GASTROENTEROLOGY AND UROLOGY DEVICES PANEL

OF THE

MEDICAL DEVICES ADVISORY COMMITTEE

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FRIDAY,

JANUARY 17, 2003

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

[PRESENT]{.underline}:

KAREN L. WOODS, M.D. CHAIR

SAMI ACHEM, M.D. VOTING MEMBER

ABDELMONEM AFIFI, Ph.D. VOTING MEMBER

ANDREW BALO INDUSTRY REPRESENTATIVE

NANCY C. BROGDON FDA

JEFFREY W. COOPER, DVM EXECUTIVE SECRETARY

BRIAN FENNERTY, M.D. VOTING MEMBER

MARK FERGUSON, M.D. TEMPORARY VOTING MEMBER

MARY GELLENS, M.D. VOTING MEMBER

MICHAEL MANYAK, M.D. VOTING MEMBER

CHRISTINE MOORE CONSUMER REPRESENTATIVE

NICHOLAS SHAHEEN, M.D. TEMPORARY VOTING MEMBER

[SPONSOR PRESENTERS]{.underline}:

ALAN STEIN, Ph.D.

President and Chairman, Enteric Medical Technologies

LUCAS BRENNECKE, DVM, DACVP

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

GLEN LEHMAN, M.D.

Professor of Medicine and Radiology, Indiana University

DAVID JOHNSON, M.D.

Professor of Medicine, Eastern Virginia Medical School

[FDA PRESENTERS]{.underline}:

KATHLEEN OLVEY

FDA/ODE/DRARD/GRDB Scientific Reviewer

KATHARINE MERRITT, Ph.D.

FDA/OST/DLS/HSB

ARON YUSTEIN, M.D.

FDA/ODE/DRARD/GRDB Medical Officer

MELVIN SEIDMAN, FDA/OSB

S. LORI BROWN, Ph.D., FDA/OSB

I‑N‑D‑E‑X

[AGENDA ITEM]{.underline} [PAGE]{.underline}

CALL TO ORDER 5

OPEN PUBLIC HEARING 18

OPEN COMMITTEE DISCUSSION 19

1\. Sponsor Presentation: 20

1\. Company, Device Description & 20

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

President and Chairman, Enteric Medical

Technologies

2\. Histopathology Review: Pre‑Clinical 42

Studies ‑ Lucas Brennecke, DVM, DACVP,

Director, Medical Device Pathology,

Pathology Associates, a Division of

Charles River Laboratories, Inc.

3\. Study Design and Results: Safety ‑ Glen 60

Lehman, M.D., Professor of Medicine and

Radiology, Indiana University

4\. Study Results: Effectiveness ‑ David 101

Johnson, M.D.,Professor of Medicine,

Eastern Virginia Medical School

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

President and Chairman, Enteric Medical

Technologies

2\. FDA Presentation: 153

1\. Overview/Pre‑Clinical Studies ‑ Kathleen 153

Olvey, FDA/ODE/DRARD/GRDB Scientific

Reviewer

2\. Histopathology Considerations ‑ Katharine 159

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

3\. Clinical Considerations ‑ Aron Yustein, 164

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

4\. Statistical Considerations ‑ Melvin 206

Seidman, FDA/OSB/

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

Ph.D. FDA/OSB/

I‑N‑D‑E‑X (Continued)

[AGENDA ITEM]{.underline} (Continued) [PAGE]{.underline}

3\. Panel Discussion: 222

The committee will discuss FDA charges,

make recommendations and vote on a

pre‑market approval application P020006

from Enteric Medical Technologies and

Boston Scientific for a device for the

treatment of gastroesophageal reflux

disease.

1\. Dr. Brian Fennerty ‑ Primary Review 222

and Lead Discussant.

2\. Reading of Questions and Discussion. 227

OPEN PUBLIC HEARING 324

4\. Final Comments 325

1\. FDA Comments 325

2\. Sponsor Comments 325

5\. Panel Deliberations and Vote 339

P‑R‑O‑C‑E‑E‑D‑I‑N‑G‑S

(8:32 a.m.)

[CALL TO ORDER]{.underline}

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

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

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

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

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

Brian?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

DR. COOPER: Thank you, Dr. Neuland.

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

\"For the record, they are special government employees and consultants
to this panel or other panels under the Medical Devices Advisory
Committee. They have undergone the customary conflict of interest review
and have reviewed the material to be considered at this meeting,\"
signed David W. Figal, Jr., M.D., MPH, Director, Center for Devices and
Radiological Health.

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

The conflict of interest statutes prohibit special government employees
from participating in matters that could affect their or their
employers\' financial interests. However, the agency has determined
participation of certain members and consultants, the need for whose
services outweighs the potential conflict of interest involved, is in
the best interest of the government.

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

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

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

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

With respect to all other participants, we ask in the interest of
fairness that all persons making statements or presentations disclose
any current or previous financial involvement with any firm whose
products they may wish to comment upon.

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

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

Dr. Woods will now continue the meeting.

[OPEN PUBLIC HEARING]{.underline}

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

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

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

Does anyone wish to address the panel at this time?

(No response.)

[OPEN COMMITTEE DISCUSSION]{.underline}

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

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

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

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

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

Dr. Stein?

[1. SPONSOR PRESENTATION]{.underline}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

DR. STEIN: Okay.

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

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

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

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

CHAIRPERSON WOODS: Thank you.

Any other questions? Dr. Ferguson?

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

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

CHAIRPERSON WOODS: Other questions? Dr. Achem?

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

DR. STEIN: That\'s correct.

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

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

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

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

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

CHAIRPERSON WOODS: Yes, Dr. Manyak?

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

DR. STEIN: Yes?

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

DR. STEIN: The carcinogenicity studies, sir.

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

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

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

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

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

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

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

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

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

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

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

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

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

DR. STEIN: No.

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

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

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

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

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

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

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

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

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

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

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

CHAIRPERSON WOODS: Thank you.

Any other questions from the panel?

(No response.)

CHAIRPERSON WOODS: Okay. Thank you.

[2. HISTOPATHOLOGY REVIEW: PRE‑CLINICAL STUDIES]{.underline}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CHAIRPERSON WOODS: Other questions? Dr. Ferguson?

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

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

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

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

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

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

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

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

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

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

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

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

CHAIRPERSON WOODS: Dr. Achem?

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

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

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

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

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

CHAIRPERSON WOODS: Thank you.

Other questions? Yes, Dr. Gellens?

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

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

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

DR. BRENNECKE: Yes, I did.

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

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

CHAIRPERSON WOODS: Other questions by the panel?

(No response.)

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

[3. STUDY DESIGN AND RESULTS: SAFETY]{.underline}

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

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

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

CHAIRPERSON WOODS: Thank you.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Thank you.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

DR. FENNERTY: Thank you.

CHAIRPERSON WOODS: Ms. Moore had a question next.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CHAIRPERSON WOODS: Dr. Afifi is next.

DR. AFIFI: Thank you.

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

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

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

DR. LEHMAN: John Kennedy will address.

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

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

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

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

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

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

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

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

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

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

DR. KENNEDY: Not really.

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

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

DR. AFIFI: Okay. Thank you.

CHAIRPERSON WOODS: Dr. Achem?

DR. ACHEM: Good morning, Dr. Lehman.

DR. LEHMAN: Good morning.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CHAIRPERSON WOODS: Dr. Ferguson?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

DR. FENNERTY: That is not this stuff.

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

CHAIRPERSON WOODS: Dr. Achem?

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

DR. LEHMAN: Yes.

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

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

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

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

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

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

DR. ACHEM: You smell like garlic as well?

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

CHAIRPERSON WOODS: Dr. Shaheen?

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

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

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

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

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

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

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

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

DR. GELLENS: Okay.

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

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

[4. STUDY RESULTS: EFFECTIVENESS]{.underline}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Thank you.

CHAIRPERSON WOODS: Thank you.

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

You wish to address the previous question?

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

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

DR. STEIN: It\'s a clomoxyl.

CHAIRPERSON WOODS: Okay. Thank you.

Okay. Dr. Shaheen?

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

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

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

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

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

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

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

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

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

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

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

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

DR. JOHNSON: That is correct.

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

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

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

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

CHAIRPERSON WOODS: Okay. Dr. Ferguson?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CHAIRPERSON WOODS: Okay.

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

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

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

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

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

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

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

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

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

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

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

DR. FERGUSON: For heartburn?

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

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

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

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

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

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

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

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

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

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

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

DR. FERGUSON: Thank you.

CHAIRPERSON WOODS: Dr. Achem?

DR. ACHEM: Thank you, Dr. Woods.

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

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

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

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

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

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

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

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

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

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

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

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

DR. ACHEM: Okay. Regarding ‑‑

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

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

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

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

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

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

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

DR. JOHNSON: Yes.

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

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

DR. ACHEM: Thank you.

CHAIRPERSON WOODS: Dr. Afifi?

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

What was the outcome variable or the dependent variable here?

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

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

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

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

DR. KENNEDY: That is correct.

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

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

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

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

So no, no attempt was done to do that.

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

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

DR. AFIFI: Yes.

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

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

DR. JOHNSON: I can\'t answer that.

CHAIRPERSON WOODS: Briefly, please.

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

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

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

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

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

DR. FENNERTY: That responded to it?

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

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

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

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

CHAIRPERSON WOODS: Yes. We\'ll discuss labeling.

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

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

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

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

CHAIRPERSON WOODS: Other questions from the panel?

(No response.)

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

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

[5. STUDY CONCLUSIONS]{.underline}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(No response.)

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

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

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

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

[2. FDA PRESENTATION:]{.underline}

[1. OVERVIEW/PRE‑CLINICAL STUDIES]{.underline}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CHAIRPERSON WOODS: Thank you.

DR. MERRITT: Thank you.

[2. HISTOPATHOLOGY CONSIDERATIONS]{.underline}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

DR. ACHEM: Dr. Woods?

CHAIRPERSON WOODS: Yes?

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

DR. MERRITT: Correct.

DR. ACHEM: Could you comment on that assessment?

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

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

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

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

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

CHAIRPERSON WOODS: Any other questions?

(No response.)

CHAIRPERSON WOODS: Okay. Thank you.

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

[3. CLINICAL CONSIDERATIONS]{.underline}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

DR. AFIFI: Excuse me, Dr. Yustein.

DR. YUSTEIN: Yes?

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

DR. YUSTEIN: This one or the one before?

DR. AFIFI: The one before.

DR. YUSTEIN: This one?

DR. AFIFI: Yes.

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

DR. AFIFI: Seventy‑nine percent?

DR. YUSTEIN: Seventy‑nine, yes.

DR. AFIFI: Okay. Thank you.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Next slide.

CHAIRPERSON WOODS: Thank you.

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

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

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

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

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

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

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

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

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

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

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

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

DR. YUSTEIN: No, no, no.

DR. FENNERTY: Thank you.

CHAIRPERSON WOODS: Other questions by the panel?

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

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

DR. AFIFI: Yes.

DR. YUSTEIN: Age, weight, so forth?

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

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

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

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

CHAIRPERSON WOODS: Any other questions?

(No response.)

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

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

[4. STATISTICAL CONSIDERATIONS]{.underline}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(No response.)

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

[5. POST‑MARKET REVIEW]{.underline}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CHAIRPERSON WOODS: Any additional questions from the panel?

(No response.)

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

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

A‑F‑T‑E‑R‑N‑O‑O‑N S‑E‑S‑S‑I‑O‑N

(1:21 p.m.)

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

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

DR. FENNERTY: Thank you, Dr. Woods.

[3. PANEL DISCUSSION]{.underline}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(No response.)

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

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

(No response.)

CHAIRPERSON WOODS: No. Okay.

[2. READING OF QUESTIONS AND DISCUSSION]{.underline}

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

I think we will start with Dr. Shaheen.

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

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

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

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

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

CHAIRPERSON WOODS: Thank you.

Dr. Ferguson?

DR. FERGUSON: I agree with Dr. Shaheen. I don\'t think there are any
short‑term safety issues that have arisen based on the data the sponsor
has provided.

I do have some concern also that long‑term safety hasn\'t been
addressed, particularly for a device that is intended for lifetime
issue. So there are issues I think remaining regarding potential
migration. It\'s not been adequately established in my mind what happens
to the product that has been lost on serial and radiographic follow‑up.

I have concerns about foreign bodies that are placed in the vicinity of
the lower esophageal sphincter of the angiograft prosthesis cortex to
reinforce the esophageal hiatus, having had a fair amount of experience
removing those foreign bodies, having eroded into the esophagus or
stomach. And this I think has that potential.

I also am concerned about the existence of a foreign body implanted into
the LES and in patients in whom adequate symptomatic relief is not
provided, how effective subsequent therapy, such as laporoscopic
fundoplication will be in those patients.

CHAIRPERSON WOODS: Dr. Achem?

DR. ACHEM: One of the key issues, Dr. Woods, that is important, I guess,
in our analysis as I read the question of assurance of safety, would be
certainly any vets; any perforations; any hospitalizations; any events,
such as sepsis; documentation of pleural effusions; many infections or
systemic infections, such as an abscess.

I think given the data in front of me, I understand from the sponsor
that no patient underwent any of those major side effects. In terms of
that reassurance, I am comfortable with the data presented to us today,
though I recognize that post‑marketing studies are clearly needed
because, indeed, as it was pointed out by the agency, specifically the
last presenter, until you embark on larger trials, you begin to see
potential serious side effects and unusual side effects.

Now, the part of the study that is more challenging to address is that
it is pretty evident to all of us that many patients, the great majority
or 90 percent of the patients, experience chest pain and about 20
percent of those also experience dysphasia or difficulty swallowing.

So certainly the side effect profile is there. And I think as we weigh
decisions for the device approval process, one has to balance the
decision‑making with the side effect profile, although none of those
seem to be lethal based on the data presented to us by the sponsor.

Along the same lines, no patient developed a stricture, which would be a
serious consideration in my mind, one of the biases that have been
implanted at the lower esophageal sphincter nor any patient had a full
impaction as best we can tell.

Dr. Woods, in relationship to the second part of the question; that is,
the histology findings and the inflammation and mineralization, I am not
a pathology expert. Therefore, my opinion is based on the analysis
rendered by the pathologist today here. If their analysis is accurate
that there is quiescence at one year, that would at least theoretically
provide us with comfort that no subsequent inflammatory response is
taking place. Whatever this process is doing to the lower esophageal
sphincter has ceased apparently at that point.

I think one important issue regarding the histopathology that intrigues
me personally because it can\'t speak to the mechanism of action is the
question I raised regarding the damage to the Enteric plexi and
specifically to nerve trunks.

It is possible that the device may be acting via two different
mechanisms. One, maybe even, indeed, it\'s affecting lower esophageal
sphincter relaxations, but it doesn\'t exclude the possibility that it
may also be impairing neurosensory perception of the esophagus. This may
have a bearing in explaining symptom outcome of these particular
patients.

This particular concern brings up the point on study design and the need
to have a placebo‑controlled, double‑blinded investigation to try to
address this particular issue.

Finally, in specific reference to the mineralization issue, I am
reassured by the pathologist as best as I can tell on their statements
that there seemed to be a minimal amount of mineralization occurring.
And, as I asked further questions, what is the specific amount that
there is and how critical is that to the functioning and particularly to
deleterious effects to the patient, it remains to be established.

Based on the assessment given to us today, I would say that the
impression I have is that the deposits of mineral calcification is
modest at best.

CHAIRPERSON WOODS: Okay. Thank you.

Dr. Afifi?

DR. AFIFI: I am going to limit my comments to statistical or public
health issues in the sense that\'s the area I feel comfortable in. From
that point of view, I really see nothing to add to the discussion except
to emphasize the importance of the long‑term follow‑up. So if, indeed,
the device is approved, we will need to keep that in mind in the
post‑marketing analysis.

CHAIRPERSON WOODS: Thank you.

Dr. Manyak?

DR. MANYAK: I am going to make my comments brief also. I think my GI
colleagues I will defer to with a lot of the areas in their field, but
there is one question I had. And that is the multiple injection issue
appears to be fairly real.

There is a significant number of patients who need these, which is very
similar to the injection for peri‑urethral tissues in my field. And it
raises the question in my field that is safe for multiple injections,
but I am not sure that has been answered here with this data here yet.
Possibly in the short term, it has, but I think over the longer‑term,
which is something we are all concerned with.

So I think that is the concern I would like to voice today.

CHAIRPERSON WOODS: Thank you.

I would echo similarly most of the comments already made. And that is
that I believe, as presented, the data shows adequate safety within the
12‑month period of time. I am not concerned about the histologic
findings. I think that is something you would expect to see with any
implantable foreign body.

I would be concerned with repeated injection since we have no data
beyond what was presented here today. I am most interested in follow‑up
beyond the 12‑month period of time on all the patients who are studied,
but, as pertains to the question asked, I think that the device, as
presented, is safe.

Dr. Fennerty has elected to postpone his comments to the end. So we will
move on to Dr. Gellens.

DR. GELLENS: I also echo most of the sentiments already mentioned by the
panel members. I think the safety is adequate at one‑year follow‑up so
far, but it needs to be adequate because the patient population that we
are dealing with here is not incredibly sick to start with. And the job
is to do no harm. So I think it meets the safety requirement.

As far as the inflammation and the mineralization are concerned, in my
field, we have a lot of experience with tissue calcification as far as
calciphylaxis and whatnot are concerned, which can be quite devastating.
However, the pathophysiology is totally different here. I don\'t think
the mineralization issue is a real problem.

And that\'s it. Thank you.

CHAIRPERSON WOODS: Ms. Moore?

MS. MOORE: From the consumer\'s point of view, I think my major concern
has to do with the word \"permanent.\" I am not sure that the consumer
would feel comfortable with that word if, in fact, they realized that
the study has only been for a couple of years; so I think that perhaps
if we could find either another word or elaborate upon that word so that
the consumer would know, then, that this has been a short‑term study and
they wouldn\'t expect permanency.

CHAIRPERSON WOODS: Mr. Balo?

MR. BALO: I think, you know, from an industry perspective, the company
did show safety as a protocol was defined to show safety. In fact, the
company has realized I think some of the comments that are made by the
panel members here, that they need to do follow‑up. And, as the sponsor
has indicated, they are proposing to do a post‑market study that will
carry this out for longer than one year\'s period of time.

So I think that is a good step by the sponsor to make that comment. I
think I agree that safety has been indicated in the study data.

CHAIRPERSON WOODS: Thank you.

Dr. Fennerty, would you like to make your own comments and then wrap up?

DR. FENNERTY: Well, I am just going to make my comments as a summary
because I think they reflect the majority and, actually, the consensus
that we have heard today that, really, the short‑term safety issues have
been adequately addressed by the study and the sponsor.

