UNITED STATES OF AMERICA

           FOOD AND DRUG ADMINISTRATION

 

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    ORTHOPEDIC AND REHABILITATION DEVICES PANEL

                      of the

        MEDICAL DEVICES ADVISORY COMMITTEE

 

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              WEDNESDAY, JUNE 2, 2004

 

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            The above-entitled Meeting was conducted at 10:00 a.m., at the Gaithersburg Marriott, Salons A, B, C, D, 9751 Washingtonian Boulevard, Gaithersburg, Maryland, Dr. Michael J. Yaszemski, Panel Chairperson, presiding.

 

PANEL MEMBERS PRESENT:

 

MICHAEL J. YASZEMSKI, M.D., Ph.D., Chairperson, Mayo      Clinic Graduate, School of Medicine

JANET L. SCUDIERO, M.S., Acting Executive Secretary

MAUREEN A. FINNEGAN, M.D., Voting Member, University

      of Texas, Southwestern Medical Center

JOHN S. KIRKPATRICK, M.D., Voting Member, University

      of Alabama, School of Medicine

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

      Pennsylvania State College of Medicine

SALLY L. MAHER, ESQ., Industry Representative, Smith

      and Nephew Endoscopy

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

      The Toledo Hospital

MARCUS P. BESSER, Ph.D., Deputized Voting Member,

      Thomas Jefferson University

BRENT A. BLUMENSTEIN, Ph.D., Deputized Voting Member,

      TriArc Consulting

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

      Member, Detroit Medical Center

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

      University of California, San Diego


PANEL MEMBERS PRESENT: (cont.)

 

JAY D. MABREY, M.D., Deputized Voting Member,

      University of Texas, Health Science Center

CELIA WITTEN, M.D., Ph.D., FDA Division Director,

      General Restorative & Neurological Devices

 

SPONSOR PRESENTERS:

 

SCOTT L. BLUMENTHAL, M.D., Texas Back Institute,

      Plano, Texas

WILLIAM P. CHRISTIANSON, Vice President of Clinical

      and Regulatory Affairs, DePuy Spine, Inc.

BRYAN CUNNINGHAM, M.Sc., Director of Spinal Research,

      Orthopedic Biomechanics Laboratory, Union

      Memorial Hospital, Baltimore, Maryland

GEORGE DEMUTH, M.S., President, Stat-Tech Services,

      LLC, Chapel Hill, North Carolina

PAUL C. MCAFEE, M.D., Spine and Scoliosis Center,

      St. Joseph's Hospital, Towson, Maryland

 

FDA PRESENTERS:

 

SERGIO M. del CASTILLO, B.S., Biomedical Engineer,

      Lead Reviewer

JIANXIONG "GEORGE" CHU, Ph.D., MAS, Statistician

JOVE H. GRAHAM, Ph.D., Mechanical Engineer

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


                    AGENDA ITEM               PAGE

 

 

CALL TO ORDER:

Janet Scudiero.................................. 5

PANEL MEMBERS INTRODUCTION:.................... 10

UPDATE PANEL SINCE DECEMBER 11, 2003 MEETING:

Barbara Zimmerman.............................. 12

RETRIEVED CHARITE TOTAL DISC REPLACEMENT ANALYSIS:

Steven Kurtz................................... 18

SUCCESSFUL DISC PROPERTIES:

John Peloza.................................... 26

DISC ARTHROPLASTY:

David Polly.................................... 34

SPONSOR PRESENTATION:

DEPUY SPINE, INC.:

William Christianson........................ 40/77

Paul McAfee.................................... 42

Bryan Cunningham............................... 49

Scott Blumenthal............................... 60

George DeMuth.................................. 73

FDA PRESENTATION:

Sergio del Castillo............................ 80

Jianxiong "George" Chu......................... 98

Jove Graham................................... 114

CLINICAL INFORMATION REMARKS:

John Kirkpatrick.............................. 128

STATISTICAL ANALYSIS:

Brent Blumenstein............................. 144

GENERAL DISCUSSION:........................... 154

SPECIFIC FDA QUESTIONS:

Question 1.................................... 171

Question 2.................................... 183

Question 3.................................... 191

Question 4.................................... 204

Question 5.................................... 211

Question 6.................................... 219

Question 7.................................... 224

SPINE ARTHROPLASTY SOCIETY:

Steve Hochschuler............................. 237

SRS:

A. Van Ooij................................... 242

OSMA:

Pamela Adams.................................. 251


                 AGENDA CONTINUED             PAGE

 

 

FDA SUMMATION:

Celia Witten.................................. 257

PANEL RECOMMENDATION OPTIONS FOR PRE-MARKET

APPROVAL APPLICATIONS:

Janet Scudiero................................ 261

 

MOTION FOR NON-APPROVAL:...................... 266

MOTION DISCUSSION:............................ 266

VOTE ON MOTION FOR NON-APPROVAL:.............. 274

 

MOTION FOR APPROVAL WITH CONDITIONS:.......... 275

 

PROPOSED CONDITION 1:......................... 277

DISCUSSION ON PROPOSED CONDITION 1:........... 277

VOTE ON PROPOSED CONDITION 1 APPROVAL:........ 280

PROPOSED CONDITION 2:......................... 282

DISCUSSION ON PROPOSED CONDITION 2:........... 284

VOTE ON PROPOSED CONDITION 2 APPROVAL:........ 295

PROPOSED CONDITION 3:......................... 296

DISCUSSION ON PROPOSED CONDITION 3:........... 298

VOTE ON PROPOSED CONDITION 3 NON-APPROVAL:.... 300

PROPOSED CONDITION 4:......................... 302

DISCUSSION ON PROPOSED CONDITION 4:........... 302

VOTE ON PROPOSED CONDITION 4 APPROVAL:........ 304

PROPOSED CONDITION 5:......................... 305

DISCUSSION ON PROPOSED CONDITION 5:........... 305

VOTE ON PROPOSED CONDITION 5 APPROVAL:........ 314

PROPOSED CONDITION 6:......................... 318

VOTE ON PROPOSED CONDITION 6 APPROVAL:........ 319

 

VOTE FOR APPROVAL WITH 5 CONDITIONS:.......... 325

 

COMMENTS ABOUT REASONS FOR VOTING:............ 326

 

ADJOURN:

Michael Yaszemski............................. 331

 

 

 

 


               P-R-O-C-E-E-D-I-N-G-S

                                         9:58 a.m.

            MS. SCUDIERO:  Good morning.  We're ready to begin this meeting of the Orthopedic and Rehabilitation Devices Panel.  I'm Jan Scudiero.  I'm the Acting Executive Secretary of this Panel and a reviewer in the Division of General Restorative and Neurological Devices.  We have the usual housekeeping matters first.  If you haven't already done so, please, sign in at the tables outside the door.  The agenda information for this meeting is on the tables.  There is also Advisory Committee website information about upcoming meetings, summary meetings and transcripts.

            Before I turn the meeting over to Dr. Yaszemski, I'm required to read two statements into the record.  The Deputization of Temporary Voting Members statement 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 June 2nd and 3, 2004:  Marcus P. Besser, Ph.D., June 2nd and 3rd, Brent A. Blumenstein, Ph.D. on June 2nd, Fernando G. Diaz, M.D., Ph.D. on June 2nd, Choll W. Kim, M.D., Ph.D. on June 2nd and 3rd, Jay D. Mabrey, M.D., on June 2nd and 3rd, and Michael B. Maher, M.D. on June 3rd, the morning session only.

            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.  This is signed by Daniel G. Schultz, M.D., Acting Director, Center for Devices and Radiological Health on May 28th, this year.

            The Conflict of Interest statement for June 2nd.  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 Panel participants.

            The Conflict of Interest statute prohibits 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, waivers have been granted for Dr. John Kirkpatrick and Jay Mabrey for their interest in firms that could be affected by the Panel's recommendations.

            Dr. Kirkpatrick's waiver involves a stockholding in a parent of the sponsor, which is valued between $15,000 and $25,000.  Dr. Mabrey's waiver involves consulting with an unaffected division of the sponsor's firm on matters unrelated to today's agenda.  Dr. Mabrey receives less than $10,001 for this consulting.

            We would like to note for the record that the Agency took into consideration certain matters regarding Drs. Maureen Finnegan, Choll Kim, John Kirkpatrick and Jay Mabrey.  Each of these panelists recorded current and/or past interest 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 event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participant should excuse himself or herself from such involvement and the exclusion will be noted in 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 involvement with any firm whose products they may wish to comment upon.

            Please, note that Drs. Besser, Blumenstein and Diaz, Kim and Mabrey are deputized voting members for today's meeting.  The remaining tentatively scheduled meetings for this Panel, this calendar year, are August 12th and 13th and December 2nd and 3rd.  Please, remember these are tentative dates and monitor the CDRH Panel website for updated Panel meeting information.

            I would now like to turn the meeting over to Dr. Yaszemski.

            CHAIRPERSON YASZEMSKI:  Thanks, Mrs. Scudiero.  Good morning.  I'm Dr. Michael Yaszemski.  I'm the Chairperson of the Orthopedic and Rehabilitation Panel.  I'm an orthopedic surgeon and a chemical engineer.  I work at the Mayo Clinic in Rochester, Minnesota.  My area of interest in orthopedics is spinal surgery and my engineering area of interest is polymeric biomaterials.

            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 DePuy Charite Artificial Lumbar Disc intended for spinal arthroplasty in skeletally mature patients  with degenerative disc disease at one level from L4 to S1.

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

            DR. KIRKPATRICK:  My name is John Kirkpatrick.  I am an Associate Professor of Orthopedic Surgery at the University of Alabama, Birmingham.  I also have significant background in biomechanics and training in bioengineering.

            DR. NAIDU:  My name is Sanjiv Naidu.  I'm an Associate Professor of Orthopedic Surgery at Penn State College of Medicine.  My area of expertise is in orthopedic surgery and material science.

            DR. KIM:  I'm Choll Kim.  I'm an Assistant Professor at the University of California at San Diego.  I'm fellowship trained in spine surgery and that is my area of expertise.

            DR. FINNEGAN:  I'm Maureen Finnegan.  I'm an Associate Professor of Orthopedic Surgery at UT Southwestern and my area of expertise is basic science, particularly with bone healing.

            DR. MABREY:  I'm Jay Mabrey.  I've just been reassigned to Baylor University Medical Center in Dallas where I'm the Chief of the Department of Orthopedics.  My expertise is in total joint replacement, hip and knee, and I also have extensive experience in analysis of particulate wear debris.

            DR. DIAZ:  My name is Fernando Diaz.  I am a Neurosurgeon, Professor of Neurosurgery at Wayne State University.  One of my areas of interest is spine surgery and reconstruction of the spine.

            DR. WITTEN:  I'm Dr. Celia Witten.  I'm the FDA representative at the table and the Division Director of the Reviewing Division for this product.

            MS. LUCKNER:  I'm Kleia Luckner.  I'm the Consumer Rep.  I am a hospital Administrator from Toledo, Ohio.

            MS. MAHER:  My name is Sally Maher.  I'm the group Director of Regulatory and Clinical with Smith and Nephew and I'm here as the Industry Representative.

            DR. BESSER:  I'm Marcus Besser, Associate Professor at Thomas Jefferson University.  My background is in biomechanics and bioengineering.  My current interests are in gait and motion analysis and biomechanics of the hip and the knee.

            DR. BLUMENSTEIN:  My name is Brent Blumenstein.  I'm a Biostatistician working independently from Seattle.

            CHAIRPERSON YASZEMSKI:  Ms. Scudiero has already introduced herself.  I would like to also note for the record that the voting members here at the Panel table constitute a quorum as required by 21 CFR Part 14.  Next, we're going to ask Ms. Barbara Zimmerman, Chief of the Orthopedic Devices Branch at FDA to update the Panel on several matters deliberated on at the last meeting of the Panel in December 2003.  Ms. Zimmerman?

            MS. ZIMMERMAN:  Good morning, everyone.  I'm going to give a brief update today since our last Panel meeting, which was in December of 2003.  Since that meeting, we have taken action on a few items from previous Advisory Committee meetings, one of which was the infused bone graph manufactured by Wyeth.  We approved the PMA on April 30, 2004.  This PMA is now owned by Medtronic Sofamor Danek and this device is indicated for treating acute and tibial fractures that have been stabilized with IM nail fixation after appropriate wound management.  Infused bone graph must be applied within 14 days after the initial fracture.  Perspective patients should be skeletally mature.

            At that last Panel meeting on December 11, 2003, we discussed the topic that we discussed was the reclassification of inner body fusion devices, cages and I just wanted to update everyone and let them know we are in the process, FDA is in the process of generating a special controls guidance document and a Federal Register notice.  We continue to work on this and you can monitor the Federal Register notice webpage in order to see when we do this.  Although, I don't anticipate it will be in the next month.  It will be much later than that.

            Other significant approvals or clearances are the HDE for the OP-1 Putty by Stryker.  It was a humanitarian device exemption which did not require a Panel meeting.  It was a collaborative review between the Center for Drugs and Biologics and CDRH.  This approval occurred on April 17, 2004 and it is indicated for use as an alternative to autograft and compromised patients requiring revision, posterior lateral lumbar spinal fusion for whom autologic bone and bone marrow harvest are not feasible or are not expected to promote fusion.

            In addition, we have approved a PMA for the Oxford Meniscal Unicompartmental Knee, Phase III.  This is manufactured by Biomed.  No Panel meeting was necessary to approve this PMA.  It was approved on April 21, 2004 and was indicated for use in patients who have osteoarthritis or avascular necrosis limited to the medial compartment of the knee and indicated to be implanted with bone cement.

            We have also cleared two human demineralized bone matrix, DBM, based bone void fillers.  One was the Exactech Resorbable Bone based which was February 27, 2004, and there was also the right AlloMatrix Putty, which was cleared March 5, 2004.  In addition, we have cleared a PMA cement for pathological fracture of the vertebral body.  This was submitted by Kyphon for the KyphX Bone Cement and it was cleared on April 1, 2004.

            That concludes my update.  Thank you.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Ms. Zimmerman.  We are now going to proceed to the open public hearing portion of today's Panel meeting.  I would like to ask, at this time, that all persons addressing the Panel speak clearly into the microphone, the transcription is dependent upon, this means to provide an accurate recording of the meeting.  Please, also, when you come up identify yourself and your affiliation and any conflicts that you may have, so that we can enter them into the record.  Ms. Scudiero is now going to read a statement prepared for open public hearings.

            MS. SCUDIERO:  Both the 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 individuals presentation.  For this reason, FDA encourages the open public hearing speaker at the beginning of your oral statement to advise the Panel of any financial relationship 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 of your travel, lodging or other expenses in connection with your attendance at the meeting.  Likewise, FDA encourages you, at the beginning of your statement, to advise the Committee if you do not have such financial relationships.  If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.

            I would like to note for the record that seven patients and family members of patients with lumbar spine disease wrote to the FDA requesting approval of this product, the DePuy Charite Artificial Lumbar Disc.  And I have another short statement.  We received two abstracts of two presentations given at the Spine Week 2004 meeting currently being held in Porto, Portugal, May 30th through June 5th.  One abstract contains information about the complications related to the Charite device and the other was a case report of osteolysis associated with the presence of polyethylene wear debris.  Okay. 

            CHAIRPERSON YASZEMSKI:  Okay.  Thanks, Ms. Scudiero.  And prior to this meeting, we received six requests to speak at the open public hearing.  Three people will speak in the morning and three people will speak in the afternoon.  We're going to have a second open public hearing in this afternoon's session.  The morning presenters are going to be Dr. Kurtz, Dr. Peloza and Dr. Polly.  In the afternoon, we will have talks from Dr. Hochschuler, Dr. Ben Ooij and Ms. Adams.

            And I would like to proceed now if Dr. Kurtz is here.  I ask Dr. Kurtz to come up and give his presentation.  And I'll mention for all the speakers that we have a lot of time in the meeting for your presentations and I will put the time in, so that you have a two minute sum-up when the light up by you turns yellow, you've got two minutes to go.  And Dr. Kurtz, you are scheduled for 10 minutes.

            DR. KURTZ:  Thank you very much.  Good morning.  My name is Steve Kurtz and I'm a principle engineer and the office director of X-Bone in Philadelphia.  I also have a research faculty appointment at Drexel University.  The work that I'm going to present today was made possible with institutional funds provided by Medtronic Sofamor Danek.  Medtronic Sofamor Danek also covered my travel costs to be here today.

            I do not have any personal financial interests in either DePuy or Medtronic.  For the past 14 years, I have been performing research on the clinical performance of Ultra High Molecular Weight Polyethylene.  I have authored a textbook on the subject of clinical performance of Ultra High Molecular Weight Polyethylene.  I am the director of a Hip and Knee Implant Retrieval Program at Drexel University where I am studying the effect of in-vivo oxidation on the mechanical properties and surface damage of polyethylene.

            I would like to thank the FDA for the opportunity to present before the Panel.  I would also like to thank the Panel Members for their time and attention this morning.  My purpose in speaking here today is to present the analysis of a retrieved Charite total disc replacement.  This component was retrieved by Dr. John Peloza in Dallas, Texas who I understand is going to be speaking after me.  And it is my understanding from speaking with DePuy that this event has been reported to the FDA.

            The analysis I will be presenting today was performed with the consent of the patient and the revising physician.  This slide shows the polyethylene component immediately after it was retrieved in the operating room.  The larger image shows the component after it was thoroughly cleaned and disinfected.  I would like to draw your attention to the transverse cracks that were observed on the surface of the polyethylene core, but only on one side, which was labeled as Side 2.

            We can deduce that these cracks were present in the polyethylene core while it was implanted as they were observed on the surface immediately after it was removed from the patient, as is shown on the image at the right.  I don't know if you can see that here, but they are right here.  If you look closely, I have oriented the images approximately the same so the core is lined up the same way.  You can see also how blood has been drawn up under the crack and filtered in through the cracks in the material.

            I would like to also draw your attention to damage near the rim.  Dr. Peloza will provide more details about this case, but in synopsis this device was implanted at the L5-S1 level in a 49 year-old female patient in February 2001.  These are radiographs obtained prior to the patient undergoing posterior fusion on October 2002 after 1.6 years of implantation.  The device was ultimately removed in January 2004 and Dr. Peloza can comment about the reasons surrounding its removal.

            It was implanted a total of 2.9 years.  The objectives of this retrieval analysis were to answer the following questions as they pertained to the polyethylene component.  Is there evidence of oxidation and degradation of mechanical properties?  Is there evidence of adhesive abrasive wear?  Is there evidence of damage?  What are the stress distributions in the polyethylene?

            To accomplish this goal, we used a variety of methods that are available to us.  We used white light interferometry.  We used optical microscopy of thin sections, FTIR, small punch testing, MicroCT and we also used finite element modeling.  Here are the images and measures obtained from the white light interferometry at two distinct areas near the pole on the polyethylene surface.  We looked for evidence of removal of machining marks which would be indicative of abrasive or adhesive wear.

            We found only irregular machining marks as well as some evidence of multidirectional scratches.  Because of the presence of original machining marks, we concluded that there was minimal evidence of adhesive abrasive wear on the surface.  Here is a thin slice from the polyethylene component made with a Microtome.  The central axis of the component is on the right side.  The rim of the component towards the left.  During Microtoming, the section fragmented near the rim where it is only 3 millimeters thick.

            This is a cross-sectional view of one of the transverse cracks that I mentioned previously.  The crack is not parallel to the surface and its trajectory is such that it angles toward the pole or the center of the component.  This crack trajectory is not consistent with the lamination.  In addition, this image shows no evidence of a white band or any consolidation defects.

            Following the standard protocol, the oxidation index was measured through the thickness of the component, as shown here in the top right.  The oxidation as plotted here with the X axis denoting the distance from the side to surface.  We see that there are low levels of oxidation at the surface.  The oxidation drops down to near undetectable levels near the center of the component.

            In addition, using another standard protocol, we were able to assess the mechanical properties near the surface of the component where the oxidation was greatest.  Here is a comparison of the low displacement curb of the Charite polyethylene near the surface, that's in white, along with the comparison to a historical control, shown in yellow.  Consistent with low levels of oxidation, we found that the polyethylene exhibited comparable ductility and ultimate strength as a historical control.

            The retrieval analysis also included MicroCT scanning of the polyethylene core to evaluate internal crack trajectories.  Here is a two dimensional slice, MicroCT slice, where we can exam/ observe the trajectory, right here, of the transverse crack, which is consistent with what we saw in the FTIR sectioning.  On this cut view of the three dimensional reconstruction of the retrieved component, we can see some evidence of what appears to be pit formation.  Based on MicroCT images and digitized coordinance of the retrieved component, a finite element measure of the Charite was constructed.

            Contract was simulated between the end plates and the polyethylene component as well as between the metallic ring and the polyethylene.  Polyethylene material properties were based on the small punch testing described previously.  The inferior edge of the polyethylene was fixed.  The top surface was loaded axially with 800 Newtons and a 10 newton meter extension moment was applied, consistent with actually the ASTM standard for wear testing.

            To validate the model, we compared the orientation under full extension to what we observed in the patient's radiographs.  We found good agreement between the model positioning and what was observed in the radiographs.  From the finite element results and full extension, we observed peak tensile stresses at the edge of contact.  That's right there, that red line right there.  The 25 megaPascal fringes correspond to the true yield stress for polyethylene.  This tensile stress distribution is similar to what is observed in total knee replacements where the polyethylene is stretched at the edge of contact.

            A MicroCT slice here which is taken at a slightly different axial position shows the transverse crack at the location or near the location of the high tensile stresses at the edge of contact.  Here is another photograph of the retrieved Charite implant.  Especially note again the large damage region inside the rim and here are the transverse cracks.  Here are the minimum principle stress distributions superimposed on the damage patterns.

            The high compressive stresses in the model are located where the end plates pinch the rim.  The polyethylene thickness at this location is only 3 millimeters, which is a concern in this loading mode.  The magnitude of the compressive stress during this pinching loading mode was comparable to what has been reported for total knee replacements.

            In conclusion, the retrieval analysis to date has shown that low levels of oxidation were measured at the surfaces of the polyethylene component, but these were not associated with substantial reduction and mechanical properties.  The surface damage observed on the core upon retrieval indicated that the direction of these cracks was not associated with the magnitude and distribution of oxidation.

            From the finite element analysis, we found regions of both high tensile and high compressive stresses in the polyethylene where the rim of the component was pinched between the end plates under full extension.  The regions of high tensile and compressive stress in the model corresponded to locations of transverse cracks or rim damage around the polyethylene component.  The stress results presented here for the design with the 3 millimeter rim thickness are expected to be sensitive to the properties of the polyethylene, the applied loading and also on the design and the size of the component.

            Thank you all for your attention.

            CHAIRPERSON YASZEMSKI:  Thanks, thanks very much, Dr. Kurtz.  May I ask Dr. Peloza to come forward now and give his presentation?  Dr. Peloza, you are also scheduled for 10 minutes.

            DR. PELOZA:  Good morning, Members of the Panel.  My name is John Peloza.  I'm a spine surgeon, orthopedic surgeon, board certified and fellowship trained with 14 years of clinical experience.  I have also trained fellows and medical students and residents.  I'm a member in good standing with all the academies in various licensing organizations.  I've been a principal investigator for several FDA trials and I am a principal investigator for the Maverick Trial in my center, Total Disc Trial.  And I would like to thank you for your time today.

            Today, my purpose of being here is to address my concerns concerning the LINK Charite Implant.  Before I do that, I would like to express my disclosures.  I am a consultant for Medtronic Danek.  They paid for my airline ticket, hotel room, but I don't own any stock in Medtronic.  I don't have any patents, royalties, agreements concerning any total disc replacements with any company or manufacturer and again I am an investigator for the Maverick Total Disc Replacement.

            I wanted to talk a little bit about motion technology and then get into my concerns specifically with the LINK Charite and my opinions based on the analogous fine literature, biomechanics and 14 years of experience.  Also, I would like to say that my comments are not meant to disparage any investigator, engineers or company representatives.  I know these people personally, many of them anyway, and I hold them in highest regard.  Again, it's only to discuss my concerns with the treating physician with the link disc.

             I would like to basically start with an overview of the properties of a successful disc and I would like to say first and foremost it has to last the lifetime of the patient.  It has to stand the test of time.  The average age of a person that would be a candidate for this procedure is about the mid-40s.  Most of the studies with fusions average age in around mid-40s and it can actually, on the studies, go down to the age of 18.  So it is a completely different patient population that would be getting a total hip or knee prosthesis.

            I think it is critical that these implants last for the life of the patients, because revision surgery to remove the implant particular from an anterior approach will be potentially life threatening in every case.  And at present, there is no consistently successful strategy to deal with a failed implant.  Secondly, Dr. Kurtz has gone over the material properties of the implant, and again, because it needs to last approximately 40 years, I think it precludes the use of high molecular weight polyethylene.

            The other issue I have with the implant is its fixation into the bone.  You need immediate fixation as well as long-term stability and I think this is inadequate.  This would prevent any loosening, subsidence or migration to the implant, which is a major issue.  If these problems occur, the implant will fail.  It would cause altered motion at the segment in question as well as the adjacent segments.  It is important to note if that should occur, then all the advantage of a motion device will be lost and all the disadvantages of alter kinematics and applied forces to this segment of surgery and also adjacent segments would be a problem.

            The screw pegs and spikes are only adequate in short-term and will fail under tensile loading.  The other properties of the successful disc prosthesis would involve range of motion and mobility and the implant should reproduce near normal range for motion and stability.  And again, if that doesn't happen, kinematics and loading of the segment is altered.

            Regarding the link disc specifically, we have clinical series in Europe, Australia, United States that essentially report results equivalent to fusion in regard to pain relief.  The U.S. trial is a prospective randomized trial with a control, an Anterior Lumbar Interbody Fusion with a BAK cage implant.  And they have clearly defined outcome criteria.  The U.S. trial produced superior clinical outcomes to the BAK control, but there are published studies that show significant re-operation rates between 5 and 20 percent with complication rates reported greater than 10 percent.  The U.S. study has shown re-operation rates of 5 percent for implant failure at 24 month follow-up and no series has greater than 11 years follow-up.

            Regarding the materials of the disc replacement, Dr. Kurtz has talked about the polyethylene that we explanted.  It is clear that I don't think the polyethylene as they have in this implant will last anywhere near 40 years or the lifetime of the patient.  Polyethylenes can be cross- linked.  This would significantly reduce wear.  It has been shown in total hip arthroplasty, but that is not the polyethylene that is in this implant.

            The forces in the lumbar spine are far different than in the hip.  The loading is different.  The wear properties will be different.  I concede that point.  Also, the spine is not a synovial joint, so some of the things that are problematic for polyethylene in a hip would not be happening at the spine.  However, we can see that the polyethylene does break down and potential to cause polyethylene fragments, which could induce osteolysis or at least severe inflammatory reactions which make revisions far more difficult.

            The fixation of the implant to the bone is considerably compromised.  The metal base is secured with a press fit with little spikes.  This is not adequate and will predictably fail.  Since the implant in the U.S. study has no porus coding for bony ingrowth, it really doesn't have any chance to achieve significant fixation at a later time.  So it is susceptible to loosening.  There are reports of dislocation of polyethylene core as well as metal implants and incidents of subsidence of the implant anteriorly, posteriorly and laterally.

            One of the problems with implanting these devices is the base plate has to be large enough to fit the entire rim of the disc.  If it doesn't do that, it will settle into or subside into the soft portion of the end plate.  Therefore, one needs to be skilled enough to get the exposure to get this implant in the right position, otherwise, it will be susceptible to failure.

            And I guess my last point would be that the surgeons who would be doing the surgery need to be skilled at getting that exposure, otherwise there are going to be problems with the implant.  I had some comments about kinematics.  Basically, the implant, even if it is placed in the exact right position, with the way the link is designed, it is still anterior to the incident axis or rotation of disc space, which would be likely to increase forces at the facet joint, another area that can cause pain, also it has been shown that there is increased rotational translation of this implant, which would again affect the facet joints.

            We have evidence that even with the implant, in, there is a significant amount of facet degeneration that occurs either before the implant was placed, and in the case of that patient, or occurred after the implant was in approximately three years.  I would like to just conclude that because of my experience revising a failed link, I think that it is a problem and that the idea that we're just going to fail -- rescue failed disc replacement with posterior fusion will probably not work.  It didn't work in our experience and it hasn't worked in published studies so far.

            Therefore, we will have to remove them from the anterior approach and the potential complication from the anterior approach to the spine is life threatening in every case, and that only surgeons with extension training and experience with anterior lumbar spine surgery and placing of spinal implants should be involved in the surgery.  Thank you for your attention.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Dr. Peloza.  I'll next ask Dr. Polly to come up.  Dr. Polly is a professor and chief of spine surgery at the University of Minnesota.  Dr. Polly?

            DR. POLLY:  Thank you, Dr. Yaszemski and Panel Members.  You've stated my current job position and my area of expertise is in spine surgery.  My disclosure statement, I paid my own way for travel to the D.C. area where I lived until about six months ago.  I drove up on my own from Bethesda.  Given the current cost of gas, that's a different experience than it was a year ago.  In terms of relationships with companies, in the past years I have conducted teaching programs for DePuy, Medtronic and Synthes in an unpaid fashion.  Since my departure from the military, I now have a consulting relationship with Medtronic.

            I'm excited about this new technology of disc arthroplasty.  It is my professional hope that it will allow us to make patients better and to achieve these results faster than current fusion technology.  This technological advance represents a paradigm shift in our expectations of spinal implant performance.  Until now, all spinal implants were temporary internal stabilizing structures serving their purpose until the biologic solution of fusion was achieved.

            Disc arthroplasty represents a new level of demand in that it is expected to function for the remaining lifetime of the patient.  When it succeeds, it will be a quantum leap forward.  When it fails, it will be a substantial revision challenge.  The challenges facing disc arthroplasty after its approval will include the challenge of indications, both on label as approved by the FDA and off label as defined by clinical use and clinical experience as well as the challenge of revisions.

            Revisions of any implant device are inevitable.  These revisions will be due to infection, dislodgement, malposition and eventually to wear or wear debris.  The initial conventional thought as a result of our clinical experience with threaded cylindrical interbody devices, such as the BAK and the TFC was that for a well-positioned device all that was needed was an instrumented posterior or post lateral fusion.  This is a relatively low risk procedure and the benefits of a motion device would certainly seem worth it.

            Emerging non-U.S. data suggests that this unfortunately may not be the case.  Specifically, the series by Cinotti showed that only three of eight cases established in this fashion has good or excellent results.  Dr. Van Ooij will describe his own experience in those series with larger numbers.  Professor Frasier from Australia in his experience with a different motion device found that better clinical results were achieved with the combined anterior and posterior salvage strategy.  But unfortunately, this comes at a price.

            In his series of eight revisions, five were converted to ALIF where he used a contralateral anterior approach, and even so there were still two major vascular injuries.  So it is imperative that implanting surgeons understand the difficulties associated with revision procedures and that these revisions are potentially life threatening.  They must then ask themselves if they are prepared to undertake such revision cases.  If they are not prepared to do so, then they must ask themselves if they ought to be implanting the device.

            I know that my current group as a regional referral center will be facing these difficult revision cases whether we ever implant a single device or not, and I expect this will be a daunting task.  Any anterior revision case is high risk.  Iridal injuries come, but we can certainly place iridal stance to aid identification and facilitate repair should an injury occur, that's why identification and mobilization do to scar formation is extremely problematic.  To date, most of the time if the vessels could not be adequately mobilized, there were alternative salvage strategies available.

            Given the bulk of all the current disc arthroplasty designs, significant vessel mobilization will be required.  If the implant must come out, such as will be the case for dislodgement or infection, then the vessels will have to be adequately mobilized so the revision will be not be able to be accomplished.  Strategies for minimizing vascular scarring and allowing remobilization will be crucial for lessening the risk associated with inevitable revisions.

            The concept of joint registries has appeal.  Lessons learned from the Swedish Joint Registry have been helpful in early identification of problems that otherwise would have taken much longer to detect.  Such a registry could provide early warning and possible voidance of significant problems.  However, U.S. experienced today from the American Academy of Orthopedic Surgeons attempts to develop such a hip and knee registry has had minimal success with less than 300 cases having pre and post-operative data enrolled in the registry to date.

            This was an effort that initially predated the HIPAA constraints that make such prospective data collection even more difficult.  Unfortunately, I suspect that our current legal and regulatory environment would preclude this from being a successful venture.  In summary, it is in all of our best interests that this device is used prudently, trained for intensively and lessons learned disseminated widely.  I look forward to hearing the presentation of the complete clinical trial data and the Panel's deliberation.  Thank you very much.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Dr. Polly.  I would like to ask now if there is anyone else present who would like to address the Panel?  If so, please, raise your hand, get recognized and come forward.  Seeing no one, we will now proceed to the sponsor's presentation on this PMA for the DePuy Charite Artificial Lumbar Disc intended for spine arthroplasty in skeletally mature patients with degenerative disc disease at one level, from L4 to S1.

            We will have the sponsor and FDA presentations before lunch.  After lunch, the Panel will deliberate on the approvability of the PMA.  Before the Panel votes, there will be another open public hearing and a time for FDA and sponsor summations.  I would like to remind public observers at this meeting that while this meeting is open for public observation, public attendees may not participate, except at the specific request of the Panel.

