UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

MEDICAL DEVICES ADVISORY COMMITTEE

CIRCULATORY SYSTEM DEVICES PANEL

MEETING

THURSDAY,

APRIL 10, 2003

The Panel met at 9:00 a.m. in Salons A, B and C of the Gaithersburg
Hilton, 620 Perry Parkway, Gaithersburg, Maryland, Dr. Warren Laskey,
Acting Chairman, presiding.

[PRESENT]{.underline}:

WARREN K. LASKEY, M.D Acting Chairman

SALIM AZIZ, M.D. Member

ANTHONY J. COMEROTA, M.D. Consultant

THOMAS B. FERGUSON, M.D. Consultant

ALLEN A. HUGHES, Ph.D. Consumer Representative

NORMAN KATO, M.D. Consultant

WILLIAM H. MAISEL, M.D. Consultant

MICHAEL MORTON Industry Representative

GARY G. NICHOLAS, M.D. Consultant

SHARON-LISE NORMAND, Ph.D. Consultant

ANNE C. ROBERTS, M.D. Consultant

GERETTA WOOD Executive Secretary

[FDA REPRESENTATIVES]{.underline}:

BRAM ZUCKERMAN, M.D.

DOROTHY ABEL

PAUL CHANDEYSSON, M.D.

GARY L. KAMER

[SPONSOR REPRESENTATIVES]{.underline}:

DAVID P. BIGGS

TIMOTHY A.M. CHUTER, M.D., FACS

NEAL E. FEARNOT, Ph.D.

RICHARD M. GREEN, M.D.

ROY K. GREENBERG, M.D.

APRIL L. LAVENDER, RAC

A-G-E-N-D-A

**Call to Order & Administrative Matters**

CHAIRMAN LASKEY 3

**Open Public Hearing**

SENATOR ROBERT DOLE 9

DR. RODNEY WHITE 14

**Survey**

DR. KATHERINE McCOMAS 19

**Sponsor Presentation: Cook Incorporated**

**Cook Zenith AAA Endovascular Graft**

APRIL LAVENDER, 22

DR. RICHARD GREEN 25

DR. TIM CHUTER 35

DR. NEAL FEARNOT 43

DR. ROY GREENBERG 51

MR. DAVID BIGGS 80

**FDA\'s Presentation**

DOROTHY ABEL 88

PAUL CHANDEYSSON 96

GARY L. KAMER 110

**Committee Discussants**

DR. ANTHONY COMEROTA 124

DR ANNE C. ROBERTS 148

**Open Committee Discussion** 158

**FDA Questions Discussed** 203

**Recommendations and Vote** 255

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

2:15 p.m.

CHAIRMAN LASKEY: Good morning. If we can all take our seats, I\'d like
to begin. Thank you.

My name is Warren Laskey. I\'m pleased to share this mornings session
and call this meeting to order. The topic this morning is the discussion
of the pre-market application for the Cook Zenith AAA Endovascular Graft
P020018.

If the Executive Secretary could please read the paragraph regarding the
Chair of the Committee and the conflict of interest statement.

EXECUTIVE SECRETARY WOOD: The following announcement addresses conflict
of interest issues associated with the meeting and is made a part of the
record to include even the appearance of an impropriety. To determine if
any conflict of interest existed, the agency reviewed the submitted data
and agenda and all financial interests reported by the committee
participants.

The conflict of interest statutes prohibit special government employees
from participating in matters that could effect their or their
employer\'s financial interests. However, the agency has determined that
participation of certain members and consultants, the need for whose
services outweigh the potential conflict of interest involved, is in the
best interest of the government. Therefore, waivers have been granted
for Dr. Thomas Ferguson and Gary Nicholas for their interest in a firm
that could be effected by the panel\'s recommendations.

The waivers involved grants to their institutions for the sponsor\'s
product study in which they had no involvement and for which funding was
less than \$100,000 per year. The waivers allow them to participate
fully in today\'s deliberations.

Copies of these waivers may be obtained from the agency\'s Freedom of
Information Office, Room 12A-15 of the Parklawn Building.

