UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

MEDICAL DEVICES ADVISORY COMMITTEE

 

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ORTHOPEDIC AND REHABILITATION DEVICES PANEL

 

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MEETING

 

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TUESDAY,

AUGUST 31, 2004

 

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      The Panel met at 8:00 a.m. in Salons A, B, C of the Hilton Washington D.C. North/Gaithersburg, 620 Perry Parkway, Gaithersburg, Maryland, Dr. Michael J. Yaszemski, Chairperson, presiding.

 

PRESENT:

 

MICHAEL J. YASZEMSKI, M.D., Ph.D.    Chairperson

MAUREEN A. FINNEGAN, M.D.  Voting Member

JOHN S. KIRKPATRICK, M.D.  Voting Member

STEPHEN LI, Ph.D.      Voting Member

SANJIV H. NAIDU, M.D., Ph.D.    Voting Member

SALLY L. MAHER, Esq.   Industry Representative

LEELEE DOYLE, Ph.D.    Consumer Representative

FERNANDO G. DIAZ, M.D. Deputized Voting Member

JONAS ELLENBERG, Ph.D. Deputized Voting Member

CHOLL W. KIM, M.D., Ph.D.  Deputized Voting Member

SALLY A. RUDICEL, M.D. Deputized Voting Member

JANET L. SCUDIERO, M.S. Executive Secretary

 

 

 

 

 

FDA REPRESENTATIVES:

 

CELIA WITTEN, Ph.D.

BARBARA D. BUCH, M.D.

JOHN P. HOLDEN, Ph.D.

RICHARD M. KOTZ, M.S.

 

 

SPONSOR REPRESENTATIVES:

 

GUNNAR ANDERSSON, M.D., Ph.D.

CHARLES HARTJEN, M.D.

YVONNE LYSAKOWSKI, R.N., M.S.

AUGUSTUS A. WHITE III, M.D., Ph.D.

SCOTT YERBY, Ph.D.

JAMES ZUCHERMAN, M.D.


                      A-G-E-N-D-A

 

Conflict of Interest and Deputization to

Voting Member Status Statements...................... 4

 

Panel Introductions.................................. 5

 

PUBLIC COMMENT

William Christianson................................ 13

Merrie Miller....................................... 18

Allyson Washburn.................................... 22

 

SPONSOR PRESENTATION:

St. Francis Medical Technologies, Inc.

Intraspinous Process Distraction System,

the X STOP, P040001

 

Yvonne Lysakowski, RN, MS........................... 30

Augustus A. White, III, MD, PhD..................... 34

Scott Yerby, PhD.................................... 42

Gunnar Andersson, MD, PhD........................... 46

Charles Hartjen, MD................................. 55

Gunnar Andersson, MD, PhD........................... 73

 

FDA PRESENTATION

John P. Holden, PhD................................. 81

Barbara D. Buch, MD................................. 88

Richard M. Kotz, MS................................ 107

 

PANEL DELIBERATION

Clinical Reviewer, John S. Kirkpatrick, MD......... 117

Statistical Reviewer, Jonas Ellenberg, PhD......... 129

General Discussion................................. 144

Discussion of Question 1........................... 196

Discussion of Question 2........................... 197

Discussion of Question 3........................... 210

Discussion of Question 4(a)........................ 219

Discussion of Question 4(b)........................ 230

Discussion of Question 5........................... 237

Discussion of Question 6........................... 245

Discussion of Question 7........................... 248

 

Sponsor Summation.................................. 259

Vote on Motion for Non-Approval.................... 263


                 P-R-O-C-E-E-D-I-N-G-S

                                              8:02 a.m.

             DR. YASZEMSKI:  Hi, good morning everybody.  Can I ask everybody to take your seats?  We're going to go ahead and get started.

             MS. SCUDIERO:  Good morning.  I'm Jan Scudiero, the executive secretary of this panel, and a reviewer in the Division of General Restorative and Neurological Devices.  If you haven't already signed in at the tables at the doors, please do so.  The agenda information is there, and other information about advisory panel meetings, including how to get transcripts and summaries.

             Before I turn the meeting over to Dr. Yaszemski, I'm required to read two statements into the record.  They are the deputization of temporary voting members for this meeting, and the conflict of interest statement. 

             First, the appointment to temporary voting status.  Pursuant to the authority granted under the Medical Devices Advisory Committee Charter, dated October 27, 1990, and amended April 20, 1995, I appoint the following as voting members of the Orthopedic and Rehabilitation Devices Panel for the duration of this meeting on August 31, 2004.  Fernando G. Diaz, MD, PhD; Jonas Ellenberg, PhD; Choll W. Kim, MD, PhD; and Sally A. Rudicel, MD.  For the record, these people are special government employees, and are consultants to this panel or another panel under the Medical Devices Advisory Committee.  They have undergone the customary conflict of interest review, and have reviewed the material to be considered at this meeting. 

             The conflict of interest statement.  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 for this meeting, 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 interest.  However, the agency has determined that the 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, a waiver has been granted for Dr. Stephen Li for his interest in firms that could be affected by the panel's recommendations.  Dr. Li's waiver involves consulting with several competing firms on topics that are unrelated to today's agenda.  Dr. Li receives less than $10,000 for each of these consulting arrangements.  We would also like to note for the record that the agency took into consideration certain matters regarding Drs. Maureen Finnegan, Choll Kim, John Kirkpatrick, and Stephen Li.  Each of these panelists reported current or past interests in firms at issue, but in matters not related to today's agenda.  The agency has determined therefore that they may participate fully in today's deliberations.  In the event that the discussions involve any products or firms not already on the agenda for which an FDA participant has a financial interest, the participant should excuse himself or herself from such involvement, and the exclusion will be noted for the record.  With respect to all other participants, we ask in the interest of fairness that all persons making statements or presentations disclose any current or previous financial interest involvement with any firm whose products they may wish to comment upon.

             There is one more tentatively scheduled meeting of this panel for this year.  It's December 2 and 3.  Please remember that this is tentative, and check the CDRH website for updated information.  Dr. Witten, I'll give her just a moment.  This is the last meeting of some of our panel members, and Dr. Witten would just like to say something briefly.

             DR. WITTEN:  This is the last meeting as members for Dr. Finnegan, Dr. Li, and Sally Maher.  And I want to thank them for their service to FDA and their participation in this panel.  We certainly rely on the outside expertise that's provided by our panel members, and we need them to carry out our mission here.  I would like to present plaques to them, but unfortunately the plaques haven't come yet.  So we'll just have theoretical plaques today, and the actual plaques will come later.  So thank you to those three panel members.

             And I'd like to welcome Dr. Sally Rudicel and Dr. Choll Kim who will be new voting members of the panel starting September 1, and are here today as deputized voting members.  Thank you.

             MS. SCUDIERO:  I now turn the meeting over to Dr. Yaszemski.

             DR. YASZEMSKI:  Thanks very much.  Good morning.  I'm Dr. Michael Yaszemski.  I'm the chairperson of the Orthopedic and Rehabilitation Panel.  I'm an orthopedic spinal surgeon and a chemical engineer.  I work at Mayo Clinic in Rochester, Minnesota.  At this meeting, the panel will be making a recommendation to the Food and Drug Administration on the approvability of pre-market approval application for the St. Francis Medical Technologies, Inc., Intraspinous Process Distraction System, the X STOP.  The device is intended for patients aged 50 or older suffering from mild or moderate neurogenic intermittent claudication, secondary to lumbar spinal stenosis, who have undergone a regimen of non-operative treatment.  The X STOP is indicated for patients who experience relief in flexion from their symptoms of leg, buttock, or groin pain, with or without back pain.

             Before we begin this meeting, I'd like to ask our distinguished panel members, who are generously giving their time to help the FDA in the matter being discussed today, and other FDA staff seated at this table to introduce themselves.  Please state your name, your area of expertise, your position, and your affiliation.  I'll start to my right with Dr. Kirkpatrick.

             DR. KIRKPATRICK:  I'm John Kirkpatrick.  I'm a spine surgeon and associate professor of both orthopedics and engineering at the University of Alabama at Birmingham.

             DR. NAIDU:  My name is Sanjiv Naidu.  I'm an orthopedic surgeon.  I'm an associate professor of orthopedic surgery, and my interest is in orthopedic surgery and material science.

             DR. KIM:  I'm Choll Kim.  I'm an assistant professor of orthopedic surgery at the University of California - San Diego, and my specialty is in orthopedic spine surgery.

             DR. DOYLE:  I'm LeeLee Doyle.  I'm a professor emeritus of obstetrics and gynecology, and the assistant dean for faculty development at the University of Arkansas College of Medicine.  I'm a consumer rep.

             MS. MAHER:  Sally Maher.  I'm a group director of regulatory and clinical research for Smith & Nephew Endoscopy.  And I'm the industry rep.

             DR. WITTEN:  I'm Celia Witten.  I'm the division director of reviewing division at FDA.

             DR. RUDICEL:  Sally Rudicel.  I work at Tufts New England Medical Center.  I'm an orthopedic surgeon associate professor, and my specialty is foot and ankle.

             DR. FINNEGAN:  Maureen Finnegan.  I'm an associate professor at the University of Texas Southwestern Medical Center.  And my background is trauma.

             DR. ELLENBERG:  Good morning.  I'm Jonas Ellenberg.  My specialty is biostatistics, with a long history at the Neurology Institute at NIH.  I am currently a staff member at Westat as a vice president and senior biostatistician.

             DR. LI:  My name is Steve Li.  I'm president of Medical Device Testing Innovations in Sarasota, Florida.  My areas of interest are biomaterials and biomechanics.

             DR. YASZEMSKI:  Thank you very much.  I'd like to note for the record that the voting members here at the panel table constitute a quorum as required by 21 CFR Part 14.

             You'll notice on your schedule that there is an FDA update.  There is no update to present since the last meeting, and we're going to move right on now to the open public hearing.  We ask at this time that all persons addressing the panel speak clearly into the microphone as the transcriptionist is dependent upon this means of providing an accurate record of this meeting. 

             Before Ms. Scudiero reads her statement, I'm going to say it's important for everybody to state their name, their affiliation, and any interest they have in the product under consideration.  I'll ask your forbearance at this point if you forget to do that and I remind you throughout the meeting today.  Ms. Scudiero?

             MS. SCUDIERO:  This is the statement for the open public hearings.  Both the Food and Drug Administration (FDA) and the public believe in a transparent process for information-gathering and decision-making.  To ensure such transparency at open public hearing sessions of advisory committee meetings, FDA believes that it is important to understand the context of any individual's presentation.  For this reason, FDA encourages the open public hearing or industry 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, its direct competitors.  For example, this financial information may include the sponsor's payment for your travel, lodging, and 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 the issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.

             DR. YASZEMSKI:  Thanks Ms. Scudiero.  Prior to the meeting, we received three requests to speak in the open public hearing.  They'll speak in the morning open public hearing.  They are Mr. William Christianson, president, Orthopedic Surgical Manufacturers Association, Ms. Merrie Miller, and Ms. Allyson Washburn.  Will the first presenter, Mr. Christianson, come forward?  Mr. Christianson, you're scheduled for five minutes.  Good morning.

             MR. CHRISTIANSON:  Good morning, Dr. Yaszemski, and thank you.  My name is William Christianson.  I'm vice president of clinical and regulatory affairs with DePuy Spine who paid my expenses to come here today.  I do not have a financial interest in the product being discussed today.

             I speak here today representing the Orthopedic Surgical Manufacturers Association (OSMA).  And as Dr. Yaszemski said, I am president of that organization.  OSMA is a trade association with over 30 member companies.  And we welcome the opportunity to provide general comments at today's orthopedic advisory panel meeting.  OSMA's comments should not be taken as an endorsement of the products being discussed today.  We ask instead that our comments be considered during today's panel deliberations.  These comments represent the careful compilation of the member company's views. 

             OSMA was formed over 45 years ago, and has worked cooperatively with the FDA, the American Academy of Orthopedic Surgeons, and the American Society for Testing of Materials, and other professional medical and standards development bodies.  This collaboration has helped to ensure that orthopedic medical products are safe, of uniform high quality, and supplied in quantities sufficient to meet national needs.  Association membership currently includes over 30 companies who produce over 85 percent of all orthopedic implants intended for clinical use in the United States. 

             OSMA has a strong and vested interest in ensuring the ongoing availability of safe and effective medical devices.  The deliberations of the panel today, and the panel's recommendation to FDA, will have a direct bearing on the availability of new products.  We make these comments to remind the panel of the regulatory burden that must be met today.  We urge the panel to focus its deliberations on the product's safety and effectiveness based on the data provided. 

             The FDA is responsible for protecting the American public from drugs, devices, food, and cosmetics that are either adulterated, or unsafe, or ineffective.  However, FDA has another role, to foster innovation.  The role of this panel is also very important to the analysis of the data in the manufacturer's application, and to determine the availability of new and innovative products in the U.S. marketplace.  Those of you in the panel have been selected based on your expertise and training.  You also bring the view of practicing clinicians who treat patients with commercially available products. 

             OSMA is aware that you receive training from the FDA on the law and the regulation, and we do not intend to repeat that information today.  We do, however, want to emphasize two points that may have a bearing on today's deliberations.  One, a reasonable assurance of safety and effectiveness, and two, valid scientific evidence.  There's a reasonable assurance that a device is safe when it can be determined that the probable benefits outweigh the probable risks.  Some important caveats associated with this oversimplified statement include valid scientific evidence and proper labeling, and that the safety data may be generated in the laboratory, in animals, or in humans.  There's a reasonable assurance that a device is effective when it provides a clinically significant result.  Again, labeling and valid scientific evidence play an important role in this determination.  The regulation and the law clearly state that the standard to be met is a reasonable assurance of safety and effectiveness.  Reasonable is defined as moderate, fair, and inexpensive. 

             The regulation states that well-controlled investigations shall be the principal means to generate the data used in the effectiveness determination.  The following principles are cited in the regulation as being recognized by the scientific community as essentials in a well-controlled investigation: study protocol, methods of selecting subjects, method of observation and recording of results, and comparison of results with control.

             The panel has an important job today.  You must listen to the data presented by the sponsor, evaluate the FDA presentations, and make a recommendation about the approvability of the sponsor's application.  We speak for many applicants when we ask for your careful consideration.  Please keep in mind that the standard is a reasonable assurance, balancing the benefits and the risks.  The standard is not proof beyond the shadow of a doubt.

             When considering making recommendations for further studies, remember that FDA takes these recommendations seriously, often as a consensus of the panel as a whole.  And they may delay the introduction of a useful product or result in burdensome and expensive additional data collection.  Therefore, you play an important role in reducing the burden of bringing new products that you and your colleagues use in treating patients to the market. 

             OSMA thanks the FDA and the panel for this opportunity to speak today.  Our association trusts that its comments are taken in the spirit offered to help FDA decide whether to make a new product available for use in the U.S. marketplace.  OSMA members are present in the audience and are available to answer questions anytime during the deliberations today.

             DR. YASZEMSKI:  Thank you, Mr. Christianson.  Ms. Miller?

             MS. MILLER:  Good morning, ladies and gentlemen.  I am Merrie Francis Miller.  I live in Ellicott City, Maryland, and I am 73 years young.  I am here to give testimony for the X STOP device implant I received in March of 2001 for a study originating from the St. Francis Medical Technologies Incorporated of Alameda, California.  Other than transportation to this meeting, and one preliminary meeting of preparation held in Baltimore, I have not received any monetary assistance from St. Francis.

             Early in the fall of 2000, I began to experience pain from my lower back area and down my right leg.  I say pain, but it was excruciating pain as it developed.  For several years prior I had had periods of numbness in the two smallest toes of my right foot which my general practitioner doctor seemed to ignore.  I also had to curtail my 3-mile walks I took four times a week because of the pain.  Even Christmas shopping was shortened and almost cut out completely since I could no longer endure much walking to shop.  I jokingly requested a cane as a Christmas present since I was only comfortable when bent over like the old witch in the illustrated stories of Hansel and Gretel. 

             In January of 2001, I saw an ad on the back page of the Baltimore Sun paper, which had questions such as `Do you have pain in your lower back going down your leg?' `Are you relieved of this pain when sitting or lying down?' `Do you find yourself leaning on the cart when grocery shopping?  If you can answer yes to these questions, you may have spinal stenosis.'  I was able to answer yes to all, and to the last question, the shopping cart, I thought, ah, they've seen me. 

             By this time in January, I was really feeling old.  I had begun to frequently take Advil to relieve the pain.  My previous activities of tennis, 3-mile walks, long walks when touring new places, tending and taking care of three good size garden, taking care of a family of three in a 3-story house, grandmothering over a dozen grandchildren, and general daily normal active living, of all this I was severely limited. 

             I considered this ad divine providence.  So I called the phone number listed, and made a consultation appointment to see Dr. Charles Hartjen at the Greater Baltimore Medical Center.  I was examined, and diagnosed with spinal stenosis.  After a few weeks, I received word that I was accepted for the medical study of the X STOP implant. 

             Near the end of March 2001, Dr. Hartjen performed the implant surgery, which lasted only one hour.  It was minimally invasive.  I spent an uncomfortable night in the hospital, and after receiving some physical therapy lessons, I returned home.  Post-operatively, I remained on the second floor, being confined to bed when I needed it, for one week before going up and down stairs.  The pain medication I received I discontinued after the third day home.  I did not need it.  I had discomfort around the 3-inch incision, but that was all.  Six weeks later, I took a granddaughter for a 3-week tour of France. 

             To this day, over three years later, I am free of that pain, and I have full normal movement in any position needing a twist, a bend, or a turn of my back.  I can't praise enough the work of Dr. Hartjen, nor the creative doctor who came up with this X STOP, and his name, Dr. Zucherman.  I have been given not just a new life, but living proof that others with the debilitating condition of spinal stenosis might be helped with this device.

             Thank you so much for allowing me to speak before you this day.

             DR. YASZEMSKI:  Thank you, Ms. Miller.  Ms. Washburn?

             MS. WASHBURN:  Good morning.  My name is Allyson Washburn.  I am an experimental psychologist.  I teach research methods, statistics, and gerontology at the Saybrook Graduate School and Research Center in San Francisco.  I have no financial interest in St. Francis Medical Technologies.  I have received no financial compensation other than this trip to speak with all of you this morning.  And I am extremely pleased to have this opportunity to tell my story.  And it in so many ways parallels the previous speaker's story.  And I hope at the age of 73 I am as vital as she is. 

             My difficulties began when I was just 50 years old.  And my first symptoms were those of some weakness in my left leg.  It would collapse on me occasionally.  I was starting to think maybe that I had muscular sclerosis, or something like that, and didn't say anything to anybody about it.  I was too afraid. 

             The first real symptoms began in the summer of 2000, and began quite suddenly, the pain in the center of my hip, radiating down my left leg.  Very painful.  Upon walking, became increasingly painful with walking or standing.  I soon learned that the best thing for me to do would be to sit as much as possible.  Certainly, curled up was the best position of all. 

             I had an acute episode at that time that lasted about two months.  There was a lot of -- I had a lot of visits to Kaiser, a lot of diagnostic workup done.  It wasn't until I had an MRI that the diagnosis was made.  This took a couple of months.  And when I saw the diagnosis my heart sank, because I had seen that term "spinal stenosis" in charts of the nursing home residents where I was working at the time conducting research.  And I knew these patients could not be treated with regular analgesics or not even with opioids.  They were not eligible for some of the studies I was conducting with pain management in dementia patients.  So I was very dismayed.  But soon learned that what would help me were spinal injections.  And so I became someone who sought these very painful procedures because they helped somewhat.

             Although I had one particularly bad episode in the fall of 2000, where I spent the better part of two months curled up in a fetal position on my couch.  I became hooked on CNN at that point.  It was during the 2000 election.  And I think I reached a point many similar patients reach where you ask yourself is this something I can live with for the rest of my life?  And of course I decided I couldn't.  But I really didn't know what I was going to do.  But with this forced rest, I eventually got better.  The injections didn't really help me that time.  They don't work reliably.  There are a lot of side effects, I was aware of that. 

             So I was feeling pretty desperate when I happened to meet someone at a party.  We discussed similar symptoms.  It was just one of those happenstances.  She then saw an article about Dr. Zucherman's X STOP device in a newsletter.  She thought it might help me.  She hadn't gotten her diagnosis yet.  So I called Dr. Zucherman, became enrolled in the trial, but was randomized to the control group.  Dr. Zucherman, though, explained that we were towards the end of the trial, that perhaps I would be able to get the device at the end of the data collection for the experimental group. 

             But my friend in the meantime got her diagnosis.  She's 80 years old now.  And I saw her a week after the procedure.  She was randomized to the experimental group, and she was all dressed up and at a luncheon.  This was a week after the procedure.  Looked fine.  She has never had pain since then.  This was spring of 2001.  I later saw her coming home from the gym, met her in the supermarket.  I was still bent over the cart.  And she was looking quite fit. 

             So I decided, given her experience I decided to tough it out.  I would still have my injections.  I consumed a lot of NSAIDs.  They weren't all that effective. I think I was on Nortriptyline for awhile.  But found that the injections and just limiting my activity.  I walked very little in those days.  I would have friends drop me off and pick me up.  I used some of the wonderful web-based services that have since gone out of business with the dot.com bust.  Webvan was one of them.  So I just waited very patiently, hoping that I would be eligible for the X STOP at some point, seeing what it had done for my friend.

             And there were times, like I said, that the injections did not work.  I was fortunate in that I was able to work at home quite a bit, although ironically I had to find a replacement for me for data collection for this pain study, because I could not walk from one nursing unit to another.  I was involved in data analysis and doing some other research-related activities, but I couldn't help any further with that study. 

             So finally in summer of July of 2003 I got the call that I had been waiting for.  I was among those in the control group for whom the device was now being offered.  And it all happened very quickly.  I spent just a few hours at St. Mary's where Dr. Zucherman performed the procedure.  I walked out of the hospital.  I was shaky, but I was fine.  I spent a week at home recuperating.  I was told I wouldn't feel too great for a week, which I didn't, but it was mainly I was tired, the stress of undergoing the procedure. 

             The wound healed quickly without incident.  Within two weeks, I was able to entertain my sister and her family visiting from out of town.  We went to the new Asian art museum that I had not been able to visit because I wasn't going to museums in those days.  And we did a lot of walking in San Francisco.  It's a wonderful walking city, and walking has always been my exercise, walking and hiking.  And so it is, again.

             I also interestingly, another parallel with Merrie's story is I within two months was in Europe.  We flew to London.  We spent some time in the south of France, and some time in Paris.  So these were three wonderful weeks.  I was not restricted at all in my activity.  I didn't push it.  I wasn't doing any power-walking, as I called it in those days, early days of recovery, but I was walking normally.  I was going to all the museums.  I really had stopped thinking of myself as a pain patient, a back patient.  I had resisted that mightily all along, figuring it was a temporary thing and surely I would overcome it, although I was aware of the prognosis.  I saw it in the wheelchairs in the nursing home, and I knew that that could be me, and well before my eighties or nineties, as many of the residents are at the nursing home.

             So I would say that now, over one year later, I think of myself as being cured, although I do have occasional pain when I cannot lie comfortably on my right side.  That's somewhat painful.  That's just one of those things I'll live with.  It's not a big deal.  I have many other positions I can lie in comfortably.  So that's really the main thing.  And since pain memory is a very weird thing.  Friends will ask me, well, how is your back, they're always asking me that.  Less so now.  But I would have these memories of the pain in my hip, mostly, that unforgettable pain.  The memory is still there sometimes, I can feel it as if it's acutely bothering me.  It's a pain that I won't easily forget, and I hope not to experience for real other than in a few strong memories again.

             So I would say I have a normal life.  Again, mostly with some good back hygiene.  My son is a physical therapist, and watches me very carefully.  The X STOP devices, I actually have two of them, help my lower spine be more flexed.  I also help that out myself by consciously making some adjustments, particularly when I'm sitting.  And so I am back to my walks in San Francisco, and very grateful patient and recipient of this device.  And again, I appreciate the opportunity to speak with all of you this morning.  Thank you.

             DR. YASZEMSKI:  Thanks very much, Ms. Washburn.  Is there anyone else who would like to address the panel at this time?  Seeing none, we're going to move on to the sponsor presentation. St. Francis Medical Technologies will give their presentation on their intraspinous process distraction device.  We'll have the sponsor and the FDA presentations, and then begin the panel's deliberations before lunch.  After lunch, the panel will continue their deliberations on the approvability of this pre-market application.  Before the panel votes, there's going to be another open public hearing, and a time for FDA and sponsor summations.  I'd like to again remind public observers at this meeting that while the meeting is open for public observation, public attendees may not participate except at the specific request of the panel. 

             We'll begin now with the sponsor presentations.  The first St. Francis Medical Technologies presenter is Ms. Yvonne Lysakowski, vice president of regulatory and clinical affairs.  She will in turn introduce the other St. Francis Medical Technologies presenters.  Ms. Lysakowski?

             MS. LYSAKOWSKI:  Good morning, Mr. Chairman and members of the panel.  I am pleased to be here to discuss the PMA application for the X STOP device.  My name is Yvonne Lysakowski, and I am vice president of clinical and regulatory affairs at St. Francis.  I am a full-time employee of the sponsor.

             We are here today to present the results from a multi-center IDE clinical study of the X STOP intraspinous process implant.  I will begin the presentation with a brief review of our product development history from inception to the present day.

             Additional presenters are Dr. Augustus White from Harvard Medical School who will discuss the pathoanatomy and clinical presentation of lumbar spinal stenosis, along with current treatment options.  Dr. White is a professor of orthopedic surgery at Harvard Medical School, and orthopedic surgeon and chief emeritus at Beth Israel Deaconess Medical Center, and has treated spine pathologies for over 30 years.  Dr. White has authored over 300 abstracts, manuscripts, and books. 

             Dr. Scott Yerby from St. Francis Medical Technologies will discuss the design rationale for the X STOP device, and the results of our biomechanical testing. 

             Dr. Gunnar Andersson from Rush Medical University will discuss the rationale for our pivotal clinical study design.  Dr. Andersson is the senior vice president, medical affairs, and chairman of orthopedic surgery at Rush-Presbyterian-St. Luke's Medical Center.  He was president of the International Society for the Study of the Lumbar Spine from 1989 to 1990, president of the Orthopedic Research Society, and served for over four years on the NIAMS Advisory Council.  Dr. Andersson has authored over  400 publications. 

             Dr. Charles Hartjen from Greater Baltimore Medical Center will present the results of our pivotal clinical study.  Dr. Hartjen is a board-certified orthopedic surgeon and spine specialist at Greater Baltimore Medical Center.  Dr. Hartjen has been an instructor in techniques in minimally invasive spine surgery for the North American Spine Society.  Dr. Andersson will then discuss the study outcomes.  In addition, we have a number of other sponsor representatives in attendance. 

             The X STOP device has been under development since 1995.  Early on, extensive preclinical testing was conducted to establish the validity of the intraspinous implant design concept.  A 10-patient pilot study with 1-year follow-up was initiated with the first generation device design.  And based on the results from biomechanical testing in the pilot study, a randomized controlled multi-center clinical trial was initiated under an approved investigational device exemption application with the second generation version of the device.  This study is referred to as the Phase I RCT as in the slide shown here.  After a number of patients were enrolled, it became evident that a change to the device design was necessary, and enrollment of the study was halted.

             Our pivotal clinical trial with the final device design used on all X STOP patients was initiated in June 2000.  One hundred and ninety-one patients received treatment in this multi-center study, and were followed up through 24 months post-operatively.  The results of our pivotal trial will be presented later in detail by Dr. Hartjen.  St. Francis filed a PMA application with the clinical results from this study on January 6, 2004, and was granted expedited review status.

             As stated earlier, the proposed indications for use of the X STOP device are as follows.  The X STOP is indicated for patients aged 50 or older suffering from mild to moderate neurogenic intermittent claudication secondary to lumbar spinal stenosis who have undergone a regimen of non-operative treatment.  The X STOP is indicated for patients who experience relief in flexion from their symptoms of leg, buttock, or groin pain, with and without back pain.

             I am certain that after you have reviewed our data, you will agree with us that the X STOP is safe and effective for its proposed intended use.  And we hope that you will recommend approval for this device at the end of panel deliberations.  Now I would like to introduce Dr. Augustus White.

             DR. WHITE:  Good morning, Chairman Yaszemski and distinguished panel members.  My name is Augustus White, and it's my privilege to be able to describe the pathoanatomy of lumbar spinal stenosis.  I have been providing consulting service to St. Francis Medical Technologies, and I do have a financial interest in the sponsor.  It is a pleasure for me to be here this morning to present the clinical picture of lumbar spinal stenosis.  I would add that I do this with considerable humility after having heard from two courageous patients.

             I will review the pathoanatomy of lumbar spinal stenosis and its clinical presentation.  As we know, lumbar spinal stenosis often presents clinically as neurogenic intermittent claudication.  This is the salient symptom of this problem.  Neurogenic intermittent claudication is characterized by pain, tingling, numbness, and decreased strength in the legs which is attributed to narrowing of the lumbar spinal canal.  I will also describe the natural history of stenosis, and the current treatment.