Obviously we will need longer‑term follow‑up, which is already planned
and been addressed between the sponsor and the FDA. I think, though,
that some of the concerns that further work needs to be done in the
future, irrespective of the outcome of this decision on the issue of the
foreign body reaction and subsequent treatment, specifically surgery or
perhaps other endoscopic applications.

I think the consensus is address the FDA\'s concerns that the ongoing
inflammation and calcification, mineralization, is clinically irrelevant
at this point but would bear further observation with the post‑term
marketing follow‑up.

CHAIRPERSON WOODS: Thank you. We will go on to number 2, question 2,
\"Tantalum was added as a component to the device to aid in
visualization under X‑ray and to assess indirectly the residual volume
of implant at follow‑up. Please comment on the degree to which the data
in the PMA demonstrates that the amount of tantalum visualized on X‑ray
directly correlates with the amount of polymer remaining implanted.\"

Dr. Shaheen?

DR. SHAHEEN: Well, I don\'t think that we know 100 percent for sure that
the contrast agent at long‑term follow‑up is evenly distributed and
adequately reflects the amount of implant. I\'m not overwhelmingly
concerned about this because, frankly, I don\'t put that much stock in
the data about residual implant to begin with.

I think that, as the sponsors acknowledge, this is a very imprecise
measure that they are using to try to figure out basically whether or
not the stuff is there or not. I think that when you get 65 percent
versus 40 percent from 2 views on a plane X‑ray when it is a guess to
begin with, it is not compelling to me.

So I am more interested in the data they present as far as effectiveness
than I am caring all that much about the contrast agent may not be
uniformly spread throughout. I suspect there is a chance it may not be,
and I don\'t care that much.

CHAIRPERSON WOODS: Dr. Ferguson?

DR. FERGUSON: Well, I don\'t believe that the sponsor has provided any
data that directly addressed this question. I think there is some
variation in the amount of mixing. However, I suspect that the tantalum
remains within the polymer and that probably it does reflect the amount
of polymer remaining.

CHAIRPERSON WOODS: Dr. Achem?

DR. ACHEM: Dr. Woods, I agree. I don\'t think we have enough information
to provide an answer to this question. With your permission, I may
venture to speculate or say that perhaps further studies are needed if
there is an issue, such as *in vitro*, looking at mixing the solution
and X‑raying it and determining how the dispersion coefficient takes
place.

There is some data in animals from their own studies, though, where the
solution was injected and I suppose could have been X‑rayed to make
comparisons and distribution. But, as it stands, I am unable to provide
an answer to the question.

CHAIRPERSON WOODS: Dr. Afifi?

DR. AFIFI: The word \"correlates\" that is in the question makes it a
statistical question.

(Laughter.)

DR. AFIFI: To adequately analyze it, we would really have to have data
on both variables in order to then measure the correlation and perform
some significant tests or whatever for it.

But, to my knowledge, such information was not presented to us. So I
really can\'t comment on it.

CHAIRPERSON WOODS: Dr. Manyak?

DR. MANYAK: I think the issue for me here is, rather than sloughing or
exact correlation with density, it\'s more one of migration products. We
see this with radioactive seed implantations. We see this with other
products. Do these tantalum particles show up in the lung, in the liver,
and other places?

You know, I think what we know about tantalum and being as inert as it
is, this is probably not an issue. I agree with Nick about that
particular issue, but there is no data provided about that. To me, that
is the issue. And it\'s not whether it sloughs off and it\'s gone
somewhere. Does it migrate somewhere else?

CHAIRPERSON WOODS: Thank you. I agree there\'s no data presented that
demonstrates that the amount of tantalum visualized on X‑ray directly
correlates with the amount of polymer implanted.

Dr. Gellens?

DR. GELLENS: I agree with pretty much what the panel said so far in this
regard. As far as the tantalum is concerned, though, I really think
that, instead of following X‑rays, you should probably follow CT scans.
It seems to me a much better way to follow the progression of this
material.

CHAIRPERSON WOODS: Ms. Moore?

MS. MOORE: I pass on this one. I submit to the experts here.

CHAIRPERSON WOODS: Okay. Mr. Balo?

MR. BALO: Same here.

CHAIRPERSON WOODS: Okay. Dr. Fennerty?

DR. FENNERTY: I think the panel reflects that we can\'t answer this
question for the FDA that they asked us to address, but I also think
that there seems to be an underlying consensus among the experts here
that it is likely to be of clinical and safety minor importance, if at
all.

CHAIRPERSON WOODS: Thank you.

Question 3, \"Over 40 percent of evaluable subjects had a greater than
or equal to 25 percent reduction in residual implant volume (as assessed
by measurement of residual tantalum) at 6 months and 12 months when
compared to baseline at 1 month. Please discuss this finding and whether
it poses any safety or effectiveness concerns. In addition, please
comment on whether the conclusion that the \'missing\' material sloughed
into, and was passed out of, the GI tract is reasonable and supported by
this data.\"

Dr. Shaheen?

DR. SHAHEEN: I appreciate you letting me go first on all of these, ‑‑

(Laughter.)

DR. SHAHEEN: ‑‑ especially these simple ones.

I go back again to the imprecision of how they did this. I wonder how
much we should make out of these data about the measurements based on
the plane films. They have provided us essentially no evidence that the
material truly is sloughed off and comes out in the feces. I believe
that is what is happening.

I also agree with Mike that perhaps the more important question is not
so much did it all fall out, but if it is still in there, is it doing
anything nasty? And, at least as best we can tell from the data that we
have, it probably isn\'t doing anything horribly nasty.

And, for that reason, again, I am not incredibly concerned by the fact
that these patients have had a reduction in the residual implant volume.

The other thing, of course, you have to think about is that this isn\'t
a static situation. There is remodeling that is going on there. Perhaps
there is contraction. If there is collagen surrounding these injections
that that collagen is contracting, perhaps that accounts for some of it.

The bottom line is that with the imprecision of the tools used to
measure this and the fact that we don\'t have a lot of data that some of
our injection has gotten away and is doing something bad, I am not
incredibly concerned about at this point.

CHAIRPERSON WOODS: Dr. Ferguson?

DR. FERGUSON: Well, I have concerns about this point. I believe that the
sponsor hasn\'t adequately demonstrated where the missing material has
gone. Only 5 or perhaps as many as 6 animals were observed for a
12‑month period. No study of feces analysis was performed as far as I
can tell. It would have documented some sloughing of the material in
those animals.

I think it is personally alarming that that percentage of patients has
been documented to have some loss of material. And, as far as I can
tell, no substantial effort has been made to document where the material
goes to.

CHAIRPERSON WOODS: Dr. Achem?

DR. ACHEM: I would agree with Dr. Ferguson as far as a lack of
accountability of where the material is and my inability to, therefore,
tell whether this is a sloughing off, which appears an acceptable
alternative explanation. And I don\'t have concerns about accepting the
notion, but it is unclear whether everything would slough off or not.

Indeed, in fact, in some of the data, there is some material that was
actually implanted transmurally in some of the patients. So you really
wonder where it went. The fact of the matter, as Dr. Shaheen pointed
out, is that there appears to be no major migration to vital organs or
vessels.

The consequence of the migration, whatever that was, for which we can\'t
account, does not seem to have any negative effects, which to me is the
most significant finding.

CHAIRPERSON WOODS: Thank you.

Dr. Afifi?

DR. AFIFI: I would like to address the question of whether the loss of
the implant has any implications on effectiveness, rather than safety.
The question that that raises is, does it continue to produce the level
of effectiveness after it has lost such a percentage of it?

So the question, then, really is what is the point at which the
effectiveness is reduced below an acceptable level and according to some
definition, which, in turn, raises the question of, is this related to
the retreatment of the patient?

So, in my mind, these are really the issues. I don\'t think we have
enough data to address that way of looking at it. Again, it becomes a
question of long‑term data, but I think it is a relevant one, especially
from the \"How good is the device?\" point of view.

Thank you.

CHAIRPERSON WOODS: Dr. Manyak?

DR. MANYAK: I believe this question has one of three possible answers
for this. One is either the tissue sloughed and the material has gone
through the GI tract. Secondly, the migration issue we talked about. And
the third is whether or not this is actually biodegradable and we have
lost some of that because of that aspect.

Biocompatibility, many things that are biocompatible are also
biodegradable. It\'s very well possible that you are getting some
resorption here of this material that is really inconsequential from an
extent of a safety standpoint, but it would explain your decrease in
volume.

So I think you can answer the questions in a couple of ways. One would
be if you are looking for the migration issue, it would seem to me that
in your post‑market analysis, at the same time that would be being
performed, you could certainly perform animal studies, whether they are
small animals or larger animals. I am not the right person to answer
that part. But you would want to look at he lungs and the liver and
other tissues to see if there is migration of these tantalum products.

You know, we do need to consider, even though it is a biocompatible
material, the tantalum. Do we have 25‑year data on tantalum implantation
in humans? I don\'t think we do.

The question is if there are, that\'s fine. I\'m happy to hear that. But
these are younger people, some of them, and they are going to have a
long life span. So it is an issue that we should pay a little attention
to here. And it is something that I think you can answer the migratory
issue with animal studies.

The biodegradability is also something you can probably answer. So
concurrently with your post‑market analysis, you can put this thing to
bed, I believe.

CHAIRPERSON WOODS: Yes. I agree basically with everything that has been
said. I would say I felt impressed with the animal data that was
presented that there was no evidence of the tantalum in any of the other
organs remotely, of the entire Enteryx polymer product anywhere in the
bodies of the animals that were studied.

So the other side of the coin is whether or not this reduction in volume
affects the effectiveness of the product. I think the data presented
suggest that it may well as patients who had less than 5 or 6 ml of
product left were more likely to be treatment failures.

I think there are just a lot of questions here that we just still don\'t
have the answer to and hopefully with the post‑market analysis will
become more clear.

Dr. Gellens?

DR. GELLENS: I am pretty comfortable with the fact that this Enteryx is
being sloughed off into the GI tract. I agree with Dr. Woods as far as
the animal data is concerned. After X‑raying the animals, it couldn\'t
be found anywhere else. So unless it\'s turned into something else, it
has got to be sloughed out of the GI tract.

I think the histologic data is relatively convincing with this fibrous
capsule that is formed, that it is probably not degraded in the body. So
I think that it is probably sloughed off. I am comfortable with that.

Thanks.

CHAIRPERSON WOODS: Ms. Moore?

MS. MOORE: Yes. Well, I have nothing new to add. I was concerned,
though, about how we know where the sloughed‑off material went. I
didn\'t see anything in my reading to tell me that you had some definite
proof that it came out in the feces or just what. I am comfortable with
what has been said.

CHAIRPERSON WOODS: Mr. Balo?

MR. BALO: Yes. I think everything has been said about the safety of it,
but, you know, the company did do all the viability testing that is
required by the FDA to show that all of the material that is used in the
device is biocompatible. That is a standard that companies use basically
to prove that the materials themselves are biocompatible.

The animal data we spoke to already and basically said you don\'t have
any concerns about that. So I think from my perspective, we could
assume, just like other doctors have said here, that it is not really
that big of a problem where it sloughs off.

CHAIRPERSON WOODS: Dr. Fennerty?

DR. FENNERTY: I think in order to address the question the FDA asked us
to address, I think the bottom line is we don\'t know where it went.
Most of us I think are presuming that it\'s sloughing.

I think the last comment ‑‑ it was very important ‑‑ is we are all
presuming based on what we know now that these are safe, biocompatible
agents. Therefore, the real issue is, does it really make any
difference? I suspect that from a safety standpoint, it doesn\'t, but it
needs to be addressed and resolved.

I am sure Dr. Johnson would love to perform the study that he strains
all of his patients\' stools for the next two years to find out where it
is going.

CHAIRPERSON WOODS: Okay. Question 4, \"Reduction in proton pump
inhibitor dose was used as the primary effectiveness endpoint for the
clinical trial. The objective of the study; i.e., to show a greater than
or equal to 50 percent reduction in PPI dose in at least half of the
enrolled subjects, was met at 12 months. The objective secondary
endpoints, however, did not appear to demonstrate the same degree of
improvement. Please discuss the significance of the results from the
intra‑esophageal pH; esophagogastroduodenoscopy, or EGD; and manometry
procedures, and whether they support the use of Enteryx as a safe and
effective treatment for GERD. Within your discussion, please comment on
whether you believe that these results suggest patients may be at
continued risk for developing complications of GERD including erosive
esophagitis, strictures, and/or Barrett\'s Esophagus despite symptom
improvement while off their PPI medications.\" It is a complicated
question.

Dr. Shaheen?

DR. SHAHEEN: I think there are several points that need to be made here.
First of all, the safety issue I feel comfortable with. The efficacy
issue I am not quite as convinced.

There are three points here I think we need to consider. One is that
there is a pretty remarkable, actually very remarkable, improvement in
the subjective measures in the study. You are getting one year out. You
are still at 80 percent in the primary endpoint.

However, there is a much more modest improvement, in some cases no
improvement, in the objective data with about one‑third having worse
24‑hour pH Probe data and unimpressive esophagitis changes.

In addition to that, I agree with Dr. Fennerty that the graph that Dr.
Yustein showed that showed the degrading effect with time on the primary
endpoint should have been put on a 100 percent scale.

I disagree that this may not be very significant, especially if we are
talking about a lifelong therapy. I think there are very few people here
that would disagree that if this therapy becomes four or five percent
less efficient at every six‑month interval, we are going to be getting
into an awful lot of retreatments here. And we are talking about a
different beast than a true lifelong therapy.

So I do think that that is something to worry about. And I also think
that when you see this constellation of things that, hey, a slowly
degrading effect over time, very high subjective measures, very modest
objective measures, the other question you have to ask yourself is, how
much of this is placebo effect?

I would submit to you that there are several features here that suggest
at least some of this effect may be placebo effect, the fact that 97 and
a half percent of people were off medicine at one month, but that
degrades fairly rapidly, still to high levels, but certainly it gets
back to this issue of longer‑term data needed.

So I am comfortable with the safety. I think that this is doing
something, although everybody is trying to guess what it is really
doing. And it doesn\'t seem like anyone knows for sure what effect, if
this is a TLSR effect, if this is just a bulking agent, what is really
happening here. It sure would be nice to know what is going on.

I agree with Dr. Achem that a sham trial with injections of the vehicle
but with no active agent would go a long way toward helping us kind of
figure out what is going on here to decide a little bit more about the
effectiveness.

So the bottom line is that we can\'t answer the last part of the
question, which is is this going to halt progression to Barrett\'s
Esophagus, and stricture, et cetera, but remember there are very little
data.

It is kind of an unfair thing because, even for PPIs and surgery, there
are very little data about halting progression of Barrett\'s Esophagus
or to Barrett\'s Esophagus. It is not really a question that is answered
anywhere in the literature with any of our standard therapies either. I
mean, if you do a wrap on somebody with reflux, they can still get
Barrett\'s. And nobody knows whether or not there is a retardation of
the effect of the chance of getting Barrett\'s with time.

So in some respects, is there a chance that these things may happen?
Certainly. But I don\'t think that that is any different than the other
therapies we have.

CHAIRPERSON WOODS: Dr. Ferguson?

DR. FERGUSON: Well, as it states here, the primary endpoint I think was
adequately met by the sponsors with the study. I think I have also
indicated that I believe they chose the wrong endpoint for the study and
that the more objective measures are more important than getting
patients off the PPIs.

So with regard to intra‑esophageal pH, the majority of the patients at
12 months would still qualify for entry into the study based on abnormal
intra‑esophageal pH.

Similarly, an insufficient percentage of patients had regression of
esophagitis. And, in fact, a substantial number of patients developed
esophagitis after implantation of the material. The sponsors have failed
to demonstrate adequately the mechanism by which they think the device
works.

There is insufficient change in any of the manometric parameters. To
provide an explanation, I think Dr. Achem has already suggested two very
plausible explanations having to do with nerve damage, one interference
with transient relaxations. The other is interference with a feedback
mechanism so that the patients don\'t recognize that they\'re having
acid exposure in their esophagus.

The problem with this latter one is that as the patients have ongoing
exposure but don\'t recognize this exposure, they\'re perhaps at higher
risk than the typical patient with GERD for developing the compilations,
such as Barrett\'s Esophagus, stricture, and perhaps adenocarcinoma.

So I believe there are substantial questions regarding efficacy.

CHAIRPERSON WOODS: Dr. Achem?

DR. ACHEM: Thank you, Dr. Woods.

Well, unquestionably, the secondary parameters would be an ideal goal
for those of us looking at concern issues, that they be modified to a
substantial effect. That is not the case.

Let me dispense quickly with the manometry that doesn\'t concern me at
all. In fact, I am gratified that there has been no effect, no
substantive effect on distal esophageal peristalsis. It would concern me
if the peristaltic pathway or peristaltic amplitude would impair in the
spaces when you inject this device. Again, we are invoking some
potential hypotheses of nerve damage. So you can see that at least the
amplitude of distal peristaltic was not impaired.

That is the extent of how I look at the manometry in terms of being
helpful here. So I am not concerned about the LES pressure. We have
already alluded as to other mechanisms, such as transient lower
esophageal sphincter relaxations. It\'s a more important pathway to look
at.

The thing that is concerning is certainly the pH data. The fact that up
to 39 percent of the patients only normalize the pH is potentially a
bothersome issue. I was trying to think in my mind whether there is any
published data. I know there is. And I just don\'t think this is ‑‑ I am
trying to look at the applicability of the data as to the variability of
pH.

If you repeat pH studies on a single individual over time at repeated
intervals of time, how much of a change in the pH parameters can be
expected? I can\'t come up with that information. Maybe Brian might
elaborate over that and whether that can be a factor to, somehow or
another, explain the differences noted. Alternatively, clearly, though,
it means that the device is not affecting to a substantial degree the
acid clearance or acid contact time, as we see by the fact that only 39
percent of the patients normalized.

So that would be a potential serious concern. So is the fact that about
22 percent of the patients seem to have progressed to Grade 2 erosive
esophagitis, a category that is less difficult to subject intra‑observer
variability in terms of the classification by the endoscopies. That
category is easier to score by most of us. And there is more the
pendency on that grade than it would be for Grade 1\'s. So that
observation is of some concern indeed and argues to some extent that the
efficacy parameters have not been modified by this particular device.

As far as the issue of whether these factors, therefore, represent a
potential impact, I think that that certainly remains an open
consideration, whether they will lead on to further damage in the
esophagus, erosive disease, strictures.

I don\'t think that Barrett\'s will be or should be an issue, at least
based on some data that, if I am not mistake, is Alan Cameron\'s data, I
believe, where he looked at an index endoscopy and followed patients
longitudinally and found that the likelihood of somebody developing
Barrett\'s Esophagus once you had an index endoscopy which was negative
was negligible.

