GASTROENTEROLOGY AND UROLOGY DEVICES PANEL

 

                      OF THE

 

        MEDICAL DEVICES ADVISORY COMMITTEE

 

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                      FRIDAY,

 

                 JANUARY 17, 2003

 

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            The above‑entitled matter met in the Salon of the Hilton Washington, D.C., 620 Perry Parkway, Gaithersburg, Maryland, at 8:30 a.m., KAREN L. WOODS, Chair, presiding.

 

PRESENT:

 

KAREN L. WOODS, M.D.     CHAIR

SAMI ACHEM, M.D.         VOTING MEMBER

ABDELMONEM AFIFI, Ph.D.  VOTING MEMBER

ANDREW BALO              INDUSTRY REPRESENTATIVE

NANCY C. BROGDON         FDA

JEFFREY W. COOPER, DVM   EXECUTIVE SECRETARY

BRIAN FENNERTY, M.D.     VOTING MEMBER

MARK FERGUSON, M.D.      TEMPORARY VOTING MEMBER

MARY GELLENS, M.D.       VOTING MEMBER

MICHAEL MANYAK, M.D.     VOTING MEMBER

CHRISTINE MOORE          CONSUMER REPRESENTATIVE

NICHOLAS SHAHEEN, M.D.   TEMPORARY VOTING MEMBER


SPONSOR PRESENTERS:

 

ALAN STEIN, Ph.D.

President and Chairman, Enteric Medical Technologies

 

LUCAS BRENNECKE, DVM, DACVP

Director, Medical Device Pathology, Pathology Associates, a Division of Charles River Laboratories

 

GLEN LEHMAN, M.D.

Professor of Medicine and Radiology, Indiana University

 

DAVID JOHNSON, M.D.

Professor of Medicine, Eastern Virginia Medical School

 

 

FDA PRESENTERS:

 

KATHLEEN OLVEY

FDA/ODE/DRARD/GRDB Scientific Reviewer

 

KATHARINE MERRITT, Ph.D.

FDA/OST/DLS/HSB

 

ARON YUSTEIN, M.D.

FDA/ODE/DRARD/GRDB Medical Officer

 

MELVIN SEIDMAN, FDA/OSB

 

S. LORI BROWN, Ph.D., FDA/OSB       


                     I‑N‑D‑E‑X

 

AGENDA ITEM                                   PAGE

 

CALL TO ORDER                                    5

 

OPEN PUBLIC HEARING                             18

 

OPEN COMMITTEE DISCUSSION                       19

 

1.  Sponsor Presentation:                       20

 

    1. Company, Device Description &            20

       Pre‑Clinical Studies ‑ Alan Stein, Ph.D.,

       President and Chairman, Enteric Medical

       Technologies

    2. Histopathology Review: Pre‑Clinical      42

       Studies ‑ Lucas Brennecke, DVM, DACVP,

       Director, Medical Device Pathology,

       Pathology Associates, a Division of

       Charles River Laboratories, Inc.

    3. Study Design and Results: Safety ‑ Glen  60

       Lehman, M.D., Professor of Medicine and

       Radiology, Indiana University

    4. Study Results: Effectiveness ‑ David    101

       Johnson, M.D.,Professor of Medicine,

       Eastern Virginia Medical School

    5. Study Conclusions ‑ Alan Stein, Ph.D.,  147

       President and Chairman, Enteric Medical

       Technologies

 

2.  FDA Presentation:                          153

 

    1. Overview/Pre‑Clinical Studies ‑ Kathleen 153

       Olvey, FDA/ODE/DRARD/GRDB Scientific

       Reviewer

    2. Histopathology Considerations ‑ Katharine 159

       Merritt, Ph.D., FDA/OST/DLS/HSB

    3. Clinical Considerations ‑ Aron Yustein, 164

       M.D., FDA/ODE/DRARD/GRDB Medical Officer

    4. Statistical Considerations ‑ Melvin     206

       Seidman, FDA/OSB/

    5. Post-Market Review ‑ S. Lori Brown,     216

       Ph.D. FDA/OSB/


               I‑N‑D‑E‑X (Continued)

 

AGENDA ITEM (Continued)                       PAGE

 

3.  Panel Discussion:                          222

 

    The committee will discuss FDA charges,

    make recommendations and vote on a

    pre‑market approval application P020006

    from Enteric Medical Technologies and

    Boston Scientific for a device for the

    treatment of gastroesophageal reflux

    disease.

 

    1.  Dr. Brian Fennerty ‑ Primary Review    222

        and Lead Discussant.

    2.  Reading of Questions and Discussion.   227

 

OPEN PUBLIC HEARING                            324

 

4.  Final Comments                             325

 

    1.  FDA Comments                           325

    2.  Sponsor Comments                       325

 

5.  Panel Deliberations and Vote               339


               P‑R‑O‑C‑E‑E‑D‑I‑N‑G‑S

                                       (8:32 a.m.)

                   CALL TO ORDER

            CHAIRPERSON WOODS:  Good morning, everyone.  I would like to call the meeting to order.  My name is Karen Woods, and I'll be chairing the panel today.  I would like to note for the record that the voting members present here today constitute a quorum, as required by 21 CFR Part 14.

            And at this point, I would like to turn the meeting over to Dr. Jeff Cooper, the Executive Secretary of FDA.

            DR. COOPER:  Good morning.  My name is Jeff Cooper.  I am the Executive Secretary and Veterinary Medical Officer at the Food and Drug Administration.

            I would like to have each member introduce him or her self; designate your specialty; position title; and institution; and status on the panel as far as voting member or consultant voting member, industry rep, or consumer rep.  Dr. Woods?

            CHAIRPERSON WOODS:  I'm Karen Woods.  I'm a gastroenterologist, presently in private practice in Houston, Texas.  I'm a clinical associate professor of medicine at Baylor College of Medicine.

            Brian?

            DR. FENNERTY:  I'm Brian Fennerty, a professor of medicine, section chief of gastroenterology at Oregon Health Sciences University, a gastroenterologist, and a voting member of the panel.

            DR. GELLENS:  I'm Mary Gellens, associate professor of medicine at St. Louis University.  I'm a nephrologist, and I'm a voting panel member.

            MS. MOORE:  My name is Christine Moore.  I am a former dean of students at the Community College of Baltimore.  I'm the consumer representative.

            MR. BALO:  Hi.  I'm Andy Balo.  I'm vice president of regulatory and clinical and quality affairs for a company called DexCom, Incorporated in San Diego.  And I'm the industry rep.

            DR. BROGDON:  Good morning.  I'm Nancy Brogdon.  I'm not a member of the panel.  I'm the division director at FDA, Division of Reproductive, Abdominal, and Radiological Devices.

            DR. SHAHEEN:  I'm Nick Shaheen from University of North Carolina.  I'm a gastroenterologist.  I'm a consultant voting member of the panel.  I'm an assistant professor of medicine and epidemiology.

            DR. FERGUSON:  My name is Mark Ferguson.  I'm a general thoracic surgeon.  I'm a professor of surgery at the University of Chicago.  And I'm a consultant voting member.

            DR. ACHEM:  My name is Sami Achem.  I'm a gastroenterologist.  I'm an associate professor of medicine with the Mayo Medical School.  I'm a practicing gastroenterologist at Mayo Clinic in Jacksonville, Florida.  I am a voting member.

            DR. AFIFI:  My name is Abdelmonem Afifi.  I'm professor of biostatistics and biomathematics at the Schools of Public Health and Medicine at UCLA.  And I'm a voting member of the panel.

            DR. MANYAK:  Hi.  I'm Mike Manyak, professor and chairman, Department of Urology and professor of microbiology and tropical medicine at the George Washington University Medical Center here in Washington, D.C.  I'm a voting member of the panel.

            DR. COOPER:  Thank you all.  I appreciate you coming.

            Now our FDA branch chief, Dr. Carolyn Neuland, will introduce the FDA branch members and update the panel.

            DR. NEULAND:  Good morning.  Welcome.  As Dr. Cooper has stated, I am the branch chief for the Gastroenterology and Renal Devices Branch at the FDA.  And I am one of the two FDA branches that brings devices to this advisory panel.

            I would like to take this opportunity to welcome all of you to the panel meeting today and to thank you for the time and effort that you have put in into reviewing the information that was sent to you in traveling this distance in the snow to the panel meeting today and also for providing to us your expert advice on very complex issues that we bring before you.

            It is with your help and your recommendations that FDA is better able to make the difficult decisions that we must on these new technologies and to also look at the new indications for the ever‑expanding indications of medical devices that are brought to us today and throughout the future.

            Since many of you are new to the GU advisory panel, I would like to take this opportunity to introduce to you the members of the Gastroenterology and Renal Devices Branch, many of which will be interacting with you over the next couple of years.  And I thought it would be nice for you to see who they are.

            I would ask the members of the Gastroenterology Branch who are present ‑‑ I know some of them did not make it through the snow ‑‑ at this early hour to stand when I call your name.

            The first one is Dr. Aron Yustein, Dr. Aron Yustein.  Dr. Yustein is the gastroenterologist in the branch, and he is the medical officer who was the lead clinical reviewer on the application that you will be looking at in a few minutes.

            The next one is Dr. Jeffrey Cooper.  He is the Executive Secretary that has been sitting at the front table.  He is a veterinarian in our branch.

            Linda Dart.  Linda is a biochemist in the branch.  She is not present.

            Gema Gonzalez.  Gema is a biomedical engineer.  She's in the back.

            Barbara McCool.  Barbara McCool is a nurse consultant that reviews a lot of our dialysis products.

            Joshua Nipper.  Joshua is the newest member of our branch, has been here with us for three months.  He is a biomedical engineer.

            Kathleen Olvey.  Kathleen will be speaking to you shortly.  She is a biologist.  And she was the team leader for the PMA that you will be discussing today.

            Richard Williams.  Richard is a mechanical engineer in the branch.

            Linda Carr.  Linda is a consumer safety technician.  And I'm sure if you have called into our branch, Linda is the person you have spoken to on many occasions.  She will help you get any answers you need to any question.

            And Kellie Straughn.  I don't think Kellie is here, but she is a new student intern that has just joined us recently.

            I would now like to take a few minutes to update you on the two most recent gastroenterology devices that came before the advisory panel over the last basically year and a half.

            The first device is called the Lap‑Band Adjustable Gastric Banding System.  This was an implantable fluid‑filled silicone elastomer band that has been planted around the stomach to create a stoma.  This device then creates a pouch which reduces food consumption, which then induces early satiety.  This device was indicated for weight reduction in the severely obese patients.  It had a few other restrictions, which I won't go into now, but that was the basic indication.

            The device came before the panel on June 19, 2000.  At the time of that deliberation, the panel recommended for disapproval of the PMA.  The reason they recommended for disapproval is because the company had only presented two‑year follow‑up data.  And they thought that two years was not adequate for an approval at that time.  So the recommendation was that, therefore, they would like to see an additional year of follow‑up data before the PMA was approved.

            The company went back and did an additional year's worth of data that then presented the PMA to the FDA.  And on June 5, 2001, the FDA approved the PMA.  It was felt at that time that the pre‑clinical and clinical data provided reasonable assurance that the safety and effectiveness of the Lap‑Band system for weight reduction in the severely obese patients when the system was used according to its labeling.

            One of the other requirements that was also made at that time was that the company do an additional two years of data, for a total of five years of follow‑up in the post‑approval forum.  That study is currently ongoing, and I would suspect it should be done around the end of 2003.

            The second device that I would like to update you on is the Acticon Neosphincter by American Medical Systems.  This device was a fluid‑filled silicone elastomer cuff, which is surgically implanted around the anal canal.  It is used to treat severe fecal incontinence in males and females age 18 years of age and over and who have failed or are not candidate for less invasive forms of restorative therapy.

            This device came before the advisory panel on August 17, 2001.  At that time, the panel recommended approval with conditions.  The conditions involved need for additional revised position patient labeling.  They wanted to alter the indications for use so that it restricted the use of the device to 18 years of age and older.  They wanted a development of a formal physician training program, and they also wanted to see a post‑market study out to 12 months.

            On December 18, 2001, that PMA was approved.  The conditions were met.  A post‑approval study was implemented, and that study is currently ongoing, requiring additional 12‑month post‑approval data, which has seen both safety and effectiveness information looking at the effectiveness of FISS scores and fecal quality of life measures and looking at adverse events with particular emphasis looking at the revision surgeries that have been necessary and any explantations of the device and following up on those patients.

            I would like to know if anyone has any questions on these two PMAs at this time.  If not, thank you very much.  And I turn it back over to you, Jeff.

            DR. COOPER:  Thank you, Dr. Neuland.

            Before we begin, I would like to read as statement concerning appointments to temporary voting status, "Pursuant to the authority granted under the Medical Devices Advisory Committee charter dated October 27, 1990 and as amended August 18, 1999, I appoint Nicholas Shaheen, Mark Ferguson as temporary voting members of the Gastroenterology and Urology Advisory Panel for this meeting on January 17, 2003.

            "For the record, they are special government employees and consultants to this panel or other panels 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," signed David W. Figal, Jr., M.D., MPH, Director, Center for Devices and Radiological Health.

            The following announcement addresses conflict of interest issues with this meeting.  And it is made a part of the record to preclude even the appearance of an impropriety.  To determine if any conflict exists, the agency reviewed the submitted agenda for this meeting and all financial interests reported by the committee participants.

            The conflict of interest statutes prohibit special government employees from participating in matters that could affect their or their employers' financial interests.  However, the agency has determined 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.

            We would like to note for the record that the agency took into consideration matters regarding Drs. Afifi, Achem, Fennerty, Manyak, Shaheen, and Dr. Woods.

            Drs. Afifi, Fennerty, and Manyak reported current or past interest in firms at issue but matters not related to today's agenda.  The agency has determined, therefore, that they may participate fully in the panel's deliberations.

            Drs. Achem, Fennerty, Shaheen, and Woods reported past and or current involvements in firms at issue for matters related to today's discussions.  However, because of the nature of these involvements, the agency has determined that these panelists may also participate fully in all deliberations.

            In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participant should excuse him or herself from such involvement.  And the exclusion will be noted for the record.

            With respect to 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.

            On another note, we have the test of the 2003 tentative panel meeting dates.  They are Friday, April 4, 2003; Friday, July 25; and Friday, October 17, 2003.  These are very tentative.

            Also on your desk, there are two handouts.  One of them, for the panelists, has the blue cover.  That has most of all of the handouts.  It has a table of contents.  The only thing missing is the sponsor's presentation, which is this package, which is separate.

            Dr. Woods will now continue the meeting.

                OPEN PUBLIC HEARING

            CHAIRPERSON WOODS:  Okay.  We're going to now proceed with the open public hearing part of this meeting.  If there is anyone here who wishes to address the panel, I wish you would raise your hand now.  And you may have an opportunity to speak.

            I will ask of you at this time that if you do come forward to address the panel, that you speak clearly into the microphone, as the transcriptionist is dependent upon this as a means of getting an accurate transcription of the proceedings of this meeting.

            Before making your presentation to the panel, you will need to state your name and your affiliation and the nature of any financial interest that you may have in the topic that you are going to present.  Each presenter is allotted ten minutes.  And if you would please provide a copy of your remarks and any visual aids to the transcriptionist?

            Does anyone wish to address the panel at this time?

            (No response.)

             OPEN COMMITTEE DISCUSSION

            CHAIRPERSON WOODS:  Okay.  If there is no public statement to be made, then we will proceed to the open committee discussion.  We will start with the sponsor's presentation of PMA P00020006 for the Enteric Medical for the Enteryx device for the treatment of GERD.

            Again I ask that all persons addressing the panel please come forward to the microphone and speak clearly as the transcriptionist is dependent upon this as a means of providing an accurate transcription of the proceedings of the meeting.  Before making your presentation to the panel, please state your name and affiliation and the nature of your financial interest in that company.

            I remind you that the definition of financial interest in the sponsor company may include compensation for time and services of clinical investigators, their assistants, and staff in conducting the study and in appearing at the panel meeting on behalf of the applicant, a direct stake in the product under review; for instance, inventor of the product, patent holder, owner of shares of stock, et cetera, or owner or part owner of a company.  Of course, no statement is necessary from employees of that company.

            I would like to also remind the panel that they may ask for clarification of any points included in the sponsor's presentation.  I would like to suggest that we allow each speaker to complete their talk and then we save questions for the end of each individual speaker unless there is something overwhelmingly necessary to comment on on a particular table or graph.

            So the first speaker, as listed on the agenda, is Alan Stein, Ph.D., President and Chairman of Enteric Medical Technologies.  He will speak on the company device description and pre‑clinical studies.

            Dr. Stein?

             1.  SPONSOR PRESENTATION

            DR. STEIN:  Good morning, members of the panel and FDA.  My name is Alan Stein, as noted.  I am president of Enteric Medical Technologies.  We are very pleased to have the opportunity today to review with you the results of our clinical trials on Enteryx.

            First slide.  After a brief overview of the company of the description, we will review some detail provided by Dr. Luke Brennecke.  Following that, we will have a review of the entire clinical study design, the results in terms of safety and efficacy by Drs. Glen Lehman and David Johnson.  Finally, I will make some concluding remarks.

            Next slide.  In addition, to further answer any questions the panel may have, we have available to us today:  Dr. William Wustenberg, a toxicologist; John Kennedy, our biostatistician; and Jill Visor, who is our vice president and director of clinical and regulatory affairs.

            Our company was formed several years ago, in June of 1998, to develop minimally invasive procedures for GI disorders.  About a year later, we did our first patient and performed a pilot study under the supervision of Dr. Jacques Deviere at the Frie University in Brussels.

            In April 2000, an ID study that was developed in conjunction with the FDA was initiated.  In May, we received the CE mark and have been actually performing studies in Europe on Enteryx parallel to those in the United States.  In June of 2000, it should be noted that the company was acquired by Boston Scientific Corporation.

            Next slide.  The studies today that we will describe are for the following intended use.  That is, specifically, Enteryx on the basis of these studies we claim is indicated for endoscopic injection into the lower esophageal sphincter for the treatment of GERD.

            The material is a biocompatible polymer in a liquid solvent with a radiopaque marker.  Specifically, the biocompatible polymer is Ethylene‑Vinyl Alcohol.  It's a simple copolymer made up of polyethylene and polyvinyl alcohol, both of which have been individually in use in medical applications for decades.

            Polyethylene, as you know, is extensively used in orthopedic implants.  And polyvinyl alcohol has been extensively used for vascular embolization, most recently approved in a product called Bead Block.

            The liquid solvent is dimethyl sulfoxide.  DMSO has had numerous medical applications, ranging from treatment of intercranial hypertension to interstitial cystitis.  And two products on the markets using DMSO are RIMSO and Cystistat.

            Finally, the radiopaque marker is tantalum, an element with a high electron density that has been used extensively as a marker in terms of coding or specifically as beads and powders for radiographic localization.  And many products, including Strecker stent and J&J's Trufill Tantalum Powder, have been on the market again for years.

            The history of use of this product is actually fairly substantial because this type of material was first vascular embolization in 1996 under the name of something originally called Embolyx, now called Onyx, not manufactured by this company.

            It received a CE mark in 1999.  And since then, over 3,500 procedures have been performed in treatment of various vascular abnormalities, including cerebrovascular AVMs, aneurysms, and various peripheral vascular neuropathies or abnormalities.

            And in these applications, these vascular applications, there has been significant long‑term follow‑up, demonstrating excellent patient tolerance, the stability of the implant, and a lack of migration.

            In this application for treatment of GERD, the Enteryx is provided as a kit, including a sclerotherapy‑type injection catheter that is compatible with DMSO; two DMSO‑compatible syringes; and a bottle of Enteryx, which is noted on the left; a 10 cc bottle and a bottle of primer, which is actually DMSO that is used to pre‑fill the catheters to make sure that there is no fluid unintentionally in the catheter that could result in inadvertent precipitation of the material within the catheter; therefore, blocking it.  It's just a primer.

            Next slide.  In this picture, you will see that Enteryx is actually a very low-viscosity solution, allowing us to inject to as small as a 23-gauge needle, which is actually what is used in the injection catheter.  On contact with fluid or body tissue, the ethylene vinyl alcohol and tantalum precipitate together as a spongy mass as the DMSO is dissipated within the tissue.

            Next slide.  There has been extensive biocompatibility testing of the product, particularly per the requirements of ISO 1099, for permanent implant devices.  And these have all been passed successfully for cytotoxicity, systemic toxicity, intracutaneous reactivity, hemocompatibility, genotoxicity, and carcinogenicity.

            Now, we did note -- and this should not be surprising -- in the seven-day rabbit muscle implant, there was a demonstration of an acute tissue response, but this would be for the discussion issues when we get to the point of reviewing the histology over time.

            In collaboration with the FDA, the sponsor performed an extensive additional carcinogenicity study in order to determine whether there would be any long-term effects from this new implant material that were not initially anticipated.  This study was designed in conjunction with FDA's toxicology staff, who gave us a great deal of guidance.

            Again, the study was coordinated by Dr. Bill Wustenberg on our side; Dr. Raju Kammula; and Dr. Nermal Mishra at the FDA.  In the study, 400 transgenic and wild-type mice were used.  And, just to summarize it, though numerous animals in positive/negative controls were studied, there were no Enteryx-treated animals that develop tumors at any of the injection sites.

            And, similarly, the background carcinogenesis rates were identical.  The Enteryx used that for the controls.  The conclusion of this extensive transgenic mouse study is that Enteryx is non‑carcinogenic.

            Now, moving into the esophageal pre‑clinical studies, a safety and technique study was performed at the Indiana University with Dr. Glen Lehman.  In the primarily acute study, 16 dogs were studied in order to really understand what type of safety issue could be involved with an injectable product in the area of the LES as well as to optimize technique.

            In terms of the safety, a series of intentional transmural injections with long needles were placed above and below the LES.  We found, very satisfyingly, that intraperitoneal and subserosal implants had actually a minimal tissue reaction.  And most comforting was that, even when intentionally injected into the lungs and pleura, there was minimal adjacent fibrosis in the animals, already at least quite well.

            Several of the animals in the study were maintained for up to a year.  And on necropsy, there was minimal physical adjacent tissue reaction.  And there was absolutely no evidence of migration of this material outside of the injection sites.

            Now, in terms of the long‑term pre‑clinical study, this was performed at the University of Southern California under the supervision of Dr. Jeff Peters and in the department of Dr. Tom DeMeester.

            Fifteen Yucatan minipigs were endoscopically injected with Enteryx.  These were small animals at the time.  They were only 30 to 40 pounds.  So they actually had quite large injections of one to one and a half cc injected in three to four different sites, totalling up to four cc per animal.

            These were sacrificed in various time points up to one year.  And in addition to the histology studies performed on these animals, there were additional functional studies performed in a subset to give us an indication, though, of a kind of a mechanism of action that we can anticipate, even though a pig model is not really valid for any type of a GERD baseline.  By the way, these results were published in Surgical Endoscopy.

            There were no complications observed in the treatment of any of the animals.  They all ate.  They never had any dysphagia types of problems.  They gained weight and actually by the end of a year became quite large.  And there were no other behavioral changes.

            Histologically we will discuss this in detail in a few minutes, but it was demonstrated, in summary, that there was an evolution from what is not expected, an acute inflammatory response identical to that seen in the 70 rabbit studies leading to a chronic foreign body reaction that had well‑delineated fibrous capsules by as little as 12 weeks, actually even sooner.

            Now, in terms of the functional studies, it was interesting that Dr. Rodney Mason, you know, who is actually focusing on these functional studies, identified that LES length and pressure were not affected, but yield pressure was improved.  Actually, some of these yield pressure studies that I was involved with demonstrated really substantial increases in the yield pressure.

            And, as a result, ‑‑ next slide, please ‑‑ it was suggested that the mechanism of action in this application would be through a modification of the compliance to the LES and that this modification of compliance was due to the volume and mechanical properties of injected material, not unexpectedly, as well as the fibrous encapsulation of the material as it was stabilized in the tissue.  Together these two parameters would then result in a decreased distensibility of the cardia, preventing sphincter shortening during gastric distension.

            Now, in addition, Dr. Peters did a very interesting study for us because as we moved into humans, we wanted to make sure that we were understanding the correlation between the endoscopic and the fluoroscopic appearances of the injection material.

            Remember, there is tantalum in this, and this is very effective in guiding the localization of the implant.  These are not blind injections by any means.

            This paper was accepted for publication and should be out imminently.  In nine patients who were undergoing surgery for cancer, we did a series of implants in them and had the opportunity after the pathologist had finished checking the margins to review the location of the implant and actually perform correlation of the implant to the endoscopic images as well as the fluoroscopic images that were acquired.

            I believe the numbers off the top of my head are something like of the 80‑odd implants that were done in these patients, Jeff was able to recover about 95 percent of them in and along the muscular layer and 1 or 2 or 3 went transmurally and were sitting on the serosal side of the esophagus.  They hadn't migrated anywhere.  Of course, in this short term, there were no complications to the procedures.  It really was a very, very helpful guidance for training issues associated with the use of the product.

            Next slide.  At this point, I would like to turn the talk over to Dr. Luke Brennecke.  Luke is a worldwide authority on medical device pathology, and he is the director of such efforts at Pathology Associates, which is a Division Charles River Lab.

            Dr. Brennecke and Pathology Associates provided an independent assessment of the histopathology.  He will review the course of the evolution from an acute to a chronic inflammatory response that we discussed just a moment ago.

            CHAIRPERSON WOODS:  Before you turn it over, could I ask the panel if they have any questions for you regarding your statements?  I have a question.

            DR. STEIN:  Okay.

            CHAIRPERSON WOODS:  The vascular indications for this product, can you compare the volume that is typically injected for the vascular indications as compared to the volume injected for the GERD indications?

            DR. STEIN:  Approximately, yes.  The company who is doing this is a company called Microtherapeutics.  Microtherapeutics for cerebrovascular applications injects on the order of one to one and a half cc of material to fill an AVM.

            Their product, as I mentioned, is CE approved in Europe but is under an ID investigation in the United States.  However, in some of their other applications that they are under investigation to do, particularly larger dissecting aneurysms and so on, they're putting it 8, 10, 20 cc.

            So there are some very substantial amounts of material that are under evaluation, other applications than cerebrovascular AVMs.  In the AVMs, of which that 3,500 cases is the most, that's on the order of one to one and a half cc, about what we recommend to do in one quadrant of the LES during the injection for the treatment of GERD.

            CHAIRPERSON WOODS:  Thank you.

            Any other questions?  Dr. Ferguson?

            DR. FERGUSON:  I have a question, Mr. Stein.  The last study that you described that Dr. Peters did in the esophagectomy patients, could you just give us some idea of the time frame between the injection and the esophagectomy procedure?

            DR. STEIN:  It was really that in giving their consent, the patient was prepared for surgery.  They were scoped and treated immediately prior to the surgery.  The injections were done.  We collected the material.  I would say that the procedure might have taken at most 30 minutes.  And they he continued on with the esophagectomy.  So I would say that the material was, shall we say, available, on the table, a couple of hours later.

            CHAIRPERSON WOODS:  Other questions?  Dr. Achem?

            DR. ACHEM:  Dr. Stein, in this model of esophagectomy, I believe there were four patients that the injection went transmural ‑‑

            DR. STEIN:  That's correct.

            DR. ACHEM: ‑‑ according to the data that you present on the paperwork.  Are there any concerns?  I mean, these are patients that were injected by an experienced individual working in the laboratory.  What were your comments regarding the transmural injection?

            DR. STEIN:  Part of the training ‑‑ this is a great question.  When the material is injected endoscopically, you have a lot of feedback with this product.  As you saw in the little video, the material comes out as a black spongy mass.  When the material is injected superficially, you can send ‑‑ I actually think you could have a reiteration of this by Drs. Johnson and Lehman because they have been doing this procedure to great success.

            Superficial injections, you can see them.  There is bulging on the mucosa side, and it's black.  You can see a discoloration due to the tantalum.  This generally is guidance that the material is too superficial and will have a high probability of sloughing.

            When they are in an appropriate position; that is, deep in and along the muscle layer, they have a rather distinct fluoroscopic appearance.  Often they flow in arcs, but they make distinct blebs.  And there is very little bulging in the mucosal surface, giving us a good indication that it is deeper.

            When they go transmural, since the material is not being incorporated into tissue, the X‑ray density, at least in my opinion, is quite more intense and often forming thin lines as the material runs briefly along the outside of the esophagus.  Actually, in Jeff's patients, when he did the esophagectomy, the material was just binding right to the outside.  It was just adherent right along the outside of the esophagus.

            CHAIRPERSON WOODS:  Yes, Dr. Manyak?

            DR. MANYAK:  Hi.  I have a question, just a clarification probably, on a little bit of your tox studies regarding the DMSO.

            DR. STEIN:  Yes?

            DR. MANYAK:  I heard you state that you did these tox studies in conjunction with the FDA's advice.

            DR. STEIN:  The carcinogenicity studies, sir.

            DR. MANYAK:  Right.  Well, I was just curious about the DMSO.  Any of us who have worked with that in the laboratory know that that is not something that is very good to have inside of the body very much.  And so I was curious.

            In your clinical studies, it shows a bad odor and a bad taste to the mouth about five percent of the time.  That may be related to the DMSO.  I'm just curious what was done to determine the toxicity of the DMSO aside from ‑‑ I don't know that particulate assay that you used.  And I'm just curious.  Does that answer the question for toxicity on DMSO?

            DR. STEIN:  DMSO has actually been in use for decades.  As a urologist, I believe you have probably used products like RIMSO for treatment of interstitial ‑‑

            DR. MANYAK:  Yes.  The only problem with that is that stays within the inter‑vesicle.  It does not enter the systemic circulation purportedly.

            DR. STEIN:  But, actually, all DMSO enters systemic circulation because it goes across the tissue and is excreted primarily through the kidneys and as exhaled product, breakdown products, being mainly dimethylsulfide and dimethylsulfone.

            The sulfur components on DMSO give it the garlicky flavor.  Actually, any of you can go to a health food store and go buy DMSO because it's one of the most common officially unapproved uses for arthritis.  And any use of DMSO, whether you rub it in your hands, whether you instill it in a bladder, all of it will be excreted in the same manner, whether it's injected or not.

            In DMSO applications, I believe you put in 50 cc bottles at a time.  You can put multiple bottles of those.  In this application, we inject 10 cc.

            The LD50s on DMSO have been published for decades.  And they're nearly as extraordinary as matter.  I once calculated for my weight, I would need to drink maybe a liter and a half of material.  So the fact that five patients, Dr. Manyak, said that they had bad breath, all patients in their informed consent were advised that they would have a garlicky smell.

            Five patients wanted to comment on it in their compulsion to report every adverse event and comment.  We listed those in addition.  But this may come up in a different context.  There is no way to hide the fact that a patient was treated with Enteryx because they all have a garlicky smell.  Every patient knows this.

            CHAIRPERSON WOODS:  I have a question, Mr. Manyak.

            DR. MANYAK:  Thank you.  That's fine.

            CHAIRPERSON WOODS:  I have one other question as well.  You have referred in the animal models about the sloughing of the mucosal or submucosal injections of the material.  And there are many references to that throughout the data as well.

            Can you tell us exactly how you know with certainty that that material was sloughing off and passing through the digestive tract?  Did you see it?

            DR. STEIN:  No.

            CHAIRPERSON WOODS:  Did you hold it in your hand in the autopsy?  How did you know that it sloughed?

            DR. STEIN:  Okay.  I will give you some indications.  And, again, I would like to turn this and ask Drs. Johnson and Lehman to speak about the experience that they have.

            We can follow this material very clearly on X‑ray.  So if you make four circumferential injections and you look at these patients on X‑ray a month later and you see three, this is not a resorption issue.  This is a slough.

            CHAIRPERSON WOODS:  What proof do you have that it can slough?

            DR. STEIN:  Because, actually, on some of the scoping that has been done, ‑‑ and, again, I would like to defer this question to Dr. Lehman because he will give you a better conversation ‑‑ you can actually see sometimes depending how near your endoscopy is to the actual slough the erosion.  And there will be some black material in it.  And sometimes you will see the black material mostly gone.  And then if you come back a little later, you will see it smoothed over as the erosion surface has healed.

            In addition, there have been X‑ray studies that we have done on the animals actually looking to determine whether the material is still in the ‑‑ actually, it is is still in the LES, but on some of the animals that Dr. Lehman looked at, he did whole body X‑rays.  There is no other implant anywhere else but there.

            So when you have sloughing of any material into the esophageal lumen, I can only say it was not possible to get patients to, shall we say, collect their samples for the next couple of months to actually recover material, but on X‑ray, since this material is so radiopaque, you can't see anything in any of the images that we have from the abdomen and pelvis.

            CHAIRPERSON WOODS:  And in the animal model, I believe the pigs were sacrificed, some of them on day three?  Is that correct?

            DR. STEIN:  The actual animals that we did for the histological review were at two weeks and so on.  But when we worked with Dr. Peters early on, we also were assessing in two laboratories in parallel with Dr. Peters as well as that of Dr. Lehman injection techniques.

            So some of those animals were killed very quickly.  And those animals, sometimes you could absolutely look at those animals during the growths and say, "That one is going to come off."

            In fact, we talk about it internally as very much like what you see with a pizza burn.  I mean, this is all gastrointestinal mucosa.  When you have enough of a division because of an implant of material of the mucosa away from the blood supply, some pizza burns go down.  Most of them peel off.  And when the top peels off, the implant falls out.  So it's really no different than any other form of healing in the gastrointestinal system.

            CHAIRPERSON WOODS:  Thank you.

            Any other questions from the panel?

            (No response.)

            CHAIRPERSON WOODS:  Okay.  Thank you.

  2. HISTOPATHOLOGY REVIEW: PRE‑CLINICAL STUDIES

            DR. BRENNECKE:  Good morning, members of the panel and FDA.  I am Dr. Luke Brennecke.  I am being paid this morning by the sponsor as a consultant veterinary pathologist.  I have no financial or equity interest in Enteric Medical Technologies or their parent company.

            Next slide.  This morning I am going to briefly discuss the results of the histopathology examination of the tissues that were sacrificed from three months to one year.  First of all, I would like to show you, however, the area of the LES from one of the animals that was sacrificed at 12 months.

            In these slices, you can see various foci of black.  They're well‑circumscribed.  They look like blebs or blobs of material.  They're highly demarcated.  They're also in some cases surrounded by a very precise, well‑delineated capsule.

            If you looked at animals that were similarly sacrificed at earlier time points, as early as six weeks, you can also see a virtually identical picture with the absence of the thick capsules.

            Next picture.  The first photomicrograph is from an animal that was sacrificed at two weeks.  To help orient you here, we have the lumen of the esophagus up here, the squamous epithelium, the submucosa, the inner circular layer, the layer of fibrous tissue between the inner circular layer, and the outer longitudinal layer of muscle.

            In this photomicrograph, there are two sites of injection.  They actually may have been part of the same site in an adjacent or nearby slice.  Notice in this section that the normal fibrous connective tissue band between the muscle layers is slightly thickened due to the space occupying injections here.

            Of note, what we want to look at is the blue is collagen and fibrous tissue.  The red are pink, are cells.  So we see two highly demarcated, well‑circumscribed areas of injection surrounded by blue.  And in this one as well as this one, we note that there are some pink cellular infiltrations around the outside of the injection site.  We will next be looking at this area right here magnified.

            At this magnification, we can more easily see the well‑circumscribed area of the blue fibrous tissue.  We don't see the embolics or tantalum spread out in here.  We can see that these large spaces consist of the EDOH.  Intermixed within is the black tantalum.  Around the outside, we start seeing macrophages, activated macrophages, and giant cells.  We also see processes of these cells going down, interdigitating around these blebs of injected material.

            Next slide, please.  At three months, here is the lumen, the squamous mucosa of the esophagus.  This is the layer of muscle that is just beneath the layer of squamous epithelium, the muscularis mucosa.  This injection site was put just a little bit more superficially than the last one so that the muscularis mucosa has been a bit defaced by fibrosis in this area.  So it's within the inner circular layer of muscle tissue.

            Note that as in the previous sacrifice period, it is well‑demarcated, surrounded by fibrous tissue.  The other thing to note in this case is that there is a lot more pink and red material down within the injection site, representing inflammatory cells.

            The previous slide we looked at, the inflammation was moving from an acute phase, in which we saw neutrophils merging in with macrophages, activated macrophages, and giant cells.  At this point, we see mostly giant cells and macrophages.  This is part of the normal progression of virtually any type of implant from acute to chronic inflammation.  We will next be looking at the higher magnification.

            Here we see a bit of the muscle layer up here.  This is native tissue up here, as evidenced by the larger blood vessels.  Note that there is a well‑demarcated area around the outside, large numbers of macrophages, giant cells, and some clumped tantalum, as well as the spaces representing the EDOH.  Also of import here, note that the fibrous connective tissue and fibroblasts have started to invade the injected material, stabilizing it.

            Another thing of import here is that there is a lack of any type of tissue destruction along the outside.  If we saw any type of necrosis or tissue destruction, instead of the blue collagen and fibrous connective tissue, as well as the fibroblasts, we would expect to see a pink amorphous acellular thin layer.

            I will also note in the previous large focus, I did not find any areas of calcification.  Sometimes calcification is seen with tissue destruction.  But in the injection sites that I have looked at throughout this study, the calcification was very, very, very minimal, sometimes not much larger than a couple of these five‑micron tantalum pieces.

            Next, please.  At six months, again, we have the lumen out here, squamous mucosa.  This is a little deeper into the submucosa.  We have a well‑demarcated area.  Again, we have fairly large numbers of inflammatory cells, macrophages, and giant cells.  And we are going to look at this area right here.

