experienced
any problems or side effects related to injury to bowel.

We have not done a bowel preparation, which came up as well, which is a
good question, for several reasons. Simply, because there didn\'t appear
to be an indication that anybody was having bowel symptomatology either
during or after the procedure in any way. And also, because if you give
a bowel preparation what happens unfortunately is you stimulate
extensive peristalsis and cause a lot of motion. And so this, of course,
will blur the thermal imaging during the procedure. So we felt it
probably wasn\'t indicated clinically, and it would also detract from
our ability to monitor the therapy as it was ongoing.

The other question I think was about the far field, and the nerves and
the bone, and I think that we\'ve answered that several times, and I
hope that that\'s been addressed completely. And if there is anything
else, please feel free to ask. But I do want to say that only five out
of 600 patients have had problems there, and it\'s really less than 1
percent, so this is a relatively small number, and certainly something
we\'ve learned extraordinarily from. And I think that we have very good
mitigating ways to get around this problem.

Somebody else asked a question about conscious sedation and would that
be included in our training. We feel that conscious sedation is part of
standard hospital staff privileging and for procedure-based medicine,
physicians are all required in my hospital certainly, and many
hospitals, they are required to undergo conscious sedation training
directed by the Department of Anesthesiology. We would hope that would
continue to be part of it. The sponsor doesn\'t feel that training in
conscious sedation would really be their expertise, and we would request
the hospitals in their staff privileging processes would do that.

We would certainly include training with a nurse and a physician during
the treatment as we talked about earlier about the communication and the
role of medication certainly in monitoring it. And I think Dr. Wood\'s
point about requiring it to be light to ensure continued communication
will certainly be included in our training, so I hope those addressed
the remaining questions.

DR. STEWART:  Elizabeth Stewart. Just to sum up, I think that the risk
benefit ratio of this treatment is very favorable. I think there have
been concerns about the comparability of the groups to assess safety,
but I think the safety of the treatment is clear. And I think it has
provided an effective means of therapy for many women who wouldn\'t
choose any other treatment modality, that the investigators and the
company are all committed to not only continuing on with our experience,
but improving and learning. And in effect, we really have been carrying
on our post market study for the past year, and have treated 89 patients
to-date to try to optimize treatment and extend benefit. And we look
forward to continuing to understand better how this treatment can be
optimized to give more benefit to more patients.

DR. NOLLER:  Thank you. Does the FDA have any closing statement? Okay,
panel members, your attention, please. Dr. Whang will now read us our
instructions.

DR. WHANG:  We will now move to the panel\'s recommendations concerning
PMA P040003. The medical devices 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 pre-market
approval applications, 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 outweigh any probable risk.

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 will provide clinically significant results.

The recommendation options for the vote are as follows. Approvable, 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
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. If the vote is for not approvable,
the panel should indicate what steps the sponsor may take to make the
device to approvable. You will find a handout summarizing the voting
procedure in the blue folders and in the packets that were handed out
this morning at the table.

DR. NOLLER:  All right. I would now like to ask if anyone would like to
make one of the three possible motions, approve, approve with conditions
or not approved. Dr. Roberts.

DR. ROBERTS:  I move approve with conditions.

DR. NOLLER:  Is there a second? There is a second. Next we will then
discuss conditions before we vote on that motion. Anyone like to add a
condition? Dr. D\'Agostino.

DR. D\'AGOSTINO:  Can I ask a question? This is accelerated approval or
something like that. Does that \--

DR. NOLLER:  I can\'t hear you.

DR. D\'AGOSTINO:  I\'m sorry. This is an accelerated approval?

MS. BROGDON:  It\'s an expedited \--

DR. NOLLER:  It\'s expedited.

DR. D\'AGOSTINO:  It\'s an expedited approval, so that just \--

MS. BROGDON:  It\'s an expedited review.

DR. D\'AGOSTINO:  Review. Okay.

MS. BROGDON:  And that need not affect your recommendations. It affects
the timing of our review and decision making.

DR. NOLLER:  Anyone want to add a condition? Dr. Roberts.

DR. ROBERTS:  Well, I would just add the conditions that I believe that
we spoke about in terms of the indications for use, and the \--

DR. NOLLER:  Please be a little more specific.

DR. ROBERTS:  I\'ll be specific. That the indications for use contain
information regarding the study itself that was used for the approval,
that it contain the indications for the procedure, that it contain the
indications for use, contain the parameters that were used in performing
the procedure, and include the contraindications. And specifically, that
it include the importance of minimizing the possibility of nerve damage
by indicating what the mitigations should be to try and avoid that. And
I would further put in the conditions that the patient information
include the possibility of nerve damage and that the patient
information, which I assume the FDA will do anyway, that the patient
information be written in such a way that it\'s understandable. There\'s
certain, I\'ve forgotten now the terminology that\'s used for creating
ones with the appropriate reading level, but that it be geared for
anyone who might be coming in to get th is procedure, that they can
understand it.

DR. NOLLER:  Is there a second to that condition?