So I am not as concerned on the concept of Barrett\'s, at least at this
point in time. But the other aspects certainly remain an issue.

CHAIRPERSON WOODS: Thank you.

Dr. Afifi?

DR. AFIFI: There\'s really nothing for me to add from a statistical
point of view. The analysis does indeed not uncover any improvements in
the objective measures that are due to the device. So I think I will
leave the other comments to the experts.

CHAIRPERSON WOODS: Dr. Manyak?

DR. MANYAK: Well, I believe the primary endpoint, as defined, has been
answered. And I will defer comment on the secondary endpoints to my GI
colleagues since that is out of my field.

CHAIRPERSON WOODS: Thank you.

I also think the primary endpoint has been answered, but I have trouble
interpreting any answer for you on the secondary endpoints because I
think the way the study was designed does not allow you to really answer
the questions about this. It goes back to using these patients as their
own controls and not having an adequate, as I see it, control group that
received a sham procedure and then were followed for the same period of
time, re‑endoscoped, having pH studies, et cetera, all of the same data
collected on them. So I don\'t think I can answer the questions asked
adequately based on the data presented.

Dr. Gellens?

DR. GELLENS: I have additional concerns, as Dr. Shaheen did, about the
possibility of a placebo effect here, especially with the primary
endpoint that was chosen being subjective as it is. In addition, then,
the objective data doesn\'t really support the initial results.

The other possibility is the reason the secondary endpoints don\'t
really support the primary endpoints is that we don\'t really understand
the mechanism for how this works. That could be the real problem.

My major concern is that there is a huge placebo effect here that we may
be missing, but since the procedure seems to be safe and there is good
response at 12 months, I still think it is probably okay.

CHAIRPERSON WOODS: Ms. Moore?

MS. MOORE: I have nothing new to add.

CHAIRPERSON WOODS: Mr. Balo?

MR. BALO: I just think that the company did meet the primary endpoint.

I know the sponsor has the opportunity to reply at the end. I think some
of the questions brought up by Dr. Ferguson and Dr. Achem maybe could be
more adequately explained by the sponsor. If they do have more data and
more information, share it with us from some of the European studies
that are currently going on. So there may be some data you might want to
listen to.

CHAIRPERSON WOODS: Dr. Fennerty?

DR. FENNERTY: I am going to take this opportunity to deviate from my
previous comments, which were summary, to make some personal comments
and to take some of my panelists to task, especially some of the junior
members, Dr. Shaheen.

First of all, while I agree that this would not be the primary endpoint
that I would want to see the FDA agree to with a sponsor in the future.
This was the primary endpoint that the sponsor and the FDA did come up
with. And, indeed, it was met in this study.

Having said that, the accepted standard for therapeutic trial of
treating reflux patients today is symptom improvement. It is what the
GEMBO guidelines suggest. It is what the American College of
Gastroenterology guidelines suggest.

The American Gastroenterological Association suggests the primary
endpoint should be symptom improvement. PPI use could be considered a
surrogate marker for symptom improvement. Hopefully future device trials
will look at truly symptom improvement as a primary outcome. However, we
have this primary outcome. Once again, it was met. This was what was
devised for the study.

Having said that, the secondary outcome measures are important. However,
they are of secondary importance in management of patients with reflux
disease. Erosive esophagitis should not be considered a complication of
GERD. It is a finding in nearly half the patients with reflux disease.
It is not a complication; whereas, Barrett\'s and strictures are.

Having said that, we talk about the secondary endpoint that were not
met, ignoring a secondary endpoint which is subjective which was met,
which is the Velanovich GERD quality of life data. This also was an
objective secondary endpoint that we have neglected to discuss in our
deliberations that was met and was definitely significant from baseline
off of PPIs.

It also ignores the fact that nearly 40 percent of these patients
normalize their intra‑esophageal past exposure after this therapy was
devised, which is obviously not a placebo effect. It means that a
subgroup of these patients had normal physiologic response. Actually,
that group of patients, if you remember Aron\'s analysis, also had a
clinical response for the most part.

So, having said that, I have substantial concerns about designs of these
sorts of studies. I wish we could go back in time and redesign it. But
when we look at primary and secondary endpoints, we need to stay symptom
and patient‑focused and then answer the mechanistic studies, hopefully
in future design trials, in order to address those concerns as well.

So, as a summary statement, I think it is clear that primary endpoints
are met. A lot of us have concerns about the secondary endpoints and
perhaps what the primary endpoint of these trials should be in the
future.

And I think that the mechanistic issues of why continued abnormal acid
exposure occurs, despite symptom improvement, needs to be addressed so
that we can figure out if this is a neurologic issue or other issues
from that standpoint.

CHAIRPERSON WOODS: Okay. Thank you.

Question 5, \"Based on your deliberations to this point, please discuss
whether the overall benefits, including improvement in symptom as well
as objective measures, outweigh any risks associated with use of this
device.\"

Dr. Shaheen?

DR. SHAHEEN: I would like to thank Dr. Fennerty for his comments and
remind him it is only a matter of time before he gets old and dies and
we are in charge.

(Laughter.)

DR. SHAHEEN: With that, as far as the risk‑benefit ratio here, I think
this is a tough call. The reason I think it is a tough call has to do
with what several people have mentioned before, which is that you are
taking a group that is PPI‑responsive on relatively, overall relatively,
small amounts of medicine. So the bar is set pretty high here.

You have got an effective therapy. You have got a healthy patient
population. You had better be darned sure what we are going to do to
them is: a) not going to hurt them, which I feel like, in the short‑term
at least, has been adequately addressed, and b) is probably going to
help them. I think that, at least in the short term, it does appear that
for the primary endpoint, it does help them.

However, I will say that I would feel lots, lots, lots better if I had
at least another year of data on this before I talk to a 26‑year‑old and
say, \"I want to put this stuff in your lower esophagus. And it\'s going
to be there forever.\"

CHAIRPERSON WOODS: Dr. Ferguson?

DR. FERGUSON: Well, I have ongoing concerns about long‑term risks. I
don\'t believe that there are any substantial short‑term risks. Given my
concerns about long‑term risks and my concerns about, although there is
symptomatic relief, there is not normalization in most patients of any
of the other physiologic measures of reflux or LES abnormality. I can\'t
tell you that there is any way I can come down on the balance of a
benefit versus risk.

CHAIRPERSON WOODS: Dr. Achem?

DR. ACHEM: I think that one of the great difficulties for us is the
concept. We are departing from the notion that many of these people are
receiving already a therapy that seems effective and offer an
alternative therapy the effectiveness of which is being evaluated at
this point and then some side effects occurring.

When one looks at the context of somebody taking a medication and being
symptom‑free or symptom‑controlled, if you will, versus undergoing
another procedure and undergoing therapy and some side effects
occurring, it brings in the issue of deciding which of the two processes
is best and which will benefit from that.

I think there are a lot of issues that remain unknown. The overall
safety in my mind is being described and I think is there, but the side
effect profile concerns me. Naturally I think patients offered this
study will clearly be explained what those side effects represent.

This may result or this may conceivably serve as a bridge or an
adjunctive therapy for the management of GERD. I am not sure. I am not
sure of the place exactly yet.

In summary, I think that the risks at this point seem modest. And those
are primarily based on side effects, not inappreciable, by the way,
though.

CHAIRPERSON WOODS: Dr. Afifi?

DR. AFIFI: I think the question of the risk‑benefit analysis is the
heart of what we are talking about here. From the point of view of a
patient, I believe that there is something here that shows that there is
some benefit for a 12‑month period that outweighs the risks.

I think, however, since this is billed ‑‑ and I missed Christine Moore.
She said she doesn\'t like the word \"permanent. Maybe long‑term. If
this is billed as a long‑term treatment, we don\'t have enough to say
about how good it is long‑term.

It is at this point that I think my earlier comment about longitudinal
analysis comes in. There are really four points that could be quite
adequately addressed by a longitudinal analysis if there is to be a
post‑market study.

The first has to do with the effectiveness and a series of measures, be
they subjective, namely the being on or off PPI and how well do you feel
like HRQL or SF‑36. I look at those, Dr. Fennerty, as subjective as
well, even though they are combined. So that is number one.

The other is also the question of safety. Maybe there are some long‑term
side effects that would show up in a longer study than has shown up in
12 months.

The third point has to do with guidelines for who before the implant can
benefit from the procedure if it is indeed approved. And, again, I would
go back to an analysis of baseline data versus the outcomes to try to
answer that question but also in a longitudinal fashion.

The fourth one is the question coming up next, but I think this is a
good time to mention it as well. That is, is it correct to have a repeat
procedure? What are the guidelines for a retreatment if there is to be a
guideline for that?

I would suggest that we need to keep in our mind that these are four
major areas that could benefit from a longitudinal analysis.

Thank you.

CHAIRPERSON WOODS: Thank you.

Dr. Manyak?

DR. MANYAK: To make a long story short, I think essentially the
short‑term benefits exist to further pursue this procedure, but there is
no data on long‑term yet that is satisfactory, I believe. Therefore, I
think that the total picture is really somewhat inconclusive. The
short‑term looks good, but we need further data.

CHAIRPERSON WOODS: Thank you.

I completely agree with Dr. Afifi\'s comments and couldn\'t have said it
any better. I think I just want to reiterate that if this is approved,
we need to be very, very careful on patient selection criteria being
very well‑defined and the repeat injections that may be necessary for a
subgroup of patients. We have no data beyond one injection.

I am just very concerned that this be monitored carefully and guidelines
be put forth as to how to select patients for this and we try to
accumulate in a post‑marketing study further data on patients who get
more than one injection and what happens with them if patients do get
more than one injection.

Dr. Gellens?

DR. GELLENS: I agree that this is a tricky question to answer because
the long‑term benefits are not clear by any stretch of the imagination.
So I think a way to get around that is to not market this as a permanent
device but perhaps long‑term. I think that would help the physician and
the patient when making an informed decision whether or not to go with
this therapy, as opposed to the typical medical therapy.

CHAIRPERSON WOODS: Ms. Moore?

MS. MOORE: I believe my answer is yes to that question, number 5.

CHAIRPERSON WOODS: Okay. Mr. Balo?

MR. BALO: I think that the company did show short‑term effectiveness and
safety for this device, as all of the panelists have said. I also feel
that, as I said before, the company realizes that it does need to show
more long‑term in the data.

I think the panel\'s responsibility is basically to give direction and
to show what kind of data we do need so when they do that information,
we can basically feel comfortable that we are getting the data we need
to show long‑term stability and safety.

CHAIRPERSON WOODS: Dr. Fennerty?

DR. FENNERTY: I want to take this public opportunity to thank Dr. Cooper
for allowing me to take 10 divergent opinions and giving me 30 seconds
to summarize them to the FDA. Thank you, Dr. Cooper, for that
opportunity.

If I am hearing my colleagues correctly, I think that there is a
consensus here that we should not view this as a permanent device but
within a well‑defined population using one injection, the risk‑benefit
over the short term appears to be in the positive toward the benefit
side. That leaves open a number of questions, which is obviously
long‑term benefit, the issue of multiple injections, and efficacy and
risk‑benefit outside of this well‑defined population, which was put
forth in this study.

CHAIRPERSON WOODS: All right. Question number 6, \"Nineteen of the 85
patients underwent re‑injection within the first 3 months. Please
discuss whether sufficient data has been presented to support
retreatment with Enteryx. If you believe the data is adequate, please
comment on whether you believe any of the following should be
recommended: a) maximum number of repeat procedures (and if so, what
number); b) maximum number of repeat injections per procedure (if so,
what number); c) maximum implantable volume at each procedure and
overall (if so, what volumes); and d) timing of retreatment procedures
relative to the initial treatment (if so, the length of time).\"

Dr. Shaheen?

DR. SHAHEEN: In the words of Roseanne Roseanna‑Dana, \"You ask a lot of
questions.\"

No. They are inadequate data to tell us what is really happening with
the re‑injections. I think that given the small number of patients in
this study that did undergo re‑injection, it is going to be very
difficult to answer, even generally, if this is a good idea, let alone
specifically, the letters that go down there.

I think that in the small number of patients that we did see, it
certainly appears to be safe. But, again, now we are talking about even
shorter‑term data because these people are re‑dos. We are talking about
a very, very, very small number, which is quite possible to obscure any
side effects that multiples might add.

I think if we are going to allow more injections, clearly the maximum
number of repeat procedures we should allow based on the data is one.
And we only have thin data for one.

In terms of the maximum number of injections per procedure and the rest,
I think that it would be entirely speculative to even throw a hand
grenade at those questions. And I don\'t think that we can.

CHAIRPERSON WOODS: Dr. Ferguson?

DR. FERGUSON: Let me just paraphrase what he said. I don\'t think there
are sufficient data to answer this question.

CHAIRPERSON WOODS: Dr. Achem?

DR. ACHEM: I agree entirely. The only one point is that it seemed in the
very small analysis that was presented, in fact, I believe fever,
though, was the higher occurrence, almost double the study, when the
second injection took place. But despite that comment that I am making,
I think we have insufficient information to make a recommendation in
this particular regard.

CHAIRPERSON WOODS: Dr. Afifi?

DR. AFIFI: I have nothing to add to what I said to the previous
question.

CHAIRPERSON WOODS: Dr. Manyak?

DR. MANYAK: Well, I actually think we have the answer, whether it
supports retreatment. I think it has been shown to be safe to retreat.
The question is how long, how many times will we retreat are clearly not
answered. We do have answer to one question as far as volume is
concerned, and that is the minimum volume, I believe.

We saw data that suggested there was a fairly sharp cutoff in the amount
of ‑‑ and I believe it was five cc for the amount of volume that would
appear to be more effective than the lower volume. So we have some
suggestive evidence to that effect. However, we do not have clearly
enough data to talk about maximum numbers, intervals, or total volumes
on retreatments.

CHAIRPERSON WOODS: I feel similarly. In fact, I feel hesitant to make
any recommendations about retreatment based on data from 19 patients.
However, the data as presented in those 19, it appears that it is safe,
but I hesitate to make any formal recommendations based upon 19
patients.

Dr. Gellens?

DR. GELLENS: I agree with the panel. The information on the retreatment
is thin. But if we decide to approve this device, we are going to have
to make recommendations on this issue. So I think if we decide to
approve, it is going to have to be something that is looked at
extensively in post-market evaluation.

CHAIRPERSON WOODS: Ms. Moore?

MS. MOORE: I agree with Dr. Gellens.

CHAIRPERSON WOODS: Mr. Balo?

MR. BALO: I don\'t have any comment.

CHAIRPERSON WOODS: Okay. Dr. Fennerty?

DR. FENNERTY: I think the best summary is the second one that was given
by my colleague Dr. Ferguson that the data are inadequate and
insufficient to address this question for the FDA.

CHAIRPERSON WOODS: Okay. We are going to move on to labeling questions.
Number 7, \"The sponsor has proposed the following Indication for Use
for Enteryx: \'The Enteryx procedure kit is indicated for endoscopic
injection into the lower esophageal sphincter, or LES, for the treatment
of gastroesophageal reflux disease, or GERD.\' Please discuss whether
this Indication for Use accurately reflects the data obtained during the
clinical trial.\"

Dr. Shaheen?

DR. SHAHEEN: With the exception of the addition at the end of that, at
the end of the statement that it should be in the PPI‑responsive
patient, in the patient responsive to proton pump inhibitor therapy,
because that is what the trial was designed to look at and that is what
they successfully showed. Other than that, I have no problems with that.

CHAIRPERSON WOODS: Dr. Ferguson?

DR. FERGUSON: Well, I have concerns about the stated indication about
treatment of gastroesophageal reflux disease. The sponsors have
demonstrated that fewer than half of the patients will have relief of
disease as defined by esophageal acid exposure. And I would propose that
the wording be changed to \"for the treatment of symptoms due to
gastroesophageal reflux.\"

CHAIRPERSON WOODS: Okay. Dr. Achem?

DR. ACHEM: I would agree that the population was selected and the
patients who responded to PPIs were the ones chosen. That has an
implicit diagnostic message behind it that people who respond to PPI are
those who may have the disease, as opposed to those who do not. So I
think the addition of the PPI response makes sense, which was part of
the criteria for the trial.

In addition, I raise the possibility that as well a statement be made to
some extent to address the issue that most of these people did not have
great erosive disease. In other words, they had milder forms of the
spectrum of GERD.

And along those lines, I think we should qualify that in this particular
statement that people with mild disease were selected. I know that may
be addressed in the subsequent question, but I am getting ahead of the
game with that.

CHAIRPERSON WOODS: Okay. Dr. Afifi?

DR. AFIFI: In my own understanding, we haven\'t shown that the device
affects the sphincter itself. And, at best, what we have shown is that
it does relieve the symptoms. So with that in mind, I agree with Dr.
Ferguson in the change of wording.

CHAIRPERSON WOODS: I am sorry. Dr. Manyak?

DR. MANYAK: That\'s okay. My position is a hybrid of the first two
speakers, Dr. Shaheen and Dr. Ferguson. I think that is a very good
definition for what we have seen today.

CHAIRPERSON WOODS: Yes. I agree. I think it is very critical that we
make sure that patients who receive this are responsive to acid
suppressive therapy, specifically PPIs, which were the drugs of choice
in this study.

I would add the caveat that patients who have GERD who are using
intermittent therapy, H2 blockers, and getting relief, that may not be
the kind of patient who really needs to go on to this sort of treatment.
So we may wish to specific patients who have severe or regular daily
symptoms that are relieved by proton pump inhibitor would be adequately
treated with this device. So I think that is very, very important to
patient selection to get the best results.

Dr. Gellens?

DR. GELLENS: I agree with the rest of the panel members. And I think
that adding the statement that it should be for the relief of symptoms
of GERD is a good idea.

CHAIRPERSON WOODS: Ms. Moore?

MS. MOORE: I am in agreement with the panel.

CHAIRPERSON WOODS: Mr. Balo?

MR. BALO: No comment.

CHAIRPERSON WOODS: Dr. Fennerty?

DR. FENNERTY: Okay. Here\'s how it now reads based on consensus, \"The
Enteryx procedure kit is indicated for endoscopic injection into the
region of the lower esophageal sphincter (LES) for the treatment of
symptoms due to gastroesophageal reflux in patients requiring and
responding to pharmacologic therapy\" is the way I read that consensus.

DR. SHAHEEN: Brian, do you want to be more specific and say \"proton
pump inhibitor therapy\"?

DR. FENNERTY: Just to respond to Nick\'s point, it is a very good
question, but if they respond to H2 blocker therapy, they will respond
to PPI therapy. And I don\'t think I would want to handcuff a responder
to anti‑secretory therapy. That is why I left it as \"pharmacologic.\"

CHAIRPERSON WOODS: You don\'t want to comment about severity of disease?

