1       1 1             GASTROENTEROLOGY AND UROLOGY DEVICES PANEL 2 3                                    OF THE 4 5      ...
1      1 1   SPONSOR PRESENTERS: 2 3   ALAN STEIN, Ph.D. 4   President and Chairman, Enteric Medical Technologies 5 6   LU...
1       1 1                              I-N-D-E-X 2 3   AGENDA ITEM                                                    PA...
1       1 1                            I-N-D-E-X (Continued) 2 3   AGENDA ITEM (Continued)                                ...
1                      P-R-O-C-E-E-D-I-N-G-S 2                                                     (8:32 a.m.) 3          ...
1   medicine at Baylor College of Medicine. 2                 Brian? 3                 DR.      FENNERTY:         Im   Bri...
1   the panel.    Im an assistant professor of medicine and 2   epidemiology. 3                  DR. FERGUSON:         My ...
1   update the panel. 2                 DR. NEULAND:             Good morning.           Welcome.       As 3   Dr. Cooper ...
1   Gastroenterology and          Renal Devices         Branch, many          of 2   which   will    be     interacting   ...
1   member of our branch, has been here with us for three 2   months.   He is a biomedical engineer. 3                 Kat...
1   This device then creates a pouch which reduces food 2   consumption, which then induces early satiety.                ...
1                    One of the other requirements that was 2   also made at that time was that the company do an 3   addi...
1                 On      December        18,    2001,   that   PMA    was 2   approved.     The conditions were met.     ...
1                   "For     the      record,       they     are     special 2   government employees and consultants to t...
1   the agency took into consideration matters regarding 2   Drs. Afifi, Achem, Fennerty, Manyak, Shaheen, and Dr. 3   Woo...
1   firm whose products they may wish to comment upon. 2                  On another note, we have the test of the 3   200...
1                   Before     making       your     presentation     to   the 2   panel, you will need to state your name...
1   financial interest in that company. 2                  I    remind   you    that   the     definition        of 3   fi...
1                       Dr. Stein? 2                         1.    SPONSOR PRESENTATION 3                       DR. STEIN:...
1   did our first patient and performed a pilot study 2   under the supervision of Dr. Jacques Deviere at the 3   Frie Uni...
1   used in orthopedic implants.               And polyvinyl alcohol 2   has been extensively used for vascular embolizati...
1   peripheral vascular neuropathies or abnormalities. 2                    And in these applications, these vascular 3   ...
1                    Next       slide.        There    has     been    extensive 2   biocompatibility testing of the produ...
1   positive/negative controls were studied, there were no 2   Enteryx-treated animals that develop tumors at any of 3   t...
1   quite well. 2                  Several of the animals in the study were 3   maintained for up to a year.              ...
1   a GERD baseline.              By the way, these results were 2   published in Surgical Endoscopy. 3                  T...
1                    And, as a result, -- next slide, please -- 2    it was suggested that the mechanism of action in this...
1   implants in them and had the opportunity after the 2   pathologist       had       finished    checking     the    mar...
1   histopathology.            He will review the course of the 2   evolution    from        an    acute    to    a    chr...
1   of   material       that   are   under    evaluation,    other 2   applications than cerebrovascular AVMs.           I...
1                  DR. ACHEM:      Dr. Stein, in this model of 2   esophagectomy, I believe there were four patients that ...
1   sloughing. 2                When they are in an appropriate position; 3   that is, deep in and along the muscle layer,...
1                  DR. STEIN:       The carcinogenicity studies, 2   sir. 3                  DR. MANYAK:         Right.   ...
1   and is excreted primarily through the kidneys and as 2   exhaled     product,   breakdown     products,   being   main...
1   come up in a different context.             There is no way to 2   hide the fact that a patient was treated with Enter...
1   on     X-ray.         So       if   you   make     four    circumferential 2   injections and you look at these patien...
1   into the esophageal lumen, I can only say it was not 2   possible to get patients to, shall we say, collect 3   their ...
1   material of the mucosa away from the blood supply, 2   some pizza burns go down.          Most of them peel off.      ...
1   blebs    or      blobs        of     material.           Theyre          highly 2   demarcated.          Theyre also i...
1   well-circumscribed areas of injection surrounded by 2   blue.     And in this one as well as this one, we note 3   tha...
1                      Note that as in the previous sacrifice 2   period, it is well-demarcated, surrounded by fibrous 3  ...
1   is a lack of any type of tissue destruction along the 2   outside.     If we saw any type of necrosis or tissue 3   de...
1   bold     interface      between     the     surrounding        fibrous 2   connective tissue and the injection site. 3...
1   can see a blue hue throughout much of this site here 2   representing         fibrous       connective      tissue    ...
1   unable to find tantalum in any blood vessels, in any 2   lymphatics, regional lymph nodes, or any indication 3   that ...
1   quantify? 2                   I mean, this seems like this is as normal 3   a carrying from an inflammatory response a...
1   summary    that     you have minimal        chronic inflammatory 2   changes.    Is it none or is it -- 3             ...
1   centimeters above the injected area, I did not do 2   histopathologic review on those, nor did I do a review 3   on ot...
1   stated that it is a fraction of a percent in the 2   report.     Yet, the illustration that is included in the 3   mat...
1   you     may   expect     further      destruction         of   cells      and 2   further dystrophic calcification.   ...
1   preparations      a       number     of      different         sites     of 2   accumulation of the foreign materials,...
1   extent? 2                  DR.   BRENNECKE:      I    did    not   see   any 3   involvement, any destruction of nerve...
1                    CHAIRPERSON WOODS:        Thank you. 2                    Other questions?      Yes, Dr. Gellens? 3  ...
1   report the safety outcomes.           I must say that I have a 2   consulting    arrangement      with     Enteric    ...
1   resisting    mechanical          strain,     capable      of    being 2   sterilized, capable of being delivered in li...
1   the ringlike implant.         Some contrast media will be 2   injected.    And     there    will    be   impingement  ...
1                  Next.     Contrast medium swallowed shows a 2   pinch at the LES and the intramural implants. 3        ...
1   were improvement in:            GERD quality of life scores, 2   SF-36 general health survey scores, pH Probe results,...
1                      Next.       Now, the study schedule involved 2   assessing symptoms in the baseline state while tak...
1   statistically      significant      change         in     primary     or 2   secondary objectives.        Therefore, t...
1   antibiotics.       Mean procedure time was 34 minutes, mean 2   fluoro time just under 12 minutes. 3                  ...
1   days, 75 percent had resolution of their pain.                        By 30 2   days, 90 percent had resolution of the...
1   events, all of which resolved spontaneously without 2   intervention,     including the      odor    mentioned by some...
1                      DR.    LEHMAN:       He   is   starting    in    the 2   all-star game, I hear.             So we a...