            There is not much difference between this and the last slide except that there are, again, large numbers of macrophages and giant cells.  Around the outside, it is a very quiescent appearance with a very bold interface between the surrounding fibrous connective tissue and the injection site.

            Next slide.  This animal was sacrificed at one year.  We're in a little bit different location.  We're a bit lower here.  Notice that the mucosa along the margin consists of normal columnar epithelium, rather than the squamous epithelium we looked at previously.

            Notice also that this injection site was much more superficial than the previous ones.  Here is another well‑demarcated injection site over here.  Again, these may have been part of this same one in another field.

            The muscularis mucosa is partially replaced by fibrous connective tissue, but it is overlain by healthy columnar epithelium.  Notice also you can barely see it in this picture, but down in this corner down here are a couple of more pieces of injected material.

            Notice from this magnification you can't see any inflammatory cell infiltrate whatsoever.  As a matter of fact, in much of this injection site, as this one, you see very few inflammatory cells.

            Notice also from this magnification you can see a blue hue throughout much of this site here representing fibrous connective tissue within the site.

            Next slide.  In this photomicrograph, we see that there are very few inflammatory cells around the outside of there.  There is a bold interface between the injection material and the fibrous connective tissue, indicating that there is virtually no ongoing reaction whatsoever.  Notice also there is a lot of collagen and fibrous connective tissue within the implanted area itself.

            Next.  In summary, I would like to point out that there was early and persistent fibrous encapsulation.  We saw fibrous encapsulation beginning as early as two weeks.  What we saw was the normal progression from acute to chronic inflammatory response.

            This is the same type of response that one would have seen in the rabbit lumbar muscle implant study.  It is also commonly the same type of inflammatory action that you would see in any other type of implant, whether it be sutures, Dacron, or hard materials.

            The tantalum was completely stable.  I was unable to find tantalum in any blood vessels, in any lymphatics, regional lymph nodes, or any indication that this tantalum is moving to other areas.

            There is very, very minimal dystrophic mineralization or calcification, which is not to say there is none.  I saw a very minimal dystrophic calcification as early as two weeks, and I saw it as late as one year.  The important thing here to remember is that there was no increase in the amount, in the relative amount, of mineralization as we progressed from the acute to the chronic phase.

            So, based on these observations, I would have to conclude that there are no adverse sequelae to the injection of Enteryx.

            CHAIRPERSON WOODS:  Questions from the panel?  Dr. Fennerty?

            DR. FENNERTY:  Dr. Brennecke, do you mind backing up just two slides to your high‑powered histomicrograph review?  Go forward one towards the end.  I actually am intrigued because you comment on very little inflammatory changes.  Of all of these high‑powered views, I don't see any inflammatory changes.  There is not a single poly in that field.  I realize we are looking at one section, but can you quantify?

            I mean, this seems like this is as normal a carrying from an inflammatory response as normal tissue is.  Did you ‑‑

            DR. BRENNECKE:  The polys resolve very quickly and move from the acute inflammatory phase very early on.  You will occasionally see polymorphonuclear cells as late as a year.  You have to look pretty hard to find them.

            In the center of these injection sites, you will see larger numbers of macrophages and giant cells that are still around, indicating that it takes a longer time, regardless of what type of material.  You have inflammatory cells in the center of a granuloma, for example, even a tuberculosis granuloma.

            Those will resolve much, much more slowly than those around the edge.  In this case, the stimulus for any type of inflammatory reaction has pretty well gone.

            DR. FENNERTY:  Well, I guess that is what I am trying to get at.  From my looking at these histophotographs and micrographs that you are showing, there don't appear to be any mucosal based product inflammatory changes, but you report that in your summary that you have minimal chronic inflammatory changes.  Is it none or is it ‑‑

            DR. BRENNECKE:  If you take the technical definition of chronic inflammation, that includes fibrosis.  Fibrosis is an ongoing sequelae of chronic inflammation.  If you look in these things, you will find, again, macrophages and you will find some lymphocytes.  These are what you normally see in chronic inflammation.

            CHAIRPERSON WOODS:  Other questions from the panel?  Dr. Achem?

            DR. ACHEM:  Could you comment on the extent of the material distributed through the lower esophageal sphincter?  I'm interested specifically if you could tell us in your slides when you did the cuts.  Did you encounter any material above or below the lower esophageal sphincter area or was it all confined only into that area?

            DR. BRENNECKE:  Well, I will say that I did not look at the entire esophagus, nor did I look at the entire stomach.  I trimmed in the areas that showed one.  I was mostly interested in the area of injection, the lower esophageal sphincter.

            Grossly, if I did not see anything several centimeters above the injected area, I did not do histopathologic review on those, nor did I do a review on other portions of the stomach.

            These injection sites for the most part are very easily visualized grossly.  Some small ones, which have perhaps been pinched off as the fibrosis around them becomes more mature or not as easily seen grossly, is pretty well‑defined to the injected areas.

            DR. ACHEM:  If I may, just a follow‑up question.  Could you comment on the amount of the material injected in terms of a correlation between the amount injected and the degree of histopathological changes that you see?

            DR. BRENNECKE:  Well, sir, I did not do a volumetric evaluation.  Such evaluation would be possible doing sequential sections and doing histomorphometry.  That was not done on these.  And I was given no information as to how much was injected, nor of the type of volume to expect at histopathology.

            CHAIRPERSON WOODS:  Other questions?  Dr. Ferguson?

            DR. FERGUSON:  Dr. Brennecke, I have two areas I have questions about, I should say.  One, is the heterotopic or dystrophic calcification.  You stated that it is a fraction of a percent in the report.  Yet, the illustration that is included in the material shows a fairly sizeable collection of calcium in one of the specimens.  I gather that that was an exception to what you saw otherwise?

            DR. BRENNECKE:  There were a couple of areas in which I would say it reached maybe perhaps a half a millimeter in diameter.  That is about the largest you can expect.

            DR. FERGUSON:  What would the normal time course be of the development of dystrophic calcification in a foreign body like this?

            DR. BRENNECKE:  Dystrophic calcification normally occurs ‑‑ well, it can be seen in anything, icy dystrophic calcification, in everything from arteries to hearts to intestines, all sorts of things.

            So dystrophic calcification can occur for a variety of reasons.  Normally as a result of necrosis, the calcium salts form within the mitochondria of the dead and dying cells.  Those dead and dying cells are accumulated together and are phagocytized or broken down by a further number of inflammatory cells.

            If there is ongoing destruction of tissue, you may expect further destruction of cells and further dystrophic calcification.  In the areas we have seen in the center of these foci, the tissue has been either destroyed or moved out of the way by the space‑occupying injection or what cells are there have been phagocytized and moved out of the way by the inflammatory cells.

            In the center of these injection sites, there really are no cells to provide the calcification.  Now we have an influx of cells, that being the fibroblasts, which secrete the collagen and the fibrous connective tissue, but there is no indication that they would be destroyed by the ongoing inflammatory reaction.

            DR. FERGUSON:  So I'm not sure what the answer was.  In this situation, what would you expect the time course of the dystrophic calcification to be?

            DR. STEIN:  The time course would be early, within a couple of weeks.  And that's it.  I mean, I wouldn't expect it to progress or proceed in any way.  So what you see early on is about what you get.

            DR. FERGUSON:  If I may, one other question.  You have illustrated in your histologic preparations a number of different sites of accumulation of the foreign materials, the submucosa, the muscularis mucosa between layers of the muscularis propria.  Does this illustrate intended various sites of injection or does it illustrate the difficulty in achieving a correction injection into the muscularis propria?

            DR. STEIN:  Well, I am not going to comment on the injection because that is not part of my expertise.  I will say, however, I have seen injection sites all the way from the submucosa out into the outer muscular layer.

            They all react about the same.  They all represent space‑occupying lesions.  And the space‑occupying lesion, which is part of the effectiveness of the drug, as I understand it, is not only a result of the material that is injected but also the fibrosis that results.

            CHAIRPERSON WOODS:  Dr. Achem?

            DR. ACHEM:  Thank you, Dr. Woods.  Allow me to come back again to another issue, if I may.  Dr. Brennecke, do you have any information you can share with us regarding the state of the nerves, vagal trunks, whether any of these were involved and to what extent?

            DR. BRENNECKE:  I did not see any involvement, any destruction of nerves in these areas.  There are nerves throughout here, as you well know.  If they are closed to the area of injection, they are surrounded by fibrous connective tissue.  And how that affects their ongoing function I can't comment on.  In the middle of the injected area, by the time I saw the tissue, they may have been destroyed.  I also cannot comment on that.

            CHAIRPERSON WOODS:  May I ask a question?  In the two‑week autopsy specimens, did you see in the gross specimens any evidence of the mucosal sloughing theory in terms of the loss of the submucosal or mucosally injected material?

            DR. BRENNECKE:  I saw some that were very, very superficial.  They were covered by a very small amount of epithelium, which may have been epithelialized that time, or it may be in the process of sloughing.

            I can't comment on whether it sloughed before I saw it or whether it would have sloughed had the animal been allowed to live, but I did not see any evidence of ongoing sloughing.

            CHAIRPERSON WOODS:  Thank you.

            Other questions?  Yes, Dr. Gellens?

            DR. GELLENS:  How many animals did you examine histologically like this at a year?

            DR. BRENNECKE:  I believe there were three.  That's right.

            DR. GELLENS:  One other question.  In some of the other data, it mentions injecting this material in other organ systems.  Did you examine those also?

            DR. BRENNECKE:  Yes, I did.

            DR. GELLENS:  Did you see the same kind of reaction that you are seeing here?

            DR. BRENNECKE:  Actually, not quite as remarkable a reaction.  We didn't carry those out to a year, of course, but we saw some very localized inflammation.  That's about it.

            CHAIRPERSON WOODS:  Other questions by the panel?

            (No response.)

            CHAIRPERSON WOODS:  Thank you.  We can move on to the next speaker.

        3. STUDY DESIGN AND RESULTS: SAFETY

            DR. LEHMAN:  Good morning, panel members, FDA.  My charge is to review the study design and report the safety outcomes.  I must say that I have a consulting arrangement with Enteric Medical and a small equity interest in the company.  And my way has been paid here for today's presentation.

            CHAIRPERSON WOODS:  I will introduce you, Dr. Lehman, for the transcriptionist.  Most of us know you.  This is Dr. Glen Lehman.  Can you just remind us where you're from and other information pertinent to yourself?

            DR. LEHMAN:  I am professor of medicine and radiology at Indiana University Medical Center, Indianapolis.

            CHAIRPERSON WOODS:  Thank you.

            DR. LEHMAN:  A brief slide on history of endoscopic implantation for GERD.  You must remember that this is not a new technique in the sense that we did the first lower esophageal sphincter implantations back in the early 1980s and we injected collagen and Teflon in both animals and patients.  We saw limited and short‑term help in controlling GERD.

            From our initial experience with these materials, we came up with a wish list of an ideal implant.  That would be one which was chemically inert, non‑carcinogenic, hypoallergenic, capable of resisting mechanical strain, capable of being sterilized, capable of being delivered in liquid form and then it would turn to a solid and a solid that would be stable and persistent at the implant site.  Indeed, the current product today satisfies nearly all of these criteria.

            The procedure is designed to modify the distensibility of the lower esophageal sphincter and to reestablish the anti‑reflux barrier.  It's an outpatient procedure using standard endoscopic technique and standard fluoroscopic guidance.

            The needle, sclerotherapy‑type needle, short needle, four millimeters, is passed through a standard scope, penetrating around the squamocolumnar junction, and one fluoroscopically monitors.  Let's look at a short videotape of this.

            The sclero‑type needle is advanced into the distal esophagus and punctured slightly tangentially into the deep submucosa or muscle layer.  This would typically be right near the squamocolumnar junction.  The injection would be made in four quadrants unless one gets a ring forming from a single injection, as happened in this case.

            And here we see passing the scope through the ringlike implant.  Some contrast media will be injected.  And there will be impingement on the contrast column as it passes through.  And the patient here has a small hiatal hernia.  After the procedure of the mucosa, we like the mucosa essentially intact if implants have been deep in the wall.

            Next, please.  Let's look at several examples of implants.  Here again we're seeing the tantalum.  The plastic itself is not visible.  Here we have arc‑like implant with several globular foci.

            Next.  Here again a circular distribution of several globular implants.

            Next.  Here we get the concept of four quadrant injections in globular fashion.  Here the implants have a little more linear characteristic in the again three or four quadrant implant.

            Next.  Here the implants have a little more linear contour and the scope passing through the LES.

            Next.  And here we see the implants which have both the cardia position, globular.  We see a little arch‑like component right at the distal LES or squamocolumnar junction and then a more slender tubular component in the distal esophageal body.

            Next.  Contrast medium swallowed shows a pinch at the LES and the intramural implants.

            Next.  And afterward we see little focal areas of mucosal trauma and a snug LES on retroflexed view.

            Next.  Now, the study design was that of a prospective study in well‑characterized GERD patients.  Each patient served as their own control.  Baseline pretreatment parameters were compared to post-treatment outcomes over a 12‑month study.

            Next.  The null hypothesis for the study was that less than 50 percent of the patients would exhibit a clinically significant reduction in PPI use.  And the alternative hypothesis was that greater than 50 percent of patients would exhibit clinically significant reduction in PPI use.

            The sample size, calculated sample size, of 36 patients was required to achieve an 80 percent tower.  However, we enrolled 85 patients to ensure adequate representative sample size and to account for patient dropouts.

            The primary objective for the study was elimination of PPI use or reduction of PPI use by greater than 50 percent.  The secondary objectives were improvement in:  GERD quality of life scores, SF‑36 general health survey scores, pH Probe results, and manometry results.  Significances were determined by the Sign test and the Wilcoxon Signed Rank test.

            Next.  The investigators for the study are shown here and represent a mixture of European centers, Canadian centers, East Coast, Midwest, West Coast, mostly gastroenterologists, one surgical center, and then nicely a mix of community‑based private practice centers and academic centers.

            Next.  The inclusion criteria, only PPI‑dependent patients were eligible for the study.  And they were PPI‑dependent as demonstrated by GERD symptoms controlled by PPI, as shown by Velanovich GERD quality of life scores less than 11 while taking drugs, symptom relapse of equal to or greater than nine‑point worsening in Velanovich score, while off of PPIs, and documented acid reflux by 24‑hour pH Probe of greater than 5 percent abnormal total time with a pH less than 4.

            The exclusion criteria were the same ones used for nearly all the endoscopic GERD therapy studies, namely bad erosive esophagitis, big hernias, Barrett's, and so on.

            Next.  Now, the study schedule involved assessing symptoms in the baseline state while taking their PPI; taking the patient off of PPIs for 10 to 14 days; and reassessing symptoms; and quantitating pH and manometry; treating the patient; and then non‑invasively evaluating the patient at 1, 3, 6, and 12 months; and invasively assessing the patient at 6 and 12 months.

            There were 85 patients enrolled, 58 percent male, mean age about 50 years, nearly all Caucasian, body mass index, mean of 20.  There were 14 protocol deviations in the inclusion/exclusion criteria, which warranted a brief separate look.  That is, three patients were just over the upper limits for BMI, seven patients were just over the limit for equal to or greater than three‑centimeter hiatal hernia.  Indeed, six of those had a three‑centimeter hiatal hernia.  One patient had Grade 3 esophagitis, where only Grade 2 is allowed.  A couple had minor deviations in the quality of life scores.  And one patient was not on PPIs because they were allergic, was only on double dose H2 blockers.

            Data analysis with and without these subjects with the deviations resulted in no statistically significant change in primary or secondary objectives.  Therefore, these patients are included throughout the analysis for the rest of the time period.

            Now, the baseline PPI use for this group of patients, patients were on PPIs for a mean of two years prior to entry into the study.  They were on any of the four standard PPIs available at that time.  And then the dosage was quantitated as routine dose, half dose, or more than standard dose.

            Let's look at that again.  Next, please.  So seven percent of patients were on half dose, half standard dose PPI.  Sixty‑two percent were on standard dose PPI.  And 30 percent were on more than standard dose PPI.

            Additionally, beyond the PPI we just discussed, seven percent were on H2 blockers, including the one patient who was only on that.  Fourteen percent were taking supplemental antacids.

            Next.  All patients meeting entry criteria were indeed treated with the device.  All patients were treated on an outpatient basis.  All procedures were formed under intravenous sedation without general anesthesia.  All patients received prophylactic antibiotics.  Mean procedure time was 34 minutes, mean fluoro time just under 12 minutes.

            Now for the safety summary information.  There were no serious device or procedure‑related adverse events.  All device‑related adverse events were anticipated in the protocol.  All procedure‑related adverse events were anticipated and generally those expected for any therapeutic endoscopy.  All adverse events resolved without sequelae.

            The device‑related adverse events were retrosternal chest pain occurring in almost all patients, dysphagia in 20 percent of patients, fever in about 12 percent of patients, and a variety of less frequent and seemingly minor complaints or events.

            Next.  To expand on the substernal chest pain, again, patients were told to expect this.  It occurred in 92 percent of patients.  About 80 percent of the patients were given prescription or over‑the‑counter analgesics to control it.  And 20 percent required no medication.  All pain resolved without sequelae.

            The duration of the pain was by seven days half the patients had resolution of their pain.  By 14 days, 75 percent had resolution of their pain.  By 30 days, 90 percent had resolution of their pain.  And by three months, all patients had resolution of their pain.

            Twenty percent of the patients had dysphasia.  In half of them, it resolved in two weeks.  In three‑fourths of them, it resolved by two months.  And in all patients, it resolved by three and a half months.

            Most problematic was one patient who was diabetic who could not control their blood sugar levels because of poor nutritional intake.  That patient was endoscoped.  There was no apparent stricture, despite the dysphasia.  The patient was empirically dilated.  And symptoms eventually resolved without sequelae.

            Next.  Twelve percent of patients reported fever.  This lasted only a couple of days.  It was treated with antibiotics in five of ten patients.  And others, it resolved without treatment.  Importantly, no patient had signs of sepsis or obvious systemic infection.

            Next.  Other device‑related adverse events were a variety of infrequent and seemingly minor events, all of which resolved spontaneously without intervention, including the odor mentioned by some patients.

            Procedure‑related adverse events were those which would be anticipated with therapeutic endoscopy procedures:  sore throat, nausea or vomiting, and a few other minor events.  All resolved within a week.

            So, in summary, no unanticipated device or procedure‑related adverse events occurred.  No major adverse outcomes and no mortalities occurred.  All device and procedure‑related adverse events resolved without sequelae.  Based on the results of this study, we conclude that endoscopic implantation of Enteryx is safe for the treatment of GERD.

            Thank you.

            CHAIRPERSON WOODS:  Dr. Fennerty has asked to be the first one to ask questions.  So I'll pass the microphone to him.

            DR. FENNERTY:  Good morning, Dr. Lehman.  I just want to go on the public record as stating unequivocally that my Portland Trailblazers should never have traded Jermaine O'Neal to your Indiana Pacers up front.

            DR. LEHMAN:  He is starting in the all‑star game, I hear.  So we appreciate that trade.

            DR. FENNERTY:  Dr. Lehman, I realize that many of the issues that I am going to ask questions about regarding study design you may have to also ask the sponsor about some background, but one of the things that will be an issue in any therapeutic trial is we know quite clearly that the lack of randomization or blinding has an effect on inflating treatment outcomes.

            We're going to not talk about efficacy until Dr. Johnson's presentation, but you did present the study design.  So I wanted to ask you whether the crossover design had been discussed with the FDA prior to the onset of the study and the reasons for picking a crossover design versus a randomized and hopefully blinded trial, although blinding may be somewhat difficult in these sort of things.  That's the first question.

            DR. LEHMAN:  Yes.  The study design was fully discussed with the FDA ahead of time and agreed upon that this crossover approach would be appropriate.  It was discussed.

            DR. FENNERTY:  As a follow‑up of that, Dr. Lehman, the crossover design was a two‑week baseline symptom assessment off PPIs and then a 12‑month follow‑up.  That's an unequal balance in the crossover design.  Was that also, then, a priori agreed upon between the sponsor and the agency?

            DR. LEHMAN:  Yes.  That was agreed upon.  And, actually, as you point out, that puts the device at a disadvantage.  In other words, patients stopping their PPI therapy for only two weeks might not be nearly as bad off, might not have as bad symptoms as if they stopped them for a month or two.  Therefore, it probably would be easier to see a difference between off therapy and post-treatment if the time interval was longer.  As you know, getting people to stop their desired PPIs for very long is difficult.

            DR. FENNERTY:  I don't mean to be sounding like I'm picking either on the FDA or the sponsor on this, but I also want to discuss some issues of the primary endpoint and whether that was a priori discussed with the FDA.

            The typical endpoint in a trial of reflux therapy would be either absence of symptoms or attaining of a certain symptom score, such as using the Velanovich GERD-HRQL, which is used in the study, as we'll find out in a little bit.

            The endpoint of greater than 50 percent reduction in medication use is an unusual primary endpoint.  In typical studies of GERD, I know it has become an endpoint in these device sorts of studies.

            Do you know if that was also a priori decided upon as a reasonable endpoint in conjunction with discussions with the FDA before the study was started?

            DR. LEHMAN:  Yes, that was agreed upon up front, indeed was the same type of endpoint used in the Bard sewing machine study.  And since these studies are taking stable patients on drug and the goal is to take them off their drug, they were asymptomatic before, we hope they are asymptomatic after, it is a logical parameter to follow because we are trying to eliminate their drug use.

            DR. FENNERTY:  With the Chair's indulgence, I have just a few more questions.  Now, we didn't specifically address this, but approximately 90 percent of the patients had chest pain.  I realize most of those received an analgesic dose.  Within the design of the study, though, I noticed there was not a standardization in the way analgesics were used among the nine centers or the multiple centers.  Had that been discussed or is there a reason that a standardized analgesic approach was not used in the study?

            DR. LEHMAN:  Analgesic dosing was not standardized.  It was left to the discretion of the treater.  Since there are many ways to treat nonspecific pain, we thought that was fair.  Similarly, the antibiotic given was at the discretion of the individual center.  There wasn't a standardized antibiotic given.

            DR. FENNERTY:  Regarding study design as well, one of the issues that obviously has come up in some of the earlier questions was the issue of sloughing and where does the material go.

            One of the things is there was an estimation provided by the investigators on the amount of material left based on X‑ray evidence.  Was there any discussion a priori with the FDA or among the sponsor of using an adjudication process with blinded radiologists to estimate the amount of material left behind?

            DR. LEHMAN:  No.  The quantitation of residual volume was a not‑agreed‑upon parameter up front.  That was taken on after the fact when we looked like a good idea.

            DR. FENNERTY:  One final question.  Dr. Woods, I apologize for hogging the microphone.

            I think it is very intriguing on the hypothesis of the mechanism of effect of this compound.  As a matter of fact, I agree that it seems like it's affecting function at the lower esophageal sphincter.

            I would probably differ with Dr. Peters and Dr. DeMeester on the shortening of the LES.  I suspect very strongly that this may be affecting transient lower esophageal relaxations, which I think Dr. Achem was also trying to get at with some of his earlier questionings of the veterinarian data.

            Has there been any investigation or is there any planned investigation into doing ambulatory esophageal manometry with a dense sleeve or similar diagnostic tools to look at transient lower esophageal sphincter relaxations before therapy and after therapy to try to get to the mechanistic toxicity issue of what is happening at the LES?

            DR. LEHMAN:  Yes.  Dr. Deviere has done an initial study on TLESRs, showing that they basically disappear.  It's almost too good to be true; whereas, other devices are seeing a 25 percent, 30 percent reduction in TLESRs.  So that has not been published yet, but that has been preliminarily evaluation.

            DR. FENNERTY:  Thank you.

            CHAIRPERSON WOODS:  Ms. Moore had a question next.

            MS. MOORE:  Yes.  I think this is just something that I missed at the beginning of your presentation.  I believe you said that ideally an implant material should be chemically inert, non‑carcinogenic, et cetera, et cetera.  And you said that this study met nearly all of those criteria.  But I think I missed the ones that you say about the criteria that were not met.

            DR. LEHMAN:  Well, the aspect that is not met is the perfect implant.  If you put it anywhere you put it, it wouldn't slough.  It shouldn't disappear.  This sloughs if you put it too superficially.  So it's not totally inert.  It's just mostly inert.

            CHAIRPERSON WOODS:  Next we'll go to Dr. Shaheen.

            DR. SHAHEEN:  Dr. Lehman, with respect to a device like this, one issue, of course, that comes up is what is going to happen when people who are not of such uniform excellent quality in terms of endoscopy skills starts doing this.

            One question I had was, was there an analysis done in terms of the side effects on the basis of number of procedures done by the endoscopist?  Was there a learning curve on this thing?  If so, how steep was it?  How hard was it to get people to do this right?

            DR. LEHMAN:  Dr. Johnson will address that and present a little bit of data on that, but, you know, there was no apparent learning curve from the first five to the second five to the third five in the outcomes data.

            DR. SHAHEEN:  Including the dysphasia?  You were no more likely to give somebody dysphasia up front than you were at procedure five or procedure eight?

            DR. LEHMAN:  Correct.  Now, that either reflects no learning curve or that we taught each center well before they started.

            DR. SHAHEEN:  How about the hiatal hernia folks?  Was it hard to get good implantation in these people?  Was there more sloughing amongst them?

            DR. LEHMAN:  It's not harder.  There is not more sloughing.  And, actually, a hiatal hernia is sometimes helpful, gives you a little space to inject.

            DR. SHAHEEN:  One question I want to follow up with what Brian asked.  I looked at the score for trying to figure out how much residual material was left there.  And I couldn't get a real good handle on how the endoscopist did this.  Is it essentially just an eyeball and a guesstimate?  Is that what is happening?  Do you compare the PA and the lateral to the initial PA and lateral and you try to kind of guess how much is gone?

            DR. LEHMAN:  Dr. Johnson will address this a little bit more, but basically initially it's kind of hard to tell because there is some material sitting in the lumen that you backwashed.  And so the initial study right on day one, it's a little bit hard to tell how much implant is in the wall and how much is in the lumen.

            So those day one assessments aren't very good.  When the patient comes back in a month, then we're sure whatever you see is what is in the wall.  If you take that and follow it out, then there's very little slough after that.  But we'll show some slides on that.

            DR. SHAHEEN:  One other safety issue.  When you make these injections in any of the animal models, if you go submucosal all the way around, has anybody been able to purposely generate a stricture following that?  In other words, if you get a circumferential slough, theoretically at least you could get a stricture after that.

            Now, obviously if that is done correctly, you are not going to have that happen, but in these patients that have significant sloughing, is that an issue?

            DR. LEHMAN:  Right.  No patient had a stricture develop during their procedure.  However, a couple of patients did have good therapeutic result and sloughed all their material.  So it suggests that they had a little stricture.

            CHAIRPERSON WOODS:  Dr. Afifi is next.

            DR. AFIFI:  Thank you.

            I have several questions about the design and analysis, but for Dr. Lehman I will just ask the question about the design since that is what he presented.

            The initial application had in it the power calculations based on a hypothesis that there will be 25 percent reduction in the level of use of the PPI, but the hypothesis you presented today is a different one.  And that is less than or equal to 50 percent of the patients actually had a clinically significant reduction in their use of PPI.  That is a different hypothesis.

            So I wonder why you still quote a power of 80 percent when that was calculated on the basis of a different hypothesis.

            DR. LEHMAN:  John Kennedy will address.

            DR. KENNEDY:  Yes, Dr. Afifi.  My name is John Kennedy.  I am a statistical consultant for the company and assisted in the data analysis.  When we first proposed a protocol to the FDA, there was an assumption of the experts that we polled, that there would be a wide variety of dosages and levels of PPI usage among the patients enrolled in this study.

            We, therefore, set up the power calculation to be based on Dr. Nothers' concept of using the Wilcoxon Signed Rank test and how much of a shift there would be in the median value.

            Fairly soon after the inception of the study, we discovered that there were only three or four varieties of dosage that were useable or were being used on these patients.  At that point, the use of the Wilcoxon Signed Rank test became untenable.  Too many ties were involved.  The power that we had assumed it would achieve was not the same.

            So, in conjunction and in consultation with the FDA, we modified the protocol to be the stronger one and based the analysis still on the Wilcoxon Signed Rank test and the Sign test for the secondary objectives, but we did recompute the power based on the sample size that we had done and found that we had adequate power under all of the possible alternative modes of analysis that we used.

            So that is why the hypothesis changed.  The hypothesis that you see today for the study is much stronger than the original hypothesis.  And it was because our assumptions as to the degree of variation in the dosages of PPI's use was not correct.

            DR. AFIFI:  Did you actually supply that computation of the power to ‑‑

            DR. KENNEDY:  We did.  Under a variety of different scenarios, we did.  One of them was just the test on a binomial proportion, a very simple one.  The other was the exact binomial computations for use of the Sign test, which we used in a number of cases since it was the most dramatic and the data was sufficiently dramatic to show that.

            The FDA permitted us to use that as well.  So we did the power calculations under a wide variety of circumstances.

            DR. AFIFI:  Dr. Cooper, I don't think we were given that calculation in our material.  Is that right?  I didn't see it.  Perhaps we could take a look at it, you and I, later on.

            Just one quick question.  Do you have any concern that the new hypothesis is a post hoc hypothesis, one that ‑‑

            DR. KENNEDY:  Not really.

            DR. AFIFI:  Let me just finish my question.  Then I would like to hear your response.  You could argue, someone could argue, that this is a post hoc hypothesis, which means it was a hypothesis derived after looking at the data, which would invalidate the power and the significance level calculations.  What is your response to that?

            DR. KENNEDY:  The only data that we looked at at the time when we revised the hypothesis was the entrance data, the dosages of the PPIs that the patients were on at the time of admission.  This was done before any follow-up data was available.

            DR. AFIFI:  Okay.  Thank you.

            CHAIRPERSON WOODS:  Dr. Achem?

            DR. ACHEM:  Good morning, Dr. Lehman.

            DR. LEHMAN:  Good morning.

            DR. ACHEM:  I appreciate your presentation.  I have a few questions, if I may, regarding the technique of injection and the assessment of the residual amount of material that is seen on the X‑ray.

            If I may, in the first question, I would like for you to address the issue, the dynamic nature of the gastroesophageal junction and the potential technical challenges that that may represent for the endoscopist given the fact that I believe the device or the materials described in the database are to be injected over a one‑minute period of time.

            Specifically within the question, are there any difficulties or is there a correlation between the sloughing of the material or the inability of the endoscopist to inject accurately given the amount of time he has to spend to deliver the material?

            DR. LEHMAN:  In the animal studies, we thought there was some relationship between slow injection and less sloughing, but that was not a formal study.  Yes, as you know, the LES with respiration, swallowing, gagging, et cetera, moves around.  And so one cannot always penetrate within the adult and sit there calmly and deliver the material slowly over time.  Sometimes you get half an implant in and the patient moves.  You fall out.  And you've got to start over.  So it isn't always just a straight one‑minute injection.

            DR. ACHEM:  So in your opinion, that constituted a significant challenge?  Do you think that there is a correlation in certain patients or was there an effort to quantitate or qualitate, somehow or another, where technically the injection was more difficult given the dynamic nature as far as the relationship between that and sloughing of the material?

            DR. LEHMAN:  Only in the sense that if the most non‑sloughing implant is the ring and that occurs in a deep layer.  If you can hit a spot which gives you a nice ring, that can be done with maybe one or two needle entries.  And then that rarely sloughs.  So the deeper it goes, the less it sloughs.  And the deeper it goes, the easier it is to keep your needle in the spot unless a patient just overly wretches.

            But it is no more difficult than sclerotherapy was in the old days.

            DR. ACHEM:  Now, I was not clear in reading the materials whether the intent is to inject at several puncture sites or the injection was done at one site and continued provided you had a visual contact that was satisfactory, indicating a muscular layer injection.  Could you clarify that?

            DR. LEHMAN:  The initial goal was to do four quadrant implants.  And that would represent a nearly circumferential injection.  We found by happenstance that in a few patients as you injected, you got circumferential ring formation, in which case you got circumferential distribution without pulling out and starting over.  So the needle stays in for that circumferential injection.  Otherwise, the planned goal was a four‑quadrant implant.

            DR. ACHEM:  So are you comfortable that one single site injection provides adequacy for the purpose of the study?

            DR. LEHMAN:  If a ring occurs and, indeed, you get circumferential distribution.

            DR. ACHEM:  A question pertaining to the X‑ray assessment.  You're a professor of radiology.  So that is helpful in the interpretation of the data.  I believe that the documents allude to challenges on the standing, the residual amount; in part, because there is an overlap of bony structures.

            In what position is the patient X‑ray during injection?  Is it done in the horizontal position?  Is it lateral position?  How do you obtain best imaging?

            And then comment a little bit on the second part of the question.  I would like to hear you comment on the assessment of the 12‑month residual material.  It was assessed with a chest X‑ray, PAN lateral?  Was it assessed during a barium swallow?  What method was used?

            DR. LEHMAN:  Yes, all to assess circumferential distribution of material, which is going to by necessity partially overlap with itself unless it happens to be sitting like that and overlapping bony structures.  You're at the diaphragm level.  So sometimes it projects in the lung field, sometimes an abdominal field.  And so the contrast is quite variable as to how well you can see it.

            In general, one must have two plane films, PAN lateral.  And that was usually chest, sometimes abdomen, and then sometimes it was spot films taken right before the barium swallow.  So, actually, that was part of the vagaries of the assessment.  They weren't constant films, although they were bi‑plane for all patients.

            DR. ACHEM:  And during the fluoroscopy part of the injection, in what position were the patients placed to ascertain the amount of contrast being infused or injected?

            DR. LEHMAN:  Most patients are on their side, like standard upper GI endoscopy.  Therefore, lateral projection is used to monitor the injection.

            DR. ACHEM:  One last question regarding again the residual amount of contrast left or material left.  You showed in the data that CT imaging was also done in a select number of patients.  Is there a number of patients to correlate the data on CT imaging with regular radiography?

            DR. LEHMAN:  There are only a few patients that I CT examined, usually for some special circumstance.  The material has enough tantalum in that it blurs out partially.  Quantitative CT volumetric studies were not done but would be of interest in the future.

            CHAIRPERSON WOODS:  Dr. Ferguson?

            DR. FERGUSON:  Thank you.  I have just two questions for you, both regarding study design.  The first, though, regards the endpoints chosen for the study.

            I understand the hope of the sponsor is to get patients off PPIs, but the goal, as stated, is to reestablish the anti‑reflux barrier.  When we do clinical research and surgical treatment of reflux, the gold standard, for assessing the success of that is pH studies.

            I am curious as to why that was not selected as the primary endpoint of the study.

            DR. LEHMAN:  It's a good point.  I think ideally that would be the case.  No one had chosen that as a primary endpoint to date in any endoscopic technique study.  And we were sort of following the field on direct dosing and chose that as a secondary endpoint.  I think, as you will see in the next session, the pH data is actually pretty strong.

            DR. FERGUSON:  The second question has to do with retreatment.  Was retreatment written into the original protocol?  And, if so, how were patients selected for retreatment?

            DR. LEHMAN:  Retreatment was written into the initial protocol as at 30 days.  If one's Velanovich quality of life score was not less than 15 off drug, if they had not become minimally symptomatic, then they qualified for retreatment if the patient wanted to.

            Then there were a few protocol violations where the patient felt good at 30 days, but all the implant had sloughed out.  And we said, "This is not going to last.  We had better put some more in."  So a few people got retreated on that basis.

            CHAIRPERSON WOODS:  I have a couple of questions with regard to technique.  First of all, for sedation, the conscious sedation used for the procedure, the procedure technically seems to be very dependent upon keeping that needle imbedded in the muscle layer for some period of time for a very slow injection.  So, therefore, it would seem the patients really need to be fairly sedated so you don't have a lot of retching and movement during this time to have success.

            Did most of the investigators use what we would in endoscopy term standard conscious sedation with benzos and other narcotics or did many of the patients have MAC anesthesia?  What would be your comments as to what we would recommend to future physicians using this?  Would you recommend MAC anesthesia to keep the patients really sedate?

            DR. LEHMAN:  I think you're correct.  It does require a little better sedation than a standard endoscopy because it lasts some time and does hurt a little bit as you inject.  And we want the needle to stay fixed.

            Now, I think if Jill will find the amount of anesthetic ‑‑ is that going to get on the screen?  So maybe there on the screen, we can see that the average dose of meperidine, about 100 milligrams.  Average dose of fentanyl, that seems to be in error.  That is not correct.  Seven percent of people did get MAC anesthesia with propofol.  Overall it was a little higher than average anesthesia compared to a standard upper endoscopy.

            CHAIRPERSON WOODS:  If you were recommending for the physician labelling the type of sedation that be used, are you comfortable with this sort of standard sedation or would you recommend MAC anesthesia?

            DR. LEHMAN:  No.  I think standard sedation with titrating to tolerance would be appropriate.

            CHAIRPERSON WOODS:  Secondly, fluoroscopy appears to be absolutely necessary to gauging the proper injection.  Is that correct?

            DR. LEHMAN:  Probably with experience, it is not going to be mandatory.  And, indeed, I have injected in a separate study in intensive care G‑tube patients who didn't have fluoroscopy, really.  We have only injected about ten patients without fluoroscopy.  The implants look about the same.

            So we say at this point it's necessary.  It certainly guides the implant.  Whether it will be ultimately necessary, I am not sure.