We would like to note for the record that the agency took into
consideration other matters regarding Dr. Anne Roberts. They reported
interest in firms at issue, but in matters not related to today\'s
agenda. The agency has determined, therefore, that she may participate
fully in all discussions.

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
product they may wish to comment upon.

CHAIRMAN LASKEY: Thanks, Geretta.

If we can have the panel members introduce themselves, beginning to my
left.

DR. ZUCKERMAN: Bram Zuckerman, Director, Division of Cardiovascular
Devices, Food and Drug Administration.

DR. HUGHES: Allen Hughes, assistant professor of MIS at George Mason
University Consumer Rep.

DR. AZIZ: Salim Aziz, cardio-thoracic surgeon, clinical associate
professor at University of Colorado and private practice in town.

DR. COMEROTA: Anthony Comerota, Director of the Jobst Vascular Center in
Toledo and professor of surgery at the University of Michigan, Ann
Arbor.

DR. KATO: Norman Kato, private practice, cardio-thoracic surgery of Los
Angeles.

EXECUTIVE SECRETARY WOOD: Geretta Wood, Executive Secretary.

CHAIRMAN LASKEY: Warren Laskey, I\'m the Director of Interventional
Cardiology, at the National Naval Medical Center.

DR. NORMAND: Sharon-Lise Normand, associate professor of biostatistics,
the department of health care policy, Harvard Medical School and I\'m
also in the department of biostatistics, Harvard School of Public
Health.

DR. ROBERTS: Anne Roberts, professor of radiology at University of
California, San Diego and Chief of Vascular and Interventional
Radiology.

DR. MAISEL: William Maisel, associate physician and cardiovascular
division, Brigham & Women\'s Hospital.

DR. FERGUSON: Tom Ferguson, cardiovascular surgeon, professor of
surgery, Washington University School of Medicine, St. Louis.

DR. NICHOLAS: Gary Nicholas, vascular surgeon, professor of surgery at
Penn State.

MR. MORTON: Michael Morton, I\'m an employee of Sorin-COBE, and I\'m the
industry representative.

CHAIRMAN LASKEY: Thank you.

If you\'d please read the voting status statement?

EXECUTIVE SECRETARY WOOD: Pursuant to the authority granted under the
Medical Devices Advisory Committee charter, dated October 27, 1990 and
as amended August 18, 1999, I appoint the following individuals as
voting members of the Circulatory System Devices Panel for this meeting
on April 10. 2003:

Sharon-Lise Normand, Ph.D.

Anthony J. Comerota, MD

Anne C. Roberts, MD

Norman Kato, MD

Gary Nicholas, MD

Thomas Ferguson, MD

William Maisel, MD

For the record, these individuals are special government employees and
are consultants to this panel under the Medical Devices Advisory
Committee. They have undergone the customary conflict of interest review
and have reviewed the material to be considered at this meeting.

In addition, I appoint Warren K. Laskey, MD, to act as temporary
chairperson for the duration of this meeting.

This is signed by David W. Feigal, Jr., MD, MPH, Director Center for
Devices and Radiological Health, dated April 1, 2003.

CHAIRMAN LASKEY: Thank you.

I\'d like to commence with the open public hearing portion for this
morning. And it\'s a pleasure to introduce Senator Robert Dole, who has
requested time to address the panel.

Senator Dole.

SENATOR DOLE: Well, first of all, I want to thank you for permitting me
to come by as a volunteer. I sort of observed what\'s happening in this
Committee. I\'ve been in Congress so long I didn\'t know people showed
up at committee hearings that really understood the subject matter. But
in any event, maybe we can get you a little consultant work in Congress.
I\'ll talk to my wife.

Well, I\'m just here as an example of somebody who had access and
somebody who had the money to pay for this less invasive surgery. And I
must say, I was in a hospital prepared to have the old fashion surgery
where they cut you from here to here, as everybody knows. And I had a
call from Dr. Bill Frist, who was also the Senate Majority Leader at
this point, saying \"Bob, I think before you do this, you ought to\" \--
you know it\'s only 5.3 I think was the size of the aneurysm \--
\"there\'s no need to rush into this. There\'s some new things that
they\'re doing now. Why don\'t you come back and talk to me and let me
check around and so forth.\"

I left the hospital and came back. And thanks to Dr. Frist we checked it
out, and he thought I should try the less invasive, which I did at the
Cleveland Clinic. And almost been 2 years ago, 2 years ago in June. I
don\'t remember the exact date. Maybe Dr. Greenberg does. But I think
the point is, like everybody else, you learn more about a lot of these
things after you\'ve had the surgery or whatever it is.