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GASTROENTEROLOGY AND UROLOGY DEVICES PANEL

  1. 1. 1 1 1 GASTROENTEROLOGY AND UROLOGY DEVICES PANEL 2 3 OF THE 4 5 MEDICAL DEVICES ADVISORY COMMITTEE 6 7 + + + + + 8 9 FRIDAY,1011 JANUARY 17, 20031213 + + + + +14151617 The above-entitled matter met in the Salon18 of the Hilton Washington, D.C., 620 Perry Parkway,19 Gaithersburg, Maryland, at 8:30 a.m., KAREN L. WOODS,20 Chair, presiding.2122 PRESENT:2324 KAREN L. WOODS, M.D. CHAIR25 SAMI ACHEM, M.D. VOTING MEMBER26 ABDELMONEM AFIFI, Ph.D. VOTING MEMBER27 ANDREW BALO INDUSTRY REPRESENTATIVE28 NANCY C. BROGDON FDA29 JEFFREY W. COOPER, DVM EXECUTIVE SECRETARY30 BRIAN FENNERTY, M.D. VOTING MEMBER31 MARK FERGUSON, M.D. TEMPORARY VOTING MEMBER32 MARY GELLENS, M.D. VOTING MEMBER33 MICHAEL MANYAK, M.D. VOTING MEMBER34 CHRISTINE MOORE CONSUMER REPRESENTATIVE35 NICHOLAS SHAHEEN, M.D. TEMPORARY VOTING MEMBER 2 3 NEAL R. GROSS 4 COURT REPORTERS AND TRANSCRIBERS 5 1323 RHODE ISLAND AVE., N.W. 6 (202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
  2. 2. 1 1 1 SPONSOR PRESENTERS: 2 3 ALAN STEIN, Ph.D. 4 President and Chairman, Enteric Medical Technologies 5 6 LUCAS BRENNECKE, DVM, DACVP 7 Director, Medical Device Pathology, Pathology 8 Associates, a Division of Charles River Laboratories 910 GLEN LEHMAN, M.D.11 Professor of Medicine and Radiology, Indiana12 University1314 DAVID JOHNSON, M.D.15 Professor of Medicine, Eastern Virginia Medical School161718 FDA PRESENTERS:1920 KATHLEEN OLVEY21 FDA/ODE/DRARD/GRDB Scientific Reviewer2223 KATHARINE MERRITT, Ph.D.24 FDA/OST/DLS/HSB2526 ARON YUSTEIN, M.D.27 FDA/ODE/DRARD/GRDB Medical Officer2829 MELVIN SEIDMAN, FDA/OSB3031 S. LORI BROWN, Ph.D., FDA/OSB 2 3 NEAL R. GROSS 4 COURT REPORTERS AND TRANSCRIBERS 5 1323 RHODE ISLAND AVE., N.W. 6 (202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
  3. 3. 1 1 1 I-N-D-E-X 2 3 AGENDA ITEM PAGE 4 5 CALL TO ORDER 5 6 7 OPEN PUBLIC HEARING 18 8 9 OPEN COMMITTEE DISCUSSION 191011 1. Sponsor Presentation: 201213 1. Company, Device Description & 2014 Pre-Clinical Studies - Alan Stein, Ph.D.,15 President and Chairman, Enteric Medical16 Technologies17 2. Histopathology Review: Pre-Clinical 4218 Studies - Lucas Brennecke, DVM, DACVP,19 Director, Medical Device Pathology,20 Pathology Associates, a Division of21 Charles River Laboratories, Inc.22 3. Study Design and Results: Safety - Glen 6023 Lehman, M.D., Professor of Medicine and24 Radiology, Indiana University25 4. Study Results: Effectiveness - David 10126 Johnson, M.D.,Professor of Medicine,27 Eastern Virginia Medical School28 5. Study Conclusions - Alan Stein, Ph.D., 14729 President and Chairman, Enteric Medical30 Technologies3132 2. FDA Presentation: 1533334 1. Overview/Pre-Clinical Studies - Kathleen 15335 Olvey, FDA/ODE/DRARD/GRDB Scientific36 Reviewer37 2. Histopathology Considerations - Katharine 15938 Merritt, Ph.D., FDA/OST/DLS/HSB39 3. Clinical Considerations - Aron Yustein, 16440 M.D., FDA/ODE/DRARD/GRDB Medical Officer41 4. Statistical Considerations - Melvin 20642 Seidman, FDA/OSB/43 5. Post-Market Review - S. Lori Brown, 21644 Ph.D. FDA/OSB/ 2 3 NEAL R. GROSS 4 COURT REPORTERS AND TRANSCRIBERS 5 1323 RHODE ISLAND AVE., N.W. 6 (202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
  4. 4. 1 1 1 I-N-D-E-X (Continued) 2 3 AGENDA ITEM (Continued) PAGE 4 5 3. Panel Discussion: 222 6 7 The committee will discuss FDA charges, 8 make recommendations and vote on a 9 pre-market approval application P02000610 from Enteric Medical Technologies and11 Boston Scientific for a device for the12 treatment of gastroesophageal reflux13 disease.1415 1. Dr. Brian Fennerty - Primary Review 22216 and Lead Discussant.17 2. Reading of Questions and Discussion. 2271819 OPEN PUBLIC HEARING 3242021 4. Final Comments 3252223 1. FDA Comments 32524 2. Sponsor Comments 3252526 5. Panel Deliberations and Vote 339 2 3 NEAL R. GROSS 4 COURT REPORTERS AND TRANSCRIBERS 5 1323 RHODE ISLAND AVE., N.W. 6 (202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
  5. 5. 1 P-R-O-C-E-E-D-I-N-G-S 2 (8:32 a.m.) 3 CALL TO ORDER 4 CHAIRPERSON WOODS: Good morning, 5 everyone. I would like to call the meeting to order. 6 My name is Karen Woods, and Ill be chairing the panel 7 today. I would like to note for the record that the 8 voting members present here today constitute a quorum, 9 as required by 21 CFR Part 14.10 And at this point, I would like to turn11 the meeting over to Dr. Jeff Cooper, the Executive12 Secretary of FDA.13 DR. COOPER: Good morning. My name is14 Jeff Cooper. I am the Executive Secretary and15 Veterinary Medical Officer at the Food and Drug16 Administration.17 I would like to have each member introduce18 him or her self; designate your specialty; position19 title; and institution; and status on the panel as far20 as voting member or consultant voting member, industry21 rep, or consumer rep. Dr. Woods?22 CHAIRPERSON WOODS: Im Karen Woods. Im23 a gastroenterologist, presently in private practice in24 Houston, Texas. Im a clinical associate professor of
  6. 6. 1 medicine at Baylor College of Medicine. 2 Brian? 3 DR. FENNERTY: Im Brian Fennerty, a 4 professor of medicine, section chief of 5 gastroenterology at Oregon Health Sciences University, 6 a gastroenterologist, and a voting member of the 7 panel. 8 DR. GELLENS: Im Mary Gellens, associate 9 professor of medicine at St. Louis University. Im a10 nephrologist, and Im a voting panel member.11 MS. MOORE: My name is Christine Moore. I12 am a former dean of students at the Community College13 of Baltimore. Im the consumer representative.14 MR. BALO: Hi. Im Andy Balo. Im vice15 president of regulatory and clinical and quality16 affairs for a company called DexCom, Incorporated in17 San Diego. And Im the industry rep.18 DR. BROGDON: Good morning. Im Nancy19 Brogdon. Im not a member of the panel. Im the20 division director at FDA, Division of Reproductive,21 Abdominal, and Radiological Devices.22 DR. SHAHEEN: Im Nick Shaheen from23 University of North Carolina. Im a24 gastroenterologist. Im a consultant voting member of
  7. 7. 1 the panel. Im an assistant professor of medicine and 2 epidemiology. 3 DR. FERGUSON: My name is Mark Ferguson. 4 Im a general thoracic surgeon. Im a professor of 5 surgery at the University of Chicago. And Im a 6 consultant voting member. 7 DR. ACHEM: My name is Sami Achem. Im a 8 gastroenterologist. Im an associate professor of 9 medicine with the Mayo Medical School. Im a10 practicing gastroenterologist at Mayo Clinic in11 Jacksonville, Florida. I am a voting member.12 DR. AFIFI: My name is Abdelmonem Afifi.13 Im professor of biostatistics and biomathematics at14 the Schools of Public Health and Medicine at UCLA.15 And Im a voting member of the panel.16 DR. MANYAK: Hi. Im Mike Manyak,17 professor and chairman, Department of Urology and18 professor of microbiology and tropical medicine at the19 George Washington University Medical Center here in20 Washington, D.C. Im a voting member of the panel.21 DR. COOPER: Thank you all. I appreciate22 you coming.23 Now our FDA branch chief, Dr. Carolyn24 Neuland, will introduce the FDA branch members and
  8. 8. 1 update the panel. 2 DR. NEULAND: Good morning. Welcome. As 3 Dr. Cooper has stated, I am the branch chief for the 4 Gastroenterology and Renal Devices Branch at the FDA. 5 And I am one of the two FDA branches that brings 6 devices to this advisory panel. 7 I would like to take this opportunity to 8 welcome all of you to the panel meeting today and to 9 thank you for the time and effort that you have put in10 into reviewing the information that was sent to you in11 traveling this distance in the snow to the panel12 meeting today and also for providing to us your expert13 advice on very complex issues that we bring before14 you.15 It is with your help and your16 recommendations that FDA is better able to make the17 difficult decisions that we must on these new18 technologies and to also look at the new indications19 for the ever-expanding indications of medical devices20 that are brought to us today and throughout the21 future.22 Since many of you are new to the GU23 advisory panel, I would like to take this opportunity24 to introduce to you the members of the
  9. 9. 1 Gastroenterology and Renal Devices Branch, many of 2 which will be interacting with you over the next 3 couple of years. And I thought it would be nice for 4 you to see who they are. 5 I would ask the members of the 6 Gastroenterology Branch who are present -- I know some 7 of them did not make it through the snow -- at this 8 early hour to stand when I call your name. 9 The first one is Dr. Aron Yustein, Dr.10 Aron Yustein. Dr. Yustein is the gastroenterologist11 in the branch, and he is the medical officer who was12 the lead clinical reviewer on the application that you13 will be looking at in a few minutes.14 The next one is Dr. Jeffrey Cooper. He is15 the Executive Secretary that has been sitting at the16 front table. He is a veterinarian in our branch.17 Linda Dart. Linda is a biochemist in the18 branch. She is not present.19 Gema Gonzalez. Gema is a biomedical20 engineer. Shes in the back.21 Barbara McCool. Barbara McCool is a nurse22 consultant that reviews a lot of our dialysis23 products.24 Joshua Nipper. Joshua is the newest
  10. 10. 1 member of our branch, has been here with us for three 2 months. He is a biomedical engineer. 3 Kathleen Olvey. Kathleen will be speaking 4 to you shortly. She is a biologist. And she was the 5 team leader for the PMA that you will be discussing 6 today. 7 Richard Williams. Richard is a mechanical 8 engineer in the branch. 9 Linda Carr. Linda is a consumer safety10 technician. And Im sure if you have called into our11 branch, Linda is the person you have spoken to on many12 occasions. She will help you get any answers you need13 to any question.14 And Kellie Straughn. I dont think Kellie15 is here, but she is a new student intern that has just16 joined us recently.17 I would now like to take a few minutes to18 update you on the two most recent gastroenterology19 devices that came before the advisory panel over the20 last basically year and a half.21 The first device is called the Lap-Band22 Adjustable Gastric Banding System. This was an23 implantable fluid-filled silicone elastomer band that24 has been planted around the stomach to create a stoma.