             This is perhaps the most important visual presentation for orientation and understanding of this particular disease.  If we look at this schematic, first looking to your left, you see a section of the lumbar spine viewed from behind.  By rotating this image, we get an axial or cross-section view.  Here we can see the space available in the central canal, which is a key element of the pathology of this disease.  As we look at this image, we see that there is a certain amount of space that contains the dura spinal fluid and nerve rootlets.  As long as there's enough space in this particular canal, there's no compression on the nerves.  But as we look at this diagram though, on the far right we see several changes to the normal anatomy that results from the process of aging, which can contribute to the loss of that space.  A protruding disc can come in from the front to press on the dura, and can compress the dura from that particular side.  On each side, degenerative changes to the facet joint can reduce the space available posteriolaterally.  Posteriorly, the yellow ligament can compress the dura, so that all of these things contribute in varying degrees progressively to the point that enough space is lost and patients experience back and leg pain due in part also to changes in axoplasmic fluid flow, as well as venous congestion resulting in inflammation and pain.

             Here we see on an MRI image the difference between a pathologic canal with lumbar spinal stenosis and a spacious normal canal.  And as we've described on this schematic, we see anteriorly here coming from the front pressing on the spinal canal the nerve rootlets at this position.  Here we see the facet joints which are deformed and enlarged on each side contributing to the changes, and a trefoil type configuration which is part of the stenotic condition.  And then posteriorly, the major player, the major component of the stenosis oftentimes is a yellow ligament, which is thickened and which is also folding in, folds into the canal because it loses its elasticity.

             When patients walk, they extend their spines with the result being that they get their stenosis symptoms.  The best description that I've heard of these, up until today perhaps, is the patient who described to me once, "Doctor, as I walk, I feel something like an electric storm going down my leg."  This is a kind of poetic description, but it is a spontaneous response and description on the part of the patient.  This pain obviously can be excruciating, and is characteristically associated with ambulation.  Patients on their own will develop ways of ameliorating their symptoms, and quite frequently they will discover that using a cart when they are shopping allows them to flex in the lumbar spine area, as shown in this picture, when the patient sits.  And it also alleviates some of the pain from walking.

             Here's another way to depict this, with demonstration of an excellent illustration from Dr. Frank Netter, showing the lumbar spine motion segment.  And here is one of the exiting nerve roots which is compressed in extension.  In flexion of the spine, you can see that the neural canal, the foraminal canal opens up, giving more space available for the nerve root.  Here we can see radiographic correlation of this. 

             This is a colored, if you will, schematic of a myelogram, which shows a distinct block here in the case of lumbar spinal stenosis with extension from a lateral view.  Fluid is blocked.  And here we see on the AP the same blocking of the fluid.  With the flexion position, however, this is ameliorated, and the space is available for the free flow of the lumbar spinal fluid.  So the principle here is that with flexion there is more space available, less congestion of venous structures, and less pain.

             The anatomic changes that cause lumbar stenosis occur gradually as a natural progression of aging.  The majority of patients who develop symptoms are usually stable, and symptoms will usually remain unchanged, or perhaps even slightly improved in some cases.  Some patients, however, will get worse.  This observation is confirmed by studies done by Johnsson and others.  The natural course of lumbar spinal stenosis can be relatively benign, and the diagnosis of stenosis does not necessarily result in symptoms that are severe enough to require surgery.  A large percentage of patients require only medical treatment.

             This observation is confirmed by the prevalence of stenosis, which is reported in the United States to be approximately 700,000 cases per year.  The number of decompression surgeries performed in the U.S. is about one-tenth of that number, as you can see.  There are about 60,000 per year. 

             I would like to describe the current treatment alternatives that are available to stenosis patients.  First of all, non-operative care is prescribed.  The rationale for conservative treatment is to decrease pain and increase function.  Various types of analgesic and anti-inflammatory medications are prescribed for pain.  The exercise and physical therapy can help to improve function.  Conservative therapy is a continuous process, and treatment does not constitute one single application of these modalities.  Epidural steroid injections may help reduce inflammation.  Inflamed nerve roots may be swollen and worsen the effect of a narrow canal and foramen.  These non-operative approaches are considered the standard of care for these stenosis patients with mild and moderate symptoms. 

             For patients with more severe symptoms, surgical intervention becomes an option.  Surgery is characteristically some form of surgical decompression.  That is, removing of some of the elements that are causing the narrowing of the canal.  Surgery is characteristically some form of surgical decompression, often combined with a spinal fusion.  But patients typically wait for some time before considering surgery.  Mean symptom duration of patients' electing surgery was 4.3 years in Turner's meta-analysis.

             Against the clinical and epidemiological background, a different mechanism to treat patients with stenosis was conceived.  A device placed between the spinous processes to limit extension, that is the X STOP, was developed and tested by the sponsor.  We know that stenosis patients have more pain with standing or extension, and we know that with flexion the space available in the canal is increased.  The X STOP keeps the functional spinal unit out of full extension, and therefore limits impingement on the neural elements and the symptoms that it causes.  The X STOP seems to be a straightforward mechanical solution to a well understood, straightforward biomechanical problem.  The X STOP prevents the pathoanatomic positioning of the functional spinal unit which irritates the spinal nerves, and it also preserves the function of the spinal anatomy. 

             I would like to turn the podium over to Dr. Scott Yerby who will discuss the design rationale of the X STOP, as well as describe some of the biomechanical studies that were performed.

             DR. YASZEMSKI:  Thank you, Dr. White.  Dr. Yerby?

             DR. YERBY:  Thank you Dr. White.  Good morning Mr. Chairman and members of the panel.  My name is Scott Yerby.  I'm a full-time employee of the sponsor as the Director of Research and Development.  I'd first like to describe the design feature of the X STOP, and then I will present the results of some of the biomechanical tests we performed to characterize the function of the X STOP and its effect on the lumbar motion segment.

             The X STOP, shown on the right, is a titanium alloy implant that is placed in the intraspinous space and limits extension of the implanted level.  The blood tissue expander allows the implant to be inserted laterally without modifying the spinous processes.  This allows the superspinous ligament to be retained.  The tissue expander also has a slot to accept an adjustable wing.  In addition, the X STOP has an oval spacer that is designed for optimal contact between the bone and the implant.  The fixed and adjustable wings prevent lateral and anterior migration of the implant.

             These figures show the X STOP in the intraspinous space from a lateral, axial, and posterior view.  The lateral and axial views demonstrate that the lamina is left intact, and therefore shields the implant from the neural structures.  The risk of neural injury, either during or after placement, is therefore very low.  Finally, the implant is not fixed to any bony structures.  Should the implant ever have to be removed, revision surgery is straightforward.

             We performed a series of biomechanical tests during the development of the X STOP.  Today I'm going to discuss two of these tests: the change in the dimensions of the spinal canal and neural foramen, and the change in the intervertebral kinematics following X STOP placement. 

             The methodology used to measure the dimension of the spinal canal and neural foramina involved eight L2 to L5 lumbar motion segments that were placed in a custom acrylic positioning frame capable of placing the specimen at 15 degrees of flexion, 15 degrees of extension, and in the neutral position.  Each specimen was placed in a 1.5 Tesla MRI Scanner in one of these three positions, with or without the X STOP placed at the L3-4 level.  Axial and para-sagittal images were used to measure a number of parameters at the implanted and adjacent levels.  In extension, the canal area increased by 18 percent, the canal diameter increased by 9 percent, and the subarticular diameter, which represents the lateral recess, increased by 50 percent. 

             We used the same method to analyze para-sagittal images to measure changes in the foraminal area.  The foraminal increased by 25 percent, the foraminal width increased by 41 percent, and again, these results show that the critical dimensions are significantly increased.  There were no significant differences between the mean dimensions of the intact and X STOP implanted specimens at the adjacent L2-3 and the adjacent L4-5 levels. 

             To measure the spinokinematics, we measured the invertebral rotations of seven L2-L5 motion segments, loaded to 7.5 Newton-meters of flexion-extension, axial rotation, and lateral bending, with a superimposed 700 Newton axial load.  The kinematic study demonstrated that flexion-extension range of motion decreased from 7.6 degrees to 3.1 degrees.  This is demonstrated in the lower right.  The axial rotation range of motion, shown at the top, and the lateral bending range of motion, shown at the left, however did not change significantly.  At the adjacent L2-3 and L4-5 levels, there were no significant changes in the bending angles in any motion. 

             In conclusion, the X STOP is inserted between the spinous processes with only minimal tissue disruption.  It is stable without being permanently attached to the bone, and remains shielded from sensitive neural structures.  The X STOP significantly increases the dimensions of the spinal canal and neural foramen, and significantly decreases the range of motion during flexion-extension, while not affecting the range of motion during axial rotation or lateral bending.  The X STOP does not significantly the adjacent levels.  Clinically, the X STOP is designed to prevent the symptomatic extended position, and by doing so increase the dimensions of the structures that cause neural compression. 

             Thank you.  I'd now like to introduce Dr. Gunnar Andersson, who will discuss the rationale of the X STOP pivotal trial.

             DR. YASZEMSKI:  Thank you, Dr. Yerby.  Dr. Andersson?

             DR. ANDERSSON:  Thank you and good morning, Mr. Chairman and panel members.  My name is Gunnar Andersson.  I'm the professor and chairman of Orthopedic Surgery at Rush University Medical Center.

             I was not an investigator in the pivotal trial, but for five years I have been a member of a panel advising St. Francis Medical Technologies on medical matters.  In that capacity I provided guidance regarding the design of the clinical trial.  I do have a financial interest in the sponsor.

             Today I will present some background information and discuss the design rationale of the pivotal trial.  First I would like to present some data on the outcomes and risks associated with current treatment alternatives for lumbar stenosis.  Dr. White listed those for us earlier.  A discussion of the risks and benefit of non-operative care, as well as the risks and benefit of decompressive surgery will help us set the stage for a discussion of the X STOP study design.  Patients undergoing non-operative therapy who experience at least some improvement in their symptoms are typically considered as having a successful outcome.  Usually this criteria on the success of non-operative therapy ranges from approximately 28 to 33 percent, as reported in the literature by Johnsson, Amundsen, and Atlas.  These three studies are of particular interest because they report results of patients with a range of symptoms from mild to severe.  They also include outcomes of surgical treatment in addition to non-operative therapy, and these outcomes form the basis for our analysis of laminectomy surgery.

             While relatively infrequent, there are some risks associated with non-operative therapy.  Non-steroidal anti-inflammatory medication can cause well-known secondary effects such as GI bleeding, allergies, and organ toxicity.  There are a variety of procedure related problems that have been reported as a result of epidural injections.  These include dural tears, epidural hematomas, infections, and neurologic damage.  But generally speaking, non-operative therapy entails very few risks.  So as we assess the risks versus the benefit of non-operative therapy, it is fair to say that it offers a measurable benefit to a patient suffering from mild to moderate stenosis at low risk.

             Looking again at the studies of Johnsson, Amundsen, and Atlas for results of patients undergoing decompressive surgery, we see that between 57 and 69 percent of patients experience clinical improvement in their symptoms.  The most severe complications from laminectomy are listed on your left.  Deyo and collaborators analyzed a large database of patient discharge information to compile the incidence of these complications.  They found that 14 percent of patients experienced complications after laminectomy, and 20 percent of patients when laminectomy was combined with a fusion.  So if we assess the risk compared to the benefit of laminectomy surgery, I believe it is fair to say that the outcomes of surgery are good.  The risks are not insignificant, however, and are much greater than conservative therapy.  Certainly, some of the complications may have long-term sequellae, and the incident of death was reported by Deyo to be 6 in 1,000 cases.  Given the generally advanced age of this patient population, usually suffering from numerous comorbid conditions, these complications are not unexpected.

             Assessment of the current treatment options can be summarized in the following treatment algorithms.  For patients with mild to moderate symptoms of stenosis, non-operative therapy is the standard of care.  Decompressive laminectomy is generally indicated for patients with severe lumbar stenosis symptoms.  What is missing in this algorithm is a treatment alternative for patients who do not achieve satisfactory relief of symptoms from non-operative therapy, but are unwilling to consider a more invasive procedure.  There are many patients who are medically unfit to undergo general anesthesia, and have no alternative to non-operative care. 

             The population of patients with mild to moderate symptoms is the one we identified as the most appropriate for the X STOP, especially when we assess the risks of the surgical procedure to implant it.  Implantation involves minimal tissue removal, and the spinal canal is not entered so the risk of neural injury is very low.  The procedure itself can be performed under local anesthesia, typically in conjunction with conscious IV sedation, and it takes less than one hour.  Therefore, we anticipated before the study started that the X STOP would entail a low level of risk, and the potential risks were much more comparable to a non-operative therapy than the risks associated with laminectomy.  Based on this assessment, non-operative therapy was clearly the most appropriate treatment for the control group in our randomized trial.

             I will now discuss the study design, primary outcome measure, and the success criteria used in the study.  The pivotal trial was a prospective randomized multi-center controlled clinical trial comparing the X STOP to non-operative therapy.  The primary outcomes measure was the Zurich Claudication Questionnaire.  The SF-36 was also used to assess health outcomes as a secondary measurement tool.  Radiographs taken during the course of the study were sent to an independent radiologist, who made the radiographic measurements required by the study protocol. 

             The Zurich Claudication Questionnaire was designed and validated for neurogenic claudication.  So it is very specific for those symptoms.  It is divided into three distinct domains: symptom severity, physical function, and patient satisfaction.  It has been shown to be reproducible, internally consistent, and very responsive.  The questions are similar to what you see in the Oswestry, but they are more specific to the problem of lumbar spinal stenosis.

             Here are some questions from the symptom severity domain.  The questions in this section asked patients to grade the frequency and severity of their pain or discomfort experienced on a typical day within the last month.  Questions relating to symptoms are specific to neurogenic intermittent claudication, and include pain and tingling in the feet and legs, and balance disturbances. 

             Here are the questions from the physical function domain.  The first question on this slide asks patients to grade how far they are able to walk.  And this question served as a basis for the study inclusion/exclusion criteria to identify patients with severe symptoms.  The remaining questions in this domain gauge how comfortably patients are able to perform some activities of daily living, such as moving around the house or doing grocery shopping.

             Here we see the six questions that constitute the patient satisfaction domain.  Three questions address specifically patient satisfaction with their muscle strength, balance, and ability to walk.  Three questions relate to the overall satisfaction with treatment, and the amount of pain relief.

             Clinically significant improvement was defined by Stucki, et al, as a function of patient satisfaction.  They found that patients who met a threshold level of improvement of approximately 0.5 were satisfied.  And this turned out to be true independently for both the physical function domain and the symptom severity domain.  So a change of 0.5 or greater for each domain was adopted in the pivotal study as clinically significant.  In the Zurich, the lower the score the better.

             To be considered a success in the pivotal study, all patients had to achieve clinically significant improvement in the physical function domain and the symptom severity domain, and to be very satisfied or somewhat satisfied with their treatment.  Patients could not have additional surgery for stenosis symptoms.  For X STOP patients only, distraction had to be maintained, and there could be no device-related complications or dislodgement of the implant.  Individual X STOP patients were required to meet seven separate criteria at 24-month follow-up to be considered a success in this study. 

             Last I will describe the key inclusion/exclusion criteria.  Patients have to have their symptoms relieved by sitting or flexion.  Patients also had to have completed at least six months of some medical treatment.  This did not mean, however, the patients had failed treatment entirely.  As Dr. White mentioned, non-operative therapy is a continuous process of treatment that a patient will typically undergo for many years.  Patients were excluded if they could not walk at least 50 feet or were unable to sit for at least 50 minutes.

             I would like to summarize the key study design elements.  First, non-operative therapy was the appropriate control for the X STOP.  While I was not an investigator for the pivotal trial, I am an investigator in an ongoing NIH-funded study in which laminectomy treatment for lumbar spinal stenosis is being compared to non-operative therapy.  Second, the Zurich is an excellent tool to measure results of lumbar spinal stenosis treatment because of its emphasis on functional outcomes in three domains.  The greater the limitation in walking, the more severe the symptoms from neurogenic claudication.  Third, the criteria for determining success in an individual in this trial was much more rigorous compared to the criteria used in the non-operative research literature.

             I would now like to turn the podium over to Dr. Hartjen who will present the study results.

             DR. YASZEMSKI:  Thank you very much, Dr. Andersson.  Dr. Hartjen?

             DR. HARTJEN:  Good morning Mr. Chairman and panel members.  My name is Charles Hartjen.  I will be presenting the study results this morning.  I do not have any financial interest in St. Francis Medical Technologies to disclose.  I trust my expenses to drive here today from Baltimore will be reimbursed by the company.  I'm an investigator for the X STOP pivotal study, and my center enrolled the highest number of patients in the trial. 

             Investigational sites and principal investigators for each site are shown here.  Nine centers participated in the pivotal study, most of which were community hospitals.  Of the nine principal investigators, seven are orthopedic surgeons and two are neurosurgeons. 

             Patients were randomized into the study using block randomization within each center.  Because we expected a relatively small number of patients to be enrolled in each center, a block size of two was selected to help ensure equal balance of treatment and control group patients.  I would like to emphasize that the block size was not revealed to me or to any other investigator or study coordinators, and randomized assignments were centrally administered by the sponsor.  There was a necessary delay between randomization and treatment for both groups. 

             There were 114 X STOP patients and 115 control patients randomized to each group.  Fourteen X STOP patients and 24 control patients were randomized, but not treated.  Of these, eight X STOP patients and 19 control patients voluntarily withdrew.  The remainder failed to meet study entry criteria, or withdrew for health related reasons.  One hundred X STOP patients and 91 control patients were enrolled and treated in the study.  Four patients died in each cohort during the course of the study.  In the X STOP group, two patients died from cancer, one from pneumonia, one from CHF complications following implant surgery.  In the control group, causes of death were cancer, pulmonary embolism following foot surgery, Parkinson's disease, and myocardial infarction.  Six X STOP patients and 24 control patients underwent a laminectomy for stenosis during the study and were considered treatment failures.  One X STOP patient fell, causing the implant to dislodge.  The implant was removed, and the patient was a failure.  No patients were lost to follow-up.  One X STOP patient and five control patients voluntarily withdrew from the study.

             Patients were placed on their right side with their legs curled up.  This flexes the spine, placing the patient in the position in which they get relief of symptoms.  After an incision is made, the interspinous ligament is dilated.  The superspinous ligament is left intact.  The X STOP is inserted from below, and the adjustable wing is attached.  A key feature of the procedure is that there is minimal removal of tissue.  The spinal canal is not entered, and no bone is removed from the spinous processes.  The procedure is well tolerated using local anesthesia and light IV sedation. 

             Patients in the control group received at least one epidural injection upon entry into the study.  Additional epidural injections were administered at the discretion of the investigator consistent with current treatment guidelines and following standard medical practices.  Control patients also received non-steroidal anti-inflammatory medications, analgesics, and physical therapy as needed.  Patients filled out the Zurich Questionnaire and SF-36 at enrollment and at each follow-up visit, and the investigators took standing plain film x-rays, and administered a physical examination.  Patients were monitored at six weeks, six months, 12 months, 24 months, following the initial treatment. 

             Looking at the baseline data, the demographics of the two groups are quite comparable.  The mean age for the patients was about 70 years old in both groups at enrollment.  Approximately 60 percent of the patients in both groups experienced symptoms for more than two years.  The two groups were extremely well matched at the study entry.  There were no significant differences between the two groups in any baseline variable except one.  More patients in the X STOP group received epidural injections prior to study entry compared to the control group.

             As expected with this elderly patient population, there were many patients with comorbid conditions.  About 45 percent of the patients in each group had a history of cardiovascular disease.  After cardiovascular disease, musculoskeletal disorders were the most frequent reported comorbidities.  The incidence of musculoskeletal problems was more pronounced in the X STOP group at baseline. 

             The baseline Zurich scores are shown here.  And as we see, the two groups were quite comparable.  On the left are the mean baseline scores for the symptom severity domain, which were 3.14 in the X STOP group and 3.10 in the control group.  Patients in the study were in the middle of the range, indicating they had moderate symptoms as a group.  Mean baseline scores for physical function domain were on the right, and were 2.48 for both groups.  Again, these scores are in the middle of the range.  Here are the SF-36 scores at baseline.  Again, the two groups were quite comparable, and no significant differences in any of the SF-36 domains.  Higher scores on the SF-36 are indicative of better function.

             The X STOP operative variables are shown here.  The operative time averaged just under an hour, and average blood loss was negligible at 50 cc's.  Three patients had general anesthesia, 97 had local anesthesia, usually with light IV sedation.  Hospital stays were less than 24 hours in 96 of 100 patients.  Typically, physical therapy was initiated early in the morning after surgery, and the patient was discharged in the early afternoon.  One patient, a 76-year-old female who had an ischemic coronary episode during the procedure was kept in for observation and thallium stress test.  She was discharged three days later.  About one-third of the X STOP patients had two-level procedures.  The operative level was usually 4-5, with L3-4 being the second most common level. 

             Ninety-one control patients received a total of 216 epidural injections during the course of the study.  All control patients received an epidural injection upon entry into the study.  Twenty-two patients received two injections, 21 patients received three injections, and several patients received four or more injections.  Although not shown here, I would like to note that eight X STOP patients received epidural injections or nerve root blocks during the study, and six of these were treatment failures.

             Adverse events relating specifically to the X STOP group only are listed here.  There are four procedure-related adverse events.  These were limited to incisional complications which resolved with treatment.  There were no reports of any nerve injuries or neurologic deterioration as a result of X STOP implantation.  There are three device-related adverse events.  One patient fell in the early post-operative period, causing the implant to be dislodged, and it was removed.  One implant was malpositioned at the time of surgery, and was later detected on x-ray examination.  There's one spinous process fracture which occurred sometime between six and 12 months, in between those two follow-ups.  The patient experienced on symptoms from the fracture, and had healed without sequellae.

             Here we see adverse events that were determined by investigators to be related to epidural injection or the X STOP procedure.  Stenosis related pain was reported as an adverse event in six X STOP patients and 26 control patients.  In these cases, the pain was significant enough to trigger an unscheduled follow-up visit or require follow-up medical treatment.  All six of the X STOP patients, and 24 of the 26 control patients eventually underwent a laminectomy for unresolved stenosis pain during the study period.  There were no reports of complications or difficulties associated with removing the X STOP, which is what was anticipated since the implant is not adjacent to nerves or major vessels, and is not fixed to bone.

             There were five reports of adverse events in the control group as a result of the epidural injections.  These included two cases of increased pain that were severe enough to require hospitalization, and two complaints of paresthesias during or immediately following injection.  All of the events resolved without sequellae.

             Adverse events determined by the study investigators to be unrelated to treatment are shown here.  There was no statistically significant differences in the incidence of these adverse events with the exception of musculoskeletal adverse events.  Forty-three X STOP patients experienced these events, compared to 16 control patients.

             Shown here are the results of the analysis of adverse events that we performed at the FDA's request.  We examined the case histories of those events that were potentially of greatest concern, including upper and low back, lower extremity, or neurologic system.  There were 47 of these adverse events in 32 X STOP patients.  The majority of these events, 63 percent, were attributed to comorbid conditions.  Eight percent were for excess activities, 19 percent for stenosis symptoms representing nine patients who were treatment failures.  Ten patients were classified as Miscellaneous, and included peripheral neuropathy, stroke, and ataxia.  Adverse events involving the upper extremity and hip were not included in this analysis, and are shown here.  In each event, the investigators determined the events were unrelated to treatment. 

             In summary, the musculoskeletal events we observed in the X STOP group would be expected in the elderly patient population.  The patients in the X STOP group also had a higher incidence of comorbidities at baseline.  What is surprising is that the incidence was relatively low in the control group.  One reason may be that 26 percent of the control patients were terminated from the study after they had laminectomy.  We could attribute a number of events in the X STOP patients to an increased level of activity.  This unmasking effect surfaced after patients' stenosis symptoms resolved. 

             I now present the effectiveness results.  I will present the primary outcomes for the evaluable patient population for each domain under Zurich.  I will then present the results of the study, using the overall success criteria described in the protocol.  Finally, I will present the outcomes measured by the SF-36, as well as improvement in frequency and severity of back and leg pain. 

             The population of patients who experienced clinically significant improvement in symptoms' severity at each follow-up interval is shown here.  At 24-month follow-up, 58 percent of the X STOP group had significant improvement in this domain compared to 17 percent of the control group.  The difference between the two groups was statistically significant at each follow-up visit.  In the physical domain, the differences between the two groups was statistically significant at the follow-up visits.  At 24-month follow-up, 55 percent of the X STOP patients were significantly improved versus 14 percent of the control patients.  In the patient satisfaction domain, again, there was a statistical significant difference between the two groups at follow-up.  At 24-month follow-up, 71 percent of the X STOP patients were satisfied, compared to 32 percent of control patients.  Combining all three Zurich domains at 24-month follow-up, 47 percent of the X STOP patients met all three criteria for success, compared to five percent of the control patients.

             Radiographic measurements taken at the 24-month follow-up were compared to measurements taken at the 6-week follow-up.  A number of measurements were made to monitor general changes that might have occurred to the spine as a result of implanting the X STOP.  There were no significant differences at either 12 or 24 months between the X STOP group and the control group in any of these measurements.  These included anterior and posterior disc height, curvature of the spine, angulation of the spine, and degree of spondylolisthesis.  Distraction was maintained in 96 percent of the X STOP levels.  When we combine all seven criteria for determining success in the individual patient as they apply to the X STOP patient, we can calculate the primary study endpoint.  Counting patients with missing data at the 24-month follow-up as failures, 44.8 percent of the X STOP patients met all success criteria compared to 4.6 percent of the control patients. 

             As you heard from Dr. Andersson, in the Zurich Questionnaire, a 0.5 improvement in either symptom severity or physical function equates to a satisfied patient, and is defined as clinically significant.  But the X STOP patients on average improved much more than that threshold level.  X STOP patients improved 0.99, which equates to a change of 24.8 points.  At 24 months, their symptoms as a group improved from moderate to mild.  X STOP patients improved 46 percent from the baseline scores.  Control patients improved eight percent. 

            Here is the physical function score.  The X STOP patients improved 0.76 on the Zurich scale, which equates to a change of 25.4 points.  The control group improved 2.6 points.  X STOP patients improved 52 percent over baseline.

             We performed a number of subgroup analyses on success rates, three of which I will briefly describe.  The patient population in the analysis includes all evaluable patients, and it excludes only those patients who died during the study.  First we look at the success rate of the subgroup of patients that had one-level or two-level implantation.  As you see, there is no difference in overall success rates between the two groups.  There was, however, a statistically significant difference in physical function domain of the Zurich, which patients with two-level implants had a higher success rate. 

             We also looked at two subgroups of X STOP patients based on symptom duration prior to study entry.  We compared a subgroup of patients who had symptoms for two years or less to a subgroup of patients who had symptoms for longer than two years.  There were no differences in overall success rate or in any domain of the Zurich when these two groups were compared.  When we compared subgroups of clinical patients based on symptom duration, there was also no difference in the individual domain scores or overall success rates.  The results of these subgroup analyses suggests that duration of symptoms does not impact outcome.

             We also looked at success rates in each center.  Most importantly, you will note that the X STOP success rate was consistently higher than the control group success rate at every center, even with the diversity of centers, and in both small and large centers.  St. Mary's, Dr. Zucherman's site, has the highest success rate in the X STOP, and the second highest success rate in the control group.  However, even if St. Mary's is removed from the analysis, the difference between the X STOP and control groups remains highly statistically significant.

             I enrolled the highest number of patients at GBMC, and you will note that the success rate at my center was 28 percent in the X STOP group.  I am pleased with my result.  The majority of my patients had significant improvement in symptoms and were satisfied, but did not improve enough to be a success in physical function for reasons that were unrelated to the stenosis or X STOP. 

             To better understand the success rates at each center, we looked at the predictors of success in the X STOP group.  Patients with worse baselines for SF-36 scores correlate with a positive outcome, as well as patients who have fewer comorbidities, thus were healthier.  Patients who were younger did better.  Patients with lower blood loss during surgery did better.  These findings are not surprising.  We looked at these predictors at St. Mary's compared to other centers and found that the patients at St. Mary's tended to be younger, had significantly fewer comorbidities, and were employed compared to the other centers.  Investigators at St. Mary's conducted the original pilot study, and participated in the unwelded implant study.  So their experience in screening patients may have contributed to their relatively higher success rates for both control and X STOP patients.  Interestingly, the center with the lowest success rate had older patients, patients who had a high incidence of comorbidities, but were less symptomatic at baseline.

             Turning our attention now to outcomes measured by SF-36.  First, here are the mean baseline scores for the X STOP group which I showed you earlier.  For the follow-up visits, mean scores were calculated using all available data.  Here are mean scores for the 6-week, 6-month, 12-month, and 24-month visits.  The SF-36 scores at 24 months was statistically significantly improved compared to the baseline in every domain except general health, mental health, and mental component summary.  As the graph illustrates, the benefit of treatment was evident at the earliest follow-up visit, and it was maintained over the course of two years. 

             Here are the baseline scores for the control group, which you saw earlier.  And here are the scores first for the 6 weeks, 6 months, 12 months, and 24-month visits.  There are sustained improvement in both the role of physical and bodily pain domains.  However, this improvement was not statistically significant. 