DR. ASCHER:  Second.

DR. NOLLER:  Second. Discussion of the condition. Now let me reread what
I have. The indications for use include information concerning the
pivotal study, the indications for the procedure, the parameters used
for performing the procedure, the contraindications for the procedure,
the importance of attention to the mitigating factors to decrease nerve
damage, and that the patient information include the possibility of
nerve damage, and be rewritten to the FDA standard of educational level.
Discussion of that condition.

DR. BROWN:  Can I add something to it, or it has to be a totally
separate motion? It relates to \--

DR. NOLLER:  Well, let\'s discuss what you would want to add.

DR. BROWN:  The part about expanding the segment on training, that I
would also add that the training \--

DR. NOLLER:  Well, why don\'t we add that as a separate condition.

DR. BROWN:  Okay.

DR. NOLLER:  Any other \-- if not, then we\'ll vote on that condition.
Everybody understand the condition? Okay. Everyone can vote yes, no, or
abstain. We\'ll start at this end of the table. Dr. Wood, are you a
voting member? I forget who votes and who doesn\'t.

DR. WOOD:  Yes, I am, and yes, the vote.

DR. NOLLER:  Yes.

DR. ASCHER:  Yes.

DR. NOLLER:  Yes.

DR. MILLER:  Abstain.

DR. NOLLER:  Abstain.

DR. HAYES:  Yes.

DR. NOLLER:  Yes.

DR. SAMULSKI:  Yes.

DR. NOLLER:  Yes.

DR. JANIK:  Abstain.

DR. NOLLER:  Abstain.

DR. CRUM:  Yes.

DR. NOLLER:  Yes.

DR. BROWN: Yes.

DR. NOLLER:  Yes.

DR. NOLLER:  I vote yes.

DR. WHANG:  You don\'t vote.

DR. NOLLER:  Oh, I don\'t vote. That\'s right.

DR. ROBERTS:  Yes.

DR. NOLLER:  Yes.

DR. HILLARD:  Yes.

DR. NOLLER:  Yes.

DR. BRILL:  Abstain.

DR. NOLLER:  Abstain.

DR. D\'AGOSTINO:  Yes.

MR. WEEKS:  Yes.

DR. NOLLER:  That motion carries. Now other conditions? Dr. Brown.

DR. BROWN:  That the essential prescribing information and labeling be
modified that the training segment of such labeling is expanded to
indicate more specifically the steps that are required in training,
including the classroom time, the phantom lab practice to be attended by
all personnel involved, and in the subsequent on-site supervision
provided by the company. That that paragraph just be expanded to include
all of those things.

DR. NOLLER:  Is there a second to that condition?

MEMBER:  Second.

DR. NOLLER:  Second. Discussion of that condition. Hearing no
discussion, we\'ll vote on that. Dr. Wood.

DR. WOOD:  Yes.

DR. NOLLER:  Yes.

DR. ASCHER:  Yes.

DR. NOLLER:  Yes.

DR. MILLER:  Abstain.

DR. NOLLER:  Abstain.

DR. HAYES:  Yes.

DR. NOLLER:  Yes.

DR. SAMULSKI:  Yes.

DR. NOLLER:  Yes.

DR. JANIK:  Abstain.

DR. NOLLER:  Abstain.

DR. CRUM:  Yes.

DR. NOLLER:  Yes.

DR. BROWN:  Yes.

DR. NOLLER:  Yes.

DR. ROBERTS:  Yes.

DR. HILLARD:  Yes.

DR. BRILL:  Abstain.

DR. D\'AGOSTINO:  Yes.

MR. WEEKS:  Yes.

DR. NOLLER:  That motion also passes. Are there other conditions? Dr.
Diamond.

DR. DIAMOND:  I would like the group to discuss whether or not there
ought to be a need to conduct a small randomized \--

DR. NOLLER:  I\'m sorry, we really only discussion motions, so if you\'d
like to make a motion.

DR. DIAMOND:  Well, I can\'t make a motion. That\'s why I was planning
something for discussion.

DR. NOLLER:  You can\'t make a motion.

DR. JANIK:  I can make a motion, can\'t I? Yes. I would like to make a
motion that we add a small line to my study to look at efficacy between
either the sham study or UAE.

DR. NOLLER:  Do I hear a second?

MEMBER:  Second.

DR. NOLLER:  Second. Now we can discuss it, and Dr. Diamond can discuss.

DR. DIAMOND:  I think I probably have made my point fairly well before
as to why I think it would be necessary. I think actually, though, it
would also be beneficial to the company to have objective data where
they could show to practitioners who will have patients come in to see
them, and have hard data to be able to show this would be a benefit to
the patients where they have a control group, who end up I would expect
with high degree or failures in a very short period of time. So I think
actually it would be to their benefit to conduct such a study.

DR. WHANG:  I\'d like to make the point that you cannot \-- I don\'t
know if you mean the pre-market or post market study. You cannot require
a pre-market study as part of a condition of approval. If you think
additional pre-market studies are required, then you would have to
consider recommend not approvable, and list this as a reason for not
approvable.