  11. 11. 1 This device then creates a pouch which reduces food 2 consumption, which then induces early satiety. This 3 device was indicated for weight reduction in the 4 severely obese patients. It had a few other 5 restrictions, which I wont go into now, but that was 6 the basic indication. 7 The device came before the panel on June 8 19, 2000. At the time of that deliberation, the panel 9 recommended for disapproval of the PMA. The reason10 they recommended for disapproval is because the11 company had only presented two-year follow-up data.12 And they thought that two years was not adequate for13 an approval at that time. So the recommendation was14 that, therefore, they would like to see an additional15 year of follow-up data before the PMA was approved.16 The company went back and did an17 additional years worth of data that then presented18 the PMA to the FDA. And on June 5, 2001, the FDA19 approved the PMA. It was felt at that time that the20 pre-clinical and clinical data provided reasonable21 assurance that the safety and effectiveness of the22 Lap-Band system for weight reduction in the severely23 obese patients when the system was used according to24 its labeling.
  12. 12. 1 One of the other requirements that was 2 also made at that time was that the company do an 3 additional two years of data, for a total of five 4 years of follow-up in the post-approval forum. That 5 study is currently ongoing, and I would suspect it 6 should be done around the end of 2003. 7 The second device that I would like to 8 update you on is the Acticon Neosphincter by American 9 Medical Systems. This device was a fluid-filled10 silicone elastomer cuff, which is surgically implanted11 around the anal canal. It is used to treat severe12 fecal incontinence in males and females age 18 years13 of age and over and who have failed or are not14 candidate for less invasive forms of restorative15 therapy.16 This device came before the advisory panel17 on August 17, 2001. At that time, the panel18 recommended approval with conditions. The conditions19 involved need for additional revised position patient20 labeling. They wanted to alter the indications for21 use so that it restricted the use of the device to 1822 years of age and older. They wanted a development of23 a formal physician training program, and they also24 wanted to see a post-market study out to 12 months.
  13. 13. 1 On December 18, 2001, that PMA was 2 approved. The conditions were met. A post-approval 3 study was implemented, and that study is currently 4 ongoing, requiring additional 12-month post-approval 5 data, which has seen both safety and effectiveness 6 information looking at the effectiveness of FISS 7 scores and fecal quality of life measures and looking 8 at adverse events with particular emphasis looking at 9 the revision surgeries that have been necessary and10 any explantations of the device and following up on11 those patients.12 I would like to know if anyone has any13 questions on these two PMAs at this time. If not,14 thank you very much. And I turn it back over to you,15 Jeff.16 DR. COOPER: Thank you, Dr. Neuland.17 Before we begin, I would like to read as18 statement concerning appointments to temporary voting19 status, "Pursuant to the authority granted under the20 Medical Devices Advisory Committee charter dated21 October 27, 1990 and as amended August 18, 1999, I22 appoint Nicholas Shaheen, Mark Ferguson as temporary23 voting members of the Gastroenterology and Urology24 Advisory Panel for this meeting on January 17, 2003.
  14. 14. 1 "For the record, they are special 2 government employees and consultants to this panel or 3 other panels under the Medical Devices Advisory 4 Committee. They have undergone the customary conflict 5 of interest review and have reviewed the material to 6 be considered at this meeting," signed David W. Figal, 7 Jr., M.D., MPH, Director, Center for Devices and 8 Radiological Health. 9 The following announcement addresses10 conflict of interest issues with this meeting. And it11 is made a part of the record to preclude even the12 appearance of an impropriety. To determine if any13 conflict exists, the agency reviewed the submitted14 agenda for this meeting and all financial interests15 reported by the committee participants.16 The conflict of interest statutes prohibit17 special government employees from participating in18 matters that could affect their or their employers19 financial interests. However, the agency has20 determined participation of certain members and21 consultants, the need for whose services outweighs the22 potential conflict of interest involved, is in the23 best interest of the government.24 We would like to note for the record that
  15. 15. 1 the agency took into consideration matters regarding 2 Drs. Afifi, Achem, Fennerty, Manyak, Shaheen, and Dr. 3 Woods. 4 Drs. Afifi, Fennerty, and Manyak reported 5 current or past interest in firms at issue but matters 6 not related to todays agenda. The agency has 7 determined, therefore, that they may participate fully 8 in the panels deliberations. 9 Drs. Achem, Fennerty, Shaheen, and Woods10 reported past and or current involvements in firms at11 issue for matters related to todays discussions.12 However, because of the nature of these involvements,13 the agency has determined that these panelists may14 also participate fully in all deliberations.15 In the event that the discussions involve16 any other products or firms not already on the agenda17 for which an FDA participant has a financial interest,18 the participant should excuse him or herself from such19 involvement. And the exclusion will be noted for the20 record.21 With respect to all other participants, we22 ask in the interest of fairness that all persons23 making statements or presentations disclose any24 current or previous financial involvement with any
  16. 16. 1 firm whose products they may wish to comment upon. 2 On another note, we have the test of the 3 2003 tentative panel meeting dates. They are Friday, 4 April 4, 2003; Friday, July 25; and Friday, October 5 17, 2003. These are very tentative. 6 Also on your desk, there are two handouts. 7 One of them, for the panelists, has the blue cover. 8 That has most of all of the handouts. It has a table 9 of contents. The only thing missing is the sponsors10 presentation, which is this package, which is11 separate.12 Dr. Woods will now continue the meeting.13 OPEN PUBLIC HEARING14 CHAIRPERSON WOODS: Okay. Were going to15 now proceed with the open public hearing part of this16 meeting. If there is anyone here who wishes to17 address the panel, I wish you would raise your hand18 now. And you may have an opportunity to speak.19 I will ask of you at this time that if you20 do come forward to address the panel, that you speak21 clearly into the microphone, as the transcriptionist22 is dependent upon this as a means of getting an23 accurate transcription of the proceedings of this24 meeting.
  17. 17. 1 Before making your presentation to the 2 panel, you will need to state your name and your 3 affiliation and the nature of any financial interest 4 that you may have in the topic that you are going to 5 present. Each presenter is allotted ten minutes. And 6 if you would please provide a copy of your remarks and 7 any visual aids to the transcriptionist? 8 Does anyone wish to address the panel at 9 this time?10 (No response.)11 OPEN COMMITTEE DISCUSSION12 CHAIRPERSON WOODS: Okay. If there is no13 public statement to be made, then we will proceed to14 the open committee discussion. We will start with the15 sponsors presentation of PMA P00020006 for the16 Enteric Medical for the Enteryx device for the17 treatment of GERD.18 Again I ask that all persons addressing19 the panel please come forward to the microphone and20 speak clearly as the transcriptionist is dependent21 upon this as a means of providing an accurate22 transcription of the proceedings of the meeting.23 Before making your presentation to the panel, please24 state your name and affiliation and the nature of your
  18. 18. 1 financial interest in that company. 2 I remind you that the definition of 3 financial interest in the sponsor company may include 4 compensation for time and services of clinical 5 investigators, their assistants, and staff in 6 conducting the study and in appearing at the panel 7 meeting on behalf of the applicant, a direct stake in 8 the product under review; for instance, inventor of 9 the product, patent holder, owner of shares of stock,10 et cetera, or owner or part owner of a company. Of11 course, no statement is necessary from employees of12 that company.13 I would like to also remind the panel that14 they may ask for clarification of any points included15 in the sponsors presentation. I would like to16 suggest that we allow each speaker to complete their17 talk and then we save questions for the end of each18 individual speaker unless there is something19 overwhelmingly necessary to comment on on a particular20 table or graph.21 So the first speaker, as listed on the22 agenda, is Alan Stein, Ph.D., President and Chairman23 of Enteric Medical Technologies. He will speak on the24 company device description and pre-clinical studies.
