68TH MEETING



                   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.




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


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

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


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

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

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


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

JOYCE WHANG, Ph.D., Panel Executive Secretary










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
















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.)