UNITED STATES OF AMERICA
DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

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MEDICAL DEVICES ADVISORY COMMITTEE

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GASTROENTEROLOGY AND UROLOGY DEVICES
ADVISORY PANEL MEETING

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Friday,

August 17, 2001

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The Committee was called to order at 9:41 a.m., at the Food and Drug Administration, 9200 Corporate Boulevard, Conference Room 20B, Rockville, Maryland 20850 by Chairman Anthony N. Kalloo, M.D., presiding.

PANEL MEMBERS PRESENT:

DR. ANTHONY N. KALLOO, Chairperson

DR. JEFFREY COOPER, Executive Secretary

DR. MARY GELLENS, Member

DR. ARTHUR D. SMITH, Member

DR. JOSEPH H. STEINBACH, Member

DR. KAREN WOODS, Member

MS. KAREN NEWMAN, Member

MR. MICHAEL S. BANIK, Member

DR. MICHAEL EPSTEIN, Member

DR. WALTER KOLTUN, Member

DR. STEVEN MCCLANE, Member

DR. MARK A. TALAMINI, Member

DR. NANCY BROGDON, FDA Representative

PUBLIC SPEAKERS:

NANCY LOITZ

LARRY GETLIN

DAVID WORRELL

DR. DOUGLAS WONG

DR. SUSAN CONGILOSI

DR. ARON YUSTEIN

KATHLEEN OLVEY

C-O-N-T-E-N-T-S

I. Greeting and Introduction 4

II. Chairman's Opening Remarks 6

III. Open Public Meeting Hearing 7

IV. Open Committee Discussion/ 19

Sponsor Presentation

V. FDA Presentation 112

VI. Panel Discussion 148

VII. Panel Deliberations and Vote 156

VIII. Closing Remarks 254

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

(9:41 a.m.)

CHAIRMAN KALLOO: Good morning. Welcome to the Gastroenterology and Urology Devices Panel of the Medical Devices Advisory Committee. My name is Anthony N. Kalloo, and before we proceed any further, I would like to hand the meeting over to Jeffrey Cooper, the Executive Secretary for the Committee.

SECRETARY COOPER: Good morning. I would like to read a statement concerning the appointments to temporary voting status. Pursuant to the authority granted under Medical Devices Advisory Committee Charter, dated October 27th, 19990, and as amended August 18th, 1999, I appoint Michael Epstein, M.D., Walter A. Koltun, M.D., Steven McClane, M.D., Mark A. Talamini, M.D., and Lawrence Way, M.D., as voting members for the Gastroenterology and Urology Devices Advisory Panel for this meeting on August 17th, 2001.

For the record, that there 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 interests review and reviewed the materials to be considered at this meeting, signed by the Director, Center for Devices and Radiological Health.

The following announcement addresses conflict of interests associated with this meeting, and is made a part of this record to preclude even the appearance of an impropriety, and to determine if any conflicts exist, and that the Agency review the submitted agenda, and all financial interests reported by the Committee participants.

The conflict of interest statutes prohibit special government employees from participating in matters that could affect their or their employer's financial interests.

However, the Agency has determined that participation of certain members and consultants, the need for whose services outweighs the potential conflict of interest involved, is in the best interest of the government.

We would like to note for the record that the agency took into consideration a certain matter regarding Dr. Arthur Smith. He reported an interest in a firm at issue, but in matters that are not related to today's agenda. Therefore, the Agency has determined that he may participate fully in today's deliberations.

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

With respect to all the 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 tentative 2002 panel meeting dates, and they are February 1st, 2002, and May 17th, 2002, August 9th, 2002, and November 7th, 2002. Thank you.

CHAIRMAN KALLOO: We will now proceed ot the open public hearing session of this meeting. If there is anyone wishing to address the panel, please raise your hand, and you may have an opportunity to speak.

I would ask at this time that all persons addressing the panel come forward to the microphone and speak clearly as the transcriptionist is dependent on this means of providing an accurate transcription of the proceedings of the meeting.

Before making your presentation to the panel, state your name and affiliation, and the nature of any financial interests you may have with the topic that you are going to present.

Each presenter can be allotted 10 minutes. Please provide a copy of your remarks and any visual aids to the transcriptionist. Dr. Cooper has received one written set of comments.

SECRETARY COOPER: And that is the National Association for Continence has submitted a request for approval of the device, and copies of that letter are available at the desk.

CHAIRMAN KALLOO: We have one scheduled presenter, and we will begin with Nancy Loitz.

MS. LOITZ: Good morning. My name is Nancy Loitz, and I am a recipient of the artificial bowel sphincter, and I am here to try and put a human face on the matter under consideration today. Excuse me for the emotion.

But it is has been a long journey, and one that I am very proud to speak about today. I am going to read my written remarks, but I would be very open to any questions that the panel might have.

In November of 1997, as I sat down for Thanksgiving Dinner with friends, we began our annual ritual of sharing with the group the one thing for which we were most thankful.

And that year my choice was easy. I am thankful, I said, for my new sphincter. We all laughed, but everyone at that table understood the significance of my statement, since as my closest friends, they had witnessed my struggle prior to receiving my implant, and they had seen me joyfully reclaim my life afterward.

Today, I thank you for allowing me to be here. Preparing to tell my story today has given me the opportunity to reflect upon it myself. It had been a while I had thought much about what life was like before receiving my implant.

I had just gotten too busy getting on life. I am afraid that I had begun to take it for granted. The medical journey that has led to my appearance today began in 1993, when I underwent a bowel resection to repair a complete rectal prolapse, a condition that I had had since childhood.

The surgery, performed by a general surgeon in my hometown of Bloomington, Illinois, was only partially successful, and within two years the prolapse returned. Wit it became the beginning of a gradual, and ultimately a complete, loss of bowel control.

At this time, I was a 36 year old single woman. I had always lead a very active life. I had a rewarding and successful career as a professor of theater, and I enjoyed hiking, working out at the gym, and an occasional bike ride.

And being a rather stubborn person, I initially refused to allow my incontinence to affect the way I lived my life. I was lucky that the onset of my condition was gradual.

Over time, I developed an intricate system of coping mechanisms. I had spare undergarments stashed everywhere -- in my purse, in the desk drawer at work, in the glove compartment of my car.

I prided myself on knowing where every public bathroom in Bloomington, Illinois, was located. And, of course, I always carried with me a complete change of clothes for those times when I didn't get to one in time.

Despite my absolute determination not to let this condition rule my life, it eventually worsened to the point that those around me couldn't help but notice that something was wrong.

My incontinence became so severe that I had to leave class, rehearsals, or meetings, sometimes as several times in an hour, to address the almost constant leaking.

I began to exercise at home since physical activity exacerbated my problem, and working out at the gym guaranteed a major accident in a public location, something I got very good at negotiating around.

The use of enemas, for example, prior to special events such as weddings, opening night performances, or air travel, allowed me to continue to participate fully in such activities without having to share with anyone the severity of my condition.

While normally I was pretty successful at not letting my physical problem get the best of me, a day came in April of 1966 when I had frankly had enough. It had been what I jokingly referred to as a "BBD" or a particularly "Bad Bowel Day."

And that night I made a phone call to an old friend, and it was a phone call that would change my life. An engineer at American Medical System, Bob is the husband of a woman with whom I had worked for a short time nearly 15 years before.

For some reason, on that night I remembered the conversations that we had had many years before about the products that they made at AMS. On this evening 14 years later, it dawned on me that the solution to my problem would be an artificial bowel sphincter, and if anybody made such a thing, it would be AMS.

Since Bob knew nothing of my medical condition, I caught him a bit off-guard when I called him out of the blue, and I asked does AMS make an artificial bowel sphincter.

Unsure whether he could share information about the study, Bob put me in touch with Cari Voda from AMS, who suggested that I contact Dr. Douglas Wong. Within a week, I sat in Dr. Wong's office, hoping desperately to be a part of the clinical trial of the AMS artificial bowel sphincter.

Although Dr. Wong agreed that I might eventually benefit from the implant, he dod not rush to include me in the study. He suggested that first he surgically repair my recurrent prolapse, a procedure that had the possibility of alleviating the incontinence as well.

Unfortunately, it did not. We then tried biofeedback in a hope that I could retrain my sphincter muscle to do the job that it was intended to do. Still, there was no improvement in my condition.

Having exhausted all other possibilities, it was only now that Dr. Wong determined that I was a suitable candidate for the implant, and agreed to include me in the clinical trial.

My first implantation surgery took place in June of 1997. Despite a 9-day hospital stay due to unexplained high fevers, the surgery was a complete success. The improvement in my condition was immediate and profound.

I need not go into detail about life after receiving the implant, since life with the implant is simply that, life. I now had complete control of my bowels for the first time in years. Suddenly I felt like I had my life back.

And with it came possibilities that I had abandoned during the peak of my medical difficulties. Although I had always hoped to have children, my health problems had made single parenthood out of the question.

But on March 10th, 1999, less than two years after receiving my first implant, I gave birth by caesarean section to my daughter, Zoe. My implant continued to function perfectly throughout my pregnancy, and for more than a year following my daughter's birth.

Last summer, however, I detected that something had changed with the device. Tests confirmed that fluid had leaked from my implant and a revision surgery would be necessary. I felt no need to rush forward with the second surgery since life with the implant, even when it was broken, was far superior to life without one.

I did, however, begin experience enough occasional episodes of incontinence that I decided that it made sense to go forward with the replacement.

My revision surgery was performed 12 weeks ago today by Dr. Susan Congilosi.

It was determined at that time that the leak in my first device was due to a stress tear in the cuff. Although the surgery went well, I later developed an infection near the site of the abdominal incision.

I am delighted to report that following a long course of antibiotics, I am now free of infection and am again in possession of a fully functioning AMS Artificial Bowel Sphincter.

My journey to this place has not been without difficulty. But now once have I regretted by decision to get on board. At each bump in the road -- during the fevers following my first surgery, when we discovered the leak in my first device, when I developed the infection following my revision -- what I always feared most was that I could lose the implant.

I knew all too well what life was like without it, and now that I have it, I am not giving it back. I would like to close today with one last offer of thanksgiving to those people who have been with me at teach stage of this adventure.

Thank you to Dr. Wong, to Dr. Congilosi, to Linda Jensen, and to the staff at AMS. Thank you for making an investment in me. You have given me a really great gift.

And I hope that by being here today I can contribute in at least a small way to making that same gift available to others who are suffering now as I once did. Thank you.

CHAIRMAN KALLOO: Thank you, Ms. Loitz. For the sake of completeness could you tell us if you have any financial interests in the company AMS?

MS. LOITZ: I do not.

CHAIRMAN KALLOO: Thank you.

DR. STEINBACH: Do you know if your first sphincter was an early model or the new improved one?

MS. LOITZ: I don't know.

DR. STEINBACH: Maybe you are the wrong person to ask.

MS. LOITZ: Oh, it was the new one.

CHAIRMAN KALLOO: Okay. Thank you, Ms. Loitz. Are there any other public comments? If not, Jeff.

DR. COOPER: I wanted to go about and do the introductions. The first thing I wanted to do was introduce Nancy Brogdon. She was recently named the Director of the Division of Reproductive Abdominal and Radiological Devices. She is microbiologist with several years of clinical laboratory experience.

She was most recently the Deputy Director of the Division of Athalmec, and Ear, Nose, and Throat Devices.

In that division, she had been a scientific reviewer, and held various division management positions, including interim director for a total of 21 years, and we welcome her to our division.

DR. BROGDON: Thank you.

DR. COOPER: Would each member of the panel him or herself, designate your specialty, position, title, institution, and status on the panel, whether you are a voting member or consultant, or temporary voting member, industry rep, or consumer rep, and we will start with Dr. Talamini.

DR. TALAMINI: Mark Talamini, Associate Professor of Surgery, at the Johns Hopkins University School of Medicine, temporary voting member.

DR. MCCLANE: Steven McClane, and I am a colorectal surgeon, Stamford, Connecticut, and I am a temporary voting member.

DR. GELLENS: Mary Gellens, Associate Professor of Nephrology, St. Louis University, and I am a standing voting member.

DR. EPSTEIN: I am Michael Epstein, Annapolis, a Gastroenterologist, temporary voting member.

DR. BROGDON: Nancy Brogdon.

MR. BANIK: Michael Banik, Vice President of R&D, Boston Scientific, Industry Representative and non-voting member.

DR. COOPER: We have two people who have not come yet, and I am not sure if they are or not, and that is Diane Newman, who is our Consumer Rep; and Dr. Lawrence Way.

DR. KOLTUN: Dr. Walter Koltun, and I am an associate professor of surgery at the Penn State University Hershey Medical Center.

DR. STEINBACH: Joseph Steinbach, associate project biomathematician, at the University of California at San Diego.

DR. WOODS: Karen Woods, and I am a clinical associate professor of medicine at Baylor College of Medicine, in Houston, and I am a gastroenterologist, and in private practice.

DR. SMITH: Arthur Smith, and I am a urologist, a Professor of Urology at Albert Einstein College of Medicine, and I am a voting member.

CHAIRMAN KALLOO: I am Tony Kalloo, and I am the Panel Chair, and an associate professor of medicine at Johns Hopkins University, and clinical director for the division of gastroenterology.

DR. COOPER: And I am Jeff Cooper, the Executive Secretary for the FDA.

CHAIRMAN KALLOO: Okay. We will now proceed to the open committee discussion. We will start with the sponsor's presentation of PMA PO10020, from American Medical Systems for the AMS Acticon Neosphincter, for the treatment of fecal incontinence.

I would ask at this time that all persons addressing the panel come forward to the microphone and speak clearly, as the transcriptionist is dependent on this means of providing an accurate transcription of the proceedings of the meeting.

Before making your presentation to the panel, state your name and affiliation, and the nature of your financial interests in that company. Let me quickly remind you that a 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 the behalf of the applicant; a direct stake in the product under review, that is, inventor of the product, patent holder, owner of shares of stock, et cetera, an owner or part-owner of the company.

And of course no statement is necessary from employees of that company. I would like to remind the panel that it may ask for clarification of any points included in this sponsor's presentation.

The first speaker as listed on the agenda is Larry Getlin, a vice president of regulatory medical affairs and quality systems.

MR. GETLIN: Mr. Chairman, distinguished panel members, good morning. My name is Larry Getlin, and I am the vice president of regulatory and medical affairs for American Medical Systems.

And we are very pleased this morning to present our data in support of our pre-market application for the Acticon Neosphincter to treat patients with severe fecal incontinence.

And before I present our agenda for this morning, what I would like to do is just provide you with a few brief comments. We believe that the clinical data, the results that you will see today, and that are also in your panel packs, will be clarified, and they indicate three things.

One, that we have met the primary and secondary end points for the study. And, number two, the device is safe and effective to treat patients with severe fecal incontinence; and, three, that the device is one that will be able to be used for the patients that are so indicated.

Also, this device presents, and the data, a compelling benefit to risk ratio for patients who basically have lost all other options to treat their fecal incontinence, and has virtually left them housebound, and has significantly impacted their quality of life.

In addition the Acticon Neosphincter device, although designed specifically to treat fecal incontinence, severe fecal incontinence, is not a new device, and I say that because the Acticon Neosphincter device is essentially the same device as the AMS artificial urinary sphincter, which has been in the marketplace for over 28 years, and has an approved PMA to treat severe -- I'm sorry, urinary incontinence as a result of ISD following prostate surgery.

At this time, I would like to just cover a presentation. Mr. David Worrell, who is a project lead on this for the regulatory group, and senior regulatory specialist, will cover the indications for us, and the device indication and history.

Dr. Douglas Wong, principal investigator, will cover the effectiveness results. Dr. Susan Congilosi, who happens to also have implanted more artificial bowel sphincters in the U.S. than any other physician, will present the safety results.

And Mr. Worrell will then conclude with AMS' summary statements and remarks. I have one footnote for Dr. Wong. Dr. Wong will be departing at 2:15 today. So I encourage us to use the benefit of his expertise and knowledge for any questions that you may have today. Thank you. I would like to now introduce Mr. Worrell.

MR. WORRELL: Good morning, Mr. Chairman, and distinguished panel members. My name is David Worrell, and I am the senior regulatory affairs specialist for American Medical Systems.

Before I proceed with the indication and the device information, I would like to state that the device has undergone extensive pre-clinical testing to demonstrate that it functions as intended. The device shares materials and operating principles with a similar device manufactured by American Medical Systems, the AMS Sphincter 800.

The AMS 800 has been legally marketed for 28 years, and has been used to treat urinary incontinence in over 50,000 patients. In September of 1999, the FDA approved the commercialization of the Acticon Neosphincter in the Humanitarian Device Exemption.

The approval recognized that the device is safe for use in patients, and that the probable benefits outweighed the risks associated with the use of the device. The HDE approval also demonstrated that device design, functionality, biocompatability, and sterility, have been demonstrated.

Now I will proceed with the indication for use and the device information. Fecal incontinence is a distressing and isolating condition. As we heard during the public presentation, fecal incontinence dramatically impacts the emotional, social, and work-related aspects of a person's life.

Fecal incontinence presents a range of severity, severe or end-stage fecal incontinence, means the involuntary loss of solid or liquid stool on a frequent basis, and frequent used here means in the kinds of episodes that occur daily, or more than once a week.

Patients with severe fecal incontinence form a subpopulation from patients with fecal incontinence. Mild cases of fecal incontinence can be successfully managed with medical therapy, including anti-diarrheals, bulk laxatives, and biofeedback training.

With good compliances, these therapies produce acceptable results in mild cases. However, in general, these therapies are not very effective for moderate to severe cases of fecal incontinence due to neurogenic or traumatic origins.

Surgical treatment can benefit selected patients. Overlapping sphinctoplasty is a procedure of choice for an isolated anal sphincter defect, improving the health between 60 to 70 percent of these patients.

Post-anal pelvic flow repair has been advocated for significant occult sphincter defects. However, long-term results from this procedure have been disappointing.

If a patient fails these treatments, or if their physician thinks that their chances of success are not good using these treatments, the Acticon offers an additional option instead of permanent stoma.

The Acticon is used to treat severe fecal incontinence in post-pubescent males and females who have failed, or who are not candidates for, less invasive forms of restorative therapy.

Fecal incontinence itself is not rare.

"The true community prevalence of fecal incontinence is unknown," concluded colorectal surgeon, Dr. Robert Matoff in a recent report. Part of the reason for this is that many people fail to report fecal incontinence to their physicians.

The literature reports that the prevalence of fecal incontinence ranges from 2.2 to 7.1 percent in the general population. This means that about

5-1/2 to 18 million persons suffer from some degree of fecal incontinence.

The prevalence of severe incontinence is conservatively estimated at less than 170,000 persons in the United States, between the ages of 18 and 65 years old.

In 1996, AMS received FDA approval to begin its pivotal IDE clinical trial, with a device designed specifically to treat severe fecal incontinence, using the same materials and operating principles as the AMS 800 urinary sphincter, the new Acticon Neosphincter featured a reinforced cuff tab, increased cuff widths and lengths, higher balloon pressure ranges, and larger balloon volumes.

The modifications were intended to create a device more suitable for the higher pressures encountered in the anal canal, versus the urethra, and a cuff more compatible for implant around the anus. Also in 1996, the Acticon was CE marked and European distribution began.

Today, the device is sold in over 30 countries, including Australia, Brazil, Canada, China, Israel, and the European Union, and about 1,000 devices have been distributed so far.

Here you will see a photograph of the Acticon Neosphincter. At the top of the photograph, you will see the pressure regulation balloon, and at the bottom of the photograph, you will see the control pump, and in the middle of the photograph is the cuff that encircles the anus.

From the pump to the pressure regulating balloon is kink resistant tubing that is color-coded black, and from the pump to the cuff is kink resistant tubing that is color-coded clear.

In this line drawing on the left, you will see a side view of the pump, and this is the kink-resistant tubing on the left there that is color-coded black, that goes to the balloon; and this is the kink-resistant tubing color-coded clear that runs to the cuff.

And this is what is of interest in this line drawing right here. What is not noticeable in the photograph, but is seen clearly right here, this is the cuff shell. As fluid enters the cuff, this cuff shell inflates, and as fluid leaves the cuff, this cuff shell deflates.

To defecate, the patient squeezes and releases the lower soft part of the pump several times. This causes the fluid to move out of the cuff and into the pressure relating balloon, and that is demonstrated in the line drawing here.

When the patient squeezes the pump, the fluid leaves the cuff, and moves through the pump, and into the pressure regulating balloon. As the fluid leaves the cuff, the cuff opens and removes the occluding pressure on the anal canal.

And the anal canal opens, allowing stool to pass through the anal canal and leave the body. Pressure from the balloon automatically returns fluid through the pump to the cuff, and after several minutes, the cuff closes and continence is restored in the patient.

At this time, I would like to introduce Dr. Doug Wong. Doug Wong is our principal study investigator. He has participated in two studies with the device, and he will present the effectiveness results from the study.

DR. WONG: Thanks very much, David. Good morning, Mr. Chairman, and Panel Members, my name is Doug Wong, and I am the Chief of Colorectal Surgery at Memorial Sloan-Kettering Cancer Center. I do not have any financial interests in American Medical Systems, apart from being a study investigator.

I am pleased to present the effectiveness portion of this presentation this morning of a device that I believe really does offer us a device that is safe and effective for the treatment of end-stage fecal incontinence for patients so afflicted.

I was a principal investigator for the pilot study and initial IDE in 1988, and also for this study that began in 1997. And in the presentation, I am going to give you an overview of the device implantation, as well as the effectiveness of the device in this particular study.

This is the Acticon device that is implanted, both in males and in females. It is a 3-piece device that is comprised of a cuff, a control pump, and a pressure regulating balloon. So the first aspect of the operation is to implant the cuff around the anus.

We size the cuff with a little sizer to tell us what the appropriate size is. The implantation is made by making a tunnel around the anal canal, and then the control pump is placed in the scrotum in the male, and in the labium majora in the female.

And then a pressure radiating balloon is placed in the space arestis in that area there, and then there is a connection tubing that connects all three components, and it can be regulated.

The patient can control the regulation as Mr. Worrell demonstrated, and at the end of the implantation, we cycle the device, and then we deactivate it with that little deactivation button and leave it deactivated for about 6 to 8 weeks after implementation.

The actual operating time takes approximately 90 minutes for an implantation. Our study was a multi-center prospective, non-randomized study, in which patients served as their own controls. It was conducted under a common protocol, and the end points were measured at pre-implantation, at 6 months, and at 12 months, post-activation.

Our inclusion criteria were patients with fecal incontinence, who had had at least one non-surgical attempt at treatment prior to, and the exclusion criteria included patients with Croyns Disease, patients who had had irritable bowel syndrome, as the only ideology, or the only potential ideology of their incontinence, and patients who had extensive pelvic radiation were excluded from the trial.

There are 19 clinical sites for implantation; 13 in the United States, and 3 in Canada, and 3 in Europe. The numbers documented in the brackets represent the proportion of patients that were performed in each of these global sites.

And 115 patients were initially enrolled in the study, and three of the patients had to be aborted during the surgery because of interoperative complications, generally a perforation of a scarred area, usually in the vagina or in the rectum.

So that left us with 112 patients that we implanted with the device, and you can see that the majority of patients are female, which those on the panel will recognize as being the commonest group that has problems with incontinence.

And the mean age is 49, with a duration of incontinence, a mean duration of incontinence of some 14 years. The etiology of the incontinence in the study population is listed here.