  19. 19. 1 Dr. Stein? 2 1. SPONSOR PRESENTATION 3 DR. STEIN: Good morning, members of the 4 panel and FDA. My name is Alan Stein, as noted. I am 5 president of Enteric Medical Technologies. We are 6 very pleased to have the opportunity today to review 7 with you the results of our clinical trials on 8 Enteryx. 9 First slide. After a brief overview of10 the company of the description, we will review some11 detail provided by Dr. Luke Brennecke. Following12 that, we will have a review of the entire clinical13 study design, the results in terms of safety and14 efficacy by Drs. Glen Lehman and David Johnson.15 Finally, I will make some concluding remarks.16 Next slide. In addition, to further17 answer any questions the panel may have, we have18 available to us today: Dr. William Wustenberg, a19 toxicologist; John Kennedy, our biostatistician; and20 Jill Visor, who is our vice president and director of21 clinical and regulatory affairs.22 Our company was formed several years ago,23 in June of 1998, to develop minimally invasive24 procedures for GI disorders. About a year later, we
  20. 20. 1 did our first patient and performed a pilot study 2 under the supervision of Dr. Jacques Deviere at the 3 Frie University in Brussels. 4 In April 2000, an ID study that was 5 developed in conjunction with the FDA was initiated. 6 In May, we received the CE mark and have been actually 7 performing studies in Europe on Enteryx parallel to 8 those in the United States. In June of 2000, it 9 should be noted that the company was acquired by10 Boston Scientific Corporation.11 Next slide. The studies today that we12 will describe are for the following intended use.13 That is, specifically, Enteryx on the basis of these14 studies we claim is indicated for endoscopic injection15 into the lower esophageal sphincter for the treatment16 of GERD.17 The material is a biocompatible polymer in18 a liquid solvent with a radiopaque marker.19 Specifically, the biocompatible polymer is20 Ethylene-Vinyl Alcohol. Its a simple copolymer made21 up of polyethylene and polyvinyl alcohol, both of22 which have been individually in use in medical23 applications for decades.24 Polyethylene, as you know, is extensively
  21. 21. 1 used in orthopedic implants. And polyvinyl alcohol 2 has been extensively used for vascular embolization, 3 most recently approved in a product called Bead Block. 4 The liquid solvent is dimethyl sulfoxide. 5 DMSO has had numerous medical applications, ranging 6 from treatment of intercranial hypertension to 7 interstitial cystitis. And two products on the 8 markets using DMSO are RIMSO and Cystistat. 9 Finally, the radiopaque marker is10 tantalum, an element with a high electron density that11 has been used extensively as a marker in terms of12 coding or specifically as beads and powders for13 radiographic localization. And many products,14 including Strecker stent and J&Js Trufill Tantalum15 Powder, have been on the market again for years.16 The history of use of this product is17 actually fairly substantial because this type of18 material was first vascular embolization in 1996 under19 the name of something originally called Embolyx, now20 called Onyx, not manufactured by this company.21 It received a CE mark in 1999. And since22 then, over 3,500 procedures have been performed in23 treatment of various vascular abnormalities, including24 cerebrovascular AVMs, aneurysms, and various
  22. 22. 1 peripheral vascular neuropathies or abnormalities. 2 And in these applications, these vascular 3 applications, there has been significant long-term 4 follow-up, demonstrating excellent patient tolerance, 5 the stability of the implant, and a lack of migration. 6 In this application for treatment of GERD, 7 the Enteryx is provided as a kit, including a 8 sclerotherapy-type injection catheter that is 9 compatible with DMSO; two DMSO-compatible syringes;10 and a bottle of Enteryx, which is noted on the left; a11 10 cc bottle and a bottle of primer, which is actually12 DMSO that is used to pre-fill the catheters to make13 sure that there is no fluid unintentionally in the14 catheter that could result in inadvertent15 precipitation of the material within the catheter;16 therefore, blocking it. Its just a primer.17 Next slide. In this picture, you will see18 that Enteryx is actually a very low-viscosity19 solution, allowing us to inject to as small as a 23-20 gauge needle, which is actually what is used in the21 injection catheter. On contact with fluid or body22 tissue, the ethylene vinyl alcohol and tantalum23 precipitate together as a spongy mass as the DMSO is24 dissipated within the tissue.
  23. 23. 1 Next slide. There has been extensive 2 biocompatibility testing of the product, particularly 3 per the requirements of ISO 1099, for permanent 4 implant devices. And these have all been passed 5 successfully for cytotoxicity, systemic toxicity, 6 intracutaneous reactivity, hemocompatibility, 7 genotoxicity, and carcinogenicity. 8 Now, we did note -- and this should not be 9 surprising -- in the seven-day rabbit muscle implant,10 there was a demonstration of an acute tissue response,11 but this would be for the discussion issues when we12 get to the point of reviewing the histology over time.13 In collaboration with the FDA, the sponsor14 performed an extensive additional carcinogenicity15 study in order to determine whether there would be any16 long-term effects from this new implant material that17 were not initially anticipated. This study was18 designed in conjunction with FDAs toxicology staff,19 who gave us a great deal of guidance.20 Again, the study was coordinated by Dr.21 Bill Wustenberg on our side; Dr. Raju Kammula; and Dr.22 Nermal Mishra at the FDA. In the study, 40023 transgenic and wild-type mice were used. And, just to24 summarize it, though numerous animals in
  24. 24. 1 positive/negative controls were studied, there were no 2 Enteryx-treated animals that develop tumors at any of 3 the injection sites. 4 And, similarly, the background 5 carcinogenesis rates were identical. The Enteryx used 6 that for the controls. The conclusion of this 7 extensive transgenic mouse study is that Enteryx is 8 non-carcinogenic. 9 Now, moving into the esophageal10 pre-clinical studies, a safety and technique study was11 performed at the Indiana University with Dr. Glen12 Lehman. In the primarily acute study, 16 dogs were13 studied in order to really understand what type of14 safety issue could be involved with an injectable15 product in the area of the LES as well as to optimize16 technique.17 In terms of the safety, a series of18 intentional transmural injections with long needles19 were placed above and below the LES. We found, very20 satisfyingly, that intraperitoneal and subserosal21 implants had actually a minimal tissue reaction. And22 most comforting was that, even when intentionally23 injected into the lungs and pleura, there was minimal24 adjacent fibrosis in the animals, already at least
  25. 25. 1 quite well. 2 Several of the animals in the study were 3 maintained for up to a year. And on necropsy, there 4 was minimal physical adjacent tissue reaction. And 5 there was absolutely no evidence of migration of this 6 material outside of the injection sites. 7 Now, in terms of the long-term 8 pre-clinical study, this was performed at the 9 University of Southern California under the10 supervision of Dr. Jeff Peters and in the department11 of Dr. Tom DeMeester.12 Fifteen Yucatan minipigs were13 endoscopically injected with Enteryx. These were14 small animals at the time. They were only 30 to 4015 pounds. So they actually had quite large injections16 of one to one and a half cc injected in three to four17 different sites, totalling up to four cc per animal.18 These were sacrificed in various time19 points up to one year. And in addition to the20 histology studies performed on these animals, there21 were additional functional studies performed in a22 subset to give us an indication, though, of a kind of23 a mechanism of action that we can anticipate, even24 though a pig model is not really valid for any type of
  26. 26. 1 a GERD baseline. By the way, these results were 2 published in Surgical Endoscopy. 3 There were no complications observed in 4 the treatment of any of the animals. They all ate. 5 They never had any dysphagia types of problems. They 6 gained weight and actually by the end of a year became 7 quite large. And there were no other behavioral 8 changes. 9 Histologically we will discuss this in10 detail in a few minutes, but it was demonstrated, in11 summary, that there was an evolution from what is not12 expected, an acute inflammatory response identical to13 that seen in the 70 rabbit studies leading to a14 chronic foreign body reaction that had well-delineated15 fibrous capsules by as little as 12 weeks, actually16 even sooner.17 Now, in terms of the functional studies,18 it was interesting that Dr. Rodney Mason, you know,19 who is actually focusing on these functional studies,20 identified that LES length and pressure were not21 affected, but yield pressure was improved. Actually,22 some of these yield pressure studies that I was23 involved with demonstrated really substantial24 increases in the yield pressure.
  27. 27. 1 And, as a result, -- next slide, please -- 2 it was suggested that the mechanism of action in this 3 application would be through a modification of the 4 compliance to the LES and that this modification of 5 compliance was due to the volume and mechanical 6 properties of injected material, not unexpectedly, as 7 well as the fibrous encapsulation of the material as 8 it was stabilized in the tissue. Together these two 9 parameters would then result in a decreased10 distensibility of the cardia, preventing sphincter11 shortening during gastric distension.12 Now, in addition, Dr. Peters did a very13 interesting study for us because as we moved into14 humans, we wanted to make sure that we were15 understanding the correlation between the endoscopic16 and the fluoroscopic appearances of the injection17 material.18 Remember, there is tantalum in this, and19 this is very effective in guiding the localization of20 the implant. These are not blind injections by any21 means.22 This paper was accepted for publication23 and should be out imminently. In nine patients who24 were undergoing surgery for cancer, we did a series of
  28. 28. 1 implants in them and had the opportunity after the 2 pathologist had finished checking the margins to 3 review the location of the implant and actually 4 perform correlation of the implant to the endoscopic 5 images as well as the fluoroscopic images that were 6 acquired. 7 I believe the numbers off the top of my 8 head are something like of the 80-odd implants that 9 were done in these patients, Jeff was able to recover10 about 95 percent of them in and along the muscular11 layer and 1 or 2 or 3 went transmurally and were12 sitting on the serosal side of the esophagus. They13 hadnt migrated anywhere. Of course, in this short14 term, there were no complications to the procedures.15 It really was a very, very helpful guidance for16 training issues associated with the use of the17 product.18 Next slide. At this point, I would like19 to turn the talk over to Dr. Luke Brennecke. Luke is20 a worldwide authority on medical device pathology, and21 he is the director of such efforts at Pathology22 Associates, which is a Division Charles River Lab.23 Dr. Brennecke and Pathology Associates24 provided an independent assessment of the
  29. 29. 1 histopathology. He will review the course of the 2 evolution from an acute to a chronic inflammatory 3 response that we discussed just a moment ago. 4 CHAIRPERSON WOODS: Before you turn it 5 over, could I ask the panel if they have any questions 6 for you regarding your statements? I have a question. 7 DR. STEIN: Okay. 8 CHAIRPERSON WOODS: The vascular 9 indications for this product, can you compare the10 volume that is typically injected for the vascular11 indications as compared to the volume injected for the12 GERD indications?13 DR. STEIN: Approximately, yes. The14 company who is doing this is a company called15 Microtherapeutics. Microtherapeutics for16 cerebrovascular applications injects on the order of17 one to one and a half cc of material to fill an AVM.18 Their product, as I mentioned, is CE19 approved in Europe but is under an ID investigation in20 the United States. However, in some of their other21 applications that they are under investigation to do,22 particularly larger dissecting aneurysms and so on,23 theyre putting it 8, 10, 20 cc.24 So there are some very substantial amounts
  30. 30. 1 of material that are under evaluation, other 2 applications than cerebrovascular AVMs. In the AVMs, 3 of which that 3,500 cases is the most, thats on the 4 order of one to one and a half cc, about what we 5 recommend to do in one quadrant of the LES during the 6 injection for the treatment of GERD. 7 CHAIRPERSON WOODS: Thank you. 8 Any other questions? Dr. Ferguson? 9 DR. FERGUSON: I have a question, Mr.10 Stein. The last study that you described that Dr.11 Peters did in the esophagectomy patients, could you12 just give us some idea of the time frame between the13 injection and the esophagectomy procedure?14 DR. STEIN: It was really that in giving15 their consent, the patient was prepared for surgery.16 They were scoped and treated immediately prior to the17 surgery. The injections were done. We collected the18 material. I would say that the procedure might have19 taken at most 30 minutes. And they he continued on20 with the esophagectomy. So I would say that the21 material was, shall we say, available, on the table, a22 couple of hours later.23 CHAIRPERSON WOODS: Other questions? Dr.24 Achem?