            CHAIRPERSON WOODS:  I will just make a statement that there is no mention in the physician labeling component for this product of requiring or not requiring the use of fluoroscopy.  I think that should be addressed by the sponsor.

            I don't have any other questions.  Anyone else?

            DR. FENNERTY:  Dr. Lehman, just one follow‑up question.  It seems to have been brought up by Dr. Achem and also our Chair, Dr. Woods.  Those doses don't seem actually out of line at all.  They're actually quite a bit less.  I am assuming that is 130 milligrams of fentanyl.

            DR. LEHMAN:  I'm sure.  I apologize for ‑‑

            DR. FENNERTY:  But the Demerol dose, those doses are actually less than what we normally see in perhaps ERCP and many other therapeutic procedures.  It seems to be the forebearing the needle in the technique ‑‑ and it goes back to I think what Sami was asking about ‑‑ forebearing the needle is actually quite a bit easier to hold position here than it would be, for instance, putting a tattoo in what we're saying, just below the submucosa in attempting to form a bleb.

            Just as an experience issue, how do you rate those two?  I mean, sclerotherapy seemed to me very difficult if a patient is moving.  Tattooing is very difficult.  This sounds like you're bearing the needle a little deeper.  Is it easier to hold on there?

            DR. LEHMAN:  Degree of difficulty.  It's clearly easier than an ERCP.  I don't do mucosal resection.  So I'm not quite sure I can compare there.  It's harder than a standard upper endoscopy and taking a few biopsies.  It's somewhere in the middle.

            I'd say it's still back to sort of sclerotherapy difficulty with patient moving and sclerotherapy, a little blood in the lumen.  Here you've got a little bit of spilled implant in the lumen.  There are some small problems, but they are easily manageable.

            DR. FENNERTY:  One brief follow‑up question is I don't know if you are aware of these data, but the MUSC group apparently has done some work doing this under endoscopic ultrasound guidance.

            Do you have any information whether the results are different if their tolerability or their success rates, sloughing, et cetera, is any different than what was seen in this pivotal study?

            DR. LEHMAN:  Well, now, if I can be corrected, I don't think MUSC has any material.  Is that right?.  They're using a different material, the South Carolina group.  They have no materials.

            DR. FENNERTY:  That is not this stuff.

            DR. LEHMAN:  But we have done in Europe and ourselves a few animals with the U.S.  It does help with initial needle tip placement, but once you start to inject, you get this puff cloud and it destroys all the landmarks.  And so I doubt that that is going to be an important player.

            CHAIRPERSON WOODS:  Dr. Achem?

            DR. ACHEM:  Excuse my number of questions back again, Dr. Lehman.  Dr. Lehman, if you would, were there any patients that at the time of the procedure during injection experienced pain immediately?

            DR. LEHMAN:  Yes.

            DR. ACHEM:  What should be going?  Is that because you stopped or that's a good sign, it's a bad sign?  Obviously I would take it as a bad sign.  What does it mean in terms of injection?  For instance, has it happened at very small volumes and then precluded from injecting anymore.

            DR. LEHMAN:  There were a few patients which hurt as you injected.  You're putting volume in.  And DMSO maybe has some chemical heat burn to it.  So there is some reaction to it in some people.

            Only in the rare patient did we have to stop and anesthetize more.  Almost always you just titrated up the anesthetic a little bit and they tolerated it.

            DR. ACHEM:  I am sure there have been no accidents, but is there any data on the material falling in the mucus membranes or in the eye, for instance, any information to that effect?

            Let's say an accidental spill occurs, falls in the eye of either the paramedical personnel or, God forbid, the patient as well.  Any concern about injury to the eye or any eye data or thoughts, toxicology contrast table data?

            DR. LEHMAN:  Probably a little chemical irritation, but no data.

            DR. ACHEM:  You smell like garlic as well?

            DR. LEHMAN:  Garlic eye drops, yes, sir.

            CHAIRPERSON WOODS:  Dr. Shaheen?

            DR. SHAHEEN:  Any of the patients that you were just describing that Dr. Achem asked about buck and actually displace the needle, kick it out so that it left the open track?  And if so, how quickly does the stuff readily ooze back the track if you can't do what you want to do, which is hold that needle in place to let it set?

            DR. LEHMAN:  Right.  You inject slowly so that the material has time to shift from liquid to solid.  And then after injecting, you sit still, sit there for another 30 seconds, allow it to solidify.

            If you pull out too early, you get more back leak of liquid.  And then that's some loss of implant.  Usually volume‑wise it's small, but it's annoying because it's sitting in the lumen and taking up space and makes it dark gray and you can't see as well.

            DR. SHAHEEN:  Did any of those chest pain folks actually get uncomfortable enough to kick your needle out?

            DR. LEHMAN:  Probably I can recall one that I think we had to stop and switch to propofol, but that's an exception.  Usually it's just a little more Demerol versed.

            CHAIRPERSON WOODS:  Okay.  Any other questions?  Yes, Dr. Gellens?

            DR. GELLENS:  I had one quick question under adverse events.  In the binder under "Unrelated Adverse Events," two patients had abscesses.  Where were they?

            DR. LEHMAN:  I don't recall.  Abscesses?  Why don't you hold that question while we look it up?  We'll address it in a little bit.

            DR. GELLENS:  Okay.

            CHAIRPERSON WOODS:  Okay.  Why don't we move on to, then, the next speaker?  And you can come back with the answer to that question when he is finished.

            DR. LEHMAN:  All right.  Next is Dr. Dave Johnson, professor of medicine at Eastern Virginia Medical School.  He will report on the effectiveness studies here.

          4. STUDY RESULTS: EFFECTIVENESS

            DR. JOHNSON:  Good morning, members of the panel, FDA.  It is a privilege to be here and have the opportunity to present this study affecting this data.

            Per your request, disclosure, I would suggest that I have no financial interest in an ownership position in the company.  I am a clinical consultant and have a consulting arrangement and am a clinical investigator for the sponsor.  My way has been paid here by the sponsor today.

            The charge today was to present to you the clinical data.  I would like to refresh your memory from the study design, ‑‑ if we can have the next slide? ‑‑ to present the study objectives so you can better contextualize the information that I am about to present.

            The primary objective, as you recall, was to eliminate PPI use or to provide a reduction in proton pump inhibitor use by greater than 50 percent from baseline.  Secondary objectives were the improvement in related quality of life symptom scores, Standard Form 36 health survey, the age assessment, or manometry.

            The data that I am going to present to you will keep these in perspective.  Where appropriate, I will present this all at a protocol analysis and, where appropriate, will also present this as an intention to treat analysis to keep things in perspective.

            I am going to present the data with focus on 6 and 12‑month intervals.  The duration of this study was 12 months.  Highlight the six‑month interval assessment.  The six‑month interval assessment has already been through a peer review process and will appear in the American Journal of Gastroenterology in two weeks.

            Next slide, please.  Turning first to the primary objective, if we look at the primary objective results at 6 months, the efficacy for being totally off PPIs or dose reduction greater than 50 percent, that number is 84 percent.  As you can see here, as has been alluded to in some of the preceding discussion, the good news is that this represents the vast majority of PPI patients being entirely off proton pump inhibitors.  About 10 percent showed at dose reduction, but 74 percent were totally off their proton pump inhibitor use.

            At 12 months, this efficacy was sustained for the population in the study.  It was 80.2 percent.  And the efficacy of patients being totally off PPIs was 70.4 percent, stability as far as the percentages in dose reduction at 9.9 percent.  Four patients were not available for this data analysis.  And so by intention to treat analysis, the data was reanalyzed to compare with the per‑protocol analysis.  And there is no statistical difference between both of these analyses' endpoints.

            Next slide.  Dr. Lehman presented to you the baseline entry criteria for the medication use.  This data presentation now compares that reanalysis at the 12‑month endpoint.  If we recall the baseline use of PPI use as quite high, 62 percent for standard PPI use and 30 percent taking higher than the standard doses, contrast, however, at the 12‑month exit from this analysis, the numbers fall from 62 percent down to 16 percent, from 30 percent down to 4 percent.

            This represented not only a reduction in use of medication, but, actually, a withdrawal of the PPI use.  As you can see here, this was not representing shift to lower dose PPI use and not skewing the use of the PPIs to half dose or lower.  In fact, it was not skewing towards supplemental use, skewed the data provided for the baseline and 12‑month analysis for both supplemental H2s and supplemental antacids.  In fact, 51 percent of the patients, the exit at the 12‑month analysis, were off all PPI H2 receptor antagonists and supplemental antacids.

            Next slide.  Turning now to the secondary objectives, the first assessment point was the Velanovich heartburn score, the standardized and validated measure for assessing GERD response in regards to intervention.

            The patients were evaluated, as the study design alluded, on the proton pump inhibitors to represent a baseline.  They were then withdrawn for this for a period of 10 to 14 days and their baseline reestablished off proton pump inhibitors.  As you can see here, there is a rapid rise in recurrence of symptoms.

            Here the heartburn score is dramatically increasing.  Abnormal here was defined as greater than 11, the rise then representing the new baseline for comparison, then, with the intervention of the Enteryx to follow.

            Following withdrawal of PPIs, the Enteryx was interposed here and sequential assessments at 1, 3, 6, and 12‑month interval data as presented.  You can see that there is a rapid resolution of the symptom scores and actually reestablishment of the baseline that was established on PPIs.  This was statistically different in comparison now to the baseline off PPIs at 1, 3, 6, and 12 months.  So there was no waning of effectiveness as it relates to heartburn scores.

            Next slide.  If we compare the patient data that was lost and analyze this and compare it, per protocol and intention to treat, eight patients were not available for this data analysis at the completion of the trial.  In contrasting both per protocol and intention to treat, there was no difference as far as the p‑values as far as the efficacy and statistical improvement evident between these two analyses.  So, hence, in the worst‑case scenario, attributing these people as non‑responders, there was no change in the ultimate study intent.

            Next slide.  We turn, then, to regurgitation scores, again, looking at the same type of presentation of data based on established on PPIs, which all the PPIs' reestablishment of the baseline symptoms and then interposing Enteryx here, you can see again sequential follow‑up, reestablishment of a good control of the regurgitation scores, not different than the baseline on PPIs, and highly statistically different as a comparison to patients that were off their PPIs.  And, again, there was no waning of this benefit as far as the progressive follow‑up at 1, 3, 6, and 12 months.

            Comparing now, the next slide, again, the per‑protocol and intention to treat analysis in looking at statistical endpoints here, again, accounting for the eight patients that were not available for the follow‑up for inclusion of data, there was no difference in the study message here as far as statistical efficacy between the per‑protocol and the intention‑to‑treat analysis, again, using this infuted data as a worst‑case scenario.

            Next slide.  We turn to the second secondary objective; that is, the Standard Form 36 health survey, first looking at the physical component score.  The data is very analogous in the previous presentations based on on PPIs, interposing Enteryx therapy.

            You can see that there was a rapid reestablishment of a good control of the SF‑36 physical component score comparing to baseline on PPIs not statistically different, statistically different, and maintained through the 1, 3, and 6‑month, 12 interval follow‑ups in comparison to those baselines off PPIs.

            If we look at the mental component score on the next slide, baseline on PPIs, withdrawal, again, interposing Enteryx therapy here, there was a statistical difference that was evident at the 1, 3, and 6 months.  It did not reach statistical significance at 12 months.  It was clearly back to where the baseline was on PPIs and numerically greater than it was off PPIs.

            In a subset analysis of this, if we looked at those patients that met their primary objective, it was statistically significant at p‑value of .012.

            Turning to the third parameter, secondary objectives, that is pH assessment, on pH monitoring was done at baseline in comparison analysis at 6 and 12 months.  The duration of the pH assessment shown here is comparable for each of these interval assessment points.  Paired analysis was performed for all of the available data.

            This slide presents that pH assessment contrasting the 6 and 12‑month interval assessments comparing to the baseline the median pH score shown here with the intraquartile range shown in parentheses.

            Standard assessments here with total pH, supine, upright, and total episodes, statistical significance was seen at 1, 6.  And there was no waning of statistical significance, at least evident at month 12.  There was no statistical benefit, as evident for the longest episode of duration of abnormal pH reflux episode but clearly significant for all of the other parameters.

            If we look at some additional pH assessment, the percent normalized patients between 6 and 12 months, 37 percent at 6 months and 39 percent of patients in the population normalized their pH.  If we look at these for patients with improvement in their PPI use; that is, meeting their primary objective, the number was 43 percent.  It normalized at 12 months.

            In contrast, only one of nine of these patients with no improvement in their PPI use had normalized at 12 months.  What we see here does not require normalization of pH to reach the primary study objective; that is, withdrawal of PPI use or 50 percent reduction in that medication use.

            Of note, 82 percent of the patients showed at least a 20 percent improvement in one or more of the pH parameters assessed.  We use this as an intention to treat analysis.  There were 18 patients who were not available for repeat pH assessment at 12 months.  There was no statistical difference as far as the study endpoint, even with ITT analysis.

            The results are still significant.  In fact, if we look at this for these patients, remember, we're not available for any of the data analysis.  That leaves 14 patients.  Seventeen patients actually had met their primary study objective; that is, they are off their PPIs, or they had a 50 percent reduction.  So, again, even with the worst‑case scenario, assuming all of those people as treatment failures, 50 percent of those actually had met their study objective.

            If we turn to the final secondary objectives; that is, manometric assessment, there was no significant change from baseline in lower esophageal sphincter pressure, peristaltic amplitude, where the post‑swallow residual lower esophageal sphincter pressure at 6 or 12 months is very much the same message that we have seen for all the intervention GERD therapies, endoscopic GERD therapies, for the commercially available trials and applications of interventions that are available at present.  There was no difference, at least from the Enteryx study, from what we have seen for the studies to date.

            There was a significant increase in the LES length that is reported in the manuscript that we alluded to at six months.  At 12 months, there was a similar increase in the LES length, although it did not reach statistical significance.  It did reach statistical significance if you looked at it as a function of medication responders so the PPI withdrawal or those people meeting their primary objective, the p‑value was .026.

            Next slide.  Endoscopy was not an a priori objective of this study, but the results are provided for the 12‑month assessment.  Savary‑Miller scale was used for the endoscopic interpretation.

            Seventy‑two percent of these people demonstrated improvement or no change compared to the baseline esophagitis scores while on their PPIs.  Eighteen percent had a one‑point worsening.  The majority of these people were off their PPIs.  Ten percent had a two‑point worsening.  And the majority of these people, five of seven, had actually resumed their PPI use.  No patient at exit had a Grade 3 esophagitis.

            As has been discussed, to date investigators were asked to ascertain the durability of this product over time.  And radiologic interpretation was provided by plain film radiography.

            The comparison was at the one‑month baseline and then ascertained over the 3 and 6‑month and 12‑month intervals.  The data presented here shows that there is a remarkable stability evident once they get to three months.  And there is really no waning of the residual implant volume as estimated by the investigators once they reach three months.

            We believe that the one to three‑month transition decrease in volume represents the sloughing, as alluded to in those that have a too superficial injection.  This occurs before generally three months.  Basically, this attrition here we believe represents sloughing but stability evident at three months on.

            The one‑month interval was chosen as the baseline.  As Dr. Lehman alluded to, there are some artifactual things that can develop if you use the immediate post‑procedural analysis of the X‑ray.  Because of some splash‑back, as you see here, there is some back‑splash or leakage from the needle as you reposition the catheter.  This would create an artifact if you interpreted the X‑ray immediately after the procedure.  So one month was chosen to represent the viable true implanted assessment point.

            DR. FENNERTY:  Dr. Johnson, can you point that out a little clearer?

            DR. JOHNSON:  This is the injection point.  The back‑splash is in this area here.  There is just some residual material in the hiatal hernia.

            Next slide.  As also has been discussed, this implant will slough if injected very superficially.  In sequential endoscopy, this patient demonstrates the slough.  And this develops and occurs as this implant is passed in through this ulcerated area.

            And in follow‑up at this patient, you can see that this heals over and the residual at six months.  There is a little bit of a residual implant here.  The implant then passes into the GI tract and is passed through the normal GI transit.

            CHAIRPERSON WOODS:  What time frame was that first endoscopy with the ulceration done?

            DR. JOHNSON:  A matter of days.  The follow‑up X‑rays are presented in the present submission for 12 months, but there is data from the pilot series from previously published study from Europe that does present longer follow‑up from a radiologic perspective.

            This is, again, a plane film radiograph on one of the index patients shown here contrasting the 1999 to the 2001 follow‑up, again, demonstrating the durability, at least from the radiologic perspective, of the implant.

            From a CT perspective, again, from the same pilot series on spiral CT shown in another transaxial image here, you can see this circumferential image here of this radiopaque density, demonstrating stability over time here at 2.5 years after the initial injection.  No evidence of migration was evident.

            This slide contrasts the residual implant as a function of meeting the primary objective at 12 months.  What we can see is that there is an array of residual volume that is seen, even though they meet the primary objective at lower volumes across to higher volumes.

            There is a trend evident that at higher volumes, there is a greater tendency towards meeting the primary objective.  And, in fact, if greater than 6 cc was evident at 12 months, 100 percent of these patients met their primary objective.

            As alluded to, retreatment was part of the protocol.  Twenty‑two percent of the patients were retreated in a single additional session.  As mentioned, the subjects are retreated for inadequate symptom control and/or loess of implant.

            Per protocol, all the retreatments occurred early, within 1 to 3 months after the original treatment in analysis of 12 months for those patients meeting the primary objective, 68.4 percent.  And device‑related adverse events were similar, be it that they were treated with one session or retreatment.

            We looked at this as alluded to in some of the comments by Dr. Achem and Dr. Shaheen as far as predictors of outcome.  We looked at these as independent analyses vectors of meeting the primary objection.

            The presence or absence of hiatal hernia did not differentiate nor did the size of hiatal hernia, body mass index, the duration of medication use, or the standard or high dose was not an independent predictor; age, gender, race, again, not independent predictors.  And, as alluded to I think by Dr. Shaheen, the investigator experience was a learning curve.  We did not find that evident as far as a predictor of outcome, nor was there a site variation as far as independent predictors of outcome.

            So the summary of the effectiveness data, I would present in the context of the primary sector objectives as follows:  80.3 percent of patients were able to eliminate or reduce the PPI use in a highly statistically significant fashion.  The vast majority of these were those patients that were actually off entirely PPI use.  To refresh your memory, it was 70 percent and 9.9 percent.  So basically these people are off their medications as far as their primary objective.

            Secondary objectives.  There was highly statistically significant impact in a positive sense as a result of Enteryx ascertaining GERD‑related, health‑related quality of life symptom scores, the physical component score, the SF‑36, the mental component score was statistically significant up through six months.  And it was not statistically significant from the off PPI at 12 months.  pH assessment throughout the 12 and 6 months, again, highly statistically significant.  And there was no statistical difference overall at 12 months for manometry.

            Based on the results of this study, the investigators from this trial would conclude that an endoscopic implantation of Enteryx is effective for the treatment of systematic patients with gastric esophageal reflux disease.

            Thank you.

            CHAIRPERSON WOODS:  Thank you.

            We have a lot of questions already.  I am just going to start on this side, and we will move around.  Dr. Shaheen?

            You wish to address the previous question?

            DR. STEIN:  Yes.  You asked about the two abscesses.  One was a root canal abscess.  And the other one, without having our database here, the treatment was with a urinary antibiotic.  So we assume it's a urinary tract abscess.

            CHAIRPERSON WOODS:  You don't know, but you assume?

            DR. STEIN:  It's a clomoxyl.

            CHAIRPERSON WOODS:  Okay.  Thank you.

            Okay.  Dr. Shaheen?

            DR. SHAHEEN:  Thank you, Dr. Johnson, for the presentation.  A question for you on Table 10, which is on page 121 of the submission, which is the primary endpoint.  It looks like this is the month 1, month 3, 6, and 12 data on p‑values after treatment.  It looks like there is a decline in the primary endpoint at each evaluation.  It goes from 97.6 to 89 to 84 down to 80.

            Since you show us that implant volume doesn't really change much after month three, to what do you attribute the declining efficacy that is demonstrated here in the primary endpoint?  And, secondarily, do you think this is reaching ‑‑ do you think it is going to level out at 80‑ish percent reaching the primary endpoint?  And if you do think that it is going to plateau, what do you base that on, Table 10, page 121?.  These are follow‑up visits, months 1, 3, 6, and 12, 97, 89, 84, 80.

            DR. JOHNSON:  Until I see the table, I can address some of your comments as far as the primary objective.  There was really no major difference between 6 and 12 months.  If you used the primary objective at 84 percent and you reassessed that at 12 months, it's 80.3 percent.

            The stability is really in the PPI use.  There is really no change in those people that are at greater than 50 percent reduction and the numbers are minimal as far as the change in daily continual use of PPIs.  They really don't change.  They go from 74 to 70.3 percent.  So I don't think that represents a significant waning.

            We certainly don't see this major shift when you start to look at the ancillary use.  We're not driving people to lower dose of PPIs.  That's very clear from the data presented.  The same from the supplemental use because those are pharmacologic therapies that they would turn to if they were symptomatic, ancillary use of antacids or H2s.  There is a minuscule difference as far as the follow‑up.  So representing a waning of benefit would be hard to surmise based on the data that we presented, at least from my interpretation.

            DR. SHAHEEN:  So the trend from 97 to 80 is not statistically significant.  Is that correct?

            DR. JOHNSON:  I can't comment on a trend analysis from that.  I can tell you what the analyses are at 6 and 12 months.

            DR. SHAHEEN:  In the safety data, you show that there is really no increased danger with the higher volumes.  It appears that the people that had bad outcomes are evenly distributed throughout the volume data.

            In the efficacy data, you show that it looks like, at least for residual volume, effectiveness goes up with residual volume.  Is six to eight cc the right amount given that or should you be trending on a higher side if you can increase the amount of implant without causing more safety issues, is this the right volume or should volume be increased?

            DR. JOHNSON:  It's certainly speculative, but 6 cc seems to be a target where once you got to six cc, 100 percent of patients were meeting a primary endpoint.  So it at least would not make sense based on the data that we have to say that you need to go beyond that by any margin.  It would be speculative.

            Clearly we see that it is hard to predict at lower volumes.  Still a sizeable percent of those patients meet primary objectives, even down to two cc.  So we can say that there is a threshold once you get beyond.  We know you are going to do well, but representing the other side of that threshold and saying what percent tend to respond at the lower dose would really be impossible.

            DR. SHAHEEN:  And that is six cc that stay in?.  That is not six cc in general?

            DR. JOHNSON:  That is correct.

            DR. SHAHEEN:  That is six cc that are still there.

            DR. JOHNSON:  Absolutely, that stay in because the interval assessment there is at 12 months.

            DR. SHAHEEN:  Okay.  Am I correct in understanding that the Velanovich score on PPI is no different from the 12‑month efficacy score after Enteryx?  Because looking through the tables that present the Velanovich scores, it looks like PPI is as good or better for every one of those, but as a group, there is no significant difference.  Is that correct?

            DR. JOHNSON:  That is correct.  There is no significant difference there.

            CHAIRPERSON WOODS:  Okay.  Dr. Ferguson?

            DR. FERGUSON:  I have a few questions regarding the outcomes.  The first has to do with the pH monitoring results, 6 and 12 months.  Clearly you have shown that there is a statistically significant improvement in those comparing the patients at 12 months to their measurement off PPIs.

            My question is, what percentage of patients still were defined as having GERD based on their pH result?.  The mean values, the median values all are clearly within the GERD range as you have defined it for entry of patients into this study.  And if the intent of the product is to reestablish the anti‑reflux barrier, how successfully has this been accomplished?

            DR. JOHNSON:  It's a good question.  The numbers are 37 and 39 percent for the 12 and 6‑month people that have truly normalized their pH.  Recognize that that didn't correlate as far as an absolute predictor of people that met their primary objective.

            We see this in pharmacologic trials.  People don't normalize their pH on standard therapies with PPIs.  I mean, if we do pH assessment on people on standard PPIs, we don't see normalization as the surgical targets would potentially derive.  So looking at symptoms and looking at medication use doesn't require true normalization to meet efficacy.

            DR. FERGUSON:  Well, I guess I would disagree.  The concern about reflux is not just symptoms but the risk of development of adenocarcinoma, one, or complications of reflux.  And if the patients are exposed to a continuing abnormal levels of acid in their esophagus.  They don't have the symptom trigger to seek therapy anymore if you have successfully treated their symptoms, but so has the abnormal pathology going on.

            DR. JOHNSON:  The symptoms in the esophagus don't relate to what we see in regards to objective measures sometimes, pH assessment or even endoscopy.  If you look at the people in the PPI trials and you look at maintenance studies of people that are on ongoing therapy with prescription PPIs, there is a sizeable percent; in fact, over 50 percent, in some trials actually have endoscopic esophagitis.  And they don't have any symptoms.  They have relapsed by one criteria, but they have no symptoms.

            So using that as a parameter for guiding PPI therapy, we would be off base in regard to saying that we fix things by prescription medication.  And it's much the same here, I think.  We're seeing that there's an improvement in pH enough to hit the threshold to make them at a level of control that they would take medications or report symptoms along with what we see for PPI use.

            DR. FERGUSON:  I wonder if you could comment on what you think the mechanism of action of the product is given the fact that at 12 months, there are no differences in any of the physical measurements of LES.

            DR. JOHNSON:  Yes.  Again, it's speculative, but based on what we have seen to date is the best surmisable as transient relaxations.  We have the canine model showing compliance differences in the cardia and preliminary evidence from Dr. Deviere that shows the transient relaxation.  It certainly makes sense to us physiologically.  That is what we are seeing a difference in the efficacy.

            DR. FERGUSON:  I would suggest that that would be something important to investigate clinically.  I know that there is an objection made by the sponsor regarding comments about the device as a bulking agent.  Yet, several of the radiographs shown here suggest that, in fact, that is what it is.  If I could just comment a little further on that, please?  Go ahead.

            DR. STEIN:  Just a comment on the bulking.  We are putting bulk into the esophagus.  So, of course, there is some bulk component to this.  Particularly because there are urologists on the panel, the training, for instance, in injections of collagen for urinary incontinence, trained to, at least in the labeling, actually coapt and create an obstruction in the middle of the urinary tract, against which the woman would have to perhaps push through in order to void.

            We don't train to create a code obstruction in our training.  And that is the differentiation we want to get across in terms of a bulking agent because we think if we actually did pillow it, we would increase the opportunity to have a dysphasia, which may not be transient.

            It's to differentiate the collagen urinary incontinence approaches to definitions of bulking, as opposed to what we are trying to teach and train in this application, but material is going in.  So, of course, there is a bulk component.

            DR. MANYAK:  But isn't that the mechanism of action of this, then?  Is that primarily because the more coapt the engine ‑‑

            DR. STEIN:  Not really.  If you'd like another analogy, if you have a trick knee and you have a knee brace on it and your knee is going to give out, it gives you that support and presents that moment of unfolding, that TLSR or that moment of shortening response.  He just has to do it for that moment and you won't have the relaxation.

            So it doesn't have to be an obstructive event.  And that is why we think that modification of the compliance is the appropriate approach.

            DR. FERGUSON:  I share some of the concern expressed by some of the other panelists about the methods used to assess residual volume of implant at 6 and 12 months.  According to one of your tables, it appears that 70 percent of the patients at the time of final assessment had less than 6 in amount of the implant remaining.

            And, yet, you report very high symptomatic success rate.  That again opens a question as to what you think would be the most appropriate recommendation for injectate volume.

            DR. JOHNSON:  Recognizably, the radiologic assessment of volume was not an a priori assumption in this study.  So this was a way, at least, to demonstrate durability more than anything else.  And the calculation in trying to interpret what that durability was weighed against the best estimates of the investigator and the clinical response meeting primary objective is what that presentation was designed to do.

            It would be impossible to make a comment beyond that.  I think that it's clear that the intent of initial volume is six to eight cc.  We know that if you maintain that initial volume, the 100 percent of patients that maintain 6 cc met that primary objective.

            Below that, it was impossible to predict, although there was success seen across that wide array of the population that you just alluded to that lesser volumes clearly were the trigger enough for patients to impede their need for PPI use or major dose reduction.

            CHAIRPERSON WOODS:  Okay.

            DR. STEIN:  If I may, Dr. Ferguson, the company's use of tantalum in the product was primarily to help provide guidance to the gastroenterologist and the surgeon during the injection of this material about where the material actually was going.  So that this is not a blind procedure.  And we thought that this was very important.

            The use of X‑ray to do follow‑up was to assess whether there was any gross loss and to assess during the procedure whether there was a gross understanding of the coverage of the circumferential distribution.

            Now, if you do inject one to two cc at three to four different positions, you would get by definition a range of four to eight cc.  We saw in the course of the study that it is our impression that at six to eight cc, circumferential distribution given optimum result in a single session.

            I think that as a physician, that the purpose of the X‑ray is not try to say that 82.3 percent of material is there because a plane film X‑ray can't give you that kind of accuracy.  You would have to do quantitative CT.  And even in the quantitative spiral CT, you would have, as Dr. Lehman pointed out, some of the limitations of the artifact due to the scatter from this tantalum itself.

            We actually have in the course of the expansion study, which FDA also approved for us, baselines now on eight patients with spiral CT because we do intend to follow them to see if we can actually better quantify exactly the volume that's there.

            To your other question about the ongoing studies, Deviere is actually performing TLSR studies using the dense sleeve, as Dr. Fennerty has asked.  And we do want to continue to evaluate the mechanism of action because I'm sure over the years that go by, like in any procedure, there will be further optimization.

            But X‑ray per se is not an endpoint or a claim.  It's a tool.  Otherwise we wouldn't have put the tantalum in and we wouldn't be having this discussion.  We think it is a very helpful tool for follow‑up with the patients and a very helpful tool for the procedure.

            CHAIRPERSON WOODS:  Dr. Ferguson, do you have any other questions?

            DR. FERGUSON:  I have one more question.  Could you comment, please, on the summary statements on pages 131 and following in each of the individual tables regarding the health‑related quality of life scores for heartburn?

            Obviously you have achieved statistically significant improvement comparing the patients at 12 months after injection to the scores off of PPI.  You state in most cases that there's no difference or equivalent scores between the patients 12 months after injection to when they were on PPIs, although you also show that there are statistically significant differences between those 2 scores with the PPI use being higher in each case than after injection.

            DR. JOHNSON:  Just so I understand your question, in the health‑related quality of score, you talk about ‑‑

            DR. FERGUSON:  For heartburn?

            DR. JOHNSON:  For heartburn.  Your question is, is there a difference at 12 months and baseline off PPIs?

            DR. FERGUSON:  Well, the statement in your presentation is that the scores were comparable comparing patients injected at 12 months to patients when they were on PPI.  Yet, you demonstrate in the tables that there were statistically significant worse scores after injection compared to while on PPI.  Are you suggesting that those just aren't clinically important differences?

            DR. STEIN:  According to  Dr. Velanovich, when we spoke to him, we said, "Dr. Velanovich, what is normal using this GERD questionnaire?"  And he said, you know, "If you use 11, everybody is happy on that."

            What we can't tell and I think what Dr. Lehman and Dr. Johnson would tell you is within that range of 1 to 11, maybe I would be happy at 10.  Maybe you would hate it.  Maybe you would need to be at two.

            I can't tell you what the difference between a GERD score of two and three actually means.  I know that they are all comparable to their on baseline numbers, and I know that they are very, very statistically significantly improved compared to off PPI's.

            That is about all I can really tell you, but I can tell you that a two to three makes a difference because these patients functionally don't go back to their PPIs.  Obviously the improvement is that they're off of their insignificantly reduced dose.

            It's not like taking the temperature.  I can't tell you how fine a two to three is.

            DR. JOHNSON:  I guess another way to look at that, Dr. Ferguson, is to look at if they were off their PPIs and they were symptomatic, would they be driving to other ancillary medication use?  We really didn't see that.  These people really didn't drive to OTC, H2s, or antacids.  So a minimal symptom score didn't translate into a symptom enough that required some ancillary medication use.

            DR. FERGUSON:  Just to simplify, what I am getting from you is although there is a statistically significance in the scores, you do not believe it was clinically significant?

            DR. STEIN:  No.  I know that the off PPI is very significant.  I can't tell you from on PPIs.  That is why we have only stated that the scores are comparable because we don't know how to interpret them.

            DR. JOHNSON:  The answer to your question is yes.

            DR. FERGUSON:  Thank you.

            CHAIRPERSON WOODS:  Dr. Achem?

            DR. ACHEM:  Thank you, Dr. Woods.

            I would like to first make a comment, Dr. Johnson.  Thank you for your presentation.  Going back to Dr. Ferguson's question, I think it's an issue, the pH parameters, instead of flux.  And I do recognize that, I think all of us recognize that, many of the trials in the past, certainly pharmacological trials, I don't think have mandated a focus issue on the reversal of pH parameters and have actually assessed both symptom and healing endoscopically.

            I suspect that, clearly, as Dr. Fennerty alluded to that in your discussions with the agency, this was what at the time was customary for any trials dealing with reflux disease.

            Naturally, one ideally would like to see, though, a significant improvement in pH parameters.  There is some data.  And, Dr. Johnson, I know you're familiar with some of that data.  Just for the record, I want to mention a couple of studies, mostly in the elementary pharmacology of therapeutics, actually, that looked at patients with erosive disease and looked at the amount of PPI required to normalize pH.

            Indeed, actually, I myself, for one, was surprised.  Just to cite one of them, Galmiche, a study from Italy, 2001, Volume 15, page 1,343 alludes to addressing a number of patients with erosive disease, normalization of pH in 95 percent of the patients with omeprazole and 78 percent of patients on single dose omeprazole.  There are related studies from other centers as well with some significant normalization of the data on pH.

            Again, I'm trying to make the comment for the record.  Yet, I recognize fully that in this study design, that was not the issue and despite the fact that we will likely be normalized pH, I'm sure.

            Let me just ask a few number of questions.  And I realize that I may have to go back to even Dr. Lehman on these questions or maybe if you want to address them.

            I want to go back to one of the points on the chest pain.  There are a number of patients that had both symptoms, actually, chest pain and fever.  I just wonder whether any plural effusions or efforts, if any of those patients had developed any significant pulmonary infiltrates.

            DR. JOHNSON:  Since Glen presented the safety side, I am going to ask him to address that comment specifically.

            DR. LEHMAN:  I am not sure how many patients had the chest X‑ray during the acute symptoms.  These symptoms usually occurred in the first week or two.

            Everybody had a chest X‑ray at 30 days.  No pleural effusions were seen.  And I'm not aware of any pleural effusions if any early films were done.

            DR. ACHEM:  Dr. Lehman, you may want to hang around just a little longer, if I may, although I will come back to Dr. Johnson.  Had any of the patients had laboratory testing?  I noticed throughout the entire study that there seems to be no laboratory validation, such as CPK muscle enzymes done in any of the patients throughout, although there was some data in animals where you yourself in the university did some CPK analysis.  Can you comment on that?

            DR. LEHMAN:  The animals showed no significant laboratory alterations other than some very minor CK, as I recall, but we thought they were trivial.  I am not sure total study‑wise.  A few people who had symptoms, fever, pain, whatever, had some laboratory values done.  In our institution, they were all normal.  So they were not systematically done.  And what limited data we had, to my knowledge, was normal.

            DR. ACHEM:  Okay.  Regarding ‑‑

            CHAIRPERSON WOODS:  I'm going to interrupt just for a moment and say we are running very behind.  If the panelists could please confine their questions to questions and not discussion?  And, similarly, the respondents answer the questions directly with objective information?  And we'll have more time for discussion later after lunch.

            DR. ACHEM:  Thank you, Dr. Woods.  We'll try to follow your guidelines.

            Dr. Johnson and Dr. Lehman, the question is what is the ideal injection?  What does it look like, either endoscopically or fluoroscopically?

            DR. JOHNSON:  Well, it's a combined ideal image.  One is the endoscopic image, where you don't really see much.  That is the way we tell if it is too superficial.  We see a graying in the mucosa.  And that is evident very early.  .1‑.2 cc you can tell very quickly that this is not in the right place.

            Fluoroscopically what we see is a tracking as it hits into the deep injection plane.  And you can see the vast array that Glen discussed as far as either deposition of a globular form or an arc or in some cases just a tracking that goes all the way around as a ring pattern.

            So it's a two‑image view for an optimal view.  You're looking endoscopically, at the same time fluoroscopically.  You can tell very quickly that you are in the right area.

            DR. ACHEM:  In the retreated patients at 22 percent or so, I believe, ‑‑

            DR. JOHNSON:  Yes.

            DR. ACHEM:  ‑‑ do you have motility pH data?  Were those patients any different than the rest of the population?

            DR. JOHNSON:  Yes.  We looked at actually predictors of outcome for treatment and also for treatment failure.  There was no difference in those patients.  Some patients he thought had the perfect implant.  Just there was no predictor.

            DR. ACHEM:  Thank you.

            CHAIRPERSON WOODS:  Dr. Afifi?

            DR. AFIFI:  Thank you.  I'm going to ask questions about some fun stuff.  That is statistics.  I think it is fun. The first question has to do with this slide just before this one.  You may want to put it back up to remind everybody what it is.  It was about the predictors of outcome.

            What was the outcome variable or the dependent variable here?

            DR. JOHNSON:  I'm going to go ahead.  This is against the primary objective, but I will ask John to make any comments specifically about statistical analysis.

            DR. KENNEDY:  I agree with you, Dr. Afifi.  I think statistics is a lot of fun, but that is why I don't get invited to many parties.