             When we looked at the patients who experienced any improvement in leg pain over the baseline pain, we find a few patients in either group experienced improvement in leg pain while sitting, but 80 percent or more of X STOP patients had some improvement in leg pain while standing and walking in both frequency and severity.  In the control group, the greatest improvement was seen in leg pain while walking, where 37 percent of the patients showed some improvement in frequency of leg pain, and 43 percent experienced some improvement in severity of leg pain.  Outcomes for back pain mirrored results for leg pain.  Significantly more X STOP patients experienced improvement in back pain while they were standing and walking, both in frequency and severity compared to the control groups. 

             I would like to recap the results of our safety and effectiveness analysis.  The X STOP procedure can usually be performed as a same-day procedure under local anesthesia with minimal blood loss.  Patients recover rapidly.  There is a minimal risk of systemic or local complications, and there is little risk of neurologic injury.  Musculoskeletal adverse events were largely attributable to preexisting comorbid conditions, the prevalence of which is expected in this patient population.  Revision surgery, if necessary, is straightforward.  Future treatment options are not compromised.  Finally, the procedure is especially suitable for patients who cannot tolerate general anesthesia. 

             The effectiveness of the X STOP treatment was immediate, and the superiority over control group was sustained over the follow-up period.  The relative benefit of X STOP was demonstrated at all participating study centers, where X STOP success rates were consistently greater compared to the control at every center.  The magnitude of the improvement seen in the X STOP patients exceeded the threshold level defined as clinically significant.  Patients improved almost double the amount defined as clinically significant.  Back and leg pain symptoms improved significantly in the X STOP patients when compared to their baseline symptoms.  In summary, the X STOP represents a significant breakthrough in the treatment of patients with mild to moderate symptoms of lumbar spinal stenosis.  And the key findings from the pivotal trial demonstrate the device is safe and effective for use in this patient population.

             I would like to turn the podium back over to Dr. Andersson for final remarks.

             DR. YASZEMSKI:  Thanks very much, Dr. Hartjen.  Dr. Andersson?

             DR. ANDERSSON:  Thank you.  Good morning again, Mr. Chairman and panel members.  I would like to address the topic of interpreting the outcomes of this study. 

             To place the study results in a frame of reference, we reviewed the published literatures and outcomes of both non-operative therapy and decompressive surgery.  There is a subset of this literature reporting outcomes for patients with mild to moderate symptoms which is particularly relevant to the pivotal trial.  In addition, there are studies reporting outcomes in a broader lumbar spinal stenosis population using the Zurich as well as the SF-36.  Finally, we have outcomes from study patients who underwent laminectomy where we can apply the same success criteria in matched patient populations. 

             The observation has been made that success rates in the pivotal trial were lower than anticipated when the study was designed, and appeared to be low in comparison to results reported in the literature.  It seems appropriate to first acknowledge that those criteria used in the literature to measure outcomes are different from the method used in the pivotal trial.  To make a true comparison, we should apply similar standards to both.  This can be done by applying the same success criteria in the pivotal trial to the clinic literature which uses the Zurich to measure outcomes.  We can also analyze the results using the criteria that are commonly applied in literature reporting results of patients with mild to moderate symptoms. 

             Any improvement in symptoms is typically considered a success in non-operative literature.  We analyzed the pivotal trial results using the single criterion and found that 32 percent of controlled patients had some improvement in symptoms at 24 months.  Thirty-two percent is comparable to outcomes reported for conservative care patients in the studies I discussed previously.  This confirms that patients enrolled in the pivotal trial did not fail conservative care just because they completed six months of medical treatment.  As Dr. White mentioned, stenosis patients typically experienced many years of symptoms.  Six months is a relatively short period of time in the course of this disease. 

             We compared the improvement in symptom severity of X STOP patients to laminectomy outcomes reported by Johnsson, Amundsen, and Atlas, which I showed you earlier.  In these studies, 57 to 69 percent of patients reported symptom improvement following laminectomy, where follow-up ranged from one to four years.  In the pivotal trial, 58 percent of X STOP patients reported a clinically significant improvement in symptom severity.  You can see the results are quite similar. 

             There are several published lumbar spinal stenosis studies using the Zurich.  Dr. Katz and coauthors reported outcomes of a 199-patient study using individual questions from the Zurich.  At our request, Dr. Katz analyzed his data using the same criteria from the pivotal trial.  As you can see, the success rates are quite similar to the X STOP results.  Though not shown here, mean score changes in each domain were also very similar.  His patient population was more symptomatic at baseline than our patient population was.  This historical comparison should not be interpreted to infer that X STOP results are comparable to outcomes from laminectomy, but it is appropriate to measure success rates of laminectomy surgery using the pivotal trial criteria if the purpose is to provide a general frame of reference.

             I would like to point out that 272 patients were treated in Dr. Katz's study, and no outcomes were imputed for the 73 patients with missing data at two years.  I mention this to illustrate that methods typically employed in the clinic literature to analyze data are not as stringent as those used in the pivotal trial where patients with missing data were treated as failures.

             Outcomes data from 36 study patients who underwent laminectomy were also recorded.  Applying the study criteria for success to this matched patient population, we get very similar outcomes as you can see here.  This statistical comparison is not made for the purposes of supporting a claim of comparability to laminectomy.  This does, however, indicate the true success rate from laminectomy when you apply the strict criteria used in the pivotal trial. 

             There are a number of studies reporting outcomes of stenosis surgery that use the SF-36 to measure success.  This slide shows the mean post-operative scores of X STOP patients in the pivotal trial compared to the range of post-operative SF-36 values for patients undergoing decompressive surgery.  SF-36 outcomes for the X STOP patients fell within the range of outcomes reported in the literature.

             Success rates in the clinical trial appear to decline from one year to two years.  And this trend was observed in both the X STOP and control groups.  Similar findings have been reported in the literature where success rates tend to decline over time in laminectomy patients.  This is clearly evidenced by the re-operation rates reported in these studies.  As shown here, the rates of re-operation varied from 6 to 17 percent, depending on the length of follow-up, which ranged from one year to four years in these studies.  This re-operation rate is quite comparable to the six percent observed in the X STOP patients. 

             The findings from a longitudinal study of 105 patients conducted by Johnsson and coauthors are consistent with the previous studies.  This graph is reproduced from Johnsson's article, and illustrates the decline in effectiveness of operative therapy over a 5-year period.  In summary, when you apply the same standards, the results of the pivotal trial for both the control and X STOP patients are quite similar to the results reported in the literature. 

             With respect to achieving the primary clinical study endpoint, the statistical superiority of X STOP treatment compared to control treatment was clearly demonstrated.  We anticipated a difference of 22.5 percent between the two groups at the start of the trial.  Despite the lower than anticipated success rate in both the X STOP and the control groups, the difference between the groups was approximately 40 percent.  This was also true for each of the Zurich domains. 

             I would like to end the sponsor's presentation this morning with some final remarks from the surgeon's perspective.  The X STOP device can offer the surgeon a new treatment alternative for patients with lumbar spinal stenosis.  Patient outcomes in the X STOP group were good, and far superior to the control group in the pivotal trial.  The incidence of operative complications was low and without significant clinical sequellae.  The procedure was by and large done under local anesthesia with same-day discharge from the hospital.  The advantage of having the patient out of the hospital quickly is obvious, particularly the elderly patient it certainly contributes to a low level of morbidity.  The X STOP procedure does not significantly alter the functional anatomy, so it can be easily revised and replaced if necessary.  From a risk-benefit perspective, the benefit clearly outweighs the risk. 

             The X STOP offers an immediate and quantifiable benefit to patients suffering from stenosis at low risk.  I believe that the results from the pivotal trial along with the results of extensive biomechanical testing constitute valid scientific evidence, and provide reasonable assurance of the safety and effectiveness of the X STOP device.  I trust the data that have been presented to you will support your recommendation for approval to the FDA today.  Thank you.

             DR. YASZEMSKI:  Thanks very much, Dr. Andersson, and thank you to the sponsor for your thorough presentation.  I'd like to ask if any panel members have a question that they'd like to ask of the sponsor at this time.  I'll note, however, that we have a long block of time devoted to asking the sponsors questions this afternoon.  If there's something that needs to be asked now, please do so.  Otherwise, I'd like to proceed to the FDA presentation.

             Let's move on to the FDA presentation.  The first FDA presenter is Dr. John Holden who is the lead reviewer for this submission.  Dr. Holden?

             DR. HOLDEN:  Good morning.  My name is John Holden.  I'm a review scientist with FDA's Orthopedic Devices Branch, and I'm also the lead reviewer for the PMA application from St. Francis Medical Technologies. 

             FDA will provide several presentations this morning.  First I will give a brief introduction and summary of the pre-clinical evaluation of the device.  Dr. Barbara Buch will provide an FDA summary of the clinical study, and Mr. Richard Kotz will discuss some statistical analysis issues from FDA's perspective.  Finally, we will present the questions that FDA is posing for consideration by the advisory panel today.  I would also like to point out that a large number of other FDA personnel have also made important contributions to the review of this PMA application. 

             As an overview, this presentation will include a very brief device description and summary of the pre-clinical testing.  As the company has presented much of the data on which FDA would like to comment, my presentation will mostly highlight a few points that we wish you to consider as you address the panel questions. 

             From this point forward, I will simply refer to the device as the X STOP.  The indications for use currently proposed by the sponsor are shown again on this slide.  This statement is the same as that already presented by the sponsor. 

             The X STOP is manufactured from a titanium alloy that conforms to ASTM Standard F136.  It consists of two components, a spacer assembly and a wing assembly.  During implantation, the spacer assembly is implanted first, then the wing assembly is attached, the width is adjusted, and the locking screw is tightened.  The sizes of the device are based on the minor diameter of the oval spacer component.  The sizes range from 6 to 14 millimeters in 2-millimeter increments.  The system also includes an instrument set specifically for the X STOP that includes dilators, a distracter, and some insertion instruments.

             Original designs of the device were used in a 10-patient pilot study, and in 22 patients who were implanted in Part One of the pivotal clinical trial.  To their credit, the sponsors stopped the study when they recognized some serious device issues early on.  Several design modifications were made, including a manufacturing step to laser-weld two parts of the device, a change in the taper angle of the tissue expander, and a more rounded tissue expander tip.  So this new, quote, "welded" design, was used throughout the pivotal clinical study.  Much of the pre-clinical testing was performed on the original unwelded version of the device, and then, following the changes leading to the welded design, additional testing was performed to validate the new design. 

             The pre-clinical testing included mechanical tests to characterize the X STOP and determine its ultimate strength.  And as described by the sponsor, a number of biomechanical cadaver tests were also conducted to investigate the loads required to implant the X STOP, the loads experienced by the device in vivo, some spinous process failure loads, and the stability of the implanted device when it is subjected to high loads. 

             I will not describe all of this testing which was summarized in the review memo in your panel packs.  But I will focus on just three sets of tests in particular.  One set of studies examined the effect of placement location on device expulsion or dislodgement.  The two other sets of tests have already been described by the sponsor.  In all three cases, I will simply provide a brief summary, and a few brief comments or observations that FDA would like to highlight for the panel as it considers our questions.

             A set of studies was undertaken to reproduce in vitro X STOP implant dislodgement.  Human cadaver specimens were tested at each intraspinous process level.  Specimens were loaded with an axial force, and flexion-extension or axial rotation was applied.  Pre and post test radiographs were taken to identify any spinous process fractures or deformations.  The results showed that proper anterior placement of the X STOP is essential to preventing dislodgement of the device and/or deformation of the spinous processes.  As a result, the surgical technique manual was modified during the study to emphasize that the X STOP must be placed in the concavity between the spinous processes.  Also, surgeons are instructed to remove part of any hypertrophied facet if the device cannot be correctly positioned.

             The measurement of spinal canal and foramen dimensions was described previously in the sponsor's presentation.  Recall that eight lumbar cadaver specimens were placed in an acrylic frame for measurements in an MRI scanner.  The specimens were scanned in three positions, with and without the X STOP placed at the L3-L4 level.  Axial slices were used to measure canal area, lateral recess distance, and AP canal depth.  Para-sagittal slices were used to measure foramen area, foramen height, and foramen width. 

             This table summarizes the data presented in the PMA application.  For the mean values of the dimensions in the extended position at the implanted level, the table shows that the presence of the X STOP resulted in increased dimensions for five of the seven measures.  This table includes the same kind of dimension data for the implanted level, but for the specimen when it was in the flexed position.  We note that in the flexed position, the presence of the X STOP actually resulted in smaller values for six of the seven dimensions, although these differences are not statistically significant.  So the results of this pre-clinical study show that the X STOP limits canal narrowing at the implanted level in extension.  However, FDA notes that these results are based on seven cadaver specimens, and were not confirmed by any in vivo measurements in patients. 

             The measurement of spinal kinematics was also described previously by the sponsor.  Recall that seven human lumbar cadaver specimens were used for the testing.  With a 700 Newton compressive force, specimens were first tested intact by applying a moment in flexion or extension, axial rotation, and left and right lateral bending.  The specimens were then removed from the loading frame, a spacer was placed between the L3 and L4 spinous processes, and the loading and measurement regimen was repeated, this time with the device in place.

             The results showed that there was no significant difference in the mean range of motion during axial rotation or lateral bending, but that the mean flexion-extension range of motion was significantly reduced at the L3-L4 level.  The ranges of motion at the adjacent levels were not significantly changed.  FDA notes that these results are based on studies using seven lumbar cadaver specimens, and may not be indicative of changes seen clinically.  As will be pointed out later, the ranges of segment flexion and extension were not measured in the clinical study patients. 

             So FDA asks the panel members to keep this pre-clinical testing in mind, especially as you consider the first three of the panel questions, which will be read in full later.  Question Number 1 will ask about possible device effects on adjacent segments, and on spinal biomechanics, as reflected in the clinical data, in particular the higher incidence of other musculoskeletal events.  Question Number 2 will ask about the implications of having no pre-clinical data on the effects of two-level implantation, and Question Number 3 asks the panel to comment on the fact that the clinical patients' radiographs were not taken in flexed and extended positions. 

             At this time, I would like to introduce Dr. Barbara Buch, who will provide FDA's clinical review summary.

             DR. YASZEMSKI:  Thanks very much, Dr. Holden.  Dr. Buch?

             DR. BUCH:  Good morning members of the panel and guests.  As Dr. Holden introduced me, I am clinical consultant to the Orthopedic Devices Branch at FDA. 

             What I'd like to do this morning is not repeat the details of the study.  I think the sponsor has done an excellent job in describing the details for you.  What I would like to do is highlight some issues and raise some questions that we at FDA would like the panel to consider during the deliberation over the panel questions, as well as provide some input into the interpretation of the study outcomes.

             I put these slides up just to remind you that although there have been four versions of the device, and three studies initiated to investigate this device and these versions.  FDA would like you to focus your attention on the fourth version of the device which was studied in the second pivotal trial as this is the device that is intended to be marketed.

             These entry criteria you have seen before.  I would like to highlight the last two criteria to emphasize that these are objective means by identifying the levels of stenosis and potentially quantifying the amount of canal compromise for patients enrolled in this study.  The success criteria are also familiar to you, and are based on a patient self-assessment scale, secondary surgical intervention, device-related events, and placement retention of the device, both radiographically and clinically. 

             The Zurich Claudication Questionnaire is a validated scale for the determination of outcomes after surgery for the treatment of stenosis.  During the validation study for these outcome measures, I'd like to point out that Stucki, et all, concluded that a 0.5 difference in the physical function scale and symptom severity scores was clinically significant when comparing the satisfied and unsatisfied patients.  In the validation study, however, the studies state that while two years would be most appropriate for assessing clinical effectiveness, the point of maximal benefit was six months, and was deemed most appropriate for assessing responsiveness.  This 6-month time point is a time point used to validate this scale in the population study. 

             The minimal clinically important difference was determined using the difference in mean change in the symptom severity and physical function scales for patients who were somewhat satisfied and patients who were unsatisfied.  The reason I point this out is the time of validation becomes important in the X STOP study, and I would like you to keep this concept in mind as the presentation continues, and as you are considering the panel questions that follow.

             The next issue I want to present is the ability to interpret the long-term effectiveness.  Because of rapid enrollment, there is no longer term data available for patients enrolled in this study.  In many instances, trials have long enrollment periods, which allow for some longer term, that is 3-, 4-, or 5-year data.  However, since this is not available in this study, further clinical assessment at later follow-up periods may be needed, especially when we look at trends in overall outcome in this trial.  Again, I'd like you to keep this issue in mind when discussing the effectiveness of this device.

             Now let's look at the control patients in this trial.  The control patients had continuing symptoms despite conservative treatment for six months, and the majority had symptoms for greater than two years.  In the study, the control patients received additional conservative treatment, including varying numbers of epidural injections as we heard.  When we look at the overall end results, 95 percent of the population in the control group failed conservative treatment, and 26 percent of the patients had symptoms that warranted a surgical decompression procedure.  Based on this perspective, the question arises to us as to whether the conservative control treatment was appropriate as a comparative group to the operative treatment, given the high rate of failure in this population.

             Next let's consider what potential impact the study design had on the interpretation of patient outcomes.  The study protocol did not specify the criteria for progression to laminectomy or additional epidural injections.  Thus the frequency and timing of repeat injections was left to the discretion of the investigator.  It appears that patients were not treated the same within a group or between groups when deciding who had symptoms requiring surgical decompression, or who required an additional injection.  Some patients in the control group received only one injection, while others have received two, three, four, or more injections. 

             In addition, in the X STOP group, eight patients had pain injections after the implantation of the device.  Although there may be a lack of consensus in the literature for a clinical trial, FDA believes that all patients should be treated equally according to a pre-described protocol to avoid any confounding factors that will confuse study outcomes.  As an example, an X STOP patient with progressing pain who required serial nerve root injections did not progress to laminectomy as a result of his symptoms, while another did progress, but was not operated on until 66 days following injection failure, despite progressive neurologic deficit pain and a loss of sexual function less than two weeks after epidural injection.  Overall, it is not clear if additional epidural injections in either group delayed the progression to laminectomy as the criteria for performing decompression by laminectomy was not well-defined. 

             As has been described, the overall safety profile shows that this is a surgical procedure that is minimally invasive, and most patients are treated as outpatients.  The device-related adverse events were few in number and were relatively minor.  The deaths that occurred were not considered device-related, and those that occurred related to the device were few, including spinous fracture, device migration, and local wound events that occurred only in one patient each.  These safety events on the whole are unremarkable, except for a difference between the X STOP and control patients when it came to documenting musculoskeletal adverse events that were considered not device-related. 

             The mostly lower extremity events occurred with greater frequency in X STOP patients, and the X STOP patients experienced 3.4 times more types of these events than the control patients.  The majority of these events were admittedly classified as moderate in severity, but they did trigger an additional unscheduled visit to the clinic.  A percentage were attributable to excess physical activity and exercise, but I'd like to point out that 20 percent were attributed to a return of stenosis symptoms.  One possible explanation, as has been delivered by the sponsor shows that stenosis associated pain was potentially relieved and other comorbid conditions responsible for this pain were unmasked and came to the forefront.  Another consideration and possible explanation is that there are potential changes in spinal dynamics and biomechanical function that occur within the limitation of extension.  And these also may be responsible for pain.  This investigational study does not evaluate further whether either of these or an additional explanation is the cause.  This issue should be considered when evaluating the effect of this device on the biomechanical dynamics of the spine as you complete your discussion.

             You've seen this chart before.  Based on the low effectiveness achieved as compared to that expected in both groups, the question arises on our part whether the enrollment criteria in the patient demographics were able to discern comparable patients.  In essence, was the population a homogenous population.  Additionally, did the study define the population in the continuum of lumbar spinal stenosis as has been emphasized today, as identifying the patients who would most benefit from this device, or did this population of stenosis patients all require some type of intervention surgically to decompress their stenosis at the time of entry in this study. 

             When we look at back and leg pain separately at 24 months, mean back and leg pain scores were significantly less frequent and less severe in the X STOP group as compared to the control group when standing or walking.  Based on this secondary endpoint information, it appears that the treatment with the X STOP has the most effect on leg pain when standing and walking as compared to the relief of back pain, but not on other symptoms such as those experienced while sitting. 

             Even though the goal of this study was accomplished, showing a significant statistical difference between the investigation and control groups, more patients reported improvement in pain at 12 months than at 24 months.  In contrast to what has been observed in spinal fusion studies, which is also a treatment for degenerative spinal disease, in this study a percentage of patients whose symptoms improved at 6 and 12 months showed a trend of regression of pain and function symptoms towards baseline levels. 

             Let me explain what this chart shows.  On the X axis are the three domains of the Zurich Claudication Questionnaire, and the overall success score on the questionnaire is to the far right.  Each colored bar represents the percentage of patients in the X STOP treated group who were considered a success by the pre-defined criteria on each section at four different time points.  The dark blue bar represents a 6-week time point.  The light blue bar represents the 6-month time point.  The red bar represents the 12-month time point, and the yellow bar represents the 24-month time point. 

             This chart shows the progression of effectiveness over time.  As we start to the left, we note at 6-week time point the rate of success with patients on the ZCQ, or Zurich Claudication Questionnaire, is high, and remains somewhat consistent to the 12-month time point, as noted in the red bars.  When we compare the 12- to 24-month successes, that is the red to the yellow bars, we can see that in each domain, pain severity, function, satisfaction and overall success, there is a decrease in the number of patients with pain and function success in the X STOP group.  I'd like to point out that the previous table was constructed using this data for the X STOP group, and I want you to note that the denominator changes very little for each category over time.  That is, the majority of the patients in the X STOP group were included in this trend calculation.  Please keep this effectiveness trend in mind when considering the panel questions that follow.

             Now I'd like to touch on a slightly different perspective on the outcomes of a subgroup study which defined the number of levels that were treated by the X STOP device.  The use of this device at one or two levels may have different outcomes with regard to patient populations and their post-operative results, and what the long-term impact of the device implantation on spinal mechanics may be.  As has been noted, the majority of patients in both groups had multiple coexisting variables noted on radiographs and by history.  Some of these radiographic findings include a thickened ligamentum flavum, narrowed lateral recess, hypertrophied facets, and central canal narrowing by 50 percent or less.  And also, up to 25 percent spondylolisthesis.  In both treatment groups, there were patients with more than one level involved.  In the subgroup analysis, it was noted that patients with two-level implantation had a slightly better outcome in all aspects of the effectiveness evaluation, although this was not statistically significant.  More single-level patients underwent laminectomy than those with two levels implanted.  Adverse event occurrence in the two-level treated patients were also less frequent than those with single levels.  Again, these were not statistically significant, and the samples were small.

             Cadaveric biomechanical studies, as were described by Dr. Holden, were performed by the sponsor.  These showed that the dimensions of the spinal canal were larger in the X STOP implanted levels than without the X STOP.  However, I'd like to highlight that these results were observed only at the implanted level, but not at adjacent levels, and only one-level implantations were studied.  Please also recall that as Dr. Hartjen explained, the surgical technique instructs surgeons to ask patients to flex the spine as much as possible to achieve maximal distraction when the device is inserted.  These effects were not evaluated pre-clinically. 

             Given the outcome results, and the results of cadaveric biomechanical studies, our question to you is whether it's clear that it's appropriate to treat just one or two levels in cases where there are multiple level changes in the spine.  Please keep this issue in mind when deliberating the answers to the panel question.

             Another perspective.  When we look at the number of levels that were actually decompressed at surgery, we see that not all single-level implants had single-level decompressions.  For example, in the pilot study there were two failures.  One patient had a two-level laminectomy at a two-level implantation sites.  However, the second patient had a three-level laminectomy where one level had been implanted.  This table shows the number of levels that were decompressed in each group in the pivotal trial.  Again, not all the patients had single-level decompressions.  We note that two patients with single-level implantations had single-level decompressions.  Four patients had multiple levels decompressed who had previous single-level implantations, and five patients had multi-level decompressions in two-level implantations.  When we look at the controls, 7 out of 24 patients had single-level laminectomy, and 13 out of 24 had multiple level laminectomies. 

             This trial included radiographic evaluations as determined by AP and lateral x-ray.  I'd like to point out that no flexion or extension radiographs were performed.  The radiographic measurements at each level were made only on the plain AP and lateral views to determine this list of measurements, which include interspinous process distance, anterior and posterior disc height, angulation, foraminal height, and the percentage with spondylolisthesis.  These measurements were performed before and after implantation. 

             I'd like to highlight some of the radiographic results, specifically the distraction levels.  There were no significant differences between the X STOP and the control groups in any of the mean radiographic measurements made at either 12 or 24 months follow-up.  Measuring the maintenance of distraction in the X STOP patients was determined by the distance between spinous processes.  I'd like to focus for a moment on the results of these radiographic measurements.  The information supplied showed that of the 113 levels treated, a decrease greater than four millimeters, which was considered significant in this study, was measured at five levels at baseline, as compared to -- was measured at 24 months as compared to six weeks.  Fifty levels remained radiographically the same as baseline.  The remainder showed some change, that is loss of distraction of one millimeter or more, with 59 percent of those patients showing a greater than two millimeter measurement of apparent loss of height from baseline at six weeks. 

             Recalling the pre-clinical studies, the radiographic studies performed, the absence of flexion-extension radiographs, the instructions to surgeons to flex the spine as a pre-insertion event, our question to you is what is the best way to interpret the radiographic measurements as they relate to device effectiveness.  As an example, these radiographs were samples that were included in your panel packs.  One is an example of a patient who was an overall success, and one is an example who was an overall failure.  It is not clear that the radiographic measurements that were made were able to predict which patients were a success or a failure, except where obvious dislodgement was noted.  This will also be an issue that we'd like you to comment on in your response to the panel questions.

             I'd just like to say a brief comment about the differences in successful outcomes that were observed by sight.  There is a significant difference in outcome between the patients treated by investigators, as noted in this table.  The investigators in the first site were the most experienced in the use of this device.  The question arises as to whether or not there is a learning curve for the implantation technique, or there is an improved ability to properly select patients who would benefit from this device.  As you can see, there's a wide range of overall successful outcomes depending on the site.  The effect of this site to site difference will be further discussed in the statistical review, but again, this is something we'd like you to keep in mind when making your recommendations related to this device, particularly to labeling.

             Next I'd like to briefly discuss the sponsor's additional analysis, wherein the sponsor provided comparison between the outcomes for the successful X STOP patients and the patients who were failures in both the X STOP and the control groups, and then went on to have laminectomies.  Thirty-six patients treated with laminectomy had continued ZCQ scores in follow-up evaluations based on their index procedure or epidural injection.  Symptom severity, physical function, and satisfaction data was collected from the failures who had laminectomies up to a mean of 1.2 years.  Improvement was based on ZCQ scores assessed just before and then after laminectomy, up to 24 months.  It is difficult to draw any conclusions from such a comparison, for the following reasons.  There was a pooling of patients with failed treatments in different treatment cohorts, which included patients who received different versions of the device.  In addition, there was pooling of patients who were treated with primary laminectomy with those who were treated with a secondary laminectomy.  In total, there was a comparison of successful outcomes groups to failure groups.  This comparison of successes to failures we believe is not a valid comparison.  It is also important to note that the patients who failed initial treatment may have been in worse physical condition, and may have been more likely to require a laminectomy, and this was not considered in the comparison.  It is difficult to discern the clinically meaningful implication of this comparison.  The statistical presentation will expand further on this issue.

             Finally, I'd like to point out the indications for this device, and the population it defines.  The X STOP is indicated for patients aged 50 or older suffering from mild to moderate symptoms who have undergone a regimen of non-operative treatment, and who experience relief in flexion from symptoms of leg, buttock, and groin pain, with and without back pain.  I'd like you to keep this in mind when considering the panel questions we present later.

             In summary, there are several points that I have presented that the FDA would like you to consider when answering the panel questions.  The points we'd like you to keep in mind include the following: the appropriateness and adequacy of the control group, whether the appropriate evaluations for pain and function have been made to show the effect of this device, whether the radiographic evaluations assist in the determination of safety and effectiveness, whether we know or can discern the long-term biomechanical effect on the spine, whether the device is effective and for how long, and whether we know in whom it should be used.  Thank you for your attention.

             DR. YASZEMSKI:  Thanks very much, Dr. Buch.  Mr. Kotz?

             MR. KOTZ:  I am Richard Kotz.  I will be presenting a statistical review of the clinical trial for the X STOP.  Briefly, my outline will include a discussion of the study design, deviations from the protocol, and patient accountability.  Then I will comment on the comparability of the treatment groups at baseline, present an analysis of device effectiveness based on the primary endpoint, and critique the sponsor's comparison of their device to laminectomy.  In conclusion, I will comment on the safety profile and then summarize my presentation.

             The study was designed as a controlled partially blinded randomized clinical trial.  The control group was conservative care and epidural injections.  Note that the patients in this group had already failed conservative care, and about half of them had had epidural injections prior to being enrolled in this study.  Note that only the evaluating physician was blinded.  Patients, the treating physician, and radiologists were not blinded.  The study was randomized with patients equally likely to receive X STOP or the control.  The randomization was stratified by site, with a fixed block size of two.  I will elaborate upon this momentarily.  Also, the patients were randomized upon determination of study eligibility. 

             The primary endpoint, as already discussed, was a composite based on the ZCQ scores, x-ray, and no complications or dislodgements.  The ZCQ scores are based on subjective measurements of symptom severity, physical function, and satisfaction.  It should be noted that there is a potential for significant bias when patients and investigators aren't blinded to the randomization assignment, and when the study endpoint is driven by patient assessment.  That is, the control patients know that they're receiving a treatment that has not worked for them in the past, while X STOP patients believe they are receiving a treatment that may have great potential to help them.