I\'ve been through prostate surgery, radical prostatectomy. I\'ve had a
colectomy. I\'ve had a kidney taken out. I haven\'t got much left that
they can \"ectomy.\" But anyway, the aneurysm is something I didn\'t
know anything about. A knew a little about \-- I take that back. I knew
a little about it because my father came to attend our wedding in 1975
and never made it back home because of an aneurysm. And when I learned
this happened, I remember getting a call from former Seantor Baker who
said you\'ve got to get this, you\'ve got to take care of this right
away and then he told me about his father who was in shaving one morning
and never came out of the bathroom. And, of course, that\'s what happens
in many cases when it breaks.

And since my surgery and after talking with everybody in the office
about it \-- I\'m not trying to harass anybody about my surgery, but a
long time associate of mine named Joanne Coe who was really \-- you
probably all have somebody like that in your office, you just sort of
turn your life over to them. And I did that for 35 years and I was in
North Carolina campaigning for my wife, I might add, and I called Joanne
that night. She said I\'ve got this terrible backache. I said \"Joanne,
you\'ve had kidney stones, you think it\'s kidney.\" I said \"I don\'t
know, go to a doctor.\" And six hours later she was gone.

And, of course, there are about 2 million people probably walking around
at this time don\'t even know it.

And so I guess my point would be, first of all, to thank the panel and
thank all the individuals who study and analyze and determine whether a
new device should be released. And it\'s not an easy task, but it\'s
certainly important to millions of people.

The public is entitled if it\'s safe and effective to have access to
these new devices as quickly as possible. And, of course, the emphasis
on safety. It also, of course, shifts the emphasis in some cases on
cost. In my case, I could pay for it, but in other cases you have to be
figure out some other way to make that possible.

And we need the cooperative work of doctors and panels, and the FDA and
companies to provide the public with access to safe and effective new
technologies.

So I\'m just one story that, you know, I\'m happy to be here today. And
I might add just as a matter of when I leave here, I\'m going to go to
New York and going to ground zero where there are going to be 50,000
hardhats assembled, and we\'re going to have a rally there to support
the troops in Iraq. And it\'s going to be a magnificent thing. And I\'m
honored as the speaker. So it\'s going to be a great day. And we\'re not
choosing up sides or anything, but we\'re just saying we support the
American forces and they\'re doing a spectacular job.

I know everybody in this audience is proud of what they have done. I
just say that as an afterthought. But we wouldn\'t have all these
privileges and rights and opportunities in America if we didn\'t have
young men and young women willing to make the sacrifice from
time-to-time that they\'re making right now. So they\'re part of the
story, too.

I\'m not here to endorse any specific product. But I\'m here to say that
in my case I was, think, back home in 5 or 6 days rather than 5 or 6
weeks. And been in good health, or better health since it happened. And
I just thank the panel very much for listening to me. Thank you.

CHAIRMAN LASKEY: Thank you very much, Senator, for taking time out of
your schedule. And good luck in New York.

Dr. Rodney White has also requested some time this morning during the
open sessions. Dr. White?

Tough act to follow.

DR. WHITE: Thank you very much. I\'m not going to try to follow that.
I\'ll just continue on with our usual vascular stuff here.

My name is Rodney White. I\'m chief of vascular surgery at Harvard UCLA
Medical Center in Torrence, California, and I\'m professor of surgery at
the UCLA School of Medicine.

My conflicts of interest are that I\'m a vascular surgeon. I make my
living treating vascular patients and primarily implanting endoluminal
grafts. I\'m also representing here today the SVS/AVSS, and I\'m
secretary of that organization and Chairman of the Committee of the
Lifeline Registry.

I\'d like to just very briefly tell you about the registry, because it
plays an important role in collecting information on patients like
Senator Dole who have endoluminal grafts as part of IDE studies.