DR. FENNERTY: Just to go back to Sami\'s point because I did put
symptoms ‑‑

CHAIRPERSON WOODS: Severity of symptoms?

DR. FENNERTY: Eighty‑five percent of patients with reflux disease will
have Grade 1 or 2 esophagitis or less. Therefore, this is applicable,
this definition, to 85 percent of the GERD population, which I think is
sufficient in general. That\'s personal opinion, Sami.

DR. ACHEM: But what if a practitioner already, as you know frequently
does, have the results of endoscopy and finds Grade 3 esophagitis? Would
you think that that is an issue that, at least on the labeling, should
be addressed? And he should be aware that that is not a group of people
that was involved in this particular trial.

DR. FENNERTY: I think it\'s an infrequent occurrence in the typical
practice of reflux disease. I understand your concerns, but I would
rather not handcuff our colleagues in using this as a therapeutic agent
if it, indeed, is approved.

CHAIRPERSON WOODS: Brian, you don\'t think there should be any comment
anywhere about frequency of symptoms in here?

DR. FENNERTY: Actually, the way I read this, I said for the treatment of
symptoms due to gastroesophageal reflux in patients requiring and
responding to pharmacologic therapy. So, Karen, I think that encompasses
the patient meeting a baseline requirement. At least the semantics of it
seem to fit that for me.

CHAIRPERSON WOODS: Yes. Okay. I agree. Thank you.

Any other comments here?

(No response.)

CHAIRPERSON WOODS: All right. Moving on to question 8, \"The proposed
labeling lists portal hypertension as the only contraindication for use.
Please discuss any other clinical conditions for which you believe the
labeling of the device should include specific contraindications,
warnings, or precautions. In your discussion, please include comments on
the following: patients with Barrett\'s Esophagus, patients with erosive
esophagitis, patients with esophageal ulcers, patients with esophageal
strictures, and patients with GERD symptoms refractory to proton pump
inhibitors.\"

Dr. Shaheen?

DR. SHAHEEN: With respect to the contraindications, a lot of the things
that we have listed there are into the precautions. I am not sure which
would be a precaution, which would be a contraindication.

I will say that I am not incredibly worried about the use of this
material in Barrett\'s Esophagus patients. I take care of a lot of
patients with Barrett\'s Esophagus. I don\'t think that it would
necessarily be incredibly detrimental to them, but since they weren\'t
in this study, I certainly agree that it should be listed at least as a
precaution.

I think that we need to specifically, either in the contraindications or
the precautions, list stricture at this point. The precautions do list
something, persistent high‑grade esophagitis, but I do think that we
need to specifically say that this may not be such a great idea for
folks with strictures.

CHAIRPERSON WOODS: I am sorry. Dr. Ferguson?

DR. FERGUSON: I have no opinion about Barrett\'s Esophagus or erosive
esophagitis. I believe patients who have complications such as ulcers
and strictures, those should be contraindications, as opposed to
cautionary notes.

And patients with GERD symptoms refractory to proton pump inhibitors
should not be candidates for this procedure. So I also believe that that
should be a specific contraindication.

CHAIRPERSON WOODS: We have a question from the FDA. Ms. Brogdon?

DR. BROGDON: It\'s actually just a comment. We treat contraindications
as cases where there have been demonstrated cases of harm so that it has
been demonstrated you should not use this procedure in a given patient.
If it\'s a more general warning that is more theoretical or you are
afraid this might happen, that would be appropriate for a warning.

So contraindication is where you have data that say this should not be
done. And that puts much greater limitation on the physician after
approval.

DR. FENNERTY: Can I ask for a point of clarification? As it stands on
there, portal hypertension is listed as a contraindication. I am not
aware of any data presented by the sponsor in the medical literature
that suggests this has been studied in that group. Could you clarify
that?

DR. BROGDON: We will have to look at that if we proceed with the
labeling review.

DR. FERGUSON: Well, with that in mind, then, I would change my comments
to reflect portal hypertension, ulcers, strictures, and non‑responsive
GERD should be listed as warnings.

DR. ACHEM: I remain concerned about that notion that we again offer
advice for which we have in some areas insufficient information to
patients with the more severe forms of the spectrum of the disease.

I would move to consider that these patients here with Barrett\'s
Esophagus disease, ulcers, strictures, and those refractories to proton
pump inhibitors can expand to those who have atypical form of GERD or
gastroesophageal manifestations with GERD be not included until we have
further data on the safety and efficacy during long‑term studies.

CHAIRPERSON WOODS: Okay. Dr. Afifi?

DR. AFIFI: No comment.

CHAIRPERSON WOODS: Dr. Manyak?

DR. MANYAK: I have no comment either.

CHAIRPERSON WOODS: My comments would be I will leave it up to the FDA on
the semantics of contraindications or warnings, but strictures I think
absolutely should not be treated. Patients with GERD symptoms refractory
to proton pump inhibitors should not be treated. And the portal
hypertension intuitively, it would seem, you would not wish to treat
those patients. The rest I think I don\'t have a problem with.

Dr. Gellens?

DR. GELLENS: I don\'t have anything to add, actually. I agree with that.

CHAIRPERSON WOODS: Ms. Moore?

MS. MOORE: I pass.

MR. BALO: I don\'t have anything to add.

CHAIRPERSON WOODS: Okay. Dr. Fennerty?

DR. FENNERTY: I think just from a standpoint of our message to the FDA,
that the areas of concerns we have are: portal hypertension, esophageal
ulcers, strictures, and those refractory to therapy, be that as a
warning or whatever labeling would be appropriate from the FDA\'s
definition.

CHAIRPERSON WOODS: Okay. Question number 9, \"Please discuss whether\"
‑‑

DR. ACHEM: Dr. Woods, sorry. Do you have any concerns or issues
regarding those with atypical forms of GERD to be included, chest pain,
pharyngeal symptoms, cough, asthma?

DR. FENNERTY: We really haven\'t discussed this as a specific question
being addressed to the FDA. I am just going to presume, Karen, that you
would want this maybe brought out more in the discussion perhaps.

Sami, as a gastroenterologist and as a reflux specialist, if I felt that
those were manifestations of reflux disease and I chose to adopt any
therapy that was approved, I would assume that that would be acceptable
to many clinicians.

DR. ACHEM: Do we have enough data from this device that it ‑‑

DR. FENNERTY: That is what I am saying. I think we are opening up an
area that we even haven\'t started discussion on here.

CHAIRPERSON WOODS: There was no data on that indication in this PMA
either.

DR. ACHEM: Well, what I guess I am pointing out is I am trying to say
that I guess because of the confusion, the semantics, I was seeing those
as a potential contraindication of potential areas where you would not
want the device to be used.

DR. FENNERTY: If you\'re asking me, if I were to use the device, those
would not be areas of concerns to me. They are manifestations of reflux
disease. And if I could control the reflux, I would be happy to see the
cough or asthma improve.

If you are asking me as a physician, as a gastroenterologist, would I
use such a device if it were approved in those patients, probably not,
but they are clearly not contraindications.

DR. ACHEM: No. I am asking the panel whether that should be included. I
am still confused regarding a contraindication or a precaution. I am not
sure exactly of the appropriate wording.

MR. BALO: Doctor, aren\'t you really saying that these are conditions
that really haven\'t been studied yet and you\'re concerned that there
has been no data and that maybe what we want to do is to have these
areas looked at in a future study? Is that where you are going with
this?

CHAIRPERSON WOODS: Maybe I should allow FDA to answer, but my answer to
this is this can come up as a condition or a post‑marketing evaluation
subject that we would like the company to provide information to us on.

DR. BROGDON: It is, indeed, up to the panel to decide what you want to
do with this. If it is still unclear what is a contraindication and what
is a warning or a precaution, I can\'t distinguish between the latter
two. It is more a matter of seriousness, I suspect.

A warning is more serious than a precaution. But a contraindication is
used where you have data that say, \"Use in this type of patient is
harmful.\" You have adverse data in hand or in the literature. It is
something more than a potential or a theoretical concern.

CHAIRPERSON WOODS: Okay. Dr. Manyak?

DR. MANYAK: Just one comment. Would these other indications or
conditions that you brought up be considered contraindications for other
therapy that is similar that has already been done in the past with
patients with these problems? I have heard that you have had different
technologies that are involved with that kind of thing. If that is the
case, then that would fall in the same category.

DR. ACHEM: No, no. On the contrary, those are usually indications for
the use of aggressive. By that, I mean intensive acid suppressive
therapy since it appears from the available literature that people with
so‑called extra‑esophageal manifestations of the disease do not respond
to simple doses of proton pump inhibitors.

That was my position. That was my problem in trying to introduce that
until we have more data, this may be either a caution or a
contraindication. I am not sure of the appropriate semantics to place ‑‑

DR. MANYAK: But then you answered the question all right because if they
are not going to respond to the PPIs, then ‑‑

CHAIRPERSON WOODS: Then they are not going to qualify as to what is
treatment.

DR. MANYAK: ‑‑ they are not going to qualify for the treatment anyway.

DR. ACHEM: Well, yes, that is true, and you would hope that in doing the
careful reading of the label, that that will be the case. I was trying
to underscore the notion and to make it very clear that these are areas
where this device has not been explored yet.

CHAIRPERSON WOODS: Okay. Let\'s move on to the question number 9,
\"Please discuss whether you believe the Physician and Patient Labeling
brochures, as written, are adequate or whether certain major additions,
deletions, or revisions should be made.\"

Okay. Dr. Shaheen?

DR. SHAHEEN: Other than what I have said to the last two questions, I
have nothing to add.

CHAIRPERSON WOODS: Okay. Dr. Ferguson?

DR. FERGUSON: Well, in addition to what we have already discussed, there
is some concern about the use of the terminology \"permanent\" or
\"long‑term.\" I think we as the panel need to sort that out before we
leave today because the sponsor has done their best to assure us that
this is a permanent device. And for us to then label it something else
becomes problematic.

CHAIRPERSON WOODS: Dr. Achem?

DR. ACHEM: Dr. Woods, in this respect, I have a few remarks. I would be
inclined to propose that we bring out to the patients a little more
information, such as the duration of the symptoms, like chest pain and
dysphasia, that the patient labeling brochures also address the fact
that about two‑thirds of the patients have two side effects related to
the device, a general statement also regarding the number of patients so
far treated. I think the patients ought to be informed of what is the
total number of patients so far that have been treated to this point.
And the length of follow‑up should be clearly stated as well.

CHAIRPERSON WOODS: Okay. Dr. Afifi?

DR. AFIFI: No comment.

CHAIRPERSON WOODS: Dr. Manyak?

DR. MANYAK: I echo Nick\'s comment that what we discussed today should
be incorporated where it needs to be. Other than that, I don\'t have a
comment.

CHAIRPERSON WOODS: I have comments with respect to physician labeling. I
mentioned it earlier in the discussion about fluoroscopy. In the packet
provided to the panelists, at least, under the portion labeled,
\"Enteryx Injection Procedure,\" there is no mention of the use or the
need for fluoroscopy.

On item number 4, it says, \"Place at least 6 ml of Enteryx solution
circumferentially into and along the muscle layer of the lower
esophageal sphincter,\" talks about an arc or ring but doesn\'t mention
how you are to determine that an arc or a ring is present. And then it
goes on to advise, \"Otherwise use multiple discrete injections of 1 to
2 ml.\"

I would like to see that section clarified a bit so that the novice user
would understand whether to make one long injection of six ml and how to
determine that an arc or a ring is forming by using fluoroscopy, maybe
even a photo to demonstrate what it is they\'re looking for, and then
when to decide that you should go to the four‑quadrant injection with
one to two ml and what that should look like if you have done it
correctly.

Dr. Gellens?

DR. GELLENS: I totally agree that the fluoroscopic indication or
recommendation should be put into the physician labeling since it is not
present there. I know we already talked about the indications for use,
but I think in the physician labeling, where it says it is indicated for
the treatment of GE reflux, I do think that a provision there for the
severity of reflux should be put in there.

Even though the study included patients based on the GERD quality of
life survey, we are not going to give that to all of our patients. But,
still, there should be some recommendation of the severity of the
disease for use of this device. I don\'t think we want every single
patient with GERD to undergo this procedure.

CHAIRPERSON WOODS: Ms. Moore?

MS. MOORE: Yes. I just want to make one comment about the patient
brochure. I think that this brochure should be written in very specific
terms and quantified wherever possible.

As an example, here it says, \"For the first several days after the
procedure, you should only eat bland, non‑spicy and soft foods.\" I
submit that the word \"several\" has different meaning for different
people. I think it would be clearer for the patient if he or she would
know that for the first three or four days or two to five days or
whatever, rather than using general terms. That\'s all I have to say.

CHAIRPERSON WOODS: Thank you. Mr. Balo?

MR. BALO: No, I have no further comment.

CHAIRPERSON WOODS: Okay.

DR. ACHEM: Dr. Woods, can I interject before Dr. Fennerty ‑‑

DR. FENNERTY: Well, I want to do my personal ones first here also. I had
a number ‑‑

DR. ACHEM: Sorry. Just a simple question for the sponsor.

DR. FENNERTY: Actually, go ahead, Sami.

DR. ACHEM: The question I guess pertains to the use of the type of
scopes. It states in page 50 that Olympus endoscopes \"have been found
to be DMSO compatible.\" Does this mean that no other endoscopes can be
used for the injection of this device?

CHAIRPERSON WOODS: \"Yes\" or \"No\"? Please address the panel. The
sponsor, please. State your name and a brief answer.

DR. STEIN: My name is Alan Stein with Enteric Medical.

We have contacted all the major manufacturers of scopes to find out that
they are actually using Teflon sheaths within their scopes because, of
course, we don\'t want to have any DMSO impact on the much more
expensive endoscope.

I think you pointed out something that we should specifically identify
in the labeling, the scope manufacturers that are compatible.

CHAIRPERSON WOODS: So the answer is?

DR. STEIN: Fuji, Pentex, and Olympus.

CHAIRPERSON WOODS: They are?

DR. STEIN: Compatible.

CHAIRPERSON WOODS: Compatible. Thank you.

DR. STEIN: I can\'t tell you and we have to watch. I don\'t know if you
have an 11‑year‑old scope whether that is true. I think we have to put a
date on it.

CHAIRPERSON WOODS: Okay. Thank you.

DR. FENNERTY: I am glad you clarified that because I was wondering why
the physician instructions were that the user should verify the
compatibility of the gastroscopes. I think that is a sponsor issue.

A couple of things just from my point. I am not sure why we are using
prophylactic antibiotics when a much more dirty procedure, injection
sclerotherapy, we don\'t recommend that clinically. And I thought maybe
some of the other members of the panel would let us know what they think
about that. I think it does not belong in the labeling. It was part of
the protocol.

The injection procedure description of visualizing the lower esophageal
sphincter, it\'s not possible. The labeling, the squamocolumnar junction
is very visible. And that is the second part of the labeling. The first
part should be deleted.

Also, going back to Ms. Moore\'s comments as well, I don\'t see any
evidence to suggest that patients should be tortured for eating bland,
non‑spicy airplane‑type food for five days after this procedure. There
is no physiologic basis for such a recommendation. And I would not make
any recommendation and delete that from the labeling as well.

From a summary, I think that there are a number of things. The
fluoroscopic issue seems to be acceptable to everybody. As Dr. Achem
pointed out, I think it is the sponsor\'s obligation to make sure that
this material is compatible with the instruments that we use to perform
this procedure.

DR. AFIFI: Dr. Woods?

CHAIRPERSON WOODS: Yes?

DR. AFIFI: I would just point out to thank Dr. Fennerty for correctly
calling non‑spicy food to be torture.

CHAIRPERSON WOODS: Okay. Let\'s see. That was question number 9. We will
move to question number 10, \"Post‑Market Issues. Please comment on the
sponsor\'s proposed post‑market evaluation of the device. Please
specifically comment on and make recommendations concerning the: a)
study design, b) number of patients, c) length of follow‑up, and d)
endpoints to be evaluated, e) need to evaluate repeat procedure, and f)
need for additional post‑market studies.\"

Dr. Shaheen?

DR. SHAHEEN: I think the post‑marketing plan is going to bring some
welcome patient years, especially patient years beyond patient year one
to this which is going to help clarify a lot of the questions that we
have asked today.

In addition to the plan that is currently in place, I would love to hear
a plan for a randomized sham procedure with a possible crossover because
patients who are going to be getting just vehicle won\'t be very happy
for very long. But this can be done. It\'s been done with other devices.

And I think that this would be a highly pertinent and very important
post‑marketing issue.

CHAIRPERSON WOODS: Thank you.

Dr. Ferguson?

DR. FERGUSON: I think the length of follow‑up proposed is satisfactory
and overall the study design is satisfactory. I do think specific
attention needs to be paid to the re‑injection patients and some sort of
prospective registry perhaps of those patients be suggested to the
sponsor so that we don\'t just catch them upon long‑term follow‑up.

CHAIRPERSON WOODS: Dr. Achem?

DR. ACHEM: I would also be interested in a long‑term study done with a
sham application. I think it is crucial to try to answer some of the
issues we have been talking about this afternoon. In terms of the number
of patients, I would defer that to a statistician to determine the
power, the size of the study, sample size.

In terms of the length of the follow‑up, I realize the sponsor has made
a comparison to some of the studies out there at three years, equating
the data, I believe, with the pharmacological literature as well as the
laparoscopic literature, but I am not sure that it is necessarily
applicable or comparable to a device that has been injected. So I would
be interested certainly to go to at least three years, but I may like to
see data go beyond the three years, perhaps up to five years.

And the endpoints have been already I believe addressed by most of us,
what those endpoints would be.

CHAIRPERSON WOODS: Dr. Afifi?

DR. AFIFI: Yes. I think we do need some justification for the *n* of
300. I think also this is an opportunity to do some placebo controls or
sham controls with the least invasive procedure possible. I think also
that we should specify that a longitudinal analysis of the data be made,
rather than just the cross‑sectional, as was done.

Also, looking at the time points at which the measurements are made,
they follow approximately a logarithmic scale, which is you double the
previous one, 1, 3, 6, 12, 24, and then it goes to 36. From a
mathematical point of view, 48 would be the next one, but I wonder
whether 4 years is just very different enough form 3 years for the
sponsor to consider, at least, that change.

Finally, the other point that we need to look at, why was the SF‑36
dropped? It\'s just as easy to collect. I mean, it is an additional few
minutes. Why only the GERD‑HRQL, not the SF‑36? Maybe the sponsor can
answer that particular question.

CHAIRPERSON WOODS: Would you like an answer to that now? Sponsor, why
did the SF‑36 get dropped in the follow‑up, questionnaires for patients?