            We will begin now with the sponsor presentations.  The first, DePuy Spine Incorporated speaker is Mr. William Christianson, Vice President of Clinical and Regulatory Affairs.  He will introduce the other DePuy Spine presenters.  Mr. Christianson?

            MR. CHRISTIANSON:  Good morning, Mr. Chairman and ladies and gentlemen of the Panel.  I am very pleased to be here today to report the results from the PMA for the Charite Artificial Disc.  My name is Bill Christianson and I am the Vice President of Clinical and Regulatory Affairs.  I am a full time employee of the sponsor, DePuy Spine.

            The Charite Artificial Disc is a lumbar disc prosthesis.  It is composed of two cobalt chromium end plates and an ultra high molecular weight polyethylene core.  The device is indicated for degenerative disc disease at a single level, at either L4-L5 or L5-S1 and we're here today to present the results from our multicenter IDE study with 24 months follow-up.

            The presenters today will be myself, I've already been introduced, Dr. Paul McAfee from Towson Orthopedic Associates of Towson, Maryland, Bryan Cunningham from the Union Memorial Hospital, Baltimore, Maryland, Dr. Scott Blumenthal from the Texas Back Institute of Plano, Texas and George DeMuth a statistician from Stat-Tech Services.  In addition, we have a number of other consultants with us who we may introduce later to answer specific questions that may be raised by the Panel.

            This device is different from previous devices presented before this Panel because it has an extensive clinical history outside the U.S.  The device studied in our IDE study has been available in Europe since 1987.  You will hear today about the extensive biomechanical characterizations and animal studies we have performed on this device and the Level 1 randomized prospective data from our IDE study.  We believe that you will agree with us that the Charite Artificial Disc is safe and effective after you have reviewed our data, and we hope that you recommend approval for this device at the end of deliberations.

            I am currently passing around an instrumental model of the Charite Disc and the spine model and a loose device for you to look at during the course of our presentations.  Now, I would like to introduce Dr. Paul McAfee.

            CHAIRPERSON YASZEMSKI:  Thanks, doctor.  Thank you, Mr. Christianson.  Dr. McAfee?

            DR. MCAFEE:  Thanks very much.  I'm Paul McAfee.  I'm the Chief of Spine Surgery at St. Joseph's Hospital.  I'm a consultant with DePuy Spine.  I have a financial interest in the product.  I'm the inventor of a cervical disc replacement made out of the same biomaterials.  Five key points I want to emphasize.

            First, the design of often the experience with two early prototypes.  Second, the design mimics the motion of the intact disc.  Third, there are substantial clinical use outside the USA.  Fourth, there are some minimal reports of adverse events, but there are good results long-term.  The inventor of the SB Charite Prosthesis, the S is for Schellnack, the B for Karin Buttner-Janz, two time olympic gold medal winner in Munich in 1972 and by 1984 she had developed with Schellnack the world's first artificial disc.

            There was Type I and Type II, but these were just experimental prototypes.  They were never commercially available and there is only 58 implants in 49 patients, so nine of these were double implantations.  The original biomaterial was manufactured out of non-forged stainless steel, similar to a bottle cap.  It was not inserted by spinal specialists.

            The first SB Charite patient is still doing well.  He is playing tennis.  He is coming up on 20 year follow-up.  He still has eight degrees range of motion.  The current design, it refined by Helmet Link, a Waldemar Link.  It is cobalt chrome cast end plates, ultra high molecular weight gamma radiated, so partially cross-linked.  It is compression molded from sheets of 10-20 polyethylene, first released in 1987.  Okay.  There are 7,000 implanted worldwide and 700 in the United States.

            It was introduced in 1987 and we will be talking about the same prosthesis in the U.S. IDE study.  It has a 16 year track record.  It is the uncoated version.  The design rationale two end plates and a convex sliding core, which is an intermediate bearing.  There is less stress of the metal bone interface, decrease incidents of loosening and decrease wear debris.

            Now, on the right side of the slide is anterior, so with normal flexion and normal center of the nucleus displaces dorsally and this is exactly what happens with flexion of the artificial disc, because of the intervening intermediate bearing.  Now, the mobile bearing also allows the rotation and translation to be independent and it does reproduce the centrad, the instantaneous mapping of the center of rotation of the disc.

            There are actually five different sizes, five sizes of footprints to match the normal spine.  Four different inclinations of each end plate, 0, 5 degrees, 7.5 and 10 degrees.  Now, I do want to go over reports of adverse events.  The first is a report by Van Ooij, published of 29 patients, but will be presented later today as 49 patients.  These are infrequent complications.  There is one single case of documented osteolysis in Australia and there is a single case of a fractured core in a series in Europe.

            Experience with, we'll call it, 49 patients, since that's what will be presented today, but I have studied this right from the beginning with Dr. Van Ooij, I feel these are largely problems due to improper indications and they are largely approach related complications.  It is from a personal series of one surgeon.  In short, these are technical complications and I believe they are not problems inherent in the disc itself.

            For example, this is a case that was published as a case of osteolysis, but it actually was not loose, was not revised and this I interpret to be a degenerative cyst and this was not histologically confirmed.  This was a histologically confirmed case which I heard presented at the Spine Society of Australia.  It was a case that would not have been included in the U.S. study for several reasons.

            First, the case was performed adjacent to a fusion at this lower level.  Secondly, the polyethylene was irradiated in air and since 1997, this has been irradiated in nitrogen in a vacuum.  The case was successfully revised, by the way, with a post-year fusion in Side 2.  This is from Dr. David's experience, a 42 year-old woman after nine and a half years she was asymptomatic, but this core fractured.  The important things are: (1) It was successfully revised with the SB Charite implant after nine and a half years, and (2) There was no systemic spread of wear debris and all this material was encapsulated within a fibrous pseudocapsule.

            Now, there are some long-term results of the prosthesis.  To date, there are 315 patients with at least 12 months follow-up in the literature.  The main one is JP LeMaire in Rachis 2002.  He reported 107 patients, 146 implants, the mean follow-up of 11.3 years.  And what he found was the range of motion at 10 years was 10.3 degrees flexion-extension and 5.4 degrees lateral bending and 82 percent of the patients were able to return to work.

            There is one patient that had 9 degrees flexion, 12 degrees extension for a total of 21 degrees flexion-extension at 10 year follow-up.  The side bending was 8 degrees to each side.  So that's a total of preserved 16 degrees lateral bending after 10 years.  Terry David's experience of 43 patients for the first three years and then in sequences of three more years.  The interesting thing was that he went from a clinical result of 63 percent excellent and good to his next series of 82 percent excellent and good and finally to 93 percent of his patients in the excellent and good category.

            So the important take home message is not only did he technically get better, but he also -- this should be thought of as a learning curve for the indications, so in the U.S. study we have got the benefits of the worldwide honing down of the indications and mainly in our inclusion criteria in the discogenic back pain, but it is important to remember that around the world they were also operating for back pain with sciatica.

            So the range of motion, the best way to look at this is the bar on the left, you go flexion, extension and then lateral bending.  This is a bench top study of the normal disc.  This is a bench top study with the artificial SB Charite in place and this is JP LeMaire's experience with 100 cases at 10 years follow-up.  And you can see the remarkable consistency.  This is directly from the core laboratory.  Every case was digitized at Union Memorial Hospital and it does document 2 millimeters of anterior translation which is afforded in our patients as a result of the mobile bearing core.

            So in summary, the design does reproduce the motion of the intact disc.  There is substantial clinical use outside the United States.  The majority of the long-term data is with the uncoated end plates.  The FDA wanted to do the study on the design with the most experience.  The company will seek approval with the coated design.  This is two layers of titanium and calcium phosphate that has been used since 1998 worldwide and extensively tested in the lab.

            There are good results in the literature and there are anecdotal reports of adverse events and we have done our best to study these so that we can make a better prosthesis.  St. Joseph's Hospital was the second largest enrollment in the IDE study and I'm proud that our clinical nurses are here today.  It is safe and effective.  The keys are appropriate patient selection and it does require specialized surgical training.  And our whole team would recommend it be approved for use in the United States.

            Thank you very much and I'll introduce Bryan Cunningham from Union Memorial Hospital in Baltimore.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Dr. McAfee.  Mr. Cunningham?

            DR. CUNNINGHAM:  Thank you, Paul, and good morning.  Jack, if you could que my slides?  My name is Bryan Cunningham and I serve as Director of Spinal Research at Union Memorial Hospital in Baltimore, Maryland and I have a financial interest in the Charite Artificial Disc.  Preclinical laboratory investigations on the Charite Disc have focused on three specific areas, these include mechanical testing and wear simulation, in-vitro biomechanical modeling and in-vivo animal modeling.  Collectively, these three areas serve as the framework for the current presentation.

            Preclinical mechanical testing of the device includes the preliminary in-vitro analyses conducted prior to 1994, as well as the FDA recommended supplementary testing, which serve to characterize the intrinsic static and fatigue properties of the Charite Disc, as well as the wear characteristics of the implant.  The results obtained from the preliminary dynamic testing indicated an endurance limit of 3.7 kN based on axial fatigue loading.  This is greater than the estimated 3.4 kN maximum in-vivo load reported from the literature.

            Moreover, dynamic compression simulation indicated the calculated 10 year deformation of the Charite core to be less than 8 percent under cyclic loads peaking from 2.5 to 4.5 kN.  Supplementary mechanical testing undertaken to further characterize the static properties indicated the average yield strength of the Charite core and axial compression with flexion and extension to be equal to or greater than the lumbar vertebral fracture strength which ranges from 5.0 to 8.2 kN.

            Axial fatigue testing carried out to 10 million cycles at a peak load level of 3.75 kN demonstrated a mean deformation of 6.8 percent.  Moreover, compressive shear fatigue loading carried out to the same number of cycles indicated a mean deformation of 5.2 percent without evidence of gross specimen damage in any case.

            As a third component to the preclinical mechanical testing, wear simulation with subsequent particle analysis were performed.  The test materials included a total of nine Charite Lumbar Disc cores and 12 end plates of the smallest configuration to represent the worst case scenario.  Fatigue testing was carried out and a bovine calf serum had 25 percent concentration at 37 degrees celsius.  The fluid was replaced every 200,000 to 300,000 cycles.  Six of the test samples served as experimental, while the remaining three were controls.

            Under an applied compressive load ranging from -900 to -1850 N, three of the six test samples were evaluated under coupled flexion-extension with axial rotation as shown in the left picture.  The remaining three were evaluated under combined lateral bending and axial rotation.  Analysis conducted by Drs. McKellip and Campbell include particulate cleaning, gravimetric assessment and dimensional characterization of the implant core.

            In plodding the average mass change per cycles completed, the Charite core indicated an average mass decrease of 1.1 milligram per 10 million cycles with a range of .4 to 1.8 milligrams.  These wear rates are considerably less than those reported in the literature for total joint replacement at similar load cycles as shown.  The Charite core design permitting both motions of rotation and translation may account for these findings.

            Moreover, the lower segmental ranges of intervertebral motion and loads on the lumbar disc versus those observed in total hip arthroplasty may account for these lower wear rates.  The wear particulates average .21 to 1.5 microns in size with a definitive trend of a decrease in particulate size with increasing cycles.  Particle counts ranged from 39 to 264 per sample.

            Based on preclinical mechanical testing, the Charite Disc offers high compressive strength properties adequate to address physiologic demands.  The device provides sufficient resistance to permanent compressive deformation under fatigue loading conditions and to that end, afford sufficient fatigue strength for intended in-vivo use.  Based on wear analysis, the implant generates lower levels of particulate wear debris compared to arthroplasty devices utilized in total joint replacement.

            As a second area of investigation, an in- vitro biomechanical study was undertaken to quantify the multidirectional flexibility properties of the Charite device versus that afforded by conventional methods of spinal stabilization.  A total of eight human cadaveric spines were utilized in this study.  Following analysis of the intact condition, three reconstructions were performed at the L4-L5 level.  These included the Charite device, two BAK cages and, as a final construct, Pedical screws were added posteriorly to create a 360 degree arthrodesis.

            Multidirectional flexibility testing was performed using a Six-Degree-of-Freedom Spine Simulator.  Loading parameters included axial rotation, flexion-extension and lateral bending, each applied at plus minus 8 Newton Meters with peak range of motion at the operative level quantified using an optoelectronic tracking system.

            Based on multidirectional flexibility testing, flexion and extension and lateral bending testing indicated similar results in that no statistical differences were observed between the intact condition and Charite reconstruction.  However, both conditions afforded significantly more segmental motion than the BAK device or the BAK combined with Pedical screws.

            Axial rotation indicated the segmental range of motion produced by the Charite as significantly greater than the intact condition, and both the intact and Charite were greater than either method of conventional stabilization.  Analysis of the plain film flexion-extension radiographs indicated segmental translation at the operative levels averaging 2.06 for the intact condition, which was nearly reproduced at 1.9 millimeter for the Charite reconstruction.

            Based on the preclinical biomechanical testing, the Charite reestablishes near normal kinematics to the operative functional spinal unit when compared to conventional methods of spinal stabilization.

            The third area of preclinical investigations was based on in-vivo animal modeling.  The first in-vivo project served to determine the histopathologic response following epidural application of ultra high molecular weight polyethylene particles.  Histological analyses were based on review of the epidural structures, spinal cord, as well as the systemic and reticular endothelial tissues.

            A total of 20 New Zealand White Rabbits were included in the study.  These were randomized into two treatment groups, including operative Sham and the experimental group of ultra high molecular weight polyethylene.  The animals were randomized into two post-operative survival periods of three and six months.  In terms of particulate specifications, the particles ranged from 1 to 10 microns in size with 95 percent of the implanted particles being less than or equal to 5 microns.  Samples were shown to be endotoxin free based on limulus assays prior to implantation and total of 3 milligram of particulate was applied directly to the epidural site.

            This particulate load represents, approximately, 38 times the average amount of debris generated in 10 million cycles when normalized to a 70 kilogram individual.  The surgical procedure consisted of a midline surgical approach followed by resection of the L6 spinose process, ligamentum flavum.  Finally, we had exposure of the epidural sac.  The particles were applied directly to the epidural site in dry, sterile format.

            Postmortem blood chemistry and cerebrospinal fluid profiles were within normal limits for all assays at both time periods.  Histopathologic analysis of the local epidural fibrosis using macrophage staining indicated the presence of histiocytes.  There was no evidence of polymorphonuclear giant cells, spinal cord lesions or cellular apoptosis at either the three or six month post-operative intervals.

            Based on preclinical neurotoxicity testing of ultra high molecular weight polyethylene, the debris elicits can be characterized as a chronic histiocytic reaction localized primarily within the epidural fibrosis as evidenced by macrophage infiltration.  There was no evidence of an acute neural or systemic histopathologic response in any case.

            The second in-vivo project served to evaluate the Charite device using a non-human primate model.  Analyses were based on postmortem radiography and functional biomechanical testing of the operative segments, as well as histopathology of the local tissues.  Baboons served as the experimental model.  In this investigation these animals served as a semi-upright model for both inner body spinal arthrodesis, as well as total disc arthroplasty.

            Following a six month survival period, plain film radiography indicated no evidence of heterotopic ossification, disc migration or end plate radiolucencies at any operative level.  Multidirectional flexibility testing compared the range of segmental motion afforded by the intact spine, Charite device in blue bars, as well as a historical fusion control in yellow.  No differences were observed under axial compression between the three groups.  The Charite device permitted more motion than the intact spine under axial rotation and slightly less in lateral bending.  No differences were observed in flexion-extension.

            As a general trend, both the intact and Charite groups afforded significantly more segmental motion to the operative level than the autograft control under each of the three rotational loading modes.  Histopathologic analysis of the local tissues directly overlying the device indicated no evidence of ultra high molecular weight polyethylene, cobalt-chrome wear debris, macrophages or cytokines based on plain and polarized light microscopic review.

            Based on preclinical evaluation of the Charite device using a worst case scenario functional animal model, the device restored the range of segmental motion to near intact levels without evidence of end plate radiolucencies or device migration.  There was no evidence of polyethylene or cobalt-chrome wear debris based on local tissue analysis.

            As an overall summary to the preclinical investigations conducted on the Charite Artificial Disc, multiple biomechanical test batteries have demonstrated the biomechanical performance in safety margins of the smallest, thinnest, Charite Artificial Disc under extreme loading conditions.

            Fatigue wear testing has shown very low levels of particulate generation when compared with other arthroplasty devices due to the unique design of the disc and spinal loading conditions.  Cadaveric and functional animal studies have shown the device to restore motion at the operative level and, most importantly, there is no evidence of an acute neuro or systemic histopathologic response due to wear debris in the rabbit epidural model or in functional animal characterization.

            Thank you very much.  And with that, I would like to turn the podium over to Dr. Scott Blumenthal.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Mr. Cunningham.  Mr. Blumenthal?

            DR. BLUMENTHAL:  Thank you.  My name is Scott Blumenthal.  I'm a spinal surgeon at the Texas Back Institute.  I had the privilege of serving as the lead investigator.  I do have a financial interest in the Charite Artificial Disc and I will be presenting the clinical results.

            Some of the key points that we would like to emphasize is that this study will provide comprehensive, valid scientific Charite Artificial Disc is both safe and effective.  The Charite Artificial Disc is at least as good as an Anterior Interbody Fusion with BAK cage for treatment of single level degenerative disc disease and we'll see that in the study design, and the Charite Artificial Disc provides several important advantages over Anterior Interbody Fusion in appropriate patients.

            We have 15 centers across the United States.  After agreeing upon a protocol with the sponsor, physicians and FDA, all local sites, gained local IRB approval.  Each center was allowed five training cases followed by the randomization schedule at 2 to 1 Charite to BAK with the targeted enrollment seen at the bottom of the slide.  These were the principal investigators at all the clinical sites.

            The objective of the study was to compare the effectiveness of the Charite Artificial Disc to Anterior Lumbar Interbody Fusion with BAK cage for the treatment of single level degenerative disc disease with the hypothesis that being a non-inferiority study, that the success rate in the Charite Artificial Disc group will be at least as good as in the ALIF BAK group.

            Key inclusion criteria, age range of 18 to 60, single level degenerative disc disease at either L4-5 or L5-S1 confirmed by positive provocative discography.  Minimum Oswestry scores and VAS scores were required, failure of six months or greater of nonoperative care.  These patients had primary back pain with or without a pseudoradicular type leg pain, no nerve compression.  They have to be judged to be able to tolerate an anterior surgical approach and agree to comply with the two year follow-up schedule.

            Key exclusion criteria includes previous thoracal lumbar fusion, symptomatic multilevel lumbar degeneration, non-contained disc herniation, osteoporosis or other metabolic bone disease, spondylolisthesis greater than 3 millimeters or scoliosis greater than 11 degrees, spinal stenosis manifested as a midsagittal diameter of less than 8 millimeters, positive straight leg rays for radiculopathy and the other exclusion criteria shown at the bottom of the slide.

            Proposed indications for use.  The Charite Artificial Disc is indicated for spinal arthroplasty in skeletally mature patients with degenerative disc disease at one level from L4 to S1.  Degenerative disc disease is defined as discogenic back pain with degeneration of the disc confirmed by patient history and radiographic studies.  These patients may also have up to 3 millimeters of spondylolisthesis without a pars defect at the involved level.

            To judge success criteria we utilized four primary endpoints, that being the Oswestry Disability Index improvement of greater than or equal to 25 percent from baseline to 24 months, no additional surgery at the treated level, no major complications and maintenance of neurologic status from baseline to 24 months.  To be considered a study success all four criteria need to be satisfied.

            The secondary efficacy endpoints include improvement in Oswestry, pain as measured by VAS, SF-36, change in disc height, displacement of device, range of motion, duration of hospitalization and patient satisfaction.

            Methods utilized to minimize bias included validated patient self report questionnaires, independent reviewers of both neurologic results and the radiographic results and randomization treatment was assigned the day of surgery, such that the patients were consented for either procedure and didn't find out what they got until they woke up.

            The BAK group was chosen as the control group after a discussion with the FDA.  The surgical approach is the same with similar morbidity and, at the time, the BAK was the only accepted state of the art approved technology, stand alone for the same diagnosis that we're studying.

            The enrollment in analysis population.  Enrollment started in March of 2000 and at 25 months, 205 subjects were enrolled into the treatment arm receiving the Charite 99 into the BAK.  Safety data will be presented on all randomized patients, effectiveness data on the intent-to-treat group, which excludes subjects not complete through 24 months, those not yet due and overdue subjects, and I will also present additional information on the 71 training cases.  The follow-up status, at all follow-up intervals the total follow-up was greater than 90 percent.

            The demographics are shown in this slide looking at gender, age, age categories greater than or less than 45 years, body mass index and a target level, medical history including gait, spondylolisthesis, baseline activity level before injury and pre-op activity level were looked at as well.  The summary was that no differences were noted between the groups in the majority of baseline characteristics evaluated.  Statistical differences were seen in that the BAK group had a slightly higher body mass index and had a slightly lower pre-op activity level.  These differences were further factored into covariate analyses and will be presented later.

            This looks at the hospitalization and operative data with, again, in terms of levels, surgery time, estimated blood loss, similar between the two groups with the only difference being the duration of hospitalization, which favored the Charite group by, approximately, one half day.

            As mentioned, the safety data will be looked at in the all randomized population.  In summary, the Charite Artificial Disc and Anterior Interbody Fusion with BAK cage have similar adverse events profiles.  These are the adverse events profiles, and I would like to highlight a couple of them.

            There were very few AEs related to the device in either arm.  The neurologic AEs were similar between the two groups.  The approach problems are pretty close to identical.  Obviously, fusion related issues to the fusion group only.  Additional surgery favored the Charite group and, of note, there was no device infections in either arm.  This further details the neurologic adverse events.

            This details the approach in fusion related events and I would just like to highlight a couple of them.  Retrograde ejaculation, always a concern in anterior retroperitoneal surgery, was low in both groups consistent with the literature.  Obviously, donor site complications were seen just in the BAK fusion group and the instances of pseudoarthrosis in the BAK was 9 percent.  Turn that around and it's a 91 percent fusion rate, which is consistent with the BAK IDE data.

            There were five Charites which fulfilled the criteria for displacement or migration.  Four out of five remained stable and in place.  One out of five required additional fixation.  In terms of the need for additional surgery, there was a lower rate seen in the Charite group.  The Charite group had two removals, one early, one late.  The BAK group had one re-op and one revision.

            Revision strategies and, obviously, that's an issue here.  If there is a need for revision early in the post-operative period, these can be repositioned by a repeat anterior approach.  If late revisions are required, if the device is in good position, a posterior lateral fusion leaving the device in place can be performed.  If the device position presents a risk, then careful redissection with repositioning or replacing the device, removing the device and performing a fusion or repositioning and fusion with the device in place.

            The conclusion of this part is the Charite Artificial Disc is safe when compared to the ALIF with BAK cages.  In the efficacy, in the intent-to-treat population, the Charite Artificial Disc is at least equivalent in overall success to the BAK.  This actually shows the clinical success looking at the primary efficacy endpoints.  The Charite Disc is at least as effective as Anterior Lumbar Interbody Fusion with the BAK cage with a small P-value indicating a high degree of certainty.  The Charite success rate, however, is numerically superior.  This breaks down the four primary endpoints with statistical significance favoring the Charite approaching, but not yet reached, in the improvement in Oswestry.

            Other factors were considered in the covariate analysis, age, baseline, Oswestry, gender, operative level, hormone replacement therapy, pain medication, BMI, baseline activity level, sight and osteopenia.  In all cases the equivalence hypothesis remained highly significant regardless of the factors considered.  Sensitivity analysis was preformed to evaluate the effect of non-completers via a last observation carried forward with these analyses also further supporting the primary analysis.

            This looks actually at the Oswestry scores over time and at all follow-up intervals, the Charite group performed numerically superior with statistical superiority seen at six weeks, three months and six months.  The VAS scores similarly showed numerical superiority at all follow-up intervals with statistical superiority seen at the six month.

            In terms of pain relief, the pain relief was better in the Charite subjects than the BAK at all post-op time points, but remember this is a challenging patient population, those with symptomatic lumbar disc degeneration.  The percentage of non-responders was similar or lower than prior literature for all treatment modalities for this particular diagnosis, and in the non-responders there was no evidence to implicate the facet joints.

            The physical component score of the SF-36 showed statistical superiority at all follow-up time points favoring the Charite.  The mental component score showed equivalence with a change in baseline for the BAK showing statistical superiority at three months.  The conclusion is that the Charite Artificial Disc is effective compared to the ALIF with BAK cages.

            Patient satisfaction data was also looked at.  The Charite outperformed the BAK at both time periods, 12 and 24 months, with statistical significance achieved at 24 and when asked whether they would choose the same treatment, the same results were seen with statistical superiority at the 24 month follow-up.

            Radiographic results, we found near physiological range of motion on flexion-extension for the Charite patients, good maintenance of disc height.  We talked about the five device displacements and we also looked at heterotopic ossification.  There were six at 12 months in Charite patients, 11 at 24 months with an incidence of about 4 percent.  Of note though, the mean range of motion on those patients at 12 and 24 months was preserved to the amount of 4.8 degrees and 5.9 degrees, respectively.

            This shows diagrammatically the range of motion data, which certainly mimics the in-vitro data showing superiority of the Charite as to be expected.  Disc height also shows that disc height was better gained and maintained in the Charite patients.

            We also wanted to look at the all randomized patients and see how that would affect the efficacy data.  The baseline characteristics were very similar.  Statistical significance superiority was demonstrated, however, in more of the intervals than in the intent-to-treat group.  The proportion of patients with 25 percent ODI, which was close in the intent-to-treat group, achieved statistical significance in all randomized and at more follow-up intervals, Oswestry and VAS achieved statistical significance now at six, three months, six months and 12 months.

            The SF-36 physical component still favors the Charite.  Patient satisfaction favors the Charite more strongly.  Range of motion and disc height results, the same as the intent-to-treat, and this further analysis supports the intent-to-treat population.  This just highlights that one primary efficacy endpoint, achieving statistical significance.

            Training cases, a couple brief words on that.  We looked at the demographics and the demographics were similar between the randomized and the training cases.  The AE events, however, as would be expected, were higher in the training cases.  As to be expected in terms of operative data, we also found that the median length of surgery was greater in the training cases, not surprising.  What was surprising is that the training cases in the VAS and Oswestry outperformed the study patients.  So with the same exclusion criteria, similar baseline characteristics, we had longer surgeries, higher rates of AEs in the training cases, but greater average improvement in pain and Oswestry.

            So in conclusion, this is Level 1 data, randomized study design with minimized bias utilizing validating instruments and independent reviewers, very robust data with extremely high rates of follow-up and a high statistical significance supporting the equivalence.  The Charite Artificial Disc provides advantages over the ALIF in early clinical improvement, function, pain and quality of life, shorter mean hospitalization, higher patient satisfaction and maintains its range of motion through 24 months as well as disc height.

            So going back to the primary hypothesis, I believe that we have proven this device, the Charite Artificial Disc, to be both safe and effective.  Thank you.  I would like to introduce George DeMuth.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Dr. Blumenthal.  Mr. DeMuth?

            MR. DEMUTH:  Thank you.  I'm George DeMuth.  I'm a consultant to DePuy Spine and I do not have a financial interest in the company or the product.

            I want to just touch on some statistical topics and provide some comments.  I will start with the primary efficacy endpoint and the definition, some study populations of interest and that will lead us into some sensitivity analyses.  After that I just want to give one slide about the response over time and then offer some conclusions from a statistical viewpoint.

            Here the primary efficacy is one endpoint.  It has four components of success and as we defined it in advance, anybody that had incomplete information just in any of the components would be treated as a failure at 24 months.  In the case of this study where there are some ongoing patients, those patients obviously have missing data at 24 months, and they were going to be treated as failures.  And if we include those patients in the analysis under this rule, that will always lower the response rate and it may well change the estimate of the treatment difference depending upon the distribution of the ongoing patients between the treatment groups.

            So our ITT population consisted of completers and discontinued subjects.  This is subjects that we know about their 24 month information.  However, we didn't do the primary efficacy analysis on all randomized and ITT plus the overdue patients.  FDA pointed that out and I think that was an oversight on our part, and I would like to present them in the next slide.

            So our center line here our ITT analysis.  We get these observed rates, 63, 53 percent in the groups.  If you go up to the top two rows, you see the all randomized and the all randomized minus the not yet due, those are subjects that just haven't been followed quite long enough to make it to the 24 month window.  You can see the observed rates are lower there.  Two sensitivity analyses included in the PMA was an LOCF based on the all randomized and a repeated measures model for the all randomized population.  Those have similar observed event rates, success rates, that we saw in the ITT.

            Most importantly though, I think, here is the difference between the BAK and the Charite.  It ranges from 9 percent to 11 percent regardless of the population you choose.  And if you look at the 95 percent confidence balance, they are well below the 15 percent barrier or a 10 percent barrier.  So they clearly support a non-inferiority claim here, treatment differences consistent across the populations and our ITT population looked like the LOCF and repeated measures analysis.

            The FDA offered some other imputations in the Panel package and only in the most extreme case where all ongoing Charite patients were failures and all ongoing BAK patients were successes could the result be made nonsignificant in terms of non-inferiority.  That's an unlikely result based on what we know about the data.

            So I just want to make a few comments on the response over time we saw in Dr. Blumenthal's presentation, some significant differences at six months and three months and six weeks, and more similar results between 12 and 24 months.  We did try and look at this briefly in the primary efficacy endpoint in the repeated measures model where we got a significant difference at six months, an overall contrast that was different.

            We also did another life table type analysis looking for a time to sustained or durable response.  That wasn't significant.  So there is clearly some trends towards the earlier improvement in the Charite, but we got at least one response where we didn't get analysis that was significant.

            So just some conclusions and comments.  I think these results strongly support the non-inferiority claim.  The response profile is consistent with an earlier response in the Charite subjects.  The all randomized results through 12 months continue to the trends that we see in the ITT analysis and the follow-up rates were well-maintained and pretty good throughout the study.

            So I think that -- and Dr. Blumenthal touched more on the safety and I wanted to talk about it, so in conclusion I think the results strongly support the efficacy and safety of Charite relative to the BAK.  Now, I'm going to return the podium back to Bill.  Thank you.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Mr. DeMuth.  Mr. Christianson?

            MR. CHRISTIANSON:  I'm Bill Christianson with concluding remarks, full-time employee of DePuy Spine.  Obviously, physician training is going to be very important for the successful launch of this product if approved in the U.S., and DePuy Spine is committed to a very robust and vigorous training program that will initially start at the Spine Arthroplasty Institute.  It's owned by Ethicon Endo- Surgery, a sister J&J company to DePuy Spine and a site where the IDE surgeons will be the primary faculty.

            This will be augmented by, after a number of surgeons are trained to gain experience, regional centers dispersed around the country who will offer visitation, case consultation and web based resources.  These are some scenes of the Ethicon Endo Institute.  There are both classroom and operating room teaching facilities, and we will use both to train surgeons in the post-approval period.

            The Spine Arthroplasty Institute will start with 12 training modules.  We already have content developed in all of these areas, including many of the areas that you have seen presented here today.  The training will be identical regardless of faculty, because everything is already built and will be reproduced by all the course faculty and then, in addition to the didactic, there will be hands-on training using a Calf Spine Model in an anterior lumbar surgery simulator.

            This concludes our presentation.  You have seen a device that has got a long clinical history.  It has been available outside the U.S. since 1987.  It has been thoroughly biomechanically characterized by our company.  You see robust clinical data constituting valid scientific evidence that the Charite Artificial Disc is safe and effective, and we believe you should recommend approval to the FDA today.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Mr. Christianson.  I would like to thank the sponsor for their presentation.  We're going to move next to the FDA presentation and while Mr. del Castillo is getting ready, I will ask the Panel.  We have adequate time this afternoon to ask questions of both the sponsor and the FDA, but if any Panel Members have a question that they need to ask right now, we'll do it while Mr. del Castillo is getting ready.

            DR. NAIDU:  I have a quick question.  Now, all the mechanical tests done to date have been on the polyethylene.  Are they on freshly irradiated specimens or aged specimens?  Can anybody answer that?

            CHAIRPERSON YASZEMSKI:  Mr. Christianson, would a representative from the sponsor care to answer that question?

            DR. SERHERN:  I'm Hassan Serhern.  I am with DePuy Spine.  They are shelf products.

            DR. NAIDU:  Well, what was the shelf life?

            DR. SERHERN:  Around three years.

            DR. NAIDU:  Three years?  And what was the radiation dose that you used?

            DR. SERHERN:  This was 2.7 plus minus .2 megarad.

            DR. NAIDU:  2.7 megarads.  So these are on three year aged specimens.  Am I correct?

            DR. SERHERN:  Correct.  They are in a shelf package, that is vacuumed with nitrogen.

            DR. NAIDU:  Okay.  Thank you.

            CHAIRPERSON YASZEMSKI:  Okay.  Thanks, Dr. Naidu.  Thank you.

            MR. DEL CASTILLO:  Good morning.  My name is Sergio del Castillo.  I'm a biomedical engineer, a reviewer in the Orthopedic Devices Branch and the lead reviewer for the Charite Artificial Disc Pre-Market Approval Application.