DR. BROWN:  Question. But you can recommend it as a post market study.

DR. NOLLER:  I have a problem with the word \"small\". I don\'t know
what that means.

DR. JANIK:  Well, because if it is randomized your end number for
statistical significance will inherently be small, so it won\'t have to
be large.

DR. NOLLER:  It depends on the \--

DR. DIAMOND:  But if it\'s not adequately pallid, it would just leave us
in a quandary.

DR. NOLLER:  Dr. Roberts.

DR. ROBERTS:  I would speak very strongly against this. I think that
we\'ve been presented with a study. We have to decide either it\'s a
good enough study that we vote approval or it\'s not. And if it\'s not,
it\'s not. And if it is, then it is. But to tell the sponsors that well,
gee, we really like your study, and we think that we\'re going to
approve it, but we really want you to do something else I think is
wrong, and I think we can\'t do that. I just don\'t think that\'s the
right thing to do.

I think that we can encourage the investigators, we can encourage the
company to think about the fact that they would be much better in terms
of their marketing or selling this thing or whatever, that they go ahead
and this would be a great study to do as some kind of a randomized study
with something else. But I think in terms of saying that this is either
approved or not approved, we can\'t \-- I would speak very, very
strongly against this. I don\'t think it\'s the right thing to do.

DR. NOLLER:  Ms. Mooney.

MS. MOONEY:  I just would like to agree with Dr. Roberts in terms of the
distinction here, and again remind the panel of Dr. Whang\'s comments in
terms of the definitions. The threshold here for safety and efficacy is
reasonable assurance. And I think clearly there\'s a lot to be learned
and gained by additional studies, but in terms of the approvability of
this application, I think it\'s important to stay focused on the
reasonable assurance. And I think again we\'ve debated the merits and
limitations of the control that was used, but in terms of the company
demonstrating that its met its endpoints, I think that\'s been clear
with a fair margin, so I think it is important, as Dr. Roberts is
pointing out, to make a clear distinction.

DR. NOLLER:  Dr. Janik.

DR. JANIK:  I think that a number of us are concerned about the
endpoints, if they were agreed upon with the FDA, but I think there are
a number of us that have insecurities if efficacy is truly demonstrated
here, that I think we need more information to really confidently say
that is the crux of the problem.

DR. NOLLER:  Dr. Wood.

DR. WOOD:  I was just going to say that scientifically a sham study
makes great sense, and it would be great to see. But ethically, I\'m not
sure, and to put it passed five IRBs, conservative ones may not approve
it given the data available. And I, for one, would probably not feel
comfortable going to a patient and saying you may or may not be treated,
although if you are treated it might help you, albeit short-term
efficacy.

DR. NOLLER:  Dr. Brown.

DR. BROWN:  I would just say I think the problem is not with the safety,
but with the efficacy and depending on how this vote goes, if this is
voted not to do the study, I am going to make another condition about
what\'s specified about the endpoints in the information because I think
that that\'s \-- if you\'re not going to do something else, I think it
has to be very clear to the people reading this booklet what the
endpoint was, and exactly what it was, and not lead them to think
something else. Specifically, I think all the comparisons to
hysterectomy then need to come out. You need to just say it shows this
10 point change, period.

DR. NOLLER:  Dr. Brill.

DR. BRILL:  Just to accelerate things. Grace, are you suggesting a pre
or a post market study?

DR. JANIK:  I would suggest pre-market.

DR. BRILL:  So it\'s not really germane to where we are right now in the
motion, because we\'re here with conditions, so I think it\'s going to
have to follow our discussion.

DR. MILLER:  As a point of order, just for clarification for myself, can
we be at a point in discussing conditions if we haven\'t decided
approval or disapproval?

DR. NOLLER:  Yes.

DR. MILLER:  WE can be? Okay.

DR. NOLLER:  Yes, that\'s what we do.

DR. BROWN:  But just a point of clarification, so you\'re talking about
a pre-market study, then you have to wait and vote down the approval
with conditions, and then \--

DR. NOLLER:  Right. I was just going to make that point.

DR. MILLER:  That\'s my point.

DR. NOLLER:  Ms. Mooney, you were next.

MS. MOONEY:  Yes. Just again to emphasize Dr. Brown\'s point. There is a
lot of latitude the panel has in terms if adding wording to the
instructions for use, the training. They can clearly spell out what data
were generated in this trial, and what data were left unanswered for
subsequent study. So again I think the key is the reasonable assurance
in that threshold in terms of deciding whether something should be pre
or post market.

DR. NOLLER:  Dr. Diamond.

DR. DIAMOND:  I was just going to say, in as much as what is now being
discussed is approval with conditions, Dr. Janik may want to think about
suggesting the study at this point as a post marketing study, although
it sounds like her ultimate goal and her ultimate desire might be to
have as a pre-approval study.