The obstetric injuries were the leading cause of injury, and then the other causes in the next three are pretty evenly distributed between neurogenic incontinence, congenital etiologies, and anorectal trauma.

The other indications are listed at the bottom and comprise some 14 patients, and there were 3 patients with rectal prolapse, and 3 with endopathic incontinence. One was radiation injury, and one other with miscellaneous causes.

Now, virtually all patients had significant treatment by other modalities during the course of their management. All patients really had a long history of fecal incontinence.

Many had tried medical therapies and the majority had had previous surgical attempts at repair, all of whom had failed conventional treatment. And 38 patients, in fact, had previous sphincteroplasties listed there, and in fact of those 38 patients, 10 had had multiple attempts at sphincter repair surgically and had failed multiple attempts.

And 30 patients had a stoma or preexisting stoma at some point in time in an attempt to manage their fecal incontinence; and five had failed the dynamic graciloplasty procedure, and were then entered in the Acticon trial.

So really this surgical procedure now is really a last resort for this patients, and they are going to have severe end-stage fecal incontinence once they have failed conventional management, often many times over.

CHAIRMAN KALLOO: Did you have any patients who did not have conventional management?

DR. WONG: And they all had conventional management. So had -- they had all failed conventional medical management, and the majority of patients had surgical attempts that failed.

The ones that had no potential option for surgery, like the neurogenic incontinence, there is no appropriate surgical procedure. They had all failed medical management, including biofeedback, bowel management regimes, changing things.

The primary end-point for the study was the fecal incontinent scoring system, which we will discuss in a moment. This would take place at pre-implant, at 6 months, and at 12 months.

It was a statistical comparison of the pre-implant, and the 12 month fecal incontinence scoring system. The second end-points for the study were a measurement of anal manometry, a health status questionnaire, and a fecal incontinence quality of life questionnaire.

Now, this is the fecal incontinence scoring system, and which is referred to as FISS. This was developed by a small group of investigators and the sponsor of the study. This was specifically designed for this study, and specifically designed for fecal incontinence.

And it consisted of a five item, self-administered, questionnaire that patients filled out. The scores, as you can see, range from zero to 120. A score of zero is a patient who is fully continent, and a score of 120 is a patient is incontinence to liquid or solid stool on a more than once a day basis.

Eligibility criteria for the study was a score equal to or greater than 88, meaning the patients were incontinent to liquids or solids on a more than weekly basis.

The success rate was defined as a 24 point drop from FISS levels. So a two component drop constituted a success for study criterion.

DR. EPSTEIN: Dr. Wong, can I ask you -- can you go back one slide, please.

DR. WONG: Sure.

DR. EPSTEIN: What is the difference between, let's say, a 73 and a 84, and where does the range come in?

DR. WONG: The fecal incontinence scoring system had -- there were five questions, basically stated, are you incontinent of gas, and each had a score. and incontinent of liquids, and there was a series of scores, and then the fifth question was a quality life score that gave five points for quality of life effectiveness.

If quality of life was not affected at all, then it was zero. If your quality of life was affected it was five. So it was a cumulative of those five questions, and so there is a range that represents the scores.

These are the matched fecal incontinence scores. On the left-hand side, you will see the six month data, and the pre-implant mean fecal incontinence score was 106. You will remember that 120 is maximum.

As you can see, at six months at the follow-up fecal incontinence score, they are given the same questionnaire at six months. You can see that their mean score at six months had dropped 56 points to 50, and by the 24 point criteria of success is an 81 percent success rate in those patients that had functioning devices.

At the 12 month follow-up, a very similar picture. We now have again a mean incontinence score prior to implantation of 106, and which fell to 49 at 12 months, and that has maintained over that period of time, and again represents a significant reduction in the mean score.

And in fact this average point drop is in fact twice the 24 that we consider a success by the criteria that were done. Some of these average patients then who had then improved by that magnitude of a drop really went from an average incontinence of at least being incontinent once a day, to being incontinent of seepage only based on that scoring system that I presented to you.

This was statistically significant to the P value of .001, and I think that it does show that the primary end-point for the study, in terms of effectiveness, was met. Now, I think that all --

CHAIRMAN KALLOO: Do you have a simply quality of life, because if you are able to reduce the scores from a statistically significant amount, in terms of just leakage, do the patients still have to wear underwear and all that. And do you have or have you isolated just quality of life scores?

DR. WONG: Well, we have quality of life data that I will present, in terms of the fecal incontinent quality of life score, and it wasn't a scoring system that we went with based on percentages.

And so actually a specific analysis was not done on that. There is a specific analysis done on the health status questionnaire on patients prior to and after.

But the data on the fecal incontinence quality of life I will present. I think that all treatments for fecal incontinence should be evaluated on an intent to treat basis, and I would just like to take you through this intent to treat status line.

So we enrolled 115 patients, and 78 have implanted devices, and 3 were aborted, and 34 were explanted, and that will be discussed later in the safety regulation or safety presentation.

So we have 75 functioning sphincters that we know about, and three have been lost to follow-up in the study. Now, of these 75, seven had preexisting stomas. If they had a preexisting stoma, you can't determine their pre-operative incontinent status on the fecal incontinence scoring system, because they don't have bowel incontinuity.

And 68 were done without stomas, and so these ones that had preexisting stomas, we assigned or we felt that they had surgery, and had a stoma applied, I think it is fair to success that their mean incontinent score is probably equal to the mean of the study participants who did not have stomas.

So we applied that same mean in order to calculate whether it was success or not. One has not reached a one-year follow-up in the stoma patients; and five in the patients done without stomas have not yet reached the one-year follow-up.

We really have six stomas and 63 non-stoma patients who were seemed successful based on that 24 point drop. So we have 59 successes, and I felt that it was fair to exclude those, even on an intent to treat basis, as they are lost to follow-up, and have not reached one year follow-ups. I really don't know what their follow-up is.

So on an intent to treat basis, 59 successes out of the 106 for an intent to treat basis, a success rate of 56 percent. If you look at the clinical successes, and the score at 12 months in that matched data that I showed you a couple of minutes ago, was 85 percent. The intent to treat success rate here is 56 percent. So we can see that patients who do retain a functioning device, the success rate or device is actually very successful in controlling their incontinence.

And even on an intent to treat basis, we have a 56 percent success rate with the study. And I think we should put that into perspective. Again, we are talking about patients who are looking at a last resort for their fecal incontinence.

That list of operative procedures that I listed for you previously included patients or I listed sphinctoplasty, and patients with post-anal repair, and who have anterior and a posterior post-anal repair.

And if you critically look at the literature, with the success rates for those particular operative procedures, which are mainline procedures for treating people with incontinence, the success rate overall is very similar to this.

At our Society meeting just this past June, there were two papers that were presented, in terms of sphincteroplasty, which is the commonest operative procedure we do for restoring incontinence, and the long term results were in the 50 to 60 percent range with the conventional mainstream patients.

These are patients who have already been down that road, and we still have an intention to treat success rate of 56 percent.

Anorectal manometry was a secondary end-point in the study, and you can see that at pre-implantation the average resting pressure was 26 in this group of patients.

You can see that after implantation we increased the resting pressure in these patients at activation to 47 millimeters of mercury, and it has pretty much stayed very stable over the course of this follow-up on this study population.

And again, a pre, compared to 12 month, anorectal manometry score is again specifically significant. So that the secondary end-point, in terms of anorectal manometry again has been met.

The health status questionnaire was developed by the Health Outcomes Institute. This is a validated questionnaire. It is a 39 item self-administered instrument. It is based on the SF-36 and MOS-20.

And it really measures eight domains of health, and these eight domains include health perception, physical functioning, role limitations, role limitations in terms of physical functioning, as well as emotional functioning; and social functioning, mental health, pain, and energy levels.

The scale is from zero to 100, where 100 is ideal functioning, and the total health status questionnaire adds the scores from each of these eight domains. This was given to patients at pre-implant, and again at 12 months, and here are the cumulative scores.

And again you add all the scores in those eight domains, and pre-implant compared to post-implant, in terms of the health status questionnaire. Again, a significant improvement with the implantation of the device.

And these are the eight domains listed. You can see that in each of the eight domains there was improvement, again with 100 being the ideal functioning. So there is improvement in each of the 12 month scores, compared to pre-implant.

And 6 of these 8 were statistically significant. with emotional problems and pain not quite reaching statistical significance. So in terms of the health status, again the secondary end-point for the study was met.

The fecal incontinence scoring system was specifically designed for this study, and it is a 39 item, self-administered, instrument. And this was developed by the investigators and by the sponsor of the study.

And this led to the 29 item instrument that was validated subsequently by the American Society of Colon and Rectal Surgeons Outcome Group. It measures the physical, psychological, and the social impact of fecal incontinence.

The reported rates are really in percentages, and are listed in these subsequent slides. You can see that for physical functioning that in the blue bars we have the pre-implant.

And you can see that 42 percent of patients avoided certain foods, and 34 percent used medications, and 42 percent prior to implantation used diapers; and 77 percent used pads on a regular basis.

And you can see that after implant, at a 12 month review, only 9 percent altered their diet significantly. And 27 percent of patients still used some medications, but only 9 percent needed to use diapers, and 39 percent still used some form of protective pads.

And 81 percent, as Nancy Loitz told you this morning, it is very common that patients will look for where all the bathrooms are, and stay very near a bathroom. And 81 percent in the study prior to implantation sought out where the bathrooms were, and stayed very near them when they left home.

After the implantation, only 33 percent felt the need to do this. And 47 percent leaked stool unknowingly, and 57 percent couldn't hold the bowel movement long enough to make it to a bathroom; and 89 percent I had a feeling that they could not control their bowel movements.

And again you can see very dramatic improvements in these percentages when we look at the post-implant, 12 month review, of these aspects.

DR. KOLTUN: I assume that all this data was handled in the same way, and that your post-implant data was presumably on the successful patients, and the 50 percent figure; and the pre-implant data is the full 115?

DR. WONG: That's correct.

DR. KOLTUN: Did you look at this matched?

DR. WONG: No, we did not look at the matched data, in terms of the -- well, these are just patients that have a functioning sphincter.

DR. KOLTUN: And my next question is when it came to quality of life issues, such as this, social functioning, why couldn't you have assessed the social functioning and included those patients who felt they may have ended up worse?

DR. WONG: Well, this was administered to -- well, at least the fecal incontinence quality of life was administered to all study representatives.

DR. KOLTUN: And this includes all the patients?

DR. WONG: This includes all the patients in the study, correct.

DR. KOLTUN: Pre-and-post?

DR. WONG: That's right.

DR. KOLTUN: And those who failed?

DR. WONG: That's right, but we did not statistically compare the results of this. It is hard to apply a score to this, and this is the percentage of patients who responded to these, but did include patients who actually had -- any patient who had the device implanted, and had functioning devices, whether they were successful or not, were included in this.

CHAIRMAN KALLOO: Do you have the same data beyond 12 months? Have you looked at it at 24 months?

DR. WONG: We have not yet by this point in time. There are not many patients that have reached the 24 month point yet. Again, in terms of social functioning, 83 percent were not able to make it to a bathroom, and 64 percent planned their schedules around bowel movements.

And 81 percent who went away stayed near a bathroom, and 69 percent avoided wearing light clothes because of the fear of having an accident and it being evident.

After the implantation, the results are 21 percent, 21, 33, and 24. Again, a significant improvement clinically.

MS. NEWMAN: I just want to make sure that I am clear on this. So this is the matched groups pre-and-post?

DR. WONG: These are patients, all the patients.

MS. NEWMAN: And all the ones -- and it doesn't matter what happened with them?

DR. WONG: All the ones that had a functioning device.

MS. NEWMAN: So the red is only the individuals that had a functioning device?

DR. WONG: That's correct.

MS. NEWMAN: And you did not match those with their pre-scores?

DR. WONG: These were not.

DR. KOLTUN: So the end of the blue is 112, and the end of the red is 60 something?

DR. WONG: At 12 months, 67, right. In terms of psychological functioning, 48 percent considered their job more difficult; and 76 percent worried about odor; and 86 percent worried about accidents; and 68 percent said they could not do many things that they would otherwise want to do.

And again the red bars are those having functioning devices at 12 months, and there was improvement. So I think the primary objectives of the study clearly were to assess incontinence before and after activation of the device.

The primary end-points, in terms of effectiveness, showed significant improvement at 6 and at 12 months. And the primary end-point was met, and the secondary end-points, in terms of improvement and quality of life in these patients, likewise as well as the anorectal manometry, did show that the secondary end-points were met.

So I think based on the study that it is fair to say that the patients who do have a functioning device can significantly have improved continence, and that they do have a greatly enhanced patient quality of life if they are able to have a functioning device at the end of the study.

So I thank you for your attention, and I would like to turn the podium over now to --

CHAIRMAN KALLOO: First, are there any questions?

DR. WOODS: I am specifically interested in a little bit more on sub-group analysis, and the main question is that when you look at the FISS scores, there appear to be three groups of patients that would have qualified to enter into this study according to a three point score analysis.

And those are those that had greater than weekly, and those who had daily, or those that had more than daily episodes of incontinence.

DR. WONG: Yes.

DR. WOODS: Did you look at the data according to those sub-groups to see whether or not the most severe and the least severe within those groups were more likely to respond; and where the point drops more dramatic in one group than in the other.

DR. WONG: I would ask one of the statisticians to address that if they would. Mark.

MR. ANTIL: My name is Mark Antil, and I am the biostatistician for American Medical. We didn't break them down into sub-categories by what their score was pre-versus-post.

What was presented here was an overall mean drop across time, basically looking at the pre-implant, the 6 month, and then the 12 month, and that is how we analyzed it.

DR. WOODS: I am really interested in knowing whether there are certain patients that may be more likely to respond, and should we tell those with the most severe fecal incontinence -- you know, a patient with a score of 120 -- that they may be less likely to have a good outcome than those who have --

MR. ANTIL: I understand your question.

DR. WOODS: -- a lower score, and also with respect to ideology of their --

MR. ANTIL: Yes, we did do a sub-group analysis by etiology, which we listed for the obstetric, neurological, and so on. There was no statistical difference for the HSQ or the FISS scores between those 4 or 5 groups.

Also, we looked at those for explants, and revision rates, and those were not different also with the long range tests. So we did look at a number of sub-group analysis, and they did not indicate a difference there.

But again going back, we did not categorize these by if you had a higher score to begin with or not. But the average score of most of this overall group, and I believe it was over a hundred, a 102 or so, of the FISS score. So they did all start off pretty high to begin with, but we did not break them down.

CHAIRMAN KALLOO: My question is that you started this pilot study in 1988, and it seems to have taken one hell of a long time to get it together and put it all forward. And I just wondered is that because of some lack of enthusiasm on your part?

And the other question that follows that naturally is that you have 19 sites, and out of the 19 sites, you only gathered 118 patients. Why is that so limited?

DR. WONG: Those are excellent questions. You are right. The pilot study was done in 1988, and it was not because of a lack of enthusiasm on our part. We were very excited about the results of the initial pilot study, and we are very anxious to actually proceed.

I am talking about study investigators when I was at the University of Minnesota. There was a decision by American Medical Systems at that time that held up proceeding with the use of the device for fecal incontinence. So it was not until 1997 that we were able to move forward with what we felt was a very promising device for this problem.

And someone from American Medical Systems may want to address that question separately as well. I'm sorry, but your second question was?

CHAIRMAN KALLOO: The 19 sites and the approval is so small.

DR. WONG: Well, these again were in-stage fecal incontinence patients. It did take time to accrue those patients. There was training that each of the sites needed to go through.

There are a lot of patients that present for fecal incontinence, and there are a lot of potential mainstream treatments that these patients need to have and to go through in order to make sure that all other avenues have been addressed.

And so, yes, it did take a period of time to accrue those patients. And again we have limited it to really quite in-stage frequent incontinence.

DR. KOLTUN: I have a question, but I guess you are talking about the effectiveness, and my question relates to safety, but also as to the data that you have here.

And that specifically is that when I look at the FISS score, there is -- let's say there is a score of 84, and the patient is incontinent to liquids or solids, more often than monthly, but not as often as weekly. Could such a patient be in the study?

DR. WONG: I don't know. Well, was the 88 equal to or greater than 88 was the score?

DR. KOLTUN: The patient would have to be incontinent to liquids or stools more often than weekly.

DR. WONG: Okay.

DR. KOLTUN: But not more often than daily.

DR. WONG: That's correct.

DR. KOLTUN: I am asking what happened to those patients in that category who were not of the worst incontinence if they failed? What was their subsequent incontinence, and in fact did you make them worse?

DR. WONG: Did we make them worse by incontinence?

DR. KOLTUN: Yes, after going through the procedure.

DR. WONG: I haven't got specific data that I can give you antidotal experiences and things that the patients -- even the patients that were incontinent to that level that were facing or having a device done as a last resort.

And from my own experience, when I meet with those patients, I basically tell them -- and we have discussed -- the next step in their incontinence is a colostomy or a stoma.

And that is the same group of patients that have a score of 88, and if their quality of life is so affected that they would agree that if they were to fail this device that they would have a stoma, then I would consider them a potential candidate for that.

So I don't have any evidence that we made any patient worse that failed, but some of those patients that did fail went on to have a stoma at the time of explanation because we knew that their incontinence was such that they were facing that decision is it this, or is it a stoma at that point in time.

CHAIRMAN KALLOO: I have a question, and I am not sure that you can answer it, but obviously there has been a tremendous or lots of experience in Europe, where this device has been obviously inserted in many more patients. Do you have any data on the effectiveness of the European experience?

DR. WONG: Well, from the published experience, the success rates have been generally in about the 80 percent range, and their morbidity rate is somewhat lower than with this study.

Those tend to be in centers where one investigator has been doing the implants, and has far more experience than what we can bring to bear in a 19 center study, where some people only do 2 or 3 implants over the course of things. But the success rate has been good.

DR. MCCLANE: To follow up on that, were there any centers where the success was better than in other centers in the study?

DR. WONG: Again, I would ask Mark. I don't believe that there was any difference in the things. Again, pretty small numbers to be making any statistical statement of that. I don't believe there is a difference. Mark.

MR. ANTIL: We did test the pre-scores to look for site differences, and they were not statistically different, but the numbers were pretty small for some of the sites. So we didn't evaluate them on a post-by-site difference. So we didn't evaluate that.

DR. MCCLANE: And my other question is I assume now that the patients with the colostomy have had -- well, is that something that has been considered?

DR. WONG: That was not part of the initial trial. They did something that I am personally interested in pursuing with this device at some point, but that was not part of the study.

MS. NEWMAN: Well, in the urinary field, we have this sphincter, but in women it is not really used in this fashion. What is your views on this, on male versus female?

DR. WONG: Well, I think that when we put the -- well, the integral part of this procedure is the placement of the cuff, and --

MS. NEWMAN: Well, no, it was really the balloon, and dealing with erosions, and those things.

DR. WONG: You mean the pump, of the pump, and not the balloon?

MS. NEWMAN: Right, the pump.

DR. WONG: In terms of -- or in our setting, basically it has been the cuff that has been the main anatomic difference, in terms of things. We have had some infections in the labia, but that has not been a major difference between putting it in the scrotum and the labium.

Most of the anatomical differences have been in trying to get that tunnel between the vagina and the rectum in female patients, particularly having a child birth injury, with a scarred perineum. So the cuff placement has been more of an anatomical sex difference between males and females.

MS. NEWMAN: Maybe there are better surgeons in your offices?

DR. WONG: I wouldn't want to say that.

CHAIRMAN KALLOO: Okay. Thank you.

DR. WONG: Thank you.

DR. CONGILOSI: Good morning, Mr. Chairman, and distinguished panel members, my name is Susan Congilosi, and I am a study investigator. And I am pleased to report on the safety results for this device. I have no financial interest in American Medical Systems other than that of an investigator.

I am going to review this in terms of two safety objectives; first looking at adverse events associated with the actual implant of the device, and then adverse events that occurred after implantation of the device.

There were 15 adverse events that occurred at implant. As you can see at the bottom, the majority of these involved in perorations to the vagina or the rectum at the time of implantation.

As Dr. Wong just pointed out, a number of these patients have a scarred and fragile perineum, and the actual surgical procedure of performing blunt tunnels around the anal canal can be technically difficult, particularly in these scarred patients. If a perforation to the rectum occurred, we did not go on to the placement of the device.

And if a perforation of the vagina occurred, we would repair the device and would go on to placement and were successful in that venue. All of these injuries were identified at the time of surgery and repaired, and going on as I stated, not placing a device if the rectum is perforated, and going on if the vagina was, and all resolved without long term sequelae.

These other two adverse events occurred at the time of removal of devices. The remaining adverse events involved those that occurred after implantation of the device.

There were no deaths, no life-threatening events, and no unanticipated adverse events in this study. There were a total of 395 adverse events, approximately half of which were thought to be device related.

This is a list of the more common adverse events that occurred in at least 10 patients. These events are not mutually exclusive. A patient may have had more than one event, and there may be multiple events for any one patient, and multiple interventions for any one event.

For example, a patient who presented with a mechanical malfunction may also have been reporting recurrent fecal incontinence. A patient with constipation and impaction may also have been reporting pain and discomfort. A patient with pain, discomfort, infection, and erosion were often reported together.

DR. TALAMINI: Dr. Congilosi, can I ask a question? The infections I am particularly interested in, because obviously in this region an infection can be all the way from mild, requiring some antibiotics to necrotizing fascitis.

Can you give us some more details on what these infections entailed, and how they were treated?

DR. CONGILOSI: I will go into more detail on the infection, but I will make brief comments now that in general the majority -- well, I think the number of infections were 36, eight of which we could treat just with antibiotics.

The other ones went on to explanation of the device. So, yes, infection and erosion is usually the reason that we had to explant the device. But these patients would often present with critical symptoms of pain, a small amount of bleeding, change in drainage, and possibly near fecal incontinence.

There were no patients with necrotizing infections. We would go on to explant these devices, and usually it was a hospital stay of 1, 2, or 3 days; a day of P/O antibiotics, and then oral antibiotics for a week.

Wounds were left open in the perineum if they had eroded, and in my experience all of these would heal quickly over several weeks. So, no necrotizing infections, but septic admissions for this.

DR. TALAMINI: And going back to the previous point. Were any of those patients reattempted at implantation, or on the other hand, had to go quickly to an ostomy?

Do we have more information on what happened to that group that had infection and implantation, and whether we made them worse by having tried to put this in and wound up with an infection?

DR. CONGILOSI: Again, in that group, as Dr. Wong said, a number of these did go on to reimplantations and some successful, and I can ask to be given the exact numbers on that again.

But some chose not to go on to reimplantation, and again were a group that would go on to a stoma because that had been the decision prior to surgery that that was their last option.

DR. TALAMINI: Thanks. I think that is a key thing that many of us are thinking about, did we make people worse by trying this, and I think you will probably hear that question a few times.

DR. CONGILOSI: Our counseling of these patients, I think you probably got that sense from Doug that at the University of Minnesota, because we have implanted more of these, we get a lot of patients referred from out-of-State and out-of-country.

And we do not go on and implant all these patients. I actually insist that they come up for an initial meeting with no plans for surgery, although many would like to have surgery, combined with an out-of-town trip, because we found that a number of these patients are amenable to other procedures.

We redo all their physiology testing, and if they are still a candidate for another surgical procedure, or another treatment, we do that. These are truly our end-stage patients, and we certainly have refused a large number, and had them go on to other treatments.