            FDA will provide several presentations for you this morning.  First, I will be presenting a summary of the preclinical and clinical assessments.  Dr. Jianxiong Chu will present the statistical analysis of the PMA data.  Finally, Dr. Jove Graham will summarize the wear debris testing conducted.

            The company who has presented the data has submitted their pre-market application.  Therefore, my presentation will highlight the preclinical and clinical analyses that we feel are particularly important for the Panel to consider today.  Specific to the preclinical data, I will provide a brief description of the Charite Artificial Disc, highlights from cadaver and animal testing and a summary of the mechanical testing conducted.  I will also discuss the clinical study design, adverse events and study results.  After Drs. Chu and Graham have completed their presentations later on this afternoon, we will then ask seven specific questions for the Panel's consideration.

            Let me begin with a description of the Charite Artificial Disc, which I will refer to as the Charite from this point forward.  The Charite is intended for spinal arthroplasty in patients with single level lumbar degenerative disc disease or DDD from L4 to S1.  The Charite is a multi-component artificial spinal disc.  It is composed of two cobalt-chrome alloy end plates and an ultra high molecular weight polyethylene core.

            The end plates are offered in two versions, parallel and oblique.  The parallel plates are designed such that the end plate service is parallel with the core midline.  The oblique end plates are designed to provide varying degrees of lordosis, hence the end plate surface is angled with respect to the core midline.

            The surgeon is capable of forming various combinations of these end plates to match the anatomy of the patient.  Although there are some references to porous coated end plates within the company's application, please, note that the device for which the company is seeking approval contains only uncoated end plates.

            The sponsor states that the Charite permits motion at the treated spinal level with up to a total of 15 degrees bending and flexion-extension, and lateral bending and axial rotation ranges of motion that are similar to that observed for the natural disc.  However, do consider that the device designed, based on the chemical testing, would permit up to 24 degrees of flexion, 32 degrees of extension and lateral bending and would be unconstrained to axial rotation.

            This provides an excellent segueway into the preclinical portion of my presentation.  The sponsor presented data from several studies utilizing human cadavers, spinal units and animal specimens to study range of motion.  The sponsor has already presented the Cunningham Adult Study where the range of motion in human cadaver spine units were compared to the range of motion of spine units implanted with the subject device.

            I would just like to highlight that the results of that testing showed that the instrumented specimens exhibited a statistically significant increase in axial rotation.  However, no statistically significant differences were observed in flexion-extension or lateral bending.

            Similarly, in a study conducted by McAfee et al, biomechanical analyses were performed on implanted baboon spinal segments and control functional spinal units, which the company has also already presented.  I would just like to highlight that there appear to be an increased range of motion in flexion-extension and a significant increase in axial rotation for specimens implanted with the Charite compared to intact functional spinal units.

            Because the sponsor has already summarized the mechanical testing quite nicely that was conducted, I will not elaborate on this testing any further with the exception of two comments.  First, while the mechanical testing results appear to represent the expected physiological loads and range of motion, the correlation of these results to the clinical performance of the device is not known.  Second, I will refer to Dr. Graham's presentation for an account of the wear debris testing conducted.

            I would now like to summarize the clinical trial used to generate the clinical data presented in the company's application.  The purpose of the study was to evaluate the safety and effectiveness of the Charite and compare it to the BAK Interbody Fusion device, which I will refer to as the BAK from this point forward.

            Further, the studies have to demonstrate the non-inferiority of the Charite compared to the BAK.  That is the intent of the study was to show that the Charite would be at least as good as the BAK within a non-inferiority margin or delta of 15 percent.  This study was not designed to demonstrate superiority of one group over the other.

            For the purpose of a comparison, allow me to provide some background on the control device.  The BAK was approved by the pre-market application process on September 20, 1996.  It is a hollow threaded titanium alloy cylinder indicated for use with autogenous bone graft in patients with degenerative disc disease at one or two contiguous levels from L2 to S1.  Two devices are implanted per level.

            Although the BAK may be implanted by an open interior or posterior approach, for the purposes of this study, all control subjects were implanted with the BAK devices only via an open anterior approach.  It should be noted that the Charite is also implanted using only this approach.

            The sponsor conducted a randomized prospective multicenter clinical trial.  The subjects were randomized in a 2 to 1 ratio to either treatment with a Charite or treatment with a BAK, respectively.  The first five subjects at each investigational site were treated with the Charite as part of the training of the surgeons.  These training subjects were not included in the assessment of effectiveness.

            As stated in the study protocol, the Charite is indicated for spinal arthroplasty in skeletally mature patients with degenerative disc disease at one level from L4 to S1.  DDD is defined as discogenic back pain with degeneration of the disc confirmed by patient history and radiographic studies.  Study subjects may also have up to 3 millimeters of spondylolisthesis at the involved level.

            Subjects were also to have at least six months of conservative treatments prior to implantation.  These treatments may include discectomy, laminotomy, laminectomy without an accompanying facetectomy or nuclear lysis at the level to be treated.

            Safety and effectiveness were evaluated in terms of the complications that arose during implantation and post-operatively, including infection, thrombosis, migration and subsidence, re-operation, the incidence of adverse events, the level of the subject's disability as measured by the Oswestry Disability Index or ODI and assessment of the subject's neurological status.  Further assessment of the subjects was conducted radiographically by measuring changes in disc height, range of motion and flexion-extension at the involved level, displacement or migration of the implants and radiolucencies around the implant.

            Most measures were conducted at baseline, six weeks, three, six, 12 and 24 months.  This includes an assessment of the subject's functional level as measured by the ODI, the subject's neurological status, any incidence of adverse events, the subject's level of pain as measured by the Visual Analog Scale or VAS and the subject's work status.

            Quality of life as measured by the SF-36 Survey and range of motion were measured at baseline, six, 12 and 24 months.  Patient history and physical examinations were recorded at baseline and 24 months only.

            Within six months of enrollment, all subjects were measured anteriorly, posteriorly, laterally and in flexion-extension.  These same measures were repeated at six weeks, three, six, 12 and 24 months.

            The primary endpoint for effectiveness in the study consisted of four components, pain in function as measured by the ODI, any device failures requiring revision, re-operation or removal, any major complications and neurological status.

            An individual subject was determined to be a success if all of the following conditions were met.  The subject's ODI score increased by at least 25 percent at 24 months compared to the subject's baseline score.  It should be also noted that FDA also analyzed this component with a success defined as a 15 point improvement compared to baseline.  Moving on, the subject experienced no device failures requiring revision, re-operation or removal, the subject did not experience any major complications defined as major blood vessel injury, neurological damage or nerve root injury.  And finally, the subject's neurological status should be maintained or improved at 24 months with no new permanent neurological deficits compared to baseline.

            Again, an individual subject is considered a success only if he or she is a success in all four components.  The study was defined as a success if the overall success rate of the Charite study group is non-inferior to the overall success rate of the BAK group.  In this study safety was assessed by comparing the rate of incidence of all adverse events observed in the Charite and BAK study groups.

            The secondary effectiveness endpoints consisted of all the primary endpoint components, which I listed previously, which are pain in function as measured by ODI, device failures requiring a revision, re-operation or removal, any major complications and neurological status.  Also included are pain as measured by the VAS, quality of life as measured by the SF-36 Survey, disc height, device displacement, range of motion, length of hospital stay and patient satisfaction, including a satisfaction with the procedure and whether or not the same treatment would be chosen in the future.  Only descriptive statistics were used in the assessment of the secondary endpoints.  I would also just like to point out that range of motion was measured only in flexion and extension.

            Overall the subjects in both study groups were similar demographically in terms of age, body mass index and baseline ODI scores.  It is noted that a higher percentage of females were enrolled in the Charite group compared to male subjects with the opposite trend noted in the BAK group.  Pre-operative activity levels also differed slightly between these groups.  Also of note are the higher percentages of subjects in both study groups with degenerative disc disease at the L5-S2 level compared to the L4-L5 level.

            Adverse event information was collected from all randomized subjects.  Adverse events were categorized as typical or unusual, severe or life threatening, device related or not device related, severe and device related occurring within two days of surgery and by date of onset.

            This table here presents an account of the adverse events reported during the study.  The percentages of Charite and BAK subjects experiencing at least one adverse event is essentially equal.  However, I have highlighted some adverse events reported for a higher percentage of Charite subjects compared to the BAK group.  These include infection, abdominal events, device related events and severe life threatening events.

            This table shows some of the device related adverse events reported.  It is noted that 7.3 percent of Charite experienced device related adverse events compared to 4.0 percent of BAK subjects.  A greater percentage of Charite subjects were reported to have experienced the following adverse events compared to the BAK group.  Back or lower extremity pain, neurological events, such as numbness, motor deficit or nerve root injury and additional surgery at the index level.

            It should be noted that the rate of adverse events was higher in the training subjects group compared to the randomized subjects in the study as the sponsor has already pointed out.  In the training group this may be true primarily to the slightly higher rates of prosthesis related events and additional surgeries at the index level.  However, please, note that the training subjects were not included in the assessment of safety.

            I will now present assessments of the primary and secondary endpoints.  Unless otherwise noted, the analysis population, which I will refer to, which was only used to assess these endpoints, is referred to as the completers population.  It is a subset of all randomized subjects who are evaluated at the 24 month time point regardless of when the 24 month measurements occurred.  For clarification, I have included here a table indicating which randomized subjects are not included in the completers population.  This population contains 86 percent and 79 percent of all randomized Charite and BAK subjects, respectively.

            Using the completers population, the overall success rates for the Charite and the BAK groups are 64 percent and 58 percent, respectively.  Although these rates differ slightly from what the company has presented, considering the overall success rate is within a non-inferiority margin or delta of 10 percent of the BAK overall success rate, it appears the study has demonstrated the non-inferiority of the Charite compared to the BAK.  Dr. Chu will provide more details regarding the assessment of overall success and effectiveness during his presentation.

            Listed here are the success rates for the individual components of the composite endpoint.  None that the success rates among the completers are comparable between the two groups and the ODI component or ODI score appears to be the major reason of overall failure at 24 months.

            A subject was considered improved in the Oswestry secondary endpoint if the subject's ODI score had increased by at least 25 percent at 24 months compared to the baseline ODI score.  At 24 months using the completers analysis population, 72 percent of Charite subjects had improved compared to 63 percent of BAK subjects.

            Here is a listing of the SF-36 Quality of Life Survey scores for all randomized subjects who had data available.  73 percent of Charite subjects and 66 percent of BAK subjects had a 15 percent or greater improvement in the Physical Composite Score or PCS at 24 months.  50 percent and 55 percent of subjects had a 15 percent improvement for the Mental Composite Score or MCS, respectively.

            Note that the amount of data used to assess the PCS and MCS rates of improvement are much less compared to the number of randomized subjects in the study.  Further, the observed differences in improvement between the Charite and BAK groups are not statistically significant.

            In the Charite group radiolucencies were identified in 1 percent of the subjects at 24 months.  Longitudinal ossifications were identified in 6 percent at 24 months.  It is noted that in the BAK group, 5 percent of subjects experienced pseudoarthrosis at 24 months.  Note also that the interpretations of these radiolucencies are inconclusive.  We believe these data were adequately captured in the safety analysis.  Therefore, we will not provide any further comment.

            Neurological status was maintained at 24 months for 77 percent of Charite subjects and 76 percent of BAK subjects.  About 5 percent of Charite subjects experienced slight or significant deterioration of their neurological status compared to about 8 percent of BAK subjects.

            A subject was considered a success in pain if the individual's VAS score decreased by at least 20 millimeters compared to the individual's baseline score.  Within this definition, 75 percent of the Charite subjects were considered successes compared to 70 percent of BAK subjects at 24 months.  It is noted that 12 percent of Charite subjects reported only some pain relief and 13 percent experienced no change or an increase in pain.  The etiology of this unrelieved pain is unknown.  However, the data do demonstrate non-inferiority of the Charite in terms of maintenance or improvement in pain.

            No conclusions can be made regarding the time to improvement.  The study was designed to demonstrate non-inferiority at the 24 month time point only.  In the Charite group, no subjects had a decrease in disc height greater than 3 millimeters at 24 months while 4 percent of BAK subjects lost more than 3 millimeters in disc height.  Overall, disc height is maintained or improved over time in both study groups with roughly equivalent maintenance of a 24 month time point.

            Vertebral range of motion was measured on lateral flexion-extension views using the Cobb Method at the operating level with measurements recorded at the three, six, 12 and 24 month time points.  The mean flexion-extension range of motion for subjects with available data was 4.9, 6.0, 7.0 and 7.4 degrees, respectively.

            The histogram shown here displays the range of values recorded for subjects with available data at 24 months.  Notice the wide range of values obtained, which range between 0 degrees and 24 degrees.  Again, please, note that lateral bending and axial rotation were not measured in this study.

            Considering that one of the principal theoretical advantages of disc replacement devices is the preservation of segmental motion, FDA considered the correlation between overall success and range of motion observed.  An analysis of these two variables was conducted.  In this table, success and failure rates at 24 months for Charite subjects are compared with a range of motion data.  It appears that subjects experiencing range of motion in the 5 to 7 degrees range were more likely to be successful than subjects experiencing different ranges of motion.  However, the association of range of motion with overall success is not statistically significant.

            This concludes my presentation of the preclinical and clinical assessments.  So allow me to highlight the major points we would like you to keep in mind as we continue with the remaining presentations.

            The study was designed to demonstrate non-inferiority of the Charite compared to the BAK.  It was not designed to demonstrate superiority over the BAK in any of the clinical measures.  The Charite demonstrated non-inferiority to the BAK with respect to the primary endpoint.  Overall, the number of adverse events in the Charite and BAK groups were roughly the same with a higher rate of incidence in only a few categories for the Charite group.

            The Charite was able to maintain pain and function up to 24 months.  Some subjects reported only some pain relief and a few experienced no change or an increase in pain.  And finally, it is unclear how range of motion is related to the clinical outcomes if at all.  I will now turn the podium over to Dr. Jianxiong Chu who will provide a presentation of the statistical analysis of the PMA data.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Mr. del Castillo.  Dr. Chu?  While Dr. Chu is getting ready, I will ask my Panel colleagues to remember that our discussion this afternoon will need to be focused on answering these questions that the FDA presents to us and ask that you begin to consider them.

            DR. CHU:  Hi.  Good morning.  My name is Jianxiong "George" Chu.  I am an a statistician at the CDRH.  I'm glad to have this opportunity to present some statistical summary for the Charite Artificial Disc and today my talk will focus on the sensitivity analysis for the primary endpoint, which is patients' overall success at 24 months followed by my comments with regard to the sponsor's claim about some of the secondary endpoints.

            To demonstrate that Charite provide equivalent functional improvement and pain relief, as well as equivalent to the way the device fares compared to the BAK cage, the study was designed to be a prospective multicenter randomized controlled non-inferiority trial.  Patients of age 18 to 60 years-old with single level DDD at L4 to S1 were to be randomized at 2 to 1 ratio of Charite to BAK.

            Please, also note that the patients ODI score have to be at least 30 in order to be included in this study.  After implantation, the patients will be followed at six weeks, three months and up to 24 months.  Please, note that the primary endpoint individual success rate was evaluated at 24 months.

            As our lead reviewer has mentioned, the study's primary endpoint consists of four components and the patient's overall success rate at 24 months has to meet all the following four criteria, 25 percent at least improvement in ODI score compared to the baseline, no major device adverse event, no device failure requiring revision of the operation or removal and also the maintenance or improvement in neurological status with no new permanent neurological deficit.

            So what does non-inferiority really mean?  To demonstrate that Charite Disc is not worse than the control, BAK, by more than a certain margin called a delta with regard to the success rate at 24 months.  So you can think of the delta as a maximum tolerable inferiority.  We are waiting to accept, considering the other potential benefits, for the Charite potential benefits.

            Please, also note the delta was pre-specified at 15 percent in the sponsor's protocol, but the FDA believes that 10 percent non-inferiority margin is more clinically appropriate.  So all my little analysis will use 10 percent delta margin.

            Corresponding to the study objective to demonstrate that Charite Disc is not worse than the control by more than 10 percent, the alternate hypothesis for this non-inferiority trial is that the difference of the success rate between BAK and the Charite is less than 10 percent, and non-hypothesis is that the difference of the success rate between BAK and Charite is more than delta.  So the detraction of the non-hypothesis will conclude that Charite is at least as good as BAK.

            Alternately, a more informative way is to construct the one-sided 95 percent confidence interval for the difference of a success rate, P sub BAK minus P sub Charite.  If the upper bound of this one-sided 95 percent confidence interval is less than 10 percent delta, then we can claim non-inferiority of Charite compared to the BAK.  As an example shown here, Case A, the upper bound is below the red line marked by delta.  And in Case B we cannot conclude that Charite is non-inferior to BAK.

            The Statistical Analysis Plan in the original IDE protocol was far from complete.  Most of the patients 24 months data became available when the Statistical Analysis Plan was finalized in November 2003.  The sponsors state that there is -- no income analysis was conducted and also, there is no preliminary analysis was conducted to modify the Statistical Analysis Plan.

            For the primary endpoint, the overall success rate at 24 months, the primary analysis is basically a simple two group comparison of the success rate and non-inferiority hypothesis, as I mentioned in the previous slide.  And also, the one-sided 95 percent confidence interval for the success rate difference between the two groups was also constructed.

            And the second analysis is to evaluate the potential confounding facts from several important covariates, such as age, gender, pain medication, operative level and investigation of site, and also correlated could be added later on as needed, such as body mass index, pre-operative activity level.  And also, I would like to point out there was no plan in the protocol trying to demonstrate any superiority for all the secondary components, secondary endpoints.

            After randomization, a total of 205 patients were implanted with the Charite and 99 patients receiving the BAK.  Overall, compared to only 79 patients in the BAK group has completed the study at 24 months without any missing data.  87 percent of patients in the Charite group had completed data at 24 months.

            The non-completers with missing data at 24 months were classified into three categories, the discontinued, overdue and the not yet due patients.  There were 7 percent patients in the BAK group and five patients in the Charite, 2 percent, in the Charite groups has early discontinuation.  So you have noticed there is about three or more than three times more discontinued patients in the BAK compared to the Charite.

            The overdue patients was defined as those patients who have not received all the components of the primary endpoint at 24 months and have not been classified as early discontinuation.  And for such a population with missing data at 24 months, there is an 8 percent of BAK patients versus 5 percent Charite patients as overdue patient, and there is about the equivalent percentage of patients, which was not yet due, because this PMA was submitted before all the randomized patients completed the 24 follow-up evaluation.

            Although in the protocol the sponsor defined the ITT analysis population will be all the randomized patients, but the actual sponsor's ITT analysis include only completers and discontinued, and they treat the discontinued patients as failures, because there is a high percentage of discontinuation in the BAK compared to the Charite, so such analysis is strongly biased against the BAK in favor of the Charite.  FDA believed that the true ITT analysis should include all the randomized patients with those missing data handled appropriately.

            To assess the impact of missing data on the comparative evaluation of the success rate between the two groups, sensitivity analysis was conducted under several different scenarios as shown in this slide, and this slide, the bar is a 95 percent confidence inflow, a one-sided, for the difference of a success rate at 24 months.

            Again, as shown in the left panel, there was a high percentage of non-completers, 21 percent in the BAK group compared to Charite, 13 percent.  Therefore, any analysis excluding those non-completers or including them all failures will lead to a biased estimate in favor of Charite device.

            For example, if you include only completers, all the actual sponsor's ITT analysis, which is completers plus discontinued, or all the randomized patients including non-completed as failures will be biased against the control, BAK, in favor of the Charite.

            But if we include all randomized patients with missing data at 24 months and treat them as all success in favor of the BAK, the upper bound of the 95 percent confidence interval for the difference of a success rate is almost 7 percent, meaning that the Charite could be worse than BAK by almost 7 percent in terms of the success rate at 24 months.  But using the non-inferiority margin, delta 10 percent, we still can claim the non-inferiority of Charite compared to BAK.

            The sponsors also the last observation carried forward to impute the missing data at 24 months for the non-completers, and FDA also looked at the details of the sponsors as LOCF and proposed a modified conservative LOCF, and that I'm going to talk about in the next three slides.

            Before going there, I also would like to point out that in the worst case scenario where we treat all the non-completers as success for the BAK, but a failure for the Charite, such a conservative way in favor of the BAK, then the one-sided 95 percent confidence interval of the difference, the upper bound of that is 21 percent.  It's well beyond the non-inferiority 10 percent margin.  So under the worst case scenario, the Charite device will not be claimed as non-inferior to BAK.

            So now let's move onto the last observation carried forward analysis.  The last observation carried forward analysis carries forward the last available observation available at the last time to impute the missing data at the final follow-up time point.  In this case, last observation for the primary endpoint at six months or 12 months will be carried forward to the 24 months missing data.

            For this approach to be valid, there is two underlying assumptions, because the primary endpoint is the composite one, so we should assume there is no adverse event, device failures or neurological failure between the last follow-up and 24 months post-implantation.  And also, we would assume that ODI score changed a little, at least improved from six months to 24 months post-implantation.

            To assess such assumptions, here I present a table for those, all the completers in both groups.  There is a high percentage of completers, more than 70 percent in both groups, who have maintained the success status from the previous follow-up time at six or 12 months.

            Since ODI score is a major reason for the device, for the individual overall failure at 24 months, and it's a major dominant reason for the observed difference between the success rate of the two groups at 24 months, I'm going to take some time to talk about how ODI score changed over the follow-up time between these two groups.

            As a visual summary of ODI score distributions over the whole follow-up period from month 0 to 24 months, this slide shows the box prods of ODI score over the 24 months follow-up with the median values connected by the line.  The blue solid line is for Charite and the red box with dotted line is for the control, BAK.

            The main message for this slide is that, as you can see, at early follow-up time from baseline to six months, both BAK patients and the Charite have a decreased ODI score, relatively faster compared to the later follow-up period.  At six months, the ODI score in the Charite group reached, plateaued and maintained the single level through 24 months.  In contrast, the BAK patients were continuing to improve in ODI score, i.e. decrease.  The small ODI score is better, so the ODI score continued to improve from six months to 12 months for the BAK and reached the plateau at 12 months for the BAK patients.

            Therefore, it is reasonable to carry forward the last observation at 12 months to 24 months for both groups, because they all reached the plateau at 12 months.  But if you carry forward six months follow-up date to 24 months, because the BAK patient continued to improve from six to 12 months, such carry forward will be in favor of the Charite and against BAK.

            Here is the detailed comparison between sponsor's LOCF and the FDA's modified conservative LOCF.  In the sponsor's LOCF after imputation with LOCF, the success rate for all the non-completers is 57 percent, which is near a lower bound of the 95 percent confidence interval from the completers analysis population.

            In contrast, at the sponsor's LOCF, the success rate for the BAK is only 28.5 percent, which is far below the lower bound of the 95 percent confidence interval of the completers indicating a bias against the BAK with this approach.  The major reason, as mentioned in previous slide, because the ODI score continued to improve from six months to 24 months for the BAK.  As you can see, for these six months to 24 months, LOCF, majority of BAK patients, 10 out of 11, was carried forward as failures.

            So in a conservative way, we maintain the 12 to 24 month LOCF same as the sponsors did, but we modified the LOCF from six to 24 months in a very, very conservative way in favor of the BAK, treat majority of them as success, 10, except for one patient who showed neurological deterioration at six months, so we treat this patient as failures.

            And also, very conservatively, we treat all the six months to 24 months LOCF for Charite group as failures.  With such conservative LOCF the success rate for the non-completers in the Charite is only 39 percent below the lower bound of the 95 percent confidence interval of the success rate among the completers, and we have 71 percent success rate for the non-completers in the BAK, which is more than the upper bound of the 95 percent confidence interval of the success rate among the completers.

            So as you can see, such treatment is biased in favor of the BAK against the Charite in a way that such conservative LOCF, the 95 percent confidence interval, ranged from -10 to 9.5 percent since the upper bound still below 10 percent delta margin, we still can claim the non-inferiority of the Charite compared to BAK.

            So far all the sensitivity analysis I presented had not taken into consideration any potential confounding fact of some covariates.  As the sponsor and our lead reviewer has pointed out, a couple of important covariates need to be considered such as age, gender, body mass index, base level ODI score, pre-operative activity, the disc level, L4 to S1 or pain medication and investigational site.

            A repeat measure analysis was updated to evaluate the covariate adjusted comparison between the two groups.  Please, note that in this model we treat all missing data as success, because the BAK group has a higher percentage of missing data at 24 months, so such treatment will be in favor of the BAK.  With such conservative repeat measure model adjusting for all the covariates, the odds ratio -- before I get into the details of this odds ratio, I would like to spend some time explaining what odds ratio means in case some of you don't know this.

            The odds of success is the property of success divided by the property of failure, and the odds ratio of Charite over BAK is the odds of success Charite divided by the odds of success BAK.  Corresponding to the 10 percent delta margin, the equivalent odds ratio for Charite over BAK is 0.67.  So if the upper bound of the one-sided 95 percent confidence interval for the odds ratio is beyond -- I'm sorry, if the lower bound, if the one-sided 95 percent confidence interval for the odds ratio is beyond 0.67, then we can conclude the Charite device is at least as good as the BAK.

            As you can see from this slide, over the several follow-up times from six months to 24 months, the lower bound of the 95 percent confidence interval of the odds ratio is beyond 0.67.  And overall, the average across the follow-up time is still beyond 0.67.  So we can conclude, based on the covariate adjustment analysis, the Charite is non-inferior to the BAK.

            All the sponsor's claims of the Charite's superiority compared to the BAK goes back to the second endpoint, such as ODI score, pain Visual Analog Score, quality of life, disc height or may be the primary endpoint at the earlier time point were based on their own adjusted P-values without any pre-specified plan to control the study-wide type and error rate.

            I would also like to point out to demonstrate that Charite device provides a benefit at the earlier time point after implantation than BAK.  Time to sustain benefit should be compared between the two groups.  And actually, one of the sponsor's analysis for time to sustain the success for the primary endpoint did not show any superiority of Charite over BAK.

            So to summarize, the statistical analysis provides evidence that Charite is at least as good as BAK, except for the worst case scenario where you treat all missing data as failures for Charite, but success for the BAK.  Please, also note that the sponsor's sensitivity analysis using completers plus discontinued of all the randomized patients were treating missing data as failures in favor of the Charite, thus it may be biased against the control, BAK group.

            So based on the conservative FDA single imputation LOCF, there is actually almost equivalent success rate between the two groups, 61 percent, and the true success rate for the Charite patients can range from 54 percent up to 68 percent, and the true success rate for the BAK patients could range from 50 percent to 70 percent.

            With regard to the second endpoints, no formal claim should be made without any multi-facility adjustment to control the study-wide type and error.  Please, also note that the adverse event might be under reported in the current earlier submission.  Most recent available data including those discontinued, overdue and not yet due patients need to be analyzed and submitted.  Thank you very much.  Now, I would like to turn the podium over to Dr. Graham.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Dr. Chu.  We'll hear from Dr. Graham now and at the conclusion of Dr. Graham's presentation, we're going to break for lunch.

            DR. GRAHAM:  Good morning.  I'm Dr. Jove Graham.  I'm an engineer and reviewer with the FDA and I have asked to conclude the FDA's presentations this morning by commenting on the testing and evaluation of wear debris for this PMA submission.

            Wear debris is an issue that concerns us because materials, even when biocompatible in bulk form, can elicit a different biological response when they are in the form of small particulate debris.  Specifically, particles that are smaller than 5 microns in size can be engulfed by a macrophage cell causing macrophage activation and inflammatory response and in other orthopedic devices, this can lead to osteolysis and bone resorption.

            This wear debris induced osteolysis is a contributing factor in aseptic loosening of other total joint replacements and is thought to be one of the limiting factors on the lifetimes of those devices.  So here with the Charite Artificial Disc, we have two articulating surfaces that are going to be sliding against each other under a compressive load over the entire lifetime of the device.  The surfaces are ultra high molecular weight polyethylene against cobalt chrome, one on the top and one on the bottom.

            So under these conditions, we expect that some wear debris will be generated.  Our question is does this wear debris pose a risk to the safety and effectiveness of the device?

            The sponsor has performed three kinds of testing to address this issue as previously presented and the tests are listed here.  The wear testing of their actual device is what establishes how much debris we think will be generated and the wear rate.  Then by looking at the particles that are generated during that testing, this tells us what the size and expected shape of the particles are going to be.  And then finally, the sponsor has conducted a small animal study using a rabbit to evaluate the biological response to that debris.

            I think the sponsor has identified exactly the three questions that need to be asked with respect to this issue and they have identified and carried out the appropriate tests to answer those questions.  I think we need to keep in perspective what the results can and cannot tell us.  What these results do a very good job of is thoroughly characterizing the expected wear behavior of this device.  The thing to remember though is the other thing that we would like to do with these results would be to take them and compare them to results from another spinal disc replacement that would be in the literature, that would be well- characterized with the long well-understood clinical history, and because this is the first PMA for a spinal disc replacement, we cannot do that at this time.  That literature and data is not available.

            So the closest thing that we can try and compare the results to would be wear data from other orthopedic joint replacements like total hips and total knees, and that literature is certainly abundant and the sponsor has drawn that comparison.  I think we just need to be careful about the statements or the conclusions that we can draw, because a spinal disc joint is very different than a hip joint or a knee joint.  The anatomy is different.  The geometry, the conformity.  We would test them differently.  There are different loads and different ranges of motion.

            And because of that, there are always limitations to what kind of conclusions we draw about clinical performance based just on preclinical results.  But here, I think we want to be specifically careful about trying to make clinical conclusions by comparing preclinical disc testing results to testing of hips and knee replacements.

            Okay.  The first testing was wear testing of the sponsor's actual device in a simulator machine.  The testing parameters the sponsor used are in very good agreement with the ASTM standard that is currently being developed.  I emphasize currently being developed, because not ASTM, not ISO, no one has a wear test simulator method for spinal disc replacement that has been validated yet in the way that we consider hip simulators or knee stimulators to be validated.  In order to do that validation, you really have to be able to take the devices that have been in your machine and take devices that have been in the body, look at those surfaces and see if they have the same wear patterns, the same wear behavior.

            And at this time, we just don't have those specimens from in the body to make that comparison.  We only have the devices that have been in the machine to look at.  So everyone's wear test method, at this point, ASTM's, ISO's and the sponsor's is sort of a best guess at how we think we should best simulate the in-vivo psychologic loading conditions.  I think it is a good sign that the sponsor's choices match very well with ASTM's best guess.

            That said, there are two small differences between what ASTM suggests and what the sponsor has done.  ASTM suggests the static compressive load of 1,200 Newtons.  Although, ISO actually suggests a cyclic load and the sponsor has chosen to use a cyclic load, which is probably going to be more physiologically relevant than a static load.  And you see the numbers are different, but they are all in the same ballpark.

            There is also a difference in the modes of motion that were tested.  ASTM suggests testing each of the three axises that is flex extension, lateral bending and axial rotation in sequence or all three simultaneously.  The sponsor has chosen to use two of these modes at once and either couple flex extension with axial rotation or couple lateral bending with axial rotation.  I think it is important to do some kind of couple testing, so it is good that that the axises haven't been tested individually.

            And for this device, from the polyethylene's point of view, the polyethylene core is round.  It is radially symmetrical, so I think from its point of view there is not much difference between flex extension and lateral bending.  And the sponsor has also chosen to use the same range of motion in those two directions.  So I think this is an appropriate mode of testing for this device.

            The results showed an average wear rate of .11 milligrams per million cycles with a small height loss.  And the sponsor states that this average wear rate is lower than most reported wear rates for polyethylene hip and knee replacements.  That statement is true.  I would just add that we don't yet know what wear rates are going to be acceptable and tolerable in the spine until we have more spinal wear data.

            There were results of looking at the particles that were generated during that testing.  Most of the particles were described as smooth flakes, very few elongated particles, an average diameter between .2 and 1.5 microns.  And one of the key points here, I think, is that the majority of the particles generated were less than 1 micron in size and submicron.  The sponsor again says that the particle size range is typical of simulator testing retrievals from other polyethylene joints, and that is true.  I would just add that particles of the same size could elicit a different reaction in different parts of the body.

            For an example, I think, particle transport that is where do the particles go once they are generated could be different in the different locations because of differences in the anatomy.  We don't have a synovial capsule around the disc space.  The epidural space is continuous up and down along the length of the spine, and the difference is in things like lymphatic drainage.  All of these can contribute to differences in the reaction to the same size particle in different places.

            Finally, the small animal rabbit study was conducted to evaluate the biologic response to these particles.  Two note to make on the sponsor's methods.  A 3 milligram dose of the sterile drug polyethylene particles were implanted.  These particles were manufactured by freezing and grinding polyethylene resin, but this is a standard way or a typical way of doing things.  It is very hard to collect enough particles from the actual simulator testing to even be able to look at the size and shape let alone try and collect enough to actually implant into the rabbit.

            So that change should just be noted, but I think this is a reasonable way of generating the particles for this test.  The dose used was 3 milligrams, and if that wear rate of .11 milligrams per million cycle is right, then this dose should represent almost 30 years worth of accumulated debris.  And I think that's an appropriately conservative dose.  One other difference between the particles that were implanted into the small animal and the particles that were seen in the wear testing is the size range.  Particles implanted into the animal were between 1 and 10 microns.