             The sponsor designed their study with the randomization stratified by site and used a fixed block size of two.  This means that they randomly selected the first patient at a site, and thus the second patient would automatically receive the other treatment.  Therefore an investigator could predict which treatment the second patient of each pair in a block would receive.  This could potentially lead to investigator bias.  In order to avoid this possibility, it would be better to use a variable block size design.  That is, the block size at each site would vary randomly.  For example, the first block might be randomly selected to be size six, and the second block might be randomly selected to be size two, a third could be four, or six, and so on.  In such a system, there is no predictable pattern, making it difficult to subvert randomization.

             Another issue of importance is the problems associated with randomizing patients several days to weeks before they will receive their treatment, especially when the patients are unblinded.  When patients know their treatment assignment, they can drop out based on this assignment.  In this trial, eight subjects dropped out when they learned they were randomized to the control treatment.  Early assignment also gives patients more time to drop out for any number of reasons.  The surgeries have to be scheduled in advance.  When possible, it is best to randomize patients as close to time of treatment as possible. Doing this should help to reduce the number of patients dropping out of the study before the treatment is given.

             The study was designed as a comparison of proportions, the alternate hypothesis being that the success proportions were different for the X STOP and control groups.  Thus, the study was designed as a 2-sided test.  It had a significance level of 0.05 and a power of 80 percent.  The expected success percentages were 60 percent for the X STOP and 37.5 percent for the control, with an expected loss to follow-up rate of 15 percent.  This resulted in a needed sample size of 100 subjects per study, and the study was conducted across nine centers.

             There were four X STOP and three control enrollment deviations.  Four subjects had previous disc surgery, and three others had stenosis at the wrong level.  In addition, eight X STOP patients had post treatment deviations.  Six X STOP patients who received epidural injections for unresolved stenosis were treated as study failures.  There were an additional two X STOP patients who received injections for pain following car accidents.  These two patients were successes at two years and were treated as such in the pivotal study. 

             Two hundred and twenty-nine patients were enrolled in the study.  Thirty-eight of these were not treated under the study protocol for various reasons.  Fourteen of these were X STOP, and 24 were controls.  As already noted, eight subjects withdrew after they were assigned to the control group, five withdrew for health reasons, two because they didn't meet the inclusion/exclusion criteria, six had scheduling problems, and another 17 elected to forego treatment.  This included one X STOP and four controls who chose to go directly to laminectomy instead of being treated under the study protocol.

             Of the remaining 191 patients, 100 received the X STOP and 91 were in the control group.  Of these, 82 X STOP and 54 controls completed the 2-year follow-up.  Another seven died, and 30 went on to laminectomy.  Twenty-four of these laminectomy patients were from the control group.  An additional eight patients had less than one year follow-up, and another 10 had less than two year follow-up.  It should be noted that all these patients in the last four categories are considered as failures at two years, except for one X STOP patient who was a success at Day 710, but failed to have a 2-year radiographic exam.  Note that this patient at one year was also a success, and had a successful radiographic exam.  It should be noted that the results that I am presenting are based on all 191 patients, and will be slightly different from the results the sponsor presented which were based on -- mine are based on all treated patients.  Theirs were based on evaluable patients, and basically they excluded the eight patients with less than 1-year follow-up from the presentation of their results.

             There were no significant differences at baseline between the X STOP and control groups with respect to age, gender, weight, height, duration of symptoms, occupational status, baseline radiographic findings, current medications, and most medical treatments.  But there was a significant difference with respect to previous epidural injections.  Sixty-three percent of the X STOP patients versus 44 percent of the controls had previous injections.  It should be noted that this test was not adjusted for multiple endpoints.  I give a p-value of 0.01 up there.  Also, it appears that this difference is mostly accounted for at one site, where 12 of 16 X STOP and only two of 15 controls had previous epidural injections.

             The patients treated with X STOP had a statistically significantly greater proportion of successes at two years than those who received the control treatment.  That's the column with the As Treated patients.  In addition, I have presented the results for an intent-to-treat analysis, or as abbreviated on the slide, an ITT analysis, where the 24 controls and the 14 X STOP patients who were randomized but not treated are counted as failures.  It should be noted this is probably not an appropriate analysis since there was a large imbalance between the two groups with respect to patients dropping out before being treated.  In the next row, note that even if we take the worst case scenario in which all 24 patients who were not treated are considered successes, and all 14 untreated patients randomized to the X STOP are considered failures, the p-value still indicates a significant difference between the two success proportions.

             This graph shows the distribution of X STOP success percentages across sites, ordered from the site with the lowest percentage at 12 percent, to that with the highest at 81 percent.  In the parentheses at the top of each bar I give the number of subjects treated with the X STOP for that site.  We see from this graph that the last site appears to have a percentage much greater than the others.  In fact, this site had a significantly greater proportion of X STOP successes than the rest of the sites.  The site which treated the most patients had a success rate of 81 percent, while the rest of the sites had success rates ranging from 12 to 50 percent.  When this site was removed, there was no statistical difference among the remaining sites with respect to the X STOP proportion of successes.  Note that without this site, the overall success rate for the X STOP decreases from 43 percent to 33 percent.  It has been noted that the investigators at this site were the inventors of the device, and presumably had a great deal of experience with it.

             The sponsor also presented a statistical comparison of the percentage of successes of their X STOP with laminectomy and claimed they were comparable.  But note that this was not a randomized study.  Furthermore, most of the laminectomy patients were pivotal study failures who then went on to laminectomy.  Seven additional patients were failures from the unwelded study, and seven others came from untreated patients in the pivotal study who went directly to laminectomy.  Given the unrandomized nature of this comparison, and the potentially severely biased selection of the laminectomy patients, it would be very difficult to draw a statistically meaningful comparison of these two groups. 

             Though the adverse event profile was comparable for most areas of the body, the overall difference with respect to musculoskeletal system was statistically significant.  In the second column, under the Control, the 22 for patients with adverse events should really be 16.  I mistyped.  But in particular, there were notable differences among the lower back, lower extremity, and hip. 

             In summary, the X STOP success percentages was superior to that of the control, 43 percent versus 4.4 percent, but the percentages were less than that expected, the expected percentages of 60 percent and 37.5 percent.  We also discussed several potential sources of bias in the study that could affect the results.  These included the use of a fixed block size of two for randomization, a subjective primary endpoint, lack of blinding of patients and investigators, and the significant difference in the success rates among one of the sites.  Finally, the musculoskeletal adverse events rates were greater in the X STOP group.  And that concludes my presentation.

             DR. YASZEMSKI:  Thanks very much, Mr. Kotz.  Now if any of the panel members have questions for any of the FDA presenters, we can do that now.  I'll remind you again, though, that we will have time this afternoon to deliberate and ask questions of both the sponsors and the FDA.  If there are no questions, I'd like to suggest that we take a break now for 10 minutes.  Okay, I've got a request to make it 15.  We'll make it 15.  It's now 10:25.  We'll reconvene at 10:40 with the presentation from the panel lead reviewers.

             (Whereupon, the foregoing matter went off the record at 10:25 a.m. and went back on the record at 10:47 a.m.)

             DR. YASZEMSKI:  Please take your seats so we can resume. 

             DR. KIRKPATRICK:  I'm John Kirkpatrick.  I'm humbled to be asked to present a review from a panel member's perspective of the clinical findings that we've heard this morning as well as in the packet.  I would like to thank first of all the two patients that came forward and spoke to us earlier.  They demonstrated great courage and candor in their comments, I was blessed by hearing their stories, and I think their efforts on behalf of their other patients or fellow patients needs to be recognized.  And that's appreciated very much. 

             I also would like to acknowledge that I have many colleagues and friends on both sides of the discussion today.  The sponsor has done outstanding work in assembling a great deal of data that we need to analyze critically, and I'll try and give some comments on how we might be able to proceed with that.  And finally I would like to make the observation that this morning has seemed a little bit like a polite version of CNN's Crossfire.  So I hope we can all smile and enjoy the whole day.

             As we've heard, lumbar stenosis involves the narrowing of the spinal canal.  It can be regional, which needs to be clarified, I think.  There can be a central canal stenosis, there can be lateral recess stenosis or subarticular stenosis, and there can be foraminal stenosis.  The most common that I see as a surgeon is probably combinations of those three areas.

             Neurogenic claudication, the symptom that we are hearing about being addressed today, involves the pain into the legs, or one leg.  It typically results from a number of etiologies.  On the basic science level it's thought to be either from direct compression, from the compression causing a root ischemia, from the compression causing a venous congestion, or from direct blocking of axoplasmic flow.  None of those has clearly been identified as the predominant mechanism.  They may work all in combination.  Unfortunately, we don't have specific studies to tell us one predominates over the others.

             The X STOP philosophy is basically a device which takes advantage of the posture relief that occurs in flexion of the spine in some patients with spinal stenosis and resultant claudication.  Their indications we've heard about several times.  I won't belabor that, as well as the contraindications, I won't belabor that. 

             The evaluation that they presented goes over some pre-clinical issues, and basically demonstrates that it's structurally sound in its final form, that it does effect a change in the space available for the roots, demonstrated in the cadaver model.  The clinical study demonstrated some safety issues, some degree of an anatomic change, and showed some improved symptoms and function. 

             Their pre-clinical studies, again, I think the mechanical testing was satisfactory to demonstrate that the device will hold up over time.  The insertion and pull-out loads appear to be reasonable and provide what appeared to me to be a reasonable safety factor as an engineer.  The kinematics is only affected at the index level, did not appear at other levels, although I do acknowledge that they did a one-level study as opposed to two-level studies.  I'm not convinced that that would make a huge difference based upon my own studies with fusion mechanics in actually a T-12 to sacrum model.  We did not find a two-level fusion altered the kinematics at the open levels significantly.  So I'm not that concerned about the fact that they don't have a two-level kinematic study.

             And they also mentioned that canal and foramen dimensions were changed.  It does raise some questions that we'll hear about in a few minutes.  Basically, the dimensional changes did show that there was a prevention of the amount of decrease of the foraminal area.  The subarticular diameter did not decrease as much, and the canal area did not decrease as much in extension with the X STOP.  So it does appear to prevent the natural canal narrowing that occurs in extension.  It appears to prevent the natural decrease in the subarticular diameter in extension, and it appears to prevent natural decrease in the foraminal area in extension.  All of these being, obviously, in a cadaveric model.  It's unclear why some of the flexion dimensions seemed to decrease as well after the implantation of the device, but those changes were minor, and may have simply been measurement differences.

             The clinical results, as we've all heard.  They enrolled 229.  They basically at the 24-month data they had 92 in study and 81 controls.  Their primary measure was the Zurich Claudication Questionnaire.  The symptom function and satisfaction scales on that, additional surgery, maintenance of distraction and device for construct failure.  The Zurich Claudication Questionnaire I'll let my colleagues know is also known as the Swiss Spinal Stenosis Questionnaire.  In doing search engines, it was easier to find it under the SSS than it was under the ZCQ.  It involves the seven symptom questions we've heard about.  And I would discuss also the fact that what they describe as a significant difference in the article that Stucki wrote, he describes it as a minimum clinically important difference between unsatisfied and somewhat unsatisfied patients.  And that is where the 0.5 comes from.  But I would ask that our statisticians among our group as well as those clinicians that are familiar with outcomes data help me understand whether the minimum detectable difference is the same as a clinically significant improvement. 

             An independent study of the Swiss Stenosis Questionnaire was also done in 2002.  It is the most reproducible among those measures that were looked at in that study, and as such I think it was a valid questionnaire to use.  The same authors that evaluated it did acknowledge that it may not be reproducible enough to judge the outcome after surgery for an individual patient.  The point of view that was associated with that article also indicated that fairly large changes are necessary for the confident determination that a true change has occurred.  When we look at the sponsor's definition, 0.5 improvement is success.  Depending on how you want to look at the numbers, 0.5 improvement represents about a 10 percent change in symptoms.  It's a scale of one to five.  Perhaps my math would have been better if I looked at zero to five, then it truly would be a 10 percent, but we're talking a few percentage differences there.  At any rate, it's going to be less than 20 percent improvement.  On the same token, when we look at the improvement in the function, it's a scale of one to four, so my number really should be changed.  I'm doing it in my head very well, but it will be a little bit higher there.

             The predictors of success that they found raise questions in my mind.  They looked at femoral stretch.  However, as we heard this morning, the two patients that described their symptoms sounded a lot more like closer to sciatica than femoral stretch issues.  And in that case, why didn't they look at sciatic tension signs, which is also a significant number of spinal stenosis patients in my practice present with as opposed to femoral stretch.  I do acknowledge literature recognizes femoral stretch as well, but why not look at all things that are relevant rather than just one particular area.

             The second thing is about the radiographic signs that they evaluated.  Did they look at the specific types of stenosis?  Both the patients today talked about unilateral leg pain.  That was probably not a central canal stenosis involvement.  So I'm wondering if there may be a stratification of the results and find different success rates with different areas of stenosis anatomically. 

             They also presented radiographic data at 12 and 24 months.  I couldn't find whether there was pre-op or post-op data, and I would ask the sponsors if they have the pre-op data that I missed please call my attention to it.  I could not find flexion-extension data in the clinical study.  They did it in the pre-op, and they tried to make the statement that they prevented any extension with the use of the device.  I can't verify that in the clinical study.  And then they did an excellent MRI analysis pre-clinically to demonstrate the opening up of the foramen, the opening up of the subarticular facet diameter, and the canal diameter.  Could this not have been duplicated in the clinical study as well to demonstrate the effectiveness of the device anatomically, and not just with a clinical outcome.

             Random check of the data.  I must say that having a daughter that undergoes math homework, I have to double-check her work sometimes, and I have to remind her of attention to detail.  On Table 35, Page 53, they indicate that the symptom severity is a 5-point scale, and their division is on that scale.  My concern is that if we're looking at the five points that you have, the denominator should be five instead of one.  So 0.99 over 5 would be 19.8, as opposed to the 24.8 indicated there.  When I double-checked the next category on the same table, they used the same denominator to get the same percentage.  So one of those needs to be changed.  Perhaps the function scale needs to be a higher percentage on their computation, or the symptom severity needs to be lower, depending on which convention we're going to assume.  And the question is, with that difference, are there other areas in the data reports that might need to be double-checked.  I did not have time to review all the tables.

             Our panel deliberations will involve the FDA reviewers' questions, and the clinical review questions, as well as the independent questions that we've come up with.  Our key focus should be the safety and efficacy of the device.  As you remember, our definitions are, and this is shortened to make it simple, reasonable assurance based upon valid scientific evidence that the benefits outweigh the risks.  In my opinion, the safety events related to the device or implantation were few or relatively minor, and are considered reasonable for a surgical procedure.  I did not find that the life-threatening complications or irreversible complications appeared to be related to the device itself, and were more likely related to the patient population instead of the intervention. 

             Efficacy is the reasonable assurance that in a significant portion of the population, the use of the device will provide clinically significant results.  A significant portion of the population, 45.7 percent is not a significant portion of the population in most surgical circumstances.  Of course, you can't compare back pain with knee pain, but when you look at arthritis in the knee and look at success rates, patient satisfaction's in the 95 percent range at 15 years.  That's certainly a difference in a device evaluation.  However, I do think we need to temper our thoughts on what sort of percentage would be significant because we are dealing with a much more complicated and difficult pain relief situation to deal with in the spine than we are in the knee.  I think that a better definition of the population may help clarify some of these issues.  As I mentioned a few moments ago, stratifying by the type of stenosis may be of benefit, eliminating or limiting comorbidity. And then they found that the patients with worse function scores did better with the procedure, yet their indications indicate that they want mild to moderate symptoms.  And I'm wondering if they looked at the more severe functions for symptomology issues they would find that those patients since they did better might be a better patient to have the indicated procedure.

             Clinically significant results.  This means does the patient find a significance.  The 0.5 improvement was selected by the sponsor.  Again, I mentioned that my numbers may be a few points off as far as how you want to compute them, but essentially the way I computed it was between a 10 and 12.5 percent change.  That may go up five points or so if we change the computation method.  However, the question is is that a clinically significant improvement to an individual.  It also approximates the minimum clinically important difference as described in the original paper discussing the measure.  And the question I would pose to you all is is this amount of improvement significant to the individual patient.

             Thank you very much.

             DR. YASZEMSKI:  Thanks very much, Dr. Kirkpatrick.  We've heard Dr. Kirkpatrick's lead clinical review from the panel.  We'll now ask Dr. Jonas Ellenberg to give the panel's lead statistical review.  Dr. Ellenberg?

             DR. ELLENBERG:  I would like to echo the prior speaker's commendation to the sponsor for providing us with an excellent overview and ability to look at facts very quickly, and have everything cross-referenced. 

             What I'd like to talk about now, fortunately, is somewhat redundant.  I'm the last formal speaker, so I'll be talking about things that have been to some degree covered already.  And my main theme will be the flow that we have with the pivotal clinical trial, starting with study design, going to observed results, and then taking the observed results and see how we can use those to come to conclusions.  That is our task here as a panel.  What I'll talk about is how we judge the smooth and credible flow related to equivalent patient populations in the two groups that were randomized, and the issue of uniform intervention, and the issue of whether or not we have an objective outcome in the analysis that has been presented.  And then the time that the analyses were done, that is, the primary analysis being done at 24 months.

             So, beginning with the issue of the equivalent patient populations.  In terms of the randomization, the statistical review has already mentioned the issue of block size of two, and I am reasonably concerned about that.  It's already been explained that if you have a block size of two an investigator can theoretically select a patient coming through the door to put them on which arm they feel they might do better with.  And what we're sort of challenged with here as a group that's reviewing this is in no way, shape, or form a question of impugning anyone's integrity, but basically the issue of this opens up the door for an opportunity for investigators to inadvertently, with no intended bias, to push patients towards one arm or the other.  And we have to, in the end, ask the question is this reasonably -- are we reasonably sure that this did not happen.  And with a block size of two, and not being there at the time that these decisions were made, we have to make that decision.  So that's one of the considerations we'll have as we deliberate.

             The second issue in terms of the equivalent patient populations goes to the expectations.  And for this I go to the informed consent document.  This is in the panel's workbooks.  These are the three points that relate to the issue of what the patient is told in coming on to this study.  The first point, "My physician will explain the study to me and how the X STOP may relieve my symptoms that I experience."  Second bullet relevant to the informed consent, "The alternative to this procedure is to continue a conservative care program that may include physical therapy and/or medications or a laminectomy procedure."  Third statement, "Neither my surgeon nor I will know what group I am in until the sponsor of the study tells us."  Now, I'm not sure why that statement was in the informed consent.  It seems to me not to be true.  But the first two points, in my view, do not give the potential for success for the alternative therapies.  And in light of what we heard this morning whereby most people coming onto this study are essentially failed patients for the conservative flow, my sense is that going into this study, patients who will know what arm they are on by definition come into the study with an expectation that is different between the two arms.  So this fact, coupled with the issue that the block size is two, it seems to me at a minimum could show an appearance of the potential for a biased selection of subjects onto the study arms.

             The second issue with regard to the equivalent populations.  Actually, this was just brought up indirectly by Dr. Kirkpatrick.  The association of baseline with later assessments for severity and physical score components.  If we look at the results of the physical score changes from baseline, in those subjects who did not have a laminectomy, and they maintained the distraction in the X STOP group versus the control group, it's not important to see all the individual points, but just note that the red X's are those on the X STOP treatment, and the black squares or circles are those that are in the control group.  If you have a terrific eye, you might notice that the relationship between the baseline physical score and the change in the score over time, which is one component of the outcome that is the primary outcome, that one treatment, the arm for the X STOP, appears to be related in a different fashion than the control arm.  Statistically, this is the case.  This arm has a steeper slope than that arm.  And basically what this is showing, since the measurement is higher scores are good in terms of achieving success.  Going up means that you've reduced your score.  And on the CVQ it is good to reduce the score, rather than increase the score.  It's seen that as you go up with baseline physical score, the more dramatic increase is going to come from the X STOP group than from the control arm.  And this relates specifically to one of the panel questions: is there a group of patients in which this procedure might be most effectively used.  So again, do we have equivalent patient populations?  It's not clear.  This may be strictly a treatment effect being shown here, or it may be the fact that there's some differential in the way the patients came in to the two arms.

             Next issue.  Do we have a uniform intervention?   We've seen already, and it's been mentioned by several of the speakers, that there is a differential center by X STOP success rate.  One center being as high as 80 percent plus in success.  That's disconcerting when you look at a study like this and try to see whether or not all patients within center and between the centers actually were receiving the same uniform intervention. 

             The second issue is there is no protocol for the use of laminectomy.  And if one goes back to the issue of the informed consent, and the issue of expectations of the patients and the investigators, I would like to raise for the panel's consideration the potential that the use of laminectomy in the X STOP group for which I believe the number was six, as contrasted to the control group where the number was 24, the use of laminectomy conceivably, indirectly, without any potential bias, could have been forestalled in the X STOP group.  Because of an expectation or a wanting to make the X STOP group work better. 

             The use of epidural in the X STOP arm.  Again, there was no specific procedure in either the control or the X STOP arm.  The use of epidural was considerably less frequent than in the X STOP arm than in the control arm.  Nonetheless, there's no protocol for the use of an epidural in either of the arms, and there's no protocol for the use of laminectomy.  And laminectomy is a major endpoint.  We know that 24 of the control patients had a laminectomy, and they were considered a failure.  And six of the X STOP patients had a laminectomy, and they were considered a failure.  So do we have a uniform intervention?  This is something that I think we as a panel have to consider as we look at the numbers that very simply say, okay, success was 45 percent in the X STOP group versus five to six percent in the control group.

             Do we have an objective outcome?  Mr. Kotz has already covered some of these issues.  But we need to make sure that we're considering this as we look at the results being seen, which appear to be extremely objective.  As has already been stated, the ZCQ is a totally subjective series of questionnaires in three parts.  I couldn't find in the package that we had to review exactly what circumstances the patients were given these tests in.  Were they allowed to be prompted with questions with the investigator in the room, or someone else associated with the study, or was this simply done on their own.  So there's the potential for an influence by the investigator.  But even if the ZCQ was totally done by the subject, if there were from the IC or other discussion with the entering investigator, would the patient -- that push the patient to have a higher expectation.  Then it's really, really difficult to understand the subjective outcome.  And I think it was interesting today when that was mentioned, that the ZCQ outcome score for clinical significance was noted at 0.5 in this study, but that's not really necessarily the clinically important result.  And I'll bring in some data that I think is very interesting to address that.

             There was no masking possible.  So everyone, mostly everyone knew what was going on.  In the informed consent, was there really equipoise, which ethically and legally is required in order for someone to be randomized into a study.  And from my reading of the informed consent, it's not clear that that was the case.  But that's a legal issue, not an issue that I think this panel is addressing.  Was there balanced expectations?  I'm bringing this point up again under the objective outcomes, even though I've already mentioned it, because it carries through everything that we do. 

             Was there an objective component as part of the primary outcome?  Well, the laminectomy appears to be an objective component, but as I've already discussed before, if the laminectomy was held off on, then perhaps there is a subjective element, even in that objective component.

             The analysis.  Do we have an analysis that fairly assesses what we have done and what we have seen?  The statistical review has already covered the missing data.  The randomized but not treated issue has been covered by the sponsor in terms of doing a sensitivity analysis.  So in my view in reading that I don't think that's a major issue. 

             The ZCQ cutpoint choice that Dr. Kirkpatrick just raised, is this clinically meaningful.  What I did was look at the frequency distribution of the differences in the ZCQ scores.  And let me explain the graph.  On the X axis, what you see here is a difference from baseline in the change of the severity score.  And this is the epidural group, the control group, and this is the X STOP group.  Again, because this confused me for awhile, a positive score is a good thing, and a negative score is a bad thing.  That means that there's a worsening.  The score that was chosen for this study to be a clinically meaningful result was a change of 0.5 in the good direction.  Meaning that the score dropped from baseline.  And if you compare the two arms, it is clear that we have a shift in the distribution from the control group to the X STOP group.  And the shift is in the right direction.  You're supposed to be going to the right if you want to show improvement. 

             The meaningfulness of the 0.5 as a measure of success is not at all clear to me.  It's clear that there are more subjects who were to the right of 0.5 in the X STOP group than there were to the right of 0.5 in the control group, and that is a good thing.  It wasn't clear to me that if you used a higher cutpoint that this difference might change.  So if we're looking at a comparison of 45 percent versus four or five percent, maybe that's due to the fact that this cutpoint was too low, that 0.5 is not a clinically important difference.  And if you're really looking for something important, maybe you should be having a cutpoint that's higher.  I went through essentially redoing the analysis using all values up to the value of 2, and found no difference.  No matter where you put the cutpoint, the shift in the X STOP group was clearly better than the shift in the control group.  Looking at the actual values at baseline for the control group and the X STOP group, it turns out that this 0.5 is approximately one standard deviation of the baseline data for the severity score and equivalently for the physical exam score.  Whether or not this is something I think the panel should look at, 0.5 as one standard of deviation as a meaningful clinical difference I think it's important.

             However, and let me just show this.  The next slide is for the baseline physical score, and the comments are exactly the same.  There's no difference.  I think it's important to note that this is a complicated composite endpoint.  The primary endpoint includes three components of the ZCQ.  It includes the use of laminectomy in both groups, and it includes an assessment of whether in the X STOP group there was a maintenance of distraction.  So to me, I sort of started getting confused as to how we deal with the lumping of all this data together as one endpoint.  And as a result, I looked at many, many configurations of this where I only included patients in looking at these baseline physical and severity scores, and looking at that change.  And I overrode the laminectomy if there were scores available for the physical and the severity score ZCQ components.  No matter which way I did it, the results came out the same.  So I'm feeling fairly confident that whatever this endpoint is, if you like it, don't like it, no matter which way you really thrash it, move it around, the results are still the same from the point of view of having a statistically significant result.  But the issue remains as to whether or not the result is clinically important. 

             The analysis aspects.  The missing data issues were covered in the statistical review in the packets that you've received.  The randomized but not treated group was covered.  And I'm sorry -- time to laminectomy.  I've already covered the first part.  I wasn't sure what would be found here.  And I went through several machinations on how to look at this.  This is a Kaplan-Meier curve where we're looking at the time to laminectomy in the two groups.  The red line is the X STOP group, and the other color line, probably green or black, is the control group.  These are all subjects that were actually evaluated.  As would be expected, the time to laminectomy curve for the X STOP group is higher than the curve for the control group, which reading up here.  This says over time.  Reading up here, at the end of the day, after 24 months, fewer patients actually had a laminectomy in the X STOP group as contrasted to the control group.  And that's to be expected.  Everything that we've seen so far would indicate that would be the result. 

             The only data that I had available to me was so to speak disjoint.  I knew the results for laminectomy at six weeks, six months, I've forgotten.  There were four points at which it's presented in the book.  When I looked at only those subjects that had a laminectomy, the six subjects in the X STOP group and the 24 subjects in the control group I found the results surprising.  I would have expected that it might take longer for the subjects on the X STOP group to need a laminectomy than the subjects in the control group. And from this curve, you can see that the curve's essentially superimposed.  The sample sizes are not huge.  I don't know how much we can relate to any p-values here, but clearly the curves are superimposed on each other.  And it raises the question as we deliberate why this is the case.  If this treatment is effective, why are those subjects that are destined to go on to laminectomy essentially going on to laminectomy at the same speed, so to speak.

             Under the results and conclusions part of what's been presented by the sponsor, and also by panel members today, the time of the outcome is 24 months.  It's been noted that there appears to be a lessening of the difference between the control and the X STOP group between the 12 months and 24 months.  And it would seem to me, given that these patients are probably available for contact, it might make some sense for us to consider re-looking at the success rates at, say, 36 months, something along that line, with a possible additional follow-up. 

             And I believe that covers what I wanted to talk about that I hope complemented, rather than was a series of redundant comments.  And I'll stop there.

             DR. YASZEMSKI:  Thanks very much, Dr. Ellenberg.  We're going to move on now to the general panel discussion regarding the presentations we've heard this morning.  I'll remind the panel members that you may call any member of the FDA or of the sponsor to answer a question that you have concerning the presentations.  Any questions.  Dr. Kirkpatrick?

             DR. KIRKPATRICK:  I asked this in my presentation.  Can the sponsor help me in the computations on Table 35, please?

             DR. YERBY:  It was a very good observation, Dr. Kirkpatrick.  And we in fact made that same mistake in our draft of the PMA to the FDA.  What it seems to me is that you're looking at a difference of 0.99, and you've divided by the upper limit of the scale of that domain.  However, the appropriate thing to do is to divide by the range of that domain.  Since each one starts at 1, if you subtract that 1 off you divide by 4.  so 0.99 divided by 4 should be about 24 percent.

             DR. KIRKPATRICK:  Thank you for that clarification.  Can you also clarify how you computed the physical function number on the same table?

             DR. YERBY:  Sure, that's right.  0.76 I think was the change you're referring to, is that correct?

             DR. KIRKPATRICK:  That's correct.

             DR. YERBY:  So 0.76 divided by the range of that scale would be 4 minus 1, which would be 3, which is a little over 25 percent.