And if they were then unsuccessful, then to advise us, because a stoma was their last point. Again, this reflects at least 10 patients in each group, and these are not again mutually exclusively, and many of them are multiple --

DR. MCCLANE: Do you know what percentage of patients have had an adverse event? Did some get through with no events, or do you have anything on that data?

DR. CONGILOSI: Well, 100 patients had adverse events.

DR. MCCLANE: So 100 out of 115? So, 15 didn't?

DR. CONGILOSI: Yes.

DR. EPSTEIN: A question. Was the erosion -- well, going back, was it mostly the pump that was eroding, or --

DR. CONGILOSI: I will get to that in further slides. Yes, a like number of patients had adverse effects, but the majority of these were mild and moderate. Severe was termed an adverse event that prevented a patient from continuing with their daily activities.

The majority of the adverse events did not require surgical intervention, and 17 percent required no intervention. Reflective of this would be someone complaining of constipation, and even without medical management it resolves.

Or early complaints of pain after the device has been activated, but does resolve with time. An examination of the patients who would be treated medically, it would be possibly some variation in bowel regimen, and constipation was an issue for some patients.

And surprisingly, they would sometimes have to be placed on laxatives. My routine post-operative instructions to these patients were to stop all the anti-diarrheals which they were used to for years of using, so that we could see what their function was like, because many were still very nervous about not talking those usual medications, and would develop constipation.

And not evasive intervention. Let me think. Well, I can add some if you want more clarification on that. Well, 36 percent had surgical intervention for these adverse events. So there are 142 adverse events that required surgical intervention.

Again, remember that these aren't mutually exclusive. Many patients had several adverse events that might be resolved by a single surgical procedure. And 60 patients underwent 101 procedures. There were 81 device revisions in 56 patients.

And 20 other ancillary procedures, and those ancillary procedures included disimpactions,and incision and drainage of would infection, implantation of a cuff sizer, or procedures like that.

DR. KOLTUN: What was that last phrase?

DR. CONGILOSI: Implantation of a cuff sizer.

DR. KOLTUN: And what is that?

DR. CONGILOSI: The sizer is what we use at the time of surgery to decide on the size of the cuff.

DR. SMITH: So why do you use that on implantation?

DR. CONGILOSI: Well, it is solely not recommended by the company, and very discouraged, and an investigator might have chose -- and I think this is on a very small number of patients, but that if they had a perforation to leave the sizer in to preserve the tunnel.

And if they didn't develop an infection, then go back and place a device. In many of these patients where there are very, very scarred and fragile parineums, we often feel that we probably have one good attempt to get a tunnel in this area.

And if we lose that attempt, we probably have lost the opportunity to provide them with this device.

DR. KOLTUN: I was going to ask this question about this device later, but since we are kind of on it, it seems as if there are many sizes. There are different sizes of balloons --

DR. CONGILOSI: From 8 to 14 centimeters, the majority of which received sizes 10, 11, and 12.

DR. KOLTUN: And so my questions are two; one, how do you decide the sizes of each of those devices and the cuff; and, two, with the revisions, could the revisional surgery be minimized by improvement in that regard?

In other words, were some of these revisions simply because of choosing the wrong sized cuff, and if so, how do you do that?

DR. CONGILOSI: Okay. That is a very good question. There is a number of reasons for the revisional surgeries, but specifically regarding the cuff sizes, when we make the tunnels, we then put the sizer around and pull it to snug.

And I realize that is a vague term, snug, and it is probably the hardest thing to teach the new surgeons on how tight is tight enough. We actually went to placing them slightly looser later in our experience because we found that incontinence was not the problem if these were functioning successfully.

It was tending towards constipation. As Nancy told you, even where a cuff that had no fluid in it, she was having some element of control. So we went to slightly looser cuffs, and in that we may have seen more instances of tissue shrinkage, and then the cuff being on the loser side, and having to go back and place a tighter cuff.

But when I would do that, often the resizing of the cuff was two sizes down. We did not err two centimeters on the cuff. It really was tissue shrinkage. So some of this is an element of the change in their anatomy with time.

This is probably going to be a little bit more likely in patients such as with a perforated anus, with even less muscle around the anal canal. The other issue is device revisions, and was a problem with the tab on the cuff for buttoning.

This was realizing that the tab was revised, and with a new tab, but that was not available during this study period. So if a cuff became unbuttoned, we would have to go in and replace the cuff in that instance.

DR. KOLTUN: So explain that process to me. In other words, you create a tunnel, and that is defined by the physical nature of the patient?

DR. CONGILOSI: Right. Incisions are made either two -- well, one on each side of the anal canal, or an anterior incision. In females with very thin parineums, we often might do an anterior incision because that plane would be so narrow, but there is no real difference between those two options and investigators use both.

DR. KOLTUN: And if you make your tunnel, then what is this sizer? Are there different sized sizers, or is there just one sizer?

DR. CONGILOSI: There is one sizer with a small hole in it that you can pull the end through. I mean, sort of tighten it down.

DR. KOLTUN: Is that like a wire, or is it loose, or what?

DR. CONGILOSI: It is a silicon band, with a small hole in it. You pull the end of it through, and as you snug it down, it will read off the centimeter size.

DR. KOLTUN: And so that centimeter size read off that band then correlates with the cuff size that you use?

DR. CONGILOSI: Yes, the cuff size that we use.

DR. KOLTUN: So how often do you think cuff size was inappropriately chosen at the time of the initial surgery?

DR. CONGILOSI: I don't know how you would judge that.

DR. KOLTUN: How often did you have to revise the prosthetic cup due to leakage or failure of control unassociated with infection, or --

DR. CONGILOSI: How many of those do we have for fecal incontinence or constipation? It would be those two categories.

DR. KOLTUN: Well, how technically demanding is this, and how much of the complications, which are obviously somewhat high, related to the technical nature of the procedure itself? That is what I am trying to get a feel for.

DR. CONGILOSI: Well, I will have them pull those numbers, but if it was simply because it was too tight or too loose, most of our revisions -- and I will refer to another slide here, where were there was a pump malfunction, or cuff openings, or component malfunction.

DR. KOLTUN: So it wasn't frequent that you had to go back because the cuff did not --

DR. CONGILOSI: No, it was not frequent for pure incontinence because the cuff was too loose, or pure constipation because it was too tight. As far as resolution of these events, 91 percent of them are resolved, and there are 37 or 9 percent are continuing events, the majority of which are mild and moderate.

This was three severe events, and that are unresolved. The one was where the patient had fecal impaction, and was at a loss to follow up. The other patient was explanted and exited from the study, but did not return to see the investigator, and therefore could not be technically exited. And the third patient had rectal pain, which did resolve, but after the closure of the study.

DR. KOLTUN: A quick question. How does this compare in terms of the frequency of adverse events to the urinary sphincter?

DR. CONGILOSI: I don't personally place the urinary sphincter. Obviously the infection rate is certainly higher, and my sense is that the revisions are probably also higher involving the technical difficulty of working on the anal canal on these patients.

But I do not place the urinary device. We had -- you had asked about revisions. There are 81 device revisions in 56 patients. The vast majority were revised once, but a number of patients did go on to multiple revisions.

I think this speaks to two things. One is the willingness of these patients to undergo repeat revisions, particularly if they have a functioning device, and a component is not working, or if there is migration of the pump.

It also speaks towards the minor nature of some of the revisions, again often involving overnight hospital stay, and more morbidity. Six of these revisions have to do with staging explants. If a patient presents with erosion in the perineum of the cuff, the cuff can often just easily be explanted right in the office.

And where removal of the pump in the labia, or the scrotum, and the reservoir balloon, does involve an operative procedure in a hospital. So that is why six of these involved two procedures.

This gets into why we have the device revision, and so I can explain a little bit more about your questions about cuff sizing. The majority obviously were due to infection or erosion.

These are reasons that would commonly lead to total explanation of the device. The other etiologies are those that would be the patient is undergoing partial revision, or a changing of a component, and these often led to patients retaining a functioning device.

DR. KOLTUN: I'm confused. The device revision to me means you fixed it and left it in. Wouldn't you have an infection or erosion and therefore an explant?

DR. CONGILOSI: Right. So for a patient with reoccurring incontinence, again these are not mutually exclusive, and so with an infection or erosion could also have reoccurring incontinence. So that is why it is a little difficult to pull out with pure incontinence and pure constipation.

Something like mal-position would be a pump in the labia that is in an uncomfortable position, and migration, the same thing. Possibly a pump that has moved higher in the scrotum or labia is harder to access, and that would be a revision possibly of just that component, where again these would be full explanations of the device.

Regarding the erosions, there are 27 erosions that occurred in 24 patients. Not surprisingly, the majority of our erosions were to the cuff, the rectum, and the perineum.

Again, this reflects forming a blunt tunnel around the anal canal in patients that have previously often been operated in this area, and the area is scarred and fragile.

There were four that were of the pump; two in the scrotum, and two in the labia. And one of the two being in the perineal skin. And 47 pre-implant and implant variables were analyzed to determine possible factors that could be associated with the risk of erosion, and these were the significant events of which diabetes and preoperative musculoskeletal abnormalities were significant, and in a multi-variant analysis.

Musculoskeletal abnormality refers often to the trauma patients. An example of this would be a patient in a motor vehicle accident with a scarred perineum, and a patient who had a propeller injury, and had had 19 prior operations for this.

And a gentleman who was caught in a trash compactor and had a hemipelvectomy. These are the type of multiple skeletal abnormalities of patients that we were operating on.

There were 36 patients who had infections in the study, and 30 infections were in these 28 patients who had device revision, and eight of the patients who had infections, their infections were resolved with antimicrobial therapy.

Most of the infections occurred early on. Remember that we were activating at 6 to 8 weeks, and so that is between that 30 and 60 day period. This led to the revision of our preoperative antimicrobial therapy, and I will get to that in a slightly later slide.

Again, those 47 factors were looked at for their significance for infection, and these list the significant factors. Again, preoperative musculoskeletal abnormalities stands out reflecting the trauma patients.

The preexisting stoma was a very small number of patients, and this may be due to the low end. The majority of patients had a standard cuff width. So that also may reflect that factor.

DR. KOLTUN: Does that mean preexisting stoma increases your risk?

DR. CONGILOSI: Yes.

DR. KOLTUN: Why do you think that?

DR. CONGILOSI: Again, it was a very small number of patients that had --

DR. KOLTUN: You don't give these patients operating stomas?

DR. CONGILOSI: No, we don't. These are patients who presented to us with a stoma that had been placed because either after trauma, or they had been so incontinent that years earlier they had received a stoma. We did not routinely divert these patients for the procedure.

DR. KOLTUN: Well, if they had gotten their stoma for neuropathic incontinence due to diabetes, then maybe it wasn't the stoma, but was the preexisting illness of diabetes that you already showed was significant. I mean, I don't understand that. I just don't understand the preexisting stoma.

DR. CONGILOSI: Well, the majority with preexisting stomas were not neurogenic patients. They were trauma patients usually.

DR. MCCLANE: Were they at the time of the implant, the stoma?

DR. CONGILOSI: No, the stomas would be -- we would implant the device, and we would wait until activation, and then if we could successfully activate, we would then the takedown the stoma.

So they did have two instances where they were at risk of infection of this device. One, when we put it in, and one with the takedown of the stoma.

DR. MCCLANE: And when you put it in, there was no stool device --

DR. CONGILOSI: Right. But still --

DR. TALAMINI: But on the other hand, they would have some diversion effects in their rectum, and some atrophy of --

DR. CONGILOSI: Yes, and there were certainly patients that had -- well, I personally, and this is antidotal, but I did personally have patients that I perforated into their rectum, and have been diverted for many years, and aborted in patients with stomas.

DR. TALAMINI: I'm afraid that I am still not understanding the standard cuff width, and why that would be a risk for infection.

DR. CONGILOSI: The vast majority of patients had a standard cuff width used. I can't explain that.

MR. ANTIL: Maybe I can. Maybe I can either make it cloudy or clear on that question. But the univarian analysis is really an exploratory to look at the incidents rates.

Now, the multivaria looked at -- it is basically a log rank test to look in a forward fashion to see which factors up there might increase the risk of a revision.

Now, there may be an association, like what you were seeing with diabetes with the preexisting stoma, and for some reason that one came out versus the diabetes. So there could be an association with that.

DR. CONGILOSI: Okay. Regarding the infection rate, we obviously did notice this high rate of infections early in the course of this study. We therefore had this reviewed by an infectious disease specialist who looked at the organisms involved in the infection, which was a broad range of organisms.

But advised a new antibiotic regimen, which was then subsequently used in 16 patients. While this is not statistically significant, it certainly is clinically compelling, and we saw a drop in this infection rate from 27 percent to 12.5 percent.

DR. MCCLANE: And there were no antibiotics used in the first operation?

DR. CONGILOSI: Well, there were antibiotics used in the first operation, but those would usually be at the discretion of the investigator, and would reflect what a colorectal surgeon would typically use for an anorectal procedure.

And in particular I would say that the change often from this would be better coverage, and in your package is the regimen, but for example, the addition of achromycin --

DR. KOLTUN: Was up to the --

DR. CONGILOSI: Actually, no. The antibiotic regime was a dose pre-op, and the early regime of two doses is post-op. It was the discretion if anything was carried on orally later on.

The antibiotic regime beforehand was similar in the amount, but it was actually just the change in the actual antibiotics.

DR. KOLTUN: Now, I don't understand. Your first comment says antibiotic regime not used.

DR. CONGILOSI: They got antibiotics, but it was the antibiotic regime that was advised by an infectious disease specialist.

DR. KOLTUN: In column one?

DR. CONGILOSI: In column two. In column one, an antibiotic was used, but not a specific regime that we later devised. So in the first column would be patients that had the device placed, and probably got, for example, sepitan and flagella in pre-op, or something like that.

We then advised a regime of different antibiotics and that was used in this 16 patients.

DR. MCCLANE: And did you look at the volume based on what antibiotics they got? Supposed they got no antibiotics? Did anyone not get antibiotics?

DR. CONGILOSI: They only looked at the two regimens. There were no patients on no antibiotics.

MS. BEAURLINE: We did prepare the use of antibiotics.

CHAIRMAN KALLOO: If you could please come up to the podium and state your name. Thank you.

MS. BEAURLINE: Diane Beaurline, American Medical Systems. We did analyses for use of -- well, if pre-operative antibiotics were used or not used, those groups were analyzed, and for infection on univarian analyses the P value was 0.1106, and so not significant. And again not significant on multivariet at 0.2615 being the P value in that instance.

DR. KOLTUN: And let me just say that nobody did not get any antibiotics. I thought everybody got antibiotics.

MS. BEAURLINE: There were some patients who were reported to not receive pre-op antibiotics. The vast majority of patients did receive pre-operative antibiotics.

DR. KOLTUN: I am confused by this because a colorectal surgeon knows what the organisms are, and I am surprised to think that an infectious disease person couldn't improve upon that.

So it seems to me that the spectrum of organisms targeted by both of those antibiotic regimens, the first one being the colorectal specialist, and the second one being the infectious disease specialist, was probably very similar were they not? What were the antibiotics that we are talking about?

DR. CONGILOSI: Will you pull up the regimens?

MS. BEAURLINE: I have it here.

DR. TALAMINI: It kind of sounds like early in the study that there wasn't an antibiotic protocol.

DR. CONGILOSI: There was not a specific protocol.

DR. TALAMINI: And later there was.

DR. CONGILOSI: And later there was.

DR. TALAMINI: And in the early part of the study, that included some who neglected to give antibiotics on an occasional basis. So it really is just comparing a hodge-podge of whatever people gave to when --

DR. KOLTUN: A hodge-podge of colorectal surgeons' recommendations.

DR. TALAMINI: Correct.

DR. CONGILOSI: All right. This is the variety of microorganisms that were cultured, which as you can see is a long list, although the majority -- well, there is a wide variety here.

This was the recommendation for the infectious disease consultant, and not surprising, the infusion should be at zero to 60 minutes before incision, and that is a routine surgical recommendation.

This was the regimen that was recommended, cefotetan and vanconycin. And this is the current one?

MS. BEAURLINE: Yes.

DR. CONGILOSI: The actual prior one was

-- there was another one that was used in the study. This is the current one. The previous one was zosian and vanconycin. We actually weren't giving the cefotetan and what he recommended.

The cefotetan was often used, and again a hodge-podge, but he came back with a recommendation of -- I believe it was zosian and banko, which was the recommendation.

We have since modified it, and this is even a further modification, because one of the antibiotics he recommended if they were allergic was trovan, which is not on the market. This again goes on to allergies.

Therefore, in the current training of surgeons to do this, a number of factors do seem important to minimize the risk, and the antibiotic issue we have discussed. The use of a specific regime, and all patients get a full bowel prep, and other things to limit infection in the operating room.

Patient counseling refers to those variables that we demonstrated with both infection and erosion that seem to indicate that some patients that are going to be at higher risk for this being unsuccessful.

Patients with diabetes, and patients with multiple traumas, and multiple perineum operations. That said, in our practice we would use this to counsel a patient, but not necessarily to refuse a patient based on those criteria, because again this is their last attempt at receiving continence, and they are a high risk group of patients.

Many of the patients in this study were very difficult patients for us to perform obviously, the musculoskeletal trauma patients, and patients with few other options, and stomas.

DR. GELLENS: I have a question. Do you have data on co-morbid conditions, like how many patients were hypertensive, or had diabetes, or vascular disease? Did you collect that data?

DR. CONGILOSI: Yes. Let me pull that out.

CHAIRMAN KALLOO: While he is doing that, why don't you continue, please.

DR. CONGILOSI: Okay. Again, there were no deaths, and no life-threatening adverse events, and no one anticipated adverse events. The adverse events, while they appear numerous, were manageable, and could be resolved without long term sequelae.

And despite even requiring multiple revisions in some patients, a successful device could be achieved. And you heard that from Nancy today, because she is a patient who has undergone two placements of a device, and an infection, and there were no serious long term sequelae from the device revisions. Thank you.

CHAIRMAN KALLOO: I have a question before you go. Does this device preclude a -- if you have to do a colposcopy on these patients who have this device, and if so, are there special precautions?

DR. CONGILOSI: You deactivate the decide to do a colposcopy or a flexible sigmoidoscopy. You pump it open, and then you hit the deactivation button on the pump. It is in their scrotum or their labia, and that locks it open.

You then perform the procedure, and then resqueeze the pump and that reactivates it.

DR. TALAMINI: If I could ask both you and Dr. Wong whether in this study did you have patients where the device was removed for patient dissatisfaction? Patients who just said I don't like this thing, and I would rather have a stoma, or I would rather go back to my previous state?

DR. CONGILOSI: Well, not pure patient dissatisfaction. There might be --

DR. TALAMINI: There were some revisions for dissatisfaction.

DR. CONGILOSI: Right.

DR. TALAMINI: But what about removals?

DR. CONGILOSI: Not for pure patient dissatisfaction. The other ones for dissatisfaction would have also been with people with recurrent fecal incontinence and dissatisfaction.

DR. EPSTEIN: I have a question, and again addressing Dr. Talamini's previous question. Were there any cases of severe infections requiring prolonged hospitalization?

DR. CONGILOSI: No.

DR. EPSTEIN: You said that you believed that some of the wounds opened, and --

DR. CONGILOSI: Obviously, as someone who has put in a large number of these, and I have also taken out a large number of these, and I would routinely have them in the hospital a day, and then on oral antibiotics for a week, and the wounds would quickly heal.

And that includes the erosions. You know, rectum through to the vagina, which to a colorectal surgeon, a rectal-vagina fissel can be tremendously difficult to heal, and these would quickly heal.

DR. EPSTEIN: How do you define the outcome of the adverse events? In adverse events, you have erythema, fever, and abscess, and were organisms cultured?

DR. CONGILOSI: Organisms were not cultured at all in the removals for infection, and those would be signs of infection. Pain could be an indication of infection, and we wouldn't realize that it was infection until we went to remove the device, and would find drainage.

Routinely, you would find drainage around the device, and that would be very clear, but there may be a few skin and external indications of the infection if they didn't have an erosion, or if they didn't have localized erythema.

DR. MCCLANE: There is a trend to look at the pelvic in women, which is an old time area, I know, in some specialties. Do you know anything about prolapse?

A large portion of your population was older, in the 50s or 60s. What do you think about that? What happens if they have a prolapse? It doesn't matter? Do you have inclusion or exclusion criteria?

DR. CONGILOSI: I actually see a number of those patients myself. I work with a urogynocologist and I am obviously familiar with that. If they had -- if there were some patients who would present with evidence of other prolapse, I would repair that first.

My worry then would be that might preclude having a successful device. Obviously, if having a vaginal prolapse, I am not going to put a cuff around the anal canal.

Some patients who -- and as Nancy pointed out, with recurrent rectal prolapse, we would repair the prolapse first, and do those procedures first, and then stage it, and later place the device.

MS. NEWMAN: And what would you recommend? Should they be evaluated first?

DR. CONGILOSI: That is part of our routine evaluation preoperatively. Most of them I do defacography on, or with evaluating them with a pelvic examine, and looking at those factors.

But if they have obvious pelvic prolapses, or a vaginal prolapse, I have to repair that first, because I think that would technically make it difficult to put the cuff in. And technically to go later and repair that.

And to go back in obviously to the lower abdomen, where the reservoir balloon is, one has to be careful of that incision in the tubing. So if we felt that they needed surgery, if would be transabdominal. We would recommend that that be done first.

DR. SMITH: If you have erosion do you have to do a colocolostomy?

DR. CONGILOSI: If we have a revision?

DR. SMITH: If you have an erosion.

DR. CONGILOSI: An erosion?

DR. SMITH: Yes.

DR. CONGILOSI: No, we would usually just take the device out and then it would heal.

DR. SMITH: And then it would heal?

DR. CONGILOSI: Yes.

DR. KOLTUN: Doug presented 34 explants out of the original 115. Have any of those full explants been recent implants?

DR. CONGILOSI: Yes. Do we have the number on that, of the full explants that were reimplanted? Yes. The protocol was to wait 3 to 6 months if it was explanted for infection, and steering towards the 6 months range, and then to go back for a full reimplantation. So there are a number of those, yes.

DR. KOLTUN: Could you speak up? I'm sorry, but diabetics, that was a .00001. How many diabetics did you have and how many infections were there in that diabetic group?

CHAIRMAN KALLOO: I think there is a question about co-morbid data.

DR. CONGILOSI: We are still looking for the numbers on that, and --

CHAIRMAN KALLOO: Do you have that data available now, the co-morbid data, patients with co-morbidities?

MR. ANTIL: We are going to have to pull that up.

DR. KOLTUN: Okay. Then related to that is --

DR. CONGILOSI: Well, that explains it. It got reimplanted.

DR. KOLTUN: -- that with you being the most experienced, is there someone that you would say that I will not put this in you? Is there a patient that you would say I will not put this in you based upon my experience?

DR. CONGILOSI: Certainly.

DR. KOLTUN: And who is that someone?

DR. CONGILOSI: It takes morbidity to open and close the pump. If they don't have mobility, I would not do it. They need to be aware that -- I advise patients that there is about a 50 percent chance that they are going to need a revision, and if they are not mentally or psychologically up to that, I wouldn't do it.

If they have been -- there are some in the series that have been radiated, and I personally have not placed anyone who has had radiation in their perineum. Those would be the big categories of patients that I would not do it in.

DR. KOLTUN: Would you do it in a transplant patient on immunosuppressants?

DR. CONGILOSI: No. Well, I would qualify that; unless their transplant -- well, we have had somebody who has come for a consult regarding that who is 12 years out from that transplant, and are on minimal immunosuppressants and it is in discussion right now, because we are not sure on that patient.