            The dependent variable here was a dichotomous variable, which was responder or not responder.  In terms of whether the person achieved either complete elimination of PPI usage or greater than or equal to 50 percent elimination.  They were scored as a one.  People who did not were scored as a zero.  This was nominal logistic regression that did this.

            DR. AFIFI:  And so each patient appeared only once in the study?

            DR. KENNEDY:  That is correct.

            DR. AFIFI:  So that leads me to my next question.  I was pleased to see the longitudinal nature of a lot of the analyses that you looked at, the graphs that you presented.

            Did you try to model that longitudinal nature in any way by the use of GEEs or mixed models or any such analysis?

            DR. KENNEDY:  No, we didn't.  The FDA, quite frankly, was interested only at the single‑point 12‑month analysis.  And we restricted our submission attention to that.  All of the other analyses and plottings were done for our own internal information.

            So we did not attempt to model it.  Sometimes the graphs include the same number of patients.  Sometimes they are different numbers of patients.  it turned out that getting the people who had data at all the time points restricted the data set to such an extent that there was a real question as to whether such a modeling would be useful.

            So no, no attempt was done to do that.

            DR. AFIFI:  Okay.  Dr. Woods, just a point of information that this is a topic that is very current in statistical literature.  Over the past ten years or so, there has been a tremendous improvement in the methodology for analyzing sequential longitudinal data.  And I think we need to come back to that for a discussion later on.

            CHAIRPERSON WOODS:  Thank you.  Does that conclude your questions?

            DR. AFIFI:  Yes.

            CHAIRPERSON WOODS:  Okay.  Any other questions from the panel?  Dr. Fennerty?

            DR. FENNERTY:  I have some very brief questions and hopefully brief answers.  Dr. Johnson, is there a reason the sponsor only provided the intention to treat data in your presentation versus in the package to us earlier?

            DR. JOHNSON:  I can't answer that.

            CHAIRPERSON WOODS:  Briefly, please.

            DR. STEIN:  Normally the sponsor is only supposed to provide information that's in the panel books.  However, we had the opportunity to review the FDA's presentation, where we sought the intention to treat analysis.  And, therefore, we thought that we should be providing our own analysis ourselves so that we weren't seeing it and having to comment blind.  That's all.

            DR. FENNERTY:  It's impossible to analyze data with ITT data.  I appreciate Dr. Johnson's presenting it.  Dr. Johnson, is there a planned durability study?

            DR. JOHNSON:  The ongoing assessment of this is really going to be with the helical CT.  And that durability study assessed radiologically as part of the extension study.  Obviously ongoing clinical assessment is part and parcel of that parallel extension.

            DR. FENNERTY:  The third question is that the study was done in patients that had a response to a PPI, which all of us would feel very comfortable as an inclusion criteria.  The labeling, though, is for patients with GERD.  Is there a reason there is a difference between the labeling and the patient population study in the study?

            DR. JOHNSON:  I am going to defer a labeling question to the sponsor on this.  The clinical entry were people who had symptomatic GERD.

            DR. FENNERTY:  That responded to it?

            DR. JOHNSON:  That responded to a medication.  So it was a clearly defined ‑‑

            DR. FENNERTY:  It's very different than the labeling recommendation.

            DR. STEIN:  We're very happy to seek guidance on this.  The basis of this was on other minimally invasive devices who use similar labeling in their products.  That's all.

            DR. FENNERTY:  Okay.  Perhaps we can come back to that in the discussion.

            CHAIRPERSON WOODS:  Yes.  We'll discuss labeling.

            DR. FENNERTY:  Dr. Johnson, is there a reason the Savary‑Miller classification was used, instead of the more commonly accepted LA classification, for esophagitis?

            DR. JOHNSON:  No.  It was done three years ago.  And the study sponsor design was by the experts at the time that we're putting this together.

            DR. FENNERTY:  The final question, as pertains to many of my colleagues' questions, is there a planned study using a blinded adjudication radiologic assessment of pared X‑ray samples to finalize and understand what the heck is happening with the stuff versus the continuing process that has been ongoing with the investigators who know what was injected, estimating the volume, residual volume.

            DR. JOHNSON:  I have been told the answer is yes.

            CHAIRPERSON WOODS:  Other questions from the panel?

            (No response.)

            CHAIRPERSON WOODS:  If not, we'll move on to the next presenter.

            DR. JOHNSON:  I would like to reintroduce Dr. Alan Stein, the President and Chairman of Enteric Medical, to make some concluding remarks.

               5. STUDY CONCLUSIONS

            DR. STEIN:  And, for the sake of time, I will be brief.

            First slide.  In addition to the patients described in this study, you should be aware that under the expansion study, there are 75 patients that have been approved.  And we have completed additional work on 60 of those patients.

            Worldwide approximately 400 patients have been treated at over 40 institutions, giving us a significant leg up in terms of what the training requirements are.  In particular, what we have provided into the panel's review material is that the safety and effectiveness profile worldwide is consistent with that reported in this more narrow clinical trial.

            Next slide.  Our recommendations for physician training, which I know will be a further point of discussion today, is, of course, we focus on gastroenterologists and surgeons experienced in endoscopy, injection techniques, and fluoroscopy.

            It is the company's intention to establish five to ten training centers nationally, where there will be the opportunity for expert physician preceptorships, there will be formal didactic sessions, including procedure review and patient care review.  And there will be the opportunities for case observation.

            On site, after these courses, the on‑site review by the company representative will be performed with the site staff in order that they have the opportunity to further understand that instructions for use in the patient brochure.  This has actually worked very well for us in the field.  Actually, again, because, as Dr. Lehman has pointed out, this is predominantly a sclerotherapy‑type injection procedure.

            The training requirements are already resident in the gastroenterology community.  It is more a matter of a few details associated with this specific application.

            Now, recognizing that this is a new indication for an injectable endoscopic procedure, that this is a new material, the sponsor is committed to perform significant post‑market evaluation studies.

            We have committed to the FDA to do a minimum three‑year follow‑up on 300 patients.  We have about 150 patients, as noted in the FDA base study and the expansion study that we would intend to follow for three years.  Those patients are already under IRB and are already being followed with significant objective follow‑up.

            In addition, we will actively recruit an additional 150 to 200 patients so that we total 300 patients for 3‑year follow‑up, which will also give the FDA the opportunity to determine whether our training programs are, in fact, doing the job that they should do in keeping the adverse event level as exceptionally low as we have demonstrated so far in the course of our study.

            Patients will be followed at the minimum for GERD medication use; symptom scores; but, most importantly, adverse events.  And we will follow adverse events as diligently as we have done during the entire PMA study.

            The overall conclusions that we would like you to consider are that there had been no major adverse outcomes and no mortalities in the entire study population of the FDA, the expansion study, or any studies worldwide.

            All device and procedural adverse events were anticipated.  We have had no surprises in the course of this study.  And all of these have resolved without any sequelae.

            Particularly study, 80.3 percent of subjects eliminated or reduced PPIs by greater than 50 percent.  This is the primary hypothesis of the study.  But, in addition, among the secondary objectives, GERD‑HRQL symptom scores, the physical component of the SF‑36 score, and a number of pH‑metry parameters demonstrated significant improvements.  Again, these findings have been reproduced in our European and Canadian work.

            So, overall, based on these results, we conclude that the endoscopic implementation of Enteryx is safe and effective for the treatment of GERD.  And, therefore, altogether we would like to suggest that the data presented support the safe and effective use of Enteryx for the indication as described, indicating for endoscopic injection in the lower esophageal sphincter for the treatment of GERD with further guidance from Dr. Fennerty and the rest of the panel on the specific labeling.

            Thank you all for your consideration.  Again, any further questions and discussions we are happy to entertain.

            CHAIRPERSON WOODS:  Other questions by the panel at this point?

            (No response.)

            CHAIRPERSON WOODS:  Okay.  Thank you.  We are going to take a five‑minute break to allow the FDA to set up for their presentation.  And we will reconvene, then, at that time.

            (Whereupon, the foregoing matter went off the record at 11:13 a.m. and went back on the record at 11:24 a.m.)

            CHAIRPERSON WOODS:  Next will be the FDA presentation of the open public hearing.  Again, I would like to remind the panel that they may ask for clarification of any points included in the FDA presentation, but discussion should not go beyond clarification.

            The speaker for the FDA is Kathleen Olvey, FDA Scientific Reviewer.  She will discuss the overview and preclinical studies.

               2.  FDA PRESENTATION:

         1. OVERVIEW/PRE‑CLINICAL STUDIES

            MS. OLVEY:  Good morning.  My name is Kathy Olvey.  And I am going to begin the FDA presentation for the PMA submitted by Enteric Medical Technologies for Enteryx.

            Reviewers from several offices within the center evaluated the data in the PMA.  In addition to my review, data relating to the nonclinical performance of the device were reviewed by Drs. Katharine Merritt and Raju Kammula.  Dr. Merritt will be presenting the animal data.

            The clinical data were reviewed by Dr. Aron Yustein and Mel Seidman.  Both Dr. Yustein and Mr. Seidman will be presenting their data to the panel.  Dr. Lori Brown has reviewed the proposed post‑market study and will be presenting her recommendations to the panel.

            The manufacturing information was reviewed by Sharon Ellerbe in the Office of Compliance.  On December 19 of 2002, the Office of Compliance gave final approval for the manufacturing and sterilization sites.

            Barbara Crowl from the Office of Compliance, Bioresearch Monitoring, is coordinating the site visits with the FDA field offices to review the patient data at several investigational sites.  These inspections are expected to completed by the end of this month.

            Patient labeling was reviewed by Jack McCracken from the Office of Health and Industry Programs.  And Dr. Carolyn Neuland is responsible for ensuring that the whole operation runs smoothly.

            My presentation will be a brief overview of the regulatory history and some of the preclinical studies conducted by the sponsor.  The other FDA presentations will focus on the animal data, clinical data, and data that may be collected post‑approval.

            The investigational device exemption for the clinical study was approved in April of 2000.  The IDE was approved for 75 subjects at 5 investigational sites.  There were 85 subjects enrolled in the clinical trial.  However, only 64 of the subjects were enrolled at U.S. sites.  The other 21 were enrolled at 2 sites outside of the United States and are not counted against the 75.

            During the course of the clinical study, the number of U.S. sites was expanded to include a maximum of ten, although only six U.S. sites enrolled subjects.  In March of 2002, the study was expanded to include an additional 75 subjects in an expanded access arm.  This allows the sponsor to continue patient enrollment while the PMA is under review.  These 75 subjects are not part of the pivotal study.

            The sponsor asked for and received approval in August of 2001 to submit the PMA as a modular PMA.  Although the sponsor submitted manufacturing and preclinical modules, the modules were still under review by the FDA when the clinical data were submitted.  And so they were enrolled in the PMA.

            The PMA was submitted by the sponsor and filed by the FDA in March of last year.  In June, the FDA sent the sponsor a major deficiency letter.  The sponsor responded to that letter in September.  The FDA reviewed the information and determined that the data provided was sufficient to take the PMA to the FDA advisory panel.

            As proposed by the sponsor, Enteryx is indicated for endoscopic injection into a lower esophageal sphincter for the treatment of gastroesophageal reflux disease.

            Enteryx is composed of ethylene vinyl alcohol copolymer and a dimethyl sulfoxide carrier.  Tantalum is suspended in the polymer solvent mixture to provide contrast for visualization under fluoroscopy.

            The Enteryx procedure kit contains 10 ml vials of both Enteryx and DMSO.  Both are supplied sterile and for single use.  The sponsor conducted testing, demonstrating the stability of the product for a three‑year expiration date.

            The kit also contains two syringes and an injection catheter.  Since DMSO is an organic solvent, the sponsor conducted testing demonstrating a compatibility of these components on exposure to DMSO.

            To use Enteryx, the injection catheter is primed, first with DMSO and then Enteryx.  Using standard endoscopic techniques, one to two ml of Enteryx is injected into the muscle in four quadrants of the lower esophageal sphincter.

            The goal is to inject a total of between six and eight ml.  Upon injection and contact with body fluids, the DMSO diffuses away, causing precipitation of the polymer.  Solidification occurs over three to ten seconds.

            Viability testing was conducted on sterilized samples of Enteryx in accordance with the FDA guidance, the FDA modified guidance, the use of international standards, ISO 10993, biological evaluation of medical devices, guidance on selection of tests.

            Testing was carried out in compliance with good laboratory practice regulations.  Short‑term and chronic toxicity testing were conducted in accordance with ISO standards.

            The results of the testing showed no adverse reaction with the exception of the seven‑day implantation study in the rabbit.  The reason that Enteryx did not pass this test was attributed to an acute reaction to the DMSO.

            Since this is a new implant material, carcinogenicity testing was also required.  The sponsor conducted this testing using the H2 transgenic mouse model.  The results of this testing showed that the material is non‑carcinogenic in that animal model.

            In addition to the testing outlined in ISO 10993, long‑term testing by implantation of a device into the target organ, lower esophageal sphincter, in both the minipig and dog was conducted and will be discussed by Dr. Merritt.

            Now I would like to introduce Dr. Katharine Merritt, who will discuss the results seen in the long‑term animal testing.

            CHAIRPERSON WOODS:  Thank you.

            DR. MERRITT:  Thank you.

         2. HISTOPATHOLOGY CONSIDERATIONS

            DR. MERRITT:  I'm Katharine Merritt from the Office of Science and Technology.  Acute inflammation is a normal response to injury that neutralizes toxic substances, removes a foreign substance, or forms a fibrous capsule around it to wall it off.

            With inert materials, the fibrous capsule is formed within one to two weeks.  However, if the foreign substance is not removed or neutralized and is not inert, a chronic inflammatory response will occur.  The persistence of a chronic inflammatory response can lead to sequelae.  And mineralization at the inflammation site is one of the possible sequelae.

            Next slide.  The animal studies included a standard rabbit muscle implant study for biocompatibility.  This assesses the tissue response to the material.  A dog study in the sphincter and a minipig study in the sphincter were done to establish safety in the site of intended use.  In all three studies, there was an initial acute inflammation, progressing to chronic inflammation.

            At the six‑month and one‑year implantation times, a fibrous capsule, indicating healing around the implant, was evident at some sites, but the chronic inflammatory response was still present at others.

            The sponsor prepared a table of the inflammation's scores from the rabbit muscle implant study.  The scores were based on a four‑point scale, with one being minimal and four being marked.

            These results show that the maximum inflammation scores occurred at 90 days.  However, they had not completely resolved at the one‑year time period.  This would have resolved in one to two weeks with inert material.

            A series of histology slides from the sponsor's submission ‑‑ and I want to make the point that all of these slides came from them ‑‑ will be shown to illustrate some of the issues.  This is a rabbit model, a six‑month study, and shows some chronic inflammatory responses, some wispy fibrous elements, and an area of mineralization marked by the arrows.  The sponsor marked the mineralization.

            Next slide.  The one‑year study also shows an area of mineralization marked by the arrows and a fibrous capsule around the implant.  I would like to point out that these slides were stained with H and E, and the slides you saw earlier were using trichrome stain.

            Next slide.  This slide shows chronic inflammation at the site of the implant in the sphincter in the minipig at six months.  The tantalum is easily observed.

            Next slide.  The implant site at one year in the minipig has some wispy fibrous capsule elements and perhaps some chronic inflammatory components.  The tantalum is not evenly disbursed.

            Next slide.  This slide shows the implant up against the mucosal surface in the minipig at one year.  The lower right may be a sectioning artifact or may show erosion of the implant through the mucosal surface for elimination from the site.  Again, the tantalum is not evenly disbursed.

            The issues raised in these studies include the importance of persistent inflammation, the importance of mineralization, and the importance of chronic inflammation in the loss of the material from the implant site, requiring repeat injections.

            If there are no questions, I will turn it over to ‑‑

            CHAIRPERSON WOODS:  Any points of clarification for the first two speakers by the panel?

            DR. ACHEM:  Dr. Woods?

            CHAIRPERSON WOODS:  Yes?

            DR. ACHEM:  Just a brief question.  I know that the one indication of the mineralization has been given by the sponsor as less than .01.

            DR. MERRITT:  Correct.

            DR. ACHEM:  Could you comment on that assessment?

            DR. MERRITT:  When I looked at the rabbit histology slides, I was concerned about the mineralization.  And the sponsor was asked to go back and look at the issue in the minipig.  They did the quantitation of the mineralization in their sections.

            Now, I have to point out all we get is sort of a glimpse.  They give us a few sections.  They  have the full slides.  They went back, and they did do the mineralization index in the minipig and I believe in the rabbit.

            I think there is no question from what I saw and from what they presented that the mineralization in the minipig site is less than it was in the rabbit site, but there is some.  And the question remains, how important is this?

            DR. ACHEM:  Will there be a critical level at which you would be concerned?  I mean, is there a way to quantitate and then translate into a function of assessment?

            DR. MERRITT:  I cannot answer that question.  That is what I hope you are going to help us with.  The question is how much is going to impair the function of the sphincter?  I have no way of answering that question.

            CHAIRPERSON WOODS:  Any other questions?

            (No response.)

            CHAIRPERSON WOODS:  Okay.  Thank you.

            DR. MERRITT:  I will now introduce Dr. Aron Yustein, who will give the clinical review.

            3. CLINICAL CONSIDERATIONS

            DR. YUSTEIN:  Good morning.  My name is Aron Yustein.  I am with the Office of Device Evaluation.  I'm a gastroenterologist.  And my job this morning is to present the FDA's review of the clinical data.

            I just wanted to mention that I will try to reduce the redundancy compared to the sponsor's slides, although I had not seen all of their slides prior to today.  So we may have a little bit of redundancy.

            Here is an outline of what I am going to discuss today.  I am going to start with a very brief review of the two clinical feasibility studies.  Then I will move on to the pivotal trial.  I will discuss a brief amount on the protocol, the safety results, the effectiveness results.  I will talk separately about the retreated subjects, a very brief discussion on the proposed physician training program.  I will review the supporting clinical data, which is in the PMA outside of the pivotal trial, and then try to summarize the clinical results.

            Before I do, however, I wanted to mention two statements from a recent AGA consensus panel on improving the management of GERD.  This was from last spring.  I would like you to keep these in mind as we go through the talk because they will come back at the end.

            The first statement is that GERD manifests as a combination of symptoms and signs and that the goals of treatment are to relieve and prevent symptoms and complications.  I have just shown some pictures at the bottom here of what some people might consider esophageal complications of GERD, including erosive esophagitis, peptic stricture, and Barrett's Esophagus.

            First, the clinical feasibility studies.  The sponsor performed two human trials prior to the IDE.  One was in the U.S.  One was in Europe.  The U.S. study was nine subjects at one site at the University of Southern California.  These are the patients who went for immediate esophagectomy after injection, as the sponsor had mentioned in their talk.

            Just to mention the numbers, there were 34 implants attempted.  Eighty‑eight percent, or 30 of those, were planted successfully.  Four, however, as the sponsor had mentioned, found lying subserosally or attached to the exterior of the gastroesophageal junction without any untoward reaction or evidence of migration, although I do want you to remember that those were done immediately after injection.

            The second study was a European study, consisting of 15 patients at 2 sites.  The patients enrolled were on proton pump inhibitors for at least three months with a response in symptoms.  All had a positive pH study and less than a Grade 2 esophagitis.  They all received four to six milliliters injected circumferentially.

            Safety‑wise post‑procedure retrosternal pain occurred in 53 percent.  All of those cases lasted less than three days.  Post‑procedure dysphasia occurred in one patient, or seven percent, and no interventions were required.

            Effectiveness showed that the mean heartburn score on a scale of one to four decreased from 3.4 to 1.9 at 6 months.  All patients were off their PPIs, but 27 resumed PRN use of PPI at 6 months.  Mean LES pressures increased from 12.2 to 16.7 millimeters of mercury.  And also six‑month X‑rays were compared back to baseline.  The ratio of tantalum to polymer is stable throughout the time length.  Sixty percent of subjects had at least 50 percent remaining on eyeball estimates.

            I would like to now move into the pivotal clinical trial.  Just for completeness' sake, we have been talking about the GERD‑HRQL questionnaire.  I just wanted to show you what that looked like just in case you weren't 100 percent sure, it's a nine‑item questionnaire dealing with various components of heartburn, when it occurs.  Patients are instructed to rate them on a scale of zero to five, with zero being asymptomatic and five being essentially incapacitating.  Possible scores, then, therefore, could be from zero to 45.  On this example, the patient would have scored a 34.

            I wanted to mention a couple of points that the sponsor did not bring up in their talk.  There were 85 subjects enrolled.  This chart breaks down the reasons for dropouts.  At three months, there were no dropouts in patients, but between 3 and 6 months, 4 patients out of the 85 had dropped out.

            I listed the reasons that were listed on the discontinuation forms as to why, "no satisfaction," one patient.  One patient was considered a treatment failure and did not wish to continue.  One patient did not wish to continue with the evaluations.  And the fourth one did not have a specific reason on the discharge form.

            Between 6 months and 12 months, another 4 patients dropped out.  Again, that brings a total of 77, reaching 12‑month follow‑up.  Again, I have quoted the four reasons listed on the dropout forms as to why they were not, as you can see, recurrent symptoms and/or wishing to pursue surgical options were among those.  All four of those patients we know are back on their proton pump inhibitors or at least went back on their proton pump inhibitors after dropping out.

            The sponsor also mentioned several protocol deviations.  I wanted to just add to that for completeness' sake.  Some that were not mentioned by the sponsor prior, there were 11 events where the patient was not off their proton pump inhibitor for 10 to 14 days prior to baseline.  There were five subjects whose pH study lasted less than a total of 12 hours.  And there were two patients who were not off their proton pump inhibitor for ten days prior to their pH study.

            I also included on the bottom of the slide what I consider post‑procedure deviations as patients were supposed to all have pH endoscopy and manometry performed at 12 months.  I have included a number of subjects who did not have those performed or reported in the PMA.

            And, also briefly alluded to by the sponsor, although there was a requirement for retreatment to have a GERD‑HRQL of 15 or more, 7 patients that were retreated did not meet that requirement.  And so technically that is a protocol deviation as well.  Mel Seidman will be talking a little bit more about the protocol deviations in his statistical review.

            Okay.  I wanted to go out to the safety/adverse events of the clinical trial.  As the sponsor mentioned, the two most common adverse events were retrosternal pain and dysphasia.  You have seen a large amount of these numbers in their talks.  So I am not going to reiterate there.  A point to remember is that 70 percent of the patients did receive prescription pain medicines for retrosternal pain.

            The reason for the retrosternal pain offered by the sponsor was either due to the injection or sloughing.  I also just wanted to make one point about the dysphasia.  Almost all of the patients or a large majority of the patients did not require any treatment.

            There was one patient who had dilation.  And, just to kind of jump the gun here, if you are wondering how that patient did, that patient did receive 2 dilation therapies, one 25 weeks and one 35 weeks after initial implant.  And at 12 months, that patient was off of all medications and had an HRQL score of 3.

            We had asked the sponsor to analyze the adverse events based on the injection volume and see if there was any correlation.  The graph on the left demonstrates the rate of occurrence of retrosternal pain and against a volume of injection on the bottom and on this axis the number of patients.  And, as you can see, all patients who had eight or more cc injected did experience retrosternal pain, although there were some with as little as four injected that did experience a symptom as well.

            The graph on the right shows the rate of occurrence of dysphasia against the injection volume, again, the volume on the bottom and the number of patients on this axis.  You can see that patients experienced dysphasia with as little as five and as high as eight or more and so really not as much consistency because there were some patients who had the higher limits who did not develop dysphasia.

            I just wanted to comment on some of the other adverse events.  Kind of a busy slide, but I have highlighted some of the ones I just want you to focus on.  Just for a comparison, as you may or may not wish to compare to these with other therapies:  Gas, bloating, 6 percent; belching and burping, 7 percent.  I believe the sponsor did make an error in their analysis.  Nausea and vomiting were actually 12 percent.  Heartburn was actually listed as an unrelated adverse event in 25 percent of the subjects.

            Not to beat a dead horse, but going back to the 12‑month residual implant volume, I would like to include this in the safety, rather than the effectiveness part.  You will be asked to address this issue in the panel questions later this afternoon.  As has been explained, the physicians were asked to estimate the approximate volume at 12 months compared to a baseline value and to put subjects into a quartile percentage of remaining Enteryx.

            I also want you to remember that this is assuming that the relationship of tantalum to polymer that is in situ is the same at 12 months as it is at the time of injection and that the tantalum is an accurate marker of actual polymer still in situ, and that is an assumption.

            The subjects only treated once were compared back to their one‑month X‑ray.  And there were 53 subjects.  The subjects who were retreated, there were 17 who had X‑rays at 12 months.  They were compared back to the three‑month X‑ray as they were required to have their retreatment prior to the three‑month point.

            What this basically shows is that 45 percent of subjects between 1 month and 12 months have lost at least 25 percent.  They had 75 percent remaining.  About a quarter of patients lost at least 50 percent between 1 month and 12 months.  And, similarly, on this side for the retreated subjects, approximately 41 percent still had lost at least 25 percent.  And about a fifth had lost at least 50 percent.

            Now, I just want to qualify something.  I had access to all of the line data.  So some of these analyses you may not have seen before.  If you look at the patients who had both 6 and 12‑month X‑ray results and compare when the loss occurred, there were 62 subjects who had X‑rays at both 6 months and 12 months.  And based on this estimate, 60 of those, or 97 percent, had stable amounts from the 6 to 12‑month point.  So, in other words, most of this loss that was seen occurred prior to the six‑month X‑ray.

            Those two subjects who didn't, there was one single treated subject who lost 50 to 75 percent between 6 and 12 months and 1 retreated subject who lost between 25 and 49 percent between 6 and 12 months.

            I wanted to move on to the effectiveness results.  I am going to start with the primary endpoint, which, as you recall, is reduction in proton pump inhibitor use.  This chart is both evaluable patients and ITTs, although I am only going to concentrate on the intent to treat analysis, which is based on all 85 originally enrolled subjects.

            The first set of numbers on top are patients that were able to come off all medications, not just proton pump inhibitors but H2 blockers, over‑the‑counter antacids.  You can see at 3 months, it was 69 percent; 64 percent at 6 months; and 56 percent at 12 months.

            This next line of patients is all of those who were able to come off all PPIs.  So it includes these patients plus those who may have been on H2 blockers, over‑the‑counter antacids.  And you can see at 6 months, 76 percent were able to come off all PPIs, 71 percent at 6 months, and 67 percent at 12 months.

            The final set of numbers is the official final objective, greater than 50 percent reduction or more in PPI use.  And at 3 months, 89 percent met that requirement; at 6 months, 80 percent; and down at 76 percent at 12 months.

            Next slide.  Just a crude graph.  If you look at that, I think this gets to what Dr. Shaheen was pointing to earlier.  These are the three from the columns before, greater than 50 percent or more reduction, and the rough graph lines coming down here from 3 to 12 months, off all PPIs and off all medications.  And you can see a slow trend down.  We don't know where these lines go beyond 12 months.

            Next slide.  Although the study was not powered to detect statistically significant changes based on subgroup populations, I did go back through the line data and look at some of the baseline demographics or characteristics of the patients on enrollment and see what their success rates were.

            Now, remember, by percent success here, I mean those meeting at least 50 percent reduction in PPI use at 12 months.  Although, as I said, these cannot necessarily be statistically significant, I just wanted to point out some interesting findings here.

            If you go back and look at the baseline PPI use, less than standard dose, such as half dose, standard dose, greater than standard dose, and all patients who are taking supplemental medications besides their PPIs, you can see that, even though the number is very small, the patients who started on a lower dose had a less success rate.

            When looking back at the patients who had baseline esophagitis, there were a total of 30 patients who had esophagitis at baseline and 55 who did not.  The rates are fairly similar between none and all grades, but if you separate out Grade 1 esophagitis and Grade 2 esophagitis, you see that the patients who started with Grade 2 esophagitis did not do quite as well.

            Somebody on the panel asked earlier about the patients with hiatal hernia.  And, although this may not reach statistical significance, if you recall, there were 7 patients admitted to the study with a protocol deviation of more than 3‑centimeter hiatal hernia.  So I went back and looked at those.  Those had a success rate of 43 percent versus those who didn't at 79 percent.

            The last one that I just wanted to mention, I broke it down by BMI.  And the patients with a higher BMI did slightly worse than those with less than 30.

            We asked the sponsor to assess the endpoints by injected volume.  I think you have already seen this slide.  So I am not going to spend a lot of time on it.  But 5 cc and over, all of those patients with that remaining, not necessarily injected but residual, at 12 months met the success criteria, where; whereas, 75 percent with less than 5 cc remaining met that criteria.

            I wanted to move on to the secondary endpoints and start with the subjective secondary endpoints, the first one being the GERD‑HRQL.  And I am not going to spend a lot of time on this.

            Just for your information, I only included in my analyses questions number 1 through 9 as those are the only questions that are in the validated questionnaires.  Questions 10 through 13 were added by the sponsor on their own.  You have seen these numbers.  These are from matched patients.  So at 6 months, there were 81 patients who had matched data, both a baseline value and a 6‑month value.  At 12 months, there were 77 subjects who had a 12‑month value and a baseline value.

            You can see the mean values at the time went from 26.2 to 7.8 or 70 percent reduction at 6 months and from 26.2 to 8.9 or 66 percent reduction at 12 months.

            DR. AFIFI:  Excuse me, Dr. Yustein.

            DR. YUSTEIN:  Yes?

            DR. AFIFI:  You went over the previous slide too quickly for me.  Put it up one more time, please.

            DR. YUSTEIN:  This one or the one before?

            DR. AFIFI:  The one before.

            DR. YUSTEIN:  This one?

            DR. AFIFI:  Yes.

            DR. YUSTEIN:  The sponsor showed the slide.  We asked them who may have met the medication success criteria based on how much volume was implanted.  And they weren't able to find any correlation with the amount implanted, but when they estimated the volume that was residual at 12 months, you can see that all of the patients who had 5 cc or more met that success criteria.  And if you add these numbers up and include the patients that didn't meet it, it was 79 percent who have had less than 5 cc.

            DR. AFIFI:  Seventy‑nine percent?

            DR. YUSTEIN:  Seventy‑nine, yes.

            DR. AFIFI:  Okay.  Thank you.

            DR. YUSTEIN:  Next slide.  I'm not sure how much means mean to people.  So I went back and looked at how people did individually with GERD‑HRQL reduction.  And what I did was I compared each patient's 12‑month point to their baseline off‑medication value.

            What you see here is the percentage of reduction.  You can see that 21 patients, or 27 percent of those enrolled, had 100 percent reduction in their score.  In other words, they had a zero at 12 months.  For those people having a 51 to 99 percent reduction, 35 subjects in total met that.  And that accounts for 45 percent of the subjects.

            So you can see that over 70 percent of the subjects had at least a 50 percent reduction in their GERD score over time.  And a lower number of patients didn't do as well.  There were several patients that actually had an increase in score over their baseline off medications.

            In this column, for each of these number of subjects, I just wrote down how many of them met the endpoint for medication and reduction.  You can see that people who dropped their score by at least 50 percent did very well; whereas, those that didn't did less.

            I also wanted to tell you that there were 77 subjects who had 6 and 12‑month GERD scores.  If you asked when you compared their 6‑month score to their 12‑month score, how many got worse between 6 and 12 months.  Actually, 40 percent, or 31 out of the 77, increased their score between 6 and 12 months.  Those numbers come out to be a mean of 7 points, a median of 4, and a range of anywhere from 1 up to a 26‑point increase from 6 to 12 months.

            Just very briefly, I want to talk about the SF‑36 quality of life questionnaire.  The sponsor mentioned these, the mean changes compared to baseline off.  All I have done in this chart is tell you that for the physical component, there was a 12 percent improvement at 6 months and a 14 percent improvement at 12 months, a 7 percent improvement in the mental component at 6 months, and a less than 1 percent improvement in the mental component.

            I also wanted to point out that if you went and looked at each patient individually, at their 12‑month score, and compared it back to their baseline while off medications, a fifth of patients actually had a lower score on the physical component when compared back to the baseline off medication and over a third of patients had a lower score on the mental component when compared back to baseline off medication.

            Okay.  I want the secondary endpoints and what I am calling the objective endpoints, intra‑esophageal pH, esophagitis, and manometry.  You will be asked to comment on these during your panel questions and the significance of these results.

            A busy chart, but the sponsor has presented many of this.  I think Dr. Ferguson might have been asking or Dr. Shaheen might have been asking, about the mean or median values over time.  This top set of numbers here is the percent total time with a pH of less than 4 for matched data for 71 patients who had both baseline at 6‑month and then 67 patients who had baseline in 12‑month data to evaluate.  And you can see the mean went from 14.6 to 8.6 at 6 months, for a decrease of about 41 percent and at 12 months from 14.3 to 9.2, or a decrease of about 36 percent.

            I have the same information here for medians, which decreased 26 percent on and 28 percent at 12 months.  I have also included some information on supine times and the total of acid reflux episodes over 24 hours.

            Getting into normalization, this was touched on earlier by the sponsor.  At 6 months, 26 out of 71 evaluable patients were 37 percent had normalized their pH time with using 5 as the cutoff time since that was the exclusion inclusion criteria.  At 12 months, that was 26 patients over 67, which is 39 percent, the number mentioned earlier by the sponsor.

            I also give you a normalization of supine time, which was considered less than three percent.  Again, the numbers are slightly higher.  But if you add all of the patients together and looked at who at 12 months normalized both their total percent time and their supine time, it's still approximately 40 percent.

            Next slide.  Wait.  Can you go back one slide?  If you notice here, there are 26 patients at six months who normalized, and there are 26 patients at 12 months who normalized.  So the next question I asked myself is, are these the same 26 patients?

            So what I did was I went back and I looked at the data.  There were 63 patients who had pH data at both 6 months and 12 months to compare to themselves.  So across this top axis here, you have the pH status at six months.  And the person was either normalized at six months or not normalized at six months.  And then down this axis, you have their status at 12 months.  They were either normalized at 12 months or not normalized at 12 months.

            What I want you to take home from this chart is that there were 15 subjects, or 24 percent of these 63, who had normalized both at 6 months and remained normal at 12 months.  But twice that number, 30, or 48 percent, were neither normalized at 6 months or 12 months.

            If you look at the number of patients who were normalized at 6 months and tried to figure out where they went, there were a total of 25 subjects who were normal at 6 months based on the 5 percent.  Fifteen of them remained normal at 12 months.  Ten were no longer normal.  So of the 25 subjects who had normalized at 6 months, 10, or 40 percent, failed to remain normalized at 12 months.

            Conversely, if you look at the number of patients who had not normalized at 6 months and asked how many of them went on to normalize at 12 months, there were 38 patients who were not normalized at 6 months.  Eight of them, or 21 percent, went on to normalize at 12 months.  So the answer to the previous question is no, it's not the same 26 patients.

            Next slide, please.  This chart just looks at intra‑esophageal data on everybody who had data at 12 months, regardless of whether they had 6‑month data to correlate with, and just some findings here.  You have seen this number before.  The percentage who normalized was 39 percent.  If you asked what percentage of those people who normalized met the medication success, the vast majority of them did, 96 percent.

            I went back, and I looked at each individual patient's pH score at 12 months and compared it to what it was at baseline while off medications.  Kind of surprisingly, a third of patients actually had a higher percent score at 12 months compared to what they were doing baseline off medication.  Yet, still, 73 percent were able to meet the medication success criteria.

            I picked three points here to assess where people were at 12 months as far as where they stood at the total percent time with pH less than 4.  I chose 7, 11, and 15.  Don't ask me why.  I just randomly chose those numbers.

            What you can see here is that half the patients at 12 months still had a total percent time of at least 7.  Over a third had a total time of at least over 11.  And still a fifth of patients were over 15 percent at 12 months.  Again, down here is the correlating success percentage we were able to get off of medication for those groups of patients.

            Then, finally, looking at the number of reflux episodes at 12 months compared to baseline, 31 percent had a higher number of reflux episodes when compared to their baseline off medication.

            I wanted to move on to esophagitis here.  This chart is composed of 68 subjects who had both an EGD at baseline and an EGD at 12 months.  Remember, there were several patients who did not have their EGD at 12 months, which was protocol deviation.

            What the chart shows is the numbers in green represent those who improved their grade of esophagitis from baseline to 12 months.  The darker green represents those that resolved or healed their esophagitis.  So, for example, there were three patients who had Grade 2 baseline esophagitis who were grade zero at 12 months.

            The gold represents patients who had the same level of esophagitis at baseline and 12 months.  And the blue represents those patients who had a worsening of their greater esophagitis from baseline to 12 months.  So, for example, there were seven patients who had grade zero at baseline but had grade 2 at 12 months.

            Next slide.  Just to kind of go over some of these patients in more detail, as you remember, I mentioned that there were 30 patients who had esophagitis at baseline.  Twenty‑three of them had their follow‑up EGD done at 12 months.  There were 7 that by protocol deviation did not have their EGD to follow up on.

            So, now, this chart just addressed those 23 subjects who had baseline esophagitis and who also had a 12‑month EGD to follow up on.  Ten of those 23, or 43 percent, resolved.  Two patients, or nine percent, improved their esophagitis grade but still had esophagitis; i.e., they went from Grade 2 to Grade 1.

            Four patients had stable esophagitis.  These were the ones in gold.  And this is 17 percent.  If you look at who increased their esophagitis, there was a total of seven who went from Grade 1 to Grade 2.  That represents 31 percent of the patients.

            So if you bring all of these numbers down, 13 of the 23 who originally started with esophagitis still had residual esophagitis at 12 months.