And in this, the key stakeholders are the societies and the clinicians,
the foundation itself which is part of the SVS/AAVS. Obviously, the
manufacturers, the federal agencies, in particular FDA and CMS and
Industrial Advisory Committee which is made up of the manufacturers
represented here. Each of these manufacturers have from day one
supported the registry. And I think the most important part of the setup
of the registry itself is that it, through a central steering committee,
coordinates activities. And this involves the ex officio members, which
are the government agencies, the Industrial Advisory Committee from the
manufacturers and has looked at all the issues related to these new
technologies, particularly the endoluminal grafts, translates that to a
data center. And through a process of validations even beyond what goes
on here, to make sure that the data gets translated accurately. The
outcome would then be a master data set across all of these follow-up
studies to make a very comprehensive ongoing effort.

There\'s two parts to the registry. One is to collect the five year data
surveillance after the patients complete the approval process so that
there\'s an ongoing collective registry effort. And then secondly, to
address the surveillance that\'ll be mentioned later on these patients
so that there is an effort there to make that cost effective efficient.

For the post-PMA follow-up patients, this five year requirement, in many
cases the registry meets that follow-up requirement if the manufacturers
would like to use that option. And as they are continuing to fund the
clinical centers, that makes it a very important part then of the
overall effort.

The PMA data set itself, this accumulated data is published in the
[Journal of Vascular Surgery]{.underline}, and it ends up being
tabulated. This is from a June publication last year, there\'ll be
another one this year in June.

Just to give you an idea of, in this case, distribution of patients by
age. But the overall data set can be particularly important. At the
present time following the approval of the first three devices and the
patients in each of those groups and an anticipated enrollment of the
Cook patients, there will now be over 2,000 patients in the registry.

And another important group are the surgery control group, which is
approaching 400 patients.

And if you look at the data from last year, and this will be updated
again in June, but you can see now that at that data point there were
1600. And again now there\'ll be over 2,000 patients.

And where we are is that as these numbers get out further and further,
the average follow-up interval now for patients in the registry is
beyond 3 years. That makes it a very long follow-up, highly
comprehensive and the value of that data set becoming specifically very
important.

The clinical surveillance part is a difficult issue. It requires a lot
of things; patient compliance, efficient registry data and an imaging
data set that gives us over time a very quick assessment of any
potential problems. We want to know what the aneurysms look like, and
you\'ll be hearing these things later, the sizes and connections. And
the way it works is to collect that information, basics about how they
function. To put that into the registry through a series, again, of
validations and auditing processes. And then through as secured website,
because the patients are only identified by numbers, be able to have
important variables that each intervals. These are the specific
measurements, those that may be a little out of line get red flagged so
you can look at them. And a series of images and comments that then
given an ongoing record so that it\'s a very accurate collection data
system now available for patients.

Again, to look at the prospective aspect of this. There\'s a thoracic
component to this registry. Just examples of the data available and the
sequential imaging.

And for those that are interested, a couple of references with updated
papers to show, again, in the [Journal of Vascular Surgery]{.underline}.

I think it\'s important for the panel to understand the registry\'s
goals. It was initiated before there were any approved devices with the
cooperation of all the manufacturers supporting this. The agencies being
involved with that prospective collaborative effort being to enhance
patient care and make this a very progressive activity.

I thank the panel for their time.

CHAIRMAN LASKEY: Thank you, Dr. White.

Is there anyone else who wishes to address the panel for the open
session?

If not, I\'d like to close the open public hearing portion this morning.

And before we begin with the festivities, there\'s one more item. I\'d
like to introduce Dr. Katherine McComas from the University of Maryland
who will present the context of a recent survey conducted amongst the
panel members.

Dr. McComas?

DR. McCOMAS: Thank you, and good morning.

And my comments are both for the panel members as well as people in the
audience. I am Katherine McComas, and I\'m an assistant professor at the
University of Maryland. And I\'m here today with permission to collect
data.

I\'m collaborating with researchers within the FDA to examine the
public\'s understanding and perceptions of the conflict of interest
procedures that the FDA uses to manage and monitor real or potential
conflicts of interests among its advisory committee members. So I\'m
responsible for all of those surveys that are in your chairs. And I\'ve
also distributed a different survey for people on the advisory committee
members.