            95 percent of those were below 5 microns, and this is important, because, as I said in the beginning, 5 microns is about the threshold size that a particle needs to be below in order to be engulfed by the macrophages.  So these particles here were small enough to be engulfed by the macrophages and probably activate the same kind of pathways that smaller particles would have.  However, remember that the majority of the particles that their actual device generated were submicron in size.  And from what I can tell, none of the particles implanted here were submicron.  So there could have been a different degree or a different response had the particles been smaller, but we don't know.

            Finally, the results, some of the results of that animal study.  The first two here emphasize that the cerebrospinal fluids seemed normal and there were no lesions or neuropathology of the cord.  This is important because it emphasizes that the sponsor did not observe any reactions that would be specific to the spinal cord or the nervous system.  In the group that received particles versus the Sham control group, there was a greater amount of epidural fibrosis and an increased level of the cytokine aisle six at the three month time point.

            Aisle six is one of the cytokines that has been associated with the osteolysis pathway.  However, that level seemed to decrease back down to normal at the six month time point and the sponsor looked for and did not see increases in any of the other cytokines that we associate with the osteolysis pathway.  There was a marked infiltration of macrophages with phagocytosis particles described as a chronic macrophage reaction in the epidural fibrous tissue.

            The particles could clump together in a glomerate of 50 to 300 microns in dense macrophage clusters were described adjacent to these.  However, there was giant cell reaction, no evidence of cellular apoptosis and the sponsor looked for and did not see any particles in the lymph nodes or in the distant organs.

            So I will just conclude by summarizing what we know and what we don't know.  The wear testing of this device has demonstrated that the device will generate some wear debris.  The wear rate was measured at .11 milligrams per million cycle.  The wear debris was mostly submicron with an average diameter between .2 and 1.5 microns.  And the small animal study demonstrated that particles of polyethylene implanted into the spinal region could cause epidural fibrosis, a macrophage reaction, a transient percolation of aisle six that went away later, but no reactions were seen specific to the spinal cord, registry of the spinal fluid.

            Finally, we should just consider the preclinical testing has done a good job of characterizing the expected wear behavior of this device, but we can't necessarily establish safety and effectiveness of any spinal device just by comparing preclinical results to those from the hip or a knee device.  Also, the wear test simulator needs to be compared to implanted retrievals any wear test simulator does in order to validate that that simulator is applying the proper loads to the motions.

            And finally, just keep in mind that wear induced osteolysis for other orthopedic devices is a long-term complication.  It is probably not going to show up in the first two years of one to two years follow-up and may not become a problem or be observed until 10 or 15 years of follow-up.  Thank you very much.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Dr. Graham.  I would like to ask that we hold our questions for FDA until after lunch and that we take a break for lunch now.  It is now about 20 minutes or so after 12:00.  Let's reconvene at 1:20.  Thanks.  Let's break for lunch.

            UNIDENTIFIED SPEAKER:  We're eating on the 8th floor, but this will be secure.

            (Whereupon, the meeting was recessed at 12:23 p.m. to reconvene at 1:25 p.m. this same day.)

 

 

 

 

 


         A-F-T-E-R-N-O-O-N  S-E-S-S-I-O-N

                                         1:25 p.m.

            CHAIRPERSON YASZEMSKI:  We're going to start the Panel discussion as soon as we start and then you are going to go ahead.  We're just waiting for Dr. Diaz.  Okay.  He can show up.  Good afternoon.  It is now 1:25.  I would like to call the meeting back to order.  I would like to remind the public again that while this meeting is open for public observation, public attendees may not participate except at the specific request of the Panel.

            We will now begin the Panel discussion.  Two voting members of this Panel will open this part of the meeting with their remarks.  Dr. John Kirkpatrick will give his remarks on the clinical information and Dr. Brent Blumenstein will address statistical evaluation of the study.  Then the Panel will have a general discussion after which the Panel will focus their deliberations on the FDA questions.  Then there will be a second open public hearing and FDA summation and sponsor summation.

            After that, the Panel will conclude their deliberations and vote on their recommendation concerning this pre-market application.  The Panel can ask the sponsor or the FDA questions at any time, so, please, interrupt and ask any time any Panel Member has a question.  The first lead Panel reviewer is Dr. Kirkpatrick.  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  Thank you, Fellow Panel Members, sponsor, of course, and then the public.  I appreciate the opportunity to review this.  I am both humbled and honored to be able to provide this review to you.  I'm also a little bit stronger after having carried around that box to do the review itself.  I would like to -- Mark, the page up does not do anything.

            MARK:  Page down.

            DR. KIRKPATRICK:  Okay.  Just to go over some basics about my review method, since this is a first product of its kind, I look to what would make common sense, so what are the goals of disc replacement.  Then I wanted to look at general principles as stated in the literature.  We'll review how the literature has followed those principles.  We'll review how the PMA followed those principles.  We'll expand on an important area that, I think, warrants further consideration.  Then we will review the goals once again and then summarize some key issues.

            As I did not have the amount of time available to me, I would also ask, as the FDA, the sponsor if they could, please, try and keep track of any areas where I may have missed something in your PMA.  There was an extensive amount of data and I have already found one correction that I had to make.  So if you find other things that I say that are inaccurate, by all means, please, make me aware of it so I can refocus any further discussion after this.

            The goals of disc replacement, of course, are to remove the presumed pain generator, which is thought to be the degenerative disc.  We then replace that with a device restoring normal motion to the functional spinal unit.  The key aspects of the reason that this should be better than a fusion of a lumbar disc is the fact that it prevents adjacent segment degeneration.  Long-term pain relief would then be better than arthrodesis, because the pain at the adjacent segment does not degenerate, because of the continued motion at the affected segment, and so that's the key focus of why you would do a disc replacement rather than a fusion, at this point.

            General principles from the literature, we should have normal unconstrained psychologic motion.  We should have anterior column support, normal biomechanics, wear resistance, a stable bone implant interface or osteointegration, biocompatability.  The device should be set fail safe.  By that, we mean that if it does fail, it does not cause further damage, in other words, damaging other structures or other areas of the body.  It should be revisable, meaning you can salvage the situation and it should be monitorable.

            How does the literature deal with these issues and how well can they cover those general principles?  With preclinical testing, normal unconstrained motion has been demonstrated in multi-segmental flexibility testing of a cadaver model.  Motion profiles among all the segments as well as testing the individual segment and then testing before and after replacement of the disc.  Preclinical testing on anterior column support has been poorly addressed in the literature.

            Normal biomechanics has also been poorly demonstrated in the literature from the standpoint that we do not know, in particular, how the facets are affected.  Wear resistance should be studied.  Wear testing should include cyclic loading replicating the load in motion for the region intended.  Failure or 50 million cycles is what has been cited in the literature studies that I was able to find.  Wear assessment and particle analysis every 10 million cycles is an appropriate interval, according to the literature, and the debris analysis, of course, is a key component as well.

            Osteointegration of biocompatability or the host device interactions are important.  One should look at local tissue cytokines in response to the disc and/or the debris generated.  No where debris should be found in the reticuloendothelial tissues.  Ingrowth or fixation over a minimum of 30 percent of the bone implant interface or surface should be demonstrated and the materials, of course, should be biocompatible.

            As far as clinical studies, that's where we get into the "failsafe" issue, and that is that failure should not risk other injury to the body.  It should be revisable or salvaged by either revision or fusion.  It should be monitorable with clinical outcomes, radiographic outcomes, complications incidents and other issues.  In general, clinical studies of the literature talk about indications, comparison groups, and in this case, fusion is used.  Could non-operative treatment also be a consideration for a comparison group?  Complications, success rates, follow-up intervals and length are all key features of clinical studies.

            Complications should include loss of function, especially through subluxation, subsidence or dislocation, but also in the literature they talk about loss of motion.  Heterotopic ossification is another complication that is reported in the literature as a concern.  Excessive wear, migration or breakage, facet degeneration at the index level, adjacent segment degeneration and, of course, infection of the device itself.

            Efficacy measures have included visual analog scales, region and disease specific validated outcome measures, such as the ODI, prevalence of revision or additional procedures to the index level and then radiographic measures, including motion analysis or osteolysis or other radiographic changes.  This PMA should be commended for its extensive report.  They did a good job at trying to be comprehensive.  They made a significant effort on preclinical studies.  They coordinated a rather elaborate multicenter trial, which recognized learning curve.

            It was randomized after a learning curve at each center.  They followed their patients for two years.  They had reasonable patient accounting, although we have already heard from some statistical follow-up they have some that are yet to complete the study should be included.  And we want to see how they compare to the literature standard.  With mobility testing, the mobility testing that was in the PMA, as far as I could tell, was referring to a published study.  They had a two paragraph summary, which for somebody with an interest in biomechanics, it was difficult for me to get enough information to convince me that unconstrained motion is attained.

            Anterior support, I think, they did a very good job in the study and I have no concerns.  As far as general biomechanics of the replaced spine, the test methods are not well-defined in the literature and, of course, as I mentioned earlier, the difficulty of finding out whether the facets have normal stresses across them after the disc replacement, there is not a good method for it in the literature yet, but I would have hoped that the PMA sponsor would have tried to address that in some sense, and perhaps they have and can provide that data to us later.

            As far as wear, the date they presented was up to 10 million cycles.  They used coupled motion in an axial rotation and flexion-extension.  These two issues, I think, should be considered a little bit further.  The 10 million cycle number is low compared to those in the literature.  It is also low with respect to what the intended life of the device is to be.  As far as coupled motion, their selection of axial rotation in a flexion-extension mode or axial rotation with a lateral bending mode presents some problems.

            They also indicated that in their specimens that they looked at, they found grooves in the specimens in the line of the direction of motion.  I would have to question whether if they did flexion-extension coupled with lateral bending, whether that extra motion trying to come out of the groove would actually cause more wear debris or a different type of wear debris.  So that would be one suggestion I would have as far as additional data.

            They also looked at submicron debris with their animals or excuse me, they found submicron debris with their wear analysis, but their neurotoxicity data looked at from 1 to 10 micron and my concern echos that of the FDA and that is would a different response occur if they used a larger volume of the submicron particles as opposed to the micron and above particles?

            With regard to osteointegration, this is one thing I had to change.  I actually missed the sentence that said in there summary of the osteointegration in the PMA.  I missed the sentence that said that they are presenting data or reference data that was not in the actual clinical study, so I do need to emphasize that the osteointegration information that I was able to review in the PMA was a reference study, but it was not one that was relevant to the surface coating of the device that is being presented in the clinical arm.

            In an ingrowth model, they did have adequate osteointegration.  I don't see any data in the PMA that represents any kind of long-term biologic fixation with the device that they circulated.  Cytokines and reticuloendothelial tissues were examined well in the reference study as well as in a subsequent study that was published using the same device in the U.S. literature as compared to the European spine literature.  And I think that demonstrates the fact that the wear debris doesn't cause a problem.  But I can't really give it a true pass on the osteointegration side.

            Failsafe, I think, the device is failsafe based upon the two year study.  Failures did not result in device related further injury in the study.  I think the difficulties with revising it are more approach related.  And then revisability, the fusion was used for failures predominately.  They did have a retrieval or two, but I think it is potentially salvageable from the standpoint of what they presented.  Again, this has to be limited with a two year follow-up.

            Is it monitorable?  I think they did a good job in clinical outcomes.  They used the Oswestry scale for a lumbar spine, which is appropriate, a visual analog scale, work status, SF-36.  I do have questions with regard to the neurologic status, their specific measure of how they could do statistics on the neurologic outcome was difficult for me to understand.  To do statistics it would seem a lot easier to have a number scale to be able to determine.  The changes in neurologic function seem to be more qualitative, rather than defined in quantitive.

            Radiographic monitoring, they did range of motion studies that I thought were good.  Other measures for disc replacement were unclear.  The radiolucency, I don't think has been defined in the literature or by the sponsor as how to grade that or determine how much is there.  In addition, they did not look at adjacent segment radiographic changes.  And as far as complications, I think, they adequately reported them within the limits of their study and the goals defined.

            Their indications were clearly defined.  The comparison group was clearly defined.  The success criteria were defined.  The results were found mostly to be comparable to fusion.  I do have some additional questions on stratification among different indication groups and whether that would improve our understanding.  In their indications groups, they did include people with facet changes at that disc level and combined those with people that did not have facet changes at the index level.  And my curiosity would be would those two different groups result in a different outcome long-term?

            Their follow-up intervals and length were well-defined, but I question whether it was adequate length.  Their complications they talked about loss of function.  I think it was reasonably well-reported.  It was poorly reported for range of motion and it may be just that I didn't find all the data easily.  Heterotopic ossification, I could not find that incidence well-described in the PMA.  Wear was not found, which is a good thing in the clinical study.

            And then facet degeneration, I didn't see an indicator of whether that was examined.  Adjacent segment degeneration, the same question there.  And then infection, I didn't see any device specific infections reported.  Of course, they did have wound problems, arrythmia around the wound and that sort of thing.

            Overall, if you were to look at a grade card like my daughters bring home to me from school, we would see that the literature passes on motion.  A failure, in my opinion, on the materials provided, because the reference was not contained in the materials, I think that reference probably does cover enough to satisfy me, but technically I can't approve that, because I have not seen the entire reference.

            Anterior column, I think the literature fails, but our sponsor did a much better job and I would give them a pass on that.  Biomechanics, I have to give a failing grade to both the literature and our sponsor.  Wear, I think is an almost pass.  I think their technique was great, except for the alteration of trying to do the coupled motion in both lateral bending and flexion-extension, and I do think they should extend the length of their wear testing.

            As far as osteointegration, I had to give them a fail.  Biocompatibility, I believe, they passed.  Failsafe, again, is poorly described in the literature, although, it describes what the problem would be and the same thing for the PMA.  Fortunately, neither have shown disastrous secondary consequences from the device failing.  Revisability, I think they passed for the length of follow-up.  And then monitorable, I think, they could use some help on the radiographs as well as I mentioned the neurologic scale.

            I'm sorry, I'm hitting the wrong button.  On the length of follow-up, I think, this warrants a further consideration.  A key issue on disc replacements is the fact that again the concept of not fusing, but replacing with a disc, is to both remove the pain generator, but also prevent adjacent segment degeneration.  With that as the fundamental concept, we need to look at how frequently do you get adjacent segment degeneration after a fusion?

            Two reasonable references in the literature on a lumbar spine reasonably well- controlled found that there are -- excuse me, 35 percent at five years will develop adjacent segment degeneration and that study did include multi-level fusions.  And in another study that looked at four years with a single level fusion, they found 17 percent at four years.  So putting that together, we need to think how soon will we see adjacent segment disorders to be able to prove that the fundamental goal of a disc replacement is actually being attained.

            So is two years adequate, is a key question.  We might be able to look at some statistics to kind of predict how many patients at what time period would be appropriate to see that knowing that the literature has given us some data for four and five years of adjacent segment development.  And of course, there are also additional suggestions in the literature on the length of time that would be considered appropriate for a disc follow-up, and most of those in the literature do suggest a five to 10 year pivotal time span to be able to determine whether these are effective devices.

            Once again, adjacent segment degeneration, I think, the sponsor has failed to demonstrate the absence of this occurring, even at two years, because I could not find, again, the radiographic data to back this up.  If they did do this, I would appreciate their showing me how and pointing out to me the proper pages in their PMA.

            Summarizing, there are some key issues to consider where the literature reported 50 million cycles, I think, they need to bring up to that level.  Representative range of motion, is that truly near physiologic?  That also opens up the other questions of how much motion are we going to accept as a preservation of function and what criteria we would set for loss of motion.  And then finally, the adjacent segment degeneration is there less with the disc than with fusion?  I don't think it is demonstrated and I also am concerned that two years is not adequate to demonstrate this.

            Thank you very much.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Dr. Kirkpatrick.  We're going to next ask Dr. Blumenstein.

            DR. KIRKPATRICK:  Excuse me.  If I may do one other liberty at this point?

            CHAIRPERSON YASZEMSKI:  Yes, sir.

            DR. KIRKPATRICK:  I have prepared a list of items that I think would be opportunity for us to consider suggestions to the sponsor.  If I may, I would like to just dispense with these to the Panel and to the sponsor?

            CHAIRPERSON YASZEMSKI:  Please, do.  Thank you.  While Dr. Kirkpatrick is doing that, we'll ask Dr. Blumenstein to come up and give us his statistical analysis next.  And I will ask the Panel Members immediately after Dr. Blumenstein's remarks we're going to proceed to a general discussion.  Any questions the Panel Members have for either of our two lead presenters, Dr. Kirkpatrick or Dr. Blumenstein, you may ask them or any questions you have of either our sponsor or the FDA, you may ask.

            When we get through those general questions, we'll then proceed to individually looking at the specific questions the FDA has asked us to consider and we will go around the table on each of those questions.  Dr. Blumenstein, we're ready when you are, sir.

            DR. BLUMENSTEIN:  So I basically agree with the FDA statistician's review.  I especially liked all of the finer analyses to make sure everything is meeting all the assumptions.  I don't like the sponsor's analysis and I will tell you why in a minute.  It's more in the category of nitpicking, but despite the flaws, the product appears to meet the non-inferiority criteria and my goal here is to identify the single best characterization of the non-inferiority outcome.

            I personally hate the term intent-to-treat.  I think that the correct term is analysis by arm.  However, it is a little bit late for me to be making these objections, because the term intent-to-treat is very pervasive.  I also hate the term population when referring to a part of the data to be analyzed.  The population is that from which we sample, unless you are a Camp Thornian, and most people in here won't know what that means.  But the term population, so when you use the term ITT population, that to me doesn't make sense at all.

            The sponsor's definition of the ITT population not only does the term not make sense, but it is incorrect, because it deletes randomized patients.  The ITT is analysis by arm and it includes all randomized patients.  To modify the definition of ITT or analysis by arm by deleting patients is tantamount to saying someone is only partly dead.  The FDA statistician also apparently agrees with me on this.

            So I'm going to give you a little course in randomized clinical trials 101.  In a randomized clinical trial, the arms that you create is a partition of the patients enrolled based on some random process.  As a result of that, these arms represent patient groups, that is the subsets of the patients enrolled, that are stochastically equivalent.  And the primary analysis is to compare the arms with respect to whatever effect measure is being used.  You are not comparing the interventions.  The primary analysis is therefore an analysis by arm, that is comparing the arms enrolled as randomized.

            If there is no intervention difference, then the probability of the type one error is that declared in the planning of the trial and so forth, provided all of the other principles are followed, such as repeated analyses and so forth.  And so the analysis by arm compares the arms with respect to the outcome measures as influenced by all arm specific actions.  Now, ideally, arm specific actions are related to the intervention only.  That is in the nice clean trial, everybody gets the intervention intended and they have an outcome measured and you are able to compare the two arms and then the comparison of the arms really does relate to the interventions.

            But the degree to which the differences reflect intervention differences depends on the purity of the implementation of the intervention, that is if some patients don't get the intended intervention or the patients are dropped out from the analysis and so forth, then you may or may not, by comparing the arms, actually be comparing the interventions.  The deletions from the arms, that is the groups of patients, erode the stochastic equivalence and between armed differences when there are deletions, represent a combination of the differences in the interventions that might or might not exist and the differences due to deletions.

            So that when you have deletions in the pure conical randomized clinical trial sense, you have eroded, you have introduced a factor that is eroding the stochastic equivalence that you implemented through randomization.  And deletions based on post-randomization events are particularly honoris, because they are more likely related to an intervention, that is a patient may drop out because of side effects or decide not to come back because of side effects or you may have intervention implementation issues that affect the arm.

            The primary outcome in the trial should be defined for all possible contingencies.  In a dichotomous outcome, that is you have success or no success observed, and this can be defined for all contingencies, and this is what should have been done in this trial.  If we had a time-to-event outcome, we could have incomplete follow-up and we can handle that through censoring provided certain other assumptions are met.  The qualitative measures, such as things like quality life and other kinds of things of that nature, laboratory values are difficult because missing data has to be imputed or you have to use some other technique to fill in where data are missing.

            The exceptional outcomes, I call them EOs here for lack of a better term, for a dichotomy are no success, but no opportunity to observe a failure.  In other words, a patient drops out before the two year follow-up is -- before you can measure the two year follow-up, in this case, or something along those lines.  If EOs are equally distributed between the arms and independent of the intervention, then we have a minimal problem and it becomes a random thing that perturbs our trial a little bit and we just keep them in and we hope they are working out.

            But an existence of an EO, that is an exceptional outcome, can be due to side effects and when that happens then we have the potential for bias.  The conservative reproach is to call the EOs not successes and this preserves the ability to do the analysis by arm.  That is all patients included.  So the primary effective efficacy analysis here is really a non-inferiority analysis.  And, in my opinion, this is the analysis by arm that is a true intent-to-treat with a conservative EO coating, that is patients that aren't observed to have the success or failures.

            The protocol, as far as I could tell in the massive materials that I was provided, did not specify how to handle EOs.  And then there was some fussing about whether the analysis plan existed prior to the time that the database was actually analyzed and so forth.  Whatever.  The definitive analysis is analysis by arm, and it best characterizes the magnitude of the benefit and also to the extent that the trial matches the real world.  It would also match the real world in the sense that there are patients who drop out before you can measure success.

            So the Type 1 error specified in the protocol is .05 one-sided.  Now, some would argue with this and say that really the criterion should have been .025, that is .05 divided by 2, and other parts of the FDA are very, very strict about this, that if you are doing something one-sided, then you are always doing it at .025 one-sided.  But that's a controversy we won't get into much here.  The FDA apparently in early meetings accepted a one-sided .05 criterion for success here.

            Now, however, the FDA believes that delta should be 10 percent instead of what was apparently agreed upon earlier as 15 percent.  So we have some drift in the definition of success.  We also have, you know, the primary analysis not being cleanly defined.  A lower significance level for final analysis should also be considered, because there may have been some data snooping.  And if there was an interim analysis, we would be decreasing the final criterion to just under .05 as declared in the protocol.

            For example, .048, something along those lines.  And therefore, if we can look at a tighter Type 1 error probability of .025, we could have a conservative indication of the robustness of the data.  Now, what I'm going to show you now is similar to the sensitivity analyses that were done both by the sponsor and by the FDA.  So there's really four analyses here.

            The first has delta at 15 as specified in the protocol and alpha as a one-sided .05, and a true intent-to-treat or analysis by arm.  We have those rates of success of 55.6 percent versus 45.5 percent.  And, of course, this meets the non-inferiority criterion using the black welder test and also the confidence interval that is a little different than the FDA presented it.  I can't remember how the sponsor did it, but the confidence interval doesn't include the -15 percent, which would cause it to be inferior.

            The next analysis is just going down to the delta at 10 percent, but using the one-sided .05.  Again, quite clearly, the sponsor meets the non-inferiority criterion.  The next one is delta 15, one-sided .025, just to get an idea of if you were to go for a stricter criterion for making Type 1 error, you still meet the criterion, because you have the P less than .0001 and 95 percent confidence interval still precluding the -15 percent.

            Finally, the strictest case of delta 10 and alpha .025 and so these are the conical analyses, that is analysis by arm, the true intent-to-treat with some sensitivity testing varying the delta and the overall alpha, and it is consistent with the sensitivity testing that was done in other situations where all but the worst case scenario was also indicated, success with respect to the non-inferiority criterion.

            Now, I can't help but say this.  If I were to have the opportunity to design this trial today, I would sure look hard at a failure time primary endpoint, that is something like failure free survival.  And the definition of failure time would be possible in a revision, time to revision or significant side effects or perhaps a decrease in that score that was used or something like that.  The arms could be compared using a log rank test.

            The advantages of this kind of a primary outcome would be that it captures time and it handles missing data better, and that's just my own opinion.  I wanted to get that out.  Any questions?

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Blumenstein.  I'll ask the Panel if they have any questions now for Dr. Kirkpatrick or Dr. Blumenstein.  We'll have, of course, an opportunity to do that throughout the general discussion.  If there are none, we can begin the general discussion now.  And this is an opportunity for Panel Members to bring up any questions they would like to ask of either each other, the FDA or the sponsor.

            And perhaps I can start it off while folks are thinking about it.  And I would like to start with a sponsor question.  Dr. McAfee, may I address a question to you?

            DR. MCAFEE:  Sure.

            CHAIRPERSON YASZEMSKI:  Several people have brought up the issue of revisions and have used words like life threatening and maybe impossible to do, and I would just like your opinion.  I mean, the study center, I would submit, contain the most experienced surgeons and Mr. Christianson showed us that the training centers are well-setup and that the expectation would be that surgeons who want to do this for the first time get training.  It has been also shown, however, that you surgeons in the study center did have a training effect and there was a time to getting good at this.

            And would you think that when a surgeon has gone through the training and started to do this, and then is confronted with her or his first revision, what would be your opinion?  Would such a surgeon be ready to do that?  Should perhaps the most experienced surgeons, like yourself, at the training centers be available for consultation or to, you know, maybe decide whether they should see the patient?  I would just like to hear your thoughts on that on revisions.

            DR. MCAFEE:  All right.  And, please, direct my answer, because I have a lot of different ways I could answer that.  I have been dedicated to trying to reduce the incidence of these complications.  Honestly, I don't see a difference in a dynamic spacer versus any anterior instrumentation device.  And I'm going to go right to the more serious problems, and if you could put up slide 166.

            I think it's important to focus on the number of cases that really required an anterior revision and personally, I have never had to redo a Charite from the front, but I have published a series of 28 cages.  The title of the article is "Revision Strategies for Failed Interbody Fusion Cages," so that's 28 cases.  And Ensor Transfeldt from Minneapolis presented 40 cases along the same lines of failed Interbody Fusion cages.  And the fact of the matter is you want to do everything possible to avoid having to go from the front again.

            It's nice to say well, we have gone the left anterior retroperitoneal approach and then for the revision, we'll go from the right side or, if it's L5-S1, you would want to do the revision through a transperitoneal approach anteriorly at L5-S1.

            The keys are in the randomized part of the series, there are really only two cases that required a repeat anterior procedure, and I'm going to add on here the Kurtz/Peloza case report that we heard, so that would actually be three cases being redone from the front.  And actually, one of my points is we heard the case report, but we never heard what the indications were for anterior revision.  That Charite device was totally confined within in the disc space and, personally, I do everything humanly possible to try to salvage that for the safe posterior fusion in Side 2, Pedical screws, posterolateral bone graft and that is how you would revise any Anterior Interbody Fusion cage.

            So for the first case up there, it was revised at one month.  This was a technical problem.  Fortunately, it was able to be revised anteriorly.  A smaller Charite was placed three days post-operatively.  The second case was 20 months.  The Charite had to be removed from the front and this was revised with the Anterior Interbody Fusion.  So that's really three cases out of the total 205 randomized series.

            And I can tell you that, personally, I try to track down the revisions, because that's what I'm interested in, and so far in the United States of the 700 cases, there have been 13 that have required anterior revisions and nine of those were able to be revised with the Charite.

            So one of the key points is you are highly dependent on a well-trained access surgeon.  The Van Ooij's series that I presented, in Europe the surgeons tend to do their own anterior procedures.  We use three different access surgeons.  Their primary interest is vascular mobilization and being able to deal with the great vessels.

            So we go from here to slide 167 and 168 and these are the total series of re-operations of the Charite.  And to me, you know, we're going to be arguing about adverse events and what constitutes a real neurologic problem, but to me it's really cut and dried.  It's very objective.  If a patient goes back to the operating room, that's a failure.  So there are 11 patients.  There are some on this slide and then the next slide, 168.  And you will see that by far the majority of the problems were able to be successfully salvaged with what should be a routine operation for a spine surgeon, and that is a posterior approach.

            If the patient has leg pain, then you use that as an opportunity.  I have had two cases like this in my 93 patients.  The patient wakes up with more leg pain, so immediately we get a CT myelogram.  I honestly didn't see anything compressing the nerve root, but I felt obligated to explore the patient, so you do a posterior approach, decompress the nerve roots and then do a fusion in Side 2 with Pedical screws.  So that's 11 patients re-operated on in the series of 205.

            CHAIRPERSON YASZEMSKI:  All right.  Thanks very much, Dr. McAfee.  May I go around the table and ask now for general discussion questions by any Panel Members for either FDA or the sponsor.

            DR. DIAZ:  I would just like to make a comment on that last answer.  Being a neurosurgeon, I tend to be a little bit more purist on the view of approaches, and to me a revision is limited strictly to going back to where the operation was.  A salvage operation, which is the Pedical screw, I do not believe is a revision.  So I think I am glad to see that you presented the 12 cases with a true anterior revision, because those answer the very question that was asked, and also I think they are in agreement with the European experience, which indicates that they are doable.  So even though the cases are potentially threatening, I think the approach is possible.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Dr. Diaz.  I would like to come around the table now and let's just come in clockwise order and I will ask, Dr. Mabrey, have you any general comments to make?

            DR. MABREY:  Yes, for Mr. Cunningham regarding the retrieved material from the animal model.  How did you determine the absence of wear debris?

            DR. CUNNINGHAM:  The retrieved materials from the animals were based on selecting tissue directly overlying the operative level.  So there are two animal studies.  There was a rabbit study and a primate study.  Which one are you referring to?

            DR. MABREY:  The primate study.

            DR. CUNNINGHAM:  Yes, we collected tissue right over the top of the operative level, this was a six month follow-up, and we assayed it for a variety of cytokines, as well as macrophage activity, and we used both plain and polarized light microscopy to assess any evidence of wear particulate.

            DR. MABREY:  And did you use an Oil Red O Stain?

            DR. CUNNINGHAM:  Excuse me?

            DR. MABREY:  Did you employ an Oil Red O Stain for this determination?

            DR. CUNNINGHAM:  No, we did not.

            DR. FINNEGAN:  Actually, don't sit down.  Mr. Cunningham, don't sit down.  A couple questions.  Why did you only take your baboons at six months?

            DR. CUNNINGHAM:  Well, primate studies, first and foremost, are very expensive.  So the six month follow-up we decided was optimal based on our experience with Interbody Fusion cages.  These are typically run at three with six month as our longest follow-up, so that's why it was selected.

            DR. FINNEGAN:  And secondly, what kind of activity level did they have?  Were they caged or were they out?

            DR. CUNNINGHAM:  Yes, they were individually housed in cages and the primate has a rapid post-operative ambulation.  They typically are recovered by the second day post-operatively and are back to normal activities of bouncing around their cages, but they were not group housed.

            DR. FINNEGAN:  And they were not where they could do a large amount of swinging and jumping?

            DR. CUNNINGHAM:  No, the cages themselves are kind of a double decker style, so they are about 8 feet in height and 4 feet by 4 feet deep, so they do have the capacity to elevate themselves and then land.

            DR. FINNEGAN:  And then I have one other question for the company, but I don't think this is one you want.

            Cross-link polyethylene was brought up, and is that something that is being considered?

            DR. SERHERN:  I am Hassan Serhern, DePuy Spine.  Actually, we are using ultra high molecular weight 10-20, guard 10-20 grade, which is cross-linked only by sterilization of 2.7 megarad.

            DR. FINNEGAN:  Okay.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Finnegan.  Dr. Kim, have you any general comments?

            DR. KIM:  I have a question for Dr. McAfee.  It's more a theoretical question.  An interesting point that was brought up is that we're putting these implants into relatively young people, and I think it's a compelling argument that these implants will need to last about 40 years.

            What are your thoughts on that?  Do you think they will really last 40 years and, if not, what would be your second treatment for this problem?

            DR. MCAFEE:  Well, I hope they will last 40 years.  I tell my patients to really look at LeMaire data, which is up to 11 years, which is pretty good.  There are five different main surgeons in Europe that have long-term experience.  Honestly, to talk to the patients, 10 years is pretty good outcome.  In other words, if I can avoid doing a fusion for 10 years, most of them would consider it a success, because you look at Allen Hildebrandt's study, you know, 2.9 percent risk of adjacent segment disease, Etebar and Cahill, the same kind of range, 4 percent annual incidence of adjacent segment disease.  And you compare that to over 10 years, it's actually a 25 percent, in other words one in four chance, of having to redo the adjacent level.

            So I can be honest.  I have looked all over and I cannot find a single study on any motion preserving device, whether it's anterior or posterior, and there honestly is not a study to date that I have been able to identify that does show a motion preserving device reducing incidence of adjacent segment disease.

            I do think the motion is physiologic and theoretically, it looks pretty good, but having said all that, if I can give a patient 10 years longevity then most of them will accept that.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. McAfee.  Thanks, Dr. Kim.  Dr. Naidu?

            DR. NAIDU:  You know, I'll reserve my comments to when we actually consider the specific questions.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  I would like to ask just a couple of follow-ups to Dr. McAfee.  What specific indications would you list for an anterior revision other than what I understand you have said, which is inappropriate sizing of the implant or inappropriate placing of the implant, which would then be revised within a reasonable short post-operative period?

            DR. MCAFEE:  Okay.  I'll try to just think off the cuff, because I'm really looking at any Anterior Interbody Fusion case, but I have had to redo those, for example, for a severe infection.  You definitely want to redo that from the front, because with a foreign body, you want to remove that.  I would use some type of autograft and then go posteriorly after a week's worth of antibiotics.