DR. STEIN: We focused on the post‑market surveillance on those
particular issues that were related to GERD. The SF‑36 measures a
general quality of life measure. It is also 36 questions. And over time
trying to get the compliance on these patients is really the issue
because we don\'t want to start a study and then find out that we have
too significant attrition over time. So we are trying to make sure that
we maintain high levels of compliance.

And, as I said, the SF‑36 mental and physical component scores are
generic assessments of patient satisfaction but not GERD‑specific.

DR. AFIFI: Okay. And while you are up there, what do you think of 48
months, instead of 36?

DR. STEIN: I think it is 12 months longer than 36.

(Laughter.)

DR. AFIFI: So you would be concerned about compliance at the same point?

DR. STEIN: I also think that ‑‑ you know, I don\'t really know the
statistical approach about looking at this long‑term, but I have looked
at enough of the literature associated with the longer‑term follow‑ups
that are being performed on post‑surgical and PPI studies. The intervals
are pretty much annual for at least three, out to five years because I
don\'t think it is appropriate to have a gap, certainly, between two and
four. Okay?

CHAIRPERSON WOODS: Okay. Dr. Manyak has stepped away. I will comment. I
agree with basically everything that has been said as to issues with the
post‑market follow‑up.

The one thing I would like to emphasize is follow‑up on the patients who
have retreatment and trying to better define who is most likely to
benefit from retreatment, how many retreatments can you do. I don\'t
think we should be doing this in clinical practice without having more
data on this.

I also think there were some variances in how the patients were selected
to be retreated. In fact, as I recall, several were retreated just
because the X‑ray at three months showed there wasn\'t very much of the
product left behind.

Is that a reason to retreat or not? I would like those questions
answered in this follow‑up period of time so that we can better define
who can be retreated, how many times, how safe is it, et cetera.

Dr. Gellens?

DR. GELLENS: I agree with Dr. Woods as far as the post‑market evaluation
and the retreatment issue is concerned. I think you need a longer than
average post‑market evaluation here because of the retreatment issue. We
have such little data on that. And we don\'t really know what
recommendations to make in the labeling as far as retreatment is
concerned.

Other post‑market recommendations. I think the X‑ray evaluation of how
much of the product is left is poor. I think CT evaluation should be
used as follow‑up in post‑market evaluation.

That\'s it. Thanks.

CHAIRPERSON WOODS: Ms. Moore?

MS. MOORE: I am in agreement with what has been said.

CHAIRPERSON WOODS: Mr. Balo?

MR. BALO: No further comment.

CHAIRPERSON WOODS: Dr. Fennerty?

DR. FENNERTY: I think that the panel would be in absolute agreement that
one of the things we would like to emphasize in a post‑market agreement
for this device application is clearly either an active control or a
sham placebo control so that we can accurately measure the placebo
effect or at least its comparability versus other standard accepted
therapies and reflux disease. I think that seems to be a unanimous
opinion.

Having said that, it is an opportunity for the panel I think to deliver
a message as we go forward with these surprisingly very numerous devices
in development that future dealings between sponsors and the FDA I think
a priori we need to change what we require or recommend to them
performing their pivotal trials therapy before they come forward to us
so that we don\'t have to look at this as a post‑marketing issue in the
future, but we will have this data at the time of the initial
application so we can make probably a more reliable decision to the
public and the FDA regarding recommendations of acceptance.

CHAIRPERSON WOODS: Dr. Gellens?

DR. GELLENS: I have a question for the FDA. Is it okay to approve this
device with the requirement of a post‑marketing study that is a
prospective sham‑controlled trial? Can we do that?

DR. BROGDON: You can make that recommendation. We need to be clear on
what you are proposing would be investigated after approval. And then
the FDA staff is going to have to talk about whether this is feasible.
You have to decide whether there is sufficient safety and effectiveness
data for approval and then describe what data would be needed and what
data can be deferred until later.

CHAIRPERSON WOODS: Okay.

DR. BROGDON: Dr. Yustein would like to ask a couple of questions of
clarification on your answers to number 10.

DR. YUSTEIN: Just one question. I don\'t know if you recall what the
sponsor proposed, but their endpoints on the post‑market follow‑up were
specifically for the HRQL, medication dosage, and adverse events. I was
just wondering if you could all comment on where you stood as far as the
requirements for EGD and/or pH studies along the way.

CHAIRPERSON WOODS: All right. Dr. Shaheen? Actually, Dr. Fennerty has an
opinion. We will let you go. Then we will see if anybody else has
comments.

DR. FENNERTY: Go ahead, Nick.

DR. SHAHEEN: Well‑put, Brian.

I guess my thought is that it is going to be a really big problem or
potentially a big problem for a long‑term study to require repeat
invasive investigations. I assume you are referring to things like
24‑hour pH Probe data, e‑mano.

I would love to have those data, but I think that as an investigator,
just thinking to myself, trying to get somebody to sign up for a study
that has got five years of Q‑6 months or 2‑year, 24‑hour pH Probe is not
going to be greatly successful.

So I think pragmatically, although those data would be very useful, I
don\'t know that that is something that we should require of them.

CHAIRPERSON WOODS: Dr. Ferguson?

DR. FERGUSON: I don\'t think we can expect useful information to come
from that. The studies to date have likely documented what the
percentage responses are going to be. We are looking at the clinical
efficacy as the main endpoint, which they have pointed out. I might just
add as long as I have the microphone that the likelihood of getting
accrual to a post‑approval study, including a sham control, is highly
unlikely.

CHAIRPERSON WOODS: Dr. Achem?

DR. ACHEM: That certainly is an ideal scenario to obtain objective data,
such as EGD and pH testing. But I echo the concerns of the feasibility,
especially on the 24‑hour pH if we do it with a probe. Nevertheless, the
event of other devices, such as the so‑called Bravo pH Probe, might
allow to acquire this data.

As you know, recruitment for endoscopy patients undergoing conscious
invasion is a bit easier, it has been my personal impression as an
investigator. And, actually, there are financial incentives that we
provide, again, within the IRB guidelines and FDA guidelines to our
patients to stimulate them to undergo a second procedure.

I think it would be very useful information to have. I recognize the
expense, the magnitude of what we are asking, though. I would say that
the other edition might also facilitate the process by leaving one
single procedure for patients so you can acquire both of those pieces of
data.

CHAIRPERSON WOODS: Okay. Dr. Afifi?

DR. AFIFI: I would have concerns about the more invasive the protocol
is, the less compliance there may be. So I would keep that in mind.

CHAIRPERSON WOODS: Dr. Manyak?

DR. MANYAK: I have no comment.

CHAIRPERSON WOODS: Okay. I agree. I think, again, without having a
control group, you are following along at the same time, that expense
and the safety issues of re‑endoscoping people just because are probably
not going to be all that useful. I think what is really important is how
does the patient feel and whether they have had any problems.

Dr. Gellens?

DR. GELLENS: Yes. I think our concern is safety and efficacy. So as far
as evaluating those two things, if the patients feel all right and they
don\'t have any adverse events, that is enough. My only concern is if
there would be development of Barrett\'s Esophagus and how we are going
to look for that long‑term.

CHAIRPERSON WOODS: Ms. Moore? Mr. Balo?

MR. BALO: Yes. I agree with the panel recommendations.

CHAIRPERSON WOODS: Okay. Dr. Fennerty?

DR. FENNERTY: Just to address Dr. Gellens\' comment. Normally when a
patient has had an endoscopy in the setting of reflux disease, we don\'t
recommend further screening for Barrett\'s once a clean endoscopy has
shown no evidence of Barrett\'s.

So from a standpoint of not only the other points people have made, I
have serious ethical concerns of having patients who are completely well
undergo invasive procedures. No matter how safe we comment on the safety
of upper intestinal endoscopy as well as probe placement, there are some
safety concerns.

I would be against mandating invasive tests and otherwise as well paying
for a long‑term follow‑up study.

CHAIRPERSON WOODS: Okay. We will move to the last question, number 11,
regarding training, \"Please comment on the sponsor\'s proposed
physician training program and whether you believe it is adequate for
proper use of the device.\"

Dr. Shaheen?

DR. SHAHEEN: Given that the data that the sponsor has shown suggests
that if there is a learning curve, there isn\'t much of a learning curve
and it appears that, at least in the centers they have, efficacy at the
first procedures was essentially the same as having to see it later
procedures. I am not compelled to think that we need to have an
extensive training program.

I would, however, like to see the specifics of the training program
perhaps a little bit better fleshed out. Somebody raised the question,
are the trainers going to be physicians? Is the site of the training
going to be uniform? Where is it going to be? Perhaps a few more details
like that, but I don\'t necessarily think that we need to feel compelled
to generate a larger training program.

CHAIRPERSON WOODS: Thank you.

Dr. Ferguson?

DR. FERGUSON: I think the training as outlined in the sponsor\'s
presentation, as opposed to in the handout materials, which consisted of
five to ten, I think it was, training sites, mentoring on site, and then
supervised, first few initial procedures, is satisfactory.

CHAIRPERSON WOODS: Dr. Achem?

DR. ACHEM: I think that the question was posed to Dr. Lehman, actually,
in the past as to the number of patients. The sponsor has proposed that
two people would be sufficient. That is, two patients, on a supervision
would be the number sufficient to do so.

I would say as an endoscopist, as a gastroenterologist, that probably
seems okay to me assuming that the device poses no unique differences as
the ones that you see during injections with sclerotherapy.

I guess a concern ‑‑ and I am not sure how to answer this, Dr. Woods ‑‑
is what may happen with people who are less experienced or who may be
non‑gastroenterologists and are eager to get going with new technology.

Should we require the same expectations of training as those of
gastroenterologists? And I don\'t know the answer.

CHAIRPERSON WOODS: Dr. Afifi?

DR. AFIFI: No comment.

CHAIRPERSON WOODS: Dr. Manyak?

DR. MANYAK: Actually, I had some thoughts similar to what you have just
mentioned. The question I would have for the GI colleagues here, my GI
colleagues here, is, are two procedures enough in the proctoring session
to determine that someone is vassal enough to do this?

I think obviously your specialty is very good at endoscopy. So I think
there are going to be some basic skills there. For those who are
under‑experienced or perhaps, God forbid, they are in another specialty
and they try to do that, you know, we could almost reach them from
below, but that is not quite good enough.

There are some other training programs that are available. We have
developed two virtual reality surgical simulation programs for these
types of procedures with haptic feedback that are very similar to what
you undergo in real time. And it may be that that is something to
consider somewhere. There may be other training programs like that, too,
for people that you feel are under‑qualified to perform that procedure.

CHAIRPERSON WOODS: I am just trying to clarify a point here that
physician training that I have read is on page 247 of the PMA that I
received. There was no mention here of going to a training site to
learn. That was presented today.

I don\'t have a copy of that here in front of me. So what I see is that
\"To complete training, the physician and assistant will perform a
minimum of two treatments of the supervision of the manufacturer\'s
clinical specialist.\"

Now, quite frankly, this is merely an extension of well‑established
endoscopic technique. Anyone who does endoscopy and has clinical
privileges at their hospital to perform sclerotherapy with some
additional training from the company I think could probably do this
procedure. All of us who have endoscopic privileges or train
gastroenterologists also have basic familiarity with using fluoroscopy.

So I am not particularly uncomfortable with the recommendation that the
manufacturer\'s clinical specialists come to the site and train a
certified or privileged physician, who has privileges at their hospital
to perform gastrointestinal endoscopy and sclerotherapy, that this
become an extension of that.

And I think, as presented, it seems fairly simple that I think an
on‑site training probably is adequate as long as the specialist who
trains them feels at the end of two that that person has adequate
knowledge of the system and can perform it safely.

Dr. Gellens?

DR. GELLENS: Thanks.

I just think that it should be clear that the clinical specialist that
observes the procedures being done be a gastroenterologist.

MS. MOORE: I like the idea of the physicians being trained, and I like
the model that was presented today better than I like the one that was
in our literature. But I think maybe we ought to have the more
experienced gastroenterologists maybe having one type program; whereas,
the newly licensed gastroenterologist might have another level program.

CHAIRPERSON WOODS: Mr. Balo?

MR. BALO: I have nothing to add.

CHAIRPERSON WOODS: Dr. Fennerty?

DR. FENNERTY: Speaking to Ms. Moore\'s concerns, this really is in the
purview of anybody who has been trained in a formal endoscopic program,
including surgical endoscopists. I really think that this should not be
limited to gastroenterologists but skilled endoscopists, irrespective of
their background and training. I think Dr. Ferguson is well‑aware that
many members of SAGE\'s surgical endoscopy group are quite qualified to
perform this procedure as well.

Having said that, I would very much encourage the sponsor to use the
American Society for Gastrointestinal Endoscopy, the American
Gastroenterological Association, the American College of
Gastroenterology to set up formalized courses of instruction as well as
meet the guidelines that they have already outlined in their proposed
teaching of physicians with on‑site experience as well.

CHAIRPERSON WOODS: Okay. I think that concludes our questions. I would
like to thank Dr. Fennerty for summarizing all of the questions.

[OPEN PUBLIC HEARING]{.underline}

CHAIRPERSON WOODS: Before we take a vote, are there any additional
questions from the panel or comments from the panel? And if not, then I
need to ask if anyone from the public wishes to address the panel. If
so, please raise your hand. You may have an opportunity to speak now.

(No response.)

CHAIRPERSON WOODS: If not, then we will now proceed with the ‑‑

DR. MANYAK: We thank you, by the way.

CHAIRPERSON WOODS: ‑‑ with the final open public hearing session. I
think we already did this part. It gave me some redundant information
here.

Okay. Ms. Brogdon, does FDA have any comments?

[4. FINAL COMMENTS]{.underline}

[1. FDA COMMENTS]{.underline}

DR. BROGDON: I would like to ask the staff, are there any further
questions?

(No response.)

DR. BROGDON: None.

CHAIRPERSON WOODS: None? Okay. Does the sponsor have any comments? If
so, please identify yourself before speaking.

[2. SPONSOR COMMENTS]{.underline}

DR. STEIN: My name is Alan Stein, and I think that I would like to ask
Dr. Lehman and Dr. Johnson if they could make just a couple of small
comments that were based on the discussion today.

I would like to make one comment, which I would again like them to
elaborate on, regarding retreatment. I do want to make sure that the
panel understands what our experience in retreatment and what our
intentions have been in retreatment.

Of the 19 patients who were retreated, I would say about three‑quarters
of them had substantial loss of implant. The goal of the retreatment was
not to put in 8, then 16, then 24 cc of material into these patients but
was, in fact, to get 6 to 8 cc in a circumferential distribution around
them.

So these were patients who, by and large, lost a significant amount of
implant. And in one more session, we were able in almost every case to
get an adequate amount of implant around them.

So I hope you understand that there is a different goal of our
retreatment than perhaps particularly the urological specialists here,
who maybe I guess in contigen treatments can do up to six session of
treatments on urinary incontinence. That has not exactly been the goal
of what we have been trying to do in the retreatment, and I want you to
understand that.

DR. MANYAK: Yes. It wasn\'t for the urologists either. We would prefer
one treatment, but sometimes you have to go back.

DR. STEIN: Well, we do, too.

DR. MANYAK: And it\'s not there anymore.

DR. STEIN: Okay. Dr. Johnson?

DR. JOHNSON: Dr. Woods, if I could make my comments very brief? First, a
lot was made about esophagitis in the discussions. I want to clarify
this is not an a priori assumption, nor was it a target for the success
and efficacy standards. So the discussions need to be kept in that
context.

Secondly, the time frame for the definition of esophagitis, recognizing
that these patients were off PPIs for 10 to 14 days, as the
gastroenterologists on the panel will well‑know, the relapse to
esophagitis rate, typically it may take time. And they typically will
relapse to where they were before they were started on therapy.

These patients had a very narrow window of time frame to relapse to a
grade of esophagitis. Despite that, if you use Savary‑Miller, which is a
variable interpretation to begin with, 35 percent had relapsed to
esophagitis.

Recognizably, these are all PPI‑dependent patients. They had PPI
dependency for two years. So when we talk about definition and
progression, it is really an inappropriate discussion because we really
haven\'t defined the time windows before. Ten days is not applicable to
a 12‑month off PPI. So I think that needs to be kept in perspective.

Additionally, when we talked about relapse to esophagitis, if we take
the entry point as no esophagitis and said, \"How many people had Grade
2 esophagitis at the end?\" the number is 20 percent. If I gave you PPI
trials, the members of the gastroenterology community would attest that
is low relative to the relapse rate for people on PPI trials. The
maintenance trials for PPI range anywhere from 20 to 60 percent of
people who have esophagitis in subsequent follow‑up.

So I think we need to keep that parameter in context. So discussion of
progression is really not appropriate. It is not an a priori assumption.
And the time windows for development of esophagitis are key points.

This issue of esophagitis comes up because we like to say that we are
preventing complications. And there is no data from the surgical
literature or the endoscopic literature or the pharmacologic literature
that shows we prevent complications when we talk about strictures de
novo, complications of Barrett\'s, or complications of surgery.

In fact, if you look at patients with Barrett\'s de novo, 99.9, if not
all of them, if they\'re well‑defined, have Barrett\'s when they are
actually endoscoped and, hence, the recommendation if they don\'t have
Barrett\'s on an index endoscopy, we never re‑screen those patients. I
think the gastroenterologists would all agree with that.

So the data and concern about esophagitis progression, preventing
complications, we have to fall back. And if we say, \"What do we do with
PPIs?\" we have the same scenario. We see esophagitis relapse in
maintenance trials, and we have no data to show that they prevent
complications de novo. We do a complication prevention as a secondary
nature for patients that have strictures.

Recognizably, too, we have talked a lot about surrogate endpoints and
secondary endpoints with pH. If we go back to the same PPI trials and
put it in perspective, relapse of esophagitis in patients that have no
pill‑induced reason for esophagitis obviously have pathologic acid
exposure. Those patients in the PPI trials obviously if studied with pH
monitoring would have abnormal pH scores. So I think we need to keep
those perspectives as we start to evaluate the information.

The issue about placebo control I think really is difficult by this
trial design to get around that. I am very critical when I talk about
placebo‑controlled trials are obviously the best evidence‑based way to
construct trials.

This, the patient serving as their own control, I am personally
comfortable because I can tell you I have put 17 patients in this trial
to date. These are patients that are PPI‑dependent who all, by
definition, relapsed to a Velanovich score that was pathologic within 10
to 14 days of being off their PPI. And they reestablished very quickly
when they went back on their PPI. So their entry criteria is fairly
well‑qualified.