             DR. KIRKPATRICK:  So your table reflects 19 percent.  So that's an error?

             DR. YERBY:  In fact it is.  That's the error that I'm referring to.

             DR. KIRKPATRICK:  Okay.  So in essence, for my understanding and for the panel's understanding, I think we can agree that their argument on the range should be the denominator, correct?

             DR. YERBY:  The range, yes.

             DR. KIRKPATRICK:  The range on symptom severity is a 4-point range, because it have five responses.  So the number that they provided of 24.8 is correct as a percent change from baseline.  However, the range on the physical function scale, which gives us a scale from 1 to 4, should be 25.3 percent, as opposed to 19 percent as presented?

             DR. YERBY:  That's correct.

             DR. KIRKPATRICK:  Okay.  Now, would you mind just making sure we've done them right on the control values?  Do you have somebody with a calculator that can verify that 0.17 divided by 4 is 4.3?  In my mind it seems close.  And assuming that that's correct, how about the 0.8 divided by 3.  Is that indeed 2 percent, or should it be higher like your X STOP number should be higher?

             DR. YERBY:  I'm not sure.  I don't have my calculator.  If anybody does. 

             DR. YASZEMSKI:  May I interject.  Maybe what we can do is ask somebody during this session to just punch those numbers, and ask you folks to come back later and answer that question.

             DR. YERBY:  Yes, I think that would be more appropriate.

             DR. YASZEMSKI:  Thank you.

             DR. KIRKPATRICK:  Thank you for that clarification.

             DR. YASZEMSKI:  Any further questions, Dr. Kirkpatrick?

             DR. KIRKPATRICK:  I don't know at this time.

             DR. YASZEMSKI:  Okay.  Dr. Naidu?

             DR. NAIDU:  I have a question for the sponsor in general.  Is this device intended to be inserted by the surgeons, or is it -- is it a recommendation by the sponsor that it should be a board-certified surgeon who is inserting this device, or is it going to be relegated to any pain clinic doctors as well?  Because it seems like it can be done as an outpatient procedure.

             DR. ZUCHERMAN:  I'm Dr. Zucherman.  I'm the inventor and principal investigator.  I also have a interest in St. Francis economically.  The device is designed to be done by either neurosurgeons or spine surgeons.

             DR. NAIDU:  Thank you.

             DR. YASZEMSKI:  Thanks Dr. Naidu.  Additional questions?  Dr. Kim.

             DR. KIM:  I have a simple question about the clinical x-rays.  Were they standing x-rays or were they supine x-rays?

             DR. ZUCHERMAN:  They were all standing x-rays.

             DR. YASZEMSKI:  Thanks.  For the transcriptionist, that was Dr. Zucherman again.  Dr. Kim, any further questions?  Dr. Doyle?  No questions.  Ms. Maher?

             MS. MAHER:  I'd like to hold off.

             DR. YASZEMSKI:  I'm sorry, I didn't hear you.

             MS. MAHER:  I'd like to hold off a little bit.

             DR. YASZEMSKI:  Okay, thank you.  Dr. Diaz?

             DR. DIAZ:  I don't have a question, I just have a clarification.  Since this is a public record, I want to highlight to Dr. Zucherman that neurosurgeons are also spine surgeons.  There is no distinction.

             (Laughter)

             DR. YASZEMSKI:  Thank you, Dr. Diaz.  Dr. Rudicel?  Dr. Finnegan?

             DR. FINNEGAN:  Surprise, surprise, I actually have a couple of questions.  And they're probably for Dr. Zucherman or Dr. White.  The first one is an add-on to the radiographs.  Did you set up standard conditions for everyone as far as distance from the patient so that your measurements were actually fairly real?  We're talking very small measurements, and I'm trying to get a feel for whether these were consistent across the centers.

             DR. ZUCHERMAN:  Well, the definition of how the x-ray's done was just a standing AP and lateral.  So the variations in technique weren't accounted for.

             DR. FINNEGAN:  Okay.  And next question is I notice that you chose the age of 50, but in our present population, and this would appear to be a trend that's going to continue over the next 20 or 30 years, there's a difference between a physiological age of 50 and a chronological age of 50.  And I would suggest that the wonderful patients you had speak this morning definitely are not physiologically the same as their chronological ages.  And how are you going to account for this?  Because it would seem, at least mentally, mental calculation, that a physiological 70 is going to have different response than a physiological 50.

             DR. ZUCHERMAN:  Yes, that's a good question.  The age of -- picking 50 was fairly arbitrary.  We realize that some 50-year-olds are like 40-year-olds, and some, some 70-year-olds are like 90-year-olds.  But we found in the -- the average age of the study was 70.  In the pilot study the average age was 79.  So at the longer end where the patients demand less from the device, we've found that it seemed to work quite well in the older age group and in the --

             DR. FINNEGAN:  But flexibility, or muscle testing, that sort of thing were not done?

             DR. ZUCHERMAN:  Well, they weren't done, but in the study correlates, it showed the younger the patient was, the better result.  It correlated with better result.

             DR. FINNEGAN:  With all due respect to spine surgeons, both back pain and chronic pain have a certain amount of psychological and emotional attachments which have been well documented.  Did you do any kind of testing, MMPI, or anything like that on your patient population?

             DR. ZUCHERMAN:  The only testing that would have any mental component would be the mental part of the SF-36.

             DR. FINNEGAN:  And that was done both pre and post intervention?

             DR. ZUCHERMAN:  Yes.  And there was no change in the mental component for the X STOP and no change in the control group.

             DR. FINNEGAN:  Even in your workers -- you were very brave to include workers comp in here.  Even in the workers comp?

             DR. ZUCHERMAN:  Yes.  Although in this age group there weren't really a lot of workers comp patients.

             DR. FINNEGAN:  And my last question has to do with a bigger concern about expulsion.  Because this is an older age group, balance is a problem.  And we know from the vertebral fractures that it's mostly axial load with a little bit of lateral twist.  Was there any testing done on this?  I couldn't pull out that there had been any testing done on this kind of mechanism for expulsion.

             DR. ZUCHERMAN:  In our biomechanical testing?

             DR. FINNEGAN:  Yes.

             DR. ZUCHERMAN:  No, we only tested simple maneuvers, no complex maneuvers.

             DR. FINNEGAN:  Thank you.

             DR. YASZEMSKI:  Thank you, Dr. Finnegan.  May I ask before we move on to Dr. Ellenberg, we're going to begin the discussion of the specific FDA questions prior to lunch.  Dr. Holden, could I ask you while we're finishing up the general discussion to perhaps get them ready for us on the screen?  Mr. Melkerson's up.  Thanks.  Dr. Ellenberg?

             DR. ELLENBERG:  This is directed to the sponsor.  I wonder if you could describe briefly how the ZCQ was administered for each patient.

             DR. ZUCHERMAN:  Each of the sites had one of the clerical people assigned to the study who was the local coordinator, and that individual would hand the questionnaire to the patient.

             DR. ELLENBERG:  Was that person in the room when the patient was completing the questionnaire?  Were they available for questions?

             DR. ZUCHERMAN:  Well, they were available for questions.  They would only stay in the room -- in some cases, some of these patients are quite old and had troubles with it, or had a family member in there with them helping.  So in those patients that had mental issues with the questionnaire, the coordinators would help them out to try and explain things to them.

             DR. ELLENBERG:  And were the coordinators trained on the issue of so to speak unbiased help?

             DR. ZUCHERMAN:  The coordinators were trained.

             DR. ELLENBERG:  On the issue of --

             DR. ZUCHERMAN:  Training sessions were set up, and -- I don't know that the particular matter was set out to them, because I wasn't at that particular training sessions.  But it was clear to them that this is a study, and it's supposed to be unbiased.

             DR. ELLENBERG:  Maybe this is you also.  Can you describe the informed consent process, and who was involved with that, and how the question and answer session went with the potential subject?

             DR. ZUCHERMAN:  Well, in general, after the surgeon would have discussions with the patient about whether they were interested in this study.  The investigator would usually give the patient the questionnaire, give the patient some time to look at it. 

             DR. ELLENBERG:  The questionnaire?

             DR. ZUCHERMAN:  I'm sorry, the --

             DR. ELLENBERG:  Informed consent.

             DR. ZUCHERMAN:  The informed consent, give the patient some time to look at it, come back in and ask if there's any questions, and then sign the form with the patient. 

             DR. ELLENBERG:  So there would be a preliminary discussion with the surgeon and the potential subject.  And in general, how would that go?  That was presumably not scripted.  Again, were these surgeons trained in presenting the options to the patient in a manner that would not influence either their decision to join the study, or perhaps more importantly for the study itself not to influence their expectations as to what would happen if they went onto the X STOP arm?

             DR. ZUCHERMAN:  I think it was clear to the surgeons who went through IRB process and so forth, and almost all -- virtually all the surgeons had been involved in other studies of the responsibilities of the surgeons to explain to the patient the possible outcomes of entering the study.

             DR. ELLENBERG:  Okay.  And the final question is is it feasible at this late date to track the patients who completed the study?

             DR. ZUCHERMAN:  It would certainly be possible for many of the patients.  You know, it just depends on patients having left the areas, or patients being old.  In our pilot study patients, many of them are now in their mid-80s, and we have tried to contact them and sometimes it's difficult to get them to cooperate.

             DR. ELLENBERG:  I'm sorry, I didn't hear the last.

             DR. ZUCHERMAN:  Sometimes difficult to get them to cooperate. 

             MS. LYSAKOWSKI:  I'd like to -- My name's Yvonne Lysakowski.  I'd like to add to that, if I may.

             DR. ELLENBERG:  Sure.

             MS. LYSAKOWSKI:  Yes, well at this point in time the study is closed, so in answer to your question is it possible to contact them, yes it is.  But of course we'd have to go through the process of IRB approval, et cetera, which in fact we are very interested in doing, and plan to do in the future.  We're very interested in knowing what the longer term outcomes of these patients are. 

             DR. ELLENBERG:  And most of these patients were in care at the particular clinics, or did they get sent to the clinics as sort of a tertiary last resort?

             MS. LYSAKOWSKI:  Well, that would be a mixed bag.  And in answer to your question, again, it may not be possible to contact every single patient, but certainly that would be the effort put forth.

             DR. ELLENBERG:  Thank you.

             DR. YASZEMSKI:  Thanks Dr. Ellenberg.  Dr. Li?

             DR. LI:  Yes, I have a few questions that relate more to the mechanical testing of the device, and a couple of just general questions on function.  I'm not sure who wants to take the questions. 

             One general question is there doesn't appear to be much that actually holds this device in place.  It kind of just floats in that position.  So have you made any attempts to examine the amount of motion that that device actually goes through, especially in the AP direction?  In other words, as the patient flexes and extends, does this device actually move at all in any direction, or do you see any signs from immediately post-op and at 24 months that the device is actually where it was in the beginning?

             DR. YERBY:  I can address that from a more biomechanical standpoint than a clinical standpoint.  From a biomechanical standpoint, yes we did monitor the motion during flexion-extension experiments.  And we did this both on a gross basis as well as a radiographic basis.  And in no cases did we notice migration unless the implant was placed posterior to what we call the apices, which is a very posterior position.  In the normal position as dictated by the surgical technique, we notice no motion.  From a clinical standpoint, stepping out of my bound just slightly, what does happen is within six weeks, and this has been identified on retrievals, the implant is almost always encapsulated in fibrous tissue which indicates that it's pretty securely in place.

             DR. LI:  Okay, thank you. 

             DR. YASZEMSKI:  Please give, again, the transcriptionist your name.

             DR. YERBY:  Oh, sorry.  Scott Yerby.

             DR. YASZEMSKI:  Thanks, Dr. Yerby.

             DR. LI:  As far as detail about your cadaver testing.  I didn't notice that once you've fixed your cadaver specimen, did you cycle the implant a few times to get to some kind of equilibrium position?  Or did you just mount the samples and go right at it and start making measurements?

             DR. YERBY:  Sure, that's another good question.  Typically in experimental testing what we do is we do cyclically load it, but this type of loading is typically for creep purposes, to dehydrate the -- usually when you test a specimen, the specimen is superhydrated in the discs.  And what we do is we typically creep load it for anywhere from 15 minutes to an hour to bring the hydration of the discs back to a normal level.  And in that case, yes, we did cyclically load it to a point where we were satisfied that the test was ready to begin.

             DR. LI:  Okay.  And a follow-up question to that.  Did you do any testing -- you did tons of testing, by the way, which I congratulate you for.  Did you do any more or less kind of not really fatigue testing, but essentially the effect of cyclic loading on the measurements that you make?  In other words, after the equilibration you just discussed, you went ahead and for instance measured flexion-extension.  Did you do any experiments where you perhaps cycled the whole structure for several thousand cycles, and then measure again to see if there's any change in flexion-extension?  That would be a more direct measure if there was any motion, or any kind of change in orientation of the device.

             DR. YERBY:  That's another good question.  We didn't do any cycles, let's say beyond five cycles within a cadaver model for various reasons.  One is that it's typically not indicative of, for instance, the response that could occur between the implant and the bone in a cadaver model.  All of our cyclic loading was done just on a purely mechanical standpoint. So the migration that you're referring to wasn't addressed in any of the biomechanical studies.

             DR. LI:  Okay.  Obviously what I'm fishing for is perhaps some mechanical or biomechanical explanation of some of the clinical results that you've got that perhaps indicate that the 24-month result isn't quite as good as the 12.  So I'm kind of struggling to see if you had any laboratory or clinical data that would've suggested that would be a possible outcome.

             DR. YERBY:  No.  The only analogies that we can get from our biomechanical testing would be that -- several factors.  And these are all clinical factors as opposed to biomechanical.  But on the biomechanical standpoint, the MRI testing that we did show, possibly the amount of impingement that was occurring pre-implantation wasn't relieved enough following surgery with the X STOP procedure.  That's the only analogy that I can say, and I'm not -- it's not my expertise to say from a clinical standpoint whether or not that was the case.

             DR. LI:  In kind of a related question, and I don't know if one of the physicians wants to jump in on this question also.  It seems like the performance of this device is strongly related to the sizing of the device.  Like in other words, what size spacer do you put in this location.  But there seems to be some discussion over how much flexion, for instance, you put the patient into while you're doing the insertion.  So is there a standard method for how much the patient is flexed?  And you know, or for that matter, if the surgeon just has a penchant for wanting to make it tighter than another physician.  In other words, just exactly what variation are we seeing.  Given the same patient, for instance, can one surgeon pick a 4-millimeter insert and another surgeon pick a 6-millimeter insert, and they both felt they've done the right thing, but you would probably end up with different amounts of flexion-extension reduction.  So how do you account for all that?

             DR. YERBY:  Again, from the clinical standpoint that's a little bit outside my expertise, but what we did find, and I'll let Dr. Hartjen refer to this, is that from the clinical standpoint in terms of inserting the implant, there was an endpoint.  It was based on the tension on the superspinous ligament palpated during surgery.  And I'll let him address that.

             DR. HARTJEN:  Charles Hartjen.  The patient was basically placed in a right lateral decubitus position and asked to flex as much as they could.  That includes flexion of the hips and knees, sort of getting into a fetal position.  After the patient was in a comfortable position that they could withstand for 45 minutes to an hour, they were administered local anesthesia and IV sedation.  And then the initial dilator starter was introduced between the ligamentum flavum and the most anterior portions of the interspinous ligament.  And then there was a secondary dilator, and this was followed by a device, a distracting device.  And the selection was based on just empirically the elastic limits at the level.  We had a device with a gauge, and basically the surgeon would distract manually, and when he felt he was reaching elastic limits of the tissue, would wait for a few seconds for physiologic creep, and then just give a maximum distraction manually that he felt was safe.  And then we had a specific measurement for that height.  We selected the implants based on that.

             DR. LI:  Do you have a correlation or some association of that feel to actual clinical benefit?  In other words, should the patient be stretched as far as they could go, or do you need to go a little further than that, or should you back off?  In other words, I get your endpoint now, but how do you know that endpoint was the clinically appropriate endpoint?

             DR. HARTJEN:  Maybe Yvonne could have some numbers for that, but that was empirically how it was done for all of my patients. 

             DR. LI:  So in other words, so is it possible for one patient, you'd get to that endpoint and it's sufficient distraction, but to another patient it might be perhaps even too much or too little?

             DR. HARTJEN:  It's quite possible.  It's possible that it's too little, more likely than too much.  Most of the patients that had a small implant had fairly advanced degenerative disease, and had probably with the patients that were more in the moderate to moderately severe stenotic range.

            DR. LI:  Is there a way to break down the data for the success or failures, or perhaps even from the different centers where there were wildly different success rates, if there was a size issue in that case then?

             DR. ZUCHERMAN:  Dr. Zucherman.  From the onset of the inception of the device, we were thinking in terms of matching the sitting position, because that's the position in which the patients weren't uncomfortable in.  So by starting the procedure with the patient flexed at least as much as in a sitting position, we were all presuming that matching at or exceeding it will get us where we want to get.  And the endpoint of elastic limit that Dr. Hartjen was mentioning is pretty obvious when you do the procedure.  There's distraction, and then distraction stops, and you don't get much distraction with greater force.  And so that's been the instructions to all the investigators, do it like that.  We haven't noted that there's any size-related instance of better results.  The older people tend to take smaller sizes because their segments are stiffer.  By the fact that the patient has relief with sitting, all we have to do is match what happens with sitting.

             DR. LI:  And perhaps one last detailed question, not to beat the dead horse here.  But if you gave five surgeons the chance to tension the same patient to where they thought the endpoint was, do you have any idea what the variation in that tension would be?  Because my own experience with other orthopedic surgeons is, you know, that range could be huge and they all think they did it exactly right. 

             DR. ZUCHERMAN:  Since all the investigators were trained either by myself, or my partner, or one of the people that we trained, I can tell you that it would be within one size difference.  Because a lot of times it's borderline whether you'd go up or down to the size on the measuring device.  But I don't think the -- deciding what to do with the size gets easily conveyed to the surgeon in the training.

             DR. LI:  Then perhaps one last question then.  Basically, all this was I was fishing around for why one center seems to be so much better than the rest.  And I was kind of hoping that there was something either by process, or by design, that would actually explain that.  So do you have an explanation of why one center seems to be so much better than the other?  Or vice versa, why one center seems to be so much worse than the others?

             DR. ZUCHERMAN:  I think the best explanation was shown in the presentation.  But if you look at the variables that correlated with good results at the center that had the best results, about six or seven of the variables that correlate with good results were statistically at that center.  So they had a better selection of patients in the group.  And of course, what that selection is we didn't know until the study data came out.  And basically it was younger patients, it was patients who were employed, it was patients who started out with worse scores.  And the worse results started out with older patients, about eight years difference between the center with the best results and patients that had better scores to start out.  So it's harder for them to make the leap into success because starting out with scores that are lower.  I think that along with the fact that the center with the best results were the original inventors of the device, so they'd have more experience with it, and more experience with selection, accounts for the differences.

             DR. LI:  Well, given that list of possible explanations, then would you -- knowing what you know now, would you change the indications for use for the device?

             DR. ZUCHERMAN:  No, because it's -- even if you take the best center out and look at all the rest of the data with the best center out of it, it still is a very effective device.  So the effectiveness may drop down somewhat in certain situations, just like any surgery does, but it still is effective for this problem across the board, I believe.

             DR. LI:  Thank you.

             DR. YASZEMSKI:  Thanks, Dr. Zucherman.  We're going to move on to the questions.  I might, before we go, Dr. Yerby, has anybody from St. Francis got the number to answer Dr. Kirkpatrick's question yet?  If not, I'll ask you then to do that as part of the sponsor summary later.  Yes, Dr. Kirkpatrick.

             DR. KIRKPATRICK:  If you don't mind, I did request the opportunity to think about another question.

             DR. YASZEMSKI:  Please go ahead.

             DR. KIRKPATRICK:  Okay.  And to answer your question on the number, my brief hand calculation indicates that it should be 2.6 percent instead of 2 percent.  If you would double-check me, I'd appreciate it. 

             Now, I mentioned a couple of things in my presentation that I would like to know earlier rather than later.  One is did you stratify your results based upon unilateral leg pain versus bilateral leg pain?

             DR. ZUCHERMAN:  Dr. Zucherman.  No, we did not.

             DR. KIRKPATRICK:  Thank you.  Did you stratify your results based upon any kind of determination whether the predominant stenosis was foraminal, subarticular, or central?

             DR. ZUCHERMAN:  We did not.  When we looked at the MRI findings, over 90 percent of the patients had both lateral and central stenosis.

             DR. KIRKPATRICK:  Thank you.

             DR. YASZEMSKI:  Thanks Dr. Kirkpatrick.  Ms. Maher?

             MS. MAHER:  I was actually hoping someone else would ask this, but I was wondering if the sponsor could explain to me what a 0.5 improvement actually means to the patient's quality of life.  I mean, I've heard people say it's minimally significant.  I've heard people say it's clinically significant.  If somebody could give me an explanation, I'd appreciate it.  I would understand if it's intangible, if it means that somebody who hasn't been able to go grocery shopping all of a sudden can.  I just need to sort of get a baseline for what it overall might be.

             DR. YASZEMSKI:  Thanks.  Dr. Hartjen?

             DR. HARTJEN:  I'm far from the expert.

             DR. YASZEMSKI:  Dr. Hartjen, let me ask you again, pull the microphone a little closer so we can.  Thanks.

             DR. HARTJEN:  I'm sorry.  I don't think that I can get into great details on all of the numbers, but if you look at some of the entry points as in walking, one change in entry is from walking two blocks to two miles.  So I don't think that the sensitivity of each individual entry is that important as the patient's overall clinical improvement.  And I think the satisfaction rates reflect that more than a single entry point.

             MS. MAHER:  Thank you.

             DR. YASZEMSKI:  Thanks.  Other questions?  Okay, let's move on to the FDA's questions.  The first question, Mr. Melkerson or Dr. Holden, are you going to summarize the questions, either of you?  Then we'll start with one of the panel members and go around and ask for commentary on those questions.

             DR. HOLDEN:  We don't have so much a summary.  They're summarized on these slides.  The entire question is on the printed form, which probably should be read into the record.

             DR. YASZEMSKI:  Okay.  I'll go ahead and do the reading.  Or you can read.  Do you want to read it?

             DR. HOLDEN:  Doesn't matter.

             DR. YASZEMSKI:  Go ahead.

             DR. HOLDEN:  Okay.  Question Number 1.  Patients who had the X STOP implanted had a higher incidence of musculoskeletal events, including lower back disorders, lower extremity disorders, hip disorders, upper back disorders, and neurological and neuropathological disorders compared to the control group.  Although these adverse events were considered by the sponsor to be not device-related, changes in spinal biomechanical function that occur with the limits to extension could also be a potential source of pain.  The sponsor provides a report of a pre-clinical study which characterizes the effects of the device in cadaveric specimens showing an increase in canal and foraminal dimensions at the implanted level in the extended position with no change in the dimensions at the adjacent levels.  Please discuss the clinical significance of the musculoskeletal and other adverse events seen in the trial, and discuss whether the effects of the device on surrounding segments or on spinal biomechanics have been adequately addressed.

             DR. YASZEMSKI:  Thanks Dr. Holden.  Dr. Finnegan, let's start with you and go around the table toward Dr. Rudicel.

             DR. FINNEGAN:  Well, actually I have significant concerns in this area.  I do agree with the sponsors that not all of the musculoskeletal things that have been listed, including some of the neurologic, could possibly be related to this device.  But I think there are others that need to be explained.  Certainly over the last 20 years, which has shown a significant increase in the number of spinal instrumentations and implants that are available, ignoring the biology of altered spinal mechanics is an unwise thing for anyone to do.  And there have been a number of problems with people who have ignored the altered biomechanics. 

             One of my concerns is that there was no animal model done to look at the biology of these altered mechanics.  And while it is true that the only upright is a primate, and those are expensive and difficult to deal with, there's been a number of spinal instrumentation work done in goats and sheep, and goats appear to be a pretty good model.  So I have some concerns that there was no attempt, or there was no obvious attempt in the materials we were given to do some sort of animal model to look at the long-term biological response to this implant.

             I'm also somewhat concerned that the results ended fairly abruptly at 24 months.  I'm not exactly sure why they weren't followed out, because you obviously have patients who could be followed out.  Regardless of how you look at statistics, and I'm not a statistician, and I know you can make statistics do whatever you want them to do, there does appear to be regardless of who is looking at the statistics a decline at the 24-month period.  And this would make one concerned that perhaps the implant in its present form has a limited usefulness, and it may be time-related.  I do think that upper back pain and some of the other neurological or musculoskeletal complaints are potentially related to the implant and to altered biomechanics, and do need to be explained. 

             The other concern is that the control group really wasn't a control group.  It's people who have failed, basically, their treatment, and continue to fail the treatment.  And as a consequence, they're almost the natural history of the disease.  And the question is whether the altered biomechanics are just a different, and I'm not sure I'm explaining this properly, but it's just sort of a different natural history of the disease.

             So my response would be that I think that there are effects that have not been demonstrated or discussed, or the reasons for the problem has been outlined and I think there are several means of obtaining this information. 

             DR. YASZEMSKI:  Thanks Dr. Finnegan.  Dr. Rudicel?

             DR. RUDICEL:  The only comment I have in conjunction with the musculoskeletal complaints is I didn't quite understand how the low back pain incidence was felt to be non-device related.  If anybody could expand upon that.

             DR. YASZEMSKI:  Would you like somebody from the sponsor to comment on that, Dr. Rudicel?

             DR. RUDICEL:  I would.

             DR. YASZEMSKI:  Thank you.

             DR. ZUCHERMAN:  Dr. Zucherman.  We were asked specifically to look at those neurological and spine, musculoskeletal cases that were reported as adverse events.  This didn't include the hip.  And the charts were reviewed in detail in that group of patients, and 63 percent of them, the musculoskeletal complaints were -- this is including back and lower extremities -- were due to comorbidities that preexisted.

             DR. RUDICEL:  But specifically the back pain.

             DR. ZUCHERMAN:  Well, obviously some of the back pain patients, the patients that failed the X STOP treatment are going to be included in that group.  So the failures are included because they're failures, also reported as an adverse event.  So some of the back complaints are also counted as failures in the study.  And obviously, the study data as it comes out, if the patient has some adverse phenomena that's affecting their back, it comes out as a failure in the study data.  And the study data nevertheless, despite the increased adverse events in musculoskeletal system, came out so strongly in favor of the X STOP group.

             DR. RUDICEL:  Might some of the patients who were considered a success have also had back pain?  I mean, it seemed like there was a high number -- I guess it wasn't broken down in your musculoskeletal complaints, but I was assuming that the back pain may have been a significant number.  Were some of the patients who were successful also complaining of back pain?  Did that --

             DR. ZUCHERMAN:  Were successful?  No.

             DR. RUDICEL:  Were those mutually exclusive?

             DR. ZUCHERMAN:  No.  I would say no, that's not the case.  If they had much back pain, they would fail on the questionnaires.

             DR. YASZEMSKI:  Dr. Doyle, do you have a comment on this?

             DR. DOYLE:  This is a question that's related to it.  Am I understanding you to say that then the group that had X STOP had a higher incidence in musculoskeletal and neurologic problems going in?  That there wasn't a real increase, that it was just the distribution?

             DR. ZUCHERMAN:  They actually did have a higher incidence going in.  But there were several factors that resulted in, we believe, more musculoskeletal events in this patient population.  In addition to the fact that more of them, quite a few more, I think it was 34 versus 20 percent had musculoskeletal comorbid conditions going in.  In addition though, if you look at the patients with the stenosis, like the two that we heard earlier today, during the time they had their stenosis they're basically inactive.  They can't do anything.  And any comorbid issues they have with joints and so forth or tendencies toward tendonitis are going to be latent because the individual is fixated on the main problems preventing them from walking which is their spinal stenosis.  So when the X STOP group, when that effect is removed, and all of a sudden after not doing anything for quite awhile patients become active, they now activate these problems in their joints, which are very common in this age group of patients. 

             And in addition, the patients that were in the X STOP group were probably followed more closely by their surgeons than the patients in the control group.  The injections were often done at other centers, and in a lot of cases, the non-surgical treatment was also participated in by other doctors, either medical doctors or a physiatrist and so forth.  So it's probably a combination of closer scrutiny on the people that had the X STOP, the unmasking effect of them being inactive then allowing themselves activity, and overdoing it essentially, and the higher incidence of comorbid events -- comorbid issues in these patients that had the X STOP, which was coincident.

             DR. YASZEMSKI:  Thanks.  Ms. Lysakowski, do you have additional data to answer Dr. Doyle?

             MS. LYSAKOWSKI:  Yes, thank you.  Actually, what I was providing to Dr. Zucherman was a listing of some of the lower back adverse events that were asked about so that he might comment on that specifically.

             DR. ZUCHERMAN:  Yes.  So this is the -- looking at the low back unspecified events, there's 21 events in 16 patients.  Eight of them were pain.  And eight of them were unspecified.  There was three were due to arthritis.  And every other case is an isolated event.  Bursitis, sacro-iliac joint, disc herniation, disc degeneration, popping sensation in lower back, sciatica, back and buttock pain, stenosis pain.  These are all the sort of thing that you'd see in this elderly population. 