            The second case would be a patient who has either impingement on a neurologic structure or a vascular structure, and what I would worry about would be any case of migration, and I can get into answering that, but there's actually only five cases in the whole series where there was migration and only one of those required a re-operation, which was from the front.

            So it's really any life threatening compression on a vascular structure or neurologic structure or a severe deep wound infection, and there were no deep wound infections in this series that required an anterior removal.

            DR. KIRKPATRICK:  My second comment is really to my Panel colleagues.  Dr. McAfee did quote two cervical studies when he was talking about adjacent segment degeneration.  He did not quote any lumbar studies, and I would remain standing by the data that I presented of 15 to 35 percent, which would actually favor seeing more of it in the early phases of a follow-up study.

            And then my other question would be to the sponsor.  If you have had a chance to review my 13 items, if I have misrepresented anything that is in your PMA, I would appreciate, once again, being informed of that.  Thanks.

            CHAIRPERSON YASZEMSKI:  Mr. Christianson, would someone from the sponsor like to make a comment, at this time, or reserve that until later.

            MR CHRISTIANSON:  Reserve until later.

            CHAIRPERSON YASZEMSKI:  Thank you.  Thanks, Dr. Kirkpatrick.  Dr. Blumenstein?

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

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Besser?

            DR. BESSER:  In one of the preclinical studies, it talked about the fact that the center of rotation for the implanted device wasn't exactly the same as for the spine.

            Would someone like to comment?

            DR. CUNNINGHAM:  I'll take that one.  Jack, could you cue?

            CHAIRPERSON YASZEMSKI:  Excuse me, Mr. Cunningham, just so the transcription says Mr. Cunningham speaking.

            DR. CUNNINGHAM:  Yes.  Jack, could you cue 640 for me, please?  Sorry, I was only given 10 minutes during the presentation.  I really couldn't go into great depth in the biomechanical study undertaken at our laboratory, but in addition to quantifying the multidirectional flexibility properties of the device, as I only reported the range in motion, we also quantified the center of intervertebral rotation compared to the intact spine.  Can we move ahead three?  This is the whole lecture and I'll just key in on the main parts.  Go ahead, Jack, one more, please.  Another one.  Yes.

            What we did was in addition to the -- while we were doing multidirectional flexibility, we obtained five stepwise flexion-extension radiographs under both the intact Charite, BAK reconstructions and BAK combined with Pedical screws and these are shown here as you go from full extension through full flexion.  Next slide.

            By taking the full extension and full flexion views superimposed on each other and using the method of perpendicular bisectors, you can quantify the center of intervertebral rotation.  Now, that is in contradistinction to the instantaneous axis of rotation.  This is a single point from full extension through full flexion of the intact and then the Charite reconstruction.  And then we can schematically represent these as shown to the right.  Next slide, next slide.

            We have seen this.  This happens to be the neutral zone data that I was unable to report, which shows the relative similarity between the intact and the SB versus the other two reconstructions.  Next slide, next slide, next slide.

            And this is if we were to plot these centers of intervertebral rotation.  Now, the green ellipse represents a best fit and this is where all the centers of rotation occurred for eight specimens in the intact condition at the proximal adjacent level and the operative level.  So the green ellipses across here are identical.  In the case of the SB Charite for both the operative and superior adjacent levels, these were almost superimposable, a little bit higher here into the disc space, but very, very close to the intact condition.

            In the BAK reconstruction, of course, this is a device designed to stabilize the spine, and we would not expect it to move at the operative level, but, in fact, it does have a little bit of motion and it forms an ellipse below the intact condition, and above we see that this pattern becomes a little more diffuse both in the BAK and then when we add Pedical screws.

            So directly to answer your question, I think this does, the center of intervertebral rotation is reproduced with the SB Charite based on N8 to the intact condition.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Mr. Cunningham.  Dr. Besser, does that answer your question?

            DR. BESSER:  Yes, that answers my question.  Thank you very much.  I also had a question about the axial rotation range of motion.  It's hard to imagine getting 25 degrees in one subject, which I think was one single individual's data.

            DR. CUNNINGHAM:  Maybe that would be for another loading mode.  Axial rotation would be 5 degrees or less.  In our studies it's usually 3 to 4 for a single functional spinal unit in the lumbar spine.

            UNIDENTIFIED SPEAKER:  Flexion-extension.

            DR. BESSER:  I had thought that 25 degrees was in the axial direction, which was --

            DR. CUNNINGHAM:  No, that would not be axial rotation.

            DR. BESSER:  I would wonder how.  Thank you.

            CHAIRPERSON YASZEMSKI:  Okay.  Thank you.  I would like also to hear from our industry and consumer patient representatives.  Ms. Maher, industry representative?

            MS. MAHER:  I actually have nothing to ask right at this minute, but I will later.

            CHAIRPERSON YASZEMSKI:  Okay.  Thank you.  Ms. Luckner?

            MS. LUCKNER:  I have nothing at this moment.

            CHAIRPERSON YASZEMSKI:  Thank you.  Any other general comments?  And if not, we're going to proceed to the specific FDA questions that they have asked us to consider.  Okay.  Mr. Melkerson, could we perhaps have those questions up one at a time, so everybody can see them?

            There is copies of the questions available in the hallway outside the door if anyone would like their own copy, but we'll put each question up as we're deliberating it.  And what we will do for each question is I will ask one Panel Member to lead off the discussion and then we'll go around in a clockwise fashion until everybody has had a chance to address it.  While Mr. Melkerson is getting that up, we can go ahead and get started.

            The first question is, please, comment on the results of the wear debris testing and particulate analysis.  And I will ask Dr. Naidu to lead off with this one.

            DR. NAIDU:  The sponsors tested particles less than 5 microns and the question, the issue here is is testing the submicron particle important?  And I think that submicron particles may be more acutely inflammatory, but as far as the chronic inflammation picture goes, I don't think there would be that much of a significant difference between particles that are less than 5 microns.  I think the sponsor has adequately demonstrated that the phagocytizable particles actually induce chronic inflammation changes, and so I'm not too concerned about that as far as the submicron particles go.

            But what concerns me most in some of the slides that have been shown today as far as explanted specimens in polyethylene at 9.5 years, at 10 year retrieval where the polyethylene has completely fragmented catastrophic failure, and from what I understand at least, from 1997 on the sponsor has been using cross-linked, not cross-linked, but 2.7 megarad irradiated ultra high molecular weight polyethylene.

            The problem is that at two years, you may not see oxidation changes that are significant like the earlier slides shown by an explanted specimen at 1.6 years, but somehow or the other aging has not been accounted for in any of these sponsor studies.  When I asked earlier in the day as far as the mechanical testing on specimens, polyethylene specimens, it was quite clear that these are all vacuum packed specimens.  No mechanical testings were done on any of the aged specimens.

            By rending a 2.7 megarad radiation dose, no matter what you do, whether it be it in oxidation, oxidated in a nitrogen atmosphere, you will induce aging.  The problem is the lack of the aged data on polyethylene, one must remember that these devices are put in young, active individuals and one expects these devices to last a long time.

            And therefore, my concern here is not the particulate debris more so than the eventual catastrophic failing of the polyethylene that is actually serving as a cushion material.  I don't think that adequate polymer characterization has been done.  I don't think that adequate aging studies, mechanical studies in properly aged specimens have been done.  So I'm not sure as to the actual ultra high integrity in this case.

            What I'm concerned about is in the slides presented, the brittle nature of the polyethylene as exposed leads me to believe that, somehow, this ultra high has been degraded and has been transformed into high density polyethylene.  And therefore, I'm a little concerned about the longevity of the implant and the polyethylene liner in light of the radiation treatment.  But nevertheless, as far as inflammatory debris, I am pretty satisfied with that.

            CHAIRPERSON YASZEMSKI:  Okay.  Thanks very much, Mr. Naidu.  Dr. Blumenstein, have you any comment on Question 1?

            DR. BLUMENSTEIN:  No.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Besser, have you a comment on Question 1?

            DR. BESSER:  No.

            CHAIRPERSON YASZEMSKI:  Thank you.  Ms. Maher?

            MS. MAHER:  I would actually like to ask DePuy Spine to respond to Dr. Naidu's comments on the aging.

            CHAIRPERSON YASZEMSKI:  Okay.

            MS. MAHER:  Bill?

            MS. COURIER:  I'm Barbara Courier.  I'm a researcher at Dartmouth College.  I am a paid consultant to DePuy Spine and my transportation costs were paid to this meeting.  I would like to put up slide 303 if I could, please.

            You mentioned that the materials that have been tested were irradiated in vacuum and in nitrogen.  That is true.  However, the packaging was not the type of barrier package that one would expect for a nitrogen irradiated or vacuum irradiated component of today, and what I will show in this slide is that actually the materials that were aged on the shelf for 18 months and for 29 months, the 18 month in the pink squares and the 29 month in the solid blue line, show some oxidation with time on the shelf.  And so the materials that were wear tested that had a shelf time did, indeed, have some oxidation.  This packaging has been improved and now will be GVF packaging, approved technology in use in the knee.

            DR. NAIDU:  Can I ask a question?

            CHAIRPERSON YASZEMSKI:  Dr. Naidu, of course.

            MS. COURIER:  Yes.

            CHAIRPERSON YASZEMSKI:  Go ahead.

            DR. NAIDU:  Well, you show the key tone groups there, but I'm not concerned about the oxidation as much as the isothermal crystallization that is induced at the chain scission.

            MS. COURIER:  Yes.

            DR. NAIDU:  Do you have any calorimetric studies as far as documenting that this is really not aged, that you have not destroyed the ultra high molecular weight polyethylene integrity into a high density at 2.7 megarads, because these are catastrophic failures that you show at explanted specimens.  These are not like, you know, co-flow, anything like that.

            The thing is do you have any crystallinity studies?

            MS. COURIER:  The specimen that you are referring to, the 9.5 years, number one, we don't know what the pre-implanted shelf life was.  That particular specimen was gamma in air, and so there is a potential that it could have up to a six year shelf life prior to implantation and that is a piece of information that we're trying to obtain to determine what the shelf life was prior to implantation.

            But given the fact that it may have had a substantial shelf life before implantation, the fact that it showed fatigue failure in-vivo should come as really no surprise and that crystallinity would be extremely high.  It would no longer be characterized as an ultra high molecular weight polyethylene.

            DR. NAIDU:  Can I ask another question?  I'm sorry to take up time, but the thing is whether you gamma radiate in air or not.

            DR. GAINES:  Excuse me.

            DR. NAIDU:  Okay.

            DR. GAINES:  Mark Gaines, DePuy Orthopedics, if I could make a comment.  The packaging has been changed to GVF, which eliminates all on-shelf oxidation.  That is our material of choice currently for our knee product line and has been since 1969.  We have done extensive wear testing on that material and we have done accelerated aging and wear testing, accelerated aging with harsh conditions, five atmospheres of oxygen, 70 degrees centigrade for 14 days, which simulates a very severe oxidation condition.  And although we see some elevated wear rates, we do not see delamination problems with that and we do not see fracture problems with that material with wear studies that have gone out on a knee simulator to 8, 9 million cycles.

            DR. NAIDU:  So you do have crystallinity data on these, on the aged specimens?  What I'm talking about is not oxidation phenomenon itself.  I'm talking about the chain scission that is induced that leads to crystallization no matter whether in the presence of oxygen or not.  I'm talking about the integrity change in the ultra high itself.  So you do have some crystallinity data that is not presented.  Is that what you're telling me?

            DR. GAINES:  I do not have any here, but we have measured that, yes.

            DR. NAIDU:  Okay.

            DR. GAINES:  Yes.

            DR. NAIDU:  All right.  Thanks.

            CHAIRPERSON YASZEMSKI:  Thank you very much.  Ms. Luckner?

            MS. LUCKNER:  No.

            CHAIRPERSON YASZEMSKI:  Dr. Witten?

            DR. WITTEN:  Nothing to add.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Diaz?

            DR. DIAZ:  Nothing to add.

            CHAIRPERSON YASZEMSKI:  Dr. Mabrey?

            DR. MABREY:  I guess after having seen this device and held it in my hands and also looked at Dr. Kurtz' presentation, too, I have to wonder if we really are dealing with a new type of joint.  Whether or not there is an actual synovial capsule around it or not, you have two moving surfaces over poly that gets surrounded by scar tissue or fibrous tissue and I think, you know, if we go back to slide 2 in Dr. Kurtz' presentation you can see that that material gets pumped into all those little crevices.

            My concern is that six months or a year or even two years may not be long enough to look at the effects of the smaller particulate debris.  I can appreciate that there was no evidence of cytokine activity around the explanted material, but I would be very interested in seeing results from the explanted revisions.

            I know it's not always fair to ask people to characterize the tissues around one's failures, because that certainly doesn't look at the majority of your successes, but, nonetheless, I think looking at the tissue if that's available from those devices that have been explanted would be very helpful in characterizing the particles, and I do think that the smaller particles may be a problem in the longer run.          I think over two years it's not a problem, but at least in the total joint realm, we usually don't see evidence of osteolysis until about 36 months or later.  So we're looking at a longer time frame now to look at the effects of osteolysis, and I think we need to be aware of that.  It wasn't necessarily a question, and it's not actually addressed to any one individual, but it's just something that we have to keep in mind.

            I also wonder if we could estimate the total number of particles in those retrieved specimens.  I can appreciate the material from Dr. McKellip's and Dr. Campbell's lab.  I know them very well.  And you reported on the results from each specimen, but I think we need to go one step further and calculate the total amount of material that is in the retrieved material.  I'm sorry, the total amount of wear debris that is within the retrieved material.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Dr. Mabrey.  Dr. Finnegan?

            DR. FINNEGAN:  I guess mainly a comment, perhaps a question, and I don't mean to sound as scary as I'm probably going to sound, but this has got to be the first time I have seen spine surgeons talk calmly about epidural fibrosis and chronic inflammation, and my concern is that nerve tissue appears to have some long-term response to chronic inflammation and certainly in the brain, amyloidosis appears to be a problem.

            So my question is have you done any cell culture studies with nerve tissue with chronic inflammation and have you, in fact, done any correlation with the amyloid literature to see if, in fact, there are any concerns?

            MR. CHRISTIANSON:  Bill Christianson from DePuy Spine.  I have checked with my colleagues who are not aware of any studies that any of us have performed looking for the factors that you just mentioned.

            CHAIRPERSON YASZEMSKI:  Thank you, Mr. Christianson.  Dr. Kim?

            DR. KIM:  I have nothing to add.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Kim.  Dr. Witten, we have gone around the table and discussed wear debris and particulates.  In general, the Panel thought that the testing done by the sponsor has been adequate.  There were several concerns.  These included a request for perhaps considering data on aged specimens.  The sponsor has indicated that the same material that they use for this PMA device is a material that they have used for a long time in their total joint replacements and have, in fact, done some of that data, some of those studies, excuse me.

            Dr. Mabrey brought up that perhaps, although the disc is a synthesis, it may turn into a synovial like joint after being excised and having the device encapsulated, and cautioned us that we may need to look for a longer time to really test whether the particulates are going to have an effect and maybe the wear data needs to be done perhaps for 50 million cycles.

            And Dr. Finnegan brought up that the neural tissues do seem to have a peculiar response to inflammation and no particular studies have been done to address that question.

            Have we adequately discussed Question 1 from the FDA's perspective?

            DR. WITTEN:  Yes, thank you.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Witten.  We're going to move on now to Question 2.  If I might ask to have advanced Question 2, asks if there is a higher incidence of the following adverse events occurred in the Charite group compared to the BAK group.  These were non-device related pain, wound infections and device related additional surgery at the index level.

            We have been asked to discuss the clinical significance of these and any other adverse events seen in the trials, so this question is the clinical significance of adverse events.  Once again, we'll move in a clockwise direction and this time we'll begin with Dr. Kim.  Excuse me, Dr. Kim, I'm sorry.  Dr. Mabrey, let's start with Dr. Mabrey this time and move around.

            DR. MABREY:  Thanks.  I guess as far as the clinical significance of the differences in those incidents of pain and infection, the first thing we have to realize is we're not comparing apples with apples.  I mean, this is a moving device.  It has a slightly different micro environment around it compared to the fusion cages, number one.  But I would point out that the non-device related pain complications were, it appeared to be, twice as great with the Charite device compared with the BAK, that the infections appear to be double that of the BAK device, although these did not appear to be device related and that additional surgery related to the device appeared to be at a rate of about four times that of the BAK.

            I understand that it is a moving device and it's more prone to failure and that it may not be fair to say that something is four times the rate when you're looking at 3.9 percent versus .9 percent, but those are the figures that I was presented with.

            I guess I would ask one of the clinicians if you could comment on the infections.  These were all non-device related, meaning they did not appear to originate at the disc space.  Is that correct?

            DR. BLUMENTHAL:  Slide 130, please.  Scott Blumenthal.  In discussing this question, a few things that we have to keep in mind.  Number one is the way that the study was performed, the incidence of reporting AEs was exquisitely sensitive as it should be.  Of the three bullet points in terms of non-device related pain infections and device related additional surgery, as mentioned, the numbers were not great.  They did not achieve statistical significance.

            In terms of the infections, as mentioned in the presentation, none of these were device infections, so we have no infected total disc replacements or BAKs.  If a patient had a minor UTI or some redness around the incision, those were reported as wound infections whether they documented bacterial growth or not.  Why there is a difference between the two groups, again, the numbers were not that great.  There is not a clear explanation for that.  The next slide, 131, the next slide.

            Now, in terms of looking at the non-device related pain, most of these were at early follow-up points, again, not statistically significant.  They were transient pain complaints and, again, not device related.  And when you look at the overall outcomes, they did not seem to affect the overall outcomes particularly and including patient satisfaction scores.

            Finally, the device related additional surgery at the index level, this was an interesting one, because it's really just a matter of reporting and how it was reported.  If you add the additional surgeries for pseudoarthroses in the BAK group, some surgeons did not report this as being device related.  And if you add those nine cases in, then the numbers equalize a bit more.

            DR. MABREY:  I would like to compliment the investigators on being honest enough to report the spider bite, 685 days out of surgery.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Dr. Mabrey.  Dr. Finnegan?

            DR. FINNEGAN:  No comment.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Finnegan.  Dr. Kim?

            DR. KIM:  I do want to echo also that the complication rate is surprisingly low and I'm impressed at how low they both are.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Naidu?

            DR. NAIDU:  No further comment.

            CHAIRPERSON YASZEMSKI:  Thanks.  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  Just to help the FDA in thinking this through, from the standpoint of infections, even if they had one device related infection, I would not suspect that that's enough to say that the device itself is a problem.  It would take thousands of cases of the device to be able to get enough numbers to find a statistically significant difference, and I think that is an onerous request of the sponsor.  So, you know, if they had 10, at this time, yes, that's a major deal.  But since they have had no device specific infections, I don't think it's a concern.

            The second issue is in thinking about additional surgery at the index level, as a spine surgeon we often do multiple different procedures on the spine.  A patient with a herniated disc at age 30 may end up with a fusion at age 50.  But when you're doing the herniated disc at age 30, you don't go straight to the fusion.  That is because you're trying to maintain as much function as possible for that motion segment.

            This is another step in the anarchy between a basic spinal problem and actually eliminating the motion.  So I think it's appropriate that their number of surgeries at the index level was actually higher than what we would expect for BAK fusion, because we would expect it to fuse and no longer need a procedure at that level unless there is a pseudoarthrosis.  So that brings no concern as far as this question.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Kirkpatrick.  Dr. Blumenstein?

            DR. BLUMENSTEIN:  I have no comments.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Besser?

            DR. BESSER:  No comments at this time.

            CHAIRPERSON YASZEMSKI:  Thank you.  Ms. Maher?

            MS. MAHER:  Nothing to add.

            CHAIRPERSON YASZEMSKI:  Thank you.  Ms. Luckner?

            MS. LUCKNER:  No comment now.

            CHAIRPERSON YASZEMSKI:  Dr. Diaz?

            DR. DIAZ:  I just would like to echo the outstanding honesty and wonderful presentation of the review that the sponsor made in regard to the detail analysis that they undertook to assess clinical and clinically relevant data.  I think the infections that we see here are really probably more related to the added fussiness that the extra steps that require the implantation of the disc require.

            Having done enough ALIFs, there is a certain amount of things you need to do and when you compare that to adding the three extra little pieces to what you're doing, I can see where you would have perhaps a little bit more manipulation.  I don't view that as a major concern nor the clinical pain related problems, because these are a difficult group of people, and to get an accurate improvement in pain related complaints is asking too much.  So I think from my view of the data, I am happy with what I see.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Diaz.  Dr. Witten, with respect to adverse events and the increased frequency of these events in the Charite, in general, the Panel doesn't feel that this is a large issue and, in fact, several Panel Members complimented the sponsor on a very thorough and honest review of those events that were adverse.

            So we actually see no problem with this, and ask if we have answered this question to FDA's satisfaction.

            DR. WITTEN:  Yes, thanks.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Witten.  We'll move on to Question 3 now, Mr. Melkerson.  Although the Charite Artificial Disc was highly successful in relieving pain, there were a significant number of patients who did not obtain pain relief.  12 percent had no pain relief or had their pain worsen and an additional 13 percent had only partial pain relief.  The etiology of their unrelieved pain is unknown.  Please, comment on the interpretation of these findings.

            I will start with Dr. Kirkpatrick this time.

            DR. KIRKPATRICK:  Thank you.  In dealing in the field of medicine and in educating residents, for example, we often have to look at their statements of this is the best treatment for a patient or this is the cause of that problem, and ask the resident is that what you think or is that what you know?

            Now, in the case of a tibia fracture caused by a bumper of a car, can we say that that was a cause and effect?  Yes.  In the case of low back pain, we have to say we don't know.  It's what we think.  So we get back to the rationale of what leads to a fusion in degenerative disc disease, and that is the thought that the disc is a pain generator.  Provocative discography documents that.  The disc is then excised and replaced with a fusion or fused from posteriorly.  That has been shown in international literature not to make a huge difference, but the patient outcomes are comparable.

            It is thought to be slightly better than non-operative treatment for degenerative disc disease and that still is somewhat controversial because of the measures that are being used and that sort of thing.  If there is a difference, it doesn't appear great.  So in summarizing the basic concepts, we don't know what back pain is caused from.  We think it's caused from a painful disc and in fusing it, we're trying to get an improvement of that motion segments not moving and not being a pain generator.

            The concept behind a disc replacement is stepwise trying to preserve that motion, because the follow-up to the fusion is why does the patient still hurt if we fused the level?  And the follow-up to that, in theory, has been well, it must be the adjacent segment is wearing out, too.  And in many cases among patients that you see clinically, they will get one level fused, three years later they will get a second level fused, because their provocative discography has now moved up another level.  So the idea behind the disc replacement is to prevent that sequence of events, and so you don't see people with multiple levels of lumbar fusion trying to chase this disc pain.

            So when we're looking at the fundamental concepts, are we able to answer the question, can we stop the pain from getting worse in the future by keeping the motion going?  That would be a summary of an overall concept of what's going on.  I would suspect that in most circles, people would say that the reason people failed is adjacent segment degeneration or there was a cause of back pain that we don't quite understand.

            For example, as I mentioned I believe in my presentation, they did include some people with facet changes at the index level.  If the biomechanics is preserved, that means the facets are still getting loaded.  They still may be painful.  By the same token, the adjacent segment can do the same thing.  So overall, we don't know what the pain generator is.  We can't explain why the 25 percent don't have more pain relief than we would expect.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Kirkpatrick.  Dr. Blumenstein?

            DR. BLUMENSTEIN:  I have no comments.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Besser?

            DR. BESSER:  No comments.

            CHAIRPERSON YASZEMSKI:  Ms. Maher?

            MS. MAHER:  No comments.

            CHAIRPERSON YASZEMSKI:  Ms. Luckner?

            MS. LUCKNER:  No comments.

            CHAIRPERSON YASZEMSKI:  Dr. Diaz?

            DR. DIAZ:  I believe that assessing pain is like trying to pin jello on the wall.  It is not exactly an easy thing to do.  In dealing with resident education, we often play games with the residents trying to teach them.  Like Dr. Kirkpatrick mentioned, one of the questions we often ask is tell me what the possible reasons for back pain are, and once we listed over 65 reasons for back pain.

            So trying to isolate a result based on maintaining or preserving function at a single level joint that has been replaced answers only one of 65 reasons.  And so I do not believe that this question really helps us reach the conclusion that we want to get, whether the procedure is safe and effective, because there is no way to answer this question to anybody's satisfaction.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Diaz.  Dr. Mabrey?

            DR. MABREY:  I would just echo Dr. Diaz' comments that it's very difficult to pin down pain in this type of situation, and I think the reason the question comes up is because the investigators have been so extremely thorough about recording everything that happens with their patients that we're going to see this type of data.  And I applaud their use of the SF-36 and all the other factors as well.

            CHAIRPERSON YASZEMSKI:  All right.  Thank you, Dr. Mabrey.  Dr. Finnegan?

            DR. FINNEGAN:  I have a question for the sponsor.  Did any of the patients who developed significant heterotopic ossification have a change in their pain level and, if so, what was it?

            DR. CUNNINGHAM:  Bryan Cunningham.  Jack, could you pull up 254?  Proactively, we evaluated the incidence of heterotopic ossification, correlated both the functional kinematics based on plain film radiographs, as well as VAS and Oswestry, and I have a bar chart here that I can show you, which demonstrates the comparative ranges on heterotopic.  654, please.  Not there?  654, I believe.

            DR. MCAFEE:  I'll try to fill in while we're looking for the slides, but we had an independent evaluator.

            CHAIRPERSON YASZEMSKI:  May I interrupt and just say this is --

            DR. MCAFEE:  Sure.

            CHAIRPERSON YASZEMSKI:  -- Dr. McAfee for the transcriptionist.  Go ahead.

            DR. MCAFEE:  Paul McAfee from the same center.  It's a core lab and we proactively wanted to look at heterotopic ossification and the incidence.  So we had an independent evaluator look at the digitized films, Dr. Justin Tortolani, and he presented this as the Spine Arthroplasty Society meeting.

            In the overall incidence -- well, first we developed a generic classification for heterotopic.  This is actually some of the slides if Bryan could come back up, but the key was based on Brooker and Wills' classification in the hip, we have developed the same kind of thing for the spine.  So Class 0 was no heterotopic bone.  Class I was bone, extra bone was present, but not in the disc space.  Class III, there was extra bone present in the disc space, but it did not interfere with motion and Class IV meant spontaneous arthrodesis.

            DR. FINNEGAN:  Class III didn't interfere with motion as he is going to show us or didn't --

            DR. CUNNINGHAM:  Yes, I actually have case examples of each to show you that.

            DR. FINNEGAN:  Okay.

            DR. MCAFEE:  But fire ahead.

            DR. CUNNINGHAM:  If you could go to the next slide.  Thank you.  Next.  So we looked at, as indicated, all the plain film radiographs and quantified the range of motion, as well as how that correlated with VAS and the ODI scores.  Next.

            We actually looked at over 6,000 x-rays to quantify all this.  We had both A/P lateral and flexion and extension films for a total of 276 patients.  Next.  As indicated, we used the Cobb Method.  We quantified range and motion at the operative level.  Next.

            That was only based on flexion-extension.  Importantly, you can't do axial rotation.  You would need an RSA method or something like that to determine the rotation.  We also quantified segmental translations occurring at the operative level.  Next.

            As indicated, Paul went through the classes, but just to reiterate, we had a Class 0, that means no ectopic bone present.  I, islands of bone that were not within the disc space.  A Class II, HO is present, but not affecting range of motion.  III, it appears to be affecting range of motion on either flexion-extension or lateral bending films.  And finally a Class of IV, which is ankylosis of the operative level.  Next.  And these would just be case examples.  And this is a coronal section through a baboon functional unit.  Next.

            We looked at both the ODI, the VAS and the segmental range of motion.  Next.  At two year follow-up, the overall incidence of HO was 4.3 percent.  That's 12 of 276 patients.  The distribution, 11 of those at 4-5.  We had one at 5-1.  In terms of the classification of the 12 cases, four of those were Class I, eight, Class II.  We had no classes of III or IV.  It was either Class I and II.

            In terms of progression, most of the HO was noticed at the six weeks post-operative interval of 42 percent.  By three months we had six of 12 and at the six month time interval, one more patient presented.  So most of these patients presented by three months post-operatively.  Next.

            And this just gives you case examples of each HO.  This is an HO Class of I showing some small islands of bone lateral to the disc, but, again, on flexion-extension radiographs, this patient had a considerable range of motion, so it's not interfering with motion.  Next.

            This is an HO Class of II, a little more, as you can see on the far left of the A/P, but based on flexion-extension this patient still had a very high degree of range of motion at the operative level.  And again, this is 24 months post-operatively.  Next.

            And this just demonstrates the progression of HO in a single patient.  So if you take a patient immediately post-op and follow them through two years post-op, this is what the HO, how it presents itself.  And you can see it appearing at six months or six weeks post-operatively, and then you get some densification of the HO and by 24 months, it's very evidence on the A/P film.  Next.

            And this is just a CT scan demonstrating the location of the HO not within the disc space, but it tends to be in the peri-annular region adjacent to the disc and not in the psoas.  This happens to be four years post-op.  Next.

            And this is the Visual Analog Scale, the data of interest here.  HO and non-HO cases pre-operatively, very similar based on VAS scores by 24 month post-operatively using the Wilcoxon Rank Sum.  There was no statistical differences between the two groups in VAS.  Next.  And ODI, similar findings.  Pre-op, nearly identical and at 24 months, no differences between the two groups.  Next.

            And this is the flexion-extension range of motion.  Interestingly, if you were to group these out into HO and non-HO cases based on the pre-operative plain films, it's a little over 6 degrees of motion for both treatments.  But then interestingly, at the 24 month post-operative period, the HO cases had more, a higher range of motion at the operative level, not statistical, but pretty close compared to the non-HO cases.  So it doesn't appear to be -- actually, the range of motion is higher with the incidence of HO.  Next.  And that is pretty much what I have for that.

            CHAIRPERSON YASZEMSKI:  Thank you, Mr. Cunningham.  Thank you, Dr. McAfee.  Dr. Kim?

            DR. KIM:  Just going back to the question of why there is a proportion of people that don't get better.  A proportion of them probably is coming from the facet joint.  If that's the case, if you looked at that, and should reconsider looking at the facet joint more closely prior to having somebody undergo this procedure.  Can one of the sponsors comment on that?

            DR. MCAFEE:  I'll give it a shot after much deliberation.  Paul McAfee.  With any interbody fusion device, you tend to unload the facets.  You're increasing the disc space height.  The digitized results of all the series both at 045 and L5-S1 did show statistically that the increase in disc space height was better for the SB Charite group versus the BAK.

            In addition, from the immediate six week visit film to two years, it turns out that the maintenance of the height was also better in the SB Charite group.  In other words, there was slightly more subsidence with the BAKs.  So we thought the main thing, the main purpose of the Charite, was to unload the facets and I can start with slide 247 if you would like.  Looking at the baboons, I know it's only a six month follow-up, but the facet joints were normal at sacrifice.  Secondly, you know --

            DR. KIM:  Sorry to interrupt.

            DR. MCAFEE:  Yes.

            DR. KIM:  I guess what I was trying to get at is if you had the opportunity to sub-stratify those patients that persisted with back pain and compared them to the Charite group that did not have back pain and you just looked at the facet joint, would there be a difference that you know of?

            DR. MCAFEE:  We didn't look at that, but in a way we're selecting out patients that have problems with the facet joints pre-operatively.  Remember in our workup, if the patient has some element of mechanical back pain, we would tend to get posterior facet joint blocks and if that facet joint is a pain indicator, then they are selected out of the study.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. McAfee.  Dr. Kim, does that answer your question?

            DR. KIM:  It does.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Naidu?

            DR. NAIDU:  I agree with the rest of the group.  Pain is a subjective measure.  I think the only reason that the Charite group probably had more pain is probably the patient population itself was a more active group.  From the data presented, the Charite group had a significantly lower body mass index and, in general, more active.  So I mean, it is a subjective measure, but those are the only two reasons I can think of attributing it to.

            CHAIRPERSON YASZEMSKI:  All right.  Thank you, Dr. Naidu.  Dr. Witten, the Panel's discussion on Aim 3 is that pain being a subjective measure, there really are no concerns that the Charite group had this percentage of people who still had continued pain, and that this reflects the general treatment of low back pain be it by nonsurgical or surgical methods other than disc replacement.

            Have we adequately answered this question to FDA's satisfaction?

            DR. WITTEN:  Yes, thank you.

            CHAIRPERSON YASZEMSKI:  Thank you.  Let's move on to Question 4.  Within the Charite group, the mean range of motion and flexion-extension at the treated level at three, six, 12 and 24 months was 4.9, 6.0, 7.0 and 7.4 degrees, respectively.  Lateral bending and axial rotation range of motion were not reported in this investigation.  Please, comment on the sponsor's claim that the Charite permits "near physiological segment movement with up to 15 degrees bending and flexion-extension and a similar degree of lateral bending and axial rotation to the natural disc."  Dr. Kim?