            Now, this chart is just for the 68 patients who had EGD at 12 months and at baseline.  So now we have moved on from not just the patients who started with esophagitis.  What I have done is I have brought forward the data from the previous chart.

            So this column is the patients from the previous chart, which are the 23 subjects who started with baseline esophagitis and where they ended up at 12 months.  I split it out for you.  There were 13, as you recall.  I split it out to Grade 1 and Grade 2.

            There were 45 other subjects who had EGDs at both baseline and 12 months.  Remember, all of these subjects by definition started out without esophagitis, or Grade zero.  At the end, at 12 months, 12 of them had now developed esophagitis, 5 Grade 1, 7 Grade 2.

            So if you all up for all 68 patients and you look at who had esophagitis at the end, there were 25 subjects.  Ten of them were Grade 1, 15 are Grade 2.  And if you break that out as a percentage of the subjects who had evaluable EGDs at 12 months, which is 68, 37 percent had esophagitis, 15 percent were Grade 1, 22 percent were Grade 2.

            And, if you recall ‑‑ actually, I don't know if you recall because I am not sure if this was mentioned earlier ‑‑ 9 percent of subjects at baseline had Grade 2 esophagitis before coming into the study.

            Then, again, I have broken down the success rates at 12 months for these patients.  So if you ended with a Grade 2 esophagitis at 12 months, 66 percent of those patients still were able to come off at least half their PPIs, although they still had Grade 2 esophagitis.

            I went back and I looked at the patient who had both esophagitis information or otherwise had EGD at 12 months and pH data at 12 months and tried to see what was going on as far as who met which criteria and who met both and who didn't meet any.

            Across the top here, it's the patient's esophagitis status at 12 months, whether they had it or whether they didn't.  And then down this axis is whether their pH study was positive; i.e., pH percent time still greater than five, or whether it was negative.

            What you can see here is that 28 percent of subjects at 12 months had both positive esophagitis and an abnormal pH study.  About the same number had negative esophagitis and a negative pH study.  All in total, 69 percent still had at least one abnormality in one of these objective tests.

            I am not going to talk much about manometry.  There were, as the sponsor mentioned, not too many significant changes here.  What I have here is the mean resting lower esophageal sphincter pressure, mean LES lens, and the mean residual lower esophageal sphincter pressure during relaxation, matched data for 6 months and 12 months.

            And you can see the mean percent changes, 5 percent increase at 6 months but, yet, an 8 percent decrease at 12 months.  And I just want you to note that 54 percent of the patients actually had a lower LES pressure at 12 months when compared to their baseline value.

            Next slide.  I am just going to briefly talk about the safety and efficacy for the retreated subjects.  This was raised a few minutes ago.

            Next slide, please.  I think somebody asked about the demographics of the retreated subjects.  I just wanted to show you this.  I went back, and I looked at the demographics of the 19 patients who eventually went on to require retreatment and compared that to the 85.  I actually didn't have time to break out all of the other 66 from that, just to show you that things are pretty consistent.

            But I wanted to point out a couple of differences.  And, again, this isn't statistically analyzed for statistically significant changes but just some trends.

            The retreated subjects tend to be your higher grade esophagitis people at baseline.  Twenty‑six percent had Grade 2 or 3 at baseline compared to 10 percent of the original subjects.  They actually had a little bit of a lower mean total percent pH time, and they actually were requiring slightly higher doses of PPI at baseline.

            If you look at the adverse events for the retreated subjects, this column here is just for the patients after their second treatment.  And this represents all 85 subjects after their first treatment.  You can see that retrosternal pain occurred in 68 percent after their second treatment; whereas, it occurred in 92 percent after everybody's first treatment.  Dysphasia was about half.  Bloating was about the same.  And pharyngitis was about half as well.

            This chart is a little busy.  This is some of the effectiveness parameters.  What I have done here is looked just at the 19 retreated subjects.  And I compared that to those that only got single treatments.

            And then also here is the data that has been presented for all 85 subjects as a whole.  I wanted to just make some points.  Again, these are not powered for statistical significance, the percentage of subjects meeting medication success at 12 months, greater than or equal to 50 percent reduction, the retreated subjects at 12 months.  Sixty‑eight percent of them met that.  If you don't include retreated subjects, everybody else had a 90 percent success rate.

            The mean HRQL score at 12 months was quite a bit higher, 13.4 in the retreated subjects, 7.4 in the single.  The mean percent total time with pH of less than 4 at 12 months was higher, 10.9 percent in those that got retreated, 8.7 in the single treated subjects.  Percent of subjects who normalize with a pH percent time of less than 5 at 12 months, 31 percent in the retreated subjects, 43 percent in the single treated subjects.

            Comparing patients who had esophagitis at baseline and where they were at 12 months, looking for resolution, 25 percent resolved for the retreated subjects, 45 percent for the single treated.  And who was left with esophagitis at 12 months, 40 percent in the retreated group and 36 percent in the single treated group.

            I wanted to briefly talk about the additional supporting clinical data and the proposed training program.  In your panel pack, I believe there is information on two additional studies which are ongoing.  One is the expanded access IDE study, which has been mentioned a couple of times today.  The other is a European study.

            The sponsor has submitted information on 36 patients who have reached 3 months of follow‑up in the IDE access study.  There are essentially no demographic differences between those patients as they are being enrolled essentially on the same protocol.

            Med success at 3 months is 86 percent.  For the pivotal study, it was 90 percent at 3 months.  Sixty‑one percent of patients were off PPI at 3 months compared to 76 percent in the pivotal at 3 months.  The mean HRQLs went from 24.5 to 7.1, which is the same value it was in the pivotal study.

            The rates of adverse events, similar for retrosternal pain, similar for dysphasia, although you note that the rates of fever were about twice as high and the rates of belching, burping, gas, and bloating were also about twice as high as what we saw in our pivotal study.

            An ongoing European study, the sponsor submitted information on 40 patients who have reached 6 months of follow‑up.  The differences in the demographics are that this group of patients is slightly more male and 68 percent versus 58 percent in the pivotal and almost exclusively Caucasian.

            Med success here at 6 months is 95 percent; whereas, in the pivotal study, it was 84 percent at 6 months.  My numbers that I use in parentheses are ITT.  I can't tell you if these are ITT or evaluable.  Off PPIs are about the same, HRQL scores similar, and pH total percent time went from a median of 11 to 9.9 at 6 months.  Again, retrosternal pain occurred in over 80 percent, dysphasia about 22 percent.  And, again, we see that fever here is about twice what we saw in our pivotal data.

            This slide may be a little out of date.  This was based on what was in the panel pack.  And I think the sponsor may have changed this recently.  This is what was in your panel pack.  So it may not be relevant to what they are proposing now.  But in the panel pack, the proposed physician training program includes that the physician and endoscopy tech will review the summary of safety effectiveness, the DFU, the patient brochure.  And this differs in the PMA submission.  It actually states that the physician will perform a minimum of two treatments under the supervision of the manufacturer's clinical specialist, which isn't specified whether that is an M.D. or not.

            Next slide, please.  Okay.  I would like to summarize my talk here.  Just to summarize the safety data, there were several adverse events that occurred, although the sponsors told you that all had essentially resolved.  Ninety percent or more of the patients experienced retrosternal pain, although most lasted less than two weeks.  Some lasted several months.

            Twenty percent of the subjects experienced dysphasia, although only 1 out of the 17 required dilation.  Ten to 15 percent experienced nausea, vomiting, fever, pharyngitis, all of which seemed to be procedure‑related.  At least 40 percent of subjects had at least a 25 percent reduction in implant volume between 1 and 12 months.  Twenty‑eight percent of subjects lost at least 50 percent between those same times, but most loss occurred prior to 6 months.

            Just to go back to Dr. Merritt's talk, the issue of chronic inflammation and calcification, I think it is hard for us to say what the true rate is and whether or not these have any clinical sequelae or will have any clinical sequelae.

            The effectiveness data I believe showed some improvements in some endpoints.  The medication reduction by ITT, three‑quarters of patients were able to come off at least 50 percent of their PPI.  Two‑thirds of patients came off all their PPIs.  And over half of the patients came off all medications, including H2 blockers and antacids.  I just wanted to reiterate the fact that this 76 percent does technically meet the original protocol objectives, as proposed by the sponsor.

            The GERD‑HRQL quality of life questionnaire also showed some improvements with a mean reduction in score of 66 percent.  Two‑thirds of patients were able to reduce their score by at least 50 percent at 12 months.  And half the patients reduced it by at least 75 percent.

            However, I think that, just as important and things that we will be asking you to address later in the afternoon are the changes in the other endpoints, which are the objective findings.  Just to summarize those, the reduction in mean percent total time, pH less than 4, was 36 percent, although a third of patients had a higher value at 12 months versus baseline off.  The mean to median values of total percent time with pH less than 4 were 9.2 and 6.5, still above your 5 cutoff.  And then, as far as normalization goes, 39 percent normalized and greater than 60 percent failed to normalize.

            With respect to the esophagitis data I presented to you, the way I represented it, 43 percent healed their esophagitis compared to baseline, 37 percent of subjects still had esophagitis at 12 months, including 22 percent of all subjects who had Grade 2 esophagitis.  And I want you to recall that nine percent had Grade 2 at baseline.

            Manometry I'm not going to say much about.  There was hardly any change in the mean percent LES pressure.  And most patients actually had a reduction in pressure.

            So, to summarize the effectiveness data, I just wanted to kind of bring forward what I had shown you in one of my first slides.  And that is that I believe effective treatment for GERD should address both the symptoms and the signs of the disease as well as the prevention of complications.  I think that would be consistent with what was recommended by the AGA consensus panel back last year.

            I think the data suggests potential beneficial effects for treating the symptoms of GERD as shown by a reduction in medication use and improvements in the validation of quality of life questionnaires.  However, I think the data appears less convincing for treating the signs of GERD and for preventing complications such as esophagitis and even Barrett's.  And that evidence is borne out in the intra‑esophageal pH data and the esophagitis rates.

            Next slide.

            CHAIRPERSON WOODS:  Thank you.

            DR. YUSTEIN:  If there are no questions, I will ‑‑

            CHAIRPERSON WOODS:  I think there are some questions.  Dr. Fennerty wants to start.

            DR. FENNERTY:  Yes.  Just some very brief specific questions, Aron.  Are you aware of any data in the clinical literature or in this trial of if microscopic calcifications affected the outcome or adverse event rate at all?

            DR. YUSTEIN:  No, I don't.  And the reason I bring the whole calcification issue up on my safety adverse thing is because I think if you look in the future at how physicians might use such a device and some of the information we have seen, some of the information as far as residual amounts and sloughing, et cetera, some physicians might be prone to want to re‑inject or patient might have multiple re‑injections over multiple time.  I don't know what micro calcification means when somebody is re‑injected multiple times if you're increasing the percentage of micro calcification over time.

            I am not aware of any effects of  what the calcification is in this study.

            DR. FENNERTY:  I was asking that specifically to refer to Dr. Merritt's question to us because I am not aware of any adverse effects of micro calcifications anywhere in the gastrointestinal tract either.

            DR. YUSTEIN:  No, I'm not.  You, more than anybody, would probably know this.  If you do a PubMed search on calcification and esophageal disease, you will only get like eight or ten hits, and a lot of those are back in the '70s and deal with tuberculosis.

            DR. FENNERTY:  Can you bring up slide 35?  I just want to look at 35 and 36 extremely briefly.  You can tell you were not a chief resident.  While you're doing that, Aron, what I am going to point out on slide 35 is I think it was asked by Nick as well, if we can get back to one more, please, I think when you use a scale that is not zero to 100, it magnifies things that are clinically irrelevant.  I do want to point that out.

            I think just as a general scientific rule, that scale axis should have been zero to 100.  And there is no clinical trend here.  That would be my just observation unless you think differently.

            DR. YUSTEIN:  It's not my opinion.  It's your opinion.

            DR. FENNERTY:  Okay.  And the next slide, please, as well.  Just as a point of reference, most of us ‑‑ and I know we have a biostatistician sitting at the end here ‑‑ really like to see confidence intervals for a reason.  I did these in my head as I was sitting here.  These confidence intervals all overlap.  I think we have to be very careful about the use of the term "trend" when we do this.

            Are you aware of any of these that are statistically significant?

            DR. YUSTEIN:  No, no, no.

            DR. FENNERTY:  Thank you.

            CHAIRPERSON WOODS:  Other questions by the panel?

            DR. AFIFI:  A very brief question as well.  This is related to something you mentioned, but what was triggered in my mind is whether you attempted to relate the percent success as a function of baseline measurements that would be an attempt at finding who might benefit the most before you give them the device.

            DR. YUSTEIN:  Yes.  The sponsor did that as well, and I believe they did not find any statistically significant differences between subgroups.  Is that what you are asking, who started with certain characteristics?

            DR. AFIFI:  Yes.

            DR. YUSTEIN:  Age, weight, so forth?

            DR. AFIFI:  No.  What I meant is other things like HRQL at baseline, other variables like that.

            DR. YUSTEIN:  Based on their baseline HRQL, you mean?

            DR. AFIFI:  Yes, or any other measurement at baseline because that would be a way of deciding ahead of time who might benefit the most from the device.

            DR. YUSTEIN:  I could tell you that of the successful patients, those that met success, 80 percent of them ‑‑ okay.  Sorry.  No, I don't think I have that.

            CHAIRPERSON WOODS:  Any other questions?

            (No response.)

            CHAIRPERSON WOODS:  If not, we'll move on.  Thank you.

            DR. YUSTEIN:  I would like to introduce Mel Seidman, who will present the FDA's statistical review of the data.

           4. STATISTICAL CONSIDERATIONS

            MR. SEIDMAN:  I'm Mel Seidman from the Office of Surveillance and Biometrics.  I was assigned to review this application and have several comments concerning it.  I will discuss the following topics in my presentation:  The control; primary endpoint, including sample size and analysis; pooling of the data; and some other general comments.

            First, the control.  The sponsor states because patients with GERD must endure chronic symptoms, administer long‑term medical therapy, or they undergo anti‑reflux surgery, a minimally invasive alternative is attractive.  Enteryx is a minimally invasive procedure that can provide an alternative, lifelong PPI drug use, with lower procedure risk and at lower cost and morbidity than fundoplications.

            The control used in that study was a baseline control, where each patient is used as his or her own control.  Generally, four types of comparison groups are recognized:  baseline control, such as this study; a placebo or sham control; an active treatment control; or an historical control, where patients must be comparable.

            Typically, if we recommend randomized control trials with an active, approved device from procedure concurrent control, the sponsor suggests that subjects may serve as their own control in the clinical trial when the study endpoints lend themselves to a paired comparison, the baseline values to later measurements of the same endpoints, such that the changeover time can be determined, resulting in a reliable and precise indication of changeover time or outcome for the total study population.  It is particularly appropriate for each patient to serve as his or her own control when the design of the study involves subjective outcome measurements as a significant part of the evaluation of success.

            Please note, however, the use of patients as their own control can be problematic.  And there can be a strong potential bias, especially when subjective outcome measurements are a significant part of the evaluation of success.  The reporting investigators or patients themselves could bias the reported results when subjective measurements are used.

            There are several active comparison groups that could be considered for GERD, including PPIs, over‑the‑counter medication, surgery, placebos, diet, and other controls.  The design of the study must not only include the appropriate controls but also include primary endpoints that are clinically acceptable.

            Concerning the primary endpoint sample size analysis, the sponsor's original protocol did not clearly specific how a proposed primary endpoint would be recorded and analyzed.  A primary hypothesis was not correct.  And sample size determination that is directly related to the primary hypothesis could not be verified.  The sponsor did respond to these deficiencies.

            The primary endpoint was defined as a reduction of PPI and, more specifically, the primary hypothesis was correct.  And a successful event was defined as a reduction in administration of PPIs of greater or equal to 50 percent, as compared to baseline usage.

            Sample size determination, use non‑parametric method of note there.  And this reference was included.  The sponsor sample size calculations appear acceptable based on their given assumptions.  Sponsor's analysis included non‑parametric tests, including the Sign test with 95 percent, 2‑sided intervals in the Wilcoxon Signed Rank test.

            Again, this appears acceptable provided the primary endpoint as defined is acceptable.  Note that the primary endpoint for sample size justification was based on effectiveness and no assumptions for safety were considered.

            Pooling of data.  Typically the FDA wants data to be representative to the clinical population attendant.  Often we require the data to be stratified and analyzed by appropriate prognostic variables, such as patient demographics, investigating experience, or site.

            The sponsor reported combined or pooled data for their presentation of summary safety and effectiveness parameters.  This is typical if there is no pooling issue.  However, for the primary endpoint, the sponsor claims the expected results are not significant when site was analyzed.

            The results presented were correct ‑‑ and this is the first table that you see on the screen ‑‑ and show a p‑value of greater than .05 but may not be appropriate.  The sponsor combines sites 3 and 5, which is an expansion on the second table there.  When we do this same analysis and include sites 3 and 5, the chi‑squared test and the newly eight by two table yields a p‑value of less than .05, this indicates the expected proportions between sites may be different for the primary endpoint.  Typically if site results are not similar, we look at results by site.

            Results by site might not be very meaningful in this study due to inadequate numbers by site.  Pooling issues are not limited to the potential site variation.  Often we want to analyze data to find out if the device is better or worse for certain groups of patients.

            Subgroup analysis could include age or other baseline demographics as well as type and amount of PPI used at baseline, endoscopic rates, volume amounts, or other variables.  Dr. Yustein did present the demographics of many of these subgroups.  The sponsor did look at the baseline variables by site.  A formal subgroup analysis by effectiveness or safety was not done.

            Just a comment.  I did see some tables this morning that I did not see prior to today.  I am not sure if that is allowable by the panel.

            Other general comments.  Based on the limited data reported, there may be a downward trend in the effectiveness over time.  Note that the LES mean length had a substantial decrease from 3.1 centimeters at 6 months, 2.8 centimeters at 12 months.  Also, Dr. Yustein reported that more than half of the patients had a lower LES pressure at 12 months when compared to baseline.

            Is one‑year follow‑up sufficient?  Concerning retreatments, there were 19 patients retreated in this application that did not always follow the protocol definition for eligibility of retreatment.  Also, the protocol does not require these retreated patients to be followed for one year from retreatment.  That is the one year of data that is reported from the first procedure.  This could bias the results if there is a downward trend in time for efficacy reported.  The sponsor states these items were reviewed and there were no clinically meaningful differences noted.

            Volume.  Volume of Enteryx remaining in the patient appears to change over time.  Patient used the one‑month interval as baseline and excluded patients with retreatments in their volume amounts.  There could be from one to four injections at each procedure.

            As sponsor states, objective evaluations were classified by quartiles.  This subject of evaluation should be done by independent experts for concurrence.  And the one‑month interval used for baseline should be clinically acceptable.

            Endoscopic results.  Endoscopic results were worse at 12 months compared to baseline for several patients.  The results were compared to a literature control for comparison.  If this evaluation is subjective, the evaluation should be done by independent experts for concurrence.  The literature control should also be acceptable.

            Finally, there is a potential for bias when there are many protocol deviations, violations, or missing data.  This can be especially important when evaluating secondary measures for this study.  For example, a sponsor's analysis for pH Probe percentage total time uses only 67 of 81 subjects who completed the study.

            The sponsor's assumption in their analysis is the missing data will not be different from the completed data group.  This may not be valid.  Missing data may be due to patients without real improvement.  The sponsor's explanation for this noncompliance was that the patients refused any additional invasive procedures.

            Similarly, there are many protocol deviations in this study, including 13 at entry and 31 listed as study method deviations.  When there are many data entry and study method deviations along with substantial missing data, the conclusions from the analysis of the secondary endpoints could be biased.

            However, conclusions from the primary endpoint appear to be conclusive and missing data is not a factor while protocol deviations were either explained and/or analyzed for the primary endpoint.

            I would also like to make a comment concerning the sample size that Dr. Afifi brought up earlier.  He is correct, yes.  The hypothesis is not the same as presented in the application.  And Dr. Kennedy is also correct.  The power is sufficient for the primary endpoint as defined.

            I did confer concerning this sample size with a colleague and then more recently with my supervisor.  We all agreed that it was powered sufficiently for the primary endpoint.  The question is, did the primary endpoint change?  I discussed with Dr. Yustein, and we both thought it was acceptable as presented.

            I would like to now introduce Dr. Lori Brown, who will discuss some post‑marketing issues.

            CHAIRPERSON WOODS:  Before you leave the podium, any questions from the panel?

            (No response.)

            CHAIRPERSON WOODS:  Everybody is satisfied?  Okay.  Thank you.

               5. POST‑MARKET REVIEW

            DR. BROWN:  Good morning.  I'm an epidemiologist from the Office of Surveillance and Biometrics in the Division of Post‑Market Surveillance.

            A current theme at CDRH is total product life cycle.  The major goal of this initiative is to integrate pre‑market and post‑market staff so that the pre‑market to post‑market transition is a smooth one.  The reason for this is to meet FDA's mission to continue to ensure a product safety and effectiveness once marketed.

            The Epidemiology Branch and DRERD are part of the pilot program to include a post‑market perspective and pre‑market review.  As background and because FDA's advisory panels typically concentrate on pre‑market questions and issues; that is, whether studies are adequate to recommend device approval, I will tell you a few of the core reasons that post‑market assurance is important.  Then I will address my remarks specifically to Enteryx.

            I want to emphasize that this does not mean that I or other post‑market specialists are advocating the approval of Enteryx.  Rather, in the event that you recommend the approval, these are some issues for you to consider as part of a post‑market plan to address the safety and effectiveness of this device.

            First let me address the reason for post‑market assurance through continued study of approved medical devices.  As rigorous as the pre‑approval process is, there are several issues that are typically not addressed during the pre‑market period.  That is prior to approval.  I have listed these here.

            The study population for the pivotal trial is often small and not powered to detect rare but potentially significant adverse events.  Second, the population for these studies is often highly selected.  That is to say that when the device is used in the real world, the user population is expanded to include vulnerable subpopulations who are not studied during the clinical trial.

            Next.  Third, the duration of the clinical study is usually short and so does not capture the duration of exposure in the real world.  Another aspect of this is that pre‑market studies do not usually assess chronic use or repeated application of a device.

            Fourth, during the clinical trial, there is a highly trained, motivated staff applying the device.  When the device goes to market, there will be a much broader spectrum of users, including some who are less thoroughly trained or less rigorous than the staff for the clinical trials.

            Finally, post‑market studies may be to assess drug‑device or device‑device interactions which are not usually seen in the clinical trial.  Again, because the population is expanded when marketing begins, unforeseen interactions may occur.

            Now to speak in this framework but comment specifically on Enteryx, first, the pivotal trial was small.  And it is possible that not all adverse events were observed in such a small select population.  Since GERD is a common problem, the market for this product could conceivably be very large.

            Second, this implant is proposed to be a replacement for lifelong PPI use, but the follow‑up is for a year.  It is not clear that this implant will continue to be effective over the long run.  If it is only temporary, it is important for consumers and physicians to recognize this.

            There has already been repeated application of Enteryx to 22 percent of the pivotal population.  This retreatment was limited because of protocol restrictions on retreating after the third month.  The potential for retreatment could be much higher if marketed.  There is a difference between a product that is effective after the first treatment and one which requires periodic retreatment to maintain effectiveness.  This is important information for patients and physicians to have before embarking on this course.

            Additionally, there is little data to show whether repeated treatments will be effective or whether there are additional safety issues.  As a matter of fact, the manufacturer has shown you they have proposed to do a three‑year follow‑up of the 85 enrolled patients.  They have also proposed extending recruitment or they're extending their recruitment to the extension study.  So there will be 75 additional patients, 60 who are already recruited.  And they have also said that they will include another 150 to 200 additional patients from 10 to 20 sites, for a total of about 300 patients.

            Their proposed study extension will have endpoints limited to PPI medication, HRQL, and adverse event reports.  It will not include other endpoints.

            These are some of the issues for consideration of the sponsor's proposed post‑market study.  First, does the proposed study design adequately address the issue of repeated procedures?  Is the proposed duration of follow‑up adequate to characterize safety and effectiveness of this device long term?  Are the endpoints proposed by the sponsor adequate to characterize the safety and effectiveness of this product?  And, finally, does the sponsor need additional studies to address potential post‑market concerns with Enteryx?

            Thank you for your time.  This concludes the FDA remarks.

            CHAIRPERSON WOODS:  Any additional questions from the panel?

            (No response.)

            CHAIRPERSON WOODS:  Okay.  If not, we are going to break for lunch.  We are going to shorten the lunch to 45 minutes to try to pick up some time.  So we will reconvene at 1:15.

            (Whereupon, at 12:33 p.m., the foregoing matter was recessed for lunch, to reconvene at 1:15 p.m. the same day.)

 

 

 

 

 

 

 

 


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

                                       (1:21 p.m.)

            CHAIRPERSON WOODS:  Okay.  I would like to reconvene the meeting of the panel.  Although this portion of the meeting is open to public observation, public attendees may not participate except at the specific request of the panel.

            The first speaker is Dr. Brian Fennerty, primary panel reviewer and lead discussant.  Brian?

            DR. FENNERTY:  Thank you, Dr. Woods.

               3.  PANEL DISCUSSION

            DR. FENNERTY:  I wanted to just spend a few brief moments reviewing the burden of illness, as I would term it, regarding gastroesophageal reflux disease, for which this device is intended and has been studied.

            It is likely that one in four to one in five adult Americans reflux disease.  And when you look at the quality of life of patients with reflux disease, it is probably as bad as other chronic diseases, such as peptic ulcer disease, diabetes, hypertension, depression, et cetera.

            Therefore, when you look at this impact of the quality of life in this disease and the epidemiology or prevalence of this disease, the burden of illness of this disease is enormous, not only in our population in the United States but worldwide and, therefore, very much clinically important.

            The pathophysiology of this disease, though, is not singular.  It is a disease, probably many diseases wrapped into one symptom complex, that predominantly being heartburn and regurgitation.  In the past, we have focused on Reflux 8, which is probably the symptom generator, but we have really ignored the pathophysiologic mechanism.

            The treatment of acid reflux with anti‑secretory agents is treating the Reflux 8, not the mechanism.  And even surgical anti‑reflux therapies for the most part are simply forming a new barrier and not treating the underlying pathophysiology, which in most patients with reflux is transient lower esophageal sphincter relaxations, not an incompetent sphincter.

            As a matter of fact, interest in drug development in this arena right now is on agents such as nitric oxide inhibitors, CCK, alpha agonists, and H2 receptor antagonists, all hoping to block that transient lower esophageal sphincter mechanism.

            With that in mind, our current therapeutic options in the management of patients with reflux disease has been potent anti‑secretory therapy with either H2 receptor antagonists or proton pump inhibitors or anti‑reflux surgical therapy.  These two standard therapies have set a therapeutic bar of somewhere between 80 and 90 percent symptom relief when measured over 1 to 3 years.  Indeed, even with these therapies, we have very little long‑term data.

            The longest data we have with PPIs is the Klinkenberg Knoll study, which is evaluating less than 100 patients followed out 10 years.  And the most credible surgical literature is Laurel Lindell's data from Scandinavia, which only goes out five years.  So we, even with these standard therapies, don't have good long‑term data.

            This study has affected safety and efficacy of novel endoscopic application to treat patients with reflux disease and has extensively evaluated the safety and efficacy in this pivotal trial.

            One of the points I want to make in general, though, is in the past, our evaluation of patients with reflux disease in trials of therapies have not focused on a global assessment, which is a much more important and clinically relevant primary outcome.

            Indeed, I think from this point forward, irrespective of the outcomes of our analysis of the data today and our recommendations to the FDA, we really do have to go back and reconsider what we are going to accept for new therapies for the treatment of reflux disease, irrespective of their pharmacologic, surgical, or device‑related.

            I think the design of these therapeutic trials, we have to go back and reconsider what we are going to accept as a minimum accepted standard for these trials as well as what our primary global assessment will be.

            So, with that, Dr. Woods, I am going to turn it back over to you I think unless you want me to address any other specific points.

            CHAIRPERSON WOODS:  No.  I think that is fine.  Does anybody else on the panel have other points they would like Dr. Fennerty to address with respect to the treatment or management of GERD?

            (No response.)

            CHAIRPERSON WOODS:  Okay.  Now we will address the panel discussion points and answer each question.  Following that, Dr. Fennerty will summarize the panel comments at the end of the discussion of each question.  The panel members during this time may ask for clarifications from the sponsor and the FDA, if necessary.

            Before we proceed with that, do any of the panel members have any general comments or questions before we proceed to the discussion points?

            (No response.)

            CHAIRPERSON WOODS:  No.  Okay.

      2.  READING OF QUESTIONS AND DISCUSSION

            CHAIRPERSON WOODS:  I will now read the first question regarding evaluation of safety and effectiveness, "The device, once injected, is intended as a permanent implant.  Please discuss whether the current data provides adequate assurance of safety.  Within your discussion, please specifically address the 12‑month histology findings (persistent inflammation and mineralization) from the animal data."

            I think we will start with Dr. Shaheen.

            DR. SHAHEEN:  From what I have seen, I feel like the device appears overall to be safe.  I am not greatly concerned about ‑‑ and perhaps this is just my ignorance of histology, but I am not incredibly concerned by this issue of micro calcifications, as they have been described.

            I do think that this isn't all that different than you might expect to see with foreign bodies elsewhere in the body.  I am a little concerned about the fact that we have only got 12‑month follow‑up here.  And this is a device that in the application on page 24 is being considered, "as Enteryx offers an alternative to lifelong medical therapy."

            Certainly when you are discussing lifelong medical therapies, I think everyone here would feel a little bit more comfortable if we were dealing with a little bit longer‑term data.

            However, based on what I have seen, it appears that migration is minimal, that the loss of the material is probably to my eye intraluminal and insignificant.  I don't think that when you think about these things, you think about the worst‑case scenario, "Where could somebody potentially put this needle?" that might do harm to the patient, one less expectation for people who are doing it.  I think that the data that we have been presented suggests that even if it gets where it is not supposed to be, chances are it is not going to cause any problem.

            So I think that, all considered, I feel comfortable with the assurance of safety from the data that we have available.

            CHAIRPERSON WOODS:  Thank you.

            Dr. Ferguson?

            DR. FERGUSON:  I agree with Dr. Shaheen.  I don't think there are any short‑term safety issues that have arisen based on the data the sponsor has provided.

            I do have some concern also that long‑term safety hasn't been addressed, particularly for a device that is intended for lifetime issue.  So there are issues I think remaining regarding potential migration.  It's not been adequately established in my mind what happens to the product that has been lost on serial and radiographic follow‑up.

            I have concerns about foreign bodies that are placed in the vicinity of the lower esophageal sphincter of the angiograft prosthesis cortex to reinforce the esophageal hiatus, having had a fair amount of experience removing those foreign bodies, having eroded into the esophagus or stomach.  And this I think has that potential.

            I also am concerned about the existence of a foreign body implanted into the LES and in patients in whom adequate symptomatic relief is not provided, how effective subsequent therapy, such as laporoscopic fundoplication will be in those patients.

            CHAIRPERSON WOODS:  Dr. Achem?

            DR. ACHEM:  One of the key issues, Dr. Woods, that is important, I guess, in our analysis as I read the question of assurance of safety, would be certainly any vets; any perforations; any hospitalizations; any events, such as sepsis; documentation of pleural effusions; many infections or systemic infections, such as an abscess.

            I think given the data in front of me, I understand from the sponsor that no patient underwent any of those major side effects.  In terms of that reassurance, I am comfortable with the data presented to us today, though I recognize that post‑marketing studies are clearly needed because, indeed, as it was pointed out by the agency, specifically the last presenter, until you embark on larger trials, you begin to see potential serious side effects and unusual side effects.

            Now, the part of the study that is more challenging to address is that it is pretty evident to all of us that many patients, the great majority or 90 percent of the patients, experience chest pain and about 20 percent of those also experience dysphasia or difficulty swallowing.

            So certainly the side effect profile is there.  And I think as we weigh decisions for the device approval process, one has to balance the decision‑making with the side effect profile, although none of those seem to be lethal based on the data presented to us by the sponsor.

            Along the same lines, no patient developed a stricture, which would be a serious consideration in my mind, one of the biases that have been implanted at the lower esophageal sphincter nor any patient had a full impaction as best we can tell.

            Dr. Woods, in relationship to the second part of the question; that is, the histology findings and the inflammation and mineralization, I am not a pathology expert.  Therefore, my opinion is based on the analysis rendered by the pathologist today here.  If their analysis is accurate that there is quiescence at one year, that would at least theoretically provide us with comfort that no subsequent inflammatory response is taking place.  Whatever this process is doing to the lower esophageal sphincter has ceased apparently at that point.

            I think one important issue regarding the histopathology that intrigues me personally because it can't speak to the mechanism of action is the question I raised regarding the damage to the Enteric plexi and specifically to nerve trunks.

            It is possible that the device may be acting via two different mechanisms.  One, maybe even, indeed, it's affecting lower esophageal sphincter relaxations, but it doesn't exclude the possibility that it may also be impairing neurosensory perception of the esophagus.  This may have a bearing in explaining symptom outcome of these particular patients.

            This particular concern brings up the point on study design and the need to have a placebo‑controlled, double‑blinded investigation to try to address this particular issue.

            Finally, in specific reference to the mineralization issue, I am reassured by the pathologist as best as I can tell on their statements that there seemed to be a minimal amount of mineralization occurring.  And, as I asked further questions, what is the specific amount that there is and how critical is that to the functioning and particularly to deleterious effects to the patient, it remains to be established.

            Based on the assessment given to us today, I would say that the impression I have is that the deposits of mineral calcification is modest at best.

            CHAIRPERSON WOODS:  Okay.  Thank you.

            Dr. Afifi?

            DR. AFIFI:  I am going to limit my comments to statistical or public health issues in the sense that's the area I feel comfortable in.  From that point of view, I really see nothing to add to the discussion except to emphasize the importance of the long‑term follow‑up.  So if, indeed, the device is approved, we will need to keep that in mind in the post‑marketing analysis.

            CHAIRPERSON WOODS:  Thank you.

            Dr. Manyak?

            DR. MANYAK:  I am going to make my comments brief also.  I think my GI colleagues I will defer to with a lot of the areas in their field, but there is one question I had.  And that is the multiple injection issue appears to be fairly real.

            There is a significant number of patients who need these, which is very similar to the injection for peri‑urethral tissues in my field.  And it raises the question in my field that is safe for multiple injections, but I am not sure that has been answered here with this data here yet.  Possibly in the short term, it has, but I think over the longer‑term, which is something we are all concerned with.

            So I think that is the concern I would like to voice today.

            CHAIRPERSON WOODS:  Thank you.

            I would echo similarly most of the comments already made.  And that is that I believe, as presented, the data shows adequate safety within the 12‑month period of time.  I am not concerned about the histologic findings.  I think that is something you would expect to see with any implantable foreign body.

            I would be concerned with repeated injection since we have no data beyond what was presented here today.  I am most interested in follow‑up beyond the 12‑month period of time on all the patients who are studied, but, as pertains to the question asked, I think that the device, as presented, is safe.

            Dr. Fennerty has elected to postpone his comments to the end.  So we will move on to Dr. Gellens.

            DR. GELLENS:  I also echo most of the sentiments already mentioned by the panel members.  I think the safety is adequate at one‑year follow‑up so far, but it needs to be adequate because the patient population that we are dealing with here is not incredibly sick to start with.  And the job is to do no harm.  So I think it meets the safety requirement.

            As far as the inflammation and the mineralization are concerned, in my field, we have a lot of experience with tissue calcification as far as calciphylaxis and whatnot are concerned, which can be quite devastating.  However, the pathophysiology is totally different here.  I don't think the mineralization issue is a real problem.

            And that's it.  Thank you.

            CHAIRPERSON WOODS:  Ms. Moore?

            MS. MOORE:  From the consumer's point of view, I think my major concern has to do with the word "permanent."  I am not sure that the consumer would feel comfortable with that word if, in fact, they realized that the study has only been for a couple of years; so I think that perhaps if we could find either another word or elaborate upon that word so that the consumer would know, then, that this has been a short‑term study and they wouldn't expect permanency.

            CHAIRPERSON WOODS:  Mr. Balo?

            MR. BALO:  I think, you know, from an industry perspective, the company did show safety as a protocol was defined to show safety.  In fact, the company has realized I think some of the comments that are made by the panel members here, that they need to do follow‑up.  And, as the sponsor has indicated, they are proposing to do a post‑market study that will carry this out for longer than one year's period of time.

            So I think that is a good step by the sponsor to make that comment.  I think I agree that safety has been indicated in the study data.

            CHAIRPERSON WOODS:  Thank you.

            Dr. Fennerty, would you like to make your own comments and then wrap up?

            DR. FENNERTY:  Well, I am just going to make my comments as a summary because I think they reflect the majority and, actually, the consensus that we have heard today that, really, the short‑term safety issues have been adequately addressed by the study and the sponsor.

            Obviously we will need longer‑term follow‑up, which is already planned and been addressed between the sponsor and the FDA.  I think, though, that some of the concerns that further work needs to be done in the future, irrespective of the outcome of this decision on the issue of the foreign body reaction and subsequent treatment, specifically surgery or perhaps other endoscopic applications.

            I think the consensus is address the FDA's concerns that the ongoing inflammation and calcification, mineralization, is clinically irrelevant at this point but would bear further observation with the post‑term marketing follow‑up.

            CHAIRPERSON WOODS:  Thank you.  We will go on to number 2, question 2, "Tantalum was added as a component to the device to aid in visualization under X‑ray and to assess indirectly the residual volume of implant at follow‑up.  Please comment on the degree to which the data in the PMA demonstrates that the amount of tantalum visualized on X‑ray directly correlates with the amount of polymer remaining implanted."