             The largest group among the musculoskeletal group was the hip.  And there was actually five cases of severe hip degenerative disease that required surgery.  And that's obviously not related to the device.  There was also a group of musculoskeletal events in the upper extremity, Depuytren's contracture, superspinous ligament pain, which is shoulder bursitis.  One case of avascular necrosis.  One case reported as slipped capital femoral epiphysis, which is interesting in this age group.  And there was also a group of upper back and upper extremity symptoms, all of which are just the general thing that you'd see in the patients average age of 70 in your office.

             DR. YASZEMSKI:  May I ask Dr. Rudicel, has this answered your question?

             DR. RUDICEL:  Yes, it was just actually the back pain that I was interested in in terms of trying to decide whether there was any relationship of the device, or if it was a progression of their disease.  And that was more what I was trying to get at.

             DR. ZUCHERMAN:  Certainly all the failed cases are going to be included in the back.  It's going to come out in the data.

             DR. ZUCHERMAN:  Dr. Andersson?

             DR. ANDERSSON:  It's actually very rare that you eliminate all back pain with any type of spinal surgery.  If you look at the reported results of disc herniations, more than 50 percent have back pain.  If you look at operations for spinal stenosis, more than 60 to 70 percent have back pain.  And it probably has to do with the fact that there are so many other reasons for back pain which are not eliminated by the surgical procedure.

             DR. YASZEMSKI:  Thanks Dr. Andersson.  Dr. Rudicel, additional questions?  Ms. Lysakowski?

             MS. LYSAKOWSKI:  Yes, thank you.  I just wanted to clarify one point or question that was asked earlier, and that was that there didn't seem to be a breakdown by the categories of adverse events.  And there actually is a table provided in the PMA, and we do have that data, but it does break it down by the number of adverse events that are in the back, hip, lower extremity, et cetera.  So we do have that data.

             DR. KIRKPATRICK:  What table number?

             MS. LYSAKOWSKI:  Excuse me?

             DR. KIRKPATRICK:  What table number, please?

             MS. LYSAKOWSKI:  In the PMA clinical report I believe it's Table 50.  If someone could verify that for me?  Yes, it's Table 50.  It's Page 170 of your first binder. 

             DR. YASZEMSKI:  Dr. Kirkpatrick, do you have a comment on that now?

             DR. KIRKPATRICK:  If I could follow up.  Do you have the same breakdown in the pre-study group?  In other words, the selected patients pre-intervention?

             MS. LYSAKOWSKI:  Yes, we do.  It's a table of comorbidities.  And if you give me a moment, I could let you know what the table number is.

             DR. YASZEMSKI:  How about if we do this.  How about if we give you a moment to get that ready, and Dr. Kirkpatrick a moment to think about, and when we come around to him on the table I'll ask him to ask that question to you.

             MS. LYSAKOWSKI:  Okay, great.  Thank you.

             DR. YASZEMSKI:  Thanks.  Dr. Diaz?

             DR. DIAZ:  I don't have a lot to add to what Dr. Finnegan said.  I think she was very eloquent in the way she described the process.  I just have a couple of comments.  One that really disturbed me just now, something Dr. Zucherman just said was that the follow-up of the control patients was not as good as the follow-up that was of the study subjects.  And that to me just basically puts in question the entire study.  There should have been no difference in follow-up on either side of the equation. 

             Also, what Dr. Andersson said I think is critical.  Patients with spinal stenosis who have back pain are patients who will continue to have back pain.  Any type of inclusion of back pain as part of the spinal stenosis assessment, in my mind, does not really add up to anything.  Because back pain is not one of the primary components of spinal stenosis.  Spinal stenosis is a neurological manifestation syndrome. 

             DR. YASZEMSKI:  Thanks Dr. Diaz.  Ms. Maher?

             MS. MAHER:  Nothing at this time.

             DR. YASZEMSKI:  Thanks.  Dr. Doyle?

             DR. DOYLE:  I guess I'm still confused about this comorbidity.  Then the X STOP had a preexisting comorbidity that's significantly higher, 43 percent as opposed to 17 percent?  I realize that that's adverse events unrelated to treatment, but you're telling me there's that vast difference in the baseline? I'm still not sure I understand.

             DR. YASZEMSKI:  Does somebody from the sponsor care to address that?  Dr. Zucherman?

             DR. ZUCHERMAN:  In the additional presentation, the entry pre-comorbid data showed that there was some increase in the X STOP group.  I think it was a 14 percent increase, 20 compared to 34.  And then after the -- during the course of the study, the X STOP patients had higher musculoskeletal events that was significantly higher than the control group.

             DR. DOYLE:  What you're telling me --

             DR. ZUCHERMAN:  So what I'm saying is that they started out a little bit higher but there certainly were more musculoskeletal events in the treatment group.

             DR. DOYLE:  And which you say is because of the unmasking, that they're able to do more physical things, so this is why it becomes?

             DR. ZUCHERMAN:  Yes, and I listed the reasons as being the unmasking effect, and that these problems are ordinarily seen at a high incidence in people of this average age group.  And that I think that there was probably -- although the patients were seen in the same time periods and so forth, and received the same treatment in the two groups, there was probably greater scrutiny in the people that had the X STOP for the reason that they had the procedure done.  And number two is because they felt better, they came in and they're going to complain about what's bothering them now.  If their main problem is that their back is acting up all the time, they're not going to come in and complain about their ankle which hurts as they walk six blocks.

             DR. DOYLE:  But they didn't have that back pain before.

             DR. ZUCHERMAN:  The --

             DR. DOYLE:  The X STOP patients.

             DR. ZUCHERMAN:  Well, no.  Well, having a lot of back pain without the leg pain, that wouldn't be attributable to the stenosis in the investigator's mind, would not have included in this study.

             DR. DOYLE:  I guess I'm thinking as the potential patient.  Am I going to trade my lower leg pain for upper back pain?

             DR. ZUCHERMAN:  No.  But if you look at the breakdown of the pains, most of the pains are in the lower extremity and hips.  And there is some pain in the back, and we think it's consistent with what you see in this age population.  So it's a combination of all the musculoskeletal events that was more frequent.

             DR. DOYLE:  I guess that seeing the difference in the adverse events of 17 percent in one group and 43 percent in another group to me is a very big difference, and would concern me as a patient, that I'd be better off in the control group as far as musculoskeletal events went then.

             DR. ZUCHERMAN:  Well, yes, you'd be better off sitting at home watching TV all the time.  You'd have less musculoskeletal events.

             DR. YASZEMSKI:  Ms. Maher?

             MS. MAHER:  I think I'd like to clarify a little bit, or ask the sponsor to clarify.  I mean, we have seen, and they've brought out, the difference in the musculoskeletal adverse events.  But in fact, did you continue to track adverse events in patients in the control group who were discontinued or become failures because of laminectomies?  And/or did the patients in the treatment group do further activities, and were they followed further?

             DR. YASZEMSKI:  Ms. Lysakowski.

             MS. LYSAKOWSKI:  Thank you.  In answer to your question with regard to tracking the control patients, for those patients who had reached what we referred to as the defined failure endpoint, or in this case a laminectomy, that was considered the end of their study participation.  So no, we did not follow them.  So that meant that there were far fewer patients in the control group by the time we reached the 24-month end period.

             DR. YASZEMSKI:  Thank you.  Dr. Doyle, has that adequately answered your questions?  Thank you.  Dr. Kim.

             DR. KIM:  I'm wondering if we can get at this question another way.  The unmasking event is a reasonable explanation.  If that's the case, I wonder if you were to look at the control patients that did well and compare them to the X STOP patients that did well, they should both be more active and therefore unmask those symptoms.  Is it possible to do an analysis like that to get at this question?

             DR. ZUCHERMAN:  In this case I don't think it would be because there was only four patients that were successful in the control group.

             DR. YASZEMSKI:  Thank you Dr. Zucherman.  Dr. Kim, additional questions?

             DR. KIM:  No.

             DR. YASZEMSKI:  Dr. Naidu.

             DR. NAIDU:  I am concerned about this increased back pain in the X STOP group.  And I'm not sure that I can dismiss that.  I mean, Dr. Diaz has said that it can be dismissed, and Dr. Andersson has addressed also that it could be dismissed in this kind of population.  But nevertheless, the X STOP in all the studies, pre-clinical studies showed that the bony diameter is actually increased in the cadaver specimens.  Now, there's also a significant component from the ligamentum flavum effect from what I understand.  It is also part of the claudication process.  If it buckles, and if it has been buckled for a long time, and you tend to stretch that tissue, did you ever consider soft tissue effects with this distraction at that segment leading to back pain?

             DR. YASZEMSKI:  Dr. Zucherman.

             DR. ZUCHERMAN:  The -- In the entire study, I only know of one patient that seemed to have back pain that was a problem in relation to the device.  In our own series, which involves about 50 patients, including the continued access, there's no patient that has significant back pain.  There's obviously some soreness initially after the procedure from the wound and so forth.  So as far as pain at the level of the device, it isn't a problem.  And only, as I said, one device was removed because it was painful out of the six cases in which the device was removed.  So as far as the device causing problems, it's not an issue.  And we actually didn't expect that in the beginning.  We expected some people might have some pain from having this device in there, but it seems to be a silent area.

             DR. NAIDU:  Okay, thank you.

             DR. YASZEMSKI:  Thanks Dr. Naidu.  Dr. Kirkpatrick?

             DR. KIRKPATRICK:  May I clarify with the sponsor that Table 19 would be the pre-intervention comorbidities?

             MS. LYSAKOWSKI:  This is Yvonne Lysakowski.  Yes, it's Table 19.

             DR. KIRKPATRICK:  So then am I correct in interpreting that back pain in the upper, lower, and unspecified categories, for the X STOP was 14 percent before the intervention?

             MS. LYSAKOWSKI:  That sounds about right, but forgive me, I did not bring that table to the podium with me.  If you'll allow me a moment, I'll check that.

             DR. KIRKPATRICK:  Okay.  And if I could confirm, that would be the physician's reporting of back pain on a data collection form, not the patient's complaint.  So there's no qualitative measure of that back pain.

             MS. LYSAKOWSKI:  That would be correct.

             DR. KIRKPATRICK:  Okay.  Then, as I interpret Table 50, we have a 23 percent incidence after the intervention.  And I assume Table 50 is at two years?  Twenty-four months?

             MS. LYSAKOWSKI:  No, that's the total number of events throughout the course of the study.

             DR. KIRKPATRICK:  So included in that 23 percent could have been somebody that had back pain at six months, but not at 12 and 24?

             MS. LYSAKOWSKI:  That's a possibility.  Or it could include that same patient with perhaps a repeated episode, for example.

             DR. KIRKPATRICK:  Okay.  Thank you.  In light of that, to answer the FDA's question, I think with the higher comorbidity of the study group coming in, and with the fact that we're not seeing a very large increase in the number of patients that are having back pain, the only question I would have with relation to that is did the quantity of back pain increase in patients that had back pain when they went into the study.  Did it get worse after the X STOP.  If it did, I think it'll be a small number of patients that had that, and as such, I don't find it a significant concern that the long-term results had a different comorbidity for back pain in the study group. 

             DR. YASZEMSKI:  Thanks Dr. Kirkpatrick.  Dr. Li?

             DR. LI:  I have one more testing question, if I may.  If I understand it, the very first version of this device had a problem with the screws backing out that you subsequently welded so that wouldn't happen again?

             DR. YERBY:  That's correct.

             DR. LI:  That's correct?  Did you -- When you redesigned the device to have the welded portion, and tested that device, was the test carried out in such a way that if you put the original unwelded device that in fact the screw would have backed out?  In other words, what I'm trying to get is trying to get a feel for the robustness of your testing.  In other words, could the testing -- did the testing that you conduct actually duplicate the clinical failure of that screw backing out?

             DR. YERBY:  Yes, it did.

             DR. LI:  It did, okay.  Thank you.

             DR. YASZEMSKI:  Thanks Dr. Yerby.

             DR. LI:  So in answer to your question, I guess I'll defer to the clinicians as far as the clinical consequences of this.  I think in general, from where I sit, the answer is you can't tell.  Pain is such a -- it's just kind of an amorphous entity, and sometimes the pain is not exactly where the problem starts from.  So I think with those missing parts, I'm not exactly sure how you tell exactly.  For instance, you know, Dr. Zucherman, that the device has no effect on the post-operative pain that results.  You can say clearly that the pain doesn't seem to be at where the device is, but I'm not quite sure you could absolve it of all responsibility of pain anywhere else.  And I don't know how anybody tells that.  So as far as the biomechanical testing was adequate, I think pre-clinically the testing was adequate.  I think the question now is given that these other questions arise, and I keep harping on this fact that there's such a wide range of success rates between the institutions, I think there's a big missing question of just exactly how is this device performing.  And given that, I think there are a series of tests one could now additionally perform.  But certainly I think the tests up until the clinical results, I feel, was adequate. 

             And just to kind of throw my two cents in, with all due respect to Dr. Kirkpatrick and everybody else that measures the effect of motions away from a level where you do surgery.  It seems to me it's a simple matter of energy in, that when you put energy into a spine by flexing or extending, you put energy into that system.  And if you lock one or more levels from motion, that energy has got to go somewhere.  So you may not be able to measure it, but it seems that energy has go to go somewhere.  So either it's dissipated through everything else, in which case the energy changes for any different levels are minute, or it's happening in such a way that it kind of escapes our attention.  And I guess some evidences of where it might be an escape or detection phenomena is for instance that the younger patients seem to do better than the older patients.  The fact that two-level procedures seem to be a little bit more effective than one-level procedures.  So there seems to be some kind of effect that is beyond exactly just the simple level that you're treating.  So it seems inevitable that you're somehow affecting the levels around it, although it may not be directly biomechanically measured.

             DR. YASZEMSKI:  Thanks Dr. Li.  Dr. Ellenberg?

             DR. ELLENBERG:  No questions on this question.

             DR. YASZEMSKI:  Thank you, panel, for that thorough discussion.  Dr. Witten, as you've seen there's a wide spectrum of answers to this first question that the FDA has asked us.  Dr. Finnegan raised some concerns about considering altered biomechanics, and that there was no animal model to evaluate the biomechanics.  And Dr. Li underscored that by stating that it's really hard to tell at different levels what's going on.  And we've heard from Dr. Diaz that patients with lumbar spinal stenosis are going to have back pain and continue to do so, regardless of the treatment.  Dr. Diaz also brought up the concern that the control patients weren't followed as closely as the study patients.  And I think the summary from the panel will be what Dr. Kirkpatrick said, that he doesn't think that this discrepancy asked of us in Question One is clinically significant. 

             Have we adequately discussed Question Number One from the FDA's perspective?

             DR. WITTEN:  Yes, thank you.

             DR. YASZEMSKI:  Thanks.  I'd like to suggest now that we take lunch.  It's a little after 20 minutes past 12:00.  Perhaps we could try to come back here say at 1:15.  Take almost an hour, then we'll get started up about that time.  Thanks everybody.  See you after lunch.

             (Whereupon, the foregoing matter went off the record at 12:22 p.m. and went back on the record at 1:15 p.m.)

             DR. YASZEMSKI:  We're going to first welcome back everybody to the afternoon session.  We'll continue with the discussion of the seven questions that the FDA has asked of the panel.  And then we'll go on with summaries from both the FDA and the sponsor, and then we'll get on to voting.  We'll also have another open session this afternoon.

             We finished the discussion with Question 1 just before lunch, and we'll move on with Question 2 now.  Dr. Holden?  Thank you.

             DR. HOLDEN:  The full question is as it appears on the screen.  Based on your knowledge of the biomechanics of the spine and the nature of spinal stenosis, please discuss whether there is a clinical basis for pooling the outcomes of the one- and two-level patients.

             DR. YASZEMSKI:  Thanks very much.  We're going to start with Dr. Rudicel this time, then go around clockwise with Dr. Diaz and Ms. Maher.  Dr. Rudicel?

             DR. RUDICEL:  I'm going to be speaking more clinically than biomechanically.  I think certainly if the baseline characteristics of the two groups are similar I would see no problem with that.  So I would just like a refresher on the baseline characteristics.  And I think the second question that I have related to that is how the decision was made to do one or two levels.  I may have missed that earlier on.  But basically, if you can answer those two questions, I don't have any other concerns.

             DR. YASZEMSKI:  Thank you.  Maybe somebody from the sponsor would like to take that?

             DR. RUDICEL:  The baseline characteristics of the two groups.

             DR. YASZEMSKI:  So the summary is a clarification of the baseline characteristics of the one- and two-level groups, and how the decision was made --

             DR. RUDICEL:  Correct.

             DR. YASZEMSKI:  -- clinically to either operate on one level or two levels.

             MS. LYSAKOWSKI:  Okay.  With respect to the question about the baseline data, we did not conduct that analysis.  With regard to the clinical decision about one- versus two-level, I'd like to turn that over to Dr. Hartjen.

             DR. YASZEMSKI:  Thanks Ms. Lysakowski.  Dr. Hartjen?

             DR. HARTJEN:  You wanted me to answer about determining the levels?

             DR. RUDICEL:  Yes.  Not the levels, but whether or not to do one or two levels.  How that determination was made.

             DR. HARTJEN:  It was usually based on the degree of the stenosis, and if the patient had any signs or symptoms that would suggest a level was symptomatic.

             DR. RUDICEL:  So it wasn't MRI correlated, or anything else?

             DR. HARTJEN:  It was a combination.  I mean, if a patient had a moderate to moderately severe stenosis at a 3-4 level, and had a moderately severe stenosis at 4-5, and they had symptoms that suggested possibly some L4 radiculopathy, the 3-4 was done in conjunction with the 4-5 level.

             DR. RUDICEL:  Do we know if the patients who had two-level were more symptomatic?  If there was any difference?

             DR. HARTJEN:  I believe the numbers --

             DR. RUDICEL:  I know she's saying you don't know the baseline characteristics, but I'm just from a clinician's point of view.

             DR. HARTJEN:  I think they're approximately the same.

             DR. RUDICEL:  Okay.

             DR. YASZEMSKI:  Thanks very much Dr. Hartjen.  Dr. Diaz?

             DR. DIAZ:  I intuitively don't have a problem with the pooling of the data.  I think if the selection criteria used for doing this surgery were appropriately derived and selected the patients that had single-level disease with clinical manifestations, and patients with double-level disease with clinical manifestations, the alternate outcome would be the same.  My only concern really relates on the biomechanical aspect to what Dr. Finnegan said earlier.  That if we are fixating a level of the spine at one or two levels, we cannot consider that a meaningless undertaking because it does affect the biomechanical function of the entire spine, and there may be manifestations at other places or other sites that are directly related to the placement of these devices.

             DR. YASZEMSKI:  Thanks Dr. Diaz.  Ms. Maher?

             MS. MAHER:  I don't have anything to ask anybody on this particular question.

             DR. YASZEMSKI:  Thank you.  Dr. Doyle?

             DR. DOYLE:  Do we have any idea if we separated them out if it would make any difference?

             DR. YASZEMSKI:  Would you like someone from the sponsor to address that?

             DR. DOYLE:  Yes.

             DR. YASZEMSKI:  Would someone address please, do you feel that -- Dr. Doyle's question is do you feel that if you separated out the data from one- and two-level, rather than pooling them, would your conclusions or results in your opinion be different or the same.  Dr. White.

             DR. WHITE:  Yes.  My name is Augustus White.  And we do think that it's quite appropriate to pool these.  It would not be different if we separated one- and two-level.  I believe that what this represents is a spectrum of a broad degenerative process.  And it's a matter of levels that are involved in the degenerative process, sometimes it's more longstanding, or the disease processes are slightly different, then it will be two.  But the basic mechanisms and the basic considerations are quite the same.

             DR. YASZEMSKI:  Thank you Dr. White.  Dr. Doyle, does that answer your question?  Thank you.  Dr. Kim.

             DR. KIM:  A comparison of the one-level versus the two-level results, correct me if I'm wrong.  The two-level patients did better, particularly in the physical function component, which is pretty dramatic, 73 percent success for the two-level and 46 percent for the one-level.  Is it possible that when you do a one-level treatment, that we're not getting that second level that is needed?  And I guess my question is is there a way to look at adjacent levels again and determine if there is a threshold other than the 50 percent that you use for the criteria to do a two-level surgery instead of a one-level surgery?

             DR. YASZEMSKI:  Dr. Andersson.

             DR. ANDERSSON:  It's interesting how this discussion has moved from perhaps not doing two levels to perhaps doing two levels.  It's possible that the better result with the two-level had to do with the fact that some patients who got one level X STOP should have had two-level X STOPs.  We can look at that further.  And I think it is a possibility.  We don't know.  At this point, it seems that the results are quite similar between one- and two-levels except for that one single aspect.

             DR. YASZEMSKI:  Thank you Dr. Andersson.

             DR. RUDICEL:  I have just one comment to that, if that's okay.

             DR. YASZEMSKI:  Dr. Rudicel.

             DR. RUDICEL:  Did they actually do numerically better, or was just the increase better?  I was not clear about that.  So the level twos, their number might not have been as high but they had a better increase if they started out at a worse level?

             DR. YASZEMSKI:  Ms. Lysakowski.

             MS. LYSAKOWSKI:  Just to clarify, you are asking about the success rates --

             DR. RUDICEL:  Yes.

             MS. LYSAKOWSKI:  -- between the one- versus two-level?  It's numerical, if you will.  It's based on just the percentage of patients in each of those subgroups that met the criteria for success.

             DR. RUDICEL:  On the ZCQ, though, I was just -- their increment could have been greater, but their numerical score might not have been greater.  I wasn't clear from the material I read.

             MS. LYSAKOWSKI:  Right.  Well the criteria for success are based on a threshold level of improvement.  So to be considered a success in any single domain, you would have to have a 0.5 improvement for that domain.  So they had to have either had -- they could have had more.  They could have had --

             DR. RUDICEL:  But you don't know whether numerically they were higher or not?  You just know that they had a --

             MS. LYSAKOWSKI:  I think perhaps you're asking if we looked at the mean change scores between the two subgroups?

             DR. RUDICEL:  Well, for example, the level twos might have been a 3.5, and the level ones might have been a 3.0.

             MS. LYSAKOWSKI:  Right.  We did not compare mean change scores.

             DR. RUDICEL:  Okay.

             DR. YASZEMSKI:  Thank you.  Dr. Naidu?

             DR. NAIDU:  I have nothing to add.

             DR. YASZEMSKI:  Thank you.  Dr. Kirkpatrick?

             DR. KIRKPATRICK:  Nothing to add.

             DR. YASZEMSKI:  Thank you.  Dr. Li?

             DR. LI:  Just a question, and it may be in this packet and I missed it.  Was using two levels something that was part of the original study?  In other words, that the surgeon could decide whether or not one or two levels could be used?  And if so, were the criteria the same for all the different centers?  In other words, if you laid out who used two levels from the different centers, would the list of criteria be the same?

             DR. YASZEMSKI:  Dr. Andersson.

             DR. ANDERSSON:  Yes.  Yes, it was part of the study design.  And in fact, as you may remember, one of the inclusion criteria had to do with the size of the spinal canal. 

             DR. LI:  And the second question about those that did two levels, were their criteria the same?

             DR. ANDERSSON:  Yes, they were.

             DR. YASZEMSKI:  Thanks Dr. Andersson.  Dr. Ellenberg?

             DR. ELLENBERG:  I have no further questions on this question.

             DR. YASZEMSKI:  Thanks Dr. Ellenberg.  Dr. Finnegan?

             DR. FINNEGAN:  A question and then a comment.  The question is were the two levels done the same local, or were those ones that needed general anesthetic, and what was the time increase for the two levels?

             The comment is that if you look at the x-rays that were provided, there certainly is more significant flexion in the two-level x-rays that were in our packet than in the single level, albeit the single level actually was an expulsion.  And so one would have to assume that there are some biomechanical alterations that, again, we have not clarified.  But the question were the two levels -- how much time did they take, and were they done under general or under local, with more sedation.

             DR. YASZEMSKI:  Dr. Hartjen.

             DR. HARTJEN:  Charles Hartjen, yes.  As I understand it, none of the two-levels were done with general anesthesia.  And adding an additional level, on average, added approximately 20 minutes to a procedure.

             DR. FINNEGAN:  And how long does a two-level laminotomy take in experienced hands, in the hands of your surgeons?

             DR. HARTJEN:  Well, there's a range from limited laminotomies and facetectomies to complete laminectomies that are done, but I would say typically a two-level decompression in most people's hands would be approximately two hours.  Possibly two and a half.

             DR. YASZEMSKI:  Thank you Dr. Hartjen.  Dr. Witten?  Dr. White.

             DR. WHITE:  I don't think we addressed your biomechanical question about the two levels.  I'd just like to comment, first of all, the very beautiful description that you described of the energy and the equation of how some change ought to exist.  If you change the mechanics at one level, it has to affect other levels.  And clearly on a theoretical basis that makes sense.  However, in my opinion, in terms of practical clinical biomechanics, I think that the effect would tend to be minor.  If we think in terms of a spinal fusion where there's a very rigid immobilization of one or two levels, this impacts understandably both clinically and experimentally the adjacent levels of the spine.  However, this is not by any means a rigid immobilization that is anywhere in the range of a spine fusion or instrumentation.  It actually continues motion, but it somewhat limits the motion.  But this is in the realm of the partial immobilization, which I think will tend to have a minima biomechanical effect.  This is speaking to some degree theoretical, but it is my honest opinion about the difference.

             DR. YASZEMSKI:  Thank you Dr. White.  Other comments?  Dr. Witten, there seems to be good concordance of opinion on Number 2 that there is a clinical basis for pooling the outcomes of the one- and two-level patients.  Dr. Rudicel began by questioning and getting the answer from the sponsors that the selections are done by clinical evaluation.  And if the clinical evaluation points to one level or to two levels, and a one- or two-level procedure is subsequently done, the expectation would be the same for both of them, that the problem that exists be it one or two levels is completely addressed.  And have we had adequate discussion from FDA's perspective on Question Number Two?

             DR. WITTEN:  Yes, thank you.

             DR. YASZEMSKI:  Thank you.  Let's move on to Question Number 3.  Dr. Holden?

             DR. HOLDEN:  The device labeling states that this device limits extension.  In the pre-clinical cadaveric studies, ranges of flexion-extension were recorded under measured applied loads.  The clinical radiographic measurements, however, were performed on static plain radiographs.  Please discuss the interpretations of the measurements made on the clinical patients' radiographs as it relates to device effectiveness.

             DR. YASZEMSKI:  Thanks Dr. Holden.  This time we're going to start with Dr. Kim, and we'll come clockwise around through Dr. Naidu.

             DR. KIM:  The importance of this question is related to the findings in the pre-clinical studies, that the only difference in canal and neuroforaminal parameters are found in extension.  So we have to wonder why only static films, even though they're standing, were taken clinically since things like the neuroforaminal area, those differences we can't expect to find.  Thus x-rays in this study looks for only device failures and hardware complications, and cannot really address the issues of neuroforaminal area, for example.

             The second point I wanted to raise is that the sponsor contends that greater than 90 percent of the x-rays show maintenance of distraction.  Unfortunately, the point was raised that the x-ray technique is likely unable to detect differences that are less than a few millimeters.  There are differences in magnification, clarity, and even the angle of the tube that can affect that.  So if this is an important question, I think the meaningful radiographic study would be to get either a CT or an MRI.  I just want to ask the sponsors if they thought about this, and why they decided not to obtain that information.

             The second issue is whether or not to obtain flexion-extension views on the clinical visits, which is actually pretty common to do in clinical practice.  Because one would want to look at a couple of things.  One, over time with biologic remodeling there could be effects on the adjacent segments such as hypermobility, which may cause focal kyphosis, or other changes.  And that would be worthwhile looking at.

             And then finally, we have to wonder how the implant is behaving within that site.  For example, is it hypermobile, is it rubbing against the bone, and is there a reaction to that implant that if we waited a few more years we'd notice that it would erode the bone or somehow cause it to fail.

             And then finally, Dr. White already brought up, but I wanted him to expand a little bit further.  You're doing two-level surgeries on the patients, but unfortunately two-level pre-clinical studies weren't done.  And once again, all the points that I raised are even more important to look at when we do two-level surveys.  So I hope I wasn't too lengthy, but if you could address those issues that would be great.

             DR. YASZEMSKI:  Maybe I'll ask as Dr. Andersson just repeat your first question so he can take them one at a time.

             DR. KIM:  The first question is do you think it's useful to get a CT or an MRI to look at the degree of distraction.  You obviously didn't.  If you could just give us the reason as to why you didn't think was important.

             DR. ANDERSSON:  Actually, no, it's very difficult to determine the degree of stenosis or changes within a motion segment using x-rays or even CTs.  Measurements are so inaccurate that we essentially decided that it wasn't worth it in a study of this type.  Instead, the x-rays were used to study effects of the implant itself, and the location of the implant, and whether or not the implant had any major effect on the spinous processes.  So we did not use the x-rays to determine any stenotic aspect at all. 

             DR. YASZEMSKI:  Thanks Dr. Andersson.  Dr. Kim, second question?

             DR. KIM:  Can I ask a quick question about MRI.  Is it possible to do an MRI with this implant, or is it considered a loose foreign body that would not be okay to MRI, just out of curiosity?

             DR. ANDERSSON:  Well, it's possible to do MRI with the implant.  There is some disturbance, but it is possible to do MRI with the implant.  And in fact, we are in the process of doing a study using standing MRI to look further into some of the aspects that we are scientifically interested in.