Now, if you try and take a patient that is symptomatic with GERD,
depending on a PPI off medication for a year, the gastroenterologist
would attest it is very difficult. Certainly if we can accept that
placebo is an issue, recognizing the placebo effect lasting for a year
and attaining 70 percent efficacy of people totally off PPIs, or 10
percent having major dose reduction, would really be an issue that would
be hard for me to attribute to placebo.

The issue about this being milder patients also needs to be understood
because, again, in fact, it is my worst‑case patients of esophagitis.
That is the way I\'ve got them in the study. These people are looking
for alternatives to PPI dependency. These patients actually coming off
their medications, it\'s difficult.

When you look at esophagitis rate, you can\'t use that as a marker here
for severity of esophagitis for the reasons I just outlined. So I think
you need to keep that in perspective when you go and look at their
mediation use. This medication use in this trial, 62 percent of people
are taking daily PPIs. And 30 percent were taking high‑dose PPIs. Hence,
these are not mild patients by any means or any stretch of the
imagination.

The issue about trend analysis I think needs to be kept in perspective.
And I think Dr. Fennerty alluded to this. When you look at the data
presentation, you have to look at the scale used. And, in fact, if you
look at the trial here and just at the PPI‑dependent patients, now off
medication and relapsing from 6 to 12 months, there are 3 patients.

The subanalysis of those individual patients, these were kind of limping
along. We knew these patients were not going to last. For whatever
reason, they were continued off medication. And those are the three
patients that actually fell out at the end of 12 months.

When you look at an analysis of H2 antagonist use, the number is
consistent. So there is no trend attrition for H2s. And if you look at
the trend analysis for antacids, including daily and less than daily
use, the number goes from 13 to 17. So I hardly attribute that nor would
I start to say that this is an attrition of integrity of the procedure
or the efficacy of the procedure.

I think the final comment is to look at the issues of the efficacy and
trying to generate is this a risk‑benefit ratio. Patients are asking for
alternatives for medications. That is where a surgeon is an option and
endoscopic therapy is a potential option.

So patients that are well‑characterized ‑‑ and I would agree with the
panel\'s comments about characterization of disease, but the patients,
for whatever reason, don\'t like to take medications, for whatever
reason. There are some subsets of patients that just can\'t take it,
don\'t like it, whatever reason. So this is an alternative that needs to
be put in that perspective of the benefit ratio.

The safety I think is, as much as we can tell you, the 12 months was the
PMA submission. This study has been going on for nearly three years in
Europe. And we have reviewed 100 percent of the safety data.

I will tell you that the extension study, I have got 17 patients in this
now, close to 2 years. So nothing has changed, despite the PMA lock by
the definition. I think that needs to be kept in perspective.

I think that would conclude my remarks.

DR. STEIN: We as a sponsor can\'t discuss anything past one‑year data
because our study was closed out at one year. But Dr. Johnson, Dr.
Lehman, these are their patients still. And as of today, every patient
in the study was at 18 months. And by June, they will all be 24 months.
And we intend to follow these into the post‑market surveillance study.

CHAIRPERSON WOODS: Dr. Lehman?

DR. LEHMAN: Lehman, Indianapolis.

I would again echo that my patients in this study have had no change, no
obvious change, in their clinical or adverse effect viewpoint in their
now almost two‑year follow‑up. So that\'s promising.

Just a couple of other comments. Fundoplication was briefly commented
on. Four of the patients who have had Enteryx have now had
fundoplication. Fundoplications were done without difficulty. Surgeons
commented specifically that there were no adhesions around the LES and
that while the tissue was a little stiffer than normal tissue, it
otherwise was very easy to wrap.

This is consistent with the autopsy data from the animals that we have
done, that, indeed, it injects in the peritoneal cavity and sort of sits
there like a piece of cellophane and doesn\'t stir up virtually any
reaction.

There was some concern about whether multiple injections would be
hazardous. Having injected collagen patients with more than 130 cc of
collagen in the old days, multiple injections are well‑tolerated and do
not seem to have a problem. And, indeed, sclerotherapy we inject many
times in many sessions.

A little bit more data on information on sloughing and migration. We
have to go back to the original animal studies. We started out
intentionally placing this material submucosally because that is what we
did with collagen and Teflon and so on. Most of it sloughed out.

We saw that in the first three to seven‑day follow‑up. And so we saw a
lot of sloughing in the first few animals. And we learned that shallow
submucosals are on place for this material. So we had plenty of
experience seeing these acute ulcers with little black bases. If you
come back a week later, the ulcer is down to a little crevice.

And then histologically, if you study them at that point, you will see
either it\'s a shallow little crevice or usually a shallow little
crevice with some black base to it. But the amount of bulk is relatively
small.

In patients, we saw a few patients at 30 days usually, following for
their re‑implant, where they have ulcers, some ulcers, as we saw here,
with black lump in the center or, commonly, healed ulcer, a little
shallow depression with a little black base. Then one of our patients,
we did a CT scan at 24 hours after some new dysphasia and had apparent
implant in the colon.

So I think we have excellent evidence that it does slough if you put it
through superficially. And it isn\'t a mystery as to where it goes.

Additionally, the follow‑up animal data from our dog pilot studies
showed that total body X‑rays from pelvis to tip of nose failed to show
any evidence of migration at any point up to one year, no tantalum at
any other points in the body, random sampling, dissecting out the
injection area, saw no implant beyond a few centimeters from where we
put it, where a little bit of it was put in too deep.

Random sampling of lung, heart, kidney, liver, spleen saw no evidence of
migration at any site at any point from a few weeks to one year.

Chest X‑ray follow‑up and all of these patients looking at their
implants saw no evidence of migration ends at any point. So we have I
think excellent evidence of lack of migration to places we don\'t want
it to go and strong evidence to show that sloughing of the lumen in that
portion of patients that are losing material.

I would add in the discussion about contraindication versus warning
versus no data, I would strongly encourage you to say, \"In these areas,
such as Barrett\'s, such ulcers, such as strictures, we don\'t have any
data, rather than to tie hands of the people who want to do the next
step for the studies and say, \"It is contraindicated\" or \"warning.\"
If they put a big \"warning\" on it, then it\'s hard for Sami to do the
next generation of studies, which you want to study these strictures and
so on.

Indeed, we are injecting it into the lower edge of the lower esophageal
sphincter mostly, below the stricture, below the ulcers, et cetera. So
it shouldn\'t be hard to inject into that group of people.

Thank you.

CHAIRPERSON WOODS: Yes, Dr. Shaheen?

DR. SHAHEEN: Dr. Lehman? Will all four of the patients that underwent
the procedure, were those all able to be performed laporoscopically?

DR. LEHMAN: Yes. And the patient I had done, I asked if he took some
pictures of it. He had not. He sort of forgot the patient even had an
implant it was so ordinary.

CHAIRPERSON WOODS: All right.

DR. ACHEM: I want to thank both Dr. Lehman and Dr. Johnson for their
additional comments, which are of value to the panel.

MS. MOORE: Thank you very much, gentlemen.

CHAIRPERSON WOODS: Okay. Before entertaining a motion recommending an
action on this PMA, Dr. Cooper will remind the panel of our
responsibilities in reviewing today\'s pre‑market approval application
and of the voting options to us.

DR. COOPER: Thank you.

[5. PANEL DELIBERATIONS AND VOTE]{.underline}

DR. COOPER: I wanted to point out for the record that Dr. Fennerty has
had to leave to catch the last plane to Oregon for a commitment tomorrow
morning.

Before you vote on a recommendation, please remember that each PMA has
to stand on its own merits. Your recommendation must be supported by
data in the application or by publicly available information. You may
not consider information from other PMAs in reaching a decision on this
PMA

Do you have the first slide? I would like to remind the panel of some
definitions. I will go ahead while those come up. Safety is defined in
the medical device amendments as reasonable assurance based on valid
scientific evidence that the probably benefits to health under
conditions of intended use outweigh any probable risks.

The valid scientific evidence demonstrates the absence of unreasonable
risk of illness or injury associated with use of the device under
conditions of intended use. Effectiveness is defined as reasonable
assurance that a device is effective when it can be determined in a
significant portion of the target population, the use of the devices for
its intended use is an condition of use when adequately labeled, will
provide clinically significant results.

Next slide. Valid scientific evidence consists of well‑controlled
investigations, partially controlled studies, studies and objective
trials without matched controls, well‑documented case histories
conducted by qualified experts, and reports of significant human
experience with a marketed device.

Next. Your three recommendation options for the voters follow:
approvable, approvable with conditions, and not approvable.

Next. Approvable. There are no countdowns attached.

Next. Approvable with conditions. You may recommend that the PMA be
found approvable subject to specified conditions, such as resolution of
clearly identified deficiencies which have been cited by you or by FDA
staff. Prior to voting, all of the conditions are discussed by the panel
and listed by the panel chair.

Next is not approvable. If you recommend that the application is not
approvable, we ask that you identify the measures that you think are
necessary for the PMA to be placed in an approvable form.

Next slide. Response for recommending not approvable would be safety,
the data did not provide reasonable assurance that the device is safety
under the conditions of use prescribed, recommended, or suggested in the
proposed labeling.

For effectiveness, reasonable assurance has not been given that the
device is effective under the conditions of use prescribed, recommended,
or suggested in the proposed labeling.

For labeling, based on a fair evaluation of all of the material facts
and your discussions, you believe the proposed labeling is false or
misleading.

Next. And that\'s a flow chart of our voting procedures that I have
described.

CHAIRPERSON WOODS: I think we will go ahead and proceed. The panel will
now prepare to vote. The recommendation of the panel may be: approval,
approval with conditions that are to be met by the applicant, or denial
of approval.

I will now ask for a motion on the PMA from the panel.

DR. AFIFI: May I ask a question before we move on?

CHAIRPERSON WOODS: Yes?

DR. AFIFI: The approval with conditions, suppose one of the conditions
is that the following study will be conducted. What effect does that
have, then, on their approval, Dr. Cooper?

DR. COOPER: I will give that to Ms. Brogdon.

DR. BROGDON: If FDA agrees with you, we would approve the PMA with a
condition of approval that there be a post‑approval study that is
described.

What you have to do if you choose to recommend that is just to ensure
that the application meets the needed demonstration of reasonable
assurance of safety and effectiveness at this point. You have to be
satisfied that it is reasonably safe and effective before the approval.

DR. AFIFI: Okay. And suppose that the study we recommend shows adverse
events that we were unaware of now or something. Would that be, then,
basis for reconsideration or something? Is that how it works long‑term?

DR. BROGDON: Theoretically, if there are severe problems that are raised
with a device after approval, FDA can withdraw its approval, but that
almost never happens. Sometimes sponsors will suspend distribution of a
device or they will change labeling, provide additional mornings,
additional training, or whatever. It is very rare that the agency just
takes a device off the market due to problems that crop up.

DR. AFIFI: But it could be basis for changing the labeling ultimately or
‑‑

DR. BROGDON: Absolutely.

DR. AFIFI: Okay.

CHAIRPERSON WOODS: Okay. Any other questions for FDA from the panel
before we entertain a motion?

(No response.)

CHAIRPERSON WOODS: All right. Do I have a motion from the panel?

DR. ACHEM: Dr. Woods, I would move that we approve with conditions, the
main condition being that a ‑‑

CHAIRPERSON WOODS: Okay.

DR. ACHEM: Do you want to name the condition or do we stop at this point
with approval with condition?

CHAIRPERSON WOODS: First I think I need to have a ‑‑ we have a motion
for approval with conditions. Do I have a second?

DR. SHAHEEN: Second.

CHAIRPERSON WOODS: Okay. We have a second. Now I believe we need to
outline the conditions. Okay. You have condition number 1, Dr. Achem.

DR. ACHEM: I think that my condition would be condition number 1 would
be to address a placebo control trial, to expand the observations of
this study.

CHAIRPERSON WOODS: Are you making that a condition of the post‑marketing
study that has already been proposed by the sponsor?

DR. ACHEM: I am not clear that that particular study has been yet even
started, nor the sign.

CHAIRPERSON WOODS: So you are approving with the condition that an
additional trial with a placebo control be mandated? That is separate
and distinct from the post‑marketing evaluation and entry of new
patients into the post‑marketing group of study patients are going to be
proposed?

DR. ACHEM: That is correct.

DR. FERGUSON: Can I ask for a clarification? Are you talking about a
sham injection of vehicle?

DR. ACHEM: That could be a possibility. There is another way to design
it. I suppose you could endoscope those individuals and bring out the
needle and inject saline in the stomach for that purpose? The study, of
course, would be a double‑blind control.

CHAIRPERSON WOODS: Dr. Ferguson, do you have a comment on that?

DR. FERGUSON: Well, you can\'t make it double blind because you need to
monitor it fluoroscopically so at least the operator would know whether
it was a vehicle or the actual device.

As I mentioned, I think, before, the likelihood of accrual to patients
to such a study is quite low once the product is approved.

CHAIRPERSON WOODS: I think if you\'re going to do this, what you really
would like to see is a sham procedure and then let the patients choose
whether they are on PPIs or not. And maybe you will have the fallout on
the placebo effect or the treatment effect, I guess I should say, of the
procedure. You will see it there.

Do we need to vote on each condition as we go?

DR. AFIFI: But it hasn\'t been seconded.

CHAIRPERSON WOODS: Well, the condition, making conditions, has been
seconded. Now we are proposing placebo control and ‑‑

DR. BROGDON: You have an amendment that has been proposed that hasn\'t
been seconded yet. You have just been through clarification.

DR. COOPER: Are you done discussing?

DR. MANYAK: Well, I would just like to make a comment that I am not sure
it is our purview to decide how that placebo trial is done.

DR. ACHEM: And I would agree with that. I think that the fine tuning and
details of the signs, such as whether the patients are going to be, for
instance, all briefly fluoroscoped and who is going to blinded, the
separate investigator and so on and so forth, I think those would be
further details to fine‑tune.

I think the motion I am just asking you to entertain is considering a
sham study as a complementary study.

CHAIRPERSON WOODS: Is there any discussion of this motion?

MR. BALO: Why can\'t we take this motion Dr. Achem made and make it part
of the post‑market study that is already being proposed by the sponsor?
I don\'t see any reason to put the sponsor through an additional study
when they are already willing to make a post‑market study and we can add
things that we would like to see in that study and have that design
worked out between the sponsor and the FDA.

DR. AFIFI: Dr. Woods?

CHAIRPERSON WOODS: Yes?

DR. AFIFI: I think the condition that Dr. Achem has suggested has not
yet been seconded. According to Robert\'s Rules, or whatever, I wonder
if, Dr. Achem, you would accept the following modification, in which
case I would be willing to second it, that a controlled study be part of
the post‑marketing study that is proposed, rather than a controlled
study with the sham controls, be part of the post‑marketing study,
rather than a separate one. If you accept that, I would be happy to
second it.

CHAIRPERSON WOODS: Does FDA have any comments on this?

DR. BROGDON: No.

CHAIRPERSON WOODS: Okay. Then we have a second. Do you accept what ‑‑

DR. ACHEM: Dr. Woods, I am comfortable with that alternative proposal.

CHAIRPERSON WOODS: Okay. So we have proposed a post‑marketing study as
put forth by the sponsor with a modification that it would include an
element of a placebo control as a part of ongoing investigations. Okay.
We have a second. Dr. Afifi seconded. Dr. Achem put forth the condition.

Okay. We may now vote. So we will go around and ask for a vote by each
member of the panel on that particular condition. Okay. We will start
with Dr. Shaheen.

DR. SHAHEEN: I am in favor of the condition.

CHAIRPERSON WOODS: You\'re in favor? Okay.

Dr. Ferguson?

DR. FERGUSON: I am in favor of the condition.

CHAIRPERSON WOODS: Okay. Dr. Achem?

DR. ACHEM: I do, too.

CHAIRPERSON WOODS: Dr. Afifi?

DR. AFIFI: I vote yes.

DR. MANYAK: I am also in favor of that condition.

CHAIRPERSON WOODS: Okay. Dr. Gellens?

DR. GELLENS: I am in favor.

CHAIRPERSON WOODS: Ms. Moore and Mr. Balo, do they vote?

MR. BALO: We can\'t vote.

CHAIRPERSON WOODS: Okay. So we have a unanimous yes on the first
condition. We can move on. Is there a proposal for a second condition?

DR. FERGUSON: May I propose a condition?

CHAIRPERSON WOODS: Yes.

DR. FERGUSON: I suggest that we require a change in indication for use
of the device as identified by Dr. Fennerty earlier in our discussions.

CHAIRPERSON WOODS: Can you please define that? Be specific.

DR. FERGUSON: I think somebody wrote that down.

CHAIRPERSON WOODS: You want the sentence that says, \"The Enteryx
procedure kit is indicated for endoscopic injection into the region of
the lower esophageal sphincter for the treatment of symptoms due to
gastroesophageal reflux disease, requiring medical therapy\"?

DR. FERGUSON: \"Requiring and responding to medical treatment.\"

DR. MANYAK: \"Requiring pharmacotherapy\" I believe is how he worded it.

CHAIRPERSON WOODS: \"Requiring and responsive to pharmacotherapy.\"

DR. FERGUSON: \"Pharmacologic therapy.\"

CHAIRPERSON WOODS: \"Pharmacological therapy.\"

DR. FERGUSON: That is correct.

CHAIRPERSON WOODS: Okay. Do I have a second for this condition?

DR. GELLENS: I have one comment. Can we add severity to that?

CHAIRPERSON WOODS: You know, during our previous discussion, Dr.
Fennerty made it fairly clear that he did not think severity was
necessary since, by definition, patients requiring continuous
pharmacotherapy had symptoms severe enough to warrant treatment with
something, pharmacotherapy or otherwise.

DR. GELLENS: Okay.

DR. ACHEM: Let me, if I may, add a little bit. Dr. Johnson actually
alluded to some of that in his comments, with which I agree. I was the
one who brought up the notion of severity. So I am comfortable with the
new statement as currently worded.

DR. MANYAK: So are you seconding?

DR. ACHEM: Yes, I would second it.

CHAIRPERSON WOODS: All right. We have a second on this condition. We
will vote. Dr. Shaheen?

DR. SHAHEEN: I am in favor.

CHAIRPERSON WOODS: Dr. Ferguson?

DR. FERGUSON: I am in favor.

CHAIRPERSON WOODS: Dr. Achem?

DR. ACHEM: I am in favor, too.

CHAIRPERSON WOODS: Dr. Afifi?

DR. AFIFI: In favor.

CHAIRPERSON WOODS: Dr. Manyak?

DR. MANYAK: Yes, I am in favor.

CHAIRPERSON WOODS: Dr. Gellens?

DR. GELLENS: I agree.

CHAIRPERSON WOODS: Okay. That\'s a unanimous yes. All right. Do we have
a condition proposal for number 3?