The opinion of the transplant surgeon is that they could have it done, and they have also had an other implant done for another reason successfully.

DR. TALAMINI: And as a follow-up to that question, and this may not be a fair question. So if it is, don't answer. Based upon what you have said, and if you are familiar with the proposed labeling for this device, are you happy with it as it exists, the proposed labeling for the device? That is, if you are familiar enough with it.

DR. CONGILOSI: I don't think I am familiar enough with how the labeling is right now.

CHAIRMAN KALLOO: Karen.

DR. WOODS: I have a couple of very specific questions about some of the numbers. The first one is that in the data it says you had failure FISS at 12 months according to the point score in 10 patients, with 59 successes.

What was the reason if you know for the failure in those 10 patients? These were not listed as explants. It just says failure. Why did they fail?

DR. CONGILOSI: Let me pull those up.

MR. WORRELL: David Worrell, American Medical Systems. If they were listed as failure in the FISS analysis, they did not achieve the 24 point drop.

DR. WOODS: Right, I understand that, but what do you think the reason for that is? Is there something specific about those patients that led to failure? Was it a device that was too big, too small, or what was the reason for that?

DR. CONGILOSI: The ones that I can speak of are antidotally the ones in my series, and which are similar to some of the other groups. It may have been that the cuff was too large due to tissue atrophy, and they hadn't yet undergone a revision, and subsequently underwent a revision.

And that is true of at least one patient who subsequently got diagnosed with cancer and for that reason, for an unrelated cancer, was not going to undergo revision.

The other possibility would be poor patient selection in at least one patient who continued to abuse laxatives even afterwards, and would just sort of binge and purge, and still be incontinent.

So some of the etiologies were those medically related things, and one category certainly is for patients who may have needed a cuff change and had not yet undergone that surgery.

DR. WOODS: And surely there must be a list of who those 10 patients are and what their problems were?

MR. WORRELL: Yes, we have that data, and we can put that together during the meeting and provide that to you towards the end of the meeting.

DR. WOODS: Okay. Secondly, of the 34 explants, it says 27 exited entirely, and seven were appropriate for reimplant. Can you say why the other 27 were not appropriate for reimplant? Was that patient choice, or was there something anatomically? Was it an erosion or what was the breakdown of those who were not appropriate for reimplant and why?

DR. CONGILOSI: Patient choice not to undergo reimplantation, and the decision by the patient to then go to a stoma. That was the common reason for that. And in one patient a decision that they were medically not fit due to subsequent cardiac events.

DR. WOODS: So did most of those patients ultimately have a stoma placed?

DR. CONGILOSI: Well, 9 out of the 27 had a stoma placed.

DR. WOODS: And the others are back to baseline, or we don't know if they are even worse?

DR. CONGILOSI: Correct.

DR. MCCLANE: Do you know the FISS scores of those 27?

DR. CONGILOSI: We don't have that sub-analysis.

DR. MCCLANE: Because they probably were not followed up on?

DR. CONGILOSI: Right. If they are explanted, then further scoring is not done. So we would not have a score after explant.

DR. EPSTEIN: In the patients in whom the Neosphincter did not work, and in whom the sphincter was ineffective, did you look at the anorectal manometry pre-and-post? Do you have any information on that and as to why the device didn't work?

DR. CONGILOSI: Well, I think you will see some studies in the literature, but manometry has not been predictive of success with the cuff, which is not surprising. Manometry is not predictive of success with other operations.

DR. EPSTEIN: I understand. I was wondering if there was any data there at all that looked at that. I mean, you looked at it pre-procedure, and I was wondering if you looked at it post-procedure at all.

DR. CONGILOSI: We did follow manometry looking at how it related to the degree of continence.

DR. EPSTEIN: I guess my broader question is why didn't the sphincter work in some cases? What was the major reason why it wasn't working?

DR. CONGILOSI: I don't specifically recall those patients, because it would be a variety.

CHAIRMAN KALLOO: It sounds as if you have some data pulling to do for us. Could we just move along then. If there are no other questions from the panel, I would like to finish with Mr. Worrell.

MR. WORRELL: I do have a couple of points of clarification that we did find data on for you. There is a question about diabetic patients; and 5 of 27 diabetic patients had infection, and the analysis revealed that was not significant.

DR. KOLTUN: There were 27 diabetics, is that what that means?

MR. WORRELL: Correct.

DR. KOLTUN: And five had an infection.

MR. WORRELL: And give had an infection.

DR. KOLTUN: What was the number that we got that was 0.0001 for diabetics with regards to risk of failure?

DR. TALAMINI: That was risk of revision, things correlating with revision.

DR. KOLTUN: Okay.

MR. WORRELL: And also regarding microorganisms. We did some cultures when the infection control specialist looked at the study, and culturing patients who presented with infection was not part of the protocol. So the organisms that you did see on the slide were from patients in the study.

I would also like to address the infection control specialist we had come in. The preliminary results were of concern to the investigators, and the infection rate did seem to be high.

Initially the antibiotics were prescribed by colorectal surgeons at their individual sites. We had an infection control specialist analyze results from the study and present those results to the investigators.

And I would like Dr. Wong to speak a little bit about how the investigators received those results.

DR. WONG: Well, Walter is perfectly right. These were all done by colorectal surgeons, and everybody was on antibiotics. There was no question at all, and it was that everyone used their own antibiotic selection.

So these patients did in fact all get antibiotics, and as the study progressed, it was evidence that our infection rate was higher than where we really wanted to see it.

And at that point in time, we asked the infectious disease specialist, actually in St. Paul where we were working, to review the data, in terms of the organisms, and look at the entire spectrum of things, and then to give us his recommendation as to antibiotic regimen that we could adhere to that might be more specific to the type of organisms and infection that were seen.

And in the data that was shown there, even though the numbers are still relatively small, with only 16 in the right-hand column. And it does show a fairly significant incidence.

So, even just clinically, even though we haven't -- that is not large enough to make a decisional statement, there has been improvement in the infection rates when that particular regimen is used.

Since then, because all the investigators were very, very concerned about the infection, the majority of the investigators had it here to those regimens. Some hospitals are very rigid in terms of what antibiotics they can have, and some formulators in various hospitals don't actually have it.

So we have run into problems in the study, and not all hospitals saying that, yes, you can have this particular antibiotic. But, in general, when you have gone back to them, and to the infectious disease specialist, they have okayed it.

DR. KOLTUN: So what is the protocol now to you understanding?

DR. WONG: The protocol is as what Sue had put up on the slide, one pre-operative dose. The recommendation is for one pre-operative dose, and he presented data on other devices where post-operative doses make no difference whatsoever. There was the recommendation for one pre-op dose.

And I know that there are some investigators who have not felt comfortable with that, and gave post-operatives doses. I have gone with a one plus pre-operative dose.

DR. KOLTUN: And of the most recent 16 implants, you could not follow them long enough to --

DR. WONG: Yes, that's correct.

DR. TALAMINI: I have just one last question for Dr. Worrell or Mr. Worrell. Many of -- well, I guess the question boils down to this. There is plenty of European and now the United States experience, and I am just wondering why the company has not exhaustively studied some subset of them, particularly since the results seem perhaps a bit better?

MR. WORRELL: Some data is included in the controlled clinical trial from Europe, and we can say that those results have been studied exhaustively.

DR. TALAMINI: From the 1988 study, or --

MR. WORRELL: From this study, from the second pivotal study. They do make up less than 10 percent of the patient population, however. So it is a small sample.

There was also a question regarding revision due to patient dissatisfaction. Four patients stated dissatisfaction as a reason for revision, and that is 3.6 percent of implanted patients. It may, as Dr. Congilosi suggested, have accompanied another reason for revision, such as recurrent fecal incontinence.

So in conclusion, no gold standard currently exists for the treatment of severe fecal incontinence. In fact, no other device other than the Acticon exists today for these patients.

The device addresses the unmet medical need of controlling severe fecal incontinence for patients who have failed other therapies, and whose only remaining option is permanent stoma.

The key benefits of treatment with the device include, number one, improved fecal continence. A majority of patients achieved clinical success. Many of these patients were fully continent, or had dramatic improvement in continence status.

The results from statistical analysis of the primary effectiveness indicated that significant sustained improvements in continence were attributable to the device.

And, number two, significant improvements in the patient's quality of life. Results from the study indicated that the average patient's quality of life was significantly improved after treatment with the device.

Significant improvement was indicated in the total HSQ score, and on 6 of the 8 HSQ domains. Improvement also was indicated on the remaining two HSQ domains, although it was not significant.

Just as important, no declines in quality of life were indicated by analysis after follow-ups. The fecal incontinence quality of life instrument also measured improvements on the effect of fecal incontinence on patients' quality of life after being treated with the device.

And, number three, the device is same for use in selected patients. The device uses technology and operating principles proven in thousands of patients over two decades of clinical use with the AMS 800 urinary sphincter.

And the device itself has established its own acceptable safety profile over several years of clinical use. Morbidity is moderate to high, and to reemphasize, we were following an IDE approved controlled protocol.

And anyone who has been involved in research with the agency knows that those protocols are very prescriptive in the types of adverse events that are collected.

Sometimes we had to convince investigators to report all adverse events. We feel that we have collected all adverse events that were reported during the study.

Remember that 80 percent of the adverse events reported in the study were mild to moderate, which means that they resolved on their own, or with minimal interventions.

Study results indicate that adverse events are manageable and resolve without long term sequelae. If necessary, the device can be removed and a patient may proceed to permanent stoma.

The Acticon Neosphincter is a safe and effective treatment option for patients with end-stage fecal incontinence who have failed, or who are not candidates for other forms of restorative therapy.

The risks from use of the device are outweighed by the benefits of significantly improved fecal continence and greatly enhanced quality of life. We ask the panel for your recommendation to approve this device and to offer patients this opportunity for restored continence and for improvements in the quality of life.

Thank you very much for your attention, and as a reminder, Dr. Wong does need to leave this afternoon. So if there are any more questions to Dr. Wong or to Dr. Congilosi, we invite them at this time.

CHAIRMAN KALLOO: Thank you. Are there any questions from the panel to the sponsors?

DR. STEINBACH: Mr. Worrell, why are you not satisfied with the humanitarian device exemption?

MR. WORRELL: Satisfied in what regard?

DR. STEINBACH: This can already be marketed under a humanitarian device exception, and you are seeking a general marketing. Why? I mean, you can already sell it.

MR. WORRELL: Well, that is a good question. The device is approved and it is legally marketed at the moment. I think there are two reasons that we are looking for this.

Number 1 is that HDE is a temporary marketing status. It can be revoked. There are certain criteria that need to be fulfilled, but the PMA would provide permanent marketing status for the Acticon.

There is also another obstacle that we have run into, and that is really in terms of allowing access for patients to the device. As long as you have an HDE approval, the device must be reviewed by IRBs per regulation.

When an IRB grants their approval, and every IRB who has reviewed the device has granted approval for use at their institution, it also can carry the label of an investigational device.

Insurance carriers have denied patients the Acticon because of this IRB approval and investigational status. We do try and work with insurance carriers and explain that we have an FDA approval, but that it has not always allowed the patient to get reimbursement and to gain access to the device.

CHAIRMAN KALLOO: Any other questions?

MR. BANIK: Were there any device design changes made to the device during the protocol?

MR. WORRELL: During the protocol? Yes. We made a change to the cuff. We have a picture and let me see if I can show you. We have increased the size of the cuff adapter it is called. Let me show it to you quickly.

And you can get some feel for it right here. This has been increased in order to prevent the cuff from unbuckling in vivo. It creates a greater unbuckling force to help prevent that phenomenon.

MR. BANIK: Could those changes affect the outcome of the study?

MR. WORRELL: The new cuff adapter has not been used in a study yet, and so a change has been made, but it has not been implemented.

CHAIRMAN KALLOO: Any other questions? If not, I am proposing that we take a short break of 10 minutes. My goal is for us to lunch at 12:35. So, please if you could come back in 10 minutes while the FDA sets up for their presentation. Thank you.

(Whereupon, at 11:43 a.m., the meeting was recessed, and resumed at 11:55 a.m.)

CHAIRMAN KALLOO: Welcome back. Next will be the FDA presentation of the open public hearing. Again, I would like to remind the panel that you may ask for clarification of any points included in the FDA's presentation, but discussions should not go beyond clarification.

The first speaker for the FDA is Ron Yustein.

DR. YUSTEIN: Good morning, Mr. Chairman and panel members. My name is Ron Yustein, and I am a gastroenterologist in the Office of Device Evaluation here at the Food and Drug Administration. Kathy Olvey and I today will be presenting the FDA's review of the Acticon Neosphincter.

Quite a few of the slides that I have actually repeat some of the information already given by the sponsors, and so I may go fairly quickly through some of those and feel free to slow me down at any point if you want any clarification.

I also just wanted to quickly run through the FDA review team, including myself, Carolyn Neuland, who is our branch chief in the GI Devices Branch, and Kathy Olvey, who will talk in a couple of minutes, who did the pre-clinical review; and Elias Mallis, the engineering review; T.C. Lu, the statistical review, and Jack McCracken, patient labeling review; and Sharon Murrain-Ellerbe, consumer safety office; and Marian Linde-Serge, from the bioresearch monitoring, and Dr. Jeffrey Cooper, who is our Executive Secretary, who has done a yeoman's job in getting this ready for today.

To start with, the Acticon Neosphincter, as per the PMA submission, the indication for us, the Acticon Neosphincter is indicated for the treatment of severe fecal incontinence in post-pubescent males and females who have failed or are not candidates for less invasive forms of restorative therapy.

In this clinical protocol, severe incontinence was defined as the involuntary loss of liquid or solid stool on a weekly or more frequent basis.

The Acticon Neosphincter received humanitarian use device designation in December of 1998, and just for a quick definition, an HUD is defined as a device which is intended to benefit patients in the treatment and diagnosis of diseases, and conditions that affect or manifest in less than 4,000 individuals in the U.S. per year.

The device received a humanitarian device exemption on September 20th, which allowed for the marketing of the HUD. During the HDE, the indications for use were identical to that of the PMA currently being reviewed.

The patient population for the HDE was the same as that for the PMA, and the number of implant to patients in the follow-up period were less at the time of approval, and the HUD was approved based on demonstration of safety and probable benefit, and copies of that were included in the panel mail out.

I am going to just very, very briefly go over the clinical implications of fecal incontinence. Mr. Worrell touched on much of this. Fecal incontinence is defined as the inability to control gas or stool, and to some degree it can affect up to 7 percent of the U.S. population in general, and more than 50 percent of nursing home patients.

It is a leading cause of U.S. nursing home placement, and a substantial social problem for those affected. In the United States, it is a significant public health burden, with over $400 million a year being spent on incontinence appliances.

The associated conditions in etiology as you are all aware include diarrheal states, including fecal impaction, or short cut syndrome, neurological injury or impairment from a stroke,a nd spinal cord injuries, and mass or other neuropathies, obstetric sphincter injury following delivery, surgical sphincter injury which may occur after a fissile repair, pelvic trauma, rectal prolapse, and collagen vascular disease.

Current treatment concerned with medical therapy which centers around treating the underlying disorder using anti-diarrheal medications, changes in diet, especially fiber; disimpaction, and scheduled toileting.

Biofeedback, which in certain sub-populations can benefit 70 to 90 percent of people. Surgery, including sphincter repair, has a 70 to 90 percent success rate in those with sphincter defects.

Skeletal muscle transposition of the gluteus or vercilis muscle, rectal prolapse repair, which has been anywhere from 45 to 85 percent success rates; and then finally almost as a treatment of last option would be a diversion ostomy.

Other investigational methods which are not apparently through the United States include muscle transposition, plus stimulation, sacral nerve stimulation, and injection of bulking agents.

As Mr. Worrell and Dr. Wong pointed out, this is a picture of the device, consisting essentially of three components. There is the inflatable inclusive cup, which is placed around the anal canal, connected with kink resistant tubing to the pump control.

The pump is placed either in the labia in the female, or the scrotum in males. This can contain a septum for adding fluid post-operatively, and the bulb which the patient squeezes to operate the device.

The pump is connected with kink resistant tubing to a pressure regulating balloon, which is placed in the pre-vesical space. That controls the amount of pressure exerted on the anal canal by the cuff.

When a patient wishes to defecate as Dr. Wong explained, the patient presses the bulb several times, which moves fluid from the cuff through the mechanisms in the control pump, to the regulating balloon, opening the cuff and allowing the person to defecate.

The balloon then repressurizes the anal canal by way of the cuff over the next several minutes. Right now I would like to introduce Kathy Olvey, who we affectionately call our fecal focal point, to discuss the pre-clinical studies.

MS. OLVEY: Good afternoon. I am going to present a brief overview of the pre-clinical testing. This information was submitted in the HDE for the Acticon. That HDE was approved in September of 1999.

The same testing requirements are needed in an HDE as in an PMA. Pre-clinical testing included the results of material safety testing, evaluation of device performance, and sterilization.

The components of the Acticon Neosphincter are identical in design and materials to the American Medical Systems artificial urinary sphincter. The artificial urinary sphincter has been marked since 1973, and it received PMA approval in June of this year.

While the corresponding components of the two devices are not identical, they differ only in size. The two devices are assembled using equivalent methods and sterilized under the same conditions. The largest percentage of material in the Acticon, almost 95 percent, is solid silicon.

Biocompatability testing of the raw silicones was performed by the silicones manufacturer in accordance with FDA requirements. Testing on the finished sterilized device included identification and quantification of extractable compounds, and in vitro and in vivo biological testing.

Extracted testing was a risk analysis to identify and quantify compounds that may lead from the silicon, and that evaluate the potential risk to implant recipients based on available toxicity information.

Extracted data was obtained for the artificial urinary sphincter, and then extrapolated to account for the larger mass of the Acticon. The results of this testing showed that a recipient of the Acticon is potentially exposed to measurable amounts of several extractable compounds, monitors, and low molecular weight salosines (phonetic), catalysts images, and soluble silicon.

The potential exposure levels were compared in published results from toxicity studies to assess the possibility of significant health risks due to the extractors. The potential doses of extractable substances associated with the implant were negligible compared to doses observed to be toxic in animals.

The comparisons demonstrated that these extractors do not present significant health risks to Acticon patients. In addition to the risk assessment conducted on the potential extractors, biocompatibility testing was conducted using extracts or devices materials collected from samples of the finished sterilized device.

This testing was conducted in accordance with the FDA guidance use of International Standards, ISO 10993. The results of this in vitro testing indicate that the materials are biocompatible.

To evaluate whether there were any systemic effects of the implanted material on the host system, studies were conducted in which ground silicone was implanted subcutaneously in rats. There were no findings of toxicological or immunogenic significance associated with the implantation of the silicone.

Non-clinical bench testing was conducted to assess the physical and performance characteristics of the Acticon. The testing was grouped into three categories; performance characteristics, reliability, and component strength.

Testing was conducted to assess the performance characteristics for each of the device components, and examples of the type of testing conducted include pump squeeze force, pump refill time, kink resistant tubing performance testing, cuff balloon inflation/deflation characterization; and impact of septum access on balloon pressure.

Reliability testing repeated the tests conducted for performance characteristics testing, but was intended to evaluate the reliability of the long term use of the device.

Component strength testing assessed the integrity of the various components used in the system. This testing demonstrated that the components adequately performed the early estimated life cycle of the Acticon.

The components of the Acticon are sterilized for sterility assurance level of 10 to the minus 6. The pressure regulating balloon and attached tubing are sterilized using ethylene oxide. The cuff and control pump, with attached tubing, are steam sterilized.

The sterilization protocols were adequate to determine that the device is sterile, and the method of sterilization is identical to that used in the artificial urinary sphincter.

The Acticon is labeled with a 5 year shelf life, and an accelerated agent study was performed ont he package configuration, and results from the study show that the packaging will provide physical protection and a sterile barrier for a five year shelf life, with a 2 year safety margin.

Now, Dr. Yustein will continue with the presentation of the clinical data.

DR. YUSTEIN: The PMA pre-Acticon Neosphincter was supported by two prospective clinical trials performed in the United States. The first one was G880037, which was a feasibility study, and the second, G960116, was the pivotal trial.

With respect to the feasibility study, this was used in an earlier version of the Acticon Neosphincter, which was adapted from the AMS 800 urinary sphincter.

This was a multi-center prospective study which took place from August 1988 to April of 1995. Quickly, the objectives of this study, number one, were to demonstrate that the device could be surgically implanted without adverse sequelae to demonstrate the device providing an acceptable level of continence to demonstrate that the anticipated adverse events had a low incidence, and could be managed without long term sequelae, and to demonstrate that there were no unanticipated adverse responses associated with the device.

Now, 21 patients, including 10 males and 11 females, were enrolled at three sites. The ages ranged from 15 to 68. As you can see, over 50 percent of the etiology were either anorectal trauma or obstetric injury.

With respect to results and safety, 12 out of the 21 patients, or 57 percent, experienced adverse events. This included five patients with infection, and five with a mechanical malfunction, and two with pain.

And 9 out of the 21 patients, or 43 percent, required surgical revisions, and this included all five patients with malfunction, and 4 out of the 5 with infection.

And 5 out of the 21 patients, or 24 percent, required permanent device explanation. This was 2 out of the 5 patients with malfunction, and 3 out of the 5 patients with infection.

With respect to the effectiveness, the outcomes were based on the patient continence diaries that were kept, and the follow-up ranged anywhere from 7 to 76 months. And 10 out of 16, or 64 percent, achieved complete continence to liquid and solid stool, and an additional 18 percent, or 3 out of 16, achieved continence to solid stool, but experienced an occasional leakage of liquid stool.

If looked at with an intent to treat an analysis under five patients that were explanted and are included, this number becomes number becomes 48 percent, and this number becomes 14 percent.

Following the feasibility study, several modifications were made on the device. This included a reenforced longer cuff for improved pressure transmission, a larger pressure balloon, and the addition of a septum port to the control pump for the addition of fluid post-operatively.

The pivotal trial, and this was a multi-center perspective, non-randomized trial, with each patient serving as his or her own control. As Dr. Wong pointed out, 19 sites, mostly in the United States, and three in Canada, and three in Europe.

The study started enrollment in February of 1997, and ended enrollment in December of 1999. The objectives briefly were to demonstrate that the Acticon Neosphincter could be surgically implanted without serious adverse sequelae.

And to demonstrate that the device provided an acceptable level of continence as determined through the use of a fecal incontinence scoring system questionnaire, which was discussed by Dr. Wong.

And to report the adverse events associated with the implantation of the device, and to demonstrate that these events could be managed without serious sequelae.

The inclusion criteria briefly included fecal incontinence for greater or equal to 6 months. The patient had to have failed at least one non-surgical treatment, and have a FISS score of greater or equal to 88.

The other inclusion criteria are listed up there. The exclusion criteria notable for a FISS score of less than 88; irritable bowel syndrome is the only cause of incontinence; and inflammatory bowel disease, active pelvic sepsis; pregnant patients; history of extensive pelvic radiation; scarred and fragile perineum; patients who engage in anal receptive intercourse; and patients enrolled in another study involving investigational products.

Approximately 115 patients were enrolled, and 112 of them are implanted, and the average age was 49, ranging from 18 to 81. The average age of the females was 53, and the average age of the males' enrollment was 36.

As pointed out the majority of the patients were female and a large majority were caucasian. The etiology of incontinence, as Dr. Wong pointed out, again the number one is obstetric trauma or injury.