            DR. KIM:  I think the sponsor used very good preclinical data to show that the disc does achieve near physiologic motion at the time of implantation, but the results of the clinical study clearly show that the range of motion changes and is variable being as low as 0 and as high as 22 degrees.

            There is a table that the FDA put together to try to make a correlation between outcome and that range of motion, and there really isn't a statistically significant correlation, although there is a trend toward better results if you have 5 to 9 degrees range of motion.

            Given that, it's hard to decide whether or not this is significant.  In addition, this range of motion question is going to require long-term follow-up, because one of the advantages is potentially decreasing adjacent segment disease and we may not see that for five to 10 years.  So I don't think that this study has the ability to claim that it maintains physiologic motion and that that motion is the key to success.

            Going onto the second question as to whether or not there is an equal amount of lateral bending and axial rotation, they show that clearly in the preclinical studies, but not in the clinical study, because they only looked at flexion-extension.  The design is symmetric though and if something is moving 7 degrees in the flexion-extension plane, I have no problem assuming that in the lateral bending plane, in the actual rotation, we'll get similar degrees of motion.

            So I'm not too worried about the comment on the lateral bending and axial rotation, but I think the difficulty lies in the significance of the range in motion with clinical outcome.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Kim.  Dr. Naidu?

            DR. NAIDU:  The normal range of motion cited in the literature in the PMA provided at the L5-S1 is about 9 degrees of flexion, 5 degrees of extension with a fairly large standard deviation of plus or minus 5 degrees, and I certainly think that the sponsor's claim that 4.9 degrees is physiologic in flexion-extension plane is valid, although this validity isn't confined to the flexion-extension plane only.  Obviously, rotation is questionable, at best, at this point.  That's it.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Naidu.  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  No additional comment.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Kirkpatrick.  Dr. Blumenstein?

            DR. BLUMENSTEIN:  Could I ask George Chu a question here?

            CHAIRPERSON YASZEMSKI:  Yes.

            DR. BLUMENSTEIN:  In the, I think you called it, addendum, I didn't understand the two tables that were presented, the difference between the two tables.

            DR. CHU:  Which two, the range of motion, the histogram?

            DR. BLUMENSTEIN:  Yes.

            DR. CHU:  Or the 2 by --

            DR. BLUMENSTEIN:  Yes, the 2 by 8 tables.  I just want to make sure I understand.  I mean, I see that one of them is repeated in the question that we're addressing at this point.

            DR. CHU:  The histogram is based on the available data for the randomized Charite patients.  It's about 175.

            DR. BLUMENSTEIN:  Yes.

            DR. CHU:  So from the histogram, it looks like the range of motion at 24 months post-op is equally distributed about 10 percent among the different range.  And for the table in the Panel draft, it's a 2 by 8 table, it basically just tries to see the general association between the range of motion and the outcome at 24 months.  So the general association test, the P-value is not significant.

            DR. BLUMENSTEIN:  Yes.  But there was a second table in your addendum.

            DR. CHU:  Which table?

            DR. BLUMENSTEIN:  I received an addendum.

            DR. CHU:  Okay.  I don't have that one.  Can you show me that one?  Yes, the second table is, basically, the assessed output for the statistical test.

            DR. BLUMENSTEIN:  May I ask, do we have that table in the FDA?  That was part of your presentation, wasn't it, Dr. Chu?

            DR. CHU:  No.

            DR. BLUMENSTEIN:  Do we have that table on a slide, that everybody could see it?

            DR. CHU:  Yes, actually the main point here, just looking at the general association test between this success outcome and the range of motion.

            DR. BLUMENSTEIN:  I mean, the titles of the two tables seemed the same to me and not the second smaller table underneath the big one, but the second page of tables.

            DR. CHU:  The second table is just collapsed the last four column of the bigger table into just one column.

            DR. BLUMENSTEIN:  Oh, okay.  I'm sorry, sorry to cause that.  Then I have no comment.

            CHAIRPERSON YASZEMSKI:  Okay.  Thank you.  Dr. Besser?

            DR. BESSER:  While the ranges reported were slightly less than have been reported in the literature for physiological changes, they are well within the range of normal and I guess only time will tell whether, in fact, implanting a device that gives this extra range of motion prevents adjacent segments from needing fusing and future surgery, etcetera.

            CHAIRPERSON YASZEMSKI:  Okay.

            DR. BESSER:  No other comments.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Besser.  Ms. Maher?

            MS. MAHER:  No comment.

            CHAIRPERSON YASZEMSKI:  Ms. Luckner?

            MS. LUCKNER:  No comment.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Diaz?

            DR. DIAZ:  No comment.

            CHAIRPERSON YASZEMSKI:  Okay.  Dr. Mabrey?

            DR. MABREY:  I have no comment.

            CHAIRPERSON YASZEMSKI:  Dr. Finnegan?

            DR. FINNEGAN:  No comment.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Witten, we have talked about the ranges of motion.  We generally feel that they are within the range of normal, that the flexion-extension numbers are in the physiologic range and less so for the other modes of motion.  The range of motion link to clinical improvement shows a trend, but has not been met.  In general, the Panel doesn't have any concerns on this issue.

            And have we answered and discussed it adequately?

            DR. WITTEN:  Yes.

            CHAIRPERSON YASZEMSKI:  Thank you.  Let's move on to number 5.  Do clinical data provide reasonable assurance of safety?  Dr. Finnegan?

            DR. FINNEGAN:  Well, I would have to say that if this device was going to do its main purpose over a short-term, that is a two to three year period, and then would basically be physiologically non-functioning, then the data does suggest that this is probably safe.  Unfortunately, this device is designed for a much longer period of time and I do not think that there is data present at the present time to say that it is, in fact -- there is reasonable assurance that it is safe for the lifetime that it is predicted to be necessary for.

            CHAIRPERSON YASZEMSKI:  Okay.  Thank you.  I'm going to go around to Dr. Kim, but before I leave, based on that, Dr. Finnegan, I'm going to back to you with Question 7 and ask what you think.  Dr. Kim?

            DR. KIM:  I would agree with that.  I think the sponsors have done an excellent job in providing an honest assessment of their device, and it is absolutely clear that in the two year period that this device is safe, but, once again, I agree with Dr. Finnegan.  This is a complex device.  It's the first of its kind and designed to last for a long time, and we can't get at that question until we wait.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Kim.  Dr. Naidu?

            DR. NAIDU:  I totally concur with Dr. Finnegan and Dr. Kim.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Naidu.  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  I concur and nothing further to add.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Kirkpatrick.  Dr. Blumenstein?

            DR. BLUMENSTEIN:  I concur.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Besser?

            DR. BESSER:  I concur.

            CHAIRPERSON YASZEMSKI:  Thank you.  Ms. Maher?

            MS. MAHER:  I would just urge the Panel to remember that we also have to look at least burdensome as we're figuring out how to evaluate the safety and effectiveness of this device.

            CHAIRPERSON YASZEMSKI:  Thank you, Ms. Maher.  Ms. Luckner?

            MS. LUCKNER:  I concur with the earlier statements.

            CHAIRPERSON YASZEMSKI:  Thank you.  As we come around to Dr. Diaz, Mr. Melkerson, if you have a comment, may I go to Dr. Diaz and then --

            MR. MELKERSON:  Actually, just a question.

            CHAIRPERSON YASZEMSKI:  Okay.  Go ahead.

            MR. MELKERSON:  This is to the Chair himself.  Being that Question 5 and 6 are related to safety and effectiveness, do you want to hear the other public speakers before you answer this question?

            CHAIRPERSON YASZEMSKI:  I think that we can probably hear them afterwards and then incorporate their thoughts when we get to voting if that would be okay.  Dr. Witten, is that acceptable to you?  Thank you.  Thank you, Mr. Melkerson.  Dr. Diaz?

            DR. DIAZ:  Nothing additional.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Mabrey?

            DR. MABREY:  Well, as has been pointed out by other Panel Members, I mean, this is a complex device.  It's brand new and it's going to be eventually implanted by a lot more than the original surgeons.  So I think we're looking at two levels of safety.  One is is it safe to implant, and I think over the first two years you have demonstrated that with your trained surgeons that it is safe to implant.  And then the second question is is the device itself safe over a long period of time, and I don't think two years is long enough.

            So I do have one question, and I would address this to Dr. Blumenthal or Dr. McAfee.  At your training centers, the only analogous situation I can come up with is the experience with another company's foray into minimally invasive hip surgery and restricting access to that to those who have been trained at the company's facility.

            One comment that I have heard from the trainers there is that there is a training of the trainers that goes on, and I guess my question is do the clinicians feel that with more experience, that your initial training of those people who will be implanting the device, does that become easier and have you learned to avoid some of the major problems you encountered during the initial phase of this study?

            DR. MCAFEE:  I'll start, because one of the main concerns is neurologic problems, so there has been a great advance in instrumentation and, honestly, the key with any anterior interbody device is to keep it in the midline, so that newer instruments over the last two and half years happen to be called the centerline instruments, but they keep the implant in the midline and they prevent the surgeon from going into the lateral recess and causing a neurologic problem.

            Secondly, if you can put up -- start with maybe slide 493.  We did an analysis.  We wanted to see what the effect of the training was.  The training, you know, we had a perfect opportunity to do that, because we had a cohort of five cases from each group that were training cases, and we could compare how well the training patients did with the rest.

            Well, the idea is whether there is a surgeon volume effect.  Is the data good enough to show a surgeon volume effect, and this is from Birkmeyer's New England Journal of Medicine and "JAMA," a lead article in December.  And the key was there are 10 different operations that all show a surgeon volume effect, coronary artery bypass, grafts, aortic valve replacements, surgeons that did more and had a higher volume who had lower complications, but not a single spine procedure was in this group.  Next slide, please.

            So we looked at actually four areas.  First, we looked at the 71 training cases versus the randomized cases.  Then the next analysis was we looked at the four highest enrolling sites that all did more than 40 procedures versus the 11 remaining sites that didn't do as many cases.  Now, the key is that all four groups fulfilled the FDA's success criterion of greater than 25 percent improvement in the Oswestry, as well as no neurologic progression, no return to the OR and no major complications.  Next slide.

            But there is a definite volume effect, and if you look at the training cases, which are on the left, the surgery time was larger in the person's first five cases versus the enrolled.  The length of stay was slightly longer for those patients, and the overall number of complications was higher as well.  Next slide.

            You know, we looked at all the parameters, but I'm just showing the ones that are significant.  And then the high enrolling sites versus the low enrolling sites, the surgery time was much less for those sites that did more than 40 cases.  The length of stay was less and the device failure incidence was lower.  So in summary, surgeon volume really did have an effect.  And then the last slide.

            I think the key is to learn from the European experience, really almost memorize the IDE prospective randomized trial data.  The key to avoiding complications are to identify a vascular access surgeon, go to company-sponsored courses to learn the specific instrumentation.

            But what is even more important is what we haven't talked about and that is the model of the Scoliosis Research Society, which is something like the Spine Arthroplasty Society, what we'll hear from the public comment period, is they are going to the forefront of continuous reassessment of results and having a surgeon group take some responsibility for setting the bench mark.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. McAfee.  Dr. Witten, we have discussed the issue of safety and the consensus of the Panel is that over the study period in the short-term, this device is safe, and questions remain, of course, over the long period, because the data is not gathered yet and it's a new device without precedent.

            Have we discussed this to the satisfaction of FDA?

            DR. WITTEN:  Yes, thanks.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Witten.  We're going to move on to number 6.  Do clinical data provide reasonable assurance of effectiveness?  Dr. Diaz, can you lead off with this one?

            DR. DIAZ:  Yes.  The question that we're being asked and I will read a little bit of the definition the FDA wants us to adhere to for effectiveness.  "A device is considered effective if, when used in a significant portion of a targeted population for the intended use and under the conditions of use, it provides significant results for that population."

            To answer that question, I would look at the effect, clinical effect, on various aspects of the individual's life.  When I operate on a patient, the question the patient asks me very frequently is will I get better?  Will my pain get better?  Will I be able to get back to work?  And probably more important, will I be able to get back to play?  Work in a back pain patient group is not always what they want to do, but play certainly is what they want to get back to do.

            And as we have heard, the back problem, spine progressive degeneration is a dynamic problem.  Coming from the Rust Belt in Detroit, when I talk to patients about spine surgery, I tell them that it is like dealing with rust.  All patients in Detroit can understand rust.  If you get it on the fender and you clean it, you patch it, you fix it, it will show up on the door and a few years later, it will show up on the fender.  So they can relate to the idea that perhaps this is not the only time that we'll see Dr. Diaz to take care of their problem.

            So in regard to the effectiveness, does the device provide pain relief?  Yes, it does.  Perhaps not as well as it did for the BAK, but significantly equal.  Does it restore function?  We believe it does, based on the anatomical and on the mechanical presentations given.  Does it allow patients to get back to their usual activities?  The answer is yes.  And to my personal liking, I was very pleased to see that patients could get back to very active function very quickly.  Because within the week after surgery, they could be doing a lot of things that I keep my patients from doing when I fuse them.

            If I fuse a patient, I really keep them sedentary for a long time.  I don't like that.  I like to be able to get people up and moving very quickly and I think this device provides for that opportunity.  Do they return to work?  Yes, perhaps they do.  Maybe not as much as I would like them to see.  But I don't think we will ever be able to get back patients to get back to work as much as we would like them to do that.

            And does it prevent adjacent level disease?  I don't think that this single device will be the answer for preventing adjacent level disease, but I think it delays it, which I think is a very important achievement.  So in my mind, I believe for the intended use that the device was proposed in the population as targeted with the possible applications as provided, it does fulfill the requirements of effectiveness under the FDA guidelines.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Diaz.  Dr. Mabrey?

            DR. MABREY:  I fully concur with Dr. Diaz' comments.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Finnegan?

            DR. FINNEGAN:  I agree.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Kim?

            DR. KIM:  I agree as well.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Naidu?

            DR. NAIDU:  Same here.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  Well, we're not going to get a dissertation today.  I think there are some concerns about effectiveness, but I think by the FDA's definition, I would agree with Dr. Diaz.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Blumenstein?

            DR. BLUMENSTEIN:  I believe the device has been shown to be not inferior to the standard control device that was used in the trial.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Besser?

            DR. BESSER:  I agree with almost everything Dr. Diaz said, other than I don't think we have any evidence to support that it will, in fact, delay adjacent segment disease.  We hope, we'll see, nothing now.

            CHAIRPERSON YASZEMSKI:  Thank you.  Ms. Maher?

            MS. MAHER:  Well, I would agree with Dr. Diaz.  I would also remind the Panel that this product has been on the market since 1987 in Europe and there have been 7,000 cases or implantations.  So when you talk about only having a two year follow-up, as we did on the previous question, I want you to remember that there actually is a much longer history outside the U.S.  There is two years of good data from within the U.S.

            CHAIRPERSON YASZEMSKI:  Thank you.  Ms. Luckner?

            MS. LUCKNER:  I concur with Dr. Diaz.

            CHAIRPERSON YASZEMSKI:  Thanks very much.  Dr. Witten, the Panel feels that the device as presented is effective.  Have we adequately discussed this?

            DR. WITTEN:  Yes.

            CHAIRPERSON YASZEMSKI:  Thank you.  We're going to move on to number 7.  Number 7, if you recommend approvability for this PMA, do you recommend a post-approval study?  If so, please, discuss what types of end points would be useful for an updated label and recommend the duration of such a study.  Dr. Kirkpatrick, would you lead this one, please?

            DR. KIRKPATRICK:  I think he asked me because I already provided a list of suggestions.  I would like to see mobility testing data for the complete reference, rather than just a two paragraph summary.  And I did get a little bit more of it in the presentation today, but I would like to be able to review the data, and I think the FDA would like to be able to review that as well.

            I think a little added study in the biomechanics lab of demonstrating that facet stresses or strains or some other element of a facet function is either unchanged or minimally changed after the insertion of the disc.  I did not get that out of my read of the PMA and again, as I have repeatedly said, if you have that data and I missed it, please, tell me what page to find it on.

            The third one is I still think that the wear data to 50 million cycles would be more appropriate.  I did have concerns whether the curve on the wear data may have been accelerating over time.  Your curve on, I think it was, the weight of the specimen versus cycles was drawn as a curve going downward, which means it is accelerating as you get to the end of that 10 million cycles.  I would like to know what it does in the next four decades of the 50 million cycle testing.

            I think we need an acceptable rationale for not testing the response to submicron particles more extensively.  Number 5 that is on the list, we can exclude, because I clarified that in my presentation and you clarified it in your presentation that the osteointegration studies are not relevant to the device you are presenting, so you can eliminate number five.  However, I would like to know what the rationale is behind the long-term fixation of the device.  Is it just the pegs or do you expect there to be some bone implant interface adherence?

            6, I would like a clerical -- clarifying of the neurologic rating scale that you used, so I can understand how these statistics were applied to a qualitative physical exam.  7, I think that was handled by the FDA as far as stratifying the range of motion, and it appears that outcome is not significantly different, although there were trends.  So 7, I'll leave it up to the Panel whether we think we need to go further with that.

            8, indication groups, especially the ones that did have known facet changes at the implantation.  I would like to know if stratifying those out would make a difference in either your BAK group or your charity group.  I would suggest again based upon the literature as well as my presentation that the concept is if we're preserving motion, we need to demonstrate that.  And if people lose motion, I would like to know if that resulted in a difference in their other measures of effectiveness, such as the VAS, the ODI and that sort of thing.

            So number 9 would say include those 0 to 5 degrees as failures and see if that correlates to clinical failure.  And also, if you called them failures, what would happen to your statistics on the study success.  11 you can eliminate based upon the discussion of HO and the presentation you did in answer to one of our questions.  I'm sorry, that's number 10.  Number 11 gets back to the facet issue.  Can you do axial imaging at 24 months and look at the comparison between your pre-op and your axial imaging at 24 months and tell us whether there are facet changes.

            Number 12, adjacent segment degeneration, I think, should be looked at.  We obviously have the x-rays stored on computer data and that should be something that could be doable.  And then 13 is perhaps the most difficult and that is, I think, the follow-up should be extended to five years to get to some semblance of a number of where we would see adjacent segment, so that we can back up the rationale that we are preserving the adjacent segment from the standpoint of the philosophy of the disc replacement.  Thank you.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Kirkpatrick.  May I ask before we move to Dr. Blumenstein, may I ask that among the suggestions you made there are some that seem to be answerable by relooking at the existing preclinical and clinical data and perhaps one or more that may require further study data after approval.  Would you care to comment on?  It would seem to me that number 13 might, of course, require more study data clinically, and that maybe number 3 would require in-vitro data, but that the others perhaps could be answered by looking at the existing data.  Would that be accurate?

            DR. KIRKPATRICK:  I agree that number 3 and 13 definitely would require additional work.  I think the remaining things, as I recall, are either a discussion of their existing data or an expansion on analysis of their existing data.

            CHAIRPERSON YASZEMSKI:  Okay.  Thank you.  And then when we have the sponsor summary, I'll ask the sponsors to comment on these.  Dr. Blumenstein?

            DR. WITTEN:  Can I just mention one thing?

            CHAIRPERSON YASZEMSKI:  Dr. Witten?

            DR. WITTEN:  Yes, I'll just mention one thing which is that when you get to the vote, you'll have to clarify for us for each of these recommendations whether or not these are things that you would expect to see pre-approval or post-approval, because if it is new data, for example, then that's not a condition of approval recommendation.  It's a recommendation to put the PMA in approvable form.  So I just want a clarification of when you think we need this information.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Blumenstein?

            DR. BLUMENSTEIN:  My main concern is the long-term follow-up and I think that has been addressed.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Besser?

            DR. BESSER:  I concur.

            CHAIRPERSON YASZEMSKI:  Thank you.  Ms. Maher?

            MS. MAHER:  I'm going to sound a little bit like a broken record like I always do and again remind everybody that we do have data back to 1987.  We do have a significant patient population outside the United States, and so maybe a post-approval study following the other patients in the study now for longer would be appropriate, but some of the rest of the data may not be necessary.

            CHAIRPERSON YASZEMSKI:  Thank you, Ms. Maher.  Ms. Luckner?

            MS. LUCKNER:  Nothing else to add.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Diaz?

            DR. DIAZ:  I would like to agree with Ms. Maher, because I think there is significant clinical data available in the world literature that indicates the longevity and the effectiveness of this device in the treatment of discogenic disease.  The available literature does not answer all the questions that Dr. Kirkpatrick mentioned, but those could be answered on an ongoing type analysis, rather than trying to redesign a new study.  I believe that there is sufficient information already available to answer many of these things.  And going back to square one, I don't think is necessary.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Diaz.  Dr. Mabrey?

            DR. MABREY:  Yes, I concur with the plan to go ahead with looking at those individuals that are currently under study and also perhaps extend some of these investigations to those patients who are available in Europe.  And particularly, I'm interesting in looking at the possibility of osteolysis at four and five years out.  I think you have the potential to continue to look at radiographic data on the original 200 patients here and it's no additional great buren and it would be nice to see data from European studies indicating that there is no osteolysis.

            CHAIRPERSON YASZEMSKI:  Thank you. 

            MS. MAHER:  Can I ask for a clarification for that?  Were you talking about a post-approval type of look at it for that data?

            DR. MABREY:  Okay.  This is my first Panel meeting and so we've been talking about post-approval.

            CHAIRPERSON YASZEMSKI:  And may I interrupt?

            DR. MABREY:  And PMAs and PDPs.

            CHAIRPERSON YASZEMSKI:  May I interrupt, Dr. Mabrey?  What I'll suggest is all of these things that we recommend to FDA, we will need to recommend whether they are things that need to be done before the approval, and thus defer the approval, vote that this is non-approvable or whether we would agree that this is an approvable application, and in addition as terms of the approval, we would like them to do further work and follow the patients.

            DR. MABREY:  Okay. 

            CHAIRPERSON YASZEMSKI:  And we will just have to make that distinction when we come to voting.

            DR. MABREY:  Okay. 

            CHAIRPERSON YASZEMSKI:  And thank you, Ms. Maher, for bringing that clarification up.

            DR. MABREY:  Okay. 

            CHAIRPERSON YASZEMSKI:  Dr. Finnegan?

            DR. FINNEGAN:  Now, you've changed my train of thought.  I was getting all my thoughts together.  One of the problems with looking over the data here is that unfortunately of the 205 or so patients that had the Charite implants, a number of them have actually not reached two years yet.  And I think that we have already all pretty much agreed that two years is probably not a safe length of time to follow these patients.  So I do think that there needs to be a long-term follow-up.  I definitely agree with Dr. Kirkpatrick on that.

            And I know that we are looking at the end plate with the spikes.  If there is a change to a coated end plate, then that's obviously going to drastically change the biomechanics on the polyethylene and understanding that the company feels the polyethylene is cross-linked to some degree, it is obviously a random cross-linking.  So I think all of those are things that need to be considered.

            And as well, I do think that the company needs to be at least -- or the sponsor needs to be at least familiar with neurological response to chronic inflammation and be comfortable that that is not going to be a long-term problem.  And I certainly agree with Dr. Kirkpatrick on adjacent segments.  I think that some kind of study needs to be done on that.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Finnegan.  Dr. Kim?

            DR. KIM:  I think if we only looked at the U.S. clinical trial data, I would be nervous with just two year results.  But I agree with Ms. Maher that we have the -- we are fortunate that we have a pretty extensive European experience of 7,000 patients.  I think with the excellent U.S. clinical data of two years combined with the European data, it's a very promising device.  And based on that, I feel like this device is safe and effective.  But there are a lot of questions that remain and I think looking at the existing patients over the long-term, maybe over five or even 10 years, is a reasonable condition.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Kim.  Dr. Naidu?

            DR. NAIDU:  You know, I would like to listen to the second open public hearings prior to commenting on this.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Naidu.  Dr. Blumenstein?

            DR. BLUMENSTEIN:  I just get so enamored of the case series data that are likely to come out of Europe, other places like that.  There's nothing more valuable than the data that have been invested into this clinical trial in a comparative way and the potential for that data to come out with an unbiased comparison of the results as opposed to the uncontrolled convenient samples that are often published in the literature.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Blumenstein.  Dr. Witten, as you've heard, we've had a more extensive discussion on this question.  And I would like to review it and then to say that when we get around as a Panel to making a recommendation to vote on, we'll consider which of these suggestions might be conditions of approval and which we would want to be done after the approval vote.

            We've talked about adding mobility testing data and in-vitro study of the facets, wear data to 50 million cycles, test response to submicron particles, to consider using data from the existing European studies and we have heard pros and cons about that from several Members of the Panel, osteolysis at four to five years.  Many of the Panel Members thought that going out about five years for several of these end points would be appropriate.  Dr. Finnegan mentioned the effects of inflammation on the neurologic tissues by chronic inflammation and Dr. Kirkpatrick about adjacent segment.

            Have we discussed this to your satisfaction?

            DR. WITTEN:  Yes, thank you.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Witten.  That's going to conclude the discussion on the specific questions that the FDA has posed of us.  We are going to move now to the second open public hearing.  There are three people who wish to present to the Panel, at this point.  These are Dr. Hochschuler, Dr. Van Ooij and Ms. Adams.  Dr. Hochschuler will be first with a time of five minutes.

            DR. HOCHSCHULER:  I am Steve Hochschuler.  I am a spine surgeon.  I am Chairman of the Texas Back Institute, and today I am representing the Spine Arthroplasty Society in my presentation.  First, I want to thank you for allowing me to come to the podium today.  Secondly, despite having been a spine surgeon for about 28 years now, this is the first time I have been at an FDA Panel meeting.  And I have to say as a citizen, I'm very impressed.

            I have my own bias as to whether this should be approved or not approved, but I must say it's almost like a TV show.  I'm not sure how you are going to vote an I'm really intrigued.  I think it's a wonderful process and I don't want to be supercilious, but I would like to compliment you and thank you.

            Having said that, I feel as a surgeon that it is our primary responsibility to care for the patient.  And with that, I have been charged along with the rest of the Spine Arthroplasty Society to put together a position statement on some of the items you discussed earlier in terms of safety, how do we protect our patients, how do we get better outcomes.  With this in mind, despite the fact I usually don't like to read directly, I would like to read this statement to you, since I've got limited time, and then go from there.

            "Spinal Arthroplasty Society Educational Objectives."  "The board of directors of the Spinal Arthroplasty Society has decided to take a unique step in establishing education and training goals for spine surgeons interested in new arthroplasty technologies.  The ultimate goals of this effort are to improve clinical outcomes and reduce technical complications in patients undergoing surgical treatment utilizing these new technologies by providing a strong educational core of knowledge for surgeons.

            Traditionally, rigorous patient selection criteria have been required for inclusion in FDA trials.  Additionally, investigators are specifically selected by the companies who design the studies based on their reputations and experience.  However, when devices are approved for marketing to surgeons in the community, there has been no formal standardization for training these physicians in your use.

            Training historically has run the gamut from a product introduction by a company representative sitting across the surgeon's desk to a brief course with a lecture in the morning followed by a crowded hands-on training using saw bones models to a comprehensive training program incorporating surgeon education for diagnostic workup, patient selection criteria, management of complications and ample time in a cadaver lab developing familiarity with the instrumentation and surgical exposure.

            Ideally, comprehensive formal training should be followed by proctorship at the training surgeon's hospital for its first case or cases by a teaching surgeon with a high level of expertise.  This would serve to close the loop of the surgical proctoring process.  Obviously, this level of training is expensive and time consuming, but it offers significant long-term advantages for patients, surgeons, industry and hospitals.

            For patients, technical complications may be reduced and outcomes improved.  For surgeons, their patients' clinical results may be more gratifying and litigation avoided.  It is important for industry so that their devices can produce the best results possible.  A product may be unjustly criticized for high complications and poor outcomes if surgeons have poor technical skills or employ too broad patient selection criteria.

            Hospitals also have a vested interest in the training of surgeons.  The hospital's mission like that of the surgeon is to ensure the maximum benefit to the patient.  While the technology of spinal surgery is steadily advancing, clinical safety and outcomes cannot be expected to improve unless the appropriate patient selection and optimal surgical techniques are taught.  SAS is prepared to take a pro-active role in addressing surgeon education.  A program of organized processes for training surgeons on new devices will incorporate didactic lectures, hands-on training and proctorships.

            The role of the Society will be to develop guidelines for content of educational programs, identify training centers with adequate facilities and staffing for consistent quality training and organize access to specialists with experience with the specific devices to provide proctorships.  Due to liability issues, certification can verify that the surgeon has completed training, but not that he or she has adequate skills.  A document will be issued only to verify course attendance and subsequent proctorship.

            The fact that training is provided through a Society and performed in an organized, standardized format across the country and hopefully the world should enhance the overall quality of care for our patients.  All parties concerned recognize the importance of having surgeons properly trained when introducing new technologies.  With the rapid developments in spinal implants, SAS has an unprecedented and unique opportunity to play an important role in improving patient care, optimizing the application of new technologies and furthering the development of new implants by increasing the safety of new product introduction and adoption of these standardized training programs.  Thank you.

            CHAIRPERSON YASZEMSKI:  Thank you very much, Dr. Hochschuler.  Dr. Van Ooij?  Dr. Van Ooij is scheduled for 10 minutes.

            DR. VAN OOIJ:  Thank you, Mr. Chairman.  I am very honored to be here and to speak to you.  I am an orthopedic surgeon, spine surgeon in Maastricht, the Netherlands for 24 years and I'm a member of the SRS, the Scoliosis Research Society and the European Spine Society.  I will talk about the other side of the Charite disc prosthesis, so I talk about complications that I see in a cohort of about 500 patients that were operated in a neighboring hospital, and another 500 has been operated by countrymen of me in Munich in Germany.  So this is a cohort of about 50 patients.  They are already a little bit more, but 49 were evaluated.

            So if we could have the next slide?  Where do I have to press?  All right.  Oh, yes.  So in eight  years, I saw 49 patients, 28 women, 28 men, and with a young age, of course, because that is in the indication and there were operations performed as early as in 1989.  20 in the period of the first five years.  Then 24 in the second five years.  And seven in the last four or five years.  The next one.  So most patients were operated in one level, of course, let me see, some in two levels.  Two levels in 10 patients and three levels in two patients.  There were a lot of previous operations done, but most had no operations before this.

            Next one, please.  So there were early complications, subluxation of a prosthesis and removal after a few days, some hematoma.  In men, there is a risk of retrograde ejaculation and erectile dysfunction.  If you ask the male people, they sometimes have a dysfunction without retrograde ejaculation.  There is one patient that had a urethra lesion with a large urinoma.

            Next slide.  This is the patient with a stint in place and here a large urinoma from a urethra lesion.  This was punctured several times and there was pseudomonas involved and probably she has a low grade infect now in one of these prostheses, so this is really a problem.  She is in a bed.  All these patients have really terrible leg and back pain.  They have VAS scores about 8 to 9 mostly.

            Next patient -- sorry, next slide, please.  The leg complications are migration.  These mainly are prosthesis uncoated, so there were anterior migration, posterior migration, even the main cause of complaints after a year or a lot of them remainder complaints is disc degeneration at the other levels.  In 13 patients it was -- this was not obvious before the operation on plain x-rays and discography, but there were the other ones had more or less degenerated disc, but without pain on discography.  Facet joint degeneration is a big problem, I think.  In the late situation, we saw it 16 times.

            Next, please.  This is the patient with anterior migration.  You can see that in 10 years this is 1991 and this is 2001, this was sliding anteriorly and pressed on the big vessels and we had to remove it and luckily we were successful in doing it without lesions of the vessels, but this has been reported and undoubtedly many times if you hear the conferences and there was a fusion done, and this is the only one of the re-operations that the patient is satisfied.

            Next, please.  There is a big issue, I think, in facet joints arthrosis because it's probably the biomechanical behavior of the prosthesis.  I'm very worried about axial rotation that is increased in the prosthesis compared to the normal disc, so you get a big load, I think, on the facet joints.  Probably also when it is more anterior located, you must put the prosthesis really posterior to get some kind of motion and these are the facet joints that are really very hypertrophic and are triadic.

            Next, please.  Subsidence is a big issue in this series.  In 17 of these patients the prosthesis was obviously too small.  There was some subluxation of the core.  One big issue that was not spoken about today is breakage of the metal wire.  If you look good at the x-rays, you can see the breakage and the flattening of the polyethylene core and probably also some wear debris.  Hyperlordosis should be an issue if you distract the segments, you get easily in hyperlordosis and asymmetrical loading of your facet joints.  And I think that the patient that Mr. McAfee demonstrated had, in my mind, really aware of the prosthesis.

            Next case.  So this is the patient, a patient with a subsidence that is seen many times and it can go all the way posteriorly or anteriorly or sideways and this was fused, but the patient keeps on complaining.  Probably, I think, that the posterior stabilization and fusion is not the answer, because most people keep complaining because of micro motion in the prosthesis, despite the posterior fusion.

            Next case.  This is a patient that really bothers me with degenerative scoliosis developing after seven years.  Some patients have multiple degeneration above the discs in the Charite and they get degenerative scoliosis above or including the prosthesis.  I think mainly from axial rotation problems or because of the forces that go through the spine that are blocked by the prosthesis.  You can say that these are stones in the shoe.  If you have a stone in the shoe, you get pain in all your leg and I doubt that this will mimic the natural motion so intimately that you prevent really motion degeneration.