            Dr. Shaheen?

            DR. SHAHEEN:  Well, I don't think that we know 100 percent for sure that the contrast agent at long‑term follow‑up is evenly distributed and adequately reflects the amount of implant.  I'm not overwhelmingly concerned about this because, frankly, I don't put that much stock in the data about residual implant to begin with.

            I think that, as the sponsors acknowledge, this is a very imprecise measure that they are using to try to figure out basically whether or not the stuff is there or not.  I think that when you get 65 percent versus 40 percent from 2 views on a plane X‑ray when it is a guess to begin with, it is not compelling to me.

            So I am more interested in the data they present as far as effectiveness than I am caring all that much about the contrast agent may not be uniformly spread throughout.  I suspect there is a chance it may not be, and I don't care that much.

            CHAIRPERSON WOODS:  Dr. Ferguson?

            DR. FERGUSON:  Well, I don't believe that the sponsor has provided any data that directly addressed this question.  I think there is some variation in the amount of mixing.  However, I suspect that the tantalum remains within the polymer and that probably it does reflect the amount of polymer remaining.

            CHAIRPERSON WOODS:  Dr. Achem?

            DR. ACHEM:  Dr. Woods, I agree.  I don't think we have enough information to provide an answer to this question.  With your permission, I may venture to speculate or say that perhaps further studies are needed if there is an issue, such as in vitro, looking at mixing the solution and X‑raying it and determining how the dispersion coefficient takes place.

            There is some data in animals from their own studies, though, where the solution was injected and I suppose could have been X‑rayed to make comparisons and distribution.  But, as it stands, I am unable to provide an answer to the question.

            CHAIRPERSON WOODS:  Dr. Afifi?

            DR. AFIFI:  The word "correlates" that is in the question makes it a statistical question.

            (Laughter.)

            DR. AFIFI:  To adequately analyze it, we would really have to have data on both variables in order to then measure the correlation and perform some significant tests or whatever for it.

            But, to my knowledge, such information was not presented to us.  So I really can't comment on it.

            CHAIRPERSON WOODS:  Dr. Manyak?

            DR. MANYAK:  I think the issue for me here is, rather than sloughing or exact correlation with density, it's more one of migration products.  We see this with radioactive seed implantations.  We see this with other products.  Do these tantalum particles show up in the lung, in the liver, and other places?

            You know, I think what we know about tantalum and being as inert as it is, this is probably not an issue.  I agree with Nick about that particular issue, but there is no data provided about that.  To me, that is the issue.  And it's not whether it sloughs off and it's gone somewhere.  Does it migrate somewhere else?

            CHAIRPERSON WOODS:  Thank you.  I agree there's no data presented that demonstrates that the amount of tantalum visualized on X‑ray directly correlates with the amount of polymer implanted.

            Dr. Gellens?

            DR. GELLENS:  I agree with pretty much what the panel said so far in this regard.  As far as the tantalum is concerned, though, I really think that, instead of following X‑rays, you should probably follow CT scans.  It seems to me a much better way to follow the progression of this material.

            CHAIRPERSON WOODS:  Ms. Moore?

            MS. MOORE:  I pass on this one.  I submit to the experts here.

            CHAIRPERSON WOODS:  Okay.  Mr. Balo?

            MR. BALO:  Same here.

            CHAIRPERSON WOODS:  Okay.  Dr. Fennerty?

            DR. FENNERTY:  I think the panel reflects that we can't answer this question for the FDA that they asked us to address, but I also think that there seems to be an underlying consensus among the experts here that it is likely to be of clinical and safety minor importance, if at all.

            CHAIRPERSON WOODS:  Thank you.

            Question 3, "Over 40 percent of evaluable subjects had a greater than or equal to 25 percent reduction in residual implant volume (as assessed by measurement of residual tantalum) at 6 months and 12 months when compared to baseline at 1 month.  Please discuss this finding and whether it poses any safety or effectiveness concerns.  In addition, please comment on whether the conclusion that the 'missing' material sloughed into, and was passed out of, the GI tract is reasonable and supported by this data."

            Dr. Shaheen?

            DR. SHAHEEN:  I appreciate you letting me go first on all of these, ‑‑

            (Laughter.)

            DR. SHAHEEN:  ‑‑ especially these simple ones.

            I go back again to the imprecision of how they did this.  I wonder how much we should make out of these data about the measurements based on the plane films.  They have provided us essentially no evidence that the material truly is sloughed off and comes out in the feces.  I believe that is what is happening.

            I also agree with Mike that perhaps the more important question is not so much did it all fall out, but if it is still in there, is it doing anything nasty?  And, at least as best we can tell from the data that we have, it probably isn't doing anything horribly nasty.

            And, for that reason, again, I am not incredibly concerned by the fact that these patients have had a reduction in the residual implant volume.

            The other thing, of course, you have to think about is that this isn't a static situation.  There is remodeling that is going on there.  Perhaps there is contraction.  If there is collagen surrounding these injections that that collagen is contracting, perhaps that accounts for some of it.

            The bottom line is that with the imprecision of the tools used to measure this and the fact that we don't have a lot of data that some of our injection has gotten away and is doing something bad, I am not incredibly concerned about at this point.

            CHAIRPERSON WOODS:  Dr. Ferguson?

            DR. FERGUSON:  Well, I have concerns about this point.  I believe that the sponsor hasn't adequately demonstrated where the missing material has gone.  Only 5 or perhaps as many as 6 animals were observed for a 12‑month period.  No study of feces analysis was performed as far as I can tell.  It would have documented some sloughing of the material in those animals.

            I think it is personally alarming that that percentage of patients has been documented to have some loss of material.  And, as far as I can tell, no substantial effort has been made to document where the material goes to.

            CHAIRPERSON WOODS:  Dr. Achem?

            DR. ACHEM:  I would agree with Dr. Ferguson as far as a lack of accountability of where the material is and my inability to, therefore, tell whether this is a sloughing off, which appears an acceptable alternative explanation.  And I don't have concerns about accepting the notion, but it is unclear whether everything would slough off or not.

            Indeed, in fact, in some of the data, there is some material that was actually implanted transmurally in some of the patients.  So you really wonder where it went.  The fact of the matter, as Dr. Shaheen pointed out, is that there appears to be no major migration to vital organs or vessels.

            The consequence of the migration, whatever that was, for which we can't account, does not seem to have any negative effects, which to me is the most significant finding.

            CHAIRPERSON WOODS:  Thank you.

            Dr. Afifi?

            DR. AFIFI:  I would like to address the question of whether the loss of the implant has any implications on effectiveness, rather than safety.  The question that that raises is, does it continue to produce the level of effectiveness after it has lost such a percentage of it?

            So the question, then, really is what is the point at which the effectiveness is reduced below an acceptable level and according to some definition, which, in turn, raises the question of, is this related to the retreatment of the patient?

            So, in my mind, these are really the issues.  I don't think we have enough data to address that way of looking at it.  Again, it becomes a question of long‑term data, but I think it is a relevant one, especially from the "How good is the device?" point of view.

            Thank you.

            CHAIRPERSON WOODS:  Dr. Manyak?

            DR. MANYAK:  I believe this question has one of three possible answers for this.  One is either the tissue sloughed and the material has gone through the GI tract.  Secondly, the migration issue we talked about.  And the third is whether or not this is actually biodegradable and we have lost some of that because of that aspect.

            Biocompatibility, many things that are biocompatible are also biodegradable.  It's very well possible that you are getting some resorption here of this material that is really inconsequential from an extent of a safety standpoint, but it would explain your decrease in volume.

            So I think you can answer the questions in a couple of ways.  One would be if you are looking for the migration issue, it would seem to me that in your post‑market analysis, at the same time that would be being performed, you could certainly perform animal studies, whether they are small animals or larger animals.  I am not the right person to answer that part.  But you would want to look at he lungs and the liver and other tissues to see if there is migration of these tantalum products.

            You know, we do need to consider, even though it is a biocompatible material, the tantalum.  Do we have 25‑year data on tantalum implantation in humans?  I don't think we do.

            The question is if there are, that's fine.  I'm happy to hear that.  But these are younger people, some of them, and they are going to have a long life span.  So it is an issue that we should pay a little attention to here.  And it is something that I think you can answer the migratory issue with animal studies.

            The biodegradability is also something you can probably answer.  So concurrently with your post‑market analysis, you can put this thing to bed, I believe.

            CHAIRPERSON WOODS:  Yes.  I agree basically with everything that has been said.  I would say I felt impressed with the animal data that was presented that there was no evidence of the tantalum in any of the other organs remotely, of the entire Enteryx polymer product anywhere in the bodies of the animals that were studied.

            So the other side of the coin is whether or not this reduction in volume affects the effectiveness of the product.  I think the data presented suggest that it may well as patients who had less than 5 or 6 ml of product left were more likely to be treatment failures.

            I think there are just a lot of questions here that we just still don't have the answer to and hopefully with the post‑market analysis will become more clear.

            Dr. Gellens?

            DR. GELLENS:  I am pretty comfortable with the fact that this Enteryx is being sloughed off into the GI tract.  I agree with Dr. Woods as far as the animal data is concerned.  After X‑raying the animals, it couldn't be found anywhere else.  So unless it's turned into something else, it has got to be sloughed out of the GI tract.

            I think the histologic data is relatively convincing with this fibrous capsule that is formed, that it is probably not degraded in the body.  So I think that it is probably sloughed off.  I am comfortable with that.

            Thanks.

            CHAIRPERSON WOODS:  Ms. Moore?

            MS. MOORE:  Yes.  Well, I have nothing new to add.  I was concerned, though, about how we know where the sloughed‑off material went.  I didn't see anything in my reading to tell me that you had some definite proof that it came out in the feces or just what.  I am comfortable with what has been said.

            CHAIRPERSON WOODS:  Mr. Balo?

            MR. BALO:  Yes.  I think everything has been said about the safety of it, but, you know, the company did do all the viability testing that is required by the FDA to show that all of the material that is used in the device is biocompatible.  That is a standard that companies use basically to prove that the materials themselves are biocompatible.

            The animal data we spoke to already and basically said you don't have any concerns about that.  So I think from my perspective, we could assume, just like other doctors have said here, that it is not really that big of a problem where it sloughs off.

            CHAIRPERSON WOODS:  Dr. Fennerty?

            DR. FENNERTY:  I think in order to address the question the FDA asked us to address, I think the bottom line is we don't know where it went.  Most of us I think are presuming that it's sloughing.

            I think the last comment ‑‑ it was very important ‑‑ is we are all presuming based on what we know now that these are safe, biocompatible agents.  Therefore, the real issue is, does it really make any difference?  I suspect that from a safety standpoint, it doesn't, but it needs to be addressed and resolved.

            I am sure Dr. Johnson would love to perform the study that he strains all of his patients' stools for the next two years to find out where it is going.

            CHAIRPERSON WOODS:  Okay.  Question 4, "Reduction in proton pump inhibitor dose was used as the primary effectiveness endpoint for the clinical trial.  The objective of the study; i.e., to show a greater than or equal to 50 percent reduction in PPI dose in at least half of the enrolled subjects, was met at 12 months.  The objective secondary endpoints, however, did not appear to demonstrate the same degree of improvement.  Please discuss the significance of the results from the intra‑esophageal pH; esophagogastroduodenoscopy, or EGD; and manometry procedures, and whether they support the use of Enteryx as a safe and effective treatment for GERD.  Within your discussion, please comment on whether you believe that these results suggest patients may be at continued risk for developing complications of GERD including erosive esophagitis, strictures, and/or Barrett's Esophagus despite symptom improvement while off their PPI medications."  It is a complicated question.

            Dr. Shaheen?

            DR. SHAHEEN:  I think there are several points that need to be made here.  First of all, the safety issue I feel comfortable with.  The efficacy issue I am not quite as convinced.

            There are three points here I think we need to consider.  One is that there is a pretty remarkable, actually very remarkable, improvement in the subjective measures in the study.  You are getting one year out.  You are still at 80 percent in the primary endpoint.

            However, there is a much more modest improvement, in some cases no improvement, in the objective data with about one‑third having worse 24‑hour pH Probe data and unimpressive esophagitis changes.

            In addition to that, I agree with Dr. Fennerty that the graph that Dr. Yustein showed that showed the degrading effect with time on the primary endpoint should have been put on a 100 percent scale.

            I disagree that this may not be very significant, especially if we are talking about a lifelong therapy.  I think there are very few people here that would disagree that if this therapy becomes four or five percent less efficient at every six‑month interval, we are going to be getting into an awful lot of retreatments here.  And we are talking about a different beast than a true lifelong therapy.

            So I do think that that is something to worry about.  And I also think that when you see this constellation of things that, hey, a slowly degrading effect over time, very high subjective measures, very modest objective measures, the other question you have to ask yourself is, how much of this is placebo effect?

            I would submit to you that there are several features here that suggest at least some of this effect may be placebo effect, the fact that 97 and a half percent of people were off medicine at one month, but that degrades fairly rapidly, still to high levels, but certainly it gets back to this issue of longer‑term data needed.

            So I am comfortable with the safety.  I think that this is doing something, although everybody is trying to guess what it is really doing.  And it doesn't seem like anyone knows for sure what effect, if this is a TLSR effect, if this is just a bulking agent, what is really happening here.  It sure would be nice to know what is going on.

            I agree with Dr. Achem that a sham trial with injections of the vehicle but with no active agent would go a long way toward helping us kind of figure out what is going on here to decide a little bit more about the effectiveness.

            So the bottom line is that we can't answer the last part of the question, which is is this going to halt progression to Barrett's Esophagus, and stricture, et cetera, but remember there are very little data.

            It is kind of an unfair thing because, even for PPIs and surgery, there are very little data about halting progression of Barrett's Esophagus or to Barrett's Esophagus.  It is not really a question that is answered anywhere in the literature with any of our standard therapies either.  I mean, if you do a wrap on somebody with reflux, they can still get Barrett's.  And nobody knows whether or not there is a retardation of the effect of the chance of getting Barrett's with time.

            So in some respects, is there a chance that these things may happen?  Certainly.  But I don't think that that is any different than the other therapies we have.

            CHAIRPERSON WOODS:  Dr. Ferguson?

            DR. FERGUSON:  Well, as it states here, the primary endpoint I think was adequately met by the sponsors with the study.  I think I have also indicated that I believe they chose the wrong endpoint for the study and that the more objective measures are more important than getting patients off the PPIs.

            So with regard to intra‑esophageal pH, the majority of the patients at 12 months would still qualify for entry into the study based on abnormal intra‑esophageal pH.

            Similarly, an insufficient percentage of patients had regression of esophagitis.  And, in fact, a substantial number of patients developed esophagitis after implantation of the material.  The sponsors have failed to demonstrate adequately the mechanism by which they think the device works.

            There is insufficient change in any of the manometric parameters.  To provide an explanation, I think Dr. Achem has already suggested two very plausible explanations having to do with nerve damage, one interference with transient relaxations.  The other is interference with a feedback mechanism so that the patients don't recognize that they're having acid exposure in their esophagus.

            The problem with this latter one is that as the patients have ongoing exposure but don't recognize this exposure, they're perhaps at higher risk than the typical patient with GERD for developing the compilations, such as Barrett's Esophagus, stricture, and perhaps adenocarcinoma.

            So I believe there are substantial questions regarding efficacy.

            CHAIRPERSON WOODS:  Dr. Achem?

            DR. ACHEM:  Thank you, Dr. Woods.

            Well, unquestionably, the secondary parameters would be an ideal goal for those of us looking at concern issues, that they be modified to a substantial effect.  That is not the case.

            Let me dispense quickly with the manometry that doesn't concern me at all.  In fact, I am gratified that there has been no effect, no substantive effect on distal esophageal peristalsis.  It would concern me if the peristaltic pathway or peristaltic amplitude would impair in the spaces when you inject this device.  Again, we are invoking some potential hypotheses of nerve damage.  So you can see that at least the amplitude of distal peristaltic was not impaired.

            That is the extent of how I look at the manometry in terms of being helpful here.  So I am not concerned about the LES pressure.  We have already alluded as to other mechanisms, such as transient lower esophageal sphincter relaxations.  It's a more important pathway to look at.

            The thing that is concerning is certainly the pH data.  The fact that up to 39 percent of the patients only normalize the pH is potentially a bothersome issue.  I was trying to think in my mind whether there is any published data.  I know there is.  And I just don't think this is ‑‑ I am trying to look at the applicability of the data as to the variability of pH.

            If you repeat pH studies on a single individual over time at repeated intervals of time, how much of a change in the pH parameters can be expected?  I can't come up with that information.  Maybe Brian might elaborate over that and whether that can be a factor to, somehow or another, explain the differences noted.  Alternatively, clearly, though, it means that the device is not affecting to a substantial degree the acid clearance or acid contact time, as we see by the fact that only 39 percent of the patients normalized.

            So that would be a potential serious concern.  So is the fact that about 22 percent of the patients seem to have progressed to Grade 2 erosive esophagitis, a category that is less difficult to subject intra‑observer variability in terms of the classification by the endoscopies.  That category is easier to score by most of us.  And there is more the pendency on that grade than it would be for Grade 1's.  So that observation is of some concern indeed and argues to some extent that the efficacy parameters have not been modified by this particular device.

            As far as the issue of whether these factors, therefore, represent a potential impact, I think that that certainly remains an open consideration, whether they will lead on to further damage in the esophagus, erosive disease, strictures.

            I don't think that Barrett's will be or should be an issue, at least based on some data that, if I am not mistake, is Alan Cameron's data, I believe, where he looked at an index endoscopy and followed patients longitudinally and found that the likelihood of somebody developing Barrett's Esophagus once you had an index endoscopy which was negative was negligible.

            So I am not as concerned on the concept of Barrett's, at least at this point in time.  But the other aspects certainly remain an issue.

            CHAIRPERSON WOODS:  Thank you.

            Dr. Afifi?

            DR. AFIFI:  There's really nothing for me to add from a statistical point of view.  The analysis does indeed not uncover any improvements in the objective measures that are due to the device.  So I think I will leave the other comments to the experts.

            CHAIRPERSON WOODS:  Dr. Manyak?

            DR. MANYAK:  Well, I believe the primary endpoint, as defined, has been answered.  And I will defer comment on the secondary endpoints to my GI colleagues since that is out of my field.

            CHAIRPERSON WOODS:  Thank you.

            I also think the primary endpoint has been answered, but I have trouble interpreting any answer for you on the secondary endpoints because I think the way the study was designed does not allow you to really answer the questions about this.  It goes back to using these patients as their own controls and not having an adequate, as I see it, control group that received a sham procedure and then were followed for the same period of time, re‑endoscoped, having pH studies, et cetera, all of the same data collected on them.  So I don't think I can answer the questions asked adequately based on the data presented.

            Dr. Gellens?

            DR. GELLENS:  I have additional concerns, as Dr. Shaheen did, about the possibility of a placebo effect here, especially with the primary endpoint that was chosen being subjective as it is.  In addition, then, the objective data doesn't really support the initial results.

            The other possibility is the reason the secondary endpoints don't really support the primary endpoints is that we don't really understand the mechanism for how this works.  That could be the real problem.

            My major concern is that there is a huge placebo effect here that we may be missing, but since the procedure seems to be safe and there is good response at 12 months, I still think it is probably okay.

            CHAIRPERSON WOODS:  Ms. Moore?

            MS. MOORE:  I have nothing new to add.

            CHAIRPERSON WOODS:  Mr. Balo?

            MR. BALO:  I just think that the company did meet the primary endpoint.

            I know the sponsor has the opportunity to reply at the end.  I think some of the questions brought up by Dr. Ferguson and Dr. Achem maybe could be more adequately explained by the sponsor.  If they do have more data and more information, share it with us from some of the European studies that are currently going on.  So there may be some data you might want to listen to.

            CHAIRPERSON WOODS:  Dr. Fennerty?

            DR. FENNERTY:  I am going to take this opportunity to deviate from my previous comments, which were summary, to make some personal comments and to take some of my panelists to task, especially some of the junior members, Dr. Shaheen.

            First of all, while I agree that this would not be the primary endpoint that I would want to see the FDA agree to with a sponsor in the future.  This was the primary endpoint that the sponsor and the FDA did come up with.  And, indeed, it was met in this study.

            Having said that, the accepted standard for therapeutic trial of treating reflux patients today is symptom improvement.  It is what the GEMBO guidelines suggest.  It is what the American College of Gastroenterology guidelines suggest.

            The American Gastroenterological Association suggests the primary endpoint should be symptom improvement.  PPI use could be considered a surrogate marker for symptom improvement.  Hopefully future device trials will look at truly symptom improvement as a primary outcome.  However, we have this primary outcome.  Once again, it was met.  This was what was devised for the study.

            Having said that, the secondary outcome measures are important.  However, they are of secondary importance in management of patients with reflux disease.  Erosive esophagitis should not be considered a complication of GERD.  It is a finding in nearly half the patients with reflux disease.  It is not a complication; whereas, Barrett's and strictures are.

            Having said that, we talk about the secondary endpoint that were not met, ignoring a secondary endpoint which is subjective which was met, which is the Velanovich GERD quality of life data.  This also was an objective secondary endpoint that we have neglected to discuss in our deliberations that was met and was definitely significant from baseline off of PPIs.

            It also ignores the fact that nearly 40 percent of these patients normalize their intra‑esophageal past exposure after this therapy was devised, which is obviously not a placebo effect.  It means that a subgroup of these patients had normal physiologic response.  Actually, that group of patients, if you remember Aron's analysis, also had a clinical response for the most part.

            So, having said that, I have substantial concerns about designs of these sorts of studies.  I wish we could go back in time and redesign it.  But when we look at primary and secondary endpoints, we need to stay symptom and patient‑focused and then answer the mechanistic studies, hopefully in future design trials, in order to address those concerns as well.

            So, as a summary statement, I think it is clear that primary endpoints are met.  A lot of us have concerns about the secondary endpoints and perhaps what the primary endpoint of these trials should be in the future.

            And I think that the mechanistic issues of why continued abnormal acid exposure occurs, despite symptom improvement, needs to be addressed so that we can figure out if this is a neurologic issue or other issues from that standpoint.

            CHAIRPERSON WOODS:  Okay.  Thank you.

            Question 5, "Based on your deliberations to this point, please discuss whether the overall benefits, including improvement in symptom as well as objective measures, outweigh any risks associated with use of this device."

            Dr. Shaheen?

            DR. SHAHEEN:  I would like to thank Dr. Fennerty for his comments and remind him it is only a matter of time before he gets old and dies and we are in charge.

            (Laughter.)

            DR. SHAHEEN:  With that, as far as the risk‑benefit ratio here, I think this is a tough call.  The reason I think it is a tough call has to do with what several people have mentioned before, which is that you are taking a group that is PPI‑responsive on relatively, overall relatively, small amounts of medicine.  So the bar is set pretty high here.

            You have got an effective therapy.  You have got a healthy patient population.  You had better be darned sure what we are going to do to them is:  a) not going to hurt them, which I feel like, in the short‑term at least, has been adequately addressed, and b) is probably going to help them.  I think that, at least in the short term, it does appear that for the primary endpoint, it does help them.

            However, I will say that I would feel lots, lots, lots better if I had at least another year of data on this before I talk to a 26‑year‑old and say, "I want to put this stuff in your lower esophagus.  And it's going to be there forever."

            CHAIRPERSON WOODS:  Dr. Ferguson?

            DR. FERGUSON:  Well, I have ongoing concerns about long‑term risks.  I don't believe that there are any substantial short‑term risks.  Given my concerns about long‑term risks and my concerns about, although there is symptomatic relief, there is not normalization in most patients of any of the other physiologic measures of reflux or LES abnormality.  I can't tell you that there is any way I can come down on the balance of a benefit versus risk.

            CHAIRPERSON WOODS:  Dr. Achem?

            DR. ACHEM:  I think that one of the great difficulties for us is the concept.  We are departing from the notion that many of these people are receiving already a therapy that seems effective and offer an alternative therapy the effectiveness of which is being evaluated at this point and then some side effects occurring.

            When one looks at the context of somebody taking a medication and being symptom‑free or symptom‑controlled, if you will, versus undergoing another procedure and undergoing therapy and some side effects occurring, it brings in the issue of deciding which of the two processes is best and which will benefit from that.

            I think there are a lot of issues that remain unknown.  The overall safety in my mind is being described and I think is there, but the side effect profile concerns me.  Naturally I think patients offered this study will clearly be explained what those side effects represent.

            This may result or this may conceivably serve as a bridge or an adjunctive therapy for the management of GERD.  I am not sure.  I am not sure of the place exactly yet.

            In summary, I think that the risks at this point seem modest.  And those are primarily based on side effects, not inappreciable, by the way, though.

            CHAIRPERSON WOODS:  Dr. Afifi?

            DR. AFIFI:  I think the question of the risk‑benefit analysis is the heart of what we are talking about here.  From the point of view of a patient, I believe that there is something here that shows that there is some benefit for a 12‑month period that outweighs the risks.

            I think, however, since this is billed ‑‑ and I missed Christine Moore.  She said she doesn't like the word "permanent.  Maybe long‑term.  If this is billed as a long‑term treatment, we don't have enough to say about how good it is long‑term.

            It is at this point that I think my earlier comment about longitudinal analysis comes in.  There are really four points that could be quite adequately addressed by a longitudinal analysis if there is to be a post‑market study.

            The first has to do with the effectiveness and a series of measures, be they subjective, namely the being on or off PPI and how well do you feel like HRQL or SF‑36.  I look at those, Dr. Fennerty, as subjective as well, even though they are combined.  So that is number one.

            The other is also the question of safety.  Maybe there are some long‑term side effects that would show up in a longer study than has shown up in 12 months.

            The third point has to do with guidelines for who before the implant can benefit from the procedure if it is indeed approved.  And, again, I would go back to an analysis of baseline data versus the outcomes to try to answer that question but also in a longitudinal fashion.

            The fourth one is the question coming up next, but I think this is a good time to mention it as well.  That is, is it correct to have a repeat procedure?  What are the guidelines for a retreatment if there is to be a guideline for that?

            I would suggest that we need to keep in our mind that these are four major areas that could benefit from a longitudinal analysis.

            Thank you.

            CHAIRPERSON WOODS:  Thank you.

            Dr. Manyak?

            DR. MANYAK:  To make a long story short, I think essentially the short‑term benefits exist to further pursue this procedure, but there is no data on long‑term yet that is satisfactory, I believe.  Therefore, I think that the total picture is really somewhat inconclusive.  The short‑term looks good, but we need further data.

            CHAIRPERSON WOODS:  Thank you.

            I completely agree with Dr. Afifi's comments and couldn't have said it any better.  I think I just want to reiterate that if this is approved, we need to be very, very careful on patient selection criteria being very well‑defined and the repeat injections that may be necessary for a subgroup of patients.  We have no data beyond one injection.

            I am just very concerned that this be monitored carefully and guidelines be put forth as to how to select patients for this and we try to accumulate in a post‑marketing study further data on patients who get more than one injection and what happens with them if patients do get more than one injection.

            Dr. Gellens?

            DR. GELLENS:  I agree that this is a tricky question to answer because the long‑term benefits are not clear by any stretch of the imagination.  So I think a way to get around that is to not market this as a permanent device but perhaps long‑term.  I think that would help the physician and the patient when making an informed decision whether or not to go with this therapy, as opposed to the typical medical therapy.

            CHAIRPERSON WOODS:  Ms. Moore?

            MS. MOORE:  I believe my answer is yes to that question, number 5.

            CHAIRPERSON WOODS:  Okay.  Mr. Balo?

            MR. BALO:  I think that the company did show short‑term effectiveness and safety for this device, as all of the panelists have said.  I also feel that, as I said before, the company realizes that it does need to show more long‑term in the data.

            I think the panel's responsibility is basically to give direction and to show what kind of data we do need so when they do that information, we can basically feel comfortable that we are getting the data we need to show long‑term stability and safety.

            CHAIRPERSON WOODS:  Dr. Fennerty?

            DR. FENNERTY:  I want to take this public opportunity to thank Dr. Cooper for allowing me to take 10 divergent opinions and giving me 30 seconds to summarize them to the FDA.  Thank you, Dr. Cooper, for that opportunity.

            If I am hearing my colleagues correctly, I think that there is a consensus here that we should not view this as a permanent device but within a well‑defined population using one injection, the risk‑benefit over the short term appears to be in the positive toward the benefit side.  That leaves open a number of questions, which is obviously long‑term benefit, the issue of multiple injections, and efficacy and risk‑benefit outside of this well‑defined population, which was put forth in this study.

            CHAIRPERSON WOODS:  All right.  Question number 6, "Nineteen of the 85 patients underwent re‑injection within the first 3 months.  Please discuss whether sufficient data has been presented to support retreatment with Enteryx.  If you believe the data is adequate, please comment on whether you believe any of the following should be recommended:  a) maximum number of repeat procedures (and if so, what number); b) maximum number of repeat injections per procedure (if so, what number); c) maximum implantable volume at each procedure and overall (if so, what volumes); and d) timing of retreatment procedures relative to the initial treatment (if so, the length of time)."

            Dr. Shaheen?

            DR. SHAHEEN:  In the words of Roseanne Roseanna‑Dana, "You ask a lot of questions."

            No.  They are inadequate data to tell us what is really happening with the re‑injections.  I think that given the small number of patients in this study that did undergo re‑injection, it is going to be very difficult to answer, even generally, if this is a good idea, let alone specifically, the letters that go down there.

            I think that in the small number of patients that we did see, it certainly appears to be safe.  But, again, now we are talking about even shorter‑term data because these people are re‑dos.  We are talking about a very, very, very small number, which is quite possible to obscure any side effects that multiples might add.

            I think if we are going to allow more injections, clearly the maximum number of repeat procedures we should allow based on the data is one.  And we only have thin data for one.

            In terms of the maximum number of injections per procedure and the rest, I think that it would be entirely speculative to even throw a hand grenade at those questions.  And I don't think that we can.

            CHAIRPERSON WOODS:  Dr. Ferguson?

            DR. FERGUSON:  Let me just paraphrase what he said.  I don't think there are sufficient data to answer this question.

            CHAIRPERSON WOODS:  Dr. Achem?

            DR. ACHEM:  I agree entirely.  The only one point is that it seemed in the very small analysis that was presented, in fact, I believe fever, though, was the higher occurrence, almost double the study, when the second injection took place.  But despite that comment that I am making, I think we have insufficient information to make a recommendation in this particular regard.

            CHAIRPERSON WOODS:  Dr. Afifi?

            DR. AFIFI:  I have nothing to add to what I said to the previous question.

            CHAIRPERSON WOODS:  Dr. Manyak?

            DR. MANYAK:  Well, I actually think we have the answer, whether it supports retreatment.  I think it has been shown to be safe to retreat.  The question is how long, how many times will we retreat are clearly not answered.  We do have answer to one question as far as volume is concerned, and that is the minimum volume, I believe.

            We saw data that suggested there was a fairly sharp cutoff in the amount of ‑‑ and I believe it was five cc for the amount of volume that would appear to be more effective than the lower volume.  So we have some suggestive evidence to that effect.  However, we do not have clearly enough data to talk about maximum numbers, intervals, or total volumes on retreatments.

            CHAIRPERSON WOODS:  I feel similarly.  In fact, I feel hesitant to make any recommendations about retreatment based on data from 19 patients.  However, the data as presented in those 19, it appears that it is safe, but I hesitate to make any formal recommendations based upon 19 patients.

            Dr. Gellens?

            DR. GELLENS:  I agree with the panel.  The information on the retreatment is thin.  But if we decide to approve this device, we are going to have to make recommendations on this issue.  So I think if we decide to approve, it is going to have to be something that is looked at extensively in post-market evaluation.

            CHAIRPERSON WOODS:  Ms. Moore?

            MS. MOORE:  I agree with Dr. Gellens.

            CHAIRPERSON WOODS:  Mr. Balo?

            MR. BALO:  I don't have any comment.

            CHAIRPERSON WOODS:  Okay.  Dr. Fennerty?

            DR. FENNERTY:  I think the best summary is the second one that was given by my colleague Dr. Ferguson that the data are inadequate and insufficient to address this question for the FDA.

            CHAIRPERSON WOODS:  Okay.  We are going to move on to labeling questions.  Number 7, "The sponsor has proposed the following Indication for Use for Enteryx:  'The Enteryx procedure kit is indicated for endoscopic injection into the lower esophageal sphincter, or LES, for the treatment of gastroesophageal reflux disease, or GERD.'  Please discuss whether this Indication for Use accurately reflects the data obtained during the clinical trial."

            Dr. Shaheen?

            DR. SHAHEEN:  With the exception of the addition at the end of that, at the end of the statement that it should be in the PPI‑responsive patient, in the patient responsive to proton pump inhibitor therapy, because that is what the trial was designed to look at and that is what they successfully showed.  Other than that, I have no problems with that.

            CHAIRPERSON WOODS:  Dr. Ferguson?

            DR. FERGUSON:  Well, I have concerns about the stated indication about treatment of gastroesophageal reflux disease.  The sponsors have demonstrated that fewer than half of the patients will have relief of disease as defined by esophageal acid exposure.  And I would propose that the wording be changed to "for the treatment of symptoms due to gastroesophageal reflux."

            CHAIRPERSON WOODS:  Okay.  Dr. Achem?

            DR. ACHEM:  I would agree that the population was selected and the patients who responded to PPIs were the ones chosen.  That has an implicit diagnostic message behind it that people who respond to PPI are those who may have the disease, as opposed to those who do not.  So I think the addition of the PPI response makes sense, which was part of the criteria for the trial.

            In addition, I raise the possibility that as well a statement be made to some extent to address the issue that most of these people did not have great erosive disease.  In other words, they had milder forms of the spectrum of GERD.

            And along those lines, I think we should qualify that in this particular statement that people with mild disease were selected.  I know that may be addressed in the subsequent question, but I am getting ahead of the game with that.

            CHAIRPERSON WOODS:  Okay.  Dr. Afifi?

            DR. AFIFI:  In my own understanding, we haven't shown that the device affects the sphincter itself.  And, at best, what we have shown is that it does relieve the symptoms.  So with that in mind, I agree with Dr. Ferguson in the change of wording.

            CHAIRPERSON WOODS:  I am sorry.  Dr. Manyak?

            DR. MANYAK:  That's okay.  My position is a hybrid of the first two speakers, Dr. Shaheen and Dr. Ferguson.  I think that is a very good definition for what we have seen today.

            CHAIRPERSON WOODS:  Yes.  I agree.  I think it is very critical that we make sure that patients who receive this are responsive to acid suppressive therapy, specifically PPIs, which were the drugs of choice in this study.

            I would add the caveat that patients who have GERD who are using intermittent therapy, H2 blockers, and getting relief, that may not be the kind of patient who really needs to go on to this sort of treatment.  So we may wish to specific patients who have severe or regular daily symptoms that are relieved by proton pump inhibitor would be adequately treated with this device.  So I think that is very, very important to patient selection to get the best results.

            Dr. Gellens?

            DR. GELLENS:  I agree with the rest of the panel members.  And I think that adding the statement that it should be for the relief of symptoms of GERD is a good idea.

            CHAIRPERSON WOODS:  Ms. Moore?

            MS. MOORE:  I am in agreement with the panel.

            CHAIRPERSON WOODS:  Mr. Balo?

            MR. BALO:  No comment.

            CHAIRPERSON WOODS:  Dr. Fennerty?

            DR. FENNERTY:  Okay.  Here's how it now reads based on consensus, "The Enteryx procedure kit is indicated for endoscopic injection into the region of the lower esophageal sphincter (LES) for the treatment of symptoms due to gastroesophageal reflux in patients requiring and responding to pharmacologic therapy" is the way I read that consensus.

            DR. SHAHEEN:  Brian, do you want to be more specific and say "proton pump inhibitor therapy"?

            DR. FENNERTY:  Just to respond to Nick's point, it is a very good question, but if they respond to H2 blocker therapy, they will respond to PPI therapy.  And I don't think I would want to handcuff a responder to anti‑secretory therapy.  That is why I left it as "pharmacologic."

            CHAIRPERSON WOODS:  You don't want to comment about severity of disease?

            DR. FENNERTY:  Just to go back to Sami's point because I did put symptoms ‑‑

            CHAIRPERSON WOODS:  Severity of symptoms?

            DR. FENNERTY:  Eighty‑five percent of patients with reflux disease will have Grade 1 or 2 esophagitis or less.  Therefore, this is applicable, this definition, to 85 percent of the GERD population, which I think is sufficient in general.  That's personal opinion, Sami.

            DR. ACHEM:  But what if a practitioner already, as you know frequently does, have the results of endoscopy and finds Grade 3 esophagitis?  Would you think that that is an issue that, at least on the labeling, should be addressed?  And he should be aware that that is not a group of people that was involved in this particular trial.

            DR. FENNERTY:  I think it's an infrequent occurrence in the typical practice of reflux disease.  I understand your concerns, but I would rather not handcuff our colleagues in using this as a therapeutic agent if it, indeed, is approved.

            CHAIRPERSON WOODS:  Brian, you don't think there should be any comment anywhere about frequency of symptoms in here?

            DR. FENNERTY:  Actually, the way I read this, I said for the treatment of symptoms due to gastroesophageal reflux in patients requiring and responding to pharmacologic therapy.  So, Karen, I think that encompasses the patient meeting a baseline requirement.  At least the semantics of it seem to fit that for me.

            CHAIRPERSON WOODS:  Yes.  Okay.  I agree.  Thank you.