DR. JANIK:  That would be my primary goal, though I would take it as a
secondary.

DR. NOLLER:  I understood your motion to be for a post market study. Is
that correct? Was that your motion?

DR. JANIK:  My motion would be for a pre-market study, so that can\'t be
\--

DR. NOLLER:  We can\'t consider that here then. So we will no longer
discuss that condition. Any other conditions? Yes.

MR. WEEKS:  Yes, Jonathan Weeks. Again, I think the sponsor should
evaluate their data on uterine volumes, and to be sure that there\'s no
strong correlation between larger uteri and failed therapy; specifically
going in to get hysterectomies or second procedures.

DR. NOLLER:  Is there a second?

DR. BROWN:  What was the motion? I\'m sorry.

DR. NOLLER:  The motion is for the sponsor to evaluate the current data
on uterine volume.

DR. BROWN:  And that would be reviewed \--

DR. NOLLER:  And relate it to success or failure of the procedure.

DR. BROWN:  And that would have to be reviewed by the FDA and put in
this \--

DR. NOLLER:  Do we have a second?

DR. BROWN:  I\'ll second it.

DR. NOLLER:  Okay.

DR. BROWN:  So my question would be then that information would be
provided by the sponsor to the FDA, and that would ostensibly be
included in this packet.

DR. NOLLER:  Is that what your motion was?

MR. WEEKS:  Yes.

DR. NOLLER:  Okay. Discussion of that motion. If not, we\'ll vote. Dr.
Wood.

DR. WOOD:  Yes.

DR. ASCHER:  Abstain.

DR. NOLLER:  Abstain.

DR. MILLER:  Abstain.

DR. NOLLER:  Abstain.

DR. HAYES:  Yes.

DR. NOLLER:  Yes.

DR. SAMULSKI:  Yes.

DR. NOLLER:  Yes.

DR. JANIK:  Abstain.

DR. NOLLER:  Abstain.

DR. CRUM:  Yes.

DR. NOLLER:  Yes.

DR. BROWN:  Yes.

DR. NOLLER:  Yes.

DR. ROBERTS:  No.

DR. NOLLER:  No.

DR. HILLARD:  Yes.

DR. NOLLER:  Yes.

DR. BRILL:  Abstain.

DR. D\'AGOSTINO:  No.

MR. WEEKS:  Yes.

DR. NOLLER:  We have to count this one. Motion carries. Are there other
conditions?

DR. D\'AGOSTINO:  What was the count on the vote?

DR. NOLLER:  Seven yes, two nos, four abstain. Other conditions?

DR. MILLER:  I would move that the company provide some strategy for
handling future pregnancies beyond this procedure in the event that this
technology is approved. That there be either a registry or some other
strategy that they can work out with the FDA to capture that
information, because there will be pregnancies following the use of this
technology.

DR. NOLLER:  Is there a second to the motion?

MEMBER:  Second.

DR. NOLLER:  Second. Discussion?

DR. ROBERTS:  Are you saying that the company has to follow every single
patient that comes into the study with the idea that at some point they
might become pregnant, and that somehow they\'re going to recognize
that?

DR. MILLER:  I\'m saying that there are many pharmaceutical companies
who release medications knowing that they may not be safe in pregnancy,
but establish mechanisms for following those patients, so that
information can be understood over time.

DR. ROBERTS:  But I don\'t \--

DR. NOLLER:  There are various ways to do that, and probably the
simplest is just to create a registry with a telephone number that you
call if you have a patient that becomes pregnant with this. It\'s not a
great way to do it, but it\'s a way to do it. Ms. Mooney.

MS. MOONEY:  Another option that sponsors will sometimes be asked to do
is put something explicit in the labeling that says the effects are
unknown or have not been studied, so that\'s another option to consider.

DR. NOLLER:  Will the FDA do that automatically? Yes. Okay.

MS. BROGDON:  Yes.

DR. NOLLER:  Yes.

DR. BROWN:  We already heard the sponsor say they expressed a strong
interest in creating a registry, so I move for specifically saying they
should create a registry with an 800 number, and that be part of the
labeling package.

DR. NOLLER:  That would restrict them to one way. The notion is that
they would work out some way, a registry would be one possibility.
Clearly, you wanted it a little more open-ended than registry. Is that
correct?

DR. MILLER:  Correct. I\'m open to some mechanism.

DR. NOLLER:  Further discussion? Let\'s vote.

MS. MOONEY:  I\'m sorry. Can I just ask, you said the FDA would do that
anyway?

DR. NOLLER:  No, they would add the precaution don\'t do this in a
pregnant woman.

MS. MOONEY:  Oh, okay.

DR. NOLLER:  Are we ready to vote? Dr. Wood.

DR. WOOD:  Abstain.

DR. NOLLER:  Abstain.

DR. MILLER:  Approve.

DR. NOLLER:  Approve.

DR. HAYES:  Yes.

DR. NOLLER:  Yes. Dr. Samulski.

DR. SAMULSKI:  Yes.

DR. NOLLER:  Yes.