             DR. KIM:  And then finally, maybe this could be a combined question.  What do you think is the effects -- I guess I want to ask why flexion-extension views weren't done, because I would be interested in looking at the effects on the adjacent segment.  Even though in the pre-clinical studies there's no changes, as Dr. Finnegan brought up, over time the body will undergo a response, and that may eventually lead to hypermobility, for example, of the adjacent segments.  And I would think that that would be more risk at two levels.  So if you can just address why flexion-extension views you didn't think were that important.

             DR. ANDERSSON:  Well, we didn't do flexion-extension views again because we weren't trying to use x-rays for any other purpose than to evaluate the device.  If we had been concerned with stability of say a fusion, obviously we would have done flexion-extension views.  If we had been concerned about abnormal motion occurring, we would have done flexion-extension views.  I don't think in a patient population that you do flexion-extension views as a routine unless the patient has complaints of back problems.  And so those were the reasons why we didn't.

             DR. YASZEMSKI:  Thanks Dr. Andersson.  Dr. Kim, had you said you wanted a question for Dr. White, did I hear you when you asked your question?  Or has Dr. Andersson answered that?

            DR. KIM:  I don't have -- he answered it.  I don't have any further questions.

             DR. YASZEMSKI:  Okay.  Thank you.  Dr. Naidu?

             DR. NAIDU:  My answer to Question Number 3 is based on the current study, the PMA submitted, there is no x-ray basis for device effectiveness.

             DR. YASZEMSKI:  I'm sorry, say again?

             DR. NAIDU:  There is no x-ray basis.

             DR. YASZEMSKI:  Okay, thank you.  Dr. Kirkpatrick?

             DR. KIRKPATRICK:  My comments are basically going to emphasize what has already been said, and also raise a question.  If the sponsors felt the MRI does not give us accurate measurement ability, why did you use it in the pre-clinical study?  I thought those were reliable numbers, and I trusted the improvement in the cadaver model based upon MRI data that you presented.  And now you're telling me that in a clinical model it would not be effective in reliable measurements.

             DR. ANDERSSON:  No, I think what I was trying to say was that for purposes of determining spinal stenosis, MRI certainly can be very accurate, even in the process of an X STOP.  But for routine study of the result of the X STOP in these patients, we decided not to use MRI because it added a significant complexity, and we know that there is no direct relationship between the change in the stenosis parameters and the patient symptoms.  And so we thought the patient symptoms were the most important.

             DR. YASZEMSKI:  Thank you Dr. Andersson.  Dr. Li?

             DR. KIRKPATRICK:  If I may finish --

             DR. YASZEMSKI:  Dr. Kirkpatrick, go ahead.

             DR. KIRKPATRICK:  To answer the question, I don't believe that the sponsor has provided in the clinical patients a demonstration that the philosophy of their device has been proven in that they have not provided us with any anatomic data, whether it's radiographs, CT, or MRI, which demonstrates that the foramen or the canal is prevented from getting narrower in the clinical population.

             DR. YASZEMSKI:  Thanks Dr. Kirkpatrick.  Dr. Li?

             DR. LI:  I only have just a short comment.  I guess it appears that the FDA is circling this question around the device labeling issue about whether or not they can state the device limits extension.  I think the only possible claim they could make on that would be from the laboratory testing of cadaver spines.  There doesn't appear to be any clinical support for limiting extension.

             DR. YASZEMSKI:  Thanks Dr. Li.  Dr. Ellenberg?

             DR. ELLENBERG:  No comments on this question.

             DR. YASZEMSKI:  Thanks Dr. Ellenberg.  Dr. Finnegan?

             DR. FINNEGAN:  I agree with what's been said.

             DR. YASZEMSKI:  Thank you.  Dr. Rudicel?

             DR. RUDICEL:  No further comments.

             DR. YASZEMSKI:  Thank you.  Dr. Diaz?

             DR. DIAZ:  I concur with Dr. Kirkpatrick's view.  My basic concern with the presentation as it relates to this issue is that the anatomical confirmation that your device does what it's supposed to do was not given.  So the fact that the patients got better does not mean that you changed the anatomy one bit.

             DR. YASZEMSKI:  Thanks Dr. Diaz.  Ms. Maher?

             MS. MAHER:  Nothing further.

             DR. YASZEMSKI:  Thank you Ms. Maher.  Dr. Doyle?

             DR. DOYLE:  Nothing to add.

             DR. YASZEMSKI:  Thank you Dr. Doyle.  Further comments?  Dr. Witten, there seems to be a bit of a disparity of opinion on this.  There has been a spectrum of opinions given from fully accepting clinical data as demonstration of effectiveness to the other extreme, that the effectiveness of the device in limiting extension has not been proved unless there is an extension film that shows that extension has in fact been limited, and this would need to be done post-operatively.  Have we had adequate discussion from FDA's perspective?

             DR. WITTEN:  Yes, thank you.

             DR. YASZEMSKI:  Thank you.  We're going to move on to Question 4(a). 

             DR. HOLDEN:  Question 4 has two parts. The part that's common to both.  Fewer than 50 percent in the X STOP treated group, and fewer than five percent in the control group achieved overall successful outcome.  These results are considerably lower than what had been predicted at the outset of the study.  In this study, an operative treatment was compared to a non-operative treatment in patients who had already failed conservative treatment, including epidural injections.  A majority of patients had had symptom duration for more than two years prior to entering the study.  Patients in both groups went on to have more than one epidural injection, and/or laminectomies.  In 10 to 15 percent of the X STOP treated patients who improved, symptoms returned during the course of the study.  Moreover, there was a trend toward different results for use of this device at one versus two levels.

             (a) Based on the data from this study, please discuss the appropriate population who might benefit from this device.

             DR. YASZEMSKI:  Thank you Dr. Holden.  Dr. Kirkpatrick?

             DR. KIRKPATRICK:  With regard to (a), unfortunately I don't have enough information to discuss the appropriate population specifically who may benefit from this device.  I think that the pool of patients with their clinical symptoms has enough variability that we cannot determine which within those we can pinpoint would benefit.  Specifically, one question I would have is on the clinical symptom standpoint, the issue of one versus legs hurting.  We heard from two patients who both described single leg pain.  A lot of patients with stenosis also have bilateral leg pain.  Many times the anatomic physiology causing one versus two leg pain may differ in that one foramen may be tighter than the other, or one subarticular region may be narrower than the other, much as was shown on the MRIs demonstrated in the presentation. 

             The second issue is related to the first, and that relates to the anatomic region which predominates in the stenosis.  I am concerned that one particular type of stenosis predominating may actually show us a very successful intervention with the X STOP versus another one not having success at all.  And the things that intuitively come to mind would be, again, a foraminal stenosis on one side versus a combined stenosis involving everything and a very large central stenosis.  I would not expect to be as successful as the single foraminal stenosis with the use of this device.  I have not heard the sponsor provide data that can help me discern these questions.  If they do, I'm more than open to hear their comments.  However, if they cannot, then I cannot state that I am comfortable defining the appropriate population for this device.

             DR. YASZEMSKI:  Thanks Dr. Kirkpatrick.  If anyone from the sponsor would like to comment, we can do it now or after we've gone around the room.  If someone wants to specifically address Dr. Kirkpatrick's question and would like to do it now, please to do so.  Dr. White?

             DR. WHITE:  This is obviously an important point that you raise.  I think that the pathology of lumbar spinal stenosis is a cumulative obliteration of space available in the canal.  I think if you can take a functional spinal unit, whether it's unilateral disease primarily or circumferential disease primarily, if you can do a separation, and reach that threshold which alleviates and provides, again, enough space to avoid all of the pathologic mechanisms that you so nicely described, that you will in fact cure the disease, whether it's unilateral or whether it's bilateral.  The important thing is to open up and provide enough incremental space to reach that unknown threshold of tightness so that you get from a too-tight canal, for whatever reason in whatever region, to a not-too-tight canal, and then that alleviates the leg pain and improves the symptoms.  So I think while your point is very good, I don't think it matters really whether it's unilateral or bilateral disease, just so long as you separate the vertebrae.

             DR. YASZEMSKI:  Thank you Dr. White.  Dr. Li?

             DR. LI:  I agree with everything Dr. Kirkpatrick said.  And I think choosing the appropriate patient population is difficult, not only for what he said, but we still have this lingering issue of this variation between center to center of success rates from 13 to 85 percent. 

             And perhaps a follow-up question to Dr. White.  You know, in the best of cases the numbers worked out about a little less than 50 percent are reporting a success rate.  Maybe down to 33 percent if you take out the St. Mary's group.  So does that mean in the patients that are unsuccessful, the device did not perform its function of providing you enough separation?

             DR. YASZEMSKI:  Dr. White.

             DR. WHITE:  I don't think we know in every case why a given patient is not successful.  I think that we know that we have altered the mechanics in a way to give the patient the possible benefit of being successful.  But I don't think we can know why it might not be a successful outcome.

             DR. LI:  So you don't believe that some of the features, for instance, that appeared to tend to give you a successful result, like having a younger patient, or things like that, you don't believe those are actual patient indications that would narrow the indications for the device?

             DR. WHITE:  No, I didn't say that.  No, I don't mean to say that. 

             DR. LI:  So do you think, knowing what you know now, would you think that the patient indication is now narrowed to perhaps a younger population, or somebody with a certain amount of stenosis, or anything like that?

             DR. WHITE:  Well, I think the criteria as has been suggested and has been recommended, given currently available knowledge is the best set of indications, and the best set of criteria to determine whether or not to offer the procedure.  That may change with increased additional clinical experience, but right now I think this is a very good first approximation.

             DR. LI:  Thank you.  So my short answer is I agree with Dr. Kirkpatrick.  I don't know how you would determine the appropriate patient population.

             DR. YASZEMSKI:  Thanks Dr. Li.  Thank you Dr. White.  Dr. Ellenberg?

             DR. ELLENBERG:  In the beginning of my presentation I showed a graphic that appeared to indicate that the patients that had the increased severity at baseline tended to do better with the X STOP procedure.  And my sense would be that while we as a panel do not have the data now to look at a possible stratification by initial severity, FDA could look at that post panel and perhaps make that determination on their own.  So my sense is, from the data I've seen that is available in the dataset now, initial severity might be a way to look at compartmentalizing the groups that would most benefit from this procedure.

             DR. YASZEMSKI:  Thanks Dr. Ellenberg. Dr. Finnegan?

             DR. FINNEGAN:  Well actually, in deference to Dr. Kirkpatrick, I think there are a couple of parameters that have been defined.  They did not appear to have any problems doing this under local anesthetic, either patient problems or implant problems.  So obviously those patients who could not tolerate a general anesthetic or a prolonged surgical procedure, this might in fact be an implant for them.

             As well, certainly, those patients who are not going to because of their comorbidities have much activity post implant might be patients that are also candidates for this.  And given the limited longevity we have on the implant, perhaps those patients who have limited longevity.  So I would say a patient population, and I agree with Dr. Ellenberg, because these are probably the patients that have increased symptomology, are not good candidates for a surgical procedure, and are probably not going to put high demand on it.  The data that we have to date I think would support that.

             DR. YASZEMSKI:  Thank you Dr. Finnegan.  Dr. Rudicel?

             DR. RUDICEL:  I have nothing more to add.

             DR. YASZEMSKI:  Thank you.  Dr. Diaz?

             DR. DIAZ:  I generally agree with Dr. Finnegan, but on this one I don't think I can agree.  Because the population is so non-homogenous.  Spinal stenosis is one of those animals that is a big wastebasket of people.  There is a huge variety of patients that have stenosis caused by either bony hypertrophy, facet hypertrophy, synovial enlargement, hypertrophy of the ligamentum flavum, spondolytic changes, and not all of them are the same thing.  To provide a one bullet treatment for all of them I think, in my opinion, is not the right approach.

             Furthermore, the longevity of these patients is really one of those things that we need to be concerned with.  There is many of us sitting in this room right now who have active severe spinal stenosis and who are asymptomatic.  How do we know that those patients are going to be for one strange reason or another not going to have a CT scan or MRI scan of the spine in which they find stenosis, and for which we provide this X STOP treatment?  I am not comfortable with the definition of the population as presented, and I don't think we can select the people based on the criteria given.

             DR. YASZEMSKI:  Thank you Dr. Diaz.  Ms. Maher?

             MS. MAHER:  Well, I don't have anything to really answer on the (a) section.  I would like to remind the panel that as a whole, this was a clinical study, and the control group was developed in conjunction with the FDA.  So the decision to use conservative care of course was a joint decision with the FDA, and the sponsor going forward. 

             I'd also like the sponsor to elaborate a little bit on how they came up with the predicted outcomes.  I mean, if we all had a crystal ball and could predict the outcomes in advance, then none of us would need jobs.  So if they could explain where the predicted outcomes came from.  And I know in their presentation they went through and showed how things, you know, if you went back to what was in the literature and used those criteria things changed a little bit.  If they could just give a brief summary of that I'd appreciate it.

             DR. YASZEMSKI:  Someone from the sponsor want to comment on that?  How did you come up with the expected outcome numbers from which the study began?  Dr. Andersson.

             DR. ANDERSSON:  Those numbers were based on the literature.  And in reality, we realized after we finished the study that they were not appropriate when you use the stringent criteria that we used.  If we had used different criteria, they would have been appropriate, and we would have been much closer.  As it turns out, the difference in result actually increased, and the sample size could actually have been smaller.

             DR. YASZEMSKI:  Thank you Dr. Andersson.  Dr. Doyle?

             DR. DOYLE:  Nothing to add.

             DR. YASZEMSKI:  Thank you Dr. Doyle.  Dr. Kim?

             DR. KIM:  Nothing to add.

             DR. YASZEMSKI:  Thank you Dr. Kim.  Dr. Naidu?

             DR. NAIDU:  Nothing to add.

             DR. YASZEMSKI:  Thank you.  We're going to go around and answer Question 4(b).  Then we'll give our summary to the FDA, if that would be okay with Dr. Witten.

             DR. WITTEN:  Yes.

             DR. YASZEMSKI:  And Dr. Holden, can you read just the (b) part of the question, please?

             DR. HOLDEN:  Given the historical success rates for laminectomy, please discuss what impact the effectiveness results of this study have in relation to our interpretation of the risks and benefits of treatment with the X STOP device.

             DR. YASZEMSKI:  Thanks Dr. Holden.  Dr. Diaz?

             DR. DIAZ:  As I had mentioned earlier, the non-homogeneity of the population makes a decision to proceed with surgery in this group of people very difficult.  Many of the patients that were treated in this study with what were considered mild to moderate symptoms in my opinion had severe symptoms that were incapacitating enough for them to have failed best available medical treatment, and warranted certainly a surgical decision.  The comparison made with the best medical treatment available was in my mind the evaluation of no treatment versus some form of treatment.  In my mind, the comparison should have been made better, and with a good statistical ability to validate the procedure, by comparing laminectomy, which is something that is surgically invasive, can be minimally invasive as well.  Many of our patients can be treated through relative small incisions, be admitted to the hospital for the exact length of time that these patients were admitted, be ambulatory the night of the surgery with a laminectomy, and in essence have a relatively blinded ability to assess these patients.  In my mind, the right comparison should have been with laminectomy.  My question to the sponsor is why was that not the decision made.

             DR. YASZEMSKI:  Thank you Dr. Diaz.  Dr. Andersson?

             DR. ANDERSSON:  Well, we thought long and hard about this, and had a very difficult decision to make.  When you're comparing a procedure which is somewhere in between to other alternatives, the choice of which alternative to use as your comparison group becomes difficult. 

             There were really three things that moved us in the direction of the non-operative treatment.  One had to do with the fact that the majority of patients when they were enrolled in the study were really not ready for a laminectomy.  Their symptoms were moderate, and although their qualities of life were significantly impaired in some cases, they were not looking for a major surgical procedure.  And I do agree that you can do laminectomies as outpatient procedures or as same-day-home procedures, but they are still much, much bigger procedures, and you enter the spinal canal, and it does raise the opportunity of complications which are not really there when you use the X STOP device.

             The second reason was that the salvage procedure for both non-operative treatment and the X STOP is a laminectomy.  And so we felt that it was somewhat inappropriate to compare the X STOP to the salvage procedure for the X STOP. 

             And the third had to do with the risk profile, which the X STOP is much closer to that of non-operative treatment than a laminectomy.  And so for those reasons we ended up choosing the non-operative treatment, went to the FDA, and as stated previously, had discussions with them about this, and eventually agreed that that would be the appropriate comparison.

             DR. YASZEMSKI:  Thank you Dr. Andersson.  Dr. Rudicel, let's come around this way to you this time.  Sorry for the surprise.

             DR. RUDICEL:  I would just add that I prefer the study design that they had to comparing it to laminectomies for the reasons that Dr. Andersson has stated.  While it's not a perfect design, and it certainly presents problems with blinding, I think that it is a less invasive procedure.  And so I thought it was, that part of it anyway was the way I would have done it too.

             DR. YASZEMSKI:  Thank you Dr. Rudicel.  Dr. Finnegan?

            DR. FINNEGAN:  I agree with Dr. Diaz.

             DR. YASZEMSKI:  Thank you Dr. Finnegan.  Dr. Ellenberg?  It's 4(b).

             DR. ELLENBERG:  I'm sorry, my version is earlier.  I just want to make sure I'm understanding.

             DR. YASZEMSKI:  Would you like a moment to think about, and I'll come back to you?

             DR. ELLENBERG:  Yes.  I pass, and then come back.

             DR. YASZEMSKI:  Okay.  Dr. Li?

             DR. LI:  I agree with Dr. Diaz.

             DR. YASZEMSKI:  Thank you.  Dr. Kirkpatrick?

             DR. KIRKPATRICK:  I have to be on the fence.  I think a laminectomy control group would have been an excellent addition to this.  I still would want to see the non-operative control.  But to get to the specifics of the question, I think in perspective, compared to laminectomy, this option would be one on a scale of gradually increasing risk but gradually improving clinical results.  I see this as between non-operative interventions and the success rate of a laminectomy as far as success, and I see it as between non-operative treatment and laminectomy as far as surgical risk.

             DR. YASZEMSKI:  Thanks Dr. Kirkpatrick.  Dr. Naidu?

             DR. NAIDU:  I have nothing more to add.

             DR. YASZEMSKI:  Thank you.  Dr. Kim?

             DR. KIM:  I would concur with Dr. Kirkpatrick.

             DR. YASZEMSKI:  Thank you.  Dr. Doyle?

             DR. DOYLE:  I agree with Dr. Diaz.

             DR. YASZEMSKI:  Thank you.  Ms. Maher?

             MS. MAHER:  Nothing to add.

             DR. YASZEMSKI:  Thank you.  Dr. Ellenberg?

             DR. ELLENBERG:  I'm sorry, I have to apologize.  I've been working from a different set of questions.  My sense is that the historical success rates for the laminectomy are what they are.  They are historical, they are not controlled.  And throughout the readings and preparation for this meeting, I'm not sure I really ever understood and still don't understand the question this regards.  So I prefer not to make any comments in regard to this question.

             DR. YASZEMSKI:  Thank you.  Entirely appropriate, thank you.  Other comments?  Dr. Witten, Question 4 has, again, as some of the previous questions, a spectrum of responses.  Dr. Diaz articulated it well when he said this population is non-homogenous.  There are many different subgroups, if you will, anatomically, that result in the symptoms we see in spinal surgery patients.  Dr. Finnegan, however, mentioned that she sees from the data presented some groups that would be appropriate, those who would have difficulty with general anesthesia, those who would for other comorbidity reasons be in increased surgical risk, and other discussers, for example, talked about the one versus two sides, and perhaps to stratify the patients by initial severity.  Dr. Kirkpatrick, however, I think is in agreement with Dr. Diaz when he said that there were not a homogenous subgroup, and that he considers this somewhere in the middle.  It's a little more risky than non-operative techniques, but not quite as risky as a formal decompression.  However, it's looked at as another step, perhaps, in the care of these patients.

             Have we discussed this to your satisfaction?

             DR. WITTEN:  Yes, thank you.

             DR. YASZEMSKI:  Thank you.  We're going to move on to Number 5.  Dr. Holden?

             DR. HOLDEN:  In this study, the protocol did not define what criteria were to be used in either group to determine when or whether patients proceeded to laminectomy.  It also did not define whether to administer additional epidural injections to patients in the control group.  Some patients in the investigational X STOP group received the control treatment, epidural injection for pain, rather than proceeding to laminectomy, and it is not clear whether success in those patients was due to temporary relief from the injection, or to the X STOP.  Please describe the potential impact on the interpretation of the study result of these confounding factors.

             DR. YASZEMSKI:  Thanks very much.  We'll start with Dr. Ellenberg this time, and we'll come around this way through Dr. Li and Dr. Kirkpatrick.

             DR. ELLENBERG:  My sense in response to this question is that the lack of a protocol for the use of either epidurals or laminectomy can be added to the potential for the informed consent being optimistic for patients going onto the X STOP procedure, can be added to the issue of the trial being unmasked for whatever reasons, and can be added to the nature of the other outcomes that are subjective, the self-scoring by patients.  So my sense is that there are a whole host of things that could be influenced by investigators, could be influenced by the patients' feeling about what their expectations are for the X STOP procedure.  So in my mind, all of these things, including the two that are specifically mentioned here, the use of epidurals and the reasons for going on to a laminectomy, could have an impact on the interpretation of this study.  However, having said that, in my going through the data and trying to simulate what would happen, looking at a multitude of what-if scenarios, if this were in one extreme or another extreme, in the end the results appear to be impressive, and that the difference between the X STOP and the control group appeared to stay no matter what I could do with the data.  But all of the data are subjective.  So in my view, the interpretation that the panel considers in terms of the efficacy has to be tempered by the fact that the foundation for the study is subjective, and the use of the epidural and the laminectomy are just two more elements in that vein.

             DR. YASZEMSKI:  Thanks Dr. Ellenberg.  Dr. Li?

             DR. LI:  I have nothing to add.

             DR. YASZEMSKI:  Thank you Dr. Li.  Dr. Kirkpatrick?

             DR. KIRKPATRICK:  I think the key issue in this question in my mind is the fact that I would have considered an epidural after the X STOP as a failure period.  So I would have taken those as being an endpoint.  Because if the X STOP is doing what it's supposed to do, the epidural wouldn't ever be required unless they can demonstrate as the sponsor that they were doing an epidural block for a different level than the X STOP was intended for, which I did not see any data to show any specificity with the epidurals.  I couldn't tell whether they were transforaminal at particular levels and that sort of thing.  So I think that's not going to be answerable. 

             Whether that is a particular thing that's a high enough incidence to change the overall results I can't tell you, but my sense is it is not.  And as far as the laminectomy failure, or the steps going to laminectomy, I think that is too general of an indication with regard to individual patients and the multiple individual surgeons that has to be reserved on a one-to-one basis.  And so I don't think they could standardize when and whom would proceed to laminectomy.  So I don't fault that at all as far as the study design.  Thank you.

             DR. YASZEMSKI:  Thanks Dr. Kirkpatrick.  I'd like to give an opportunity.  Would anybody from the sponsor like to address the epidurals after X STOP?  If you do, please do so.  If not, we'll move on.  Dr. Zucherman.

             DR. ZUCHERMAN:  As Dr. Kirkpatrick said, really the timing of these things was left up to the patient-doctor relationship.  There were 10 patients who had one epidural in the control group and proceeded on to laminectomy.  Seven of those occurred within two months, and the other three occurred after a year.  And in the rest of the control group they had varying numbers of epidurals and the length of time -- this is in the group that went on to laminectomy -- the length of time reflects the number of epidurals they had because they got a period of relief after them.  And likewise for a decision to go on to laminectomy, if the conservative treatment was not being effective, the epidurals weren't effective, a patient could proceed to laminectomy at his discretion. 

             In the cases of the X STOP groups who received epidurals, there were eight.  Six of those were failures, and the only two that weren't failures were patients who both had motor vehicle accidents, had an epidural.  They were successes before the accident.  After their shots, they recovered and regained success at 2-year follow-up.  And if you take them out of the database, it still remains very strongly statistically significant.

             DR. YASZEMSKI:  Thanks Dr. Zucherman.  Dr. Naidu?

             DR. NAIDU:  I have nothing more to add.

             DR. YASZEMSKI:  Thank you.  Dr. Kim?

             DR. KIM:  I just wanted to reemphasize that I agree with Dr. Ellenberg about the subjective nature of this study.  But if you look at the X STOP patients that had this, only two of them are considered in the success rate.  So I agree with Dr. Kirkpatrick that it probably wouldn't have made a difference.  And in the end despite this flaw, the results are probably the same, that the X STOP did provide some benefit.

             DR. YASZEMSKI:  Thanks Dr. Kim.  Dr. Doyle?

             DR. DOYLE:  I have nothing to add.

             DR. YASZEMSKI:  Thank you.  Ms. Maher?

             MS. MAHER:  Nothing to add.

             DR. YASZEMSKI:  Thank you.  Dr. Diaz?

             DR. DIAZ:  I agree with Dr. Kirkpatrick and the issues that are being considered in this question are bothersome in the aggregate of the inconsistencies, or the several inconsistencies that exist in this study.

             DR. YASZEMSKI:  Thank you Dr. Diaz.  Dr. Rudicel?

             DR. RUDICEL:  I agree with Dr. Kirkpatrick.

             DR. YASZEMSKI:  Thank you.  Dr. Finnegan?

             DR. FINNEGAN:  The only thing I would add is that this is perhaps one area where doing a further follow-up from the two years may give more information and be more of a help.

             DR. YASZEMSKI:  Thanks Dr. Finnegan.  Other comments? 

             DR. ELLENBERG:  Yes, I'm sorry.

             DR. YASZEMSKI:  Dr. Ellenberg?

             DR. ELLENBERG:  It seems to me that it's potentially possible, and I can't be secure in this, that if you looked at the patients that went on to laminectomy in both the control group and the X STOP group sequentially over time, and you looked at the measurements for the three components of the ZCQ score, it may be informative to the FDA post panel deliberations to see whether or not there's any nature that we can glean from the succession of scores of both the physical and severity and the satisfaction levels over time that would distinguish between the control group and the X STOP group in terms of what actually happened in this trial with regard to who is chosen to have the laminectomy.  But obviously we don't have that here.

             DR. YASZEMSKI:  Thanks Dr. Ellenberg.  Further comments?  Dr. Witten, with respect to Question Number 5, Dr. Ellenberg's summary, which I think was confirmed by the other comments, was that there are a host of confounding factors.  The two that are listed here are just two additional ones to add to the list.  He indicated, though, that after looking at many what-if situations, the results were still the same.  Dr. Kirkpatrick commented that the epidural after X STOP should be a failure, and we had a description and a discussion of that by the sponsor.  And Dr. Finnegan added that perhaps this is one question which further follow-up past two years might yield results.  However, the overall conjecture is that this is a subjective endpoint, and there are many confounding factors. 

             Have we discussed this adequately from your perspective at FDA?

             DR. WITTEN:  Yes, thanks.

             DR. YASZEMSKI:  Thank you.  We're going to move on to Number 6.  Dr. Holden?

             DR. HOLDEN:  Under CFR 860.7(d)(1), safety is defined as "reasonable assurance based on valid scientific evidence that the probable benefits to health under conditions of the intended use when accompanied by adequate directions for use and warnings against unsafe use outweigh any probable risks."  Do the clinical data in the PMA provide reasonable assurance that the device is safe?

             DR. YASZEMSKI:  Thanks Dr. Holden.  We're going to start with Dr. Naidu and come around this way through Dr. Kirkpatrick.  Dr. Naidu?

             DR. NAIDU:  Based on the valid scientific evidence, in this study it's quite obvious that it's based on subjective evidence, which is mainly the ZCQ scores.  Based on this, my thoughts are that the events related to device or implantation were few or relatively minor.  And I think that it could be considered reasonable for such a procedure as Dr. Kirkpatrick presented in his presentation.  And life-threatening complications appeared to be more related to patient population than intervention.  So based on the subjective scientific evidence, I think it's reasonably safe.

             DR. YASZEMSKI:  Thank you Dr. Naidu.  Dr. Kirkpatrick?

             DR. KIRKPATRICK:  I think that the answer to the question `is it safe' the answer is yes.  But I do have to put an asterisk by that, and modify the definition of "intended use" to "appropriate use." 

             DR. YASZEMSKI:  Thanks Dr. Kirkpatrick.  Dr. Li?

             DR. LI:  I'm going to agree with that.

             DR. YASZEMSKI:  Thank you Dr. Li.  Dr. Ellenberg?

             DR. ELLENBERG:  My sense is that this device is safe.  But the regulations ask us to weigh the safety against the efficacy in this particular question.  So I'm not sure until we answer Question 7 that we can definitively respond to Question 6. 

             DR. YASZEMSKI:  Thanks Dr. Ellenberg.  Dr. Finnegan?

             DR. FINNEGAN:  I have to ask him, did you go to law school?  That was a great answer. 

             (Laughter)

             DR. FINNEGAN:  I agree with Dr. Naidu.

             DR. YASZEMSKI:  Thank you.  Dr. Rudicel?

             DR. RUDICEL:  I think the device is safe.

             DR. YASZEMSKI:  Thank you.  Dr. Diaz?

