UNITED STATES OF
AMERICA
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DEVICES AND
RADIOLOGICAL HEALTH
MEDICAL DEVICES ADVISORY
COMMITTEE
OBSTETRICS AND GYNECOLOGY
DEVICES PANEL
68TH
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:
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:
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:
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 26th and 27th,
so the remaining panel meeting date for this year is October 25th to
26th.
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 27th, 1990, and amended August 18th, 1999,
I appoint the following individuals as voting members of the Obstetrics and Gynecology
Devices Panel for this meeting on June 3rd, 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 27th, 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 2nd, 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.)