DR. JANIK:  Yes.

DR. NOLLER:  Yes.

DR. CRUM:  Yes.

DR. NOLLER:  Yes.

DR. BROWN:  Yes.

DR. NOLLER:  Yes.

DR. ROBERTS:  No.

DR. NOLLER:  No.

DR. HILLARD:  No.

DR. NOLLER:  No.

DR. BRILL:  Abstain.

DR. NOLLER:  Abstain.

DR. D\'AGOSTINO:  No.

DR. NOLLER:  No.

MR. WEEKS:  Yes.

DR. NOLLER:  Yes. The motion passes; 7 yes, 3 nays, 3 abstain. Are there
other conditions? Hearing none \--

DR. BROWN:  Wait. I\'m sorry. I think I need to make a motion that
within the description about the results of the pivotal study, that it
just be made clear what the primary endpoint was, the 10 point range on
the scale. And to make sure to give the appropriate references. There
may be there\'s more up-to-date references that we were given today that
could be included here to look at validating the questionnaire that the
clinician could turn to, that that reference that we heard about in the
public testimony also be included here. And if the other one gets
published before this gets done, that one would be included also that
talks about the validation of this questionnaire.

DR. NOLLER:  Is there a second?

MR. WEEKS:  Second.

DR. NOLLER:  Second. I understand this condition to be that in the
patient information?

DR. BROWN:  No, the prescribing information.

DR. NOLLER:  The prescribing information there be a description of the
results of the pivotal study, particularly the endpoints, and the
appropriate references. Is that correct?

DR. BROWN:  Right, but they update, because there are now some new
references that aren\'t currently in here.

DR. NOLLER:  Discussion? If not, we\'ll vote. Dr. Wood.

DR. WOOD:  Yes.

DR. NOLLER:  Yes.

DR. ASCHER:  Yes.

DR. NOLLER:  Yes.

DR. MILLER:  Abstain.

DR. HAYES:  Yes.

DR. NOLLER:  Yes.

DR. SAMULSKI:  Yes.

DR. NOLLER:  Yes.

DR. JANIK:  Abstain.

DR. NOLLER:  Abstain.

DR. CRUM:  Yes.

DR. NOLLER:  Yes.

DR. BROWN:  Yes.

DR. NOLLER:  Yes.

DR. ROBERTS:  Yes.

DR. NOLLER:  Yes.

DR. HILLARD:  Yes.

DR. NOLLER:  Yes.

DR. BRILL:  Abstain.

DR. NOLLER:  Abstain.

DR. D\'AGOSTINO:  Yes.

DR. NOLLER:  Yes.

MR. WEEKS:  Yes.

DR. NOLLER:  Yes. The motion carries.

DR. WOOD:  Could I add a motion for \--

DR. NOLLER:  Five conditions. You have \-- what?

DR. WOOD:  Can I add a motion?

DR. NOLLER:  Another condition? Yes.

DR. WOOD:  Yes, another condition. The prescribed information include
more information on scaring. It just says does not have extensive
scaring, just that no information has been obtained on previous
C-sections.

DR. NOLLER:  I\'m sorry. I can\'t hear you.

DR. WOOD:  Something about there not being any data on the history of
C-sections prior to use.

DR. NOLLER:  So the information, prescribing information include more
data on scars and specifically data on \-- mentioning that there are no
data on Caesarean sections.

DR. WOOD:  That\'s easily accessible. It\'s available in the database
and looking through charts. In the pivotal studies we looked back and
see how many had C-sections, so they can determine whether those
patients had scars that potentially unfocus the beam.

DR. NOLLER:  So to include the statement either that there is no
information on C-section scars, or to present the actual data.

DR. WOOD:  Yes.

DR. NOLLER:  Is there a second? Second? Discussion? Let\'s vote. Dr.
Wood.

DR. WOOD:  Yes.

DR. NOLLER:  Yes.

DR. ASCHER:  Yes.

DR. NOLLER:  Yes.

DR. MILLER:  Abstain.

DR. NOLLER:  Abstain.

DR. HAYES:  Yes.

DR. NOLLER:  Yes.

DR. SAMULSKI:  Yes.

DR. NOLLER:  Yes.

DR. JANIK:  Abstain.

DR. NOLLER:  Abstain.

DR. CRUM:  Yes.

DR. NOLLER:  Yes.

DR. BROWN:  Yes.

DR. NOLLER:  Yes.

DR. ROBERTS:  Yes.

DR. NOLLER:  Yes.

DR. HILLARD:  Yes.

DR. NOLLER:  Yes.

DR. BRILL:  Abstain.

DR. NOLLER:  Abstain.

DR. D\'AGOSTINO:  No.

DR. NOLLER:  No.

MR. WEEKS:  Yes.

DR. NOLLER:  Yes. The motion carries. Are there other conditions? Yes.

DR. JANIK:  I think I\'m going to go back and put it in again, just let
me go through. I\'d like to make a motion to put a post market
randomized study between this technique and a sham, or uterine RA
embolization, sponsor\'s choice.