             DR. DIAZ:  I agree with Dr. Kirkpatrick.

             DR. YASZEMSKI:  Thank you.  Ms. Maher?

             MS. MAHER:  I think the device is safe.

             DR. YASZEMSKI:  Thank you.  Dr. Doyle?

             DR. DOYLE:  I agree, simply because it hasn't been proven unsafe.

             DR. YASZEMSKI:  Thank you Dr. Doyle.  Dr. Kim?

             DR. KIM:  I would agree with Dr. Kirkpatrick.

             DR. YASZEMSKI:  Thanks very much.  Other comments?  Dr. Witten?

             DR. WITTEN:  Thank you.

             DR. YASZEMSKI:  Thank you.  Number 7.

             DR. HOLDEN:  Under CFR 860.7(e)(1), effectiveness is defined as "reasonable assurance that in a significant portion of the population, the use of the device for its intended uses and conditions of use when accompanied by adequate directions for use and warnings against unsafe use will provide clinically significant results.  Do the clinical data in the PMA provide reasonable assurance that the device is effective?

             DR. YASZEMSKI:  Thanks Dr. Holden.  Dr. Li, and we're going to go around through Dr. Ellenberg.

             DR. LI:  There's enough ambiguous words in here to make any lawyer happy.  I guess the issues here are the judgment calls, right?  They're asking for a reasonable assurance, significant portions of the population, adequate directions, and clinically significant results, none of which have hard definitions.  So that being said, as far as the device goes, I think the success rate is very low.  Even including the St. Mary's population, the success rate is 45 percent, less than 50 percent.  If you take the St. Mary's group out because it's so much higher than all the rest, the success rate is down to one-third.  And you superimpose upon that we're not exactly sure what the best patient population is that benefits from this particular result.  So it seems like at best you have kind of one chance in three of having improved yourself.  Now, I think it's safe because it doesn't seem to cause the patient any harm if it doesn't work.  So it's safe in that regard.  And maybe it's a good adequate mid-step like Dr. Kirkpatrick said.  But it seems to me, from the data in and of itself, based on the success rates, that I don't believe this device is particularly effective.

             DR. YASZEMSKI:  Thanks Dr. Li.  Dr. Ellenberg?

             DR. ELLENBERG:  I will concur with Dr. Li.

             DR. YASZEMSKI:  Thanks Dr. Ellenberg.  Dr. Finnegan?

             DR. FINNEGAN:  I don't know if it's effective or not because I don't think the clinical data in this PMA gives us that information.

             DR. YASZEMSKI:  Thanks Dr. Finnegan.  Dr. Rudicel?

             DR. RUDICEL:  I think we're dealing with a problem that has a low success rate with other, with laminectomies or other ways of treating it.  So while the success rates are low, I think we're dealing with a problem that doesn't have the normal types of success rates that we like to see, certainly in orthopedics.  But I would say with that caveat that I think the device is effective.

             DR. YASZEMSKI:  Thank you Dr. Rudicel.  Dr. Diaz?

             DR. DIAZ:  I concur with Dr. Li.  I don't believe that the sponsors have presented to my satisfaction the fact that there is a significant proportion of the population that is benefited by this device.  The population, as we heard earlier by the sponsors themselves, constitutes approximately an annual incidence of 700,000 patients.  The non-homogeneity of the population as such, that a group of 200 patients that they started with and came down to 170.  If we put into it all the varieties of possible etiological reasons, we cannot have a statistically meaningful analysis for any of them.  So in my mind, the significant component of the definition is not met.

             Furthermore, I cannot think of a patient who is more grateful than a patient with spinal stenosis who has had a laminectomy.  People who have spinal stenosis literally spring out of bed and kiss you they feel so much better after an operation.  And I can't imagine that based on what I have seen as Dr. Li indicated that a third of these patients get better, that this is really achieving the efficacy that we are asked to opine on.  In my assessment, the efficacy assessment has not been met.

             DR. YASZEMSKI:  Thank you Dr. Diaz.  Ms. Maher?

             MS. MAHER:  Well, I'd like to start by reminding everybody that we're actually going to alternately be talking about a risk versus benefit, and that's why -- and it has to be safe and effective.  But it is a risk-benefit analysis that we're looking at.  This also gets to the question that I asked earlier of what does a 0.5 change really mean, even if it is in only 33 percent of the population.  And if as Dr. Kirkpatrick said this is a good potential mid-step in between conservative care and laminectomy, is it the right way to consider going?  And if the sponsor has any more information that they want to provide us on what the 0.5 meant.  And I understand it has to be subjective, and it's not a hard number or a hard thing, but for a patient who's had a laminectomy, it is a very risky procedure, a relatively risky procedure, a bigger procedure than this one.  So is this a good mid-step?  And I think at least for the 33 percent of the population that were successes, this was effective.

             DR. YASZEMSKI:  Thanks Ms. Maher.  Dr. Andersson?

             DR. ANDERSSON:  I would be happy to address that more fully.  I think what hurts treatment studies in spinal stenosis generally is that the results are generally so poor, almost no matter what treatment you apply as we showed in some of our slides earlier.  What also hurts us is the aggregate score, because if you look at the results on the pain side it's almost 70 percent, and if you look at them on the function side it's almost 70 percent.  It's a little over 70 percent. 

             Thinking about a grateful patient, you remember Ms. Miller, our first patient this morning.  Her improvement was 0.8.  The average for our patients was 0.99.  Certainly she is an example of a very grateful patient.  0.5 applies to all questions in each domain.  And typically the patients don't change by 0.5 for every question.  More often there is a change, for example, in pain from severe to mild.  But these patients may still have mild pain every day, which is another question.  In the physical function domain, a patient may move from walking 50 feet to more than two miles, or from shopping always in pain to occasionally in pain.  And these are typical examples of the results with this device.

             DR. YASZEMSKI:  Thanks Dr. Andersson.  Dr. Doyle?

             DR. DOYLE:  I don't have anything to add.

             DR. YASZEMSKI:  Thank you.  Dr. Kim?

             DR. KIM:  This PMA is unfortunately burdened with a lot of problems, particularly with bias during the randomization and things that we have discussed.  But I think that the success criteria, my sense is that it's very stringent.  In fact, too stringent.  So I'm not too worried about the success rate being one-third or 0.5 because that number can be varied depending on how strict you want to be with the definition of success. 

             To get at this question is this treatment effective, I think a number of different, if I heard correctly, a number of different statistical tests were done for worst case scenarios.  And in the end, the X STOP device still wins out.  So I don't know how much better patients are going to be, but it looks like they're going to be better.  And then I combine that with its safety profile, which I think is very safe.  So it's a close call, but I feel that it is effective, since the benefits outweigh the potential risks.

             DR. YASZEMSKI:  Thanks Dr. Kim.  Dr. Naidu?

             DR. NAIDU:  Based on the ZCQ scores, the sponsors have shown definitively that the device is effective based on the subjective criteria.  Again, Dr. Ellenberg clarified this for us.  0.5 improvement, albeit minimum, is actually one standard deviation improvement.  And he has shown you distribution curves, and he has even gone up to a stricter criteria of improvement by one point, and it still didn't make a difference.  And it showed definitively that the X STOP was superior based on the ZCQ criteria.  Unfortunately, we don't have any objective criteria.  But based on the clinical definition of this study, based on the clinical criteria, I'd have to conclude, even though the success rates are low, I would have to conclude that it is effective.

             DR. YASZEMSKI:  Thank you Dr. Naidu.  Dr. Kirkpatrick?

             DR. KIRKPATRICK:  Well, being from Alabama I have to put this in perspective of what my patients experience.  It sounds to me like what this device might enable some of my patients to do is instead of getting their stenosis symptoms at the end of their shopping at the supermarket, they would get it at the end of their shopping at Wal-Mart.  Or perhaps, if they're getting their pain at the end of shopping at Wal-Mart, they can now go to the mall.  For a large number of my patients that's a significant improvement.  However, I can tell you that most of them would feel it probably wouldn't be worth a surgical procedure to get that.

             The second thing about my patients is they understand a couple of things about percentage chances.  They understand 50/50 because they toss a coin.  They understand about the top 15 percent, because NASCAR interviews at the end of the races involve the top five drivers, and that's about the top 15 percent in the race.  So when I give them an odd of being in the top five suggestive of, as I mentioned earlier, a joint replacement where they've got a 90 percent change of significant improvement over a long period of time, they're willing to put up with surgical risk.  When I talk to them about a 50/50 shot, they're not so excited.  Basically, from what I'm hearing the sponsors tell us is that 45 to 50 percent of the patient population as defined, which is all elements of lumbar stenosis, may see a 25 percent improvement in their function and their symptom severity scores according to the recomputation of our Table Number 35.  So I appreciate your help on making sure that's correct.

             So if we look at that spectrum, I don't see from a patient standpoint that we have enough effectiveness to demonstrate the balance against the safety.  In addition, the stratification of the results, I think, in different areas of lumbar spinal stenosis leads great promise, and I would very much like to hear if we can define a specific area of lumbar stenosis that does benefit better than a general category of lumbar stenosis.  In other words, specific indication of a regional anatomic deficit that we can improve with this device.  Because I believe it's an innovative device and has greet promise.

             DR. YASZEMSKI:  Thanks Dr. Kirkpatrick.  Other comments?  Dr. Witten, have we discussed this to the FDA's satisfaction?

             DR. WITTEN:  Yes, thank you.

             DR. YASZEMSKI:  Thanks so much, Dr. Witten.  We're going to proceed now to the second open public hearing, now that we've discussed the FDA questions.  Is there anyone else in the room who wishes to address the panel at this time?  If so, please come forward to the podium.  Seeing none, we're going to proceed to the FDA and sponsor summations.  I'll ask the sponsors -- the sponsors have indicated to me that they have an answer to Dr. Kirkpatrick's earlier question regarding the table, and please include that in your summation when you come up, if you would please.  FDA?

             DR. WITTEN:  Perhaps can we have a 10-minute break before the summation?

             DR. YASZEMSKI:  Yes, ma'am.  We'll have a 10-minute break.  It's now 2:25.  We'll pick up again at 2:35.  Thanks.

             (Whereupon, the foregoing matter went off the record at 2:26 p.m. and went back on the record at 2:38 p.m.)

             DR. YASZEMSKI:  Alright folks.  If I could ask everybody to wander to your seats, we'll go ahead and get started.  As I said, we were going to start with presentations by both, but the FDA will not give a summation.  We're going to proceed right to the sponsor summation.  If the sponsors are ready, please do come forward and give your summary.  Dr. Andersson?

             DR. ANDERSSON:  Thank you very much, Mr. Chairman and members of the panel.  Outcomes of clinical studies depends on your measurement tool.  As I showed in my presentation, result of non-operative treatment in our study was similar to that reported in the literature, and yet we had only a four percent success rate by our criteria.  Similarly, the X STOP results are similar to those of laminectomy reported in the literature, and yet the aggregate was only about 40 percent.  Despite the high requirements, we met our primary endpoint as we had agreed upon with the FDA.  We anticipated a difference of 22.5 percent between the groups, and ended up with a 40 percent difference.  The patient satisfaction was 70 percent, symptom severity improved by 58.3 percent. 

             We did choose non-operative treatment as control, and I would choose non-operative treatment as my control if I were to redo this study, for the reasons that I mentioned before.  The patient population, while not homogenous, really can't be homogenous because spinal stenosis is, as we've heard from panel members, such a varying disease entity, with all sorts of presentations clinically, and with all sorts of dimensions on the spinal canal addressable by different types of procedures. 

             The X STOP is a very innovative device.  It is unusual in the sense that it addresses a problem within the spinal canal without entering the spinal canal.  It's also unusual in the sense that it leaves the door open for additional procedures should they be necessary.  And so we're not closing the door as with the laminectomy, where we really have no return.  To provide patients the opportunity given the low risk in my opinion would be a major step in the right direction.  Thank you for the opportunity.

             DR. YASZEMSKI:  Thanks very much Dr. Andersson.  I'd also like to ask, Dr. Yerby did you discuss with Dr. Kirkpatrick the numbers.  And if you haven't and would like to do so, now is -- just a closing answer to a prior question.

             DR. YERBY:  Sure.  Based on your question earlier, I recalculated everything that we discussed and I agree with what you said earlier.

             DR. YASZEMSKI:  Okay, thanks Dr. Yerby.  Ms. Scudiero will now read the three possible panel recommendations options for pre-market approval applications.  Ms. Scudiero?

             MS. SCUDIERO:  The Medical Device Amendments to the Federal Food, Drug and Cosmetic Act, as amended by the Safe Medical Devices Act of 190, 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 the safety and effectiveness data in the application, or by applicable publicly available information.  Safety is defined in the act as the reasonable assurance based on valid scientific evidence that the probable benefits to health under the conditions of intended use outweigh any probable risks.  Effectiveness is defined as reasonable assurance that in a significant portion of the population, the use of the device for its intended uses and conditions of use when labeled will provide clinically significant results. 

             Your recommendation options for the PMA vote are as follows.  Approval, if there are no conditions attached.  Approvable with conditions: the panel may recommend that the PMA be found approvable subject to specific condition, such as patient or physician or patient education, labeling changes, or a further analysis of existing data.  Prior to voting, all the conditions should be discussed by the panel.  Not approvable: the panel may recommend that the PMA is not approvable if the data do not provide a reasonable assurance that the device is safe, or if a reasonable assurance has not been given that the device is effective under the conditions of use prescribed, recommended, or suggested in the proposed labeling.  Following the voting, the chair will ask each panel member to present a brief statement outlining the reasons for his or her vote. 

             DR. YASZEMSKI:  Thanks Ms. Scudiero.  Are there any questions from the panel members about these voting options before I ask for a main motion on the approvability of this PMA?  Seeing none, I'm going to ask for a motion.  I'm going to ask our lead clinical reviewer, Dr. Kirkpatrick, if he has a motion.  Dr. Kirkpatrick?

             DR. KIRKPATRICK:  I can put forth the motion, sir.

             DR. YASZEMSKI:  Please do.

             DR. KIRKPATRICK:  And if I may, I will give my reasons and then my motion so that my vote would be clear in my motion.  While verified in the cadaver model, the concept of preventing the narrowing of the canal, lateral recess, and foramen was not verified in the clinical study.  And while the specific population in my mind has not been adequately defined as far as who will benefit from this device, and the improvement in the device seemed reasonably small, although definitely measurable, I would move not approvable, with all due respect to my colleagues and friends in the sponsor's area, and my encouragement to them to define those areas so that we can have this device available for the appropriate patients.

             DR. YASZEMSKI:  Okay, we have a motion for not approvable.  And what we'll need to do is ask if there is a second for that motion. 

             DR. DIAZ:  Second.

             DR. YASZEMSKI:  We have a second so we'll no vote on that motion.  I'll go around the room and ask everybody to vote.  If you vote for the motion, you are voting to not approve this device.  If this motion passes, then this panel's work is done.  If not, I'll then ask Dr. Kirkpatrick for an alternate motion.  We have a motion for not approvable.  Dr. Kirkpatrick, you made it, and I'm going to just ask you formally to state your vote.

             DR. KIRKPATRICK:  My vote would be for the motion, and the reasons are in the motion.

             DR. YASZEMSKI:  And we're going to go around the room.  I'm going to go around the room counter-clockwise and go to Dr. Naidu.  Dr. Naidu?

             DR. NAIDU:  I will -- I'm not with the motion.

             DR. YASZEMSKI:  You're voting against the motion?

             DR. NAIDU:  I'm voting against the motion.

             DR. YASZEMSKI:  Dr. Naidu votes no, against the motion.  Dr. Kim?

             DR. KIM:  Even though I agree with so many things that Dr. Kirkpatrick states, and the fact that he's so thorough and thoughtful, unfortunately I will have to disagree with this motion.

             DR. YASZEMSKI:  Dr. Kim votes against the motion.  Dr. Diaz?

             DR. DIAZ:  For the motion.

             DR. YASZEMSKI:  Dr. Diaz votes for the motion.  Dr. Rudicel?

             DR. RUDICEL:  I vote against the motion.

             DR. YASZEMSKI:  Dr. Rudicel votes against the motion.  Dr. Finnegan?

             DR. FINNEGAN:  I vote for the motion.

             DR. YASZEMSKI:  Dr. Finnegan votes for the motion.  Dr. Ellenberg?

             DR. ELLENBERG:  I vote for the motion.

             DR. YASZEMSKI:  Dr. Ellenberg votes for the motion.  Dr. Li?

             DR. LI:  For the motion.

             DR. YASZEMSKI:  Dr. Li votes for the motion.  The votes is 5 for the motion, and 3 against the motion.  The motion for non-approvability passes.

             I'd like to go around the room now and ask everybody to comment on their reasons.  Dr. Kirkpatrick, you've already given a description of your reasons.  If you'd like to add to that, please do so.

             DR. KIRKPATRICK:  I don't really have an addition to my reasons, just a further encouragement to precisely define which of my patients will benefit from this device.

             DR. YASZEMSKI:  Thank you.  Dr. Naidu, you voted against the motion.  Your comments?

             DR. NAIDU:  Yes, I have several.  I think it is a less invasive procedure, it's a middle of the road approach.  I'm not a spine surgeon, but it makes sense that this a safe device.  I mean, the biggest concern here is dislodgement of the device posteriorly.  And provided the sponsor was going to set up a training camp to do this, I think that this is a good middle of the road approach because the sponsor met the primary endpoints, three out of four primary endpoints.  They met the physical function measurements by the ZCQ at 24 months.  Symptom severity was also significantly improved at 24 months.  Patient satisfaction was also improved.  And the only thing that really they did not demonstrate is radiographic efficacy.  And so I thought it was approvable, based on the data presented.

             DR. YASZEMSKI:  Thanks Dr. Naidu.  Dr. Naidu brought up an important point that I'd like to ask the remaining panel members to address when it becomes their turn.  And that is since the panel voted for not approvable, please make a comment to the FDA and to the sponsor as to what the sponsor needs to do to move the application from non-approvable to approvable.  Dr. Naidu has indicated that he thinks radiographic confirmation would be necessary.  And when we come back around, since I didn't specifically ask Dr. Kirkpatrick and Dr. Naidu, I'll ask them again if they have additional comments.  Dr. Naidu, is that the only thing you feel the sponsor needs to do to make this approvable, get radiographic confirmation?

             DR. NAIDU:  I'm not even so sure that should be a strict criteria.  All I'm saying is it's approvable mainly because the primary efficacy endpoints were met.

             DR. YASZEMSKI:  Okay.  Thank you.  Dr. Kim?

             DR. KIM:  There are a number of issues related to this PMA, the most significant of which is the potential bias that we've discussed on numerous occasions that could come from both the physician and the patient.  However, from what I can tell there appears to be a reasonable level of certainty that this device does provide some improvement in symptoms.  And we saw this in various different statistical analyses.  Furthermore, the device makes intuitive sense in the mechanism of action.  It's simple, and it addresses something that we see clinically in that patients do better when they're bent forward.  It's also minimally invasive, and compared to traditional open laminectomy it is far safer.  I think we can all agree on that. 

             I care for many patients that are symptomatic enough that it affects their quality of life.  I live in California, and I think people may want to be a lot more active than people from other parts of the country.  That may or may not be true, but I do care for a lot of patients that for one reason or another do not want to undergo laminectomy, but at the same time epidural steroid injections are not enough to improve their quality of life.  I think this device offers an important option in the treatment of that patient with spinal stenosis that wishes to avoid the general anesthesia and potential risks of laminectomy.  For that reason, I voted against the non-approvable motion.

             And thinking about what would make this more approvable, from the standpoint of the panel as a whole.  Obtaining 3-year data to rule out concerning issue of the loss of benefit would be one.  But probably the most important thing is to further analyze the data to address the potential biases that are raised.  Maybe there's something within the analysis that wasn't looked at that can convince the panel that the biases that we looked at and the subjectivity is not as concerning.

             DR. YASZEMSKI:  Thanks Dr. Kim.  I'm going to go around to the voting panel members first, then I want to end up with our industry and consumer representatives.  I'm going to go to Dr. Diaz.

             DR. DIAZ:  From my perspective I believe that the device is an ingenious tool that will have future applications.  My concern was that the study had too many inconsistencies.  Far too many questions were not answered to my satisfaction.  The evaluation procedures were limited to subjective criteria.  Unfortunately within those evaluations, many of these patients either during or through the course of the evaluation became not mentally capable of answering those questions themselves, so that further undermined my ability to say that the subjective criteria that were already a concern in my mind were of any value at the end of the procedure.  There was no assessment of objective radiographic criteria that could answer to my complete satisfaction that the process that you were trying to prove existed really happened.  There were no MRIs, no CT scans that showed me that the foramina or the canal became larger with your tool, other than the seven fixed specimens you had.  So in the future I do believe that there is an application for this tool.  I do believe that there will be a limited number of people that will benefit from it.  I think you need to parse out the population in sections of components so that you can really figure out for whom this device will be useful. 

             The disparity between the leading center and the other centers in my mind creates a huge question.  There shouldn't be that huge difference between the designers and developers, and the rest of the people.  It has to be a pretty homogenous population, or a pretty homogenous result for me to believe that the answer is there.  So further definition of the population, further assessment with objective criteria, greater precision in the application of what it is you're trying to do, and a comparison with a surgical procedure.  Laminectomy does not have to be a mutilating procedure.  Laminectomies can be done with micro techniques.  They can be done through limited access.  And you can have exactly the same results with laminectomies as you do with a minimally invasive procedure otherwise.  Laminectomies can be done other spinal anesthesia.  They don't need to be done under general.  So many of these things, I think, can be addressed in a different manner.  I do believe you have a useful tool, you just need to refine its application.

             DR. YASZEMSKI:  Thank you Dr. Diaz.  Dr. Rudicel?

             DR. RUDICEL:  I don't have a lot to add, except that I still like the comparison of a non-operative to this technique because I think it is the middle of the road, and it is good that it's much less invasive.  I think we know a lot about laminectomies, and so I think your study design is a good one.  Albeit as I mentioned there are known problems with that kind of a study, but I think you tried to surmount them in the best way that you could. 

             Probably the best area where you could improve something is to try to stratify those patients who did well to figure out who those patients were.  I also think using subjective criteria is an excellent way, if you have the right tool, and I don't know enough about the tool that you used, but it seems that is what's used in spinal stenosis studies, and has been used.  So I would just be sure that your tool is the most appropriate one, and certainly the SF-36 has been used in lots of orthopedic studies now.  And I think the subjective approach is very good because we all know that we don't treat x-rays, although radiographic data to substantiate what you've done would be helpful.  So other than that I don't have.

             DR. YASZEMSKI:  Okay, thank you Dr. Rudicel.  Dr. Finnegan?

            DR. FINNEGAN:  First of all I want to reiterate that this is incredibly innovative and creative, and you need to be encouraged to continue to work on this.  I do think there is going to be a patient population that this turns out to be useful for, but I don't think you've outlined that.  I think you tried to take too big a patient population on. 

             I also think that not to beat a dead horse, but the biomechanics or the biological response to altered biomechanics are going to be important for two reasons.  One, it'll help with your patient population definition, but it may also be that if you alter the material properties of your implant, that you may have different patient populations that you can work with.  So I will beat that dead horse and tell you I really think you need to look at it.

             I actually wonder if including a group with laminectomies so that you can demonstrate the difference between the conservative, your implant, and the laminectomies might not improve things.  And I also agree you need some radiological backup.

             DR. YASZEMSKI:  Thanks Dr. Finnegan.  Dr. Ellenberg?

             DR. ELLENBERG:  I believe all of my concerns and suggestions for improvements with one exception have been covered by those voting in favor and those voting against the motion.  The only point I would raise which I didn't raise during my presentation or discussion before has to do with the validation of the Zurich scale.  My understanding in reading the original paper was that was validated at six months, and the current study is using this measure as a primary endpoint at two years.  And I don't know if that has been validated, and I'm not just aware of it two months out.

             DR. YASZEMSKI:  Thanks Dr. Ellenberg.  Dr. Li?

             DR. LI:  I take no pleasure in voting against this device, because I think it's very clever in its design.  I like the fact that it's non-invasive.  And best of all, I kind of like that it's got a very clear potential mechanism for benefit, that is, reducing the amount of flexion-extension.  That being said, I'm very frustrated that there's no clinical data that actually addresses that particular mechanism, so we don't really know if that's what's going on or not.  Superimposed upon that are the very high variations, the overall success rate.  And my only comment on things like they did better in severity, and did better in these other individual scores is like the coach that says, well, we out-gained them and we had more running yards but we still lost the game.  So I think at the end of the day, I think you've got to -- I'm really just kind of reiterating what others have said in a different way, is that you've got an elegantly simple device that has the high potential of providing good patient benefit, but essentially the homework and the documentation to demonstrate that your hypothesis for action and what you actually got are in fact related.  And things like the issues with two levels being better than one, patient age.  You've identified a whole host of potential variables I think that could narrow down to a very specific patient population that you could give great comfort and care to.  But I think in the absence of that, and you take on all comers, you know, you have one chance in three or four that that particular patient is going to come out ahead.

             DR. YASZEMSKI:  Thanks Dr. Li.  Dr. Doyle?

             DR. DOYLE:  I think I probably would have voted no.  And I feel split in this, as partially it's coming from a research background but also looking at it as a consumer, and as someone who has been an orthopedic user, I suppose I should say, in full disclosure, knowing how different it is to be pain-free.  And the thing that bothered me, I think, with the study overall was that there were so many little things that I'd like to have seen a more clearly defined protocol where we didn't have epidurals in the X STOP group, and some clear, defined objectives for defining when laminectomy was done.  It concerns me that at two years the data was less good than it seemed to be at one year.  The fact that it truly wasn't a blinded group, and that we don't know what the manipulation, just in and of itself was doing when you did that, inserted the X STOP in the spine.  I'd like clearer objective criteria for the outcome.  I'd have liked a third group, too, with the laminectomies.

             And having said all of that, as a patient, I regret that this is not going to be an option for me to have, because I don't think there's anything to indicate that all of these things prove that there was anything dangerous.  I think they did prove efficacy, and they didn't prove that it was not safe, so I would have voted no.

             DR. YASZEMSKI:  Thank you Dr. Doyle.  Ms. Maher?

             MS. MAHER:  Well, I'd like to comment a little bit on some of the comments I've heard thus far.  First of all, I'd like to take a little bit of exception to the way Dr. Kim mentioned that the study had bias.  I think when you do a random size of two, a block of two, you might give the appearance for bias but I don't think there was any evidence that there was any bias in this study.  So I'd like that to be clearly on the record.

             Second, I'd like everybody to remember that our goal is to be looking at products as a reasonableness, and we're supposed to be balancing risk versus benefit.  And I heard everybody earlier say that they thought that this product was safe as it was designed.  And the only thing I heard Dr. Kirkpatrick say was that it wasn't effective in radiographs because we didn't have radiographs to show it.  But that in the patients that actually had done better through the subjective methods, it had been effective, at least in that 33 percent.  So I guess my feeling is a little bit of similar to what Dr. Rudicel said.  So you have a bad x-ray or a good x-ray. That doesn't stop you from having the pain.  And this did help the pain in that 33 percent of the patients.  It would have been and would be a good middle step.  And I think it's something that as a panel everybody needs to continue to look at and think about is reasonable assurances of safety and effectiveness, and least burdensome to get where we're going.  We have now told this company that they have to go back -- or told the FDA, recommended, that it's not approvable with the data that they have here, even for a more limited population.  Whereas, is it possible we could have come up with some conditions for them to go and slice and dice the data to get where we needed to go as well.  So I'm a little disappointed.

             DR. YASZEMSKI:  Thank you Ms. Maher.  Dr. Kirkpatrick, would you like to close up?

             DR. KIRKPATRICK:  Well, you asked after the motion what specifics would I suggest for the proposer or the sponsor to address for resubmission, and I fully hope that we'll see one soon.  I'm not fully aware of what regulations you'd have to go through to get to the panel again, but from my standpoint if you validate clinically what you showed in the lab with a reasonable radiographic study post-op with the X STOP, that would satisfy one of the three problems I had with the whole thing.  And that's a key issue, because you based your philosophy on preventing the foramen from narrowing, or preventing the canal from narrowing on extension, and yet in your clinical study you showed no evidence that that was stopped.

             I think the other issues are related to the specifics of the indications which patients will benefit.  I firmly believe that if you do study the anatomic types, you will get good information there which indicates which patients do better and which patients don't do better, as well as I have a hypothesis that two-leg symptoms versus one-leg symptom may also give you a little bit of a difference, if not a larger difference.  I think those things are potentially available to you.  But when we asked during the presentations, nobody could provide that information.  So those three things would be what I would suggest to be able to come back to panel.

             DR. YASZEMSKI:  Thanks Dr. Kirkpatrick. Dr. Witten, have you any comments?

             DR. WITTEN:  No.  I'd like to thank the panel for their work today.

             DR. YASZEMSKI:  Thank you Dr. Witten.  I also would like to take care of one final thing.  We thank the panel for their work.  I specifically thank three members of the panel for whom this is the last meeting, Dr. Li, Dr. Finnegan, and Ms. Maher.  I thank you all three for your service to this panel.  I thank the sponsors for a thorough presentation.  And we're adjourned.

             (Whereupon, the foregoing matter went off the record at 3:25 p.m.)