            Any other comments here?

            (No response.)

            CHAIRPERSON WOODS:  All right.  Moving on to question 8, "The proposed labeling lists portal hypertension as the only contraindication for use.  Please discuss any other clinical conditions for which you believe the labeling of the device should include specific contraindications, warnings, or precautions.  In your discussion, please include comments on the following:  patients with Barrett's Esophagus, patients with erosive esophagitis, patients with esophageal ulcers, patients with esophageal strictures, and patients with GERD symptoms refractory to proton pump inhibitors."

            Dr. Shaheen?

            DR. SHAHEEN:  With respect to the contraindications, a lot of the things that we have listed there are into the precautions.  I am not sure which would be a precaution, which would be a contraindication.

            I will say that I am not incredibly worried about the use of this material in Barrett's Esophagus patients.  I take care of a lot of patients with Barrett's Esophagus.  I don't think that it would necessarily be incredibly detrimental to them, but since they weren't in this study, I certainly agree that it should be listed at least as a precaution.

            I think that we need to specifically, either in the contraindications or the precautions, list stricture at this point.  The precautions do list something, persistent high‑grade esophagitis, but I do think that we need to specifically say that this may not be such a great idea for folks with strictures.

            CHAIRPERSON WOODS:  I am sorry.  Dr. Ferguson?

            DR. FERGUSON:  I have no opinion about Barrett's Esophagus or erosive esophagitis.  I believe patients who have complications such as ulcers and strictures, those should be contraindications, as opposed to cautionary notes.

            And patients with GERD symptoms refractory to proton pump inhibitors should not be candidates for this procedure.  So I also believe that that should be a specific contraindication.

            CHAIRPERSON WOODS:  We have a question from the FDA.  Ms. Brogdon?

            DR. BROGDON:  It's actually just a comment.  We treat contraindications as cases where there have been demonstrated cases of harm so that it has been demonstrated you should not use this procedure in a given patient.  If it's a more general warning that is more theoretical or you are afraid this might happen, that would be appropriate for a warning.

            So contraindication is where you have data that say this should not be done.  And that puts much greater limitation on the physician after approval.

            DR. FENNERTY:  Can I ask for a point of clarification?  As it stands on there, portal hypertension is listed as a contraindication.  I am not aware of any data presented by the sponsor in the medical literature that suggests this has been studied in that group.  Could you clarify that?

            DR. BROGDON:  We will have to look at that if we proceed with the labeling review.

            DR. FERGUSON:  Well, with that in mind, then, I would change my comments to reflect portal hypertension, ulcers, strictures, and non‑responsive GERD should be listed as warnings.

            DR. ACHEM:  I remain concerned about that notion that we again offer advice for which we have in some areas insufficient information to patients with the more severe forms of the spectrum of the disease.

            I would move to consider that these patients here with Barrett's Esophagus disease, ulcers, strictures, and those refractories to proton pump inhibitors can expand to those who have atypical form of GERD or gastroesophageal manifestations with GERD be not included until we have further data on the safety and efficacy during long‑term studies.

            CHAIRPERSON WOODS:  Okay.  Dr. Afifi?

            DR. AFIFI:  No comment.

            CHAIRPERSON WOODS:  Dr. Manyak?

            DR. MANYAK:  I have no comment either.

            CHAIRPERSON WOODS:  My comments would be I will leave it up to the FDA on the semantics of contraindications or warnings, but strictures I think absolutely should not be treated.  Patients with GERD symptoms refractory to proton pump inhibitors should not be treated.  And the portal hypertension intuitively, it would seem, you would not wish to treat those patients.  The rest I think I don't have a problem with.

            Dr. Gellens?

            DR. GELLENS:  I don't have anything to add, actually.  I agree with that.

            CHAIRPERSON WOODS:  Ms. Moore?

            MS. MOORE:  I pass.

            MR. BALO:  I don't have anything to add.

            CHAIRPERSON WOODS:  Okay.  Dr. Fennerty?

            DR. FENNERTY:  I think just from a standpoint of our message to the FDA, that the areas of concerns we have are:  portal hypertension, esophageal ulcers, strictures, and those refractory to therapy, be that as a warning or whatever labeling would be appropriate from the FDA's definition.

            CHAIRPERSON WOODS:  Okay.  Question number 9, "Please discuss whether" ‑‑

            DR. ACHEM:  Dr. Woods, sorry.  Do you have any concerns or issues regarding those with atypical forms of GERD to be included, chest pain, pharyngeal symptoms, cough, asthma?

            DR. FENNERTY:  We really haven't discussed this as a specific question being addressed to the FDA.  I am just going to presume, Karen, that you would want this maybe brought out more in the discussion perhaps.

            Sami, as a gastroenterologist and as a reflux specialist, if I felt that those were manifestations of reflux disease and I chose to adopt any therapy that was approved, I would assume that that would be acceptable to many clinicians.

            DR. ACHEM:  Do we have enough data from this device that it ‑‑

            DR. FENNERTY:  That is what I am saying.  I think we are opening up an area that we even haven't started discussion on here.

            CHAIRPERSON WOODS:  There was no data on that indication in this PMA either.

            DR. ACHEM:  Well, what I guess I am pointing out is I am trying to say that I guess because of the confusion, the semantics, I was seeing those as a potential contraindication of potential areas where you would not want the device to be used.

            DR. FENNERTY:  If you're asking me, if I were to use the device, those would not be areas of concerns to me.  They are manifestations of reflux disease.  And if I could control the reflux, I would be happy to see the cough or asthma improve.

            If you are asking me as a physician, as a gastroenterologist, would I use such a device if it were approved in those patients, probably not, but they are clearly not contraindications.

            DR. ACHEM:  No.  I am asking the panel whether that should be included.  I am still confused regarding a contraindication or a precaution.  I am not sure exactly of the appropriate wording.

            MR. BALO:  Doctor, aren't you really saying that these are conditions that really haven't been studied yet and you're concerned that there has been no data and that maybe what we want to do is to have these areas looked at in a future study?  Is that where you are going with this?

            CHAIRPERSON WOODS:  Maybe I should allow FDA to answer, but my answer to this is this can come up as a condition or a post‑marketing evaluation subject that we would like the company to provide information to us on.

            DR. BROGDON:  It is, indeed, up to the panel to decide what you want to do with this.  If it is still unclear what is a contraindication and what is a warning or a precaution, I can't distinguish between the latter two.  It is more a matter of seriousness, I suspect.

            A warning is more serious than a precaution.  But a contraindication is used where you have data that say, "Use in this type of patient is harmful."  You have adverse data in hand or in the literature.  It is something more than a potential or a theoretical concern.

            CHAIRPERSON WOODS:  Okay.  Dr. Manyak?

            DR. MANYAK:  Just one comment.  Would these other indications or conditions that you brought up be considered contraindications for other therapy that is similar that has already been done in the past with patients with these problems?  I have heard that you have had different technologies that are involved with that kind of thing.  If that is the case, then that would fall in the same category.

            DR. ACHEM:  No, no.  On the contrary, those are usually indications for the use of aggressive.  By that, I mean intensive acid suppressive therapy since it appears from the available literature that people with so‑called extra‑esophageal manifestations of the disease do not respond to simple doses of proton pump inhibitors.

            That was my position.  That was my problem in trying to introduce that until we have more data, this may be either a caution or a contraindication.  I am not sure of the appropriate semantics to place ‑‑

            DR. MANYAK:  But then you answered the question all right because if they are not going to respond to the PPIs, then ‑‑

            CHAIRPERSON WOODS:  Then they are not going to qualify as to what is treatment.

            DR. MANYAK:  ‑‑ they are not going to qualify for the treatment anyway.

            DR. ACHEM:  Well, yes, that is true, and you would hope that in doing the careful reading of the label, that that will be the case.  I was trying to underscore the notion and to make it very clear that these are areas where this device has not been explored yet.

            CHAIRPERSON WOODS:  Okay.  Let's move on to the question number 9, "Please discuss whether you believe the Physician and Patient Labeling brochures, as written, are adequate or whether certain major additions, deletions, or revisions should be made."

            Okay.  Dr. Shaheen?

            DR. SHAHEEN:  Other than what I have said to the last two questions, I have nothing to add.

            CHAIRPERSON WOODS:  Okay.  Dr. Ferguson?

            DR. FERGUSON:  Well, in addition to what we have already discussed, there is some concern about the use of the terminology "permanent" or "long‑term."  I think we as the panel need to sort that out before we leave today because the sponsor has done their best to assure us that this is a permanent device.  And for us to then label it something else becomes problematic.

            CHAIRPERSON WOODS:  Dr. Achem?

            DR. ACHEM:  Dr. Woods, in this respect, I have a few remarks.  I would be inclined to propose that we bring out to the patients a little more information, such as the duration of the symptoms, like chest pain and dysphasia, that the patient labeling brochures also address the fact that about two‑thirds of the patients have two side effects related to the device, a general statement also regarding the number of patients so far treated.  I think the patients ought to be informed of what is the total number of patients so far that have been treated to this point.  And the length of follow‑up should be clearly stated as well.

            CHAIRPERSON WOODS:  Okay.  Dr. Afifi?

            DR. AFIFI:  No comment.

            CHAIRPERSON WOODS:  Dr. Manyak?

            DR. MANYAK:  I echo Nick's comment that what we discussed today should be incorporated where it needs to be.  Other than that, I don't have a comment.

            CHAIRPERSON WOODS:  I have comments with respect to physician labeling.  I mentioned it earlier in the discussion about fluoroscopy.  In the packet provided to the panelists, at least, under the portion labeled, "Enteryx Injection Procedure," there is no mention of the use or the need for fluoroscopy.

            On item number 4, it says, "Place at least 6 ml of Enteryx solution circumferentially into and along the muscle layer of the lower esophageal sphincter," talks about an arc or ring but doesn't mention how you are to determine that an arc or a ring is present.  And then it goes on to advise, "Otherwise use multiple discrete injections of 1 to 2 ml."

            I would like to see that section clarified a bit so that the novice user would understand whether to make one long injection of six ml and how to determine that an arc or a ring is forming by using fluoroscopy, maybe even a photo to demonstrate what it is they're looking for, and then when to decide that you should go to the four‑quadrant injection with one to two ml and what that should look like if you have done it correctly.

            Dr. Gellens?

            DR. GELLENS:  I totally agree that the fluoroscopic indication or recommendation should be put into the physician labeling since it is not present there.  I know we already talked about the indications for use, but I think in the physician labeling, where it says it is indicated for the treatment of GE reflux, I do think that a provision there for the severity of reflux should be put in there.

            Even though the study included patients based on the GERD quality of life survey, we are not going to give that to all of our patients.  But, still, there should be some recommendation of the severity of the disease for use of this device.  I don't think we want every single patient with GERD to undergo this procedure.

            CHAIRPERSON WOODS:  Ms. Moore?

            MS. MOORE:  Yes.  I just want to make one comment about the patient brochure.  I think that this brochure should be written in very specific terms and quantified wherever possible.

            As an example, here it says, "For the first several days after the procedure, you should only eat bland, non‑spicy and soft foods."  I submit that the word "several" has different meaning for different people.  I think it would be clearer for the patient if he or she would know that for the first three or four days or two to five days or whatever, rather than using general terms.  That's all I have to say.

            CHAIRPERSON WOODS:  Thank you.  Mr. Balo?

            MR. BALO:  No, I have no further comment.

            CHAIRPERSON WOODS:  Okay.

            DR. ACHEM:  Dr. Woods, can I interject before Dr. Fennerty ‑‑

            DR. FENNERTY:  Well, I want to do my personal ones first here also.  I had a number ‑‑

            DR. ACHEM:  Sorry.  Just a simple question for the sponsor.

            DR. FENNERTY:  Actually, go ahead, Sami.

            DR. ACHEM:  The question I guess pertains to the use of the type of scopes.  It states in page 50 that Olympus endoscopes "have been found to be DMSO compatible."  Does this mean that no other endoscopes can be used for the injection of this device?

            CHAIRPERSON WOODS:  "Yes" or "No"?  Please address the panel.  The sponsor, please.  State your name and a brief answer.

            DR. STEIN:  My name is Alan Stein with Enteric Medical.

            We have contacted all the major manufacturers of scopes to find out that they are actually using Teflon sheaths within their scopes because, of course, we don't want to have any DMSO impact on the much more expensive endoscope.

            I think you pointed out something that we should specifically identify in the labeling, the scope manufacturers that are compatible.

            CHAIRPERSON WOODS:  So the answer is?

            DR. STEIN:  Fuji, Pentex, and Olympus.

            CHAIRPERSON WOODS:  They are?

            DR. STEIN:  Compatible.

            CHAIRPERSON WOODS:  Compatible.  Thank you.

            DR. STEIN:  I can't tell you and we have to watch.  I don't know if you have an 11‑year‑old scope whether that is true.  I think we have to put a date on it.

            CHAIRPERSON WOODS:  Okay.  Thank you.

            DR. FENNERTY:  I am glad you clarified that because I was wondering why the physician instructions were that the user should verify the compatibility of the gastroscopes.  I think that is a sponsor issue.

            A couple of things just from my point.  I am not sure why we are using prophylactic antibiotics when a much more dirty procedure, injection sclerotherapy, we don't recommend that clinically.  And I thought maybe some of the other members of the panel would let us know what they think about that.  I think it does not belong in the labeling.  It was part of the protocol.

            The injection procedure description of visualizing the lower esophageal sphincter, it's not possible.  The labeling, the squamocolumnar junction is very visible.  And that is the second part of the labeling.  The first part should be deleted.

            Also, going back to Ms. Moore's comments as well, I don't see any evidence to suggest that patients should be tortured for eating bland, non‑spicy airplane‑type food for five days after this procedure.  There is no physiologic basis for such a recommendation.  And I would not make any recommendation and delete that from the labeling as well.

            From a summary, I think that there are a number of things.  The fluoroscopic issue seems to be acceptable to everybody.  As Dr. Achem pointed out, I think it is the sponsor's obligation to make sure that this material is compatible with the instruments that we use to perform this procedure.

            DR. AFIFI:  Dr. Woods?

            CHAIRPERSON WOODS:  Yes?

            DR. AFIFI:  I would just point out to thank Dr. Fennerty for correctly calling non‑spicy food to be torture.

            CHAIRPERSON WOODS:  Okay.  Let's see.  That was question number 9.  We will move to question number 10, "Post‑Market Issues.  Please comment on the sponsor's proposed post‑market evaluation of the device.  Please specifically comment on and make recommendations concerning the:  a) study design, b) number of patients, c) length of follow‑up, and d) endpoints to be evaluated, e) need to evaluate repeat procedure, and f) need for additional post‑market studies."

            Dr. Shaheen?

            DR. SHAHEEN:  I think the post‑marketing plan is going to bring some welcome patient years, especially patient years beyond patient year one to this which is going to help clarify a lot of the questions that we have asked today.

            In addition to the plan that is currently in place, I would love to hear a plan for a randomized sham procedure with a possible crossover because patients who are going to be getting just vehicle won't be very happy for very long.  But this can be done.  It's been done with other devices.

            And I think that this would be a highly pertinent and very important post‑marketing issue.

            CHAIRPERSON WOODS:  Thank you.

            Dr. Ferguson?

            DR. FERGUSON:  I think the length of follow‑up proposed is satisfactory and overall the study design is satisfactory.  I do think specific attention needs to be paid to the re‑injection patients and some sort of prospective registry perhaps of those patients be suggested to the sponsor so that we don't just catch them upon long‑term follow‑up.

            CHAIRPERSON WOODS:  Dr. Achem?

            DR. ACHEM:  I would also be interested in a long‑term study done with a sham application.  I think it is crucial to try to answer some of the issues we have been talking about this afternoon.  In terms of the number of patients, I would defer that to a statistician to determine the power, the size of the study, sample size.

            In terms of the length of the follow‑up, I realize the sponsor has made a comparison to some of the studies out there at three years, equating the data, I believe, with the pharmacological literature as well as the laparoscopic literature, but I am not sure that it is necessarily applicable or comparable to a device that has been injected.  So I would be interested certainly to go to at least three years, but I may like to see data go beyond the three years, perhaps up to five years.

            And the endpoints have been already I believe addressed by most of us, what those endpoints would be.

            CHAIRPERSON WOODS:  Dr. Afifi?

            DR. AFIFI:  Yes.  I think we do need some justification for the n of 300.  I think also this is an opportunity to do some placebo controls or sham controls with the least invasive procedure possible.  I think also that we should specify that a longitudinal analysis of the data be made, rather than just the cross‑sectional, as was done.

            Also, looking at the time points at which the measurements are made, they follow approximately a logarithmic scale, which is you double the previous one, 1, 3, 6, 12, 24, and then it goes to 36.  From a mathematical point of view, 48 would be the next one, but I wonder whether 4 years is just very different enough form 3 years for the sponsor to consider, at least, that change.

            Finally, the other point that we need to look at, why was the SF‑36 dropped?  It's just as easy to collect.  I mean, it is an additional few minutes.  Why only the GERD‑HRQL, not the SF‑36?  Maybe the sponsor can answer that particular question.

            CHAIRPERSON WOODS:  Would you like an answer to that now?  Sponsor, why did the SF‑36 get dropped in the follow‑up, questionnaires for patients?

            DR. STEIN:  We focused on the post‑market surveillance on those particular issues that were related to GERD.  The SF‑36 measures a general quality of life measure.  It is also 36 questions.  And over time trying to get the compliance on these patients is really the issue because we don't want to start a study and then find out that we have too significant attrition over time.  So we are trying to make sure that we maintain high levels of compliance.

            And, as I said, the SF‑36 mental and physical component scores are generic assessments of patient satisfaction but not GERD‑specific.

            DR. AFIFI:  Okay.  And while you are up there, what do you think of 48 months, instead of 36?

            DR. STEIN:  I think it is 12 months longer than 36.

            (Laughter.)

            DR. AFIFI:  So you would be concerned about compliance at the same point?

            DR. STEIN:  I also think that ‑‑ you know, I don't really know the statistical approach about looking at this long‑term, but I have looked at enough of the literature associated with the longer‑term follow‑ups that are being performed on post‑surgical and PPI studies.  The intervals are pretty much annual for at least three, out to five years because I don't think it is appropriate to have a gap, certainly, between two and four.  Okay?

            CHAIRPERSON WOODS:  Okay.  Dr. Manyak has stepped away.  I will comment.  I agree with basically everything that has been said as to issues with the post‑market follow‑up.

            The one thing I would like to emphasize is follow‑up on the patients who have retreatment and trying to better define who is most likely to benefit from retreatment, how many retreatments can you do.  I don't think we should be doing this in clinical practice without having more data on this.

            I also think there were some variances in how the patients were selected to be retreated.  In fact, as I recall, several were retreated just because the X‑ray at three months showed there wasn't very much of the product left behind.

            Is that a reason to retreat or not?  I would like those questions answered in this follow‑up period of time so that we can better define who can be retreated, how many times, how safe is it, et cetera.

            Dr. Gellens?

            DR. GELLENS:  I agree with Dr. Woods as far as the post‑market evaluation and the retreatment issue is concerned.  I think you need a longer than average post‑market evaluation here because of the retreatment issue.  We have such little data on that.  And we don't really know what recommendations to make in the labeling as far as retreatment is concerned.

            Other post‑market recommendations.  I think the X‑ray evaluation of how much of the product is left is poor.  I think CT evaluation should be used as follow‑up in post‑market evaluation.

            That's it.  Thanks.

            CHAIRPERSON WOODS:  Ms. Moore?

            MS. MOORE:  I am in agreement with what has been said.

            CHAIRPERSON WOODS:  Mr. Balo?

            MR. BALO:  No further comment.

            CHAIRPERSON WOODS:  Dr. Fennerty?

            DR. FENNERTY:  I think that the panel would be in absolute agreement that one of the things we would like to emphasize in a post‑market agreement for this device application is clearly either an active control or a sham placebo control so that we can accurately measure the placebo effect or at least its comparability versus other standard accepted therapies and reflux disease.  I think that seems to be a unanimous opinion.

            Having said that, it is an opportunity for the panel I think to deliver a message as we go forward with these surprisingly very numerous devices in development that future dealings between sponsors and the FDA I think a priori we need to change what we require or recommend to them performing their pivotal trials therapy before they come forward to us so that we don't have to look at this as a post‑marketing issue in the future, but we will have this data at the time of the initial application so we can make probably a more reliable decision to the public and the FDA regarding recommendations of acceptance.

            CHAIRPERSON WOODS:  Dr. Gellens?

            DR. GELLENS:  I have a question for the FDA.  Is it okay to approve this device with the requirement of a post‑marketing study that is a prospective sham‑controlled trial?  Can we do that?

            DR. BROGDON:  You can make that recommendation.  We need to be clear on what you are proposing would be investigated after approval.  And then the FDA staff is going to have to talk about whether this is feasible.  You have to decide whether there is sufficient safety and effectiveness data for approval and then describe what data would be needed and what data can be deferred until later.

            CHAIRPERSON WOODS:  Okay.

            DR. BROGDON:  Dr. Yustein would like to ask a couple of questions of clarification on your answers to number 10.

            DR. YUSTEIN:  Just one question.  I don't know if you recall what the sponsor proposed, but their endpoints on the post‑market follow‑up were specifically for the HRQL, medication dosage, and adverse events.  I was just wondering if you could all comment on where you stood as far as the requirements for EGD and/or pH studies along the way.

            CHAIRPERSON WOODS:  All right.  Dr. Shaheen?  Actually, Dr. Fennerty has an opinion.  We will let you go.  Then we will see if anybody else has comments.

            DR. FENNERTY:  Go ahead, Nick.

            DR. SHAHEEN:  Well‑put, Brian.

            I guess my thought is that it is going to be a really big problem or potentially a big problem for a long‑term study to require repeat invasive investigations.  I assume you are referring to things like 24‑hour pH Probe data, e‑mano.

            I would love to have those data, but I think that as an investigator, just thinking to myself, trying to get somebody to sign up for a study that has got five years of Q‑6 months or 2‑year, 24‑hour pH Probe is not going to be greatly successful.

            So I think pragmatically, although those data would be very useful, I don't know that that is something that we should require of them.

            CHAIRPERSON WOODS:  Dr. Ferguson?

            DR. FERGUSON:  I don't think we can expect useful information to come from that.  The studies to date have likely documented what the percentage responses are going to be.  We are looking at the clinical efficacy as the main endpoint, which they have pointed out.  I might just add as long as I have the microphone that the likelihood of getting accrual to a post‑approval study, including a sham control, is highly unlikely.

            CHAIRPERSON WOODS:  Dr. Achem?

            DR. ACHEM:  That certainly is an ideal scenario to obtain objective data, such as EGD and pH testing.  But I echo the concerns of the feasibility, especially on the 24‑hour pH if we do it with a probe.  Nevertheless, the event of other devices, such as the so‑called Bravo pH Probe, might allow to acquire this data.

            As you know, recruitment for endoscopy patients undergoing conscious invasion is a bit easier, it has been my personal impression as an investigator.  And, actually, there are financial incentives that we provide, again, within the IRB guidelines and FDA guidelines to our patients to stimulate them to undergo a second procedure.

            I think it would be very useful information to have.  I recognize the expense, the magnitude of what we are asking, though.  I would say that the other edition might also facilitate the process by leaving one single procedure for patients so you can acquire both of those pieces of data.

            CHAIRPERSON WOODS:  Okay.  Dr. Afifi?

            DR. AFIFI:  I would have concerns about the more invasive the protocol is, the less compliance there may be.  So I would keep that in mind.

            CHAIRPERSON WOODS:  Dr. Manyak?

            DR. MANYAK:  I have no comment.

            CHAIRPERSON WOODS:  Okay.  I agree.  I think, again, without having a control group, you are following along at the same time, that expense and the safety issues of re‑endoscoping people just because are probably not going to be all that useful.  I think what is really important is how does the patient feel and whether they have had any problems.

            Dr. Gellens?

            DR. GELLENS:  Yes.  I think our concern is safety and efficacy.  So as far as evaluating those two things, if the patients feel all right and they don't have any adverse events, that is enough.  My only concern is if there would be development of Barrett's Esophagus and how we are going to look for that long‑term.

            CHAIRPERSON WOODS:  Ms. Moore?  Mr. Balo?

            MR. BALO:  Yes.  I agree with the panel recommendations.

            CHAIRPERSON WOODS:  Okay.  Dr. Fennerty?

            DR. FENNERTY:  Just to address Dr. Gellens' comment.  Normally when a patient has had an endoscopy in the setting of reflux disease, we don't recommend further screening for Barrett's once a clean endoscopy has shown no evidence of Barrett's.

            So from a standpoint of not only the other points people have made, I have serious ethical concerns of having patients who are completely well undergo invasive procedures.  No matter how safe we comment on the safety of upper intestinal endoscopy as well as probe placement, there are some safety concerns.

            I would be against mandating invasive tests and otherwise as well paying for a long‑term follow‑up study.

            CHAIRPERSON WOODS:  Okay.  We will move to the last question, number 11, regarding training, "Please comment on the sponsor's proposed physician training program and whether you believe it is adequate for proper use of the device."

            Dr. Shaheen?

            DR. SHAHEEN:  Given that the data that the sponsor has shown suggests that if there is a learning curve, there isn't much of a learning curve and it appears that, at least in the centers they have, efficacy at the first procedures was essentially the same as having to see it later procedures.  I am not compelled to think that we need to have an extensive training program.

            I would, however, like to see the specifics of the training program perhaps a little bit better fleshed out.  Somebody raised the question, are the trainers going to be physicians?  Is the site of the training going to be uniform?  Where is it going to be?  Perhaps a few more details like that, but I don't necessarily think that we need to feel compelled to generate a larger training program.

            CHAIRPERSON WOODS:  Thank you.

            Dr. Ferguson?

            DR. FERGUSON:  I think the training as outlined in the sponsor's presentation, as opposed to in the handout materials, which consisted of five to ten, I think it was, training sites, mentoring on site, and then supervised, first few initial procedures, is satisfactory.

            CHAIRPERSON WOODS:  Dr. Achem?

            DR. ACHEM:  I think that the question was posed to Dr. Lehman, actually, in the past as to the number of patients.  The sponsor has proposed that two people would be sufficient.  That is, two patients, on a supervision would be the number sufficient to do so.

            I would say as an endoscopist, as a gastroenterologist, that probably seems okay to me assuming that the device poses no unique differences as the ones that you see during injections with sclerotherapy.

            I guess a concern ‑‑ and I am not sure how to answer this, Dr. Woods ‑‑ is what may happen with people who are less experienced or who may be non‑gastroenterologists and are eager to get going with new technology.

            Should we require the same expectations of training as those of gastroenterologists?  And I don't know the answer.

            CHAIRPERSON WOODS:  Dr. Afifi?

            DR. AFIFI:  No comment.

            CHAIRPERSON WOODS:  Dr. Manyak?

            DR. MANYAK:  Actually, I had some thoughts similar to what you have just mentioned.  The question I would have for the GI colleagues here, my GI colleagues here, is, are two procedures enough in the proctoring session to determine that someone is vassal enough to do this?

            I think obviously your specialty is very good at endoscopy.  So I think there are going to be some basic skills there.  For those who are under‑experienced or perhaps, God forbid, they are in another specialty and they try to do that, you know, we could almost reach them from below, but that is not quite good enough.

            There are some other training programs that are available.  We have developed two virtual reality surgical simulation programs for these types of procedures with haptic feedback that are very similar to what you undergo in real time.  And it may be that that is something to consider somewhere.  There may be other training programs like that, too, for people that you feel are under‑qualified to perform that procedure.

            CHAIRPERSON WOODS:  I am just trying to clarify a point here that physician training that I have read is on page 247 of the PMA that I received.  There was no mention here of going to a training site to learn.  That was presented today.

            I don't have a copy of that here in front of me.  So what I see is that "To complete training, the physician and assistant will perform a minimum of two treatments of the supervision of the manufacturer's clinical specialist."

            Now, quite frankly, this is merely an extension of well‑established endoscopic technique.  Anyone who does endoscopy and has clinical privileges at their hospital to perform sclerotherapy with some additional training from the company I think could probably do this procedure.  All of us who have endoscopic privileges or train gastroenterologists also have basic familiarity with using fluoroscopy.

            So I am not particularly uncomfortable with the recommendation that the manufacturer's clinical specialists come to the site and train a certified or privileged physician, who has privileges at their hospital to perform gastrointestinal endoscopy and sclerotherapy, that this become an extension of that.

            And I think, as presented, it seems fairly simple that I think an on‑site training probably is adequate as long as the specialist who trains them feels at the end of two that that person has adequate knowledge of the system and can perform it safely.

            Dr. Gellens?

            DR. GELLENS:  Thanks.

            I just think that it should be clear that the clinical specialist that observes the procedures being done be a gastroenterologist.

            MS. MOORE:  I like the idea of the physicians being trained, and I like the model that was presented today better than I like the one that was in our literature.  But I think maybe we ought to have the more experienced gastroenterologists maybe having one type program; whereas, the newly licensed gastroenterologist might have another level program.

            CHAIRPERSON WOODS:  Mr. Balo?

            MR. BALO:  I have nothing to add.

            CHAIRPERSON WOODS:  Dr. Fennerty?

            DR. FENNERTY:  Speaking to Ms. Moore's concerns, this really is in the purview of anybody who has been trained in a formal endoscopic program, including surgical endoscopists.  I really think that this should not be limited to gastroenterologists but skilled endoscopists, irrespective of their background and training.  I think Dr. Ferguson is well‑aware that many members of SAGE's surgical endoscopy group are quite qualified to perform this procedure as well.

            Having said that, I would very much encourage the sponsor to use the American Society for Gastrointestinal Endoscopy, the American Gastroenterological Association, the American College of Gastroenterology to set up formalized courses of instruction as well as meet the guidelines that they have already outlined in their proposed teaching of physicians with on‑site experience as well.

            CHAIRPERSON WOODS:  Okay.  I think that concludes our questions.  I would like to thank Dr. Fennerty for summarizing all of the questions.

                OPEN PUBLIC HEARING

            CHAIRPERSON WOODS:  Before we take a vote, are there any additional questions from the panel or comments from the panel?  And if not, then I need to ask if anyone from the public wishes to address the panel.  If so, please raise your hand.  You may have an opportunity to speak now.

            (No response.)

            CHAIRPERSON WOODS:  If not, then we will now proceed with the ‑‑

            DR. MANYAK:  We thank you, by the way.

            CHAIRPERSON WOODS:  ‑‑ with the final open public hearing session.  I think we already did this part.  It gave me some redundant information here.

            Okay.  Ms. Brogdon, does FDA have any comments?

                4.  FINAL COMMENTS

                 1.  FDA COMMENTS

            DR. BROGDON:  I would like to ask the staff, are there any further questions?

            (No response.)

            DR. BROGDON:  None.

            CHAIRPERSON WOODS:  None?  Okay.  Does the sponsor have any comments?  If so, please identify yourself before speaking.

               2.  SPONSOR COMMENTS

            DR. STEIN:  My name is Alan Stein, and I think that I would like to ask Dr. Lehman and Dr. Johnson if they could make just a couple of small comments that were based on the discussion today.

            I would like to make one comment, which I would again like them to elaborate on, regarding retreatment.  I do want to make sure that the panel understands what our experience in retreatment and what our intentions have been in retreatment.

            Of the 19 patients who were retreated, I would say about three‑quarters of them had substantial loss of implant.  The goal of the retreatment was not to put in 8, then 16, then 24 cc of material into these patients but was, in fact, to get 6 to 8 cc in a circumferential distribution around them.

            So these were patients who, by and large, lost a significant amount of implant.  And in one more session, we were able in almost every case to get an adequate amount of implant around them.

            So I hope you understand that there is a different goal of our retreatment than perhaps particularly the urological specialists here, who maybe I guess in contigen treatments can do up to six session of treatments on urinary incontinence.  That has not exactly been the goal of what we have been trying to do in the retreatment, and I want you to understand that.

            DR. MANYAK:  Yes.  It wasn't for the urologists either.  We would prefer one treatment, but sometimes you have to go back.

            DR. STEIN:  Well, we do, too.

            DR. MANYAK:  And it's not there anymore.

            DR. STEIN:  Okay.  Dr. Johnson?

            DR. JOHNSON:  Dr. Woods, if I could make my comments very brief?  First, a lot was made about esophagitis in the discussions.  I want to clarify this is not an a priori assumption, nor was it a target for the success and efficacy standards.  So the discussions need to be kept in that context.

            Secondly, the time frame for the definition of esophagitis, recognizing that these patients were off PPIs for 10 to 14 days, as the gastroenterologists on the panel will well‑know, the relapse to esophagitis rate, typically it may take time.  And they typically will relapse to where they were before they were started on therapy.

            These patients had a very narrow window of time frame to relapse to a grade of esophagitis.  Despite that, if you use Savary‑Miller, which is a variable interpretation to begin with, 35 percent had relapsed to esophagitis.

            Recognizably, these are all PPI‑dependent patients.  They had PPI dependency for two years.  So when we talk about definition and progression, it is really an inappropriate discussion because we really haven't defined the time windows before.  Ten days is not applicable to a 12‑month off PPI.  So I think that needs to be kept in perspective.

            Additionally, when we talked about relapse to esophagitis, if we take the entry point as no esophagitis and said, "How many people had Grade 2 esophagitis at the end?" the number is 20 percent.  If I gave you PPI trials, the members of the gastroenterology community would attest that is low relative to the relapse rate for people on PPI trials.  The maintenance trials for PPI range anywhere from 20 to 60 percent of people who have esophagitis in subsequent follow‑up.

            So I think we need to keep that parameter in context.  So discussion of progression is really not appropriate.  It is not an a priori assumption.  And the time windows for development of esophagitis are key points.

            This issue of esophagitis comes up because we like to say that we are preventing complications.  And there is no data from the surgical literature or the endoscopic literature or the pharmacologic literature that shows we prevent complications when we talk about strictures de novo, complications of Barrett's, or complications of surgery.

            In fact, if you look at patients with Barrett's de novo, 99.9, if not all of them, if they're well‑defined, have Barrett's when they are actually endoscoped and, hence, the recommendation if they don't have Barrett's on an index endoscopy, we never re‑screen those patients.  I think the gastroenterologists would all agree with that.

            So the data and concern about esophagitis progression, preventing complications, we have to fall back.  And if we say, "What do we do with PPIs?" we have the same scenario.  We see esophagitis relapse in maintenance trials, and we have no data to show that they prevent complications de novo.  We do a complication prevention as a secondary nature for patients that have strictures.

            Recognizably, too, we have talked a lot about surrogate endpoints and secondary endpoints with pH.  If we go back to the same PPI trials and put it in perspective, relapse of esophagitis in patients that have no pill‑induced reason for esophagitis obviously have pathologic acid exposure.  Those patients in the PPI trials obviously if studied with pH monitoring would have abnormal pH scores.  So I think we need to keep those perspectives as we start to evaluate the information.

            The issue about placebo control I think really is difficult by this trial design to get around that.  I am very critical when I talk about placebo‑controlled trials are obviously the best evidence‑based way to construct trials.

            This, the patient serving as their own control, I am personally comfortable because I can tell you I have put 17 patients in this trial to date.  These are patients that are PPI‑dependent who all, by definition, relapsed to a Velanovich score that was pathologic within 10 to 14 days of being off their PPI.  And they reestablished very quickly when they went back on their PPI.  So their entry criteria is fairly well‑qualified.

            Now, if you try and take a patient that is symptomatic with GERD, depending on a PPI off medication for a year, the gastroenterologist would attest it is very difficult.  Certainly if we can accept that placebo is an issue, recognizing the placebo effect lasting for a year and attaining 70 percent efficacy of people totally off PPIs, or 10 percent having major dose reduction, would really be an issue that would be hard for me to attribute to placebo.

            The issue about this being milder patients also needs to be understood because, again, in fact, it is my worst‑case patients of esophagitis.  That is the way I've got them in the study.  These people are looking for alternatives to PPI dependency.  These patients actually coming off their medications, it's difficult.

            When you look at esophagitis rate, you can't use that as a marker here for severity of esophagitis for the reasons I just outlined.  So I think you need to keep that in perspective when you go and look at their mediation use.  This medication use in this trial, 62 percent of people are taking daily PPIs.  And 30 percent were taking high‑dose PPIs.  Hence, these are not mild patients by any means or any stretch of the imagination.

            The issue about trend analysis I think needs to be kept in perspective.  And I think Dr. Fennerty alluded to this.  When you look at the data presentation, you have to look at the scale used.  And, in fact, if you look at the trial here and just at the PPI‑dependent patients, now off medication and relapsing from 6 to 12 months, there are 3 patients.

            The subanalysis of those individual patients, these were kind of limping along.  We knew these patients were not going to last.  For whatever reason, they were continued off medication.  And those are the three patients that actually fell out at the end of 12 months.

            When you look at an analysis of H2 antagonist use, the number is consistent.  So there is no trend attrition for H2s.  And if you look at the trend analysis for antacids, including daily and less than daily use, the number goes from 13 to 17.  So I hardly attribute that nor would I start to say that this is an attrition of integrity of the procedure or the efficacy of the procedure.

            I think the final comment is to look at the issues of the efficacy and trying to generate is this a risk‑benefit ratio.  Patients are asking for alternatives for medications.  That is where a surgeon is an option and endoscopic therapy is a potential option.

            So patients that are well‑characterized ‑‑ and I would agree with the panel's comments about characterization of disease, but the patients, for whatever reason, don't like to take medications, for whatever reason.  There are some subsets of patients that just can't take it, don't like it, whatever reason.  So this is an alternative that needs to be put in that perspective of the benefit ratio.