DR. NOLLER:  Sufficiently powered.

DR. JANIK:  Sufficiently powered, with one year follow-up.

DR. NOLLER:  Is there a second?

DR. BROWN:  Second.

DR. NOLLER:  Second. Is there a discussion? Dr. Roberts.

DR. ROBERTS:  I don\'t know. I guess I feel like the only one that sort
of looks at what it costs to bring one of these products to market. And
quite frankly, I mean I\'ve seen this happen in other panels where
basically people spend enormous amounts of dollars, millions of dollars
to bring something to market that they present the data on the study.
Our job is to look at that data and to decide whether or not they\'ve
done an appropriate job. And if they haven\'t done an appropriate job,
then I think it\'s \-- I have no problem with voting it down and saying
go back and do another study, and come back and see us again sometime.
But I think to say well, we\'re going to approve it, but we really want
you to do another study - quite frankly, I don\'t think it\'s fair to
the sponsor.

I think if in the community there\'s a feeling that this is not really a
good technology, and we don\'t have the data for it, don\'t refer your
patients to get it. That\'s one way that the market will speak. I just
think it\'s the wrong thing to do, and I think it really puts a burden
on the sponsors to \-- they work out a deal with the FDA in terms of
deciding ahead of time what their study is going to be, and they carry
it out. And then to come back and say well, you know, we kind of like
it, and it\'s pretty good, but we really want you to do something else -
I just think is wrong.

DR. NOLLER:  I\'m going to read the FDA guidance before any further
discussion. This guidance says that post approval studies may provide
additional information about an approved device. However, the safety and
effectiveness must be demonstrated before approval. The results of a
post approval study should not be expected to change the approval status
of the device. Dr. Brill.

DR. BRILL:  I think those guidelines speak for themselves, so there\'s
no further reason to discuss this. If we mistrust the data, then we
should disapprove and move forward.

In addition to that, if we do either pre or post market study, I think
it\'s misnomerous for us to compare it to uterine artery embolization.
And where you\'re talking about total myoma treatment, and a change in
menstruation from probably some change in the endometrium itself, the
selective myoma treatment, so I think we need to intellectually separate
these procedures, and not in any way consider them equivalent.

DR. NOLLER:  Additional discussion? Let\'s vote. This vote, if you vote
aye, it is for a post market randomized study. If you vote nay, it\'s
the condition is not approved. Dr. Wood.

DR. WOOD:  No.

DR. NOLLER:  No.

DR. ASCHER:  No.

DR. NOLLER:  No.

DR. MILLER:  No.

DR. NOLLER:  No.

DR. HAYES:  No.

DR. NOLLER:  No.

DR. SAMULSKI:  No.

DR. NOLLER:  No.

DR. JANIK:  Yes.

DR. CRUM:  No.

DR. NOLLER:  No.

DR. BROWN:  No.

DR. NOLLER:  No.

DR. ROBERTS:  No.

DR. NOLLER:  No.

DR. HILLARD:  No.

DR. NOLLER:  No.

DR. BRILL:  No.

DR. NOLLER:  No.

DR. D\'AGOSTINO:  No.

DR. NOLLER:  No.

MR. WEEKS:  No.

DR. NOLLER:  No. Condition number 7 is defeated. Are there additional
conditions?

DR. BROWN:  One more.

DR. ROBERTS:  I move approval.

DR. NOLLER:  More conditions. Dr. Brown, and then Dr. Wood.

DR. BROWN:  Also, I think under a separate heading other than training,
there should be a bullet about who would be doing the procedure, and
this blurb about describing this joint multi-disciplinary partnership
between radiologists and gynecologists, and that should be in the
central prescribing information and all of that labeling information, so
that that comes across very clearly that it requires that, so that you
do not have \-- they have the appropriate people working together.

DR. NOLLER:  Is there a second? Hearing no second. Dr. Wood. Did you
have another condition?

DR. WOOD:  Okay. Yes. It would be nice to have in the prescribing
section \--

DR. NOLLER:  I can\'t hear you. I\'m sorry.

DR. WOOD:  It would be nice to have in the prescribing section a
sentence on deep sedation or lack of continuous patient feedback could
increase risk for nerve injury.

DR. NOLLER:  Is there a second. Second. Discussion? The condition is
that the prescribing information include the statement that deep
sedation or general anesthesia may increase the risk to the patient. Did
I get it right?

DR. WOOD:  Lack of feedback for whatever reason.

DR. DIAMOND:  I would think that would have to be worded that we don\'t
know whether deep sedation would cause that, because I don\'t know that
we were presented any data to demonstrate that.

DR. WOOD:  Well, we\'ve been presented with data that the patients \--
we\'ve been presented with the suggestion that patients who feel this
electrical twinge and the sonication is stopped, and the latest 50 or so
cohort have had less risk of \-- less severe nerve damage, so that would
imply that this is true.

DR. NOLLER:  Ms. Mooney.