  31. 31. 1 DR. ACHEM: Dr. Stein, in this model of 2 esophagectomy, I believe there were four patients that 3 the injection went transmural -- 4 DR. STEIN: Thats correct. 5 DR. ACHEM: -- according to the data that 6 you present on the paperwork. Are there any concerns? 7 I mean, these are patients that were injected by an 8 experienced individual working in the laboratory. 9 What were your comments regarding the transmural10 injection?11 DR. STEIN: Part of the training -- this12 is a great question. When the material is injected13 endoscopically, you have a lot of feedback with this14 product. As you saw in the little video, the material15 comes out as a black spongy mass. When the material16 is injected superficially, you can send -- I actually17 think you could have a reiteration of this by Drs.18 Johnson and Lehman because they have been doing this19 procedure to great success.20 Superficial injections, you can see them.21 There is bulging on the mucosa side, and its black.22 You can see a discoloration due to the tantalum. This23 generally is guidance that the material is too24 superficial and will have a high probability of
  32. 32. 1 sloughing. 2 When they are in an appropriate position; 3 that is, deep in and along the muscle layer, they have 4 a rather distinct fluoroscopic appearance. Often they 5 flow in arcs, but they make distinct blebs. And there 6 is very little bulging in the mucosal surface, giving 7 us a good indication that it is deeper. 8 When they go transmural, since the 9 material is not being incorporated into tissue, the10 X-ray density, at least in my opinion, is quite more11 intense and often forming thin lines as the material12 runs briefly along the outside of the esophagus.13 Actually, in Jeffs patients, when he did the14 esophagectomy, the material was just binding right to15 the outside. It was just adherent right along the16 outside of the esophagus.17 CHAIRPERSON WOODS: Yes, Dr. Manyak?18 DR. MANYAK: Hi. I have a question, just19 a clarification probably, on a little bit of your tox20 studies regarding the DMSO.21 DR. STEIN: Yes?22 DR. MANYAK: I heard you state that you23 did these tox studies in conjunction with the FDAs24 advice.
  33. 33. 1 DR. STEIN: The carcinogenicity studies, 2 sir. 3 DR. MANYAK: Right. Well, I was just 4 curious about the DMSO. Any of us who have worked 5 with that in the laboratory know that that is not 6 something that is very good to have inside of the body 7 very much. And so I was curious. 8 In your clinical studies, it shows a bad 9 odor and a bad taste to the mouth about five percent10 of the time. That may be related to the DMSO. Im11 just curious what was done to determine the toxicity12 of the DMSO aside from -- I dont know that13 particulate assay that you used. And Im just14 curious. Does that answer the question for toxicity15 on DMSO?16 DR. STEIN: DMSO has actually been in use17 for decades. As a urologist, I believe you have18 probably used products like RIMSO for treatment of19 interstitial --20 DR. MANYAK: Yes. The only problem with21 that is that stays within the inter-vesicle. It does22 not enter the systemic circulation purportedly.23 DR. STEIN: But, actually, all DMSO enters24 systemic circulation because it goes across the tissue
  34. 34. 1 and is excreted primarily through the kidneys and as 2 exhaled product, breakdown products, being mainly 3 dimethylsulfide and dimethylsulfone. 4 The sulfur components on DMSO give it the 5 garlicky flavor. Actually, any of you can go to a 6 health food store and go buy DMSO because its one of 7 the most common officially unapproved uses for 8 arthritis. And any use of DMSO, whether you rub it in 9 your hands, whether you instill it in a bladder, all10 of it will be excreted in the same manner, whether11 its injected or not.12 In DMSO applications, I believe you put in13 50 cc bottles at a time. You can put multiple bottles14 of those. In this application, we inject 10 cc.15 The LD50s on DMSO have been published for16 decades. And theyre nearly as extraordinary as17 matter. I once calculated for my weight, I would need18 to drink maybe a liter and a half of material. So the19 fact that five patients, Dr. Manyak, said that they20 had bad breath, all patients in their informed consent21 were advised that they would have a garlicky smell.22 Five patients wanted to comment on it in23 their compulsion to report every adverse event and24 comment. We listed those in addition. But this may
  35. 35. 1 come up in a different context. There is no way to 2 hide the fact that a patient was treated with Enteryx 3 because they all have a garlicky smell. Every patient 4 knows this. 5 CHAIRPERSON WOODS: I have a question, Mr. 6 Manyak. 7 DR. MANYAK: Thank you. Thats fine. 8 CHAIRPERSON WOODS: I have one other 9 question as well. You have referred in the animal10 models about the sloughing of the mucosal or11 submucosal injections of the material. And there are12 many references to that throughout the data as well.13 Can you tell us exactly how you know with14 certainty that that material was sloughing off and15 passing through the digestive tract? Did you see it?16 DR. STEIN: No.17 CHAIRPERSON WOODS: Did you hold it in18 your hand in the autopsy? How did you know that it19 sloughed?20 DR. STEIN: Okay. I will give you some21 indications. And, again, I would like to turn this22 and ask Drs. Johnson and Lehman to speak about the23 experience that they have.24 We can follow this material very clearly
  36. 36. 1 on X-ray. So if you make four circumferential 2 injections and you look at these patients on X-ray a 3 month later and you see three, this is not a 4 resorption issue. This is a slough. 5 CHAIRPERSON WOODS: What proof do you have 6 that it can slough? 7 DR. STEIN: Because, actually, on some of 8 the scoping that has been done, -- and, again, I would 9 like to defer this question to Dr. Lehman because he10 will give you a better conversation -- you can11 actually see sometimes depending how near your12 endoscopy is to the actual slough the erosion. And13 there will be some black material in it. And14 sometimes you will see the black material mostly gone.15 And then if you come back a little later, you will see16 it smoothed over as the erosion surface has healed.17 In addition, there have been X-ray studies18 that we have done on the animals actually looking to19 determine whether the material is still in the --20 actually, it is is still in the LES, but on some of21 the animals that Dr. Lehman looked at, he did whole22 body X-rays. There is no other implant anywhere else23 but there.24 So when you have sloughing of any material
  37. 37. 1 into the esophageal lumen, I can only say it was not 2 possible to get patients to, shall we say, collect 3 their samples for the next couple of months to 4 actually recover material, but on X-ray, since this 5 material is so radiopaque, you cant see anything in 6 any of the images that we have from the abdomen and 7 pelvis. 8 CHAIRPERSON WOODS: And in the animal 9 model, I believe the pigs were sacrificed, some of10 them on day three? Is that correct?11 DR. STEIN: The actual animals that we did12 for the histological review were at two weeks and so13 on. But when we worked with Dr. Peters early on, we14 also were assessing in two laboratories in parallel15 with Dr. Peters as well as that of Dr. Lehman16 injection techniques.17 So some of those animals were killed very18 quickly. And those animals, sometimes you could19 absolutely look at those animals during the growths20 and say, "That one is going to come off."21 In fact, we talk about it internally as22 very much like what you see with a pizza burn. I23 mean, this is all gastrointestinal mucosa. When you24 have enough of a division because of an implant of
  38. 38. 1 material of the mucosa away from the blood supply, 2 some pizza burns go down. Most of them peel off. And 3 when the top peels off, the implant falls out. So 4 its really no different than any other form of 5 healing in the gastrointestinal system. 6 CHAIRPERSON WOODS: Thank you. 7 Any other questions from the panel? 8 (No response.) 9 CHAIRPERSON WOODS: Okay. Thank you.10 2. HISTOPATHOLOGY REVIEW: PRE-CLINICAL STUDIES11 DR. BRENNECKE: Good morning, members of12 the panel and FDA. I am Dr. Luke Brennecke. I am13 being paid this morning by the sponsor as a consultant14 veterinary pathologist. I have no financial or equity15 interest in Enteric Medical Technologies or their16 parent company.17 Next slide. This morning I am going to18 briefly discuss the results of the histopathology19 examination of the tissues that were sacrificed from20 three months to one year. First of all, I would like21 to show you, however, the area of the LES from one of22 the animals that was sacrificed at 12 months.23 In these slices, you can see various foci24 of black. Theyre well-circumscribed. They look like
  39. 39. 1 blebs or blobs of material. Theyre highly 2 demarcated. Theyre also in some cases surrounded by 3 a very precise, well-delineated capsule. 4 If you looked at animals that were 5 similarly sacrificed at earlier time points, as early 6 as six weeks, you can also see a virtually identical 7 picture with the absence of the thick capsules. 8 Next picture. The first photomicrograph 9 is from an animal that was sacrificed at two weeks.10 To help orient you here, we have the lumen of the11 esophagus up here, the squamous epithelium, the12 submucosa, the inner circular layer, the layer of13 fibrous tissue between the inner circular layer, and14 the outer longitudinal layer of muscle.15 In this photomicrograph, there are two16 sites of injection. They actually may have been part17 of the same site in an adjacent or nearby slice.18 Notice in this section that the normal fibrous19 connective tissue band between the muscle layers is20 slightly thickened due to the space occupying21 injections here.22 Of note, what we want to look at is the23 blue is collagen and fibrous tissue. The red are24 pink, are cells. So we see two highly demarcated,