            The safety I think is, as much as we can tell you, the 12 months was the PMA submission.  This study has been going on for nearly three years in Europe.  And we have reviewed 100 percent of the safety data.

            I will tell you that the extension study, I have got 17 patients in this now, close to 2 years.  So nothing has changed, despite the PMA lock by the definition.  I think that needs to be kept in perspective.

            I think that would conclude my remarks.

            DR. STEIN:  We as a sponsor can't discuss anything past one‑year data because our study was closed out at one year.  But Dr. Johnson, Dr. Lehman, these are their patients still.  And as of today, every patient in the study was at 18 months.  And by June, they will all be 24 months.  And we intend to follow these into the post‑market surveillance study.

            CHAIRPERSON WOODS:  Dr. Lehman?

            DR. LEHMAN:  Lehman, Indianapolis.

            I would again echo that my patients in this study have had no change, no obvious change, in their clinical or adverse effect viewpoint in their now almost two‑year follow‑up.  So that's promising.

            Just a couple of other comments.  Fundoplication was briefly commented on.  Four of the patients who have had Enteryx have now had fundoplication.  Fundoplications were done without difficulty.  Surgeons commented specifically that there were no adhesions around the LES and that while the tissue was a little stiffer than normal tissue, it otherwise was very easy to wrap.

            This is consistent with the autopsy data from the animals that we have done, that, indeed, it injects in the peritoneal cavity and sort of sits there like a piece of cellophane and doesn't stir up virtually any reaction.

            There was some concern about whether multiple injections would be hazardous.  Having injected collagen patients with more than 130 cc of collagen in the old days, multiple injections are well‑tolerated and do not seem to have a problem.  And, indeed, sclerotherapy we inject many times in many sessions.

            A little bit more data on information on sloughing and migration.  We have to go back to the original animal studies.  We started out intentionally placing this material submucosally because that is what we did with collagen and Teflon and so on.  Most of it sloughed out.

            We saw that in the first three to seven‑day follow‑up.  And so we saw a lot of sloughing in the first few animals.  And we learned that shallow submucosals are on place for this material.  So we had plenty of experience seeing these acute ulcers with little black bases.  If you come back a week later, the ulcer is down to a little crevice.

            And then histologically, if you study them at that point, you will see either it's a shallow little crevice or usually a shallow little crevice with some black base to it.  But the amount of bulk is relatively small.

            In patients, we saw a few patients at 30 days usually, following for their re‑implant, where they have ulcers, some ulcers, as we saw here, with black lump in the center or, commonly, healed ulcer, a little shallow depression with a little black base.  Then one of our patients, we did a CT scan at 24 hours after some new dysphasia and had apparent implant in the colon.

            So I think we have excellent evidence that it does slough if you put it through superficially.  And it isn't a mystery as to where it goes.

            Additionally, the follow‑up animal data from our dog pilot studies showed that total body X‑rays from pelvis to tip of nose failed to show any evidence of migration at any point up to one year, no tantalum at any other points in the body, random sampling, dissecting out the injection area, saw no implant beyond a few centimeters from where we put it, where a little bit of it was put in too deep.

            Random sampling of lung, heart, kidney, liver, spleen saw no evidence of migration at any site at any point from a few weeks to one year.

            Chest X‑ray follow‑up and all of these patients looking at their implants saw no evidence of migration ends at any point.  So we have I think excellent evidence of lack of migration to places we don't want it to go and strong evidence to show that sloughing of the lumen in that portion of patients that are losing material.

            I would add in the discussion about contraindication versus warning versus no data, I would strongly encourage you to say, "In these areas, such as Barrett's, such ulcers, such as strictures, we don't have any data, rather than to tie hands of the people who want to do the next step for the studies and say, "It is contraindicated" or "warning."  If they put a big "warning" on it, then it's hard for Sami to do the next generation of studies, which you want to study these strictures and so on.

            Indeed, we are injecting it into the lower edge of the lower esophageal sphincter mostly, below the stricture, below the ulcers, et cetera.  So it shouldn't be hard to inject into that group of people.

            Thank you.

            CHAIRPERSON WOODS:  Yes, Dr. Shaheen?

            DR. SHAHEEN:  Dr. Lehman?  Will all four of the patients that underwent the procedure, were those all able to be performed laporoscopically?

            DR. LEHMAN:  Yes.  And the patient I had done, I asked if he took some pictures of it.  He had not.  He sort of forgot the patient even had an implant it was so ordinary.

            CHAIRPERSON WOODS:  All right.

            DR. ACHEM:  I want to thank both Dr. Lehman and Dr. Johnson for their additional comments, which are of value to the panel.

            MS. MOORE:  Thank you very much, gentlemen.

            CHAIRPERSON WOODS:  Okay.  Before entertaining a motion recommending an action on this PMA, Dr. Cooper will remind the panel of our responsibilities in reviewing today's pre‑market approval application and of the voting options to us.

            DR. COOPER:  Thank you.

         5.  PANEL DELIBERATIONS AND VOTE

            DR. COOPER:  I wanted to point out for the record that Dr. Fennerty has had to leave to catch the last plane to Oregon for a commitment tomorrow morning.

            Before you vote on a recommendation, please remember that each PMA has to stand on its own merits.  Your recommendation must be supported by data in the application or by publicly available information.  You may not consider information from other PMAs in reaching a decision on this PMA

            Do you have the first slide?  I would like to remind the panel of some definitions.  I will go ahead while those come up.  Safety is defined in the medical device amendments as reasonable assurance based on valid scientific evidence that the probably benefits to health under conditions of intended use outweigh any probable risks.

            The valid scientific evidence demonstrates the absence of unreasonable risk of illness or injury associated with use of the device under conditions of intended use.  Effectiveness is defined as reasonable assurance that a device is effective when it can be determined in a significant portion of the target population, the use of the devices for its intended use is an condition of use when adequately labeled, will provide clinically significant results.

            Next slide.  Valid scientific evidence consists of well‑controlled investigations, partially controlled studies, studies and objective trials without matched controls, well‑documented case histories conducted by qualified experts, and reports of significant human experience with a marketed device.

            Next.  Your three recommendation options for the voters follow:  approvable, approvable with conditions, and not approvable.

            Next.  Approvable.  There are no countdowns attached.

            Next.  Approvable with conditions.  You may recommend that the PMA be found approvable subject to specified conditions, such as resolution of clearly identified deficiencies which have been cited by you or by FDA staff.  Prior to voting, all of the conditions are discussed by the panel and listed by the panel chair.

            Next is not approvable.  If you recommend that the application is not approvable, we ask that you identify the measures that you think are necessary for the PMA to be placed in an approvable form.

            Next slide.  Response for recommending not approvable would be safety, the data did not provide reasonable assurance that the device is safety under the conditions of use prescribed, recommended, or suggested in the proposed labeling.

            For effectiveness, reasonable assurance has not been given that the device is effective under the conditions of use prescribed, recommended, or suggested in the proposed labeling.

            For labeling, based on a fair evaluation of all of the material facts and your discussions, you believe the proposed labeling is false or misleading.

            Next.  And that's a flow chart of our voting procedures that I have described.

            CHAIRPERSON WOODS:  I think we will go ahead and proceed.  The panel will now prepare to vote.  The recommendation of the panel may be:  approval, approval with conditions that are to be met by the applicant, or denial of approval.

            I will now ask for a motion on the PMA from the panel.

            DR. AFIFI:  May I ask a question before we move on?

            CHAIRPERSON WOODS:  Yes?

            DR. AFIFI:  The approval with conditions, suppose one of the conditions is that the following study will be conducted.  What effect does that have, then, on their approval, Dr. Cooper?

            DR. COOPER:  I will give that to Ms. Brogdon.

            DR. BROGDON:  If FDA agrees with you, we would approve the PMA with a condition of approval that there be a post‑approval study that is described.

            What you have to do if you choose to recommend that is just to ensure that the application meets the needed demonstration of reasonable assurance of safety and effectiveness at this point.  You have to be satisfied that it is reasonably safe and effective before the approval.

            DR. AFIFI:  Okay.  And suppose that the study we recommend shows adverse events that we were unaware of now or something.  Would that be, then, basis for reconsideration or something?  Is that how it works long‑term?

            DR. BROGDON:  Theoretically, if there are severe problems that are raised with a device after approval, FDA can withdraw its approval, but that almost never happens.  Sometimes sponsors will suspend distribution of a device or they will change labeling, provide additional mornings, additional training, or whatever.  It is very rare that the agency just takes a device off the market due to problems that crop up.

            DR. AFIFI:  But it could be basis for changing the labeling ultimately or ‑‑

            DR. BROGDON:  Absolutely.

            DR. AFIFI:  Okay.

            CHAIRPERSON WOODS:  Okay.  Any other questions for FDA from the panel before we entertain a motion?

            (No response.)

            CHAIRPERSON WOODS:  All right.  Do I have a motion from the panel?

            DR. ACHEM:  Dr. Woods, I would move that we approve with conditions, the main condition being that a ‑‑

            CHAIRPERSON WOODS:  Okay.

            DR. ACHEM:  Do you want to name the condition or do we stop at this point with approval with condition?

            CHAIRPERSON WOODS:  First I think I need to have a ‑‑ we have a motion for approval with conditions.  Do I have a second?

            DR. SHAHEEN:  Second.

            CHAIRPERSON WOODS:  Okay.  We have a second.  Now I believe we need to outline the conditions.  Okay.  You have condition number 1, Dr. Achem.

            DR. ACHEM:  I think that my condition would be condition number 1 would be to address a placebo control trial, to expand the observations of this study.

            CHAIRPERSON WOODS:  Are you making that a condition of the post‑marketing study that has already been proposed by the sponsor?

            DR. ACHEM:  I am not clear that that particular study has been yet even started, nor the sign.

            CHAIRPERSON WOODS:  So you are approving with the condition that an additional trial with a placebo control be mandated?  That is separate and distinct from the post‑marketing evaluation and entry of new patients into the post‑marketing group of study patients are going to be proposed?

            DR. ACHEM:  That is correct.

            DR. FERGUSON:  Can I ask for a clarification?  Are you talking about a sham injection of vehicle?

            DR. ACHEM:  That could be a possibility.  There is another way to design it.  I suppose you could endoscope those individuals and bring out the needle and inject saline in the stomach for that purpose?  The study, of course, would be a double‑blind control.

            CHAIRPERSON WOODS:  Dr. Ferguson, do you have a comment on that?

            DR. FERGUSON:  Well, you can't make it double blind because you need to monitor it fluoroscopically so at least the operator would know whether it was a vehicle or the actual device.

            As I mentioned, I think, before, the likelihood of accrual to patients to such a study is quite low once the product is approved.

            CHAIRPERSON WOODS:  I think if you're going to do this, what you really would like to see is a sham procedure and then let the patients choose whether they are on PPIs or not.  And maybe you will have the fallout on the placebo effect or the treatment effect, I guess I should say, of the procedure.  You will see it there.

            Do we need to vote on each condition as we go?

            DR. AFIFI:  But it hasn't been seconded.

            CHAIRPERSON WOODS:  Well, the condition, making conditions, has been seconded.  Now we are proposing placebo control and ‑‑

            DR. BROGDON:  You have an amendment that has been proposed that hasn't been seconded yet.  You have just been through clarification.

            DR. COOPER:  Are you done discussing?

            DR. MANYAK:  Well, I would just like to make a comment that I am not sure it is our purview to decide how that placebo trial is done.

            DR. ACHEM:  And I would agree with that.  I think that the fine tuning and details of the signs, such as whether the patients are going to be, for instance, all briefly fluoroscoped and who is going to blinded, the separate investigator and so on and so forth, I think those would be further details to fine‑tune.

            I think the motion I am just asking you to entertain is considering a sham study as a complementary study.

            CHAIRPERSON WOODS:  Is there any discussion of this motion?

            MR. BALO:  Why can't we take this motion Dr. Achem made and make it part of the post‑market study that is already being proposed by the sponsor?  I don't see any reason to put the sponsor through an additional study when they are already willing to make a post‑market study and we can add things that we would like to see in that study and have that design worked out between the sponsor and the FDA.

            DR. AFIFI:  Dr. Woods?

            CHAIRPERSON WOODS:  Yes?

            DR. AFIFI:  I think the condition that Dr. Achem has suggested has not yet been seconded.  According to Robert's Rules, or whatever, I wonder if, Dr. Achem, you would accept the following modification, in which case I would be willing to second it, that a controlled study be part of the post‑marketing study that is proposed, rather than a controlled study with the sham controls, be part of the post‑marketing study, rather than a separate one.  If you accept that, I would be happy to second it.

            CHAIRPERSON WOODS:  Does FDA have any comments on this?

            DR. BROGDON:  No.

            CHAIRPERSON WOODS:  Okay.  Then we have a second.  Do you accept what ‑‑

            DR. ACHEM:  Dr. Woods, I am comfortable with that alternative proposal.

            CHAIRPERSON WOODS:  Okay.  So we have proposed a post‑marketing study as put forth by the sponsor with a modification that it would include an element of a placebo control as a part of ongoing investigations.  Okay.  We have a second.  Dr. Afifi seconded.  Dr. Achem put forth the condition.

            Okay.  We may now vote.  So we will go around and ask for a vote by each member of the panel on that particular condition.  Okay.  We will start with Dr. Shaheen.

            DR. SHAHEEN:  I am in favor of the condition.

            CHAIRPERSON WOODS:  You're in favor?  Okay.

            Dr. Ferguson?

            DR. FERGUSON:  I am in favor of the condition.

            CHAIRPERSON WOODS:  Okay.  Dr. Achem?

            DR. ACHEM:  I do, too.

            CHAIRPERSON WOODS:  Dr. Afifi?

            DR. AFIFI:  I vote yes.

            DR. MANYAK:  I am also in favor of that condition.

            CHAIRPERSON WOODS:  Okay.  Dr. Gellens?

            DR. GELLENS:  I am in favor.

            CHAIRPERSON WOODS:  Ms. Moore and Mr. Balo, do they vote?

            MR. BALO:  We can't vote.

            CHAIRPERSON WOODS:  Okay.  So we have a unanimous yes on the first condition.  We can move on.  Is there a proposal for a second condition?

            DR. FERGUSON:  May I propose a condition?

            CHAIRPERSON WOODS:  Yes.

            DR. FERGUSON:  I suggest that we require a change in indication for use of the device as identified by Dr. Fennerty earlier in our discussions.

            CHAIRPERSON WOODS:  Can you please define that?  Be specific.

            DR. FERGUSON:  I think somebody wrote that down.

            CHAIRPERSON WOODS:  You want the sentence that says, "The Enteryx procedure kit is indicated for endoscopic injection into the region of the lower esophageal sphincter for the treatment of symptoms due to gastroesophageal reflux disease, requiring medical therapy"?

            DR. FERGUSON:  "Requiring and responding to medical treatment."

            DR. MANYAK:  "Requiring pharmacotherapy" I believe is how he worded it.

            CHAIRPERSON WOODS:  "Requiring and responsive to pharmacotherapy."

            DR. FERGUSON:  "Pharmacologic therapy."

            CHAIRPERSON WOODS:  "Pharmacological therapy."

            DR. FERGUSON:  That is correct.

            CHAIRPERSON WOODS:  Okay.  Do I have a second for this condition?

            DR. GELLENS:  I have one comment.  Can we add severity to that?

            CHAIRPERSON WOODS:  You know, during our previous discussion, Dr. Fennerty made it fairly clear that he did not think severity was necessary since, by definition, patients requiring continuous pharmacotherapy had symptoms severe enough to warrant treatment with something, pharmacotherapy or otherwise.

            DR. GELLENS:  Okay.

            DR. ACHEM:  Let me, if I may, add a little bit.  Dr. Johnson actually alluded to some of that in his comments, with which I agree.  I was the one who brought up the notion of severity.  So I am comfortable with the new statement as currently worded.

            DR. MANYAK:  So are you seconding?

            DR. ACHEM:  Yes, I would second it.

            CHAIRPERSON WOODS:  All right.  We have a second on this condition.  We will vote.  Dr. Shaheen?

            DR. SHAHEEN:  I am in favor.

            CHAIRPERSON WOODS:  Dr. Ferguson?

            DR. FERGUSON:  I am in favor.

            CHAIRPERSON WOODS:  Dr. Achem?

            DR. ACHEM:  I am in favor, too.

            CHAIRPERSON WOODS:  Dr. Afifi?

            DR. AFIFI:  In favor.

            CHAIRPERSON WOODS:  Dr. Manyak?

            DR. MANYAK:  Yes, I am in favor.

            CHAIRPERSON WOODS:  Dr. Gellens?

            DR. GELLENS:  I agree.

            CHAIRPERSON WOODS:  Okay.  That's a unanimous yes.  All right.  Do we have a condition proposal for number 3?

            DR. AFIFI:  Yes.

            CHAIRPERSON WOODS:  Dr. Afifi?

            DR. AFIFI:  I would like to propose that we put another condition on the post‑marketing study to be worked out between the FDA and the sponsor that specifically addresses the question of the need for and guidelines for retreatment.

            CHAIRPERSON WOODS:  Restate what you just said one more time for me, please.

            DR. AFIFI:  Yes.  It doesn't have to be exactly in the words that I used, but I want to add something that has to do with the retreatment to the post‑marketing study.  One way I was thinking about it is to say that the FDA and the sponsor could work on what would be needed in the way of additional data and also a protocol to try to answer that question of guidelines for retreatment.

            CHAIRPERSON WOODS:  Okay.

            DR. AFIFI:  But, again, I am not a GI specialist.  So I don't know how feasible how this is.

            CHAIRPERSON WOODS:  May I ask FDA?  Is that sufficient for a condition or do we need to be more specific as to what we want?

            DR. BROGDON:  I believe this is sufficient.

            CHAIRPERSON WOODS:  Okay.  Do I have a second?

            DR. FERGUSON:  Second.

            CHAIRPERSON WOODS:  Any discussion?  Further discussion?

            DR. FERGUSON:  I had suggested earlier ‑‑ and it may be going a little too far ‑‑ that the prospective entry into a registry prior to retreatment be required as part of that post‑approval analysis.

            DR. MANYAK:  Well, then what we are saying here, he has one motion.  It sounds like that is a different motion.

            DR. FERGUSON:  Well, I think I am just trying to amend his motion.

            CHAIRPERSON WOODS:  I see it as a clarification of the motion.

            DR. MANYAK:  Okay.  That's fine.  Just for purposes of proper order here.  That's all.

            CHAIRPERSON WOODS:  Okay.  Any other discussion?

            (No response.)

            CHAIRPERSON WOODS:  All right.  Then ‑‑

            DR. MANYAK:  So could you restate the motion, then, Dr. Ferguson, along the way that you would like it worded?

            DR. FERGUSON:  I think I would word it that "As part of the post‑market study, specific attention be paid to indications for and results of retreatment of patients through use of entry into a prospective registry of retreatment patients."

            DR. AFIFI:  I am comfortable with that wording.  That means I am changing my initial motion to that one.

            CHAIRPERSON WOODS:  All right.  Do we have another second?

            DR. MANYAK:  I will second.

            CHAIRPERSON WOODS:  Any further discussion on this?

            (No response.)

            CHAIRPERSON WOODS:  Dr. Shaheen, your vote?

            DR. SHAHEEN:  I am in favor.

            CHAIRPERSON WOODS:  Dr. Ferguson?

            DR. FERGUSON:  In favor.

            CHAIRPERSON WOODS:  Achem?

            DR. ACHEM:  I do, too.

            CHAIRPERSON WOODS:  Afifi?

            DR. AFIFI:  In favor.

            CHAIRPERSON WOODS:  Dr. Manyak?

            DR. MANYAK:  I am in favor.

            CHAIRPERSON WOODS:  Dr. Gellens?

            DR. GELLENS:  In favor.

            CHAIRPERSON WOODS:  Okay.  That's unanimous.  Condition number 4, Dr. Afifi?

            DR. AFIFI:  That the analysis of the data resulting from the post‑marketing study take into account the longitudinal effects of the collected data.

            CHAIRPERSON WOODS:  Do I have a second?

            DR. FERGUSON:  I second.

            CHAIRPERSON WOODS:  Any discussion?

            DR. FERGUSON:  It means statistical analysis of longitudinal effects.

            CHAIRPERSON WOODS:  Okay.  Are we ready to vote?  All right.  Dr. Shaheen?

            DR. SHAHEEN:  In favor.

            CHAIRPERSON WOODS:  Ferguson?

            DR. FERGUSON:  In favor.

            CHAIRPERSON WOODS:  Achem?

            DR. ACHEM:  In favor.

            CHAIRPERSON WOODS:  Afifi?

            DR. AFIFI:  In favor.

            CHAIRPERSON WOODS:  Manyak?

            DR. MANYAK:  In favor.

            CHAIRPERSON WOODS:  Gellens?

            DR. GELLENS:  Yes.

            CHAIRPERSON WOODS:  Condition number 5, Dr. Shaheen?

            DR. SHAHEEN:  I suggest that that esophageal stricture be added to the list of precautions for now for this product.

            CHAIRPERSON WOODS:  And my understanding is precautions now exist only for esophageal varices as put forth by the sponsor.  Is that correct, FDA?  Is that ‑‑

            DR. SHAHEEN:  Portal hypertension is their only contraindication.

            CHAIRPERSON WOODS:  Portal hypertension.

            DR. SHAHEEN:  And they have a whole list of precautions, which are essentially their exclusion criteria from the trial.  But because they use the Savary‑Miller grading, they include high‑grade esophagitis but do not list stricture explicitly.  I think that may be confusing for some people.

            CHAIRPERSON WOODS:  Could you restate your motion again, please?

            DR. SHAHEEN:  I move that under the precaution section of the label for both the patient as well as the physician, that esophageal stricture be added.

            CHAIRPERSON WOODS:  Do I have a second?

            DR. FERGUSON:  Second.

            DR. GELLENS:  Second.

            CHAIRPERSON WOODS:  Okay.  Any discussion?

            DR. FERGUSON:  I wonder if we could have a general condition regarding precautions, as opposed to adding several specific items to the list.  And I would propose adding patients with symptoms refractory to pharmacologic therapy.

            CHAIRPERSON WOODS:  Yes.  That was going to be my point as well, maybe not putting in one thing and running through this for ten more conditions.  With the rules of order here, can we modify this in the discussion?  Okay.

            DR. BROGDON:  I am sorry.  Does this conflict with the indications for use you are recommending?

            CHAIRPERSON WOODS:  No.

            DR. FERGUSON:  Actually it's consistent with the indications for use.

            CHAIRPERSON WOODS:  All right.  So, please, let's restate the motion.  Currently as stands, it says we add to precautions that patients with esophageal stricture not be treated.

            DR. SHAHEEN:  As well as those unresponsive to PPI therapy.

            CHAIRPERSON WOODS:  And those unresponsive to pharmacologic therapy.

            DR. SHAHEEN:  Yes, that's fine.

            CHAIRPERSON WOODS:  Any other conditions to go with these conditions?

            DR. AFIFI:  How about fear of needles?  Sorry.

            CHAIRPERSON WOODS:  Okay.  So the motion has been modified to include precautions for esophageal stricture and failure to respond to pharmacologic treatment for GERD symptoms.  We have a second for that already, I believe.

            Any further discussion?

            (No response.)

            CHAIRPERSON WOODS:  All right.  We will vote on that.  Dr. Shaheen?

            DR. SHAHEEN:  In favor.

            CHAIRPERSON WOODS:  Ferguson?

            DR. FERGUSON:  In favor.

            CHAIRPERSON WOODS:  Achem?

            DR. ACHEM:  In favor.

            CHAIRPERSON WOODS:  Afifi?

            DR. AFIFI:  In favor.

            CHAIRPERSON WOODS:  Manyak?

            DR. MANYAK:  Yes, in favor.

            CHAIRPERSON WOODS:  Gellens?

            DR. GELLENS:  In favor.

            CHAIRPERSON WOODS:  Okay.  We have those two.  Do we have condition number 6?

            DR. SHAHEEN:  I believe Dr. Fennerty made a couple of specific suggestions regarding the insert labeling, specifically regarding getting rid of the interdiction of spicy food as well as mandating antibiotic therapy.

            CHAIRPERSON WOODS:  Are we talking about the insert for the patients, the insert for physicians, or both?

            DR. SHAHEEN:  This is in the physician insert that I am referring to, although I think it was in the patient insert as well.

            CHAIRPERSON WOODS:  It is also mentioned in the physician.  So I think we may need to make two specific statements.

            MS. MOORE:  And when I made my comment, ‑‑

            CHAIRPERSON WOODS:  Labeling.

            MS. MOORE:  ‑‑ Madam Chairman, I made my comment, I wasn't speaking to the spicy food.  I think Dr. Fennerty ‑‑

            CHAIRPERSON WOODS:  To the timing, the amount of time.

            MS. MOORE:  I was speaking to the wording, to the generalities, you know, asking that the wording, that the brochure be more specific so that the patients would be clear about what was expected of them.

            CHAIRPERSON WOODS:  I believe your comments were related to "Don't eat these certain types of foods for several days."

            MS. MOORE:  Yes, I used that as an example, the word "several" as an example.  So I am saying if that is necessary that they shouldn't eat this, then they ought to know specifically whether they should go a week without eating or two or three days or one day or just what.  But when you used the word "several," I said it was too general and the patient wouldn't know, really, what several meant, I would think.

            CHAIRPERSON WOODS:  Okay.

            MS. MOORE:  But, then, you say it is in the physician's brochure as well.

            CHAIRPERSON WOODS:  In the physician's, I believe it says five days.  It is very specific.

            MS. MOORE:  Well, you're saying different things, then.

            CHAIRPERSON WOODS:  It should be consistent.

            MS. MOORE:  It should be consistent.

            CHAIRPERSON WOODS:  Okay.  You were in the midst of making a motion ‑‑

            DR. SHAHEEN:  So the motion specifically for the physician labeling is that under "DIRECTIONS FOR USE," section 1, "Patient Preparation," strike the second sentence, "It is recommended that patients be administered prophylactic antibiotics before and after procedure."  We don't need that.

            Under section number 4, "Instructions to Patients," point number 1, prophylactic administration of pain medication may not be necessary.  Strike number one.

            Number 3 under "Instructions to Patients," "bland, non‑spicy foods for 5 days," strike number 3.  That is the specific recommendation.

            CHAIRPERSON WOODS:  You want to strike any dietary modifications altogether?

            DR. SHAHEEN:  Yes.  Just get rid of number 3.

            CHAIRPERSON WOODS:  Are there any other additions to these conditions for the physician labeling component of the product?

            DR. GELLENS:  The issue of using fluoroscopy should be placed here.

            CHAIRPERSON WOODS:  Yes.  We need to add.  If you don't mind if I add to your motion, we should incorporate specifically information spelling out when fluoroscopy or how fluoroscopy should be used to guide injection and, as I mentioned, earlier discussion, how to decide whether you can do this with one injection or several injections.  And I think addition of some fluoroscopic photographs would be helpful to the clinician to know what they are referring to with an arc or some of the other things that you need to look for and note that you are in the right place.

            So we have four:  the issue with respect to no antibiotics, the issue with respect to prophylactic pain medications, removing dietary modifications, adding further information on technique in the use of fluoroscopy.  Dr. Ferguson, do you have an additional one?

            DR. FERGUSON:  I was just going to second the motion.

            CHAIRPERSON WOODS:  Okay.

            DR. ACHEM:  Could you clarify it for me?  Are we removing the notion of the need for antibiotics?  Is that what the motion ‑‑

            CHAIRPERSON WOODS:  It had been proposed that the prophylactic antibiotic portion that is recommended in the physician labeling be removed.

            DR. ACHEM:  May I ask the sponsor to comment on that?  I am a little concerned.  I think that there is a potential benefit to the patient that we may be withdrawing, actually, here.  Can I ask your permission to ask the sponsor to come and present it?

            CHAIRPERSON WOODS:  Yes.

            DR. LEHMAN:  I think the use of antibiotics for sclerotherapy is still somewhat controversial.  Many people would do it and some wouldn't.  This falls in that same category.  It may be beneficial.  It may not.  To leave it open to discretion seems appropriate.  And how you phrase it here for your labeling is up to you.

            CHAIRPERSON WOODS:  Do you have a specific modification to that you would like to make, Dr. Achem?

            DR. ACHEM:  No.  We'll proceed with the ‑‑

            DR. SHAHEEN:  I think just striking it leaves it open to the person who is doing it, which may be the best‑case scenario since we are not really sure of its benefit.

            CHAIRPERSON WOODS:  Okay.  So as it stands, this particular modification includes modifications to the be made to the physician labeling component for the product to include removal of the sentence that states, "prophylactic antibiotics" should be given; removal of the statement that "prophylactic pain medications" should be given; removal of the statement regarding dietary modifications; and addition of further definition to the physician technique and use of fluoroscopy.

            Do we have a second for that?  I don't think we have had one since we have gone through all of the conditions.

            DR. FERGUSON:  I will second it again.

            CHAIRPERSON WOODS:  Okay.  Any further discussion?

            (No response.)

            CHAIRPERSON WOODS:  All right.  Let's vote.  Dr. Shaheen?

            DR. SHAHEEN:  In favor.

            CHAIRPERSON WOODS:  Ferguson?

            DR. FERGUSON:  In favor.

            CHAIRPERSON WOODS:  Achem?

            DR. ACHEM:  In favor.

            CHAIRPERSON WOODS:  Afifi?

            DR. AFIFI:  Yes.

            CHAIRPERSON WOODS:  Manyak?

            DR. MANYAK:  In favor.

            CHAIRPERSON WOODS:  Gellens?

            DR. GELLENS:  In favor.

            CHAIRPERSON WOODS:  Okay.  Do I have a subsequent condition?

            DR. ACHEM:  Dr. Woods, I would like to propose knowing that there is already an ongoing study that the sponsor addresses formally the notion of what is the mechanism involved in the presumed therapeutic benefit of this device.

            I realize that the transient lower esophageal sphincter relaxation study may be out.  That may be one.  I may also suggest that, in addition to that, the neurosensory evaluation of these patients be tested as well.

            CHAIRPERSON WOODS:  So you are proposing further information in the post‑marketing evaluation study be collected?  You are adding data that you would like to see collected and information given?

            DR. ACHEM:  Specifically addressing the mechanism of action of the device.

            CHAIRPERSON WOODS:  You would like to see further information regarding the mechanism of action of the device as defined by what studies?  What are you asking for?

            DR. ACHEM:  A) transient lower esophageal sphincter relaxation; b) evaluation of neurosensory perception of these patients.

            CHAIRPERSON WOODS:  How do you evaluate neurosensory perception?

            DR. ACHEM:  The two ways would be two simple ways to do it.  There is no perfect, ideal way to do it.  But the way clinically to do it would be to simply do a Bernstein perfusion study and look at time to response symptoms.  Also, you could look at the mechanical properties of the esophagus by looking at balloon distension of the esophagus in these patients.

            DR. MANYAK:  But aren't those details that should be worked out down the road?

            DR. ACHEM:  They can.  They can be worked out subsequently.  And I don't have any troubles with that.

            DR. MANYAK:  I have one other question.  And that is, is it customary to have to demand of the sponsor to provide the mechanism of action for something that works if it is clinically acceptable?  I don't think that is necessary for a device.  As a matter of fact, I would pretty much take a wild guess and say a lot of them do not have a mechanism of action worked out for that.  And I am sure that is true for pharmacotherapy as well.

            With all due deference to you, I am not being critical here, but I don't think that should be a condition for approval personally.

            DR. ACHEM:  Well, I think you would certainly shed light.  We have had plenty of discussion as to how this works.  It certainly would be very informative, although I understand your position exonerating whether or not we need to understand the mechanism.

            My personal vote would be to claim to propose that.  Certainly it is open to the table deferring with my opinion.  And certainly they are at liberty to choose otherwise.

            DR. MANYAK:  I am just saying that sounds like a grant proposal and not a post‑market study.  I mean, seriously, that is one of the things that you would look at down the road.  In our field, that is what we do anyway.

            CHAIRPERSON WOODS:  Does FDA have a comment on that?

            DR. BROGDON:  I think Dr. Manyak has just stated FDA's position on this.  This would be not customary for us to require this sort of information be collected.  It certainly would be nice to know.

            DR. MANYAK:  And very interesting.  I agree with that, yes.

            DR. BROGDON:  But it's not the typical post‑market study that we would require.

            DR. ACHEM:  Okay.  Thanks for sharing that information.

            CHAIRPERSON WOODS:  Okay.  So are you going to make further comments on this motion?

            (No response.)

            CHAIRPERSON WOODS:  Okay.  Do we have a second to this motion?

            DR. FERGUSON:  Second.

            CHAIRPERSON WOODS:  All right.  Then any further discussion?

            MR. BALO:  Does the sponsor have anything to say about the action?  I mean, we have been talking about it.  Do they have any comments about that from the physicians who have used the device?

            DR. MANYAK:  Are they allowed to comment on this?

            MR. BALO:  They can't?

            CHAIRPERSON WOODS:  I think they are allowed to comment.  And I think they have commented previously as to the thought that the fibrosis that ensues around the implant is leading to an improvement or a reduction in the number of spontaneous lower esophageal sphincter relaxations.  Am I correct, Dr. Lehman?

            DR. LEHMAN:  That's one of the currently shown mechanisms, yes.

            CHAIRPERSON WOODS:  Do you have other comments?

            DR. LEHMAN:  We think this kind of a step is beyond usual and customary.  And we would like to work this out but without a mandate.

            CHAIRPERSON WOODS:  Thank you.  Okay.  Let's take a vote on this proposal.  Dr. Shaheen?

            DR. SHAHEEN:  Against.

            CHAIRPERSON WOODS:  Ferguson?

            DR. FERGUSON:  I'm against.

            CHAIRPERSON WOODS:  Achem?

            DR. ACHEM:  I'm in favor.

            CHAIRPERSON WOODS:  Afifi?

            DR. AFIFI:  Against.

            CHAIRPERSON WOODS:  Manyak?

            DR. MANYAK:  I'm against.

            CHAIRPERSON WOODS:  Gellens?

            DR. GELLENS:  Against.

            CHAIRPERSON WOODS:  Okay.  So we have voted down proposal number 7.  So we will move on to condition number 7.  Dr. Ferguson?

            DR. FERGUSON:  I propose that in the patient information brochure in the handout on page 61, first paragraph, the sentence, "For the first several days after the procedure, you should only eat bland, non‑spicy and soft foods," be stricken.

            CHAIRPERSON WOODS:  Do we have a second?

            DR. SHAHEEN:  I second.  Can we also more generally just make this motion that the patient handout be brought in line with the physician changes that we have made, as opposed to trying to find it everywhere, so the four conditions we put on the physician handout, pick through and yank them out of the patient handout as well?

            CHAIRPERSON WOODS:  Yes.  And I would add to that that it be very clear in the patient brochure that if they are not responsive to proton pump inhibitor therapy or medical therapy for their reflux, that they not be considered a candidate for this procedure, which actually technically would bring it into line with what we are putting into the physician insert as well, but it needs to be expanded upon in the patient information section.

            DR. FERGUSON:  So overall a condition, then, would be to bring the patient information brochure in line with the physician information handout.

            CHAIRPERSON WOODS:  Okay.  Do we have a second for that motion?

            DR. SHAHEEN:  I second it.

            CHAIRPERSON WOODS:  All right.  Any further discussion?

            (No response.)

            CHAIRPERSON WOODS:  Vote.  Dr. Shaheen?

            DR. SHAHEEN:  For.

            CHAIRPERSON WOODS:  Ferguson?

            DR. FERGUSON:  In favor.

            CHAIRPERSON WOODS:  Achem?

            DR. ACHEM:  In favor.

            CHAIRPERSON WOODS:  Afifi?

            DR. AFIFI:  In favor.

            CHAIRPERSON WOODS:  Manyak?

            DR. MANYAK:  In favor.

            CHAIRPERSON WOODS:  Gellens?

            DR. GELLENS:  In favor.

            CHAIRPERSON WOODS:  Okay.  Number 8.  Do we have another condition?

            DR. GELLENS:  I have one condition that we change the labeling from this therapy being permanent to a long‑term therapy for GERD.

            CHAIRPERSON WOODS:  Do I have a second for that motion?  Does anybody want to second?

            DR. MANYAK:  I will second.

            CHAIRPERSON WOODS:  Any further discussion or modification?

            MS. MOORE:  Excuse me.  Would you want to have FDA and the sponsors maybe look at the wording?  And maybe "long‑term" may not be the one that they come up with, but they know the sense of the panel that we don't like the word "permanent."  Would that be better than us telling them what the word should be?  I am just asking.

            CHAIRPERSON WOODS:  So it might be best to suggest changing the terminology to reflect ‑‑

            MS. MOORE:  To reflect the sentiment of the panel.

            DR. SHAHEEN:  So I guess "eternal" is out, too, then?

            (Laughter.)

            CHAIRPERSON WOODS:  Dr. Shaheen?

            DR. SHAHEEN:  How about more specifically just dropping the adjective altogether?  It's just a therapy for GERD.  I don't think we can say that it is long‑term based on 12‑month data.  Why don't we just say that it is a therapy.

            MS. MOORE:  That might be better.  I think that is better.

            DR. FERGUSON:  I have some concerns about that in that the sponsor has gone to great pains to show that this is probably going to stay in place forever.  The patients and physicians should have some indication that that is the case.

            DR. SHAHEEN:  I guess we don't know if that is the case.  I mean, based on the data we have so far, I don't feel comfortable saying it is going to be there forever based on 12‑month data.