Previous treatments, also show on a slide by the sponsor, all had undergone other treatments, including medical bowel management and other surgical procedures.

The primary study end-point. The device effectiveness was assessed by analyzing the difference between the pre-implant FISS score, which could range anywhere from 88 to 120, and the score at 12 months, post-implant, which could range from zero to 120.

A clinically significant improvement was defined as a reduction in score of greater than 24 points. The FISS score was validated in a study by Vaize, et al, which was published in Gut in 1999.

This is an example of the FISS questionnaire. As you can see, it consists of five questions. The top four relate to how often a patient experiences various symptoms, including accidental bowel leakage of gas, soiling or seepage, leakage of liquid stool, and leakage of solid stool.

The fifth question assesses the general effect on the lifestyle of incontinence. Each answer had a unique point system assigned to it, and the total is obtained by taking the highest score from the top four and adding the score from question number five.

So for this patient, the highest score is 85 in question number three, and three would be added to it to obtain a score of 88, which would enroll this patient in the study.

You have seen this slide as well. This is the breakdown of what the numbers correlate to as far as the definition. I just wanted to also point out that 25 patients pre-implant were in this category, and 35 patients were in this category, and 38 patients were incontinent to liquids or solids greater than daily.

Also of note, 23 patients had a maximum score of 120. The second end-points as mentioned included anal rectal manometry, mean resting pressure pre-implant versus 12 months.

And fecal incontinence quality of life questionnaire, and the health status questionnaire, and the adverse device effects.

Following implantation, this was the follow-up schedule for the patients. At 6 to 8 weeks, the patients were activated; and at 6 months, FISS score, and the quality of life questionnaire and manometry were performed.

And at 12 months, those same studies were performed, as well as the health status questionnaire and/or anal ultrasound. With respect to results effectiveness, Dr. Wong presented these results.

The pre-implant, the average FISS score was 106; and at 6 months, 50; and at 12 months, 49. The average drop was 57 points, and just for your reminder, 49 corresponds to seepage or soiling daily.

This slide depicts the breakdown of FISS scores at 12 months for 67 patients, with scores at that time, and if you will notice the other slide was 61, and this also includes six stoma patients, which made the 12 months time period, and had scores at that point.

Basically what this shows is that about 70 percent of patients had incontinence to liquid or solid on a less than monthly basis at 12 months, for those that did meet the 12 month criteria.

This is just a graph depicting the breakdown of FISS scores, both pre-implant in green, and post-implant at 12 months in those patients that did make the 12 months.

And 67 patients did have 12 month follow-ups, and six of these started with stomas, and therefore, they had 12 month scores on the FISS system, but no pre-implant score to compare to.

Of the remaining 61 patients, 52 had a 24 point reduction at 12 months, and this corresponds for variable patients, and this corresponds to 85.2 percent.

There was a FISS significant difference between 12 month scores for females, versus males, and no other differences between other sub-groups were noted.

An adjusted ITT was presented by the sponsor earlier, and these are the breakdown of those numbers. The FDA's ITTs differ slightly, and we have added the three patients lost to follow-up, and the six with no 12 month follow-up in the failure category.

And based on this, our success rate is 59 out of 115, with all 115 being accounted for, with a success rate of 51.3 percent. This slide goes back to a question that Dr. Woods asked before. This is just some raw data that I had compiled.

In the intent to treat analysis, you had asked about the three sub-categories and how well each patient in that category did, and this is the rough breakdown for patients with pre-implant scores of 97 or below, and 17 out of 28, or 61 percent met the success criteria.

And for the patients in the category of 97 to 108, 23 out of 49, or 47 percent. And for 109 to 120, 50 percent. Now, this category also includes the 14 stoma patients which were assigned a pre-implant score of 106.

DR. TALAMINI: Is there any statistical data?

DR. YUSTEIN: I don't have the statistical analysis on that, no, I'm sorry. So, I can't answer either way. With respect to secondary end-points, Dr. Wong already showed this. The statistical significant change in manometry from pre-implant to 12 months.

The fecal incontinence quality of life questionnaire, which he also discussed, I presented the data in a little bit form. The patients, when they answered these questions, answered such things as most of the time, some of the time, strongly agree, and somewhat agree, and I chose to take only the patients that responded most of the time, or strongly agree, and compare pre-implant and 12 months.

Again, as you recall, this is at 113 and this is at 67 patients as was discussed earlier. So, for example, 89 percent of the patients pre-implant, felt that they had no control of their bowels most of the time; whereas, 9 percent of the patients who had 12 months, said the same thing.

The other secondary end-point was the health status questionnaire. As was mentioned before, the average, the 457 average, pre-implant, and 555 post-implant, with a score of 800, represent an ideal functioning.

DR. TALAMINI: Can I just ask a question about the slide before that one. I'm sorry, but I didn't catch the end numbers of 113 and 67, but they are there.

DR. WOODS: Did you happen to break it down and look at the 67 at 12 months, and look at their answers to the questions, pre-implant?

DR. YUSTEIN: No, I don't have that. This is the eight scales for the HSQ, showing that 6 out of the 8 significantly improved. The other two which did not, there were limitations, emotional problems, and bodily pain did show some improvement, however.

With respect to safety, much of this was gone over before. A total of 456 adverse events were reported, and 395 were believed to be either device related or potentially device related, which account for 87 percent of the total adverse events.

And 67 or 17 percent required no intervention; and 142 or 36 percent required surgical intervention, including 81 surgical revisions in 56 patients.

This chart depicts the common adverse events which affected greater than 10 percent of the patients. As you can see, things to note are infection as we have discussed, and 36 patients experiencing 41 events, and 33 of which required surgery.

Erosion occurred in 24 patients, and a total of 28 events, and 27 of which required surgery. The alterations in bowel habits all were approximately 20 percent changes, and fecal incontinence, constipation, and compaction.

I wanted to spend just a minute on revisions. A definition of a revision was a repositioning, removing, and/or replacing one or more device components subsequent to initial implantation, and as was mentioned before, the overall rate was 50 percent, or 56 out of 112 implanted.

And Dr. Congilosi already described the other data. The indications for revision, the two most common being infection, which required 30 procedures in 28 patients; and erosion, which required 27 revisions in 24 patients.

Also, it is important to note that 13 of these were overlapping, and in 13 patients, infection and erosion combined were the indication for revision.

As far as infection and revision, as I already stated, 28 patients, or 25 percent, required 30 revision procedures for infectious complication, and a fair number of these occurred within 30 days or 60 days after implantation.

No significant differences in rates of infection were noted among the sites, gender, or length of operation. With respect to erosions and revision, 27 out of the 28 events required surgical revision to correct. And as has already been pointed out, the most common erosions were cuff to rectum and perineum, and in pump erosion, and in tubing accounting for less.

Explanations. A total of 34 patients, or 30 percent of those implanted underwent 38 total device explanations, and that includes four patients who underwent explanation, followed by reimplantation, and a second explanation.

The mean time to explanation was 4.2 months, and as noted with the revisions, a large majority were due to either infection, erosion, or a combination of the two.

The other three reasons for explanation was, one, a patient with recurrent incontinence, one patient with pain, and one patient that developed an anal urethral communication.

No unanticipated adverse events occurred during the course of the study, and no deaths occurred during the course of the study. In summary, fecal incontinence is a common health issue which can have a major impact on a patient's quality of life.

There are several treatment alternatives, both surgical and non-surgical, each with its own risk benefit profile. The Acticon Neosphincter has been studied under two IDEs in the United States, involving approximately 135 patients.

When patients are considered in an intent to treat analysis, 51.3 had a clinically significant

-- I'm sorry, 51.3 percent had a clinically significant improvement in fecal incontinence one year after implantation as defined by the FISS score.

And 50 percent of the patients implanted required at least one surgical revision within one year, and approximately 30 percent of patients required total device explanation within one year.

The majority of these revisions and explanations were as a result of infection and/or erosions. Thank you for your attention, and that's all I have.

CHAIRMAN KALLOO: Are there any questions or any clarifications from the panel to the FDA? If not, thank you very much. Are the sponsors prepared to provide some of the data before we break for lunch?

DR. CONGILOSI: Susan Congilosi again speaking. I can give one clarification on the questions regarding explanations. Again, there were 38 explants, and 11 were reimplanted, and 7 remain candidates. That means that there are 27 patients that are permanent explants.

These are detailed in long histories in our notes, but in general nine of those went permanent stomas, typically after 1 or 2 attempts at revision, and then a decision to go to a permanent stoma.

Four had preexisting stomas. That leaves 14 patients who were judged as not candidates, or will not go on to another implant. The various reasons included a judgment that they were at an increased risk of infection because they had had two times that implant and both had eroded.

Technical reasons that they were judged by the surgeons that they were not able to attempt another implant, and two patients were decided that they were eligible, but that they did not want to undergo this further treatment.

Development of new medical conditions, such as cancer, cardiac disease, patient choice, which also came out with ones with preexisting stoma, and three patients who you would probably categorize as poor patient selection for their general health, and not mental status.

MS. NEWMAN: Which were men versus women? You said that the majority of your patient population were women, it is interesting that you show the men. So how many were men?

DR. CONGILOSI: We can find that out. It is going to be a variety.

CHAIRMAN KALLOO: Do you have information on the co-morbid conditions?

DR. CONGILOSI: Co-morbid conditions? I don't have that either.

MS. BEAURLINE: Analyses of risk factors?

DR. CONGILOSI: No, other co-morbid conditions pre-operatively.

DR. SMITH: One question. When you have the --

CHAIRMAN KALLOO: Let her see if she can finish this, and then we will ask further questions. Are you ready to respond?

DR. CONGILOSI: The question about their status, the best way at this point that we can tell you is their FISS score preoperatively to the last one obtained before explanation, and in those the number didn't make it to the 12 month score.

But of those that did, only one was worse. So in general they hadn't improved, and then it went on possibly to infection and explanation, and that is the best that I can give you on that, because patients are not studied after explanation with that questionnaire.

CHAIRMAN KALLOO: Question?

DR. SMITH: Yes. When you had an erosion, could you not put the cuff in transabdominally at a higher position?

DR. CONGILOSI: That is not recommended at the time of the use of this device. It has in selected cases in the HDE been placed above the levators, and that may be an option for the more difficult patients, where they are placed in a prone position, and the incision is done differently, and it is done above the levator muscle.

DR. SMITH: Thank you.

DR. KOLTUN: Tell me if I am wrong, but aren't there different sized balloons or reservoirs that provide different degrees of pressure?

DR. CONGILOSI: Yes, but that was not found to be significant with risk of erosion or infection.

DR. KOLTUN: It was not?

DR. CONGILOSI: That was one of the categories that they looked at with both infection and erosion, and it was not significant.

DR. KOLTUN: So what makes you decide as to what sized reservoir or balloon that you use?

DR. CONGILOSI: In general, if we are placing a larger cuff, we would place the larger reservoir.

DR. KOLTUN: But that does not relate to erosion at all?

DR. CONGILOSI: Right.

DR. KOLTUN: Does it relate to changes in the anorectal manometry pressures?

DR. CONGILOSI: I don't know if we specifically looked at that.

DR. WOODS: Would it be an absolute recommendation that a woman who has one of these placed and who becomes pregnant be delivered by C-Section?

DR. CONGILOSI: In my mind, yes; just as I would advise a woman who has had an overlapping sphincteroplasty to seriously consider a C-Section rather than run the risk of reinjury, yes.

And we don't know that someone could not choose to do that, but my recommendation would be a C-Section.

DR. CONGILOSI: Okay. If there are no further questions, we will break for 45 minutes for lunch, and return at 1:15. Thank you.

(Whereupon, at 12:27 p.m., a luncheon recess was taken.)

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

(1:17 p.m.)

CHAIRMAN KALLOO: I would like to begin by asking the sponsor if they have managed to put together a response to the questions that were still outstanding? Again, please identify yourself by your name and affiliation.

MR. GETLIN: Yes. My name is Larry Getlin, and I am with American Medical Systems. We are still putting together a couple of slides. So we need a couple of more minutes, and if there is other business that needs to move forward, we do have some answers to the questions that you have raised.

CHAIRMAN KALLOO: About how much time do you need?

MR. GETLIN: Larry Getlin again. They are just finishing up making slides. I would imagine about 5 minutes or so.

CHAIRMAN KALLOO: What I will do then is have Dr. Talamini make some general comments, and then we will go into the specifics of each of the questions. Dr. Talamini.

DR. TALAMINI: Well, I was asked to be a lead panel reviewer for this device, and I don't have prepared slides, but I do have a couple of thoughts, and I think they are thoughts that would be shared certainly by the surgeons, and probably the gastroenterologists in the room as well.

This certainly is a field -- the avoidance of ostomies and the continence issues is a field of great interest to surgeons for many, many years, and the field of trying to come up with an alternative to a stoma, or a continent stoma, has been an endeavor that surgeons have been in the forefront really for many, many years now.

But unfortunately as we all know, it has been a very stubborn problem, and medical history is littered with attempts to succeed here that did not succeed.

It is probably going to become worse in the next number of years as the baby boom generation ages, and the women in that generation in particular begin to have their child birth related continence problems.

It is estimated by most people that the number of women with these problems is going to continue to grow. So it is certainly an important topic, and I would congratulate the company and the panel members this morning really for bringing up most of the issues that I think we need to deal with this afternoon as we discuss this particular product.

The one additional comment that I would make is that as surgeons, when we talk about procedures, we always talk about risk benefit ratio, and that question has already come up this morning.

And when the alternatives, such as incontinence, or stoma, are as extreme as they are, that certainly makes you think a little bit differently about what the risk issues are.

And I think it is going to be in that framework that we are going to need to discuss the relative merits of the application today. It looks as if our team might be ready.

CHAIRMAN KALLOO: Okay. Mr. Getlin, are you ready?

DR. CONGILOSI: Okay. Susan Congilosi. I will address some previous questions. One was a question about patient dissatisfaction as a possible sole reason for explanation. It was not. It was patient dissatisfaction listed as a reason for four patients with revisions.

They all had other reasons for the revision. There is no patient who had an explanation solely for patient dissatisfaction. The other question was regarding co-morbidities, and I guess there were variations of that question with regard to co-morbidities, and patients who had infection or erosion, and also success.

When we go through those who were explanted, in general, you can find that they all had infection erosion at some point. The co-morbidities were looked at in patients who had infection and erosion.

So there is only one patient explanted who did not fall into this study as far as knowing what their co-morbidities are, and that is a patient with other medical problems.

So the co-morbidities, if you want me to list them off, are these 47, but in general it does address the issue of age, gender, previous pregnancies, previous vaginal deliveries, musculoskeletal condition; previous conditions, such as GU condition, diabetes, allergies, respiratory conditions, CV condition, neurological, psychiatric conditions.

And previous surgeries, such as rectal prolapse sphincteroplasty, circulus, transposition, gluteus transposition, post-anal repair, pelvic radiation, Gyn-Surgery.

The only significant factor for co-morbidity again was diabetes. For factors after implantation, preoperative stay, volume in the cuff, the preoperative antibiotics used or not used, and the preoperative bowel prep.

And whether they had a stoma. As you know, in one case that did fall out. The surgical approach, and whether we did a lateral incision or an anterior incision.

Anal canal length, and anal canal circumference; cuff width, cuff length, and none of these factors were significant.

CHAIRMAN KALLOO: Thank you.

MR. WORRELL: David Worrell, AMS. A couple of other points of clarification. The question was asked what was the gender breakdown in patients who were explanted.

Out of 98 activated patients, there were 24 explants, and 20 of the patients were female. That is 83 percent of the 98. Four of the patients were males, 17 percent, and so 75 percent of the patients in the study were female.

And then a little more information. I direct you to your panel packs, and to follow up on risk benefit. Another way that everyone on the panel I am sure is familiar with analyzing risk benefit is life table analysis.

And on pages 54 and 55 of your panel packs, we have life table analysis. At 12 months the probability of remaining revision free with the device is 73-1/2 percent.

CHAIRMAN KALLOO: Which section is that?

MR. WORRELL: Section 3, clinical summary, pages 54 and 55. Table 20, there is a figure in a table, and quickly at one year, your probability of remaining revision free if treated with the device is 73-1/2 percent. That is Table 20 on page 54.

Table 21 on page 55 addresses explants, and the probability of remaining explant free at 12 months is 80 percent.

DR. TALAMINI: That is based on 98 patients? It says that at the top of page 54, is that correct?

MR. WORRELL: That is correct.

DR. TALAMINI: Which 98 is that, because that sounds like a different number from either the 150 that we started with, or the --

MR. WORRELL: Those would be patients that we have activation times on, and either an explant, or a revision time on.

CHAIRMAN KALLOO: Thank you. We will now begin with the panel discussion portion of the meeting. Although this portion of the meeting is open to public observation, public attendees may not participate, except at the specific request of the panel.

Do any of the panel members have any general comments or questions before we proceed to the panel discussion points?

DR. STEINBACH: I do, and I think it shows up several ways. This is understandably not a randomized control double-blind placebo test. I think that anyone would have a hard time getting through an IRB, saying that we are going to do patients who have failed preliminary alternative studies, and we want to just watch some of them for a year, and others we will give this treatment to.

I suspect that this option would not be approved by institutional review boards. So as a result, things like intention to treat, we don't have a real comparison. And the one where it is most important is quality of life assessments.

This measure has a very strong placebo effect, and so we don't know what the quality of life improvement would be in, for example, the stoma group, or the people who had an explant because they were not followed.

And whether they said, okay, I gave it my best shot, and now I feel better about having to wear pads. So there is no question that these people have a better quality of life.

What I don't think we have a handle on, because it is not part of the study with a real control group, what another group of patients not given this treatment, how their quality of life would improve.

I think in San Diego that we are well aware of the fact that you can play professional football with a stoma, and so I think with -- and everyone here is aware that stomas create problems.

But with proper management the patient would -- I think many would report a quality of life and just pulling studies out of the literature are not fair comparisons for this group.

And so we really don't know how much the quality of life was improved by this procedure. And I think the other point is that in two of the literature cited they suggested a control group would be dynamic -- recilioplasy, if I am pronouncing that right.

This, however, is another experimental procedure, and the FDA rules say that we can't use this as a comparison. So that we are going to have to let the sponsor do this test. We can't require that it be part of this PMA.

CHAIRMAN KALLOO: Any comments about that, the issue of the quality of life?

DR. KOLTUN: I have a comment that relates to that a little bit. There seems to have been a group of patients who went through both this procedure, and then a stoma, right? That would have been an interesting group of patients to evaluate from that, at least the QOL standpoint.

But it would have been interesting. I know that there are studies in the literature that talk about how patients frequently after they get the stoma have a very different opinion of it having now had it.

So the issue of quality of life is a real one, because frequently the perception preoperatively of what the stoma is like is not accurate enough, and in fact after the fact patients are surprised by their ability to function in that fashion.

I am not sure at what point in this forum or this meeting that we should offer maybe the ability to ask a question of the person who presented the layperson who had the sphincter.

But what was her educational process, and what was her understanding of what stomas were about, and the experience that she had with regards to knowing really what a stoma was like.

In other words, what did you think about a stoma, and what had been taught you about a stoma, and what experiences have you had to absolutely delete it from your mind.

MS. LOITZ: It wasn't deleted from my mind at all.

CHAIRMAN KALLOO: Madam, if I could ask you to come to the microphone, and again please just repeat your name.

MS. LOITZ: Nancy Loitz. The option of a stoma was not eliminated as an option for me at all, and my life was bad enough in dealing with this problem, and it was bad enough that I would have gone in that direction, I think, and that it would be there today had I not gotten an implant and had it been a success.

DR. KOLTUN: Wouldn't you feel that right now the impression that you have is that --

CHAIRMAN KALLOO: Can you speak into the microphone, please.well,

DR. KOLTUN: My impression would be that you would be exercising now, and you would be dynamic, and you would be jogging, and you would be doing all those things. You would be a person much like you are now, even with a stoma.

MS. LOITZ: I think that is probably true, but I would not want to have only that as my option, because this option has worked so well, and this option is completely under my skin. It functions as normally as I functioned, or any of you function.

So while I don't think I would have been embarrassed by that option, or would have said, no, I won't do that because it is a stoma. I am not that type of person.

I don't want it to be my only option if there is another option that could also be successful. I want to consider both of them.

DR. KOLTUN: I think from my standpoint, getting back to the more professional aspect of this, is that the issue in my mind is do no harm. And I would like to see a more thorough analysis of the failures.

In other words, I want to know that in fact those patients were as bad as they could have been, and in fact were not harmed by a failed attempt at this option; though we see a very healthy, dynamic, and great success in front of us. But I want to know that the people who are on the other side of the story are not worse off.

CHAIRMAN KALLOO: Thank you, Ms. Loitz.

MS. NEWMAN: This is not so much maybe here, but in the whole process. I have been coming here often, and sometimes we include European data, and last year they had thousands, and thousands, and thousands of people that had that procedure.

And so why aren't we including that? And then we go to panel where all you do it on is European data. And I think that this goes along with what we are saying, is that if there is more data in the world on this -- and again I am bias, because I have had -- done something with the urinary sphincter device, and we put those in every week.

And why isn't that stuff included? Is it because the FDA doesn't ask for it, or the company doesn't want you to? There is more people than just in the U.S. So I think we can learn a lot whenever we understand the whole history of these kinds of things.

And I don't understand why because there is a couple of meetings, and we go back and forth over this.

CHAIRMAN KALLOO: That is something that I myself have personally asked about -- and I guess that it is not available as best as I --

DR. STEINBACH: And as a statistician, I would say that the Europeans are not following your protocol in general. And so if you are setting up a controlled trial, you want control of what is done to the patients to be more than just -- well, I think that is the reason.

CHAIRMAN KALLOO: A under reporting of complications and adverse events would be issues that would make that data very questionable as well. Any other comments by any of the other panel members?

DR. SMITH: One question. Are we going to discuss anything about the labeling?

CHAIRMAN KALLOO: Yes. Yes.

DR. SMITH: We just have not come to that yet?

CHAIRMAN KALLOO: Yes. That is going to be in the group of questions that will be following that we will be discussing. So now I guess we will go to the questions to the panel.

And what I will do is ask each of you to comment on this question, and then Dr. Talamini will summarize the panel comments at the end of the discussion on each question.

And again you can ask for clarifications from the sponsor and from the FDA. Do you want to put up the first question, please.

A total of 395 device related or potentially device related adverse effects events were reported among implanted patients, including 43 events which required surgical intervention.

Half of those implanted required at least one surgical revision, and 30 percent underwent explanation of the device. A significant portion of these surgical interventions were a result of infection and/or erosion.

Please discuss the safety profiles of this device overall, as well as in relation to other treatments of fecal incontinence. And if Dr. Smith could please comment, and we will go around the table.

DR. SMITH: I don't think that this device is the device where you are simply putting in a sphincter and that is going to solve all the patient's problems.

And this is a device that is associated with recognizable risks, and again I think the important thing is to recognize the benefit that these patients can have from the device, as opposed to whether that would make it worthwhile for them.

So, I am not particularly concerned about the higher incidents of complications. I would be concerned if the patients were not aware of this risk before they had the procedure done.

If they are fully aware and they are cognizant of all the risks that are associated with the procedure, then I think that this is something that is acceptable to be done.

And also the other factor is that in this group, again this is cohorts of patients and who are very small in each group. And we have found in the neurological devices that the better that you get at it, and the more devices that you put in, the lower your complication rate. And I think that the statistics will improve over the course of time.

CHAIRMAN KALLOO: Dr. Woods.