  40. 40. 1 well-circumscribed areas of injection surrounded by 2 blue. And in this one as well as this one, we note 3 that there are some pink cellular infiltrations around 4 the outside of the injection site. We will next be 5 looking at this area right here magnified. 6 At this magnification, we can more easily 7 see the well-circumscribed area of the blue fibrous 8 tissue. We dont see the embolics or tantalum spread 9 out in here. We can see that these large spaces10 consist of the EDOH. Intermixed within is the black11 tantalum. Around the outside, we start seeing12 macrophages, activated macrophages, and giant cells.13 We also see processes of these cells going down,14 interdigitating around these blebs of injected15 material.16 Next slide, please. At three months, here17 is the lumen, the squamous mucosa of the esophagus.18 This is the layer of muscle that is just beneath the19 layer of squamous epithelium, the muscularis mucosa.20 This injection site was put just a little bit more21 superficially than the last one so that the muscularis22 mucosa has been a bit defaced by fibrosis in this23 area. So its within the inner circular layer of24 muscle tissue.
  41. 41. 1 Note that as in the previous sacrifice 2 period, it is well-demarcated, surrounded by fibrous 3 tissue. The other thing to note in this case is that 4 there is a lot more pink and red material down within 5 the injection site, representing inflammatory cells. 6 The previous slide we looked at, the 7 inflammation was moving from an acute phase, in which 8 we saw neutrophils merging in with macrophages, 9 activated macrophages, and giant cells. At this10 point, we see mostly giant cells and macrophages.11 This is part of the normal progression of virtually12 any type of implant from acute to chronic13 inflammation. We will next be looking at the higher14 magnification.15 Here we see a bit of the muscle layer up16 here. This is native tissue up here, as evidenced by17 the larger blood vessels. Note that there is a18 well-demarcated area around the outside, large numbers19 of macrophages, giant cells, and some clumped20 tantalum, as well as the spaces representing the EDOH.21 Also of import here, note that the fibrous connective22 tissue and fibroblasts have started to invade the23 injected material, stabilizing it.24 Another thing of import here is that there
  42. 42. 1 is a lack of any type of tissue destruction along the 2 outside. If we saw any type of necrosis or tissue 3 destruction, instead of the blue collagen and fibrous 4 connective tissue, as well as the fibroblasts, we 5 would expect to see a pink amorphous acellular thin 6 layer. 7 I will also note in the previous large 8 focus, I did not find any areas of calcification. 9 Sometimes calcification is seen with tissue10 destruction. But in the injection sites that I have11 looked at throughout this study, the calcification was12 very, very, very minimal, sometimes not much larger13 than a couple of these five-micron tantalum pieces.14 Next, please. At six months, again, we15 have the lumen out here, squamous mucosa. This is a16 little deeper into the submucosa. We have a17 well-demarcated area. Again, we have fairly large18 numbers of inflammatory cells, macrophages, and giant19 cells. And we are going to look at this area right20 here.21 There is not much difference between this22 and the last slide except that there are, again, large23 numbers of macrophages and giant cells. Around the24 outside, it is a very quiescent appearance with a very
  43. 43. 1 bold interface between the surrounding fibrous 2 connective tissue and the injection site. 3 Next slide. This animal was sacrificed at 4 one year. Were in a little bit different location. 5 Were a bit lower here. Notice that the mucosa along 6 the margin consists of normal columnar epithelium, 7 rather than the squamous epithelium we looked at 8 previously. 9 Notice also that this injection site was10 much more superficial than the previous ones. Here is11 another well-demarcated injection site over here.12 Again, these may have been part of this same one in13 another field.14 The muscularis mucosa is partially15 replaced by fibrous connective tissue, but it is16 overlain by healthy columnar epithelium. Notice also17 you can barely see it in this picture, but down in18 this corner down here are a couple of more pieces of19 injected material.20 Notice from this magnification you cant21 see any inflammatory cell infiltrate whatsoever. As a22 matter of fact, in much of this injection site, as23 this one, you see very few inflammatory cells.24 Notice also from this magnification you
  44. 44. 1 can see a blue hue throughout much of this site here 2 representing fibrous connective tissue within the 3 site. 4 Next slide. In this photomicrograph, we 5 see that there are very few inflammatory cells around 6 the outside of there. There is a bold interface 7 between the injection material and the fibrous 8 connective tissue, indicating that there is virtually 9 no ongoing reaction whatsoever. Notice also there is10 a lot of collagen and fibrous connective tissue within11 the implanted area itself.12 Next. In summary, I would like to point13 out that there was early and persistent fibrous14 encapsulation. We saw fibrous encapsulation beginning15 as early as two weeks. What we saw was the normal16 progression from acute to chronic inflammatory17 response.18 This is the same type of response that one19 would have seen in the rabbit lumbar muscle implant20 study. It is also commonly the same type of21 inflammatory action that you would see in any other22 type of implant, whether it be sutures, Dacron, or23 hard materials.24 The tantalum was completely stable. I was
  45. 45. 1 unable to find tantalum in any blood vessels, in any 2 lymphatics, regional lymph nodes, or any indication 3 that this tantalum is moving to other areas. 4 There is very, very minimal dystrophic 5 mineralization or calcification, which is not to say 6 there is none. I saw a very minimal dystrophic 7 calcification as early as two weeks, and I saw it as 8 late as one year. The important thing here to 9 remember is that there was no increase in the amount,10 in the relative amount, of mineralization as we11 progressed from the acute to the chronic phase.12 So, based on these observations, I would13 have to conclude that there are no adverse sequelae to14 the injection of Enteryx.15 CHAIRPERSON WOODS: Questions from the16 panel? Dr. Fennerty?17 DR. FENNERTY: Dr. Brennecke, do you mind18 backing up just two slides to your high-powered19 histomicrograph review? Go forward one towards the20 end. I actually am intrigued because you comment on21 very little inflammatory changes. Of all of these22 high-powered views, I dont see any inflammatory23 changes. There is not a single poly in that field. I24 realize we are looking at one section, but can you
  46. 46. 1 quantify? 2 I mean, this seems like this is as normal 3 a carrying from an inflammatory response as normal 4 tissue is. Did you -- 5 DR. BRENNECKE: The polys resolve very 6 quickly and move from the acute inflammatory phase 7 very early on. You will occasionally see 8 polymorphonuclear cells as late as a year. You have 9 to look pretty hard to find them.10 In the center of these injection sites,11 you will see larger numbers of macrophages and giant12 cells that are still around, indicating that it takes13 a longer time, regardless of what type of material.14 You have inflammatory cells in the center of a15 granuloma, for example, even a tuberculosis granuloma.16 Those will resolve much, much more slowly17 than those around the edge. In this case, the18 stimulus for any type of inflammatory reaction has19 pretty well gone.20 DR. FENNERTY: Well, I guess that is what21 I am trying to get at. From my looking at these22 histophotographs and micrographs that you are showing,23 there dont appear to be any mucosal based product24 inflammatory changes, but you report that in your
  47. 47. 1 summary that you have minimal chronic inflammatory 2 changes. Is it none or is it -- 3 DR. BRENNECKE: If you take the technical 4 definition of chronic inflammation, that includes 5 fibrosis. Fibrosis is an ongoing sequelae of chronic 6 inflammation. If you look in these things, you will 7 find, again, macrophages and you will find some 8 lymphocytes. These are what you normally see in 9 chronic inflammation.10 CHAIRPERSON WOODS: Other questions from11 the panel? Dr. Achem?12 DR. ACHEM: Could you comment on the13 extent of the material distributed through the lower14 esophageal sphincter? Im interested specifically if15 you could tell us in your slides when you did the16 cuts. Did you encounter any material above or below17 the lower esophageal sphincter area or was it all18 confined only into that area?19 DR. BRENNECKE: Well, I will say that I20 did not look at the entire esophagus, nor did I look21 at the entire stomach. I trimmed in the areas that22 showed one. I was mostly interested in the area of23 injection, the lower esophageal sphincter.24 Grossly, if I did not see anything several