DR. AFIFI: Yes.

CHAIRPERSON WOODS: Dr. Afifi?

DR. AFIFI: I would like to propose that we put another condition on the
post‑marketing study to be worked out between the FDA and the sponsor
that specifically addresses the question of the need for and guidelines
for retreatment.

CHAIRPERSON WOODS: Restate what you just said one more time for me,
please.

DR. AFIFI: Yes. It doesn\'t have to be exactly in the words that I used,
but I want to add something that has to do with the retreatment to the
post‑marketing study. One way I was thinking about it is to say that the
FDA and the sponsor could work on what would be needed in the way of
additional data and also a protocol to try to answer that question of
guidelines for retreatment.

CHAIRPERSON WOODS: Okay.

DR. AFIFI: But, again, I am not a GI specialist. So I don\'t know how
feasible how this is.

CHAIRPERSON WOODS: May I ask FDA? Is that sufficient for a condition or
do we need to be more specific as to what we want?

DR. BROGDON: I believe this is sufficient.

CHAIRPERSON WOODS: Okay. Do I have a second?

DR. FERGUSON: Second.

CHAIRPERSON WOODS: Any discussion? Further discussion?

DR. FERGUSON: I had suggested earlier ‑‑ and it may be going a little
too far ‑‑ that the prospective entry into a registry prior to
retreatment be required as part of that post‑approval analysis.

DR. MANYAK: Well, then what we are saying here, he has one motion. It
sounds like that is a different motion.

DR. FERGUSON: Well, I think I am just trying to amend his motion.

CHAIRPERSON WOODS: I see it as a clarification of the motion.

DR. MANYAK: Okay. That\'s fine. Just for purposes of proper order here.
That\'s all.

CHAIRPERSON WOODS: Okay. Any other discussion?

(No response.)

CHAIRPERSON WOODS: All right. Then ‑‑

DR. MANYAK: So could you restate the motion, then, Dr. Ferguson, along
the way that you would like it worded?

DR. FERGUSON: I think I would word it that \"As part of the post‑market
study, specific attention be paid to indications for and results of
retreatment of patients through use of entry into a prospective registry
of retreatment patients.\"

DR. AFIFI: I am comfortable with that wording. That means I am changing
my initial motion to that one.

CHAIRPERSON WOODS: All right. Do we have another second?

DR. MANYAK: I will second.

CHAIRPERSON WOODS: Any further discussion on this?

(No response.)

CHAIRPERSON WOODS: Dr. Shaheen, your vote?

DR. SHAHEEN: I am in favor.

CHAIRPERSON WOODS: Dr. Ferguson?

DR. FERGUSON: In favor.

CHAIRPERSON WOODS: Achem?

DR. ACHEM: I do, too.

CHAIRPERSON WOODS: Afifi?

DR. AFIFI: In favor.

CHAIRPERSON WOODS: Dr. Manyak?

DR. MANYAK: I am in favor.

CHAIRPERSON WOODS: Dr. Gellens?

DR. GELLENS: In favor.

CHAIRPERSON WOODS: Okay. That\'s unanimous. Condition number 4, Dr.
Afifi?

DR. AFIFI: That the analysis of the data resulting from the
post‑marketing study take into account the longitudinal effects of the
collected data.

CHAIRPERSON WOODS: Do I have a second?

DR. FERGUSON: I second.

CHAIRPERSON WOODS: Any discussion?

DR. FERGUSON: It means statistical analysis of longitudinal effects.

CHAIRPERSON WOODS: Okay. Are we ready to vote? All right. Dr. Shaheen?

DR. SHAHEEN: In favor.

CHAIRPERSON WOODS: Ferguson?

DR. FERGUSON: In favor.

CHAIRPERSON WOODS: Achem?

DR. ACHEM: In favor.

CHAIRPERSON WOODS: Afifi?

DR. AFIFI: In favor.

CHAIRPERSON WOODS: Manyak?

DR. MANYAK: In favor.

CHAIRPERSON WOODS: Gellens?

DR. GELLENS: Yes.

CHAIRPERSON WOODS: Condition number 5, Dr. Shaheen?

DR. SHAHEEN: I suggest that that esophageal stricture be added to the
list of precautions for now for this product.

CHAIRPERSON WOODS: And my understanding is precautions now exist only
for esophageal varices as put forth by the sponsor. Is that correct,
FDA? Is that ‑‑

DR. SHAHEEN: Portal hypertension is their only contraindication.

CHAIRPERSON WOODS: Portal hypertension.

DR. SHAHEEN: And they have a whole list of precautions, which are
essentially their exclusion criteria from the trial. But because they
use the Savary‑Miller grading, they include high‑grade esophagitis but
do not list stricture explicitly. I think that may be confusing for some
people.

CHAIRPERSON WOODS: Could you restate your motion again, please?

DR. SHAHEEN: I move that under the precaution section of the label for
both the patient as well as the physician, that esophageal stricture be
added.

CHAIRPERSON WOODS: Do I have a second?

DR. FERGUSON: Second.

DR. GELLENS: Second.

CHAIRPERSON WOODS: Okay. Any discussion?

DR. FERGUSON: I wonder if we could have a general condition regarding
precautions, as opposed to adding several specific items to the list.
And I would propose adding patients with symptoms refractory to
pharmacologic therapy.

CHAIRPERSON WOODS: Yes. That was going to be my point as well, maybe not
putting in one thing and running through this for ten more conditions.
With the rules of order here, can we modify this in the discussion?
Okay.

DR. BROGDON: I am sorry. Does this conflict with the indications for use
you are recommending?

CHAIRPERSON WOODS: No.

DR. FERGUSON: Actually it\'s consistent with the indications for use.

CHAIRPERSON WOODS: All right. So, please, let\'s restate the motion.
Currently as stands, it says we add to precautions that patients with
esophageal stricture not be treated.

DR. SHAHEEN: As well as those unresponsive to PPI therapy.

CHAIRPERSON WOODS: And those unresponsive to pharmacologic therapy.

DR. SHAHEEN: Yes, that\'s fine.

CHAIRPERSON WOODS: Any other conditions to go with these conditions?

DR. AFIFI: How about fear of needles? Sorry.

CHAIRPERSON WOODS: Okay. So the motion has been modified to include
precautions for esophageal stricture and failure to respond to
pharmacologic treatment for GERD symptoms. We have a second for that
already, I believe.

Any further discussion?

(No response.)

CHAIRPERSON WOODS: All right. We will vote on that. Dr. Shaheen?

DR. SHAHEEN: In favor.

CHAIRPERSON WOODS: Ferguson?

DR. FERGUSON: In favor.

CHAIRPERSON WOODS: Achem?

DR. ACHEM: In favor.

CHAIRPERSON WOODS: Afifi?

DR. AFIFI: In favor.

CHAIRPERSON WOODS: Manyak?

DR. MANYAK: Yes, in favor.

CHAIRPERSON WOODS: Gellens?

DR. GELLENS: In favor.

CHAIRPERSON WOODS: Okay. We have those two. Do we have condition number
6?

DR. SHAHEEN: I believe Dr. Fennerty made a couple of specific
suggestions regarding the insert labeling, specifically regarding
getting rid of the interdiction of spicy food as well as mandating
antibiotic therapy.

CHAIRPERSON WOODS: Are we talking about the insert for the patients, the
insert for physicians, or both?

DR. SHAHEEN: This is in the physician insert that I am referring to,
although I think it was in the patient insert as well.

CHAIRPERSON WOODS: It is also mentioned in the physician. So I think we
may need to make two specific statements.

MS. MOORE: And when I made my comment, ‑‑

CHAIRPERSON WOODS: Labeling.

MS. MOORE: ‑‑ Madam Chairman, I made my comment, I wasn\'t speaking to
the spicy food. I think Dr. Fennerty ‑‑

CHAIRPERSON WOODS: To the timing, the amount of time.

MS. MOORE: I was speaking to the wording, to the generalities, you know,
asking that the wording, that the brochure be more specific so that the
patients would be clear about what was expected of them.

CHAIRPERSON WOODS: I believe your comments were related to \"Don\'t eat
these certain types of foods for several days.\"

MS. MOORE: Yes, I used that as an example, the word \"several\" as an
example. So I am saying if that is necessary that they shouldn\'t eat
this, then they ought to know specifically whether they should go a week
without eating or two or three days or one day or just what. But when
you used the word \"several,\" I said it was too general and the patient
wouldn\'t know, really, what several meant, I would think.

CHAIRPERSON WOODS: Okay.

MS. MOORE: But, then, you say it is in the physician\'s brochure as
well.

CHAIRPERSON WOODS: In the physician\'s, I believe it says five days. It
is very specific.

MS. MOORE: Well, you\'re saying different things, then.

CHAIRPERSON WOODS: It should be consistent.

MS. MOORE: It should be consistent.

CHAIRPERSON WOODS: Okay. You were in the midst of making a motion ‑‑

DR. SHAHEEN: So the motion specifically for the physician labeling is
that under \"DIRECTIONS FOR USE,\" section 1, \"Patient Preparation,\"
strike the second sentence, \"It is recommended that patients be
administered prophylactic antibiotics before and after procedure.\" We
don\'t need that.

Under section number 4, \"Instructions to Patients,\" point number 1,
prophylactic administration of pain medication may not be necessary.
Strike number one.

Number 3 under \"Instructions to Patients,\" \"bland, non‑spicy foods
for 5 days,\" strike number 3. That is the specific recommendation.

CHAIRPERSON WOODS: You want to strike any dietary modifications
altogether?

DR. SHAHEEN: Yes. Just get rid of number 3.

CHAIRPERSON WOODS: Are there any other additions to these conditions for
the physician labeling component of the product?

DR. GELLENS: The issue of using fluoroscopy should be placed here.

CHAIRPERSON WOODS: Yes. We need to add. If you don\'t mind if I add to
your motion, we should incorporate specifically information spelling out
when fluoroscopy or how fluoroscopy should be used to guide injection
and, as I mentioned, earlier discussion, how to decide whether you can
do this with one injection or several injections. And I think addition
of some fluoroscopic photographs would be helpful to the clinician to
know what they are referring to with an arc or some of the other things
that you need to look for and note that you are in the right place.

So we have four: the issue with respect to no antibiotics, the issue
with respect to prophylactic pain medications, removing dietary
modifications, adding further information on technique in the use of
fluoroscopy. Dr. Ferguson, do you have an additional one?

DR. FERGUSON: I was just going to second the motion.

CHAIRPERSON WOODS: Okay.

DR. ACHEM: Could you clarify it for me? Are we removing the notion of
the need for antibiotics? Is that what the motion ‑‑

CHAIRPERSON WOODS: It had been proposed that the prophylactic antibiotic
portion that is recommended in the physician labeling be removed.

DR. ACHEM: May I ask the sponsor to comment on that? I am a little
concerned. I think that there is a potential benefit to the patient that
we may be withdrawing, actually, here. Can I ask your permission to ask
the sponsor to come and present it?

CHAIRPERSON WOODS: Yes.

DR. LEHMAN: I think the use of antibiotics for sclerotherapy is still
somewhat controversial. Many people would do it and some wouldn\'t. This
falls in that same category. It may be beneficial. It may not. To leave
it open to discretion seems appropriate. And how you phrase it here for
your labeling is up to you.

CHAIRPERSON WOODS: Do you have a specific modification to that you would
like to make, Dr. Achem?

DR. ACHEM: No. We\'ll proceed with the ‑‑

DR. SHAHEEN: I think just striking it leaves it open to the person who
is doing it, which may be the best‑case scenario since we are not really
sure of its benefit.

CHAIRPERSON WOODS: Okay. So as it stands, this particular modification
includes modifications to the be made to the physician labeling
component for the product to include removal of the sentence that
states, \"prophylactic antibiotics\" should be given; removal of the
statement that \"prophylactic pain medications\" should be given;
removal of the statement regarding dietary modifications; and addition
of further definition to the physician technique and use of fluoroscopy.

Do we have a second for that? I don\'t think we have had one since we
have gone through all of the conditions.

DR. FERGUSON: I will second it again.

CHAIRPERSON WOODS: Okay. Any further discussion?

(No response.)

CHAIRPERSON WOODS: All right. Let\'s vote. Dr. Shaheen?

DR. SHAHEEN: In favor.

CHAIRPERSON WOODS: Ferguson?

DR. FERGUSON: In favor.

CHAIRPERSON WOODS: Achem?

DR. ACHEM: In favor.

CHAIRPERSON WOODS: Afifi?

DR. AFIFI: Yes.

CHAIRPERSON WOODS: Manyak?

DR. MANYAK: In favor.

CHAIRPERSON WOODS: Gellens?

DR. GELLENS: In favor.

CHAIRPERSON WOODS: Okay. Do I have a subsequent condition?

DR. ACHEM: Dr. Woods, I would like to propose knowing that there is
already an ongoing study that the sponsor addresses formally the notion
of what is the mechanism involved in the presumed therapeutic benefit of
this device.

I realize that the transient lower esophageal sphincter relaxation study
may be out. That may be one. I may also suggest that, in addition to
that, the neurosensory evaluation of these patients be tested as well.

CHAIRPERSON WOODS: So you are proposing further information in the
post‑marketing evaluation study be collected? You are adding data that
you would like to see collected and information given?

DR. ACHEM: Specifically addressing the mechanism of action of the
device.

CHAIRPERSON WOODS: You would like to see further information regarding
the mechanism of action of the device as defined by what studies? What
are you asking for?

DR. ACHEM: A) transient lower esophageal sphincter relaxation; b)
evaluation of neurosensory perception of these patients.

CHAIRPERSON WOODS: How do you evaluate neurosensory perception?

DR. ACHEM: The two ways would be two simple ways to do it. There is no
perfect, ideal way to do it. But the way clinically to do it would be to
simply do a Bernstein perfusion study and look at time to response
symptoms. Also, you could look at the mechanical properties of the
esophagus by looking at balloon distension of the esophagus in these
patients.

DR. MANYAK: But aren\'t those details that should be worked out down the
road?

DR. ACHEM: They can. They can be worked out subsequently. And I don\'t
have any troubles with that.

DR. MANYAK: I have one other question. And that is, is it customary to
have to demand of the sponsor to provide the mechanism of action for
something that works if it is clinically acceptable? I don\'t think that
is necessary for a device. As a matter of fact, I would pretty much take
a wild guess and say a lot of them do not have a mechanism of action
worked out for that. And I am sure that is true for pharmacotherapy as
well.

With all due deference to you, I am not being critical here, but I
don\'t think that should be a condition for approval personally.

DR. ACHEM: Well, I think you would certainly shed light. We have had
plenty of discussion as to how this works. It certainly would be very
informative, although I understand your position exonerating whether or
not we need to understand the mechanism.

My personal vote would be to claim to propose that. Certainly it is open
to the table deferring with my opinion. And certainly they are at
liberty to choose otherwise.

DR. MANYAK: I am just saying that sounds like a grant proposal and not a
post‑market study. I mean, seriously, that is one of the things that you
would look at down the road. In our field, that is what we do anyway.

CHAIRPERSON WOODS: Does FDA have a comment on that?

DR. BROGDON: I think Dr. Manyak has just stated FDA\'s position on this.
This would be not customary for us to require this sort of information
be collected. It certainly would be nice to know.

DR. MANYAK: And very interesting. I agree with that, yes.

DR. BROGDON: But it\'s not the typical post‑market study that we would
require.

DR. ACHEM: Okay. Thanks for sharing that information.

CHAIRPERSON WOODS: Okay. So are you going to make further comments on
this motion?

(No response.)

CHAIRPERSON WOODS: Okay. Do we have a second to this motion?

DR. FERGUSON: Second.

CHAIRPERSON WOODS: All right. Then any further discussion?

MR. BALO: Does the sponsor have anything to say about the action? I
mean, we have been talking about it. Do they have any comments about
that from the physicians who have used the device?

DR. MANYAK: Are they allowed to comment on this?

MR. BALO: They can\'t?

CHAIRPERSON WOODS: I think they are allowed to comment. And I think they
have commented previously as to the thought that the fibrosis that
ensues around the implant is leading to an improvement or a reduction in
the number of spontaneous lower esophageal sphincter relaxations. Am I
correct, Dr. Lehman?

DR. LEHMAN: That\'s one of the currently shown mechanisms, yes.

CHAIRPERSON WOODS: Do you have other comments?

DR. LEHMAN: We think this kind of a step is beyond usual and customary.
And we would like to work this out but without a mandate.

CHAIRPERSON WOODS: Thank you. Okay. Let\'s take a vote on this proposal.
Dr. Shaheen?

DR. SHAHEEN: Against.

CHAIRPERSON WOODS: Ferguson?

DR. FERGUSON: I\'m against.

CHAIRPERSON WOODS: Achem?

DR. ACHEM: I\'m in favor.

CHAIRPERSON WOODS: Afifi?

DR. AFIFI: Against.

CHAIRPERSON WOODS: Manyak?

DR. MANYAK: I\'m against.

CHAIRPERSON WOODS: Gellens?

DR. GELLENS: Against.

CHAIRPERSON WOODS: Okay. So we have voted down proposal number 7. So we
will move on to condition number 7. Dr. Ferguson?

DR. FERGUSON: I propose that in the patient information brochure in the
handout on page 61, first paragraph, the sentence, \"For the first
several days after the procedure, you should only eat bland, non‑spicy
and soft foods,\" be stricken.

CHAIRPERSON WOODS: Do we have a second?

DR. SHAHEEN: I second. Can we also more generally just make this motion
that the patient handout be brought in line with the physician changes
that we have made, as opposed to trying to find it everywhere, so the
four conditions we put on the physician handout, pick through and yank
them out of the patient handout as well?

CHAIRPERSON WOODS: Yes. And I would add to that that it be very clear in
the patient brochure that if they are not responsive to proton pump
inhibitor therapy or medical therapy for their reflux, that they not be
considered a candidate for this procedure, which actually technically
would bring it into line with what we are putting into the physician
insert as well, but it needs to be expanded upon in the patient
information section.

DR. FERGUSON: So overall a condition, then, would be to bring the
patient information brochure in line with the physician information
handout.

CHAIRPERSON WOODS: Okay. Do we have a second for that motion?

DR. SHAHEEN: I second it.

CHAIRPERSON WOODS: All right. Any further discussion?

(No response.)

CHAIRPERSON WOODS: Vote. Dr. Shaheen?

DR. SHAHEEN: For.

CHAIRPERSON WOODS: Ferguson?

DR. FERGUSON: In favor.

CHAIRPERSON WOODS: Achem?

DR. ACHEM: In favor.

CHAIRPERSON WOODS: Afifi?

DR. AFIFI: In favor.

CHAIRPERSON WOODS: Manyak?

DR. MANYAK: In favor.