DR. WOODS: I agree with what Dr. Smith has said with respect to the complication rate. I think that is something that would not naturally be unexpected working in this area.

I also agree very strongly with what Dr. Kolten echoed earlier about the options that patients have with an ostomy, and the fact that there is often a psychological barrier to an ostomy that is probably the most difficult thing to overcome for patients.

And as was pointed out by the patient herself, knowing that she had another option to explore I think is a very important one for patients in making the right choice for that individual.

So I think it is a good think to have options. I think it is very important that a patient understand at the outset what those two options are and what the complication rate is with this device, and that there is at least a 50 percent chance that they are going to have to have another operation if this device is used.

But if they understand that at the outset and make that choice, I am comfortable with the complication rate.

CHAIRMAN KALLOO: Dr. Steinbach.

DR. STEINBACH: I agree with what has been said that this high rate is acceptable if the patients are prepared for the consequences emotionally, if no other way, and that they are -- that this is being restricted to a use of patients who are at risk for complications.

DR. KOLTUN: I don't have much to add. Simply, I think that the degree or number of infections is such to be expected to a large degree based upon the anatomic considerations.

That is really about it. I think the issue once again becomes one of trying to minimize those complications, and I think it would be up to the clinician largely to recognize the appropriateness of this kind of operation in the patients that they are dealing with.

There are clearly going to be risk factors that worsen the possibility of complication, and other risk factors that may in fact get so close as to be a contraindication.

MS. NEWMAN: I agree. I don't have anything more to say on this.

MR. BANIK: I also agree

DR. EPSTEIN: I think this brings up several points, and one is exactly who is going to be implanting this device. It seems like there is a learning curve here to avoid some of the complications, particularly the cuff erosion into the rectum, or vagina.

And a discussion of the fragile perineum came up a number of times as to maybe being a little bit more careful in selecting the patients who are going to undergo the procedure.

And the question that comes up in my mind in relation to this is in how are the surgeons going to be trained, and what kind of requirements are going to be there.

Is it going to be done just in selected centers where these things can be monitored and observed, and the outcomes further defined? Clearly, there is a role for a specific antibiotic regimen, and all those issues I think need to be addressed to improve what was learned in this study, in terms of the safety profile.

CHAIRMAN KALLOO: Dr. Gellens.

DR. GELLENS: Well, I am like the rest of the panel. I am very concerned with this rate of complications to tell you the truth, especially in a small number of patients, and in this well-controlled and supervised trial.

My concern is that when this device is released the number of patients that it will be used on will obviously be much greater, and the number of co-morbid conditions that the patients have will likely become much greater.

Someone has already mentioned the fact that the population is aging, and as you start having older patients to deal with, and in which many more complications, including diabetes as was mentioned, and hypertension, and vascular disease and what not, even though we saw no deaths in this study, I think it is quite possible that with the current level of understanding with this device that it could be a significant risk to the population.

I think we have already seen that advances have already been made during the study here as far as antibiotic choice, and have improved the complication rates significantly. And I think it needs to be evaluated further before it is released on the gender population basically.

DR. MCCLANE: I think the complication rate is high, and again I think you really need to look at who is going to do this operation. It probably needs to be done in certain centers at least initially, or if you are not going to do it in certain centers, keep it from those centers coming out to the hospitals to train some of the physicians in doing this operation.

I know that once it is in the public that it is hard to restrict surgeons from doing it, and it is hard to know really whether this is a high complication rate, because there is nothing really to compare this particular procedure to.

I mean, you can take other operations, but then in those patients you don't have an opened bowel, or even colonic resections which they are referred to in the packet, the compared complication rate, and to the bowel resections.

But then again in those procedures, you don't have a mesh. And even anorectal operations generally don't put mesh in or foreign bodies. So this is a high complication rate, but it is hard to compare it to anything because nothing else is really similar to this.

So it may be a mesh in a colostomy, or colostomy hernias, but again I don't know what the data is, and I know that they have high complication rates for that procedure.

So it is going to be hard to decrease the infection rate and the complication rate, because it is a dirty field, and you are putting in foreign material.

But then the idea is that you are doing a lot of good for the patient, and as long as you tell the patient that they are going to have a high rate of a complication, it is probably worth pursuing.

CHAIRMAN KALLOO: Okay. Dr. Talamini, would you summarize the panel comments.

DR. TALAMINI: Mr. Chairman, I think the opinion of the panel as a whole is that they recognize that this study reflects a high complication rate, but with one vocal exception, it appears that the panel is willing to accept those high complications relative to the perceived high level of benefit to many of these patients.

The other summary point would be concern about the indications, which I think may well speak to labeling issues that we will get to discuss a little bit later, and a further summary point would be a consideration for who puts these devices in, and how they are trained, and where they are put in.

CHAIRMAN KALLOO: Thank you. Question 2. Currently, there is no gold standard for the measure of fecal incontinence. The fecal incontinence scoring system, FISS, was developed by the American Medical Systems, Incorporated, and used as a primary end-point in this study.

Patients were considered to have a successful clinical response if scores dropped by 24 or more points 12 months after device implantation. Please discuss the clinical significance of the 24 point score reduction on the scale. Dr. Smith.

DR. SMITH: Well, I think that is quite a dramatic improvement in the clinical condition, and I think it is an effective way of assessing them.

DR. WOODS: I tend to agree. I had the same question myself as I read the protocol, but when you look at what a 24 point reduction means, going from daily incontinence, and even to weekly incontinence for some patients, I think that is still a fairly dramatic improvement for the patient who is incontinence daily.

As has already been mentioned, this is a pretty devastating problem for the patients who suffer from this, and so I would think that a patient would be very, very pleased to be incontinent weekly versus daily.

And many of the patients I think improved even more than that, having incontinence less than on a weekly basis with the device.So I think it is a reasonable assessment tool.

DR. STEINBACH: I forwarded a question to the sponsor, and it was the fecal incontinence scoring system is new and we are not sure that it is a nice, normally distributed, random variable.

And a hundred patients is not enough to establish that. However, we are not left in the lurch, because there is non-parametric statistics that as long as we can say that a fecal incontinence score of 60 is not as bad as a fecal incontinence score of 70, that it correctly orders the problem.

Then an appropriate test would be the Wilcoxon ranking test, and the sponsor did it for the 67 patients that still had it implanted, and found a very significant P value.

I did it and included the stoma patients, and their value was a mean of 106 before, and if I transpose that 106 to the other end of the column, and looked at the 114 patients, because three weren't transplanted, it was still highly significant.

There were only 25 percent of the group that was worse off with this. So there is concern that the T test and F test that are used throughout the study are appropriate, but in the event that if a less restrictive test was used, this difference still is significant.

CHAIRMAN KALLOO: Dr. Koltun.

DR. KOLTUN: I think the scoring system is intuitively correct, and the difference that they found was from a clinical perspective, and from an intuitiveness perspective, something that was real and meaningful.

I think, however, that my concern in that regard is that again what about the patients who failed? Were they made worse? I don't want to sort of belabor the point, but we have looked at a study that has about a 50 percent failure rate, and we have been favorably impressed by the successes, or the quality of the improvement in the fecal continence were deemed successes.

So that begs the question a little bit in the context of what happened to the patients who were not successfully treated with this device. So I think that the system that they instituted, the fecal incontinence scoring system, I have no problems with.

But I would like to have seen that data similarly applied in evaluating the failures.

CHAIRMAN KALLOO: Ms. Newman.

MS. NEWMAN: I agree with that, because then I want them to put that information in labeling for informed consent. I would have liked to have known, well, what if I fail, and what would happen, so that the individual patient can make the decision.

If my quality of life or my symptomatology is so severe that I can't live with this, there is an "X" percentage of people that fail with this, and then what would happen, and I just think that should be part of this, because I really believe in a hundred percent informed consent.

CHAIRMAN KALLOO: Mr. Banik.

MR. BANIK: I felt that the model was a good model. I do agree that the model probably needs some more validation as we discussed earlier. But I do think it was significant that the 24 point movement on the scale is significant.

Many of the patients I think moved much more than 24 points, and that movement from an individual perspective is quite measurable and easily determinable. So I felt comfortable with the model being used.

Relative to the patients that were not -- that there was no data collected on, I share the same concern, and would like to see some data so that patients would know, well, what happens if the procedure fails.

I think we concentrated a lot, or the company concentrated a lot on the outcome of a positive result. I think there is data that can be obtained from the patient population that can be helpful in understanding the risk and benefits of those that the product had to be explanted from.

CHAIRMAN KALLOO: Dr. Epstein.

DR. EPSTEIN: I think more telling than the 24 was the issue of the patients wearing pads and diapers, and just looking here, the comment that in pre-implant that 88 percent were using pads, and 52 percent, and that was 88 percent per-implant, to 52 percent at 12 months.

And that the use of diapers fell from 51 percent to 15 percent. And there was also improvement in the quality of life from 30 percent enjoying their life less, as compared to 81 percent prior.

So I think to me that has more clinical significance than the scale itself, and I think that the biggest thing is the use of the diapers, and the rate of diaper use going down.

MS. NEWMAN: If I could comment on that. The technology of these products have changed so much in the last 10 years that that does not mean a lot, because there are four different sizes of absorbencies in pads.

And the wrap around adult briefs, which are diapers, are not even for incontinence, where you have much more fluid leakage, are really only used in the very frail, elderly, bed bound. So the technology is used.

You are going from an undergarment, to a perennial bad, to a slide pad, and so which of those slides are we talking about?

If you are talking about undergarments, that is not much of a difference change in absorbency. So I think that -- well, I am not sure what that really means, as far as that change, because that is a big change. You know, which pad.

DR. GELLENS: I don't have any problem with this scoring system. I thought that it was informative and very descriptive, and told a pretty good story of what was going on with the patients.

It is unfortunate that it has not been validated in any other setting, but I think for purposes of this study that it was informative and that it was okay.

DR. MCCLANE: I am also a little uncomfortable with the fact that there is not that gold standard for fecal incontinence, and the scoring system was developed by the manufacturer.

However, I do think that there was a significant difference in these patients pre-and-post implant, and when you see a drop of 24, and it is much more than that. So even though you don't have a validated system, I do think there was a real improvement in patients based on this system.

CHAIRMAN KALLOO: Dr. Talamini, will you summarize, please.

DR. TALAMINI: Mr. Chairman, I think the consensus of the committee is that the 24 point reduction reported is significant, using the fecal incontinence scoring system, and that it appears to concordant with other measures within the study, and perhaps most importantly our statistician expert feels that it has a basis as well.

So I think the answer to question two would be that the panel thinks that the 24 point score reduction is significant.

CHAIRMAN KALLOO: Question Three. Two quality of life questionnaires were used as secondary end-points during the pivotal trial. Please discuss the clinical significance of the overall changes in the perimeters contained in these questionnaires.

Dr. Smith.

DR. SMITH: I think that all clinical quality of life questionnaires are very suspect. It depends on how much the patient likes you, and most people feel that whatever decision they have made in life is the right one.

So it is seldom that people would say -- well, it had to be very bad for them to say that they made the wrong decision. I think the more important aspect of the whole thing was the objective data that we have previously looked at, rather than the quality of life.

DR. WOODS: I completely agree and I especially have a little more trouble evaluating the effectiveness of the fecal quality of life score, that three page questionnaire. It is almost impossible to really decipher exactly what happened with every patient through that.

It is interesting to see the numbers look like they are better, but there is no statistics that are gleanable from that sort of data. So I agree with what Dr. Smith said.

DR. STEINBACH: I agree with my colleagues that -- and I guess that I am restating the point, but that without a control group, a change in quality of life is awfully hard to interpret.

DR. KOLTUN: I agree, and again harping, I would have liked to have known what the failures would have said about their experiences, and what the people who went through a failure, and then a successful stoma placement said about their quality of life.

And I think that there is literature, and there could have been control groups in regards to assessing alternatives to the operative procedures and placement of this prosthetic device.

You probably would find a significantly improved quality of life response in patients who go through a colostomy without having gone through a procedure like this.

So I think that trying to interpret this quality of life data is very difficult without a control group, and without the approximate control group.

MS. NEWMAN: I agree with that, too, because again it would be nice if you had these options, and what is the data on both options. And I think this is a significant procedure, and we don't have all of that data in this area.

MR. BANIK: I also agree. I felt that the quality of life information was good, but wasn't something that we could really draw any definitive conclusions from. But I do think it was helpful in having it there.

CHAIRMAN KALLOO: Dr. Epstein.

DR. EPSTEIN: Well, I think in a little bit of a different approach, and that is simply just looking at straight outcomes and not looking at it scientifically.

What was important to me was that there was an improvement overall in the quality of life just amongst this group itself, and understanding the severe limitations of that.

But I think that it is a significant non-negative, and that there was not a worsening. So in that way I think the data is helpful both at the 6 month and 12 month follow-up to at least give you an overall sense that there was a feeling of patient well-being and patient satisfaction, notwithstanding the limitations that we do not have with this control group of an ostomy or whatever other control group there might be.

CHAIRMAN KALLOO: Dr. Gellens.

DR. GELLENS: I agree with what Dr. Epstein said about the fact that it certainly was not a negative report. But the data that was presented here was a little skewed I would say, since a lot of the quality of life data was initially presented on all of the participants of the trial, but the follow-up data was just presented on people who actually got the implants.

So I thought that the data was a little bit skewed in that sense.

DR. MCCLANE: I don't think that that is the most important part of the study either. I think that the numbers are very low. There were only 48 patients in the HSQ than any other. In the FIQL there were only 67 patients at 12 months.

So again that is really less than half of the initial patients. So I think it would be better if you looked at all of the patients in these follow-up questionnaires, and you would have better data.

CHAIRMAN KALLOO: Dr. Talamini, a summary, and I know it is not an easy one.

DR. TALAMINI: Mr. Chairman, I think the panel's opinion is that the clinical significance of the quality of life data is not as powerful as perhaps other aspects of the study, and they have inherent weaknesses, which the panel has outlined, such as lack of a control group, and the omission of the initial patients that were explanted.

However, the data do seem to reflect and agree with the other parts of the study. So they are not without some significance.

CHAIRMAN KALLOO: Thank you. Question Number 4. The intent to treat analyses as submitted by the sponsor and the FDA are shown in the accompanying chart. Please comment on these analyses, and also the effectiveness of the advice for the treatment of severe fecal incontinence when analyzed by this method.

So we have the intent to treat analyses in the chart as seen on your right, and I would like for you to treat on these analyses, and the effectiveness of the device for treatment of severe fecal incontinence using this method. Dr. Smith.

DR. SMITH: Well, I think that this is very similar to the first question that we do oppose, and actually it is a matter of risk-benefit ratio, and I think that if we have success with a fair percentage of patients, 56 percent, I think that provided that the patients know this beforehand, I think that one can live with it.

I think it is very hard to know the exact follow-up of the people that drop out of the trial, and there are failures, and it is very difficult, and as was mentioned earlier, we would like to know what happened to these people.

And those of us who have done these trials know that when people fail that they often disappear, and it is very hard to get them to come back and to report any additional data.

DR. WOODS: The six patients that are included in the failure rate for FDA, because of no 12 month follow-up, is it our understanding that there was no 12 month follow-up available, and that's just because they have not reached the 12 month mark?

If so, I see very little difference between 51 percent and 56 percent when it boils down to clinical applicability of this device. And I don't have anything else to say other than what has already been stated.

DR. STEINBACH: I agree that 51 percent is a demonstration of effectiveness.

DR. KOLTUN: Again, I think the success rate of 51 or 56 percent is irrelevant. It is what happened, and it has been shown, but my concern, because we are thinking risk benefit, we are looking at benefit.

But I really want to know what the actual risk is in the context of what happened to the patients who did not succeed, although they may not come back for follow-up, and QOL isn't what I am talking about.

I am talking about the length of hospital stay for sepsis, or complications, or things like that associated with these prostheses, and whether that represents so high a risk that at least the indications for placing such a device, which as someone has already mentioned, will start to become more commonly done, whether those indications, or contra-indications, should be more carefully spelled out.

Because right now with the number of patients that have been put into this study, though we see this success rate, the issues of which patients specifically should not be considered candidates, and which patients represent excellent candidates, is not clear to me, and I think there needs to be some guidance in that regard.

Because I think the experience yet with this device is still very much in its infancy. So the success rate I am very happy about. I think it is fine. But I would like to know for a fact that patients that did not succeed not represent such a high cost to pay for the success rate.

MS. NEWMAN: I don't have anything to add to that and I agree.

MR. BANIK: I also see very little difference between the 56 and the 51 percent. I agree with all the comments made thus far. The idea here is that there is some concern that probably will be discussed relative to label copy, and that my interests are the other part of the population that was not successful.

DR. EPSTEIN: I basically agree, but the thing that strikes me again is the failure rate, and I think it speaks back to the point where, for example, when laparoscopic colocholecystostomy first became available, there was a higher complication rate, and that has gone down over time.

And particularly the surgeons that were trained in that went to various specific training programs, and I think the information that the colorectal surgeons here, the most experienced ones, have pointed out needs to be communicated to the physicians that are going to be doing this in some form or way.

And I believe that with their experience in transmitting that that the failure rate could go down further with very carefully selected patients, and meticulous attention to surgical detail, appropriate antibiotic selection, and all the things that they have talked about, and how they have learned just in this early study.

And that information needs to be applied in some form or way to the surgeons here who are going to be implanting this. And perhaps it does need to be limited initially to some centers where they can really get excellent clinical results.

DR. GELLENS: I overall agree with what has been said so far, except for the failure rate, and that I still have major concerns with, and when it is available for use.

I mean, the expertise in using a device will increase, and I think that will help decrease the failure rate. But the patient population that it is used on will also increase, and a lot more illnesses, and that could increase the failure rate.

So I don't think just because there is going to be more experience with its use that that automatically will mean that the failure rate is going to go down.

DR. MCCLANE: I think that the 50 percent success rate is a pretty good number again as long as the other 50 percent aren't worse off. I agree again that we really have to try and do these in certain centers, at least initially, and the 50 percent is a good number when you compare it to the other surgical procedures that are done for fecal incontinence.

And in particular sphincter repairs, where the success rate a year, or year-and-a-half, or two years out, is around the same number as these patients are having some problems down the line, even with the sphincter repair, which I guess is right now the best operation for fecal incontinence.

So I think these numbers are pretty good when you start coming them to other things that are available.

DR. STEINBACH: Mr. Chairman, can I speak out of order?

CHAIRMAN KALLOO: Yes.

DR. STEINBACH: There is a paper referred to by the sponsors by Maloof that was in Lancet last year, and it looked at the United Kingdom experience outside clinical trials with this device, and I think that their general conclusion was that the community was less willing to do revisions of the device.

That if it failed once, they said, okay, we will take it out. I will jus say that for what it is worth.

CHAIRMAN KALLOO: Thank you. Dr. Talamini, will you summarize the panel's comments.

DR. TALAMINI: Mr. Chairman, the intent to treat analysis that we are looking at now doesn't appear to have altered the committee's opinion regarding the general effectiveness of the device.

However, it does underscore for most committee members a concern about the failures that we will probably have the opportunity to discuss further in labeling and in other issues.

CHAIRMAN KALLOO: I will ask the panel to help Dr. Talamini and the FDA to try to specifically answer the question that has been posed, and to feel free to provide us with your wisdom and experience.

But at a very minimum to try to answer the very specific question that we are being asked to answer. Question Number 5. Based upon the data in the PME, please identify whether there are any patient populations or subgroups that you feel would either clinically benefit more from the device, or be at a higher risk for adverse events from implantation.

So, patient population of subgroups that would either clinically benefit or be of a higher risk of adverse events. Dr. Smith.

DR. SMITH: I think it has been clearly stated in the PMA.

DR. WOODS: I think they have been fairly clearly stated as well. I would point out that it seems fairly repetitive that the surgeons who have done this have said that patients with very thin parineums, or who have had multiple repeated procedures previously, seem to be at higher risk for maybe erosion and perforations during the surgical procedure.

Also, I think it should be very clearly stated that patients who only have severe fecal incontinence should be considered for implantation of this device, so that we don't see the device being offered to patients with more minor degrees of incontinence.

Or to those who have not yet tried other alternatives to solve their incontinence problem before getting to this point. I think that should be very clearly labeled.

DR. STEINBACH: I asked the sponsor to break down the revision rate and the explant rate based on the etiology of fecal incontinence, and the obstetric was the highest, and this is part of your handout, but was not significantly different.

CHAIRMAN KALLOO: So you are saying if there was no difference -- I'm sorry, I missed what you said.

DR. STEINBACH: The conclusion on the numbers available was that the etiology of the fecal incontinence does not change the explant or the revision rate.

DR. KOLTUN: My feeling is that I don't think anybody can say -- I mean, based on the data that has been presented, there just aren't that many patients in the subgroup analysis, in any one subgroup analysis, to be able to be definitive in this regard is my impression.

I mean, they have not specifically looked at patients who are in some way or another being compromised. Are there issues with regard to underlying medical conditions in any one group, and things like that.

So, I think that there probably will develop a sense of who should and who should not get these devices preferentially as experience is gathered.

There is always a balance between how long do you wait so that that experience can be gathered more rapidly, versus mandating a need for such documentation in advance.

I have concerns about implanting such a device in some one who is at high risk, and yet use it as something that they have to have. And I think the clinicians who have been involved in the study would not do such. But I think some guidance in regards to possibly labeling is necessary here.

MS. NEWMAN: I have concerns, and you have women who have multiple pelvic procedures, and you have those that are menopausal, and with thin parineums, and should they go on estrogen? I don't know. These people age, and the biggest group they did was women.

So I think there is a lot of questions to be answered, and you see women who have multiple pelvic procedures by different specialists. So I don't think there is a lot of information there. I would like to see more fine tuning of which population this would benefit, and what do you do with those individuals.

MR. BANIK: I would like to agree with Dr. Woods' comments earlier. I particularly would be concerned about any patient that has had pelvic surgery, and I think it was voiced in some of the presentations earlier whether that could definitively be outlined in labeling copy, and all the adverse kinds of events could be thought out through so that it could be more clearly defined.

And I don't know if at this point that is possible. I sort of doubt it based upon the limited experience that people have had with the device. But combining that with the successful outcome of 50 percent or more, I think we have to weigh all those alternatives in the decision process.

And so it is a rather complicated decision, and I don't think the information is clear for us to determine wholeheartedly what should be put in here. But nonetheless something should be done.

CHAIRMAN KALLOO: Dr. Epstein.

DR. EPSTEIN: Yes, I have a little bit of a different opinion about this question. I think in a way this goes into the practice of medicine, and we do have board-certified trained colorectal surgeons who will be implanting these devices.

And it is certainly part of their prerogative. We make the information available to them as to what the risk and benefits are, and certainly the information -- I think what I have heard everybody say is the information from this study, and the information that the colorectal surgeons have presented should be incorporated in the labeling.

But after that this becomes a medical -- becomes the surgeon's prerogative to work up the patient carefully, and to ensure that his own or her own outcomes are appropriate and adequate, and it goes again back to the question of training.

And I think just putting the information about the problems with erosion and infection into the labeling very specifically, and I think it should be left at that.

DR. GELLENS: The only -- one of the main groups that I am concerned about is the immumosuppressed patients, either because of medications they are on, or because of underlying medical illness.

Because of the high infection rate in this device, that is my major concern as far as the high risk group.

DR. MCCLANE: I think that this is based on the data and the PMA and that we don't really know who are the best patients and those with the highest risk, because really the only two groups that are at a higher risk were those with allergies, and those with musculoskeletal abnormalities which intuitively wouldn't be the two groups that we would try to exclude from this type of a device.