  48. 48. 1 centimeters above the injected area, I did not do 2 histopathologic review on those, nor did I do a review 3 on other portions of the stomach. 4 These injection sites for the most part 5 are very easily visualized grossly. Some small ones, 6 which have perhaps been pinched off as the fibrosis 7 around them becomes more mature or not as easily seen 8 grossly, is pretty well-defined to the injected areas. 9 DR. ACHEM: If I may, just a follow-up10 question. Could you comment on the amount of the11 material injected in terms of a correlation between12 the amount injected and the degree of13 histopathological changes that you see?14 DR. BRENNECKE: Well, sir, I did not do a15 volumetric evaluation. Such evaluation would be16 possible doing sequential sections and doing17 histomorphometry. That was not done on these. And I18 was given no information as to how much was injected,19 nor of the type of volume to expect at histopathology.20 CHAIRPERSON WOODS: Other questions? Dr.21 Ferguson?22 DR. FERGUSON: Dr. Brennecke, I have two23 areas I have questions about, I should say. One, is24 the heterotopic or dystrophic calcification. You
  49. 49. 1 stated that it is a fraction of a percent in the 2 report. Yet, the illustration that is included in the 3 material shows a fairly sizeable collection of calcium 4 in one of the specimens. I gather that that was an 5 exception to what you saw otherwise? 6 DR. BRENNECKE: There were a couple of 7 areas in which I would say it reached maybe perhaps a 8 half a millimeter in diameter. That is about the 9 largest you can expect.10 DR. FERGUSON: What would the normal time11 course be of the development of dystrophic12 calcification in a foreign body like this?13 DR. BRENNECKE: Dystrophic calcification14 normally occurs -- well, it can be seen in anything,15 icy dystrophic calcification, in everything from16 arteries to hearts to intestines, all sorts of things.17 So dystrophic calcification can occur for18 a variety of reasons. Normally as a result of19 necrosis, the calcium salts form within the20 mitochondria of the dead and dying cells. Those dead21 and dying cells are accumulated together and are22 phagocytized or broken down by a further number of23 inflammatory cells.24 If there is ongoing destruction of tissue,
  50. 50. 1 you may expect further destruction of cells and 2 further dystrophic calcification. In the areas we 3 have seen in the center of these foci, the tissue has 4 been either destroyed or moved out of the way by the 5 space-occupying injection or what cells are there have 6 been phagocytized and moved out of the way by the 7 inflammatory cells. 8 In the center of these injection sites, 9 there really are no cells to provide the10 calcification. Now we have an influx of cells, that11 being the fibroblasts, which secrete the collagen and12 the fibrous connective tissue, but there is no13 indication that they would be destroyed by the ongoing14 inflammatory reaction.15 DR. FERGUSON: So Im not sure what the16 answer was. In this situation, what would you expect17 the time course of the dystrophic calcification to be?18 DR. STEIN: The time course would be19 early, within a couple of weeks. And thats it. I20 mean, I wouldnt expect it to progress or proceed in21 any way. So what you see early on is about what you22 get.23 DR. FERGUSON: If I may, one other24 question. You have illustrated in your histologic
  51. 51. 1 preparations a number of different sites of 2 accumulation of the foreign materials, the submucosa, 3 the muscularis mucosa between layers of the muscularis 4 propria. Does this illustrate intended various sites 5 of injection or does it illustrate the difficulty in 6 achieving a correction injection into the muscularis 7 propria? 8 DR. STEIN: Well, I am not going to 9 comment on the injection because that is not part of10 my expertise. I will say, however, I have seen11 injection sites all the way from the submucosa out12 into the outer muscular layer.13 They all react about the same. They all14 represent space-occupying lesions. And the15 space-occupying lesion, which is part of the16 effectiveness of the drug, as I understand it, is not17 only a result of the material that is injected but18 also the fibrosis that results.19 CHAIRPERSON WOODS: Dr. Achem?20 DR. ACHEM: Thank you, Dr. Woods. Allow21 me to come back again to another issue, if I may. Dr.22 Brennecke, do you have any information you can share23 with us regarding the state of the nerves, vagal24 trunks, whether any of these were involved and to what
  52. 52. 1 extent? 2 DR. BRENNECKE: I did not see any 3 involvement, any destruction of nerves in these areas. 4 There are nerves throughout here, as you well know. 5 If they are closed to the area of injection, they are 6 surrounded by fibrous connective tissue. And how that 7 affects their ongoing function I cant comment on. In 8 the middle of the injected area, by the time I saw the 9 tissue, they may have been destroyed. I also cannot10 comment on that.11 CHAIRPERSON WOODS: May I ask a question?12 In the two-week autopsy specimens, did you see in the13 gross specimens any evidence of the mucosal sloughing14 theory in terms of the loss of the submucosal or15 mucosally injected material?16 DR. BRENNECKE: I saw some that were very,17 very superficial. They were covered by a very small18 amount of epithelium, which may have been19 epithelialized that time, or it may be in the process20 of sloughing.21 I cant comment on whether it sloughed22 before I saw it or whether it would have sloughed had23 the animal been allowed to live, but I did not see any24 evidence of ongoing sloughing.
  53. 53. 1 CHAIRPERSON WOODS: Thank you. 2 Other questions? Yes, Dr. Gellens? 3 DR. GELLENS: How many animals did you 4 examine histologically like this at a year? 5 DR. BRENNECKE: I believe there were 6 three. Thats right. 7 DR. GELLENS: One other question. In some 8 of the other data, it mentions injecting this material 9 in other organ systems. Did you examine those also?10 DR. BRENNECKE: Yes, I did.11 DR. GELLENS: Did you see the same kind of12 reaction that you are seeing here?13 DR. BRENNECKE: Actually, not quite as14 remarkable a reaction. We didnt carry those out to a15 year, of course, but we saw some very localized16 inflammation. Thats about it.17 CHAIRPERSON WOODS: Other questions by the18 panel?19 (No response.)20 CHAIRPERSON WOODS: Thank you. We can21 move on to the next speaker.22 3. STUDY DESIGN AND RESULTS: SAFETY23 DR. LEHMAN: Good morning, panel members,24 FDA. My charge is to review the study design and
  54. 54. 1 report the safety outcomes. I must say that I have a 2 consulting arrangement with Enteric Medical and a 3 small equity interest in the company. And my way has 4 been paid here for todays presentation. 5 CHAIRPERSON WOODS: I will introduce you, 6 Dr. Lehman, for the transcriptionist. Most of us know 7 you. This is Dr. Glen Lehman. Can you just remind us 8 where youre from and other information pertinent to 9 yourself?10 DR. LEHMAN: I am professor of medicine11 and radiology at Indiana University Medical Center,12 Indianapolis.13 CHAIRPERSON WOODS: Thank you.14 DR. LEHMAN: A brief slide on history of15 endoscopic implantation for GERD. You must remember16 that this is not a new technique in the sense that we17 did the first lower esophageal sphincter implantations18 back in the early 1980s and we injected collagen and19 Teflon in both animals and patients. We saw limited20 and short-term help in controlling GERD.21 From our initial experience with these22 materials, we came up with a wish list of an ideal23 implant. That would be one which was chemically24 inert, non-carcinogenic, hypoallergenic, capable of
  55. 55. 1 resisting mechanical strain, capable of being 2 sterilized, capable of being delivered in liquid form 3 and then it would turn to a solid and a solid that 4 would be stable and persistent at the implant site. 5 Indeed, the current product today satisfies nearly all 6 of these criteria. 7 The procedure is designed to modify the 8 distensibility of the lower esophageal sphincter and 9 to reestablish the anti-reflux barrier. Its an10 outpatient procedure using standard endoscopic11 technique and standard fluoroscopic guidance.12 The needle, sclerotherapy-type needle,13 short needle, four millimeters, is passed through a14 standard scope, penetrating around the squamocolumnar15 junction, and one fluoroscopically monitors. Lets16 look at a short videotape of this.17 The sclero-type needle is advanced into18 the distal esophagus and punctured slightly19 tangentially into the deep submucosa or muscle layer.20 This would typically be right near the squamocolumnar21 junction. The injection would be made in four22 quadrants unless one gets a ring forming from a single23 injection, as happened in this case.24 And here we see passing the scope through
  56. 56. 1 the ringlike implant. Some contrast media will be 2 injected. And there will be impingement on the 3 contrast column as it passes through. And the patient 4 here has a small hiatal hernia. After the procedure 5 of the mucosa, we like the mucosa essentially intact 6 if implants have been deep in the wall. 7 Next, please. Lets look at several 8 examples of implants. Here again were seeing the 9 tantalum. The plastic itself is not visible. Here we10 have arc-like implant with several globular foci.11 Next. Here again a circular distribution12 of several globular implants.13 Next. Here we get the concept of four14 quadrant injections in globular fashion. Here the15 implants have a little more linear characteristic in16 the again three or four quadrant implant.17 Next. Here the implants have a little18 more linear contour and the scope passing through the19 LES.20 Next. And here we see the implants which21 have both the cardia position, globular. We see a22 little arch-like component right at the distal LES or23 squamocolumnar junction and then a more slender24 tubular component in the distal esophageal body.