FDA officials are rated at this time. At another point in time we\'ve
been talking to people within the FDA.

So what I\'d like to request is that if you have a chance today to
complete this questionnaire, it should take about 15 minutes of your
time, there\'s a box outside near the registration desk marked \"FDA
Survey,\" where you can turn it back in. Otherwise, there\'s a business
reply envelop, you can just drop it in the mail.

And we greatly appreciate your time. Of course, your participation is
voluntary. But the higher number of responses we get, the more valid
data we have for understanding how people understand and know about the
conflict of interest procedures that the FDA uses.

So, thank you very much for your time and any assistance that you can
offer. And thank you very much for your time, too, to present a little
context.

Oh, and I\'ll be here throughout today if you have any questions. Please
feel free to come up and ask me.

Thank you.

CHAIRMAN LASKEY: Thank you.

Now to the Chairman\'s delight, we\'re ahead of schedule. So I\'d like
to move on to the sponsor\'s presentation. If Geretta could please read
your statement.

EXECUTIVE SECRETARY WOOD: I just want to remind the speakers to
introduce themselves and to state their conflict of interest.

MS. LAVENDER: Good morning, ladies and gentlemen, and distinguished
members of the panel. My name is April Lavender, and I\'m the Vice
President of Regulatory Affairs for Cook, Incorporated, the sponsor of
the pre-market approval application for the Zenith AAA Endovascular
Graft that is subject of today\'s panel review.

Cook is a leading designer, manufacturer and global distributor of
minimally invasive medical device technology for diagnostic and
therapeutic procedures with its international headquarters located in
Bloomington, Indiana.

Our facility includes over 900,000 square feet of manufacturing capacity
and over 1500 employees.

For 40 years Cook has created innovative technologies for implantable
devices including stents and tents grafts, catheters of all types, wire
guides, embolization coils, vena cava filters and many other varieties
of minimally invasive medical devices.

This global map indicates various Cook distribution offices, Cook
manufacturing sites and Zenith manufacturing locations in Australia,
Denmark and here in the U.S.

The Zenith AAA Endovascular Graft is a product that has been widely
investigated and is currently in commercial distribution in many markets
of the world. Along with the documentation you\'ve reviewed for this
device, in June of 2002 FDA performed the required bioresearch
monitoring inspections of the clinical trial records for this study at
our facility. In October of 2002 FDA completed the investigational site
audit activities to assure compliance with the study requirements. And
finally, in December of 2002 FDA completed its inspection of the firm\'s
manufacturing facilities and quality system procedures. There were no
notices of adverse findings associated with any of these inspections.

The agenda for today\'s presentation will include Dr. Richard Green, who
will present on abdominal aneurysmal disease.

Dr. Green is president-elect of the Society for Vascular Surgery,
professor surgery and radiology and Chairman of Vascular Surgery at the
University of Rochester School of Medicine and Dentistry, and served as
an investigator in the U.S. clinical trial of this device.

Dr. Tim Chuter is associate professor of surgery at the University of
California San Francisco and one of the U.S. study proctors, and will
present the device in its deployment sequence.

Dr. Neal Fearnot is President of MED Institute and will discuss the
design of the clinical study.

Dr. Roy Greenberg is a vascular surgeon, the Director of Endovascular
Research at the Cleveland Clinic Foundation and is the U.S. study\'s
national PI and will present the results of the clinical trial.

Mr. David Biggs is Director of Advanced Technology Management for Cook,
Incorporated and will provide a brief overview of the position training
program and post-market surveillance activities.

In addition to our speakers we have here today, representatives of the
study\'s Angiographic Core Lab, the Clinical Events Committee, the Data
Safety Monitoring Board, Statistical Consultants technical from
Australian and Europe, the principal investigator of the Australasian
Study, Dr. Michael Lawrence Brown and many of the U.S. study
investigators.

Cook is committed to the treatment of aneurysmal disease. And we thank
you for the opportunity to present this device before you today.

At this time it is my pleasure to welcome Dr. Green to the podium to
present the background of AAA disease.

Dr. Green?