MS. MOONEY:  Perhaps it could be worded to reflect what we heard from
the clinicians in terms of make sure you maintain continuous and
adequate feedback with the patient.

DR. WOOD:  Sounds good.

DR. NOLLER:  Do you accept that?

DR. WOOD:  Yes.

DR. NOLLER:  Okay. Any other discussion? For that condition, Dr. Wood.

DR. WOOD:  Yes.

DR. NOLLER:  Yes.

DR. ASCHER:  Yes.

DR. NOLLER:  Yes.

DR. MILLER:  Yes.

DR. NOLLER:  Yes.

DR. HAYES:  Yes.

DR. NOLLER:  Yes.

DR. SAMULSKI:  Yes.

DR. NOLLER:  Yes.

DR. JANIK:  Yes.

DR. NOLLER:  Yes.

DR. CRUM:  Yes.

DR. NOLLER:  Yes.

DR. BROWN:  Yes.

DR. NOLLER:  Yes.

DR. ROBERTS:  Yes.

DR. NOLLER:  Yes.

DR. HILLARD:  Yes.

DR. NOLLER:  Yes.

DR. BRILL:  Yes.

DR. NOLLER:  Yes.

DR. D\'AGOSTINO:  Yes.

DR. NOLLER:  Yes.

MR. WEEKS:  Yes.

DR. NOLLER:  Yes. It passes. Finally, a unanimous one.

DR. WOOD:  Point for discussion. Is there \-- can we discuss now? No,
only motions.

DR. NOLLER:  We can only discuss motions at this point.

DR. WOOD:  Motion for discussion. No, motion that we consider the
statement the mechanism of effect is not entirely understood or
something softer than that, if anyone has any suggestions, when we\'re
discussing the pivotal trial and the quality of life improvement.

DR. NOLLER:  Could you \-- I don\'t quite understand that.

DR. WOOD:  Just something to reflect the fact that we don\'t know
exactly why these patients have the effect, have the quality of life
improvement that they have. And I\'m not sure it belongs in the
prescribing section. And I guess this is more of a discussion point than
a motion.

DR. NOLLER:  Perhaps by raising it, the point has been made.

DR. WOOD:  Yes.

DR. NOLLER:  And you can withdraw it.

DR. WOOD:  Sure.

DR. NOLLER:  Okay. Other conditions? Hearing none, we will now vote on
approval with the seven conditions we approved. And we can now discuss
that motion before we vote. Motion to approve with conditions, and it\'s
the seven that we just voted on. No discussion. Let\'s vote. If this
passes, then we\'re finished for the day. If not \-- well, almost. If
not, then we consider possible other motions. Dr. Wood.

MS. MOONEY:  Dr. Noller, I think one of your voting members stepped out.
I don\'t know if you \--

DR. NOLLER:  Okay. Let\'s start. We\'ll go real slow. Dr. Wood.

DR. WOOD:  Yes.

DR. NOLLER:  Yes.

DR. ASCHER:  Yes.

DR. NOLLER:  Yes.

DR. MILLER:  No.

DR. NOLLER:  No.

DR. HAYES:  Yes.

DR. NOLLER:  Yes.

DR. SAMULSKI:  Yes.

DR. NOLLER:  Yes.

DR. JANIK:  No.

DR. NOLLER:  No.

DR. CRUM:  Yes.

DR. NOLLER:  Yes.

DR. BROWN:  Yes.

DR. NOLLER:  Yes.

DR. ROBERTS:  Yes.

DR. NOLLER:  Yes.

DR. HILLARD:  No.

DR. NOLLER:  No.

DR. BRILL:  No.

DR. NOLLER:  No.

DR. D\'AGOSTINO:  No.

DR. NOLLER:  No. We have one more vote to come. And, Dr. Weeks, we\'re
voting on the motion to approve with conditions or not. And we\'re
around to you.

MR. WEEKS:  Yes.

DR. NOLLER:  Yes. The motion passes 8 ayes, 5 nays, no abstentions. The
final piece of work I believe now is that we need to go around the table
and everyone is to state how they made their decision to vote yes or no,
and we will include the non-voting members, the consumer representative,
and the industry representative. Dr. Wood. I\'m not really picking o you
by starting with you.

DR. WOOD:  This can be short, I assume.

DR. NOLLER:  This should be very short.

DR. WOOD:  Yes. I think they\'ve shown enough short-term efficacy and
the safety issues have been addressed adequately with the mitigating
circumstances.

DR. ASCHER:  I would concur that they put out their hypothesis, and they
proved both safety and efficacy for the limited scope that they were
looking for.

DR. MILLER:  I wasn\'t convinced that effectiveness was demonstrated. I
had less problem with safety, and a problem for the mitigating factors,
but I wasn\'t convinced by the efficacy work.

DR. HAYES:  I voted yes because the safety and efficacy, and also with
the conditions it\'s going to contain.

DR. NOLLER:  Dr. Samulski.