  57. 57. 1 Next. Contrast medium swallowed shows a 2 pinch at the LES and the intramural implants. 3 Next. And afterward we see little focal 4 areas of mucosal trauma and a snug LES on retroflexed 5 view. 6 Next. Now, the study design was that of a 7 prospective study in well-characterized GERD patients. 8 Each patient served as their own control. Baseline 9 pretreatment parameters were compared to post-10 treatment outcomes over a 12-month study.11 Next. The null hypothesis for the study12 was that less than 50 percent of the patients would13 exhibit a clinically significant reduction in PPI use.14 And the alternative hypothesis was that greater than15 50 percent of patients would exhibit clinically16 significant reduction in PPI use.17 The sample size, calculated sample size,18 of 36 patients was required to achieve an 80 percent19 tower. However, we enrolled 85 patients to ensure20 adequate representative sample size and to account for21 patient dropouts.22 The primary objective for the study was23 elimination of PPI use or reduction of PPI use by24 greater than 50 percent. The secondary objectives
  58. 58. 1 were improvement in: GERD quality of life scores, 2 SF-36 general health survey scores, pH Probe results, 3 and manometry results. Significances were determined 4 by the Sign test and the Wilcoxon Signed Rank test. 5 Next. The investigators for the study are 6 shown here and represent a mixture of European 7 centers, Canadian centers, East Coast, Midwest, West 8 Coast, mostly gastroenterologists, one surgical 9 center, and then nicely a mix of community-based10 private practice centers and academic centers.11 Next. The inclusion criteria, only12 PPI-dependent patients were eligible for the study.13 And they were PPI-dependent as demonstrated by GERD14 symptoms controlled by PPI, as shown by Velanovich15 GERD quality of life scores less than 11 while taking16 drugs, symptom relapse of equal to or greater than17 nine-point worsening in Velanovich score, while off of18 PPIs, and documented acid reflux by 24-hour pH Probe19 of greater than 5 percent abnormal total time with a20 pH less than 4.21 The exclusion criteria were the same ones22 used for nearly all the endoscopic GERD therapy23 studies, namely bad erosive esophagitis, big hernias,24 Barretts, and so on.
  59. 59. 1 Next. Now, the study schedule involved 2 assessing symptoms in the baseline state while taking 3 their PPI; taking the patient off of PPIs for 10 to 14 4 days; and reassessing symptoms; and quantitating pH 5 and manometry; treating the patient; and then 6 non-invasively evaluating the patient at 1, 3, 6, and 7 12 months; and invasively assessing the patient at 6 8 and 12 months. 9 There were 85 patients enrolled, 5810 percent male, mean age about 50 years, nearly all11 Caucasian, body mass index, mean of 20. There were 1412 protocol deviations in the inclusion/exclusion13 criteria, which warranted a brief separate look. That14 is, three patients were just over the upper limits for15 BMI, seven patients were just over the limit for equal16 to or greater than three-centimeter hiatal hernia.17 Indeed, six of those had a three-centimeter hiatal18 hernia. One patient had Grade 3 esophagitis, where19 only Grade 2 is allowed. A couple had minor20 deviations in the quality of life scores. And one21 patient was not on PPIs because they were allergic,22 was only on double dose H2 blockers.23 Data analysis with and without these24 subjects with the deviations resulted in no
  60. 60. 1 statistically significant change in primary or 2 secondary objectives. Therefore, these patients are 3 included throughout the analysis for the rest of the 4 time period. 5 Now, the baseline PPI use for this group 6 of patients, patients were on PPIs for a mean of two 7 years prior to entry into the study. They were on any 8 of the four standard PPIs available at that time. And 9 then the dosage was quantitated as routine dose, half10 dose, or more than standard dose.11 Lets look at that again. Next, please.12 So seven percent of patients were on half dose, half13 standard dose PPI. Sixty-two percent were on standard14 dose PPI. And 30 percent were on more than standard15 dose PPI.16 Additionally, beyond the PPI we just17 discussed, seven percent were on H2 blockers,18 including the one patient who was only on that.19 Fourteen percent were taking supplemental antacids.20 Next. All patients meeting entry criteria21 were indeed treated with the device. All patients22 were treated on an outpatient basis. All procedures23 were formed under intravenous sedation without general24 anesthesia. All patients received prophylactic
  61. 61. 1 antibiotics. Mean procedure time was 34 minutes, mean 2 fluoro time just under 12 minutes. 3 Now for the safety summary information. 4 There were no serious device or procedure-related 5 adverse events. All device-related adverse events 6 were anticipated in the protocol. All 7 procedure-related adverse events were anticipated and 8 generally those expected for any therapeutic 9 endoscopy. All adverse events resolved without10 sequelae.11 The device-related adverse events were12 retrosternal chest pain occurring in almost all13 patients, dysphagia in 20 percent of patients, fever14 in about 12 percent of patients, and a variety of less15 frequent and seemingly minor complaints or events.16 Next. To expand on the substernal chest17 pain, again, patients were told to expect this. It18 occurred in 92 percent of patients. About 80 percent19 of the patients were given prescription or20 over-the-counter analgesics to control it. And 2021 percent required no medication. All pain resolved22 without sequelae.23 The duration of the pain was by seven days24 half the patients had resolution of their pain. By 14
  62. 62. 1 days, 75 percent had resolution of their pain. By 30 2 days, 90 percent had resolution of their pain. And by 3 three months, all patients had resolution of their 4 pain. 5 Twenty percent of the patients had 6 dysphasia. In half of them, it resolved in two weeks. 7 In three-fourths of them, it resolved by two months. 8 And in all patients, it resolved by three and a half 9 months.10 Most problematic was one patient who was11 diabetic who could not control their blood sugar12 levels because of poor nutritional intake. That13 patient was endoscoped. There was no apparent14 stricture, despite the dysphasia. The patient was15 empirically dilated. And symptoms eventually resolved16 without sequelae.17 Next. Twelve percent of patients reported18 fever. This lasted only a couple of days. It was19 treated with antibiotics in five of ten patients. And20 others, it resolved without treatment. Importantly,21 no patient had signs of sepsis or obvious systemic22 infection.23 Next. Other device-related adverse events24 were a variety of infrequent and seemingly minor
  63. 63. 1 events, all of which resolved spontaneously without 2 intervention, including the odor mentioned by some 3 patients. 4 Procedure-related adverse events were 5 those which would be anticipated with therapeutic 6 endoscopy procedures: sore throat, nausea or 7 vomiting, and a few other minor events. All resolved 8 within a week. 9 So, in summary, no unanticipated device or10 procedure-related adverse events occurred. No major11 adverse outcomes and no mortalities occurred. All12 device and procedure-related adverse events resolved13 without sequelae. Based on the results of this study,14 we conclude that endoscopic implantation of Enteryx is15 safe for the treatment of GERD.16 Thank you.17 CHAIRPERSON WOODS: Dr. Fennerty has asked18 to be the first one to ask questions. So Ill pass19 the microphone to him.20 DR. FENNERTY: Good morning, Dr. Lehman.21 I just want to go on the public record as stating22 unequivocally that my Portland Trailblazers should23 never have traded Jermaine ONeal to your Indiana24 Pacers up front.
  64. 64. 1 DR. LEHMAN: He is starting in the 2 all-star game, I hear. So we appreciate that trade. 3 DR. FENNERTY: Dr. Lehman, I realize that 4 many of the issues that I am going to ask questions 5 about regarding study design you may have to also ask 6 the sponsor about some background, but one of the 7 things that will be an issue in any therapeutic trial 8 is we know quite clearly that the lack of 9 randomization or blinding has an effect on inflating10 treatment outcomes.11 Were going to not talk about efficacy12 until Dr. Johnsons presentation, but you did present13 the study design. So I wanted to ask you whether the14 crossover design had been discussed with the FDA prior15 to the onset of the study and the reasons for picking16 a crossover design versus a randomized and hopefully17 blinded trial, although blinding may be somewhat18 difficult in these sort of things. Thats the first19 question.20 DR. LEHMAN: Yes. The study design was21 fully discussed with the FDA ahead of time and agreed22 upon that this crossover approach would be23 appropriate. It was discussed.24 DR. FENNERTY: As a follow-up of that, Dr.

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