CHAIRPERSON WOODS: Gellens?

DR. GELLENS: In favor.

CHAIRPERSON WOODS: Okay. Number 8. Do we have another condition?

DR. GELLENS: I have one condition that we change the labeling from this
therapy being permanent to a long‑term therapy for GERD.

CHAIRPERSON WOODS: Do I have a second for that motion? Does anybody want
to second?

DR. MANYAK: I will second.

CHAIRPERSON WOODS: Any further discussion or modification?

MS. MOORE: Excuse me. Would you want to have FDA and the sponsors maybe
look at the wording? And maybe \"long‑term\" may not be the one that
they come up with, but they know the sense of the panel that we don\'t
like the word \"permanent.\" Would that be better than us telling them
what the word should be? I am just asking.

CHAIRPERSON WOODS: So it might be best to suggest changing the
terminology to reflect ‑‑

MS. MOORE: To reflect the sentiment of the panel.

DR. SHAHEEN: So I guess \"eternal\" is out, too, then?

(Laughter.)

CHAIRPERSON WOODS: Dr. Shaheen?

DR. SHAHEEN: How about more specifically just dropping the adjective
altogether? It\'s just a therapy for GERD. I don\'t think we can say
that it is long‑term based on 12‑month data. Why don\'t we just say that
it is a therapy.

MS. MOORE: That might be better. I think that is better.

DR. FERGUSON: I have some concerns about that in that the sponsor has
gone to great pains to show that this is probably going to stay in place
forever. The patients and physicians should have some indication that
that is the case.

DR. SHAHEEN: I guess we don\'t know if that is the case. I mean, based
on the data we have so far, I don\'t feel comfortable saying it is going
to be there forever based on 12‑month data.

DR. FERGUSON: No, but if you\'re given PPI, the effects are going to be
there for a week or so. But if you\'re doing an operation, you expect
them to be present for years and the same with this sort of device.

I don\'t think that the equivalency here is being shown to PPIs, but the
duration of the effect is certainly an order of magnitude or more
greater than for the PPIs.

CHAIRPERSON WOODS: So could you put that into a formal modification of
the condition?

DR. FERGUSON: I support the original statement to leave it as changing
from \"permanent\" to \"long‑term.\"

DR. MANYAK: Excuse me. Maybe I need to be clarified here, but isn\'t the
indication as such does not contain the word \"permanent\"?

DR. AFIFI: Item 7 doesn\'t have the word \"permanent\" in it.

DR. MANYAK: The actual labeling does not use the word \"permanent\" in
it. And we just modified it, and it doesn\'t contain the term
\"permanent\" in it.

MR. BALO: It doesn\'t. The modification we just made does not have that
word in it.

DR. MANYAK: It doesn\'t have the word in it.

CHAIRPERSON WOODS: Okay.

DR. MANYAK: It kind of eliminates that part.

CHAIRPERSON WOODS: Well, we sure discussed it earlier. Well, then it
shouldn\'t contain the word \"permanent.\"

DR. MANYAK: There you go. I second that.

DR. AFIFI: I think, for the record, the proposer may want to withdraw
the motion.

DR. MANYAK: We just don\'t have to second it.

DR. AFIFI: But it has been seconded.

CHAIRPERSON WOODS: Okay. Advise me on proper protocol here, Mr.
Secretary. We just need to vote and turn it down.

DR. MANYAK: Couldn\'t the proposer withdraw? Who was the proposer?

MS. MOORE: Sure, the person who made the motion can withdraw it. And the
person who seconded it can agree. And you\'re fine.

DR. AFIFI: I think that\'s better because there is ‑‑

DR. MANYAK: I think the actual Robert\'s Rules are that you have to vote
on it. Once it is proposed and seconded, you have to vote on it \"Yes\"
or \"No.\"

CHAIRPERSON WOODS: Okay. Then let\'s vote.

DR. MANYAK: I\'m sorry. That\'s the way ‑‑

DR. GELLENS: I\'m sorry. I have one other question. So there\'s nothing
in the indication about whether it is for long‑term or permanent or
anything?

DR. MANYAK: No.

CHAIRPERSON WOODS: Could somebody pull the indication and read us the
paragraph that we are discussing?

DR. AFIFI: The indication, not the labeling. Those are two different
things. The labeling had it, but you are talking about the indication.

CHAIRPERSON WOODS: Does anybody from the FDA have the information that
we are talking about that can stand up here and read it to us? Maybe
while they are looking for that, can we table this one for the moment
and come back to it and move on to condition number 9?

I have an additional condition. I would like to propose that we approve
this for single use only as I do not feel we have enough data to justify
retreatment. And I think as a part of the post‑marketing evaluation,
that retreatment data should be accumulated before we approve or put in
writing anything regarding retreatment. I think it simply should not be
mentioned.

DR. MANYAK: Did we not just have a condition stated very specifically
what is to be done with retreatment?

CHAIRPERSON WOODS: I think that was in post‑marketing.

DR. MANYAK: Dr. Ferguson proposed that, yes.

CHAIRPERSON WOODS: That was for post‑marketing study, but it had nothing
to do with approval for general use.

DR. MANYAK: Okay.

DR. ACHEM: I was also under the impression that we had asked for the
condition to clarify or address retreatment issues on one of the
previous conditions. So that is not the case at all?

CHAIRPERSON WOODS: Well, we asked for it in the post‑marketing
evaluation. We did not mention whether it should be approved in the
labeling that retreatment could be done. I think it should be
specifically stated that there is not enough evidence to justify
retreatment. This is for single use only in the labeling.

Does anybody second that motion?

DR. FERGUSON: I second it.

CHAIRPERSON WOODS: Any further discussion?

DR. FERGUSON: Well, could you clarify your suggestion, then? I think to
specifically label it for single use only is sufficient, but did you
also want to say something in the labeling but the lack of information
about outcomes of retreatment and indications for it?

CHAIRPERSON WOODS: Yes. I think that would be a fair statement.

DR. FERGUSON: Both of those things?

CHAIRPERSON WOODS: Yes. Okay. So we will modify the motion to say,
\"indicated for single use\" and \"Sufficient information has not been
accumulated to justify retreatment.\" Is that how you worded that to ‑‑

DR. FERGUSON: \"There is insufficient information regarding indications
for and results of retreatment\" perhaps.

CHAIRPERSON WOODS: \"Or not available.\" Okay. I like that. I would like
to modify the motion to state that. Do I have a second for that?

DR. GELLENS: Second that.

CHAIRPERSON WOODS: Okay. Any further discussion?

(No response.)

CHAIRPERSON WOODS: Can we vote on this, then? Dr. Shaheen?

DR. SHAHEEN: In favor.

CHAIRPERSON WOODS: Dr. Ferguson?

DR. FERGUSON: In favor.

CHAIRPERSON WOODS: Achem?

DR. ACHEM: In favor.

CHAIRPERSON WOODS: Afifi?

DR. AFIFI: In favor.

CHAIRPERSON WOODS: Manyak?

DR. MANYAK: In favor.

CHAIRPERSON WOODS: Gellens?

DR. GELLENS: In favor.

CHAIRPERSON WOODS: Okay. Are we ready to go back to our questions on the
wording in the brochure?

DR. BROGDON: Dr. Woods?

CHAIRPERSON WOODS: Yes?

DR. BROGDON: Dr. Yustein can address the word \"permanent\" and where it
came from.

CHAIRPERSON WOODS: Thank you.

DR. YUSTEIN: I think looking through the physician labeling as supplied
in your panel pack, the word \"permanent\" isn\'t in there as far as I
can find. Where I think you are getting confused is during our panel
questions, our first question ‑‑ I believe it was our first question ‑‑
stated that \"Since it\'s not removable, it\'s considered as a permanent
implant.\" But nowhere in the labeling does it say this is a permanent
implant.

But if you consider that there is no easy way to remove this device once
injected short of an esophagectomy, I would suspect that it would be
considered a permanent implant.

CHAIRPERSON WOODS: Okay.

DR. YUSTEIN: But nowhere in the labeling as of now does it say
\"permanent implant.\"

CHAIRPERSON WOODS: Thank you for the clarification. Ms. Moore?

MS. MOORE: I was just saying I like what I see here in our materials
where it calls it an alternative to lifelong medical therapy.

CHAIRPERSON WOODS: And that\'s already stated ‑‑

MS. MOORE: That is already stated here, yes.

CHAIRPERSON WOODS: So the motion was to change the wording from
\"permanent\" to \"long‑term\" therapy. Since there is no such wording
and we have a motion that has been seconded, I am just going to be
proper. I think we just have to vote on it. So Dr. Shaheen?

DR. SHAHEEN: Against.

CHAIRPERSON WOODS: Ferguson?

DR. FERGUSON: Against.

CHAIRPERSON WOODS: Achem?

DR. ACHEM: Against.

CHAIRPERSON WOODS: Afifi?

DR. AFIFI: Against.

CHAIRPERSON WOODS: Manyak?

DR. MANYAK: Against.

CHAIRPERSON WOODS: Gellens?

DR. GELLENS: I am going to say I am against my own motion.

CHAIRPERSON WOODS: Thank you.

DR. MANYAK: That\'s the first time.

CHAIRPERSON WOODS: So our last motion was number 9. Do we have a number
10? I beg your pardon. The last one now moves up to number 8. Do we have
a number 9? Dr. Ferguson?

DR. FERGUSON: I suggest we put as a condition in labeling that the
device is a permanent implant, differentiated it from long‑term or
permanent treatment of gastroesophageal reflux disease. It\'s a
non‑removal implant.

CHAIRPERSON WOODS: Okay.

DR. ACHEM: I second that.

DR. GELLENS: I second that, yes.

CHAIRPERSON WOODS: Okay. Do we have any further discussion?

DR. SHAHEEN: Are we going to call it permanent or non‑removable or both?
Because non‑removal almost certainly is permanent probably.

DR. FERGUSON: I would leave it as permanent.

CHAIRPERSON WOODS: Any further discussion? Dr. Achem?

DR. ACHEM: I would second or be the third, I guess, to go along with
that.

CHAIRPERSON WOODS: Okay. We\'re making no additional statements about
its permanency in terms of treatment of the symptoms. We\'re simply
stating that the device once present will always be there.

Are we ready for a vote on this motion? Dr. Shaheen?

DR. SHAHEEN: In favor.

CHAIRPERSON WOODS: Ferguson?

DR. FERGUSON: In favor.

CHAIRPERSON WOODS: Achem?

DR. ACHEM: In favor.

CHAIRPERSON WOODS: Afifi?

DR. AFIFI: In favor.

CHAIRPERSON WOODS: Manyak?

DR. MANYAK: Against.

CHAIRPERSON WOODS: Gellens?

DR. GELLENS: In favor.

CHAIRPERSON WOODS: Okay. Do I have any additional conditions?

DR. BROGDON: Could we suspend these deliberations for just one moment?
About three people have questions of me, and I can\'t really
concentration.

CHAIRPERSON WOODS: Yes. Would you like to take a five‑minute break?

DR. BROGDON: That would be a good idea. Thank you.

CHAIRPERSON WOODS: Why don\'t we take a five‑minute break.

(Whereupon, the foregoing matter went off the record at 4:08 p.m. and
went back on the record at 4:18 p.m.)

CHAIRPERSON WOODS: We are going to reconvene now. FDA has brought to our
attention that we may have inadvertently crossed our wires here in two
of our motions or our amendments with respect to asking the sponsor to
provide us with post‑marketing information on retreatment and then
putting in the product labeling that this is for single use.

We may have unintentionally created a problem and, therefore, we would
like for them to clarify for us the issues. And then have some further
discussion and perhaps modification of our amendments.

DR. BROGDON: Thank you. Thank you for that recess. It allowed us to
clarify our thoughts on this.

Regarding your condition number 8, if you say in the labeling for an
approved product \"for single use only, no retreatment,\" that means
that the sponsor cannot go and do a post‑approval study of that device
under any other conditions. They would have to do it under an IDE, a
very specific investigational application. It wouldn\'t be done under
the general conditions of use. That\'s restrictive.

If you had more liberal wording in the labeling that said something like
\"Long‑term data are not known. The effects of retreatment are unknown.
There were 19 patients who were retreated in the study,\" that leaves it
more open. And then that would enable or allow the use of multiple
treatments and a post‑approval study under those conditions. And they
wouldn\'t have to do a separate IDE study for this.

CHAIRPERSON WOODS: Thank you. And that was certainly the intent of my
motion. However, I think perhaps it just went into the wrong place in
the labeling or worded incorrectly.

I would like to modify or I guess create a new amendment that says that
we strike amendment number 8 and that we reword it to state a statement
in the labeling that says there is limited information on retreatment.

Remind me how you worded that. I think it was very elegant. And provide
the data on the patients who have been retreated.

DR. BROGDON: Yes. Often for implants, there are statements in labeling
that say, \"Long‑term effects are unknown or effects of retreatment are
unknown. There were data on 19 patients, but they weren\'t sufficient to
draw strong conclusions,\" something to that effect.

CHAIRPERSON WOODS: Okay.

DR. BROGDON: So we have the sense I think of what you intend. So we can
work it out if you can ‑‑

CHAIRPERSON WOODS: I would include some information in the labeling,
then, that comments on available data on retreatment and that the
long‑term effects are unknown. Along with that amendment, we eliminate
amendment number 8 as it stands.

DR. MANYAK: Does that require a motion?

DR. GELLENS: Second.

DR. ACHEM: It is a motion, I guess.

DR. MANYAK: Then I second.

CHAIRPERSON WOODS: Any further discussion?

(No response.)

CHAIRPERSON WOODS: Okay. Can we vote? Dr. Shaheen?

DR. SHAHEEN: In favor.

CHAIRPERSON WOODS: Ferguson?

DR. FERGUSON: Approve.

CHAIRPERSON WOODS: Achem?

DR. ACHEM: Approve.

CHAIRPERSON WOODS: Afifi?

DR. AFIFI: Approve.

CHAIRPERSON WOODS: Manyak?

DR. MANYAK: Approve.

CHAIRPERSON WOODS: Gellens?

DR. GELLENS: Agree.

CHAIRPERSON WOODS: Okay. Thank you for the clarification and getting us
what we really meant to say.

Do we have any other conditions? Dr. Ferguson?

DR. FERGUSON: I regret to say yes. I move that the brochures and product
labeling eliminate from the descriptive terminology the statement that
\"The advantage of Enteryx is that it is a minimally invasive
alternative to lifelong drug use.\" I would scratch \"lifelong\" from
that because we don\'t know what the duration of efficacy of this
product is at this point.

CHAIRPERSON WOODS: So you would change the sentence to read exactly how?

DR. FERGUSON: That it is a minimally invasive alternative to drug use or
anti‑reflux surgery.

CHAIRPERSON WOODS: Okay. Do we have a second?

DR. MANYAK: Second.

CHAIRPERSON WOODS: Further discussion?

DR. SHAHEEN: Question. Is that in the actual label or is that just in
the stuff they gave us? Because if it is not in the label ‑‑

DR. FERGUSON: It\'s included in the patient information brochure on page
56.

DR. SHAHEEN: Okay.

CHAIRPERSON WOODS: Okay. Any further discussion on this amendment or
this condition?

(No response.)

CHAIRPERSON WOODS: Can we take a vote? Dr. Shaheen, are you satisfied?

DR. ACHEM: Please reword the statement again, if you will, as to the
change of ‑‑

CHAIRPERSON WOODS: Could you reread your sentence directly from the book
that you are proposing to modify in the patient labeling?

DR. FERGUSON: Yes. I propose changing the last sentence, first
paragraph, of the introduction, patient information brochure and all
applicable sentences and other product information to read, \"The
advantage of Enteryx is that it is a minimally invasive alternative to
drug use or anti‑reflux surgery procedures for treating GERD and can be
performed on an outpatient basis.\"

CHAIRPERSON WOODS: Okay. Any further questions or discussions regarding
the condition?

(No response.)

CHAIRPERSON WOODS: Let\'s vote. Dr. Shaheen?

DR. SHAHEEN: In favor.

CHAIRPERSON WOODS: Ferguson?

DR. FERGUSON: In favor.

CHAIRPERSON WOODS: Achem?

DR. ACHEM: I agree.

CHAIRPERSON WOODS: Afifi?

DR. AFIFI: In favor.

CHAIRPERSON WOODS: Manyak?

DR. MANYAK: I agree.

CHAIRPERSON WOODS: Gellens?

DR. GELLENS: Agree.

CHAIRPERSON WOODS: Okay. Do I have any other conditions?

(No response.)

CHAIRPERSON WOODS: Any other issues by FDA that we need to discuss?

DR. BROGDON: Does the staff have any other issues? No. Thank you.

CHAIRPERSON WOODS: Okay. All right. Do any of the panel members ‑‑ I
think I have already asked you if you have any final comments on the
approval with these conditions. Any other comments on these conditions
and the approval?

(No response.)

CHAIRPERSON WOODS: Will all of those voting members in favor of approval
with these conditions raise their hand?

(Whereupon, there was a show of hands.)

CHAIRPERSON WOODS: It is unanimous that it is approved with these
conditions. It is six for and zero against the motion. For the
transcript, we will go around the room, stating your name and your voted
\"Yes\" or \"No\" and your reason. Dr. Shaheen?

DR. SHAHEEN: Nicholas Shaheen. My vote is in favor. I believe that given
the changes that we have made in the labeling, that the benefits of this
product outweigh the risks for the consumer.

DR. FERGUSON: Mark Ferguson. I voted to approve. I believe that
short‑term efficacy and freedom from complications have been adequately
proven.

DR. ACHEM: I am Dr. Achem. I agree with the previous statements, and I
have nothing else further to add.

DR. AFIFI: I vote yes because I agree with the motion.

CHAIRPERSON WOODS: Dr. Manyak?

DR. MANYAK: I vote yes because the benefits, as stated in the
indications here with the conditions, outweigh the risk in this
situation.

CHAIRPERSON WOODS: Dr. Gellens?

DR. GELLENS: I vote yes with the conditions outlined because I think it
is safe and effective.

CHAIRPERSON WOODS: Ms. Moore, do you have any comments?

MS. MOORE: No comment. I agree with the motion. If I were to vote, I
would vote yes.

CHAIRPERSON WOODS: Mr. Balo?

MR. BALO: I definitely would agree that this was an approval of device
and that benefits really outweigh the risks and agree with all of the
motions.

CHAIRPERSON WOODS: Okay. I am happy to announce that this concludes the
report and recommendations of the panel on PMA P020006 from Enteric
Medical for the Enteryx device for the treatment of GERD. On behalf of
the FDA, I would like to thank the entire panel.

This meeting is adjourned.

(Whereupon, at 4:26 p.m., the foregoing matter was adjourned.)