So I think we have to wait until we get more data on it, and more patients, until we really know for sure on what patients would be at a higher risk.

CHAIRMAN KALLOO: Dr. Talamini, would you summarize the panel's comments.

DR. TALAMINI: Mr. Chairman, I believe the panel's opinion would be that based upon the data in the PMA, there are not groups that we can clearly identify that would benefit or be at a high risk.

But many panel members believe that such groups probably do exist, and will exist, and we will have more information as more of these are implanted over time, if they are.

CHAIRMAN KALLOO: Question Number 6. As proposed in the PMA submission, the indications for the use statement recommends the use of this device in post-pubescent males and females.

The pivotal study, however, only enrolls subjects 18 years of age or older. Please discuss whether the device should be labeled for use in post-pubescent patients under the age of 18 years. Dr. Smith.

DR. SMITH: I would be somewhat reluctant to employ such a device such as this in younger people that are developing, and I would be even more inclined at this stage until there is more experience with the device to use in the post-pubescent patient over the age of 18.

DR. WOODS: You know, I have no idea whether or not there is a lot of change or growth in this area after puberty is reached. I would rely on the comments from the colorectal surgeons here, but intuitively, I would think that there is not a lot of difference here in that age group.

And that the social impact of fecal incontinence in a teenager would be enormous. I would think that if we had something to offer them that we felt would be of success that we should offer it to them.

But I would like to hear the rest of the comments from the panel about the anatomy in the post-pubescent group.

DR. STEINBACH: There is some concern whether a child under 18 can give informed consent, and this is sometimes hard for the parent to understand whether this would benefit their child or not.

DR. KOLTUN: I share the concern that the children or youths probably would be more beneficially affected by the successful implantation for their long term psyche, and I think that would be someplace where this device would be a great, great benefit.

But unfortunately I get the impression that a lot of the success associated with this device relates to the actual physical nature of the device; the size of the cuff, and the length of the sphincter, and the way it is placed, and the various mechanical arrangements involved.

So I wonder in fact if that -- well, I won't wonder. I basically have a strong suspicion that the mechanical nature of it in a youth therefore will play all that much greater a role in regards to technical failure.

So I think probably there would have to be additional studies to prove this, and continued for an equivalent success rate in children, or in youthful individuals.

MS. NEWMAN: I agree, because I think, too, it is only the device that will release all those things. And I think that since the studies are done on those 18 and above, unless there are other studies of younger individuals, that it should just stay at 18 and above.

CHAIRMAN KALLOO: Mr. Banik.

MR. BANIK: I also agree. I think additional information would be required to consider what role the population below 18 would have at this time.

DR. KOLTUN: Can I speak out again?

CHAIRMAN KALLOO: Yes.

DR. KOLTUN: I was going to say that I think probably the criteria by which it would be decided would be sort of a physicality criteria. It would not be age criteria. It would be size criteria.

I am saying that I have seen 16 year olds who were 200 pounds, and looked like they had reached maturity. I think the issues would be the appropriateness of the size and the physicality of the device in relationship to the size, and the physicality of the subject.

So I know that we could probably say on age and things with regard to the legality of it, but I would be more akin to linking the appropriateness of using this device to the size of the individual, and the maturity of their physical development.

DR. TALAMINI: So you would be okay with somebody under 18 if they were the appropriate size?

DR. KOLTUN: Yes. I am not sure how you would define that, but I am sure that there are studies that can define whether someone has reached their finite mass of bone growth, et cetera. I would think it more than that in terms of the success rate.

CHAIRMAN KALLOO: Dr. Epstein.

DR. EPSTEIN: Yes, I have a little bit of a different opinion again. I think that if you have a child that has fecal incontinence that it is absolutely devastating to that child, and to their growth and development.

And I think that if this device is successful at least 50 percent of the time, that is a worthwhile endeavor. And we have heard that it can be removed, and the wounds heal, and I do think that it is going to be very difficult to do a study, because you saw how slow the accrual was in this study in adults.

So you are talking about a relatively smaller number of individuals, but individuals who may be affected in a very severe way. And if the device works in those children, then certainly it would be beneficial.

I think though that it would need to have a very strict control, and if it is possible -- and I don't know if that is possible, it should be applied for in each case, and should be kept experimental under 18.

But it shouldn't be automatically disallowed, because there are children who are physically probably able to accept the device, and who may therefore benefit from it.

So I think that if it is possible to have that stipulation that I wouldn't necessarily restrict it.

CHAIRMAN KALLOO: Dr. Gellens.

DR. GELLENS: It has not been studied in people less than 18, and so I don't think it should be labeled for use in people under the age of 18. However, it is already being used as a humanitarian device, and so with careful evaluation of people who are under 18, it still could be used in that setting without putting it on the labels.

DR. MCCLANE: I think there is no problem, and there shouldn't be any problem using it in post-pubescent patients under 18. The only issue would be the consent issue, but then again we operate on a lot of patients under 18 in the past, and get the consent, and that's fine.

The pre-pubescent patients, it probably should be okay to use them, but again they have to understand the problems that may exist, and in relation to their growth.

CHAIRMAN KALLOO: Dr. Talamini, can you summarize the comments?

DR. TALAMINI: Mr. Chairman, I believe the panel was split evenly down the middle on this question, and with half saying they thought it was okay under 18, and half saying it should be restricted to those over 18.

CHAIRMAN KALLOO: Thank you. The next question is Question Number 7. Please discuss whether the patient labeling as submitted is adequate to accurately involve the users of the risk and potential benefits of using the device. Dr. Smith.

DR. SMITH: I think that there needs to be more detail, and that all of the results be included, and I hoped that we were going to discuss this at a later time. You said we were going to discuss labeling as such?

CHAIRMAN KALLOO: This is the moment.

DR. SMITH: This is the moment?

CHAIRMAN KALLOO: Yes.

DR. SMITH: Well, I would like to see very specific details of labeling for the device. I would like to see that the patient is given a whole information kit supplied to the patient, and that this kit be given to them 72 hours before the procedure, and that they sign a form saying that they have read and understood the implications of this procedure, and that goes with part of the consent for the operation.

I think that is the one part of it that I think is very important. And the other part of it, I think, is that we should stipulate that people who are implanting the device should undergo a course of training as well to be adequately schooled in the whole technique of this device.

DR. WOODS: I agree with that, and I also think that it should be very, very clearly indicated what the expected outcomes are, be it a success or a failure. It has already been reiterated many times here that we are concerned about the failures.

And I think that those numbers need to be well defined in the labeling, and you need not to say 27 failures. You need to say what happened to those people.

I also think you should tell us in the labeling why the 10 people who had the implant for 12 months were deemed as failures. In other words, the ones that can keep the implant, and who aren't successful, we need to understand why they may not be successful.

I think it needs to be very well defined who is capable of putting in this device, and as has already been mentioned, a training course or something to that effect needs to be offered and completed, I think, before a person is credentialed or allowed to put this device in.

I think that patients who are being counseled on this procedure need to sign some sort of a consent that indicates that they have received full counseling on what their options are, and that they understand that if this fails, then their other option is a stoma.

And they need to fully understand what that means when they are making that choice. I think that the antibiotic prophylactics regimen that was outlined as the protocol that went on and that so many infections were discovered.

And your infectious disease consultant recommended a certain regimen, and I think that needs to be included in the package labeling, and any other technique issues that have been discovered along the way that would make implantation of the device have a lower complication rate need to be included in there.

I think there should be a component in there about women who subsequently become pregnant would be advised to consider C-section deliveries so as not to traumatize the perineum any further.

I think those are my major concerns, with particular emphasis on properly giving us the information on failures in the labeling device, or in the labeling insert packages.

CHAIRMAN KALLOO: Dr. Steinbach.

DR. STEINBACH: There is going to be difficulty warning to the package that right now our best guess is that it is a 50-50 chance of success. This may change as doctors get better.

And as a minor point, there is a complication that is in the literature, but not in the patient labeling that several patients were unable to pass gas at normal times, and in order to operate the device, they had to go to a private area so they would not embarrass themselves. And there should be a reference to that on the label.

DR. KOLTUN: I just reviewed this labeling now, as I didn't see it before. Is this the labeling that the individuals are getting now as educational backup? It seems to me that it could be updated if you have additional data or if you have additional information.

I think that it is an upbeat form, and I can understand why it is placed in that kind of a context. I think there has to be a fair representation of what would happened, or what would take place if something deleterious occurred.

And I know that it is largely the doctor's responsibility to advise a patient in that regard, but we also know that what a patient hears in the doctor's office is about 92 percent of what is the document, and not adequately appreciated.

But we want to have something to hold in the hand that proves carefully in the home that this is what they will have as a memory or an expectation, and I think it has to be a little more objective in regards to the success rate, and it can be updated with the data that we have.

CHAIRMAN KALLOO: Ms. Newman.

MS. NEWMAN: I want to go through this. I think you need several changes. The beginning paragraph sounds like this is my option as compared to diet changes, pads, diapers, medications.

What I am hearing is that all these other things may have been tried, and then these are the final options. So you need to state -- because maybe the patient will go to an individual center, or whatever, that they really have not offered them.

So once you put this out on the market, a lot of people are going to use it. So you need to state that this is kind of one of the last things. And on the next page, will it be replaced, and most patients do not need it.

What is most? Most could be 80 percent and you need to put the data in there on what is most. Risk and complications, I think you need to be up front. What is the complications and what is the risk to me.

You have on the next page as far as -- you know, the issues as far as erosion and infection, and that is some of it, but what are the other complications that may occur.

What kind of stool should they expect after this? I think that you should talk about that. You don't really talk a lot about stool. I would talk all about that, and what kind of stool are we talking about.

Now I have liquid, and I have this type of incontinence, and what should they expect. When you go down from manual dexterity, give them an example. Some manual dexterity. Well, I can read a book.

You really need to define manual dexterity so that they can utilize it, okay? You need to state that. It may be different for men and women. Some older women don't touch their perineum, and do they have a problem with that.

You state about migration. Do you expect them to look at their anal opening with a mirror? Is that what you are saying, or is someone going to look at it for them to see if something is happening. You need to state that. Should they look at it every day, and how do they care for them over time?

And then next page, but let me go on. I think you need more anatomical explanation on your pictures, especially since you seem to be going into the middle age population. They need to see it.

And under what to expect after surgical procedure, you need to state how long they are going to be in the hospital, and what number of days is normal. You know, what does it mean if I am going to be off from work and what do I have to do about that.

And a couple of pages later, on page 8, you take extra care when walking on ice because of falling. Does that mean that if someone falls that something can happen? Falling is a big issue as you age. Is that a concern? What are the concerns? Riding a bike; does that mean that if I do a bike on my exercise equipment.

You know, you need to get into that a little bit more. You don't ever mention sexual intercourse. You mention anal intercourse, but I know what the urinary lists, and the pump being in the labia, that is an issue with women with sexual intercourse.

What happens with that, and should they do a different position. I am sure that you have data on that. And then with men, and those are the kinds of things that I think you need to explore more with the patient.

CHAIRMAN KALLOO: Mr. Banik.

MR. BANIK: There is one particular item that I have some concern about, and to summarize it, it is will my prosthesis have to be replaced. In the labeling, it says basically that all mechanical devices fail with wear.

But it says that clinical experience has shown that most patients with an AMS implantable prostheses do not need to have their prosthesis removed or replaced for at least 5 years after the original implant.

I think that is probably a true statement relative if we are talking about the total, including the urinary device. I don't know that for sure, but all we have seen is data for one year.

And therefore I think that this whole section in this paragraph should be somewhat rewritten, and including a little bit of a discussion about the risk of having to go in and putting in another prosthesis in case of failure, because we saw high incidents of explants here, and also changes in the device.

CHAIRMAN KALLOO: Dr. Epstein.

DR. EPSTEIN: Yes, I agree with what has been said, and I also think that the labeling needs to be updated to reflect the data that is in the most recent study, and just updating the tables primarily to reflect the erosion and infection rate, and to be more specific about that.

DR. KOLTUN: Can I interrupt again? I didn't appreciate that before though. When you start on that page one, it is saying that Acticon Neosphincter, and then you work down the page and suddenly the Acticon Neosphincter becomes the AMS implantable prosthesis.

And doesn't that sort of imply to the reader that you are talking about the same thing, but in fact your AMS implantable prosthesis, that you are now referring to your urinary, as well as anal, sphincters, anal devices? That is a little misleading. That should be consistent throughout. You should be talking about one thing.

DR. GELLENS: I agree with what has been said so far. I think it should be clearly stated in the professional and in the patient labeling what the intention to treat analysis showed, that it is a 56 percent, or 51 percent chance, of effective results from this procedure.

And also the erosion and the infection rates should be included in the professional and the patient labeling. As a physician who presented here said, she tells her patients right up front that there is a 50 percent chance that you are going to need a reoperation, and I think that should be written somewhere, too.

DR. MCCLANE: Yes, again, I think a lot of people are saying that you really have to tell a patient that half will be successful in 12 months, and half will need a revision, and just include all that data. Actually, that's the only thing I have to say.

CHAIRMAN KALLOO: Dr. Talamini, if you would summarize.

DR. TALAMINI: I would like to make four comments of my own before summarizing. I had four changes that I thought would be important in the labeling, and most of them have already been reflected.

But on page one, where it says, is an implantable fluid-filled solid silicon to treat severe fecal incontinence. I think that severe fecal incontinence should be defined according to the parameters of the study, which in this case was X-number of episodes of incontinence per week or whatever it is.

And then I think perhaps adding as an alternative to a stoma in that sentence, or in another sentence, would frame this more clearly. There are two other things that I think would be important, which are that as everybody has said, include the adverse events.

But even more importantly, I would propose potentially extending this study, since we only have 12 months of data, and that is not very much for an implantable device, and continuing to update the labeling on some interval, or some defined period of time, so that the labeling keeps up with what we know about this device as we learn more about it.

Having said that, I think, Mr. Chairman, that the panel's opinion is that the labeling should really be, if approved, the primary vehicle for this device for clearly outlining the indications, and outlining the appropriate use protocols for the surgeons putting this in, and framing who is qualified to put it in, and informing the patient regarding the realistic risks of infection, and having to have the implant revised or removed.

DR. SMITH: And I would like to just reiterate one point,a nd that is that it is important that this pamphlet is not given to the patient in the holding area just before he or she goes into the operating room.

I would like to see that the patient receives this several days beforehand, and stipulates that I have received and read this document at least 72 hours prior to the procedure. So that way it gives them time to where they are actually reading it instead of another pamphlet that is simply being discarded.

DR. BROGDON: I would just like to comment on the recommendation that a couple of panel members made about an additional informed consent document, or some certification that is signed by the patient.

This is something that is very difficult for FDA to require, because it is virtually unenforceable on our part. So if the panel ends up recommending changes to the patient labeling, I think that is easy for us to deal with. But some additional signed statement would be difficult for the FDA to require and then enforce.

CHAIRMAN KALLOO: All right. I think we will move on to the next question.

DR. KOLTUN: And this thing about what you said there. What is done with implantable heart devices? Aren't those followed perpetually after implant? Patients get cards, and those with devices are registered with the company, and if there are any defects subsequently, and batteries running out too soon, and things like that?

DR. BROGDON: Yes, there are tracking systems in place with many implantable devices. There may be implant cards given to patients, and implant cards returned to sponsors so that they can track the patients and so forth.

That is different from what I was addressing regarding a signed statement from a patient.

DR. KOLTUN: When those cards and implant device registration forms are created and maintained, have those been mandated by the FDA?

DR. WOODS: In a few cases, I believe they have been mandated by the agency. Generally those data though are not held by the agency, but are held by the companies themselves.

DR. KOLTUN: But then if there is identified a problem, and like I said if a battery runs out too soon, and all of a sudden you find that out that there is a lot of them, then the FDA inspects the company's records and says there is a pattern there. Is the FDA ever an overseer of that, the registration data that the company maintains?

DR. BROGDON: I believe that the agency can require in some cases that the sponsors notify specific patients, but --

DR. KOLTUN: Like a recall?

DR. BROGDON: Yes. We can require recalls, and it certainly is easier if the manufacturers have data on specific patients.

CHAIRMAN KALLOO: Okay. Moving on to question Number 8. Please discuss whether the professional labeling as submitted is adequate to adequately inform the physician of the risks and benefits of using the device, and whether there are any additional contra-communications, warnings, precautions, or instructions for use that you believe would be appropriate.

So we are looking at the professional labeling to the physician. Dr. Smith.

DR. SMITH: I have not read it all, and I would like to look at it first.

CHAIRMAN KALLOO: Okay. Dr. Woods.

DR. WOODS: I apologize, but I think I addressed most of this in the last question, which actually was more with respect to patient labeling. So I don't really have much to add, except to say that if the package insert, or the professional labeling, is what is included here, I really don't see any data in here.

And perhaps I am not looking at the right thing, but I would encourage to include the data that I already mentioned that I thought would be important.

CHAIRMAN KALLOO: Dr. Steinbach.

DR. STEINBACH: I think the professional labeling is adequate. I think that the professionals are going to have to follow the literature and see whether this 50-50 number changes.

CHAIRMAN KALLOO: Dr. Koltun.

DR. KOLTUN: I more or less agree with that. I think there is data available now that could be added. You know, a couple of tables summarizing the success rate and the demographics of the complication rates is appropriate, and possibly consideration in regards to individuals who are at higher risk, because there has been some reference made to the issue of radiation therapy, and the perineum immuno-suppressant patients and such, should be mentioned.

CHAIRMAN KALLOO: Ms. Newman.

MS. NEWMAN: I think that this is one piece to me that is part of training, and sometimes people don't always read the little inserts because the printing is so tiny.

But I presume, along with what Dr. Epstein was saying, that this is part of a big training kind of an issue that will go forward. It should include the data.

And I would also highly recommend that you include your references that have been done all over the world, because I think that is very helpful to the clinician and to the person who is doing this. And then also do some other types of presentations other than just print.

CHAIRMAN KALLOO: Mr. Banik.

MR. BANIK: I felt the physician related labeling was good and anticipated a lot of things that people don't anticipate, and in particular there was information on MRIs which I thought was good.

I agree with the other comments that were made that relative to adding some of the performance of the device relative to the clinical performance would be helpful to add into that.

CHAIRMAN KALLOO: Dr. Epstein.

DR. EPSTEIN: Yes, I agree with that, and I also think there needs to be a training certification.

DR. GELLENS: I think the labeling is relatively adequate, except that I think the contraindications section should be expanded, and I just think that the current data that we have just seen should be included.

DR. MCCLANE: Yes, a couple of things. On page 6, again they mention the adverse events are based on 50 and we are up to 115, and that is obviously very old data.

And on pages 8 and 9, it is a little bit misleading. On the bottom, they talk about according to the PIF, 152 patients received the Acticon Neosphincter, and then on the next page, it only says 9.8 percent of the implants were revised, removed, or replaced.

I mean, that is not even close to what we have been talking about today, and that might be a little misleading.

DR. KOLTUN: What section are you under?

DR. MCCLANE: The professional labeling section. Oh, the pink is different than the black folders. I guess it has been revised from what we got.

And then they talk about the contraindications. The device is contraindicated in patients with fecal incontinence complicated by an irreversibly obstructive approximal segment of bowel. I am not sure what kind of patients they are referring to here.

Patients that come in with bowel obstructions I wouldn't think would be getting these devices. I am not sure if you need to include that.

DR. KOLTUN: Excuse me, but now I am really confused, because in the pink book there is something that is identified as labeling, the operating manual.

DR. MCCLANE: And then just one other comment. In warnings, they said that patients with urinary tract GI infections, diabetes, spinal cord injuries, open sores, have a increased risk of infection. But again the data says that there really aren't, and that there is not a significant risk of increased infection to some to these patients.

So there is an increase, but it is not significant based on the P value on some of these things that they talk about here. That's all I have to say.

CHAIRMAN KALLOO: Dr. Talamini, please summarize.

DR. TALAMINI: Mr. Chairman, it is the majority opinion of the committee that indeed there are additional contraindications, warnings, precautions, and instructions that most members believe would be appropriate specifically regarding indications, contraindications, and updated data.

CHAIRMAN KALLOO: Thank you. And for Question 9 and the final question.

DR. SMITH: Are we allowed to stipulate that there should be a training program, and that you should have a training certificate?

CHAIRMAN KALLOO: Yes, and that is what you are saying.

DR. BROGDON: If there is a training program that the panel recommends and that the FDA agrees with, we ask the sponsor to design their training program. And if they want to have a certification form that they keep on record, that is fine with us.

CHAIRMAN KALLOO: Question 9. In addition to the intent to treat analysis, please discuss whether the results of the valuable analysis should be included in the professional and patient labeling.

DR. TALAMINI: I think we already covered that and we agreed to that.

CHAIRMAN KALLOO: Yes. Well, let's have you summarize anyway just for the record.

DR. TALAMINI: Mr. Chairman, the answer is yes to Number 9.

CHAIRMAN KALLOO: Okay. Before we take a vote and actually take a break, I think, Dr. Talamini, that you need to summarize all the comments thus far.

DR. TALAMINI: Give me 30 seconds.

CHAIRMAN KALLOO: While Dr. Talamini is getting his thoughts together, does anyone from the public wish to address the panel, and if so, please raise your hand, and you may have an opportunity to speak.

(No audible response.)

MS. NEWMAN: Can we take a break before we do that?

CHAIRMAN KALLOO: We could. If the panel feels strongly about that, how many people would like to take a break?

( A show of hands.)

CHAIRMAN KALLOO: How many people would not like to take a break?

(A show of hands.)

CHAIRMAN KALLOO: So we will take a break for 10 minutes.

(Whereupon, at 2:47 p.m., the meeting was recessed, and was resumed at 3:01 p.m.)

CHAIRMAN KALLOO: Okay. Good afternoon. I would like to reconvene. I would like to start off this final session by asking the FDA if there were any comments, or does the FDA have any comments?

(No audible response.)

CHAIRMAN KALLOO:

If not, does the sponsor have any final comments?

(No audible response.)

CHAIRMAN KALLOO: Okay. Before entertaining a motion recommending an action on this PMA, Dr. Cooper will remind the panel of our responsibilities in reviewing today the pre-market approval application, and of the voting options open to us. Jeff.

DR. COOPER: Okay. 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. Next, I would like to remind the panel of some definitions. Safety is defined in the medical device amendments as reasonable assurance based on valid scientific evidence, that the probable benefits to health under conditions of intended use outweigh any probable risks.

Effectiveness is defined as reasonable assurance that for a significant portion of the population that the use of the device for its intended uses and conditions of use when labeled will provide clinically significant results.

And 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.

Your recommendation options for the vote are as follows. Approval. There are no conditions whatsoever attached.

For 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 the FDA staff.

And prior to voting, all the conditions are discussed by the panel, and listed by the panel chair. The third 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.

The reasons for recommending not approvable would be safety; the data do not provide reasonable assurance that the device is safe under the conditions of use prescribed, recommended, or suggested in the proposed labeling.

For effectiveness, if there is reasonable assurances that have not been given that the device is effective under the conditions of use and the labeling.

And labeling, based on a fair evaluation of all the material facts and your discussions, that you believe that the proposed labeling to be false or misleading. Thank you.

CHAIRMAN KALLOO: Okay. Thank you. Dr. Talamini, will you summarize the panel discussion, please.