            Next.  This is a case with a broken ring and a flattening of the core at the posterior side, but this is hard to see on this slide, but you should observe that and look very carefully at it.  Next slide.  And this is the patient with the wear, which has already been shown by Mr. McAfee, of one of my patients with holes in the bone and scoliosis and the flattening of the core.  That is indicative of wear, I think.

            Next, please.  We did 21 or 21 additional operations were done.  We did 11 of them.  10 were already performed before.  Most had posterior fusions, but most patients without much benefit, so I really would stress that it is not a good solution for the problem.  Probably this prosthesis will be a pain source afterwards.

            Next, please.  Many patients in this series, I think, had back surgery, back placement and back sizing, but also in the boot placement and boot sizing that were problems and it seems from this very experienced surgeon that it's not really -- that it is really difficult to do good surgery like this disc prosthesis placement.  And I think that it is not behaving as a normal disc.  The center of rotation has been talked about.  If you really put it posteriorly, it could be well, but then you have the risk of going over the edge and getting a rim fracture.  Two patients in my series have a posterior placement.  Nobody talks about shock absorption, but Lueck has shown that there is no shock absorption and that the normal forces that go down the disc are not going like normally when you have a disc prosthesis in.

            Next, please.  And the rotation, I already talked about.  So a lot of problems will be seen, I think.  Also, in the United States if you wait long enough, two years, in my mind, is far too short to see those problems.  Wear will be a big issue in the future.  I'm convinced of that, because the forces on the lower spine are very, very high.  Revision is dangerous and sometimes impossible and I go to series from surgeons and they say that they couldn't reach the prosthesis, because the vessels were too adherent and the claim of preventing adjacent disc degeneration is not substantiated.

            Next, please.  So that was the end.  I want to report an investigation that was presented yesterday in Porto, where I was yesterday, and it was from the Charite group.  They sell from East Berlin of Berlin now where it was originated.  They did a 17 year follow-up of 53 patients out of a group of 71 patients.  And 60 percent of the segments were fused, really fused, didn't move anything and didn't move at all and most had already bone in it and were really fused.  But they were the better one and the patients that still fused still had some motion in it were the bed one, and I think you should look also to that series.  That is the most, the longest experience to date, 17 years, and the conclusion of Mr. Brooks here was that there was no indication for a disc prosthesis in the disc disease.  Thank you to showing it to you.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Van Ooij.  May I ask before you leave, we have asked all the speakers to state for the transcriptionist for our record, the Conflict of Interest statement, the three questions and, please, your industry relations, any financial aspects that you might have and the source of funding for your trip here.

            DR. VAN OOIJ:  Yes, thank you.  I forgot to name that.  I have no personal financial relationships with any industry.  Medtronic Company brought me here, provided for the travel.  And further, I have no relationship whatsoever.

            CHAIRPERSON YASZEMSKI:  All right.  Thank you very much, sir.  The third speaker will be Ms. Pam Adams from OSMA.  And, Ms. Adams, you are scheduled for five minutes.

            MS. ADAMS:  Good afternoon.  My name is Pamela Adams and I speak here today representing the Orthopedic Surgical Manufacturers Association or OSMA.  OSMA, a trade association, with over 30 member companies welcomes this opportunity to provide general comments at today's Panel meeting.  OSMA's comments should not be taken as an endorsement of the product being discussed today.  We ask instead that our comments be considered during today's Panel deliberations.  These comments represent the careful compilation of our member companies' views.

            I would like, first, to provide a brief introduction and background.  OSMA was formed over 45 years ago and has worked cooperatively with FDA and the American Academy of Orthopedic Surgeons, the American Society of Testing and Materials and other professional medical societies 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.

            OSMA membership currently includes 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 recommendations to the 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 safety and effectiveness based on the data provided.  As regards reasonable assurance of safety and effectiveness, the FDA is responsible for protecting the American public from drugs, devices, food and cosmetics that are either adulterated or are unsafe or ineffective.  However, FDA has another role to foster innovation.

            The Orthopedic Devices Branch is fortunate to have available a staff of qualified reviewers, including a Board certified orthopedic surgeon to evaluate the types of applications brought before this Panel.  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 on 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 have received training from FDA on the law and the regulation and I 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.

            Firstly, reasonable assurance of safety and effectiveness and secondly valid scientific evidence.  As regards the first point, there is 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 over simplified statement include valid scientific evidence and proper labeling and that safety data may be generated in the lab, in animals or in humans.

            There is a reasonable assurance that a device is effective when it provides a clinically significant result.  Again, labeling and valid scientific evidence play important roles 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.

            As regards the second point, valid scientific evidence, 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, a study protocol, a method of selecting subjects, a method of observation and recording results and comparison of results with a control.

            In conclusion, 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 with the risks.  The regulatory standard is not proof beyond a 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 of a whole and such recommendations 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, products that you and your colleagues use in treating patients to the market.

            Please, be thoughtful in weighing the evidence.  Remember that the standard is a reasonable assurance of safety and effectiveness and that there is a legally broad range of valid scientific evidence to support that determination.  On behalf of OSMA, I would like to thank the FDA and the Panel for the opportunity to speak today.  Our association trusts that its comments are taken in the spirit offered, which is to help the FDA decide whether to make a new product available for use in the U.S. marketplace.  Thank you.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Ms. Adams.  We're going to break now and then proceed with the summation from both the FDA and the sponsors.  It's about 3:51.  Let's come back and start at 10 minutes past 4, 4:10.

            (Whereupon, at 3:52 p.m. a recess until 4:14 p.m.)

            CHAIRPERSON YASZEMSKI:  Can I ask everybody to take your seats, please?  We're going to get started.  We're going to ask, at this time, for the FDA and sponsor summations and then we're going to proceed to the voting.  And I will first ask FDA.  Dr. Witten, would FDA like to add anything, and I would specifically like to ask you to comment on the rules regarding conditions and their effect on the vote?

            DR. WITTEN:  I'm sorry.  You're asking me to clarify the rules on post-approval commissions and the vote?

            CHAIRPERSON YASZEMSKI:  Yes.

            DR. WITTEN:  Yes.  Okay.  Thank you for asking me.  I will just amplify what I said before the break, which is that if there is a condition that is asking for new data or a new analysis, if the request is for that new data or new analysis to be provided to us after approval to answer some focused, specific question or a series of questions then that, you know, would be what we would consider a condition of approval.

            If what you are requesting or what the Panel recommends is a condition where you're asking for new data or a new analysis, that you want it provided to us for our review prior to approval, then what that is to us in terms of the vote and the recommendation is a non-approvable recommendation, and what you're providing us with are the recommendations of how to put the application in approvable form.

            So that's why I had said prior to the break when Dr. Kirkpatrick was going through his list that we need to understand whether, for each of these that you may agree on, the Panel is recommending that we have the data in hand to review prior to approval, which would mean you're really making a non-approvable recommendation with a recommendation of how to put it in approvable form versus telling us you would like us to look at a specific, focused question and get some data around those questions after approval, which would be a post-approval condition.

            And let me just clarify one additional thing, in case the question should come up, which is, you know, under what would we take such an application back to Panel and it would be our option of whether or not we felt that we had, you know, additional issues we wanted to ask the Panel about.

            CHAIRPERSON YASZEMSKI:  Okay.  Thank you, Dr. Witten.  I would like to ask if the sponsor has any summation comments to make, Mr. Christianson?

            MR. CHRISTIANSON:  Thank you, Dr. Yaszemski.  Jack, could I have the first slide, please?  We heard some discussion today that several of the Panel Members expressed concerns that we don't know what the long-term safety profile of the Charite Artificial Disc is, and I would just like to remind the Panel that we did conduct a 24 month randomized prospective study per the FDA guidance document on spinal devices, and that has been used for all previous spinal devices and, indeed, all previous orthopedic devices have been approved based on a two year follow-up study.

            In addition, several people did remind the Panel during the course of the discussion that there are, indeed, long-term follow-up data from Europe.  There is a very good case series from Dr. LeMaire and a six year case series from Dr. David, and case series do meet the FDA definition of valid scientific evidence, so the Panel can, indeed, take those series into consideration that are available in the literature.

            And we also heard some discussion about a post-approval study.  Indeed, that's the place that's appropriate and accepted to develop the longer term data in a post-approval study after the device has been approved and the company certainly is amenable to conducting a five year follow-up study as Dr. Kirkpatrick recommended in his document.  Next slide, please.

            Sorry, Dr. Kirkpatrick, we didn't know what to title this slide when we put it together, but reviewing your list of recommendations that you passed around, we agree that most of the recommendations on your list are reasonable and we will certainly discuss them with FDA and put the answers together that we can with our existing data.

            However, I must comment on your recommendation for 50 million cycle testing.  The company believes that that is an excessive requirement for testing.  For example, for metal on a polyethylene device, that will take at least 15 weeks to conduct, probably longer, and that would potentially delay the approval of the device for a significant period of time.

            The testing that we have submitted, the 10 million cycle testing that is already in our PMA, does represent 80 years of significant bends while listing a 20 kilogram weight, so we do think that we provided adequate long-term mechanical test data.  And so if that's an issue that we'll need to negotiate with FDA, I wanted to get that statement on the record.  Last slide, please, Jack.

            And I'll close with the same statements that I made when we closed our Panel presentation.  We're presenting a device to you that's got a long clinical history of use in Europe, fully biomechanically characterized, robust, valid, scientific evidence that the device is safe and effective and we, again, ask the Panel to recommend that this device be approved for use in patients in the U.S.

            CHAIRPERSON YASZEMSKI:  Thank you, Mr. Christianson.  Ms. Scudiero will now read the three possible Panel recommendation options for pre-market approval applications.  Ms. Scudiero?

            MS. SCUDIERO:  These were in the meeting handouts.  They are entitled "Panel Recommendation Options for Pre-Market Approval Applications."  The medical device amendments to the Federal Food, Drug and Cosmetic Act, as amended by the State Medical Devices Act of 1999, allows the Food and Drug Administration to obtain a recommendation from an expert Advisory Panel on designated medical device pre-market approval applications 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 "Reasonable assurance based on valid, scientific evidence that the probable benefits of health under the conditions on intended use outweigh any probable risk."  Effectiveness is defined as "A reasonable assurance that in a significant portion of the population, the use of the device for its intended uses and conditions of use, when labeled, will provide clinically significant results."

            Your recommendation options for the vote are as follows:  (1) Approval, if there are no conditions attached.  (2) Approvable with conditions.  The Panel may recommend that the PMA be found approvable subject to specified conditions, such as physician or patient education, labeling changes or further analysis of existing data.  Prior to voting, all the conditions should be discussed by the Panel.  (3) Non-approvable.  The Panel may recommend that the PMA is not approvable if the data do not provide a reasonable assurance that the device is safe or if a reasonable assurance has not been given that the device is effective under the conditions of use prescribed, recommended or suggested in the proposed labeling.

            Following the voting, the Chair will ask each Panel Member to present a brief statement outlining the reasons for their vote, and this became effective June 14, 1999.

            CHAIRPERSON YASZEMSKI:  Thanks, Ms. Scudiero.  I would like to make a few comments before we ask for a motion.  First, with respect to voting, the eight Panel Members will vote.  Our consumer representative, our patient representative, that is, and our industry representative will not vote.  I will only vote in the event of a tie.

            Regarding the motion, the sequence that can happen is we have a motion, a second for the motion, discussion and a vote.  If that sequence occurs and the vote is for the motion, then we're finished.  If the vote is either against the motion or if there is not a second for the motion, then we'll ask for another motion.

            With that in mind, the lead reviewer for this was Dr. Kirkpatrick and I'm going to ask him to make a motion.  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  To borrow from Dr. Hochschuler, I felt a little bit like Simon at the beginning of my discussion and I hope that we can understand each other as far as where we're coming from.

            A recent editorial in the NAS Journal indicated that I am part of an increasing or a decreasing majority of spine surgeons.  The editorial was discussing the fact that there is a number of spine surgeons who will do things on patients that they would never consider for themselves.  This reminds me of what the FDA's purpose is and that is, first, protecting the public.  As such, some of my comments and my motion will be directed towards that.

            The second rationale I have for my motion is being a bone setter from Alabama means I have adopted certain habits and customs.  One of those customs happens to be watching NASCAR.  As many of you know, NASCAR is a race around a track that generally runs between 250 and 500 miles or sometimes, on one occasion a year, 600 miles in length.  The design of the tires is specific for the track and the type of racing done and is not expected to exceed the length of time that the gas tank is full.  In other words, when you run out of gas, your tires are going to need to be replaced.

            I think we need to think of the same design rationale as far as a disc replacement.  We need to make sure that we are assured of both the safety and effectiveness for the intended length of use.  Now, I know that's an onerous thing if we're talking 50 years, and I don't propose that at all.  However, I do think that a two year follow-up, in all due respect to Mr. Christianson and his colleagues as far as discussion of precedent, this is an unprecedented device and I don't think two years is adequate.

            As such, I would recommend or, excuse me, I move that we call this PMA not approvable and that would be my motion.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Kirkpatrick.  Do we have a second for that motion?  Dr. Finnegan?

            DR. FINNEGAN:  Yes.

            CHAIRPERSON YASZEMSKI:  We have a second.  Discussion?

            MS. MAHER:  Well, can I lead off the discussion?

            CHAIRPERSON YASZEMSKI:  Ms. Maher?

            MS. MAHER:  As a non-voting member, I can lead this off pretty well.  I have to take exception, Dr. Kirkpatrick, to what you're saying, because spinal cages were approved initially with two years follow-up and they also, at the time they came on board, were a first of their kind.  And if I actually recall correctly, they even had much less animal data and other data than we have on this product, which, again, as Mr. Christianson put up on the slide, we do have data since 1987 showing that it has been used safely and effectively in Europe for many years.

            So I have some deep concerns that if you tell a company they can't launch something for five years after they have started developing it, we're going to put a stop to new product innovation in the medical device or the orthopedic world.  And I'm wondering why you feel that that's more appropriate than having a post-market approval study, a post-approval study where you can follow the devices and look at what's happening.

            You have got a cohort of patients that already has two years.  You can have three more years and you will have the five year data, in which case you'll have the other patients.  It will be available for sale.  It will be being sold and being used, but I think they have provided adequate evidence that it would be safe and effective, so I have to disagree with you.

            CHAIRPERSON YASZEMSKI:  Thank you, Ms. Maher.  Dr. Diaz?

            DR. DIAZ:  I also would like to disagree with Dr. Kirkpatrick's statement, because I think we are making a statement that flies against a very large body of evidence.  There has been 17 years of use of these devices throughout the world.  We are the only country in the industrialized world that does not approve its use yet.

            To expect to compare a mechanical device like a tire that is running on a NASCAR track to the function of the human body is counter-intuitive.  If the good Lord had designed our gas tank to allow our functioning parts to last the exact same time, we would die in perfect physical condition and that is not a reality.  We run out of gas at about the same time when all our parts have fallen apart.

            So I think that the motion is not what I would endorse.  I disagree entirely that there is not sufficient evidence to indicate its use.  It can be done, I believe, with some continuing monitoring and perhaps longitudinal studies to answer some of the questions, but I believe the experience in France and Germany have already shown the various things that will happen.

            And if we were to say that ultimately, all the device does is delay the occurrence of a natural fusion, as was presented already in a relatively small comment made at the end of the presentation of Dr. Ooij, I believe is his name, from the Netherlands, Ooij, Dr. Ooij.  Even if we gain 10 years of extension on the function of a disc, I think we have provided a sufficient opportunity for the individual not to have a fusion that perhaps would occur spontaneously or that may be induced by the introduction of mechanical devices, which we have already approved.  So I think that the decision not to allow it is incorrect.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Diaz.  Dr. Mabrey?

            DR. MABREY:  Well, having trained in North Carolina at the same time that Dr. Kirkpatrick did at Duke, I can certainly share his observations of NASCAR as a NASCAR dad, but I do see an opportunity here to provide additional information after approval.  The developers of the device and the clinicians have demonstrated that they have a very good cohort of patients.  They have gone out of their way to document every complication that has occurred, and I think we have the opportunity to follow that data after approval and look at that data both at four and five years out.

            John, I agree.  I think, you know, maybe 50 million cycles isn't an unreasonable number of cycles to go through, but, again, that type of data could be ongoing rather than pre-approval.  So I would argue for approval with certain conditions.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Mabrey.  Dr. Finnegan, you were the seconder.

            DR. FINNEGAN:  Yes, I'm not sure that some of the Panel Members and maybe Ms. Maher will understand that just because we say not approval doesn't mean this is going into the closet.  Not approval means that, at the present time, the Panel is not comfortable with all of the data.  It does not mean it has to come back to Panel.  It just means that certain things have to be done before the FDA makes a decision and that it's quite possible, given the discussion today, that it will not need to come back to Panel.  But if there are some things that we really feel strongly need to be done before the FDA gives it approval, then by regulation we cannot approve it.

            Now, one of the biggest concerns is that of those two year follow-up patients, they haven't all reached two year follow-up and, in fact, if I read the numbers correctly, in fact, the latest patient to get this is probably less than 10 months ago.  So if you take all of those patients out to two years, you're actually going to have some three and a half or four year data, which will be much more helpful than doing it now when some of the patients haven't reached their two year mark.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Finnegan.  Dr. Kim?

            DR. KIM:  This is such a difficult topic to vote on because of the complexity of the disease and the fact that this is a brand new product, but I was reading the FDA Modernization Act of 1997 and what that Act basically entails is the spirit of trying to promote innovation, and I think by requiring much longer follow-up, it will deter companies from being able to produce these innovative materials and I think the burden will be too onerous.

            So I think that the two year clinical data, which is excellent, combined with the long-term follow-up of the European literature, which, as Ms. Maher pointed out, is data that we can use as an FDA Panel to make decisions, are compelling and I would lean toward approval with specific conditions that addresses some of the concerns that we have.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Kim.  Dr. Naidu?

            DR. NAIDU:  You know, after listening to the presentation from the Netherlands, the physician from the Netherlands as far as device complications, it appears as if device related complications including anterior/posterior migration is less than 1 percent.  In addition, the sponsor has conducted an excellent study where they have shown a significant improvement in objective outcomes, including the ODI and the VAS.

            They have also shown that it's non-inferior to BAK, that's the fusion device, and they have also shown that it's at least equivalent and it's not inferior, and I'm not sure as to why we are debating as to approvability of this device.  I think it's approvable without any conditions.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Naidu.  Dr. Blumenstein?

            DR. BLUMENSTEIN:  I can't go along with disapproval.  I have to think that there are some conditions that we could put on with an approval with conditions that would satisfy the long-term follow-up requirement.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Besser?

            DR. BESSER:  I would also look for approval with conditions.  I think we can resolve the issues here post-approval.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Besser.  Would anybody else like to add commentary?  Hearing none, what we're going to do now is vote on this motion, which is for non-approval.  I will go around the room and ask everybody to say yes or no for non-approval.  If you vote yes, that means you agree and you would like this to be not approved.

            If this motion passes, then we're finished and our recommendation is non-approval and we'll discuss after that conditions that need to be met to make it approvable.  If the motion does not pass, then we will ask Dr. Kirkpatrick if he might entertain a new motion.

            Let's start, Dr. Diaz, with you.

            DR. DIAZ:  I disagree with the motion.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Mabrey?

            DR. MABREY:  Disagree.

            CHAIRPERSON YASZEMSKI:  Dr. Finnegan?

            DR. FINNEGAN:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Kim?

            DR. KIM:  I disagree.

            CHAIRPERSON YASZEMSKI:  Dr. Naidu?

            DR. NAIDU:  I disagree.

            CHAIRPERSON YASZEMSKI:  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Blumenstein?

            DR. BLUMENSTEIN:  Disagree.

            CHAIRPERSON YASZEMSKI:  Dr. Besser?

            DR. BESSER:  Disagree.

            CHAIRPERSON YASZEMSKI:  The motion does not pass.  Our two remaining options are approval or approval with conditions and I will ask, at this time, Dr. Kirkpatrick, would you entertain another motion?

            DR. KIRKPATRICK:  I would be glad to.  I would also like to take a moment to recognize the beauty of democracy and the fact that we can agree to disagree, and that we have the freedom to do so at the expense of a number of our countrymen right now.

            I would suggest, I would like to make the motion that it is approvable with conditions and if that passes, I would like to itemize conditions and take them individually if that's okay with the Chair.

            CHAIRPERSON YASZEMSKI:  Yes, the way that we're going to do it is we're going to go around.  If you make a motion for approval with conditions, what we now do is consider the conditions first.  I'm sorry, a point of order.  Ms. Scudiero just reminded me that I did not ask for a second.

            Dr. Kirkpatrick has made a motion for approval with conditions.  Do I have a second?  Dr. Besser has seconded the motion.  Thank you, Ms. Scudiero.

            What we'll do prior to voting is have a discussion and ask for conditions.  And if someone brings a condition up, we'll discuss that condition and then vote on that condition, and that condition will then either be included or not included.  If persons have disagreements with the conditions that get voted in, then they can exercise their disagreement by voting no for the motion when it comes to a vote.

            So I would like to entertain now if there is a motion for a condition from anybody.  Yes, Dr. Kirkpatrick?

            DR. KIRKPATRICK:  In a follow-up to my concern about the length of follow-up, I would suggest that a condition would be that all of the currently enrolled patients, including the -- I can't remember what you termed it, but basically the patients that aren't in the IDE, but the ones that have continued to be done.

            UNIDENTIFIED SPEAKER:  The continued access.

            DR. KIRKPATRICK:  The continued access group be followed to the last of the continued access group being a minimum of two years follow-up.  That should give us close to five years on most of the IDE patients if I'm remembering correctly on your block of time.

            CHAIRPERSON YASZEMSKI:  Yes.  Thank you.

            DR. KIRKPATRICK:  That would be the first of several conditions I would propose.

            CHAIRPERSON YASZEMSKI:  We have a motion for a condition to include all the continued access patients until they have completed two year follow-up.  Is there a second for this motion?

            DR. DIAZ:  Second.

            CHAIRPERSON YASZEMSKI:  Dr. Diaz and Dr. Finnegan, we have seconds.  But is there discussion on this motion?  Dr. Besser?

            DR. BESSER:  I'm questioning as to whether two years is long enough.  I'm not sure how many of the people will be out to five years at that two years after the last patient.  If, in fact, we're looking for data out to five years, I would like to see the last patient at five years and that would give us even longer data and better data for the rest.

            CHAIRPERSON YASZEMSKI:  Mr. Christianson, could I ask you or a member of your company to comment on this question from Dr. Besser?

            MR. CHRISTIANSON:  Yes, the first patient was enrolled in 2000 and the last continued access patient was enrolled last week.  So if we follow that patient through five years, the patient from 2000, someone do the math for me quick, is going to be extensive.

            UNIDENTIFIED SPEAKER:  Nine years out.

            MR. CHRISTIANSON:  So I believe that the entire randomized cohort will be at or beyond five years if we followed the last continued access patient through two years.

            CHAIRPERSON YASZEMSKI:  Okay.  Thank you, Mr. Christianson.  Dr. Besser, does that answer your question?

            DR. BESSER:  It answers my question, but I'm not sure I'm convinced to shorten that.  I would still like -- you know, nine years of data would be great.

            CHAIRPERSON YASZEMSKI:  Okay.  Thank you.  Others?

            DR. KIRKPATRICK:  May I amend my --

            CHAIRPERSON YASZEMSKI:  No, we have a second already.

            DR. KIRKPATRICK:  Okay.

            CHAIRPERSON YASZEMSKI:  We'll have to vote on it first.  Any other discussion on this point?

            DR. BESSER:  I believe you can withdraw a motion.

            DR. KIRKPATRICK:  I don't want to withdraw it.

            CHAIRPERSON YASZEMSKI:  Let's have discussion.

            DR. KIRKPATRICK:  I want to include yours.

            CHAIRPERSON YASZEMSKI:  No, we can make another one.  More discussion?  Seeing none, Dr. Diaz, you're in the number one position here.  I'm going to keep asking you first.

            Let's vote, vote on this condition.  The condition is to include all the continued access patients until they have completed two years of follow-up.  This would be a condition to a motion for approval with conditions.  This is the first condition.

            DR. KIRKPATRICK:  That would be a report on all patients once the last of the continued access reaches two years.

            CHAIRPERSON YASZEMSKI:  Yes, that's assumed.

            DR. KIRKPATRICK:  I just wanted to clarify that.

            CHAIRPERSON YASZEMSKI:  That's assumed.  Yes, sir, Dr. Diaz?

            DR. DIAZ:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Mabrey?

            DR. MABREY:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Finnegan?

            DR. FINNEGAN:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Kim?

            DR. KIM:  I hate to do this, but wouldn't it be better to follow the IDE patients that are randomized for a total of five years?

            CHAIRPERSON YASZEMSKI:  We can do that as a separate motion.  I think we need to finish voting here.

            DR. KIM:  So based on that, I would disagree.

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

            DR. NAIDU:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  Agree.

            CHAIRPERSON YASZEMSKI:  Dr. Blumenstein?

            DR. BLUMENSTEIN:  Disagree.

            CHAIRPERSON YASZEMSKI:  Dr. Besser?

            DR. BESSER:  Disagree.

            CHAIRPERSON YASZEMSKI:  And this motion passes 5 to 3 and so one condition for Dr. Kirkpatrick's motion for approval with conditions is that the currently enrolled patients in the continued access category and all other enrolled patients in the IDE study have follow-up at the time that the continued access patients reach two years follow-up.

            Now, would anybody like to introduce a second condition?  Dr. Finnegan?

            DR. FINNEGAN:  It seems to me that this is the ultimate device for device tracking and I would, therefore, like to introduce the condition that this device be tracked.

            CHAIRPERSON YASZEMSKI:  We have a motion to include a condition for device tracking.  I would like to ask Dr. Witten to comment on the device tracking condition.

            DR. WITTEN:  Well, I just would like -- that term is always really confusion, and so I would like clarification as to what exactly that means, whether it's that we want to be able to track the device to the patients or there are specific data elements we want when it gets implanted.  Is this all patients and, for example, maybe I could start with asking what the objective would be and then we could better understand what it is.

            DR. FINNEGAN:  See, the objective would be as this is put in, one of the unfortunate problems at present is when a device is put in and five years later significant complications are known and probably, what am I thinking about, the -- what's the hip that got -- anyway, we have reason to -- yes, the Saltzer Hip, that we have had recent experience that patients are panicking, lawyers are calling everybody to find out if they have got the device in them or not and no one has the answer, which maybe the sponsor thinks would be a good idea.

            But anyway, what we're looking for is a way that a patient would know what device was in them.  The physician would know what patients they had implanted the device in.  The sponsor would know that the device was in Patient X, so that when, long-term, something came up, you would know where to go.

            DR. WITTEN:  Okay.  So it's to identify the patients and the physicians, and that's for anybody who receives the implant.  It's not a data collection mechanism?

            DR. FINNEGAN:  That is correct.

            DR. WITTEN:  Okay.

            CHAIRPERSON YASZEMSKI:  Thank you.  We have a motion for device tracking.  Is there a second?  Dr. Mabrey.  Discussion?  Dr. Diaz?

            DR. DIAZ:  I would like to just make sure that we call it device ID follow-up rather than tracking, because tracking to me implies something very different.  To me that means a responsibility on the corporation to follow every single device that's implanted wherever it happens to end, and I think that's an onerous condition of its approval.  I think it is important for the patient and the surgeon to know what device was implanted in whom when and where and leave it at that.

            CHAIRPERSON YASZEMSKI:  Okay.  Thanks, Dr. Diaz.  May I go out of the order first and I would like commentary from Ms. Maher on this.

            MS. MAHER:  Yes, I would support what Dr. Diaz just said.  Device tracking, when you go to the degree as to what that term actually means, is exceedingly burdensome to the industry and in the days of HIPAA is almost going to be impossible to do.  It's not one of those things that patients want to be followed and want to be tracked.  You know, they move.  They don't tell you they have moved.  Keeping track of where they are is virtually impossible.

            The device tracking requirements were originally put into place for products where if they were to fail, such as the heart valves, it would be catastrophic to the patient immediately and I don't see that this product necessarily fits that definition of being catastrophic immediately.

            I like what Dr. Diaz suggested, that we actually train people more and have the labeling require more, that the patient is supposed to know that you have gotten a DePuy Charite Disc.  I know many people who have gotten joint replacements and have no idea what joint they had placed in them, which I also find bizarre.

            But I think that if you go to this Nth degree, you're adding a burden that is almost impossible to meet and I'm not sure I see the benefit of it, especially given what that regulation and law was originally intended for.

            CHAIRPERSON YASZEMSKI:  Thanks.  And, Dr. Diaz, may I ask for a clarification on your use of the term follow-up?  Would it be similar to what Ms. Maher has just said?  What would you suggest the follow-up be?

            DR. DIAZ:  I think it should be limited only to providing the patient with a name of the device, perhaps an ID number that all of these devices have.  The patient would have the name of the surgeon, the place where the surgery was done and the date and leave it at that.

            CHAIRPERSON YASZEMSKI:  Thank you.  Now, I haven't yet asked for a second and I would like to--

            UNIDENTIFIED SPEAKER:  You have a second.

            CHAIRPERSON YASZEMSKI:  I have a second?  I'm sorry.  I did so.

            DR. DIAZ:  This is just a friendly editorial amendment.

            CHAIRPERSON YASZEMSKI:  Yes.  May I come first to Dr. Mabrey and then we're going to come to Ms. Luckner?

            MS. LUCKNER:  From the patient's perspective, I think you are asking for patient identification to know what device was implanted and to know the number.  That is totally reasonable from a patient perspective.  I do not wish to reveal totally in this room, but I have two knee replacements.  I carry in my wallet that I have a knee replacement, so that I have no difficulty with going through airport security systems.

            Now, I will tell you it does not say on it the manufacturer and I am one of those people that, over here my colleague said, I have no idea what knee replacement I have.  Listening to this conversation, you can believe when I return to Toledo, Ohio, I will find out exactly what is in my knees.

            CHAIRPERSON YASZEMSKI:  Thanks, Ms. Luckner.  Dr. Mabrey?

            DR. MABREY:  Yes, I agree with Ms. Maher's comments that a tracking type of program would be somewhat onerous and my chief concern is trying to keep in line with all the HIPAA regulations.  I think that becomes a quagmire, if I can borrow from another era.

            However, every one of my total joint patients get a card and they know exactly what implant they have in them and I make sure they have it, but then again, not everybody puts in total joints.  I think it's reasonable to provide the patient not only with a card that identifies what implant they have and the date it was implanted, but also a serial number much along the lines of the pacemakers.

            I believe most pacemaker implants have a serial number associated with them.  The manufacturer will be keeping at least a registry of those serial numbers and should there ever be a problem with that group, it seems like it would be a simple matter for the patient then to take the initiative and contact the physician or the company to follow-up on that serial number.

            It's certainly also helpful.  I would love to have every total hip patient and total knee patient in the country carrying around their serial numbers, so that I could call up that company and find out exactly what size implant I'm going to revise, and I don't see that as being too onerous on industry or too onerous on the patients and, certainly, you know, would put everyone's mind at ease.

            CHAIRPERSON YASZEMSKI:  Along the lines of what you have just discussed, would it be reasonable to consider having a card come with every prosthesis that has that identification number and then which the surgeon just fills out his or her name, the patient's name, date and hospital?

            DR. MABREY:  Well, I don't put these devices in, but it looks like there's three parts to it and they all come in three separate boxes.  But there are peel-off stickers that could go with that.  I would only caution you that if they go into your wallet, then after a couple of years the numbers will probably wear off.  So I'm not sure how we would handle that.

            CHAIRPERSON YASZEMSKI:  All right.  Thanks, Dr. Mabrey.  Dr. Blumenstein?

            DR. BLUMENSTEIN:  Well, as a concerned father of teenagers, perhaps we could put the tattoo parlors to work and have them --

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Blumenstein.  Dr. Kirkpatrick?

            UNIDENTIFIED SPEAKER:  They would be too busy to work on your kids.

            CHAIRPERSON YASZEMSKI:  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  May I suggest that implied in this condition would be that the FDA would work with the manufacturer in order to make sure that there is a legal way to do this, because the Joint Registry is already significantly alone working on those problems.  FDA is aware of those issues and if it can be done, it can, but if it can't be done, that the Panel would accept that, but we would encourage it to be done.  Is that implicit in the motion?

            DR. FINNEGAN:  It is implicit in the motion, but I think, Jay, I don't want to give people sort of a cop-out, because I think Jay is right.  I think if you put the serial number on and the patient has the access to the serial number, that doesn't have to have a lot of data and then you can do the same thing that, you know, Mercedes does when their brakes don't work.  They say if your car, you know, has this serial number or was between this and this date, then you need to call the company.  Here is the 1-800 number.  I mean, that's a pretty straightforward thing to do.

            DR. KIRKPATRICK:  I agree that it's straightforward, but, believe it or not, that minimal of a data set is significantly complicated in trying to get through other federal agencies as far as whether it's HIPAA compliant.

            DR. FINNEGAN:  But if the patient signs the consent, I don't think it is.

            DR. KIRKPATRICK:  Exactly.