DR. SAMULSKI:  The pivotal data wasn\'t strong enough. The pivotal data,
I think, wasn\'t strong enough.

DR. NOLLER:  The pivotal data wasn\'t strong enough.

DR. JANIK:  I voted no. I have concerns of efficacy. I think safety is
adequate. And the concerns are that its only a very short-term that\'s
been demonstrated. In fibroids it needs to be at least a year to warrant
the risk.

DR. CRUM:  I think it\'s safe. I think it\'s efficacious, and I think
that with the restrictions that the FDA has placed, that only a small
percentage of the fibroid can be treated, and yet patients have a
satisfaction level after one year of 72 percent speaks very strongly in
favor of this technology. And this gives the patient a choice, and I
think that\'s what \-- that\'s the desirable thing of this technology.

DR. BROWN:  I voted yes. I didn\'t think there was any question about
the safety. I think my efficacy concerns were answered by limiting that
the efficacy was proving their really first hypothesis about the 10
point difference.

DR. NOLLER:  Dr. Roberts.

DR. ROBERTS:  I think that they satisfied their endpoints. I think
particularly given the fact that they were limited in terms of the
amount that could be treated and still met those endpoints probably
speaks fairly strongly to the technology.

DR. DIAMOND:  I think the technology itself is very exciting, and I
think it has lots of potential for the future. I think the company has
done a great job in working through many of the safety issues. I remain
concerned about efficacy, and whether or not the benefit that they saw
in the primary endpoint could be placebo effect, as it has been in other
trials which have looked at pain in women for the length of follow-up
that have been shown here.

DR. HILLARD:  I remain unconvinced about the efficacy and the quality of
life change of 10 points. I think my concerns about safety have been
answered and addressed.

DR. BRILL:  Well, I believe the device is safe. I\'m somewhat saddened
by the design of the study which I think probably is feedback to the
FDA, as well as to the sponsor, for the efficacy suffered for lack of a
control group. I don\'t think there\'s any question about that.

I\'m not convinced that this particular instrument has been validated.
And despite the fact that it\'s the best thing we have to use, we truly
haven\'t used it that much to say in fact these surrogate measures equal
change necessarily.

I have concerns about the fact that there\'s no algorithm as far as how
fibroids are treated, and it is somewhat random, and define in
inspiration by nature. And to reflect what Dr. Spies said in his
presentation, that at least the efficacy of uterine artery embolization
seems to be dependent upon the ability to completely treat the myoma.

In this case, it\'s been presented to us that, in fact, this is only
partial treatment. And if we go with that logic then, in fact, we should
have sub-optimal treatment.

DR. D\'AGOSTINO:  I\'m unconvinced by the efficacy data. It\'s a
composite score. I really don\'t know what\'s driving it, and I\'m very
concerned also about the 12 month data. And it wasn\'t 70 percent, it\'s
only 40 percent. It didn\'t make the anticipated 50 percent that they
were looking for, over 50 percent having a better than 10 point change,
so I think the efficacy data is very problematic. The safety data looks
all right.

DR. SOLOMON:  I\'d like to commend the company for what\'s really an
incredible engineering feat that\'s taken many, many years to
accomplish. The complexity in the MRI and the focused ultrasound brought
together to do a completely non-invasive therapy is really amazing. But
that complexity emphasizes the point that training is really going to be
critical from a safety point of view, and that\'s the area that I really
recommend that they work and emphasize with all the people being
involved. Otherwise, there could be some serious complications, so
congratulations.

DR. WEEKS:  I was convinced about safety. I struggled quite a bit with
the efficacy question, and how to sort of juxtapose my concerns against
some of the constraints that the sponsor was under. Ultimately, I think
the number of motions to improve the patient brochure and training, and
physician instructions swayed me to vote yes.

SPEAKER:  I commend the company for giving women another choice for a
problem that has troubled them for a long time. I think you have met the
burden of proof as far as safety and efficacy. I think you discussed
probably at more length the study design issues, but I don\'t think that
should separate what really happened as far as the safety and efficacy.
There were study design issues, so be it.

I think you have done a good job, vis a vis the FDA of balancing two
very critical functions; and that is the patient\'s safety and do no
harm, as well as the innovation that we are continually asked to look
at, so I think we met that burden.

I remain concerned about the training, and I think it should be beefed
up as far as what has been discussed today here with the physicians,
both radiology and gynecology, as well as the other discipline of
nursing. Nursing would be the watchdog in that room, since there is no
machine that will shut off the heat source. It will be the communication
pattern, and with that in mind, that is the classic role for the nurse.
So please make sure that that is adequately included in all your
materials.

MS. MOONEY:  I have no additional comments.

DR. NOLLER:  Well, Panel, our work is done for the day. I want to
commend you on doing your reading ahead of time, and dealing very fairly
with a complex issue, and we\'re now adjourned. Oh, please leave all
your materials on the table, and they\'ll be picked up and destroyed.

(Whereupon, the proceedings in the above-entitled matter went off the
record at 4:45 p.m.)