DR. TALAMINI: Mr. Chairman, the panel has discussed the questions in some detail, and I think in summary the majority opinion of the panel is that the device is effective as just defined, and with an understanding of the risks that it entails, that it also is safe within the definition just delineated.

So I would say or my summary would be that the panel does seem to believe in large part that it is safe and that it is effective.

Two major categories of issues appear to have arisen. One is regarding significant changes in the labeling, and the second regarding training programs for surgeons implanting this device.

CHAIRMAN KALLOO: I would like to thank Dr. Talamini for summarizing the questions. 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.

DR. STEINBACH: Mr. Chairman, I move that the device be approved with conditions.

DR. WOODS: I second that.

DR. TALAMINI: I would agree. I was going to make a motion that it be approved with conditions, and give two specific conditions. Do we just discuss conditions, or do we add them to the motion?

CHAIRMAN KALLOO: We would need a second.

DR. TALAMINI: I second.

CHAIRMAN KALLOO: The condition has been seconded, and I would like to ask for the recommendation of the panel, that is, approval, or approval of this condition that has been approved, with conditions. Those in favor of the motion please raise your hands.

DR. STEINBACH: We need to discuss it first.

DR. WOODS: What are we voting on?

CHAIRMAN KALLOO: We are voting on the approval of this PMA with conditions.

DR. WOODS: When do we discuss the conditions?

CHAIRMAN KALLOO: So you want to discuss the conditions?

DR. TALAMINI: Yes, I would like to add two conditions or discuss two conditions. One of them would be a training program to be developed by the company in conjunction with the FDA, along the lines that the panel has delineated and discussed.

The second would be modifications of the labeling by the company, again in conjunction with the FDA, and again along the lines of the panel discussion this afternoon.

CHAIRMAN KALLOO: So now we are going forward on the conditions. The first condition is --

DR. KOLTUN: Are we going to vote or discuss?

CHAIRMAN KALLOO: We can discuss first and then vote. What is the first condition?

DR. TALAMINI: The first one was training.

CHAIRMAN KALLOO: Training, starting with Dr. Smith.

DR. SMITH: I would agree with that.

DR. WOODS: Agreed.

DR. STEINBACH: The studies were done with a proctor apparently for the first case. I would hope that this would continue as part of the training program.

CHAIRMAN KALLOO: Dr. Koltun.

DR. KOLTUN: I would agree. I think the question is what is going to constitute training, and I think who would decide that. You are saying or you are proposing that the FDA, in conjunction with the company?

DR. TALAMINI: My proposal would be that the FDA develop -- that the company develop that program in conjunction with the FDA, which is certainly a pattern that has been followed before, I believe.

DR. KOLTUN: I would only add to that, which may be the obvious addition, that individuals such as Dr. Wong and Dr. Congilosi be the people who would coordinate that.

CHAIRMAN KALLOO: Ms. Newman.

MS. NEWMAN: Yes, that's interesting, because with other things that come out, I guess it is whether the company is the trainer or the professionals in the field. I agree that it should be the professionals or the societies in there somewhere in the certification.

CHAIRMAN KALLOO: Mr. Banik, comments?

MR. BANIK: No comments.

DR. BROGDON: I would like to comment just briefly on who offers training. That really is up to the sponsor to decide whether they want to do the training or to contract it to someone else to do the training, a society, or private organization, or whatever.

The FDA tends to look at just what is included in the training program, and not who offers it, and how much is charged for the training. That is really up to the sponsor.

DR. EPSTEIN: Yes, and I agree with what has been said, and also would recommend that the device for under 18 remain in the human device exemption arena until such time as more data can be brought forth.

DR. TALAMINI: That would be a third condition.

DR. EPSTEIN: Yes.

CHAIRMAN KALLOO: Yes. We are talking specifically about training.

DR. EPSTEIN: Okay. Then I agree.

CHAIRMAN KALLOO: Okay.

DR. GELLENS: I don't think it should be approved with conditions. So I don't know what comments I am supposed to make.

CHAIRMAN KALLOO: If you don't, then that's fine.

DR. GELLENS: Okay.

DR. MCCLANE: I agree with the training program, and I think the decision has to be how many do you need to do, and it looks as though in the packet it was just one.

CHAIRMAN KALLOO: Any comments, Dr. Koltun?

DR. KOLTUN: I think most -- well, my experience in similar things like this is the FDA has been faithful in helping companies develop an effective training protocol for things such as this, which is why I am comfortable with this as a condition.

CHAIRMAN KALLOO: Okay. Those in favor of the condition of training as outlined by our discussion please raise their hand.

(A show of hands.)

CHAIRMAN KALLOO: Those against, please raise your hand.

(A show of hands.)

CHAIRMAN KALLOO: Okay. Six in favor, and one against. The second condition, Dr. Talamini, is?

DR. TALAMINI: The second condition that I proffered was modified labeling, and modified by the company again in conjunction with the FDA. I am not sure how fair that is, but there were so many comments regarding labeling that I think it would be difficult to delineate all of those conditions.

And I would feel more comfortable having gone through the discussion, leaving that in the perview of the FDA if that is fair.

DR. BROGDON: I think we could handle that, and if we had questions about the intent of various panel members, we could certainly contact you for clarifications.

CHAIRMAN KALLOO: And certainly we have listed multiple modifications, and some of which I thought were very excellent. So I will just ask for comments as we go around the panel. Is there any further discussions on this point, starting with Dr. Smith?

DR. SMITH: None.

DR. WOODS: One, and that is we brought up the issue previously about an informed consent, and we are told that they could not necessarily mandate that, but I would suggest then that we include in the labeling a recommendation that a patient receive some special informed consent.

And I would like to suggest that the company may even wish to provide users with a template informed consent that they might give to their patients, or patient information with consent information in it regarding the specific device.

And not consent for any kind of surgery, but with respect to the device information. A patient should know about their options and such.

DR. STEINBACH: We had previously voted to include the tables of success and failure as part of the label.

DR. KOLTUN: I agree with that, including the success and failure rate of this device, and not some other device, and not of the European data, because that is not being considered at today's meeting.

The European data is mentioned in some of the labeling documents that we have had today, and that data in no way mirrors what we have read here or seen here today.

My second point is that in regards to the patient, and even the physician, I think it should be clearly stated that this device is an alternative to a stoma. I think that sometimes gets lost as a surgeon managing this kind of a problem.

This device is an alternative to a stoma, and it is not for someone who leaks air, or who has difficulty with liquid now and then, and that needs to be clearly stipulated, because the patient's labeling here was not I think forceful enough in that regard.

I think there is some other issues as well in regards to potential risk factors that need to be addressed in the physician's labeling insert. And I think there that there is a distinct lack of data, and in some ways I think this goes to another condition, and I think it would be nice if we could generate added data in that regard. But those are the points that I would make with regard to that.

MS. NEWMAN: I agree.

MR. BANIK: I agree also.

CHAIRMAN KALLOO: Dr. Epstein.

DR. EPSTEIN: I agree.

CHAIRMAN KALLOO: Any comments or other comments? If not, we will now vote on the condition that there be significant modifications of the labeling for both the patient and the physicians. Those panel members who are in favor of making modifications to the labeling as we discussed, please raise your hands.

(A show of hands.)

CHAIRMAN KALLOO: And those against?

(A show of hands.)

DR. GELLENS: I am not only against the modifications, but I am just against it.

CHAIRMAN KALLOO: That's fine, and your disapproval is noted.

MS. NEWMAN: Did she say why she is disapproving it?

CHAIRMAN KALLOO: She just did. Any other conditions that anybody else would like to bring up? Dr. Epstein.

DR. EPSTEIN: We discussed that under age 18. And I would like to know what the vote is on that.

CHAIRMAN KALLOO: So we would like to discuss the condition of approval with the condition that the patient should be over the age of 18. So I ask for discussion of this condition. Dr. Smith.

DR. TALAMINI: Actually, if I could just modify that. I think, Dr. Epstein, that you were saying that for use under 18 that it would remain a humanitarian exemption.

DR. EPSTEIN: Right.

DR. TALAMINI: And so that the disapproval only would cover over 18; is that a legitimate distinction to make?

DR. BROGDON: Those of us from the FDA who are in the room right now aren't a hundred percent sure. It seems logical on the face of it that the HDE should be able to remain in force for those younger patients, but we are not a hundred percent certain because there is not a lot of agency experience with HDEs.

But we are willing to look into it and to try to make it work if we can.

CHAIRMAN KALLOO: I think that we should discuss that. I mean, that is a point, and over 18 approval, and under 18 for humanitarian.

DR. EPSTEIN: If applicable.

CHAIRMAN KALLOO: Yes, if applicable. Dr. Smith.

DR. SMITH: I think I would approve that it is for people under the age of 18, but that doesn't preclude that it could be put into a younger person if the surgeon sees it fit to do so. That is their decision.

DR. WOODS: I don't understand the rationale of not allowing a post-pubescent, relatively mature, teenager to have this procedure as a humanitarian device. I think I need more explanation from Dr. Epstein as to why he feels that way.

DR. EPSTEIN: Karen, I think that is what we are saying, is to allow it as a humanitarian device.

DR. WOODS: Well, I don't understand why it should be humanitarian. Why can't we just approve it.

DR. EPSTEIN: No data.

DR. MCCLANE: Well, how about over 82?

DR. KOLTUN: Well, I have a question. If it is a humanitarian device, is it obligatory that they have to continue to try to recruit data in that regard?

In other words, if they implant it as a humanitarian objective with this device do they have to keep more accurate date in those individuals?

DR. TALAMINI: No, but they do have to have IRB approval.

DR. KOLTUN: So they have to have IRB approval.

DR. TALAMINI: Yes.

DR. KOLTUN: So if a 15 year old came and he was considered a candidate the physician would have to go through the IRB?

DR. TALAMINI: Correct.

DR. KOLTUN: That might not be unreasonable.

DR. GELLENS: Right. That is not unreasonable when there is data.

CHAIRMAN KALLOO: Also, isn't it possible to approve it for under 18 with a condition that it be followed data as well? Is that possible or not?

DR. TALAMINI: That's not necessarily.

CHAIRMAN KALLOO: Okay. Then that is the answer.

DR. BROGDON: I think that would be difficult.

DR. MCCLANE: How long will this go on for humanitarian purposes, 1 or 2 years?

DR. EPSTEIN: Well, you don't --

DR. MCCLANE: Well, the expiration --

DR. BROGDON: Unless someone else gets approval for a similar device in that population.

CHAIRMAN KALLOO: Any other comments?

MS. NEWMAN: It just seems that if there is no data on that group, then I agree with you that we don't totally exclude it if there is an issue. But there is no data on it.

CHAIRMAN KALLOO: Any other comments? If not, we will vote on condition of approval, the condition being that if the patient is over 18 or rather if the patient is under 18 that we would recommend that the device be placed only under humanitarian conditions. And if I can see a show of hands raised.

DR. MCCLANE: Is it for post-pubescent, under 18?

CHAIRMAN KALLOO: Post-pubescent, under 18. Thank you for that clarification. If you could please raise your hands if you agree with this recommendation.

(A show of hands.)

CHAIRMAN KALLOO: Four. And those against, please raise your hands?

(A show of hands.)

CHAIRMAN KALLOO: Three. And could you please tell us the reason for your dissent.

DR. WOODS: I think that post-pubescent, under 18, should be included in the approval, and should not have special -- should not have to require IRB approval for a humanitarian device.

I also think as the sponsor pointed out that one of the stumbling blocks to getting this device implanted is that insurance companies may not pay for it when it is considered investigational, and I have some concerns that some of those in most need might be denied the opportunity to have the device.

DR. EPSTEIN: And one thing is that we have obviously mandated that experimental therapy be covered by insurance. I think it is going to be less of an issue.

CHAIRMAN KALLOO: Who else? Please state your reasoning.

DR. GELLENS: Okay. I actually agree with this condition, but since I don't think the PMA should be approved, then I have to disagree overall.

CHAIRMAN KALLOO: Okay.

DR. MCCLANE: I think it should be approved for post-pubescent under 18 just because there may be many obstacles for those patients, and they may not get the device if they really need them.

DR. KOLTUN: Are there amy other conditions of approval that any of the panel members would like to raise? I will therefore ask the panel members to vote in favor --

DR. KOLTUN: I would like to bring up another condition.

CHAIRMAN KALLOO: Yes, that's fine.

DR. KOLTUN: I don't like unduly restrictive qualifications on the packaging insert. Therefore, trying to list restrictions in regards to immunosuppressed patients, and patients who may represent --

CHAIRMAN KALLOO: I'm sorry, but your condition is?

DR. KOLTUN: What I am trying to say is there some way that we can explore the continuing accrual of data in regards to potentially high risk patients, and this is what I am unclear about.

CHAIRMAN KALLOO: So your question is about patient safety on patients who are at high risk?

DR. KOLTUN: The only alternatives that I have in my mind are labeling that says strongly not advised for patients on immunosuppressants that are undergoing transplantation, and patients who are otherwise at high risk because of co-morbid conditions.

I feel that is somewhat against my principles in regards to how a physician manages their patient. It should be up to the physician and patient to make such decisions.

But on the other hand, I think there is an opportunity here for us to clearly delineate who benefits from this. There is not enough data about risk, and what patients are at the greatest risk, and what are the factors in that regard.

And how can we continue to accumulate data so that five years from now we know what patients don't benefit from this, and should not be considered. That's what I am saying.

DR. TALAMINI: You can proffer a post-market study as a condition.

MS. NEWMAN: That is what we have done. Since they don't have two years, then that will give us some of the information that you need. So what we have been asking for is to continue to see information at the FDA so that maybe some of these restrictive things don't go away because the data shows up.

CHAIRMAN KALLOO: So we are talking about one of the conditions of approval being a post-marketing study on patients who specifically are immunosuppressed; is that correct?

DR. KOLTUN: Well, all the individuals who have been doing the research and doing the work in this can probably judge that. That's why I asked Dr. Congilosi that. She has feelings of radiated parineums, for example.

I can see that I don't want to be in a fantasy world, but I can see physicians, for example, considering preoperative chemo radiation for low lying renal cancer, and recepting part of the sphincter in that context after it has been shrunk by radiation, while at the same sitting putting in an artificial sphincter to avoid APR.

I can consider in my own mind some very crazy things. If those things are going to start taking place or such circumstances are going to start happening, I would like to know the data.

I don't want selective data. I don't want to see data that tells us our successes, but then does not delineate the exact failures. So what I am trying to ask is I would like to know about high risk patients with radiated perineums, and patients who are on immunosuppressants, steroids and other immunosuppressants like F.K. and cyclosporine.

Patients who the investigators have already deemed as being predisposed to failure. For example, the trauma patients that they have identified.

I mean, some categories here need to be further investigated to assess their appropriateness for being even considered for this therapy if they have an even higher failure rate than 50 percent.

CHAIRMAN KALLOO: Any other comments or suggestions?

DR. BROGDON: Well, it sounds like what you are discussing a newly designed post-approval study, is that correct, as opposed to continued follow-up of already enrolled subjects?

DR. KOLTUN: Yes, probably. But I may be confused about this approval issue. What I mean by that is that I think that the only way you are going to get the data is by getting more patients.

So the approval I would like to see put in place, but I want those patients undergoing implantation to be followed.

CHAIRMAN KALLOO: Is it possible to require the company to report on post-marketing on the data that he is trying to look for?

DR. BROGDON: I guess it is possible to require. I think you have to look at whether that is really feasible to expect the sponsor to collect data unless it is being gathered under a designed study.

DR. TALAMINI: Well, for instance, we could -- I think potentially we could proffer -- and continuing as I mentioned before, continuing to study the patients that we already have here out to two years.

DR. KOLTUN: But, you see, the problem with that is that they don't have these patients. They don't have a large group of diabetics, and they don't have a large group of radiated parineums, et cetera.

So that's why I am saying that the alternative to what I am saying, which is very difficult I acknowledge, is to say a strongly worded labeling that says not recommended for radiated perineums, and not recommended in diabetics, but then you don't really know. We don't really know whether to recommend it.

DR. TALAMINI: We don't have a condition on the table, but I think that would be very difficult to mandate as part of an approval, and I think really that is part of surgical and medical practice for that data to come out as devices operations are used and we learn more about them.

DR. KOLTUN: But that would be very difficult to put out as a condition of approval.

DR. TALAMINI: And I agree. I agree.

DR. KOLTUN: I don't see how we could do it. Dr. Smith, do you have a comment?

DR. SMITH: Yes, I agree with you that it would be pointless -- studies are done all the time about devices as they come out, and you have bigger and bigger series, and people public their results.

And that is where you accrue data, and then I think you should limit it and you should just wait and see what happens over the course of time. People will be publishing their data all the time.

DR. GELLENS: Can I make a comment?

CHAIRMAN KALLOO: Yes.

DR. GELLENS: My understanding though is that if we feel that the data that is currently being presented is not adequate to prove safety and/or efficacy, then it should not be approved. And if you want to gather more data, maybe it should be done before the device gets FDA approval.

CHAIRMAN KALLOO: Right. But the summary of the comments of the panel from when we discussed that issue was fairly clear when it was voted on, that it was felt that based on the data that we had that the device was indeed relatively safe.

But that is the consensus when we voted. So that is something that you can define in your vote when you actually vote if you still feel uncertain. Yes?

DR. EPSTEIN: Can we take a vote on this?

CHAIRMAN KALLOO: Well, we need to be sure that there are no other conditions before we bring this to a vote.

MS. NEWMAN: But do we want to say that we would like additional -- maybe another year on this current data, or that won't solve some of these issues?

CHAIRMAN KALLOO: Yes, we can. We can ask for a post-marketing follow-up of one year as a requirement for this as a condition. Is that something that we should discuss?

DR. KOLTUN: From my standpoint, it doesn't answer my questions. But having said that, prostheses --

CHAIRMAN KALLOO: I don't think anything could answer your questions.

DR. KOLTUN: Right. Exactly. I know. That's why I said the alternative in my mind is very restrictive labeling, which I don't like either. But having said that, I think that might be a good point, simply because protheses tend to erode over time, and we all know that.

CHAIRMAN KALLOO: All right. So let's just get some comments about a post-marketing for maybe another 12 months for the patients who are already enrolled in the study so we can get all the long term data. Dr. Talamini.

DR. TALAMINI: Well, actually, I will make it even a little bit more specific. I would say that we follow this data another year, and that that data be part of updated labeling as it becomes available.

So I would put that on the table as a condition to discuss.

DR. SMITH: In that form, I would agree with that. I think that there is no reason that another year would be better than when you could say 2 years or 3 years, or 5 years. So I think if it is approved, and you say you can change the labeling after one year, I think that is appropriate.

DR. WOODS: I will agree to that.

DR. STEINBACH: I think that study should -- and I would ask the sponsors to attempt to chase down the patients that were excluded from the second quality of life questionnaire.

CHAIRMAN KALLOO: I think what we are trying to do is to get your opinion on --

DR. STEINBACH: Well, as part of this second year, to include the patients that were missing from the first year data.

DR. KOLTUN: I would agree because that is the best option that we have for gathering additional data.

CHAIRMAN KALLOO: Ms. Newman.

MS. NEWMAN: I agree.

CHAIRMAN KALLOO: Dr. Epstein.

DR. EPSTEIN: I disagree.

CHAIRMAN KALLOO: Any further comments?

DR. MCCLANE: I agree, but I do think you really need to include those patients that have not been included in the one year follow-up and to try and track them down and to include that condition.

CHAIRMAN KALLOO: Okay. So we are going to vote on the condition that there is a post-marketing study of all the patients, to include the ones that were lost to follow-up, that the results of which would be included on a subsequent label change. All those in favor, please raise your hands?

(A raising of hands.)

CHAIRMAN KALLOO: Six. And against, please raise your hands?

(A raising of hands.)

CHAIRMAN KALLOO: Two. And could you give your reasons why, please?

DR. EPSTEIN: I just think that once the device is out in the market that we will learn much more about it, like we do with medications, and we will get information and follow-up, and people will figure out very quickly how to use this device and whom. And again I think the surgeons will exercise good judgment.

CHAIRMAN KALLOO: Dr. Gellens.

DR. GELLENS: Well, the same thing for me. I don't think it should be approved. I think we should get more data before it is approved. I think we should follow these patients for another year, and then look at the data after a year, and then decide whether or not to do it.

CHAIRMAN KALLOO: Any other conditions that any of the panel members would like to bring forth?

(No audible response.)

CHAIRMAN KALLOO: Okay. Will all those voting members in favor of approval with the conditions that we just listed and voted on raise their hands?

(A raising of hands.)

CHAIRMAN KALLOO: Seven. And all those against, please raise your hand?

(A raising of hands.)

CHAIRMAN KALLOO: One. Would you please give us your reason again.

DR. GELLENS: The reason that I think it should not be approved is that I think you need a longer observation period. This study is only for one year and I don't think that is adequate for that amount of time.

I think another year is a difficult thing to ask to follow these patients for another year. I think there needs to be closer attention to who gets it and who has complications from it. And that can give physicians subsequently a better idea of who to suggest putting this device in.

And I also think that changing the antibiotic regimen already showed significant improvement in the infection rate in only those 16 patients.

I think that if you followed that for another year that then the company could make much better recommendations to physicians about antibiotic regimen. And I think if it is not approved already, we could mandate a training program, and it would not be something that may or may not happen after the device is approved now.

CHAIRMAN KALLOO: Thank you. Well, in conclusion, the panel has voted in favor of approval with a vote of 7 to 1, with the conditions that are on your slide with regard to the training program, and modified labeling for both physicians and patients, age greater than 18, and a post-market follow-up study for one year on current study subjects.

This concludes the report and recommendations of the panel on P01-0020, Acticon Neosphincter for people with incontinence.

(Brief pause.)

CHAIRMAN KALLOO: And I have now been made to understand that we each have to give a short summary of why we voted like this. So if you could quickly give your comments once more.

DR. BROGDON: Could I ask for a clarification first? Is the approval recommended 18 and older, or is it greater than 18 as listed there?

CHAIRMAN KALLOO: Eighteen and older.

DR. BROGDON: Eighteen and older. All right. Thank you.

CHAIRMAN KALLOO: So, Dr. Smith, please give us your reasons for your final decision?

DR. SMITH: I approve of the device for all of the reasons that have been enumerated repeatedly at this meeting.

DR. WOODS: Ditto. I think it is an effective device when used as outlined in the protocol, and that it is an option that is absolutely necessary for patients who suffer from this devastating problem. I think it is a nice option for them short of an ostomy.

DR. STEINBACH: I think it is safe and effective with our conditions of approval.

DR. KOLTUN: I think it is very safe and very effective, and it varies from patient to patient and the patient population needs to be very careful of stipulating who should get it.

CHAIRMAN KALLOO: Dr. Epstein.

DR. EPSTEIN: I think that the device will help a certain subpopulation with severe fecal incontinence who are otherwise devastated by the illness, and in conclusion there are not a lot of good alternatives as we have heard.

CHAIRMAN KALLOO: Dr. Gellens, once more, please.

DR. GELLENS: I just don't think there is enough data.

DR. MCCLANE: I think it is an effective device, and it is going to do a lot of good for a lot of patients.

DR. TALAMINI: I think it is effective and safe within the definitions that we have reviewed, and it will help a select set of patients with a desperate problem.

CHAIRMAN KALLOO: In conclusion, I would have to say that I have been on many panels, but I would have to say that this is one of the best panels I have been on. So I would like to personally thank each and every one of you, and to let you know that the meeting is now adjourned. Thank you.

(Whereupon, at 3:36 p.m., the meeting was concluded.)