DR. GREEN: Mr. Laskey, distinguished panel members, good morning. My
name is Richard Green, and I\'m a vascular surgeon from the University
of Rochester.

My goal is to address some of the options that surgeon in the
contemporary practice of vascular surgery have when dealing with
aneurysms of the abdominal aorta.

Aneurysms have been a major focus of my career. I\'ve performed over
2000 open repairs and over 200 endovascular repairs, and have been an
investigator in multiple phase 2 clinical trials.

I\'d like to start giving you a sense, a picture sense of what an
aneurysm is. This is the aneurysms in an operative photograph. You can
see this was obviously an open procedure with retractors. This is what
we refer to as the proximal neck. These are the iliac arteries, the feet
being over here which in this case is not involved with an aneurysm, but
may be.

The ability to safety operate on the aorta was a major factor in the
development of vascular surgery as a specialty.

Aneurysms have a huge impact in the United States. There are over
100,000 new cases per year, and an 80/20 men to women gender
distribution. There are 40,000 elective operations, 13,000 deaths from
rupture and 400,000 hospital beds are utilized each year.

I\'d like to give you a sense of what open repair requires. This happens
to be an operative photograph of an open repair done through the left
flank, and you can see the retroperitoneal contents. The aneurysm is
sort of hidden here. This is a tape around the renal artery, and this is
the retractor setup to hold apart the patient\'s body for surgical
access.

In a drilldown, you can see what a complete repair looks like. This is a
polyester graft with a hand sewn connection to the aorta at the level of
the renal arteries. Right iliac artery. And this one\'s going into the
left external iliac artery.

Note the extensive nature of the dissection and the amount of work done
to connect these objects to the polyester graft.

The results of this repair are dependent upon the patient comorbidities
and the experience of the physician and the hospital.

I\'m showing here the results of a Canadian trial published \-- I have a
first authorship of Wayne Johnson, looking at 666 patients who underwent
aneurysm repair in multiple Canadian centers. You can see the incident
of cardiac renal pulmonary amputation mortality. They\'re all very real.
Look here at the incidence of cardiac complications. The red bar at
total cardiac complications and the yellow bar myocardial infarction.
The incidence of dialysis, severe renal complication of .6 percent is
very real. And, obviously, the mortality rate of 5 percent is
significant.

Open aneurysm repair is considered to be a durable procedure, and I\'d
like to try and define what that means.

Re-intervention rates have been studied, first in the Canadian trial
that I mentioned in the prior slide, and there\'s an incidence over the
5 year period of this analysis of total 6.5 or roughly 1 percent per
year, which is corroborated in the 35 year population based study in
Olmsted County performed by Jeb Hallett at the Mayo Clinic, which also
showed a one percent annual re-intervention rate.

Although this number is quite low, the mortality rate after such
re-interventions is 25 percent in both series. And I\'m going to show
you why that is.

The complications after open repair of abdominal aortic aneurysms can be
quite severe. Pseudo-aneurysm, thrombosis, erosion, infection,
hemorrhage, colon ischemia and in a review from my own institution, an
anastomotic dilation which exceeds 30 percent after 7 years.

There\'s also a very real incidence of mortality after open repair. And
this bargraph shows some representative mortality rates. Mortality rate
after open aneurysm repair is dependent, somewhat, on the method of
reporting. In collective reviews of individual hospitals or surgeons,
mortality rate is 3.5 percent. If one looks at multi-center experiences
such as the Canadian trial, the mortality rate is about 5 percent. If
one uses national hospital discharge data, the largest data set, the
mortality is 5.8 percent. And lastly, if one utilizes statewide audits,
the mortality rate approaches 7 percent.

There are two groups of determinants of outcome. Patient factors that
I\'ll discuss first, and technical factors. This has been well studied
and we know that EKG evidence of ischemia, heart failure, renal
dysfunction, pulmonary dysfunction all adversely impact results. Gender
has an effect. Women do less well then men and each advancing decade of
age adds an increment of morbidity and mortality.

The technical factors that determine outcome can be divided into patient
issues, surgeon and hospital issues.

The extent of the aneurysm, disease at the clamp site, inflammatory
changes, venous abnormalities that interfere with