            DR. FINNEGAN:  So if the patient signs, it says that they are quite happy to have the serial number and to have the company know what serial number they have, then I don't think that's --

            CHAIRPERSON YASZEMSKI:  Okay.  Thanks.  Dr. Mabrey?

            DR. MABREY:  Well, if I could just clarify.  I don't even think that we're asking that the company know which patient has it, but just that the company know what implants are out there and have been implanted, and we're placing part of the -- yes, we're putting part of the responsibility on the patient now to look at the serial number and then get in contact with industry.  I think this then keeps us out of all the problems with HIPAA.  Carrying around a serial number that only you know you have and industry having that same serial number, but having no idea who you are, I think that's reasonable, and I think it may be reasonable to at least keep track of which physician put it in.

            And I know the way industry does the total joints, they certainly know what region it goes into and I know that our distributor keeps track of just about every implant I have put in anyway.  I will have to check and see what HIPAA rules we're violating on that when I get back though.

            CHAIRPERSON YASZEMSKI:  All right.  Thanks very much.  Dr. Finnegan, do you have additional comments?  Otherwise, I'll go to Dr. Kim.

            DR. FINNEGAN:  I have no other comments.

            CHAIRPERSON YASZEMSKI:  Okay.  Dr. Kim?

            DR. KIM:  I would agree with what Dr. Mabrey said.

            CHAIRPERSON YASZEMSKI:  Thanks.  Dr. Naidu?

            DR. NAIDU:  Same here.

            CHAIRPERSON YASZEMSKI:  Thanks.  Dr. Kirkpatrick, additional comments?

            DR. KIRKPATRICK:  No.

            CHAIRPERSON YASZEMSKI:  Dr. Blumenstein?

            DR. BLUMENSTEIN:  No comments.

            CHAIRPERSON YASZEMSKI:  Dr. Besser?

            DR. BESSER:  No comments.

            CHAIRPERSON YASZEMSKI:  Thanks.  Ms. Maher?

            MS. MAHER:  I would just like a little clarification.  We're probably talking about lot numbers here, not serial numbers, and I would recommend that we actually, since the FDA now knows from this details conversation that what we really want is for patients to know what device they have had implanted and what lot numbers it was, that we leave it to the FDA and the sponsor to work out the best way to obtain that information.

            DR. MABREY:  I think lot numbers are --

            CHAIRPERSON YASZEMSKI:  Okay.  All right.  Thank you.  Now, before we vote, I want to ask Dr. Finnegan, because you made the motion and you did start with the words device tracking, but in light of the discussion, would you be okay if the motion did not include those specific words, which impose a certain level of --

            DR. FINNEGAN:  All I want --

            CHAIRPERSON YASZEMSKI:  -- responsibility on the company, but to go along with what we discussed.

            DR. FINNEGAN:  All I want is the patient to be able to know if the implant they have has a problem.

            CHAIRPERSON YASZEMSKI:  Okay.  Thank you.  I will state the motion then in the form it is after discussion.  The motion is that the patients be supplied with the name and lot number of the device, the doctor and hospital and date that it was put in, that the company know only that the device was implanted and that if problems do arise, the company can send out a notice and it would be the patient's responsibility to recognize that they have one of the implants in them that was in the notice.

            We're going to vote on this now.  Dr. Diaz?

            DR. DIAZ:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Mabrey?

            DR. MABREY:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Finnegan?

            DR. FINNEGAN:  I better agree.

            CHAIRPERSON YASZEMSKI:  Dr. Kim?

            DR. KIM:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Naidu?

            DR. NAIDU:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  Agree.

            CHAIRPERSON YASZEMSKI:  Dr. Blumenstein?

            DR. BLUMENSTEIN:  Agree.

            CHAIRPERSON YASZEMSKI:  Dr. Besser?

            DR. BESSER:  I agree.

            CHAIRPERSON YASZEMSKI:  This motion passes as the second condition of the motion for approval with conditions.

            We will now move on and ask if there are other conditions that people would like to raise and include in the motion for approval with conditions.  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  I need a clarification before I make my motion.  When Mr. Christianson said that it would be 15 weeks, there was a lot of mumbling in the background and I assume that means it's longer than that.

            CHAIRPERSON YASZEMSKI:  Mr. Christianson, would you care to comment?

            DR. KIRKPATRICK:  That's on the 50 million cycle tests.

            MR. CHRISTIANSON:  Yes.  Thank you for asking that question.  When I got back, I was told.  I meant to say 15 months.  It's not 15 weeks.

            CHAIRPERSON YASZEMSKI:  Thank you.  So 50 million cycles, 15 months.

            DR. KIRKPATRICK:  In the spirit of that, I would like to suggest a post-approval study that takes the wear data out to 50 million cycles as discussed in my presentation.  I would also like to ask if they could do a study looking at the other coupled motion, meaning flexion and extension coupled with lateral bending, and provide a rationale for the length of that testing that is reasonable.  I don't know.

            I don't think that needs to be taken to 50 million necessarily, because I think what is going to happen is we need to see what happens after somewhere intermediate range, you know, maybe 5 to 7 million and then change directions and see if that makes more wear debris come off or, if you want to, you can do the coupled motion all the time to make sure such as like a figure 8 motion doesn't make a different wear debris pattern.  Is that clear enough?

            CHAIRPERSON YASZEMSKI:  I'll --

            DR. KIRKPATRICK:  First, to summarize it, it's, basically, number one is extending data post-approval for 50 million cycles and studying the effect of coupled motion of flexion-extension with lateral bending, as opposed to axial rotation.

            CHAIRPERSON YASZEMSKI:  Okay.  I will ask for a second for this motion.

            DR. MABREY:  Second.

            CHAIRPERSON YASZEMSKI:  Dr. Mabrey has seconded.  Discussion?  Dr. Diaz?

            DR. DIAZ:  I don't have any comment.

            CHAIRPERSON YASZEMSKI:  No comments?  Dr. Mabrey?

            DR. MABREY:  No comments.

            CHAIRPERSON YASZEMSKI:  Dr. Finnegan?  Dr. Kim?

            DR. KIM:  It seems so excessive to have to test the device for 15 months, so I would question the need to do that, but I do agree with testing the other motions, but for a reasonable period of time.

            CHAIRPERSON YASZEMSKI:  Okay.  What would you consider a reasonable period of time?

            DR. KIM:  The 10 million cycles, which represents 80 years if, in fact, that is correct seems very reasonable to me.

            CHAIRPERSON YASZEMSKI:  Thank you.  Thank you, Dr. Kim.  Dr. Naidu?

            DR. NAIDU:  I concur with Dr. Kim.  It appears as if 50 million cycles will be excessive.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Blumenstein?

            DR. BLUMENSTEIN:  Let me see if I can understand this.  This is not done inside the body, but is done outside the body?  It seems excessive to me.

            CHAIRPERSON YASZEMSKI:  Dr. Besser?

            DR. BESSER:  As the testimony we have heard today, they referred to failed prostheses and the failed procedures, none of them in my memory were because of device problems with particulate matter.  There were other reasons why it failed.  I also would think that the 50 million cycles is probably excessive and the 10 million cycle data that has already been presented is adequate.

            I would, however, like to see the multiple modes.  I'm wondering whether we can separate this motion into two.

            CHAIRPERSON YASZEMSKI:  What we'll do is vote on this and if it passes, they will both occur and if it doesn't pass, we can entertain another motion for one or the other of them.  Ms. Maher?

            MS. MAHER:  Yes, I would just like to take this opportunity again.  It seems excessive to me.  I think 80 years testing is more than sufficient, and I would remind the Panel that we're supposed to be looking at reasonable assurances of safety and efficacy and we're also supposed to be looking at least burdensome, what is the least burdensome way to satisfy ourselves that this product is safe and effective.  And you have a product that has 17 years of experience in Europe.  We have seen some failures, but, as Dr. Besser mentioned, none of them seem to have been related to the devices.  I just don't understand why you would want to add this extra burden to the company.

            CHAIRPERSON YASZEMSKI:  Thank you, Ms. Maher.  Ms. Luckner?  Thank you.  Let's vote.  Dr. Diaz?  The vote is for a motion to require post-approval study both for wear data to 50 million cycles and to study coupled motion, flexion-extension with lateral bending.

            DR. DIAZ:  I disagree.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Diaz.  Dr. Mabrey?

            DR. MABREY:  On this motion I will disagree.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Mabrey.  Dr. Finnegan?

            DR. FINNEGAN:  I don't think I have a vote, but I agree.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Kim?

            DR. KIM:  I disagree.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Naidu?

            DR. NAIDU:  I disagree.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  I agree.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Blumenstein?

            DR. BLUMENSTEIN:  Disagree.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Besser?

            DR. BESSER:  Disagree.

            CHAIRPERSON YASZEMSKI:  Thank you.  This motion does not pass.  I will ask now if anybody would like to offer additional motions for conditions to be included.  Dr. Besser?

            DR. BESSER:  I would like to move that the post-marketing study be done looking at the multiple modes of wear in the prosthesis, I think, 10 million cycles with both flexion-extension and lateral bending at the same time.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Besser.  Do I have a second for this motion?

            DR. KIRKPATRICK:  Second.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Kirkpatrick.  Discussion, Dr. Diaz?

            DR. DIAZ:  Well, I think really that's the part that we haven't seen that is critical to the evaluation.  We have seen pretty much all other mechanical ways of evaluating this particular device.  I think that would compliment it well.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Diaz.  Dr. Mabrey?

            DR. MABREY:  No comment.

            CHAIRPERSON YASZEMSKI:  No comment?  Dr. Finnegan?

            DR. FINNEGAN:  No comment.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Kim?

            DR. KIM:  No comment.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Naidu?

            DR. NAIDU:  I think that's a reasonable addition.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  No further comment.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Blumenstein?

            DR. BLUMENSTEIN:  No comment.

            CHAIRPERSON YASZEMSKI:  Thank you.  Dr. Besser, you made the motion.  Any additional comments?

            DR. BESSER:  No.

            CHAIRPERSON YASZEMSKI:  Thank you.  Ms. Maher?

            MS. MAHER:  I'm okay.

            CHAIRPERSON YASZEMSKI:  Thank you.  Ms. Luckner?

            MS. LUCKNER:  I'm okay.

            CHAIRPERSON YASZEMSKI:  Okay.  We have a motion to have a post-approval study of flexion-extension in-vitro coupled with lateral bending to 10 million cycles.  We'll vote on that motion.  Dr. Diaz?

            DR. DIAZ:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Mabrey?

            DR. MABREY:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Finnegan?

            DR. FINNEGAN:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Kim?

            DR. KIM:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Naidu?

            DR. NAIDU:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  Agree.

            CHAIRPERSON YASZEMSKI:  Dr. Blumenstein?

            DR. BLUMENSTEIN:  Agree.

            CHAIRPERSON YASZEMSKI:  Dr. Besser?

            DR. BESSER:  Agree.

            CHAIRPERSON YASZEMSKI:  All right.  This motion passes.  We now have three conditions to the motion for approval with conditions.  Do I have any motions for additional conditions?  Dr. Finnegan?

            DR. FINNEGAN:  Yes, I would think that mandatory training of surgeons would be an additional condition.

            CHAIRPERSON YASZEMSKI:  Okay.  Do I have a second for this motion?

            DR. DIAZ:  Second.

            CHAIRPERSON YASZEMSKI:  Dr. Diaz.  Discussion, Dr. Diaz?

            DR. DIAZ:  I think probably of all the things we do in spine surgery, this is going to be the one that will require the most supervision, monitoring and critical analysis of the ability of the individual to do this procedure.  Unfortunately, many of these surgical interventions in the spine have been released relatively freely and this particular device, I think, has some very peculiar functional components that will require a very detailed evaluation not only of the implantation and its technique, but the surgeon as well.  So I think it is critical to have that as a requirement.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Diaz.  Dr. Mabrey?

            DR. MABREY:  No comments.

            CHAIRPERSON YASZEMSKI:  Dr. Finnegan?

            DR. FINNEGAN:  No comments.

            CHAIRPERSON YASZEMSKI:  Dr. Kim?

            DR. KIM:  No comment.

            CHAIRPERSON YASZEMSKI:  Dr. Naidu?

            DR. NAIDU:  No comment.

            CHAIRPERSON YASZEMSKI:  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  My only comment would be that it would be consistent with other products, which may have had the same kind of restriction.

            CHAIRPERSON YASZEMSKI:  Thank you.  And when we go around, I'm going to ask Dr. Witten if she'll comment on the history of this type of requirement at FDA.  Dr. Blumenstein?

            DR. BLUMENSTEIN:  No comment.

            CHAIRPERSON YASZEMSKI:  Dr. Besser?

            DR. BESSER:  No comment.

            CHAIRPERSON YASZEMSKI:  Ms. Maher?

            MS. MAHER:  No comment.

            CHAIRPERSON YASZEMSKI:  Ms. Luckner?

            MS. LUCKNER:  I'm very pleased to see this added as a condition.  It has been a concern of mine as I have heard this whole presentation that the results are directly related to the time and the experience, and I commend the company for the thoughtfulness they have taken in planning this out from the get-go before we even brought it up.  They have made provision for it, so I think that's remarkable.

            CHAIRPERSON YASZEMSKI:  Thanks so much.  Dr. Witten, may I ask you, what is the history of this type of requirement at FDA?

            DR. WITTEN:  Well, we can require that the sponsor have training available, a training program available, and I think we can actually require that they distribute to people who have had training, okay, and I think we have done both.

            CHAIRPERSON YASZEMSKI:  Okay.

            DR. WITTEN:  Is the answer.

            CHAIRPERSON YASZEMSKI:  Thank you.

            DR. WITTEN:  Or neither and neither.

            CHAIRPERSON YASZEMSKI:  Thank you.  We'll vote on this.  This is to require that training be available for surgeons before they do this procedure and we'll vote for this then.  Further commentary, Dr. Kirkpatrick?

            DR. KIRKPATRICK:  My understanding was the motion was to require training prior to distribution of the device to that individual.  Is that the motion?

            CHAIRPERSON YASZEMSKI:  Okay.  Is that

the --

            DR. KIRKPATRICK:  Then would it imply, based upon what we just heard from Dr. Witten, that there would be certification of the individual or a graduate certificate from the training program?  Is that what we're talking about?

            CHAIRPERSON YASZEMSKI:  May I comment?  If I may comment, I think that training centers may give a certificate or a statement that a person has completed the training, but they may not certify the person as having any level of expertise in the training.  They can just say what their course outline was and that the person went through that outline.

            DR. KIRKPATRICK:  As I understand your motion, it is to basically have somebody trained by the company to do it, trained by the company, not the company itself, but a training center approved by the company to do it.

            DR. DIAZ:  I don't know that the company really is the group that needs to issue that.

            DR. KIRKPATRICK:  Let me just say by approved training agency.

            DR. DIAZ:  Yes, I think that would be a better statement.  What do you think?

            DR. WITTEN:  Well, I just want to clarify something, and then I see that Ms. Maher may have some other clarification to my clarification, but our only requirement would be on what the sponsor does.  We don't have any requirements on, you know, what a hospital would allow a surgeon to do based on, you know, certain training that somebody else provided.  So it's through the sponsor either providing something or ensuring that it's available.

            CHAIRPERSON YASZEMSKI:  Thank you.

            DR. WITTEN:  And it's not, you know, having -- not engaging in having some other training occur.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Witten.  Ms. Maher?

            MS. MAHER:  Yes, I think I would like Mr. Christianson to comment on this and what they are planning, but I also would like to comment myself that I think we have to be very careful not to tell the industry that they have to certify that a doctor meets certain skills.

            CHAIRPERSON YASZEMSKI:  No, no, that's not what's being said at all.

            MS. MAHER:  Right.  What I would really like to see is that we say we want training to be done and we allow the FDA and the sponsor to work out what the most appropriate form of training is and for how many years they are going to have to train, because in 10 or 15 years this could be -- hopefully, will be state of the art and nobody is going to want to have to go through an additional training course to do it.  But, Bill, do you want to comment on the plans that you all have?

            CHAIRPERSON YASZEMSKI:  Yes, I would ask Mr. Christianson.  Would you care to make a comment?

            MR. CHRISTIANSON:  Bill Christianson.  Yes, thank you for calling me up.  One of the conditions that you mentioned, Dr. Kirkpatrick, is that an individual has to be trained before they can be sold to you.  You need to understand that as an industry, we sell to a hospital and so we're very happy to have a very robust training program.  We're absolutely committed to having the highest quality training program and we want every single surgeon who is going to use this device to go through the program.             But honestly, that is really managed at the local level by hospital credentialing committees and we would be very happy to have those committees adopt a statement saying that you must go through the training program or you must have an experienced surgeon at your side while you're doing your cases, but we can't control an individual who buys, because we sell to an individual hospital.  So we're very happy to have a condition that we have a robust training program and it has already been said, we can't certify physicians and I don't think anybody in the Panel wants us to.

            DR. KIRKPATRICK:  You have pointed out exactly my concern about communication here.  We need to make sure that the condition that's being sought can be done.

            MR. CHRISTIANSON:  We can have a robust training program.

            DR. KIRKPATRICK:  In other words, if UAB Hospital calls him and says we want the Charite Disc even though none of our surgeons have been trained on it, he doesn't have any authority or power to stop that disc from being sold to the hospital is what he just said.

            MR. CHRISTIANSON:  Well, actually, I can stop that, but once you have been trained there, I can't stop it being sold.

            DR. KIRKPATRICK:  Okay.

            MR. CHRISTIANSON:  And then your colleague.

            DR. KIRKPATRICK:  That's what I'm trying to clarify, because we got that you will ensure training.  Okay.  You can ensure training, but only if people go there.  Is there a way that FDA can require the distribution of the product only to people that have demonstrated to the distributors, I guess, or to somebody that they have had the training?

            DR. WITTEN:  Well, I don't really have anything to say beyond what I already said, which is we have done it both ways, you know, both having, you know, anybody who receives it to use it be trained and also requiring that training be available.  And I really don't know what the logistics have been in the other circumstances.

            CHAIRPERSON YASZEMSKI:  Okay.  Thank you, Dr. Witten.  So we have had a discussion on it and we can see that, I think, Ms. Maher summed it up, that if we vote for this, the details will be worked out between the FDA and the company to the satisfaction of both, and we're just voting to make that recommendation to FDA that they enter into that discussion and see that it's accomplished to their satisfaction.  So with that, we're going to vote.  Dr. Diaz?

            DR. DIAZ:  I agree.

            DR. KIRKPATRICK:  Can we hear the motion again, because what you said is different than what I understood he moved.

            CHAIRPERSON YASZEMSKI:  Okay.  The motion is that training will be made available and that the FDA will insist that the company make training available.  However, at the point of requiring (A) either certification of surgeons as being adept at the technique, we have to stop, because neither the FDA nor the company can influence medical practice, and that will have to be left to the discretion of the State Licensing Boards and the Hospital Credentials Committees.  That is the nature of the motion.

            UNIDENTIFIED SPEAKER:  That's your motion.

            DR. DIAZ:  I agree.

            CHAIRPERSON YASZEMSKI:  Agree.  Dr. Mabrey?

            DR. MABREY:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Finnegan?

            DR. FINNEGAN:  Agree.

            CHAIRPERSON YASZEMSKI:  Dr. Kim?

            DR. KIM:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Naidu?

            DR. NAIDU:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Blumenstein?

            DR. BLUMENSTEIN:  Agree.

            CHAIRPERSON YASZEMSKI:  Dr. Besser?

            DR. BESSER:  I agree.

            CHAIRPERSON YASZEMSKI:  Okay.  This motion passes.  We now have four conditions to the motion for approval with conditions.  Do we have other motions for additional conditions?  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  Here comes Simon again.  Following up with a pre-approval study on existing data of a radiographic evaluation of the adjacent segment degeneration at pre-op and 24 months.  There have been literature standards set for looking at adjacent segment degeneration as far as disc height, subluxation, facet changes and that sort of thing.

            As I understand it, those are all on plain radiographs.  You already have those at 24 months of the index segment.  I assume that means you have them of additional segments.  And so, as such, that would be a pre-approval condition and I will stop with one, because when I go to two, it tends not to work.

            CHAIRPERSON YASZEMSKI:  Okay.  That's fine.  Do we have a second for this motion?  I see no second, so this motion does not carry.  Do we have additional conditions?

            MS. MAHER:  Can I make a comment?

            CHAIRPERSON YASZEMSKI:  Yes.

            MS. MAHER:  Can I suggest that somebody might move that the FDA and the sponsor go through all of these issues and discuss them and come up with ways to resolve them, as needed to be resolved, with using the FDA's scientific expertise?

            CHAIRPERSON YASZEMSKI:  I think we can suggest that.  We also do though have to have the ability for everybody to make motions until they are exhausted.  So noted.  So noted.

            UNIDENTIFIED SPEAKER:  The motions or the people?

            DR. KIRKPATRICK:  Since you can't make a motion or vote, let me propose that as a motion, that the FDA and the sponsor consider the remaining issues on what was provided to you by me with the exception of the ones that we have already voted on, and the exceptions of number 5, which I deleted, number 7, which seems to be answered already and number 10, which has been answered already.  So that would actually cut down the number of things you have to look at.

            CHAIRPERSON YASZEMSKI:  So how about let's, if this is going to be your motion, say the ones that are included?  Number one?

            DR. KIRKPATRICK:  Okay.  Number 1 is included.  Number 2 is included.  Number 3 we have already voted down part of it and voted in the other part.

            CHAIRPERSON YASZEMSKI:  Okay.

            DR. KIRKPATRICK:  So 3 is excluded from this motion.  Number 4 is included.  Number 5 is excluded.  Number 6 is included.  Number 7 is excluded.  Number 8 is included.  Number 9 is included.  Number 10 is excluded.  Number 11 is included.  Number 12 has been voted down, so it is excluded, and number 13 has already been addressed.

            CHAIRPERSON YASZEMSKI:  Okay.

            DR. KIRKPATRICK:  So it's excluded.

            CHAIRPERSON YASZEMSKI:  So if I can repeat the motion, Dr. Kirkpatrick's motion for a condition is that on the conditions for approval that he circulated after his lead review, that the sponsor and FDA together consider numbers 1, 2, 4, 6, 8, 9 and 11 and arrive at resolution of those to the satisfaction of both.  Is that your motion?

            DR. KIRKPATRICK:  That would be my motion.

            CHAIRPERSON YASZEMSKI:  Do I have a second?

            DR. FINNEGAN:  You have a second or a question?  Can you not add 12 into this?  That might solve your dilemma.  I think that's what she was trying to do, was put 12 into this.

            DR. KIRKPATRICK:  12 didn't get a second.

            DR. FINNEGAN:  Right, but if you put --

            DR. KIRKPATRICK:  So that's defeated in my mind, so it doesn't.  I mean, they can consider everything we say.

            DR. FINNEGAN:  Okay.  All right.

            CHAIRPERSON YASZEMSKI:  Okay.  Do we have a second?

            DR. FINNEGAN:  Yes.

            CHAIRPERSON YASZEMSKI:  Yes, a second.  Any further discussion?  We'll vote.  Dr. Diaz?

            DR. DIAZ:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Mabrey?

            DR. MABREY:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Finnegan?

            DR. FINNEGAN:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Kim?

            DR. KIM:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Naidu?

            DR. NAIDU:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  I agree and I'm very grateful for our colleague's suggestion.

            CHAIRPERSON YASZEMSKI:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Besser?

            DR. BESSER:  Agree.

            CHAIRPERSON YASZEMSKI:  This motion passes.

            MS. MAHER:  Can I make one more comment on the motion even though it has passed, that the motion was not that they have to take all of these.

            CHAIRPERSON YASZEMSKI:  No.

            MS. MAHER:  But they are using their scientific rationale to determine.

            DR. KIRKPATRICK:  Exactly.

            CHAIRPERSON YASZEMSKI:  That they together mutually agree that these have been addressed, not that they take them all.  We now have a motion for approval with conditions that has five conditions.  Do we have any other conditions?  Dr. Finnegan?

            DR. FINNEGAN:  Well, actually, Dr. Kim, go ahead.

            CHAIRPERSON YASZEMSKI:  Dr. Kim?

            DR. KIM:  Can I revisit the adjacent segment problem, because in thinking about it some more, I see no reason why we can't look at that with the continued assessment of the IDE and the continued access patients.  It's all part of the radiographic study.  They looked at flexion-extension, but they could easily look at the adjacent segments.

            CHAIRPERSON YASZEMSKI:  And I think that I would submit that that's included.  The FDA has heard that message and they can discuss whatever they want to discuss.

            DR. KIM:  Okay.

            CHAIRPERSON YASZEMSKI:  And that it will be accomplished without further additions to these conditions.  Thank you.  Additional conditions?

            DR. FINNEGAN:  You know, I can't leave without giving Dr. Witten at least a little bit of a heart attack.  Because this is the first of its kind and because we are happier with efficacy than we are with safety, and that we think that safety has a longer term playtime, if you like, is it possible for us to ask that the company come up with a direct phone line for people to report adverse events for this particular device?  I suspect this has never been done before, but for this --

            CHAIRPERSON YASZEMSKI:  If I could, may I ask for commentary?

            DR. FINNEGAN:  Yes.

            CHAIRPERSON YASZEMSKI:  Both if Dr. Witten has a comment and I want to ask Dr. Christianson if he would comment or a member of his staff.

            DR. WITTEN:  Yes, actually I would suggest asking Dr. Christianson.

            CHAIRPERSON YASZEMSKI:  Mr. Christianson?

            DR. WITTEN:  To describe whatever their current mechanism would be first.

            DR. FINNEGAN:  Okay.

            MR. CHRISTIANSON:  First of all, thank you for promoting me to doctor.  We already include in the package insert for our product an 800 number, so we have already got a mechanism for primarily physicians and hospital staff to call, and it sounds to me like one of our conditions of approval is some kind of tear-away card to give to the patients.  We will be happy to put our 800 number on that, too, so that's very readily accomplished.

            DR. MABREY:  That could be on the registration card or whatever you pass out.

            CHAIRPERSON YASZEMSKI:  Dr. Blumenstein?

            DR. BLUMENSTEIN:  Did you just say to put it on the card that identified the device given to the patient?

            DR. MABREY:  No, I would just include that on the identification card that carries the lot number.

            CHAIRPERSON YASZEMSKI:  Yes.

            DR. MABREY:  And if the patient ever has a question about it, then they call your 800 number and there you go.

            DR. BLUMENSTEIN:  Okay.  I was going to say that maybe on the back of that card you could have a signed -- a place for the surgeon to sign that they had undergone the training.

            CHAIRPERSON YASZEMSKI:  I'm just suggesting that we let FDA and the sponsor work that out.

            DR. BLUMENSTEIN:  No, the FDA doesn't

have to --

            UNIDENTIFIED SPEAKER:  That wasn't a motion, was it?

            CHAIRPERSON YASZEMSKI:  No, that was not a motion.  Do we have additional motions for conditions?  Any?  If not, any additional discussion?  And if we don't, we're going to vote.  Okay.  We have a motion for approval with conditions.  There are five conditions.  A vote yes will be a vote for approval with all these five conditions needing to be accomplished.  A vote no will be a vote for non-approval under these terms and if that happens to pass, we would need to get an alternate motion.

            But here is the motion, approval with conditions.  The first condition, that all currently enrolled patients in the continuous access group reach two years.  The second, that follow-up occur and this is going to be in the form of a card that the patient would have with the identification number of the device, lot number and doctor, etcetera, as we have discussed.  The third would be to study the motion of flexion and extension coupled to lateral bending for 10 million cycles and could be done after approval.  The fourth would be training for surgeons, and the fifth would be the conditions circled on Dr. Kirkpatrick's presentation sheet, numbers 1, 2, 4, 6, 8, 9 and 11.

            I will ask for votes.  Dr. Diaz?

            DR. DIAZ:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Mabrey?

            DR. MABREY:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Finnegan?

            DR. FINNEGAN:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Kim?

            DR. KIM:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Naidu?

            DR. NAIDU:  I agree.

            CHAIRPERSON YASZEMSKI:  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  Yes.

            CHAIRPERSON YASZEMSKI:  Dr. Blumenstein?

            DR. BLUMENSTEIN:  Agree.

            CHAIRPERSON YASZEMSKI:  Dr. Besser?

            DR. BESSER:  Agree.

            CHAIRPERSON YASZEMSKI:  Thank you.  This motion for approval with conditions passes.

            UNIDENTIFIED SPEAKER:  Are you going to go around and ask everyone the reason for their vote?

            CHAIRPERSON YASZEMSKI:  No, we're not quite done yet, folks.  We're not quite done yet.  I would like to go around, as a last thing, and go around the table and ask everybody to make any comments about the reasons for their vote.  It was unanimous and we probably covered all these, but the FDA uses the information that we give them and they are very interested in the reasons why people voted.  So you can be as brief as you want, but just mention anything that may not have been mentioned yet.  Dr. Diaz?

            DR. DIAZ:  I voted the way I did, because I believe the company provided us with sufficient data to satisfy me that the safety and the effectiveness required by the FDA were, indeed, fulfilled and the recommendations for subsequent follow-up that were decided in the motion include any concerns that I may have had.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Diaz.  Dr. Mabrey?

            DR. MABREY:  Yes.  First of all, I felt that the company went far and above what it had to do to prove that this was a safe and effective device, number one.  Number two, I would like to comment that I have never seen as detailed a rebuttal with 469 slides as I had as a high school debater.  So I think this demonstrates that the company is thoroughly prepared.  They have thoroughly researched it.  They are very sincere about bringing this device safety to market, and I congratulate them on an excellent presentation.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Mabrey.  Dr. Finnegan?

            DR. FINNEGAN:  Yes, I concur.  This was a brave new step and I agree.  I think that I have less concerns about efficacy than I do about safety, and I hope that they will be diligent in guarding the safety, so that we don't have problems.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Finnegan.  Dr. Kim?

            DR. KIM:  This device represents a significant innovation in our strategy to treat a very challenging clinical problem, namely discogenic lower back pain.  The sponsor has done a thorough job in obtaining both preclinical and randomized control clinical trials.  I think we all appreciate that a key question of implant longevity cannot be answered.  Luckily, we do have some data from the European experience that helps us feel more comfortable with the fact that this is an efficacious and safe procedure, comparable to what exists today, namely the Anterior Interbody Fusion using the BAK cage.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Kim.

            DR. KIM:  Given --

            CHAIRPERSON YASZEMSKI:  I'm sorry, Dr. Kim.  Go ahead.

            DR. KIM:  Given that, that's the reason why I voted the way I did.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Kim.  Dr. Naidu?

            DR. NAIDU:  I voted to approve mainly because I think the sponsor has done an excellent job.  They have presented a very vigorous PMA with excellent basic science and clinical follow-up.  They have gone beyond what is required, I think, in showing the efficacy of the device, and that's why I approved it.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Naidu.  Dr. Kirkpatrick?

            DR. KIRKPATRICK:  I agree with the sponsor that we don't know all the issues related to the cause of back pain, and this is an empirical measure to try and solve that problem.  I agree that it is reasonably safe and efficacious within the limits of what was studied, and I believe that the motion, as approved, was a reasonable compromise of the need for long-term follow-up for both the safety and effectiveness measure, as well as the need to put innovation on the market.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Dr. Kirkpatrick, and thank you for your primary review of this application.  Dr. Blumenstein?

            DR. BLUMENSTEIN:  Yes.  I think the company did a better than average clinical trial and the canonical analysis was adequate to show non-inferiority.  The sensitivity analyses gives me confidence that the primary analyses are valid, and the conditions for long-term follow-up satisfy me as to the concerns I have about safety.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Blumenstein.  Dr. Besser?

            DR. BESSER:  With the conditions for follow-up, I believe the company has presented its case and that this device will be a benefit for those receiving it.

            CHAIRPERSON YASZEMSKI:  Thank you, Dr. Besser.  Ms. Maher, I would like to ask for your comments.

            MS. MAHER:  I think that the company did do an excellent job in the clinical study.  Actually, it's better than better than average, and I think that as a Panel we have done a good job at looking at all the issues and trying to take the best case of least burdensome approach to getting --

            CHAIRPERSON YASZEMSKI:  Thank you, Ms. Maher.  Ms. Luckner?

            MS. LUCKNER:  I think the company has discharged their duty to bring to the FDA Panel a product that meets the FDA definition of safe and effective.  I think I am totally impressed with the sponsor's response to all the Panel questions, that they were totally prepared for all the issues that were presented.  Very well done.  And finally, I believe the Panel and the FDA discharged their duty to protect the public and balance promoting innovation.

            CHAIRPERSON YASZEMSKI:  Thanks very much, Ms. Luckner.  Let me do two final things.  I would like to thank all the Panel Members for their preparation and participation today, including and especially our consumer and industry reps.  I would like to ask Dr. Witten if she has any comments from the FDA's perspective?

            DR. WITTEN:  No.  I would like to thank the Members of the Panel for participating today, to the FDA review team and the sponsor also for their presentations.

            CHAIRPERSON YASZEMSKI:  Thanks, Dr. Witten.  I would like to also end with saying the sponsor has heard from the Panel congratulations about the thoroughness of their presentation, and I would like to add my thanks to them for a very thorough presentation today.  And with that, we adjourn this meeting.

            (Applause)

            (Whereupon, the meeting was concluded at 5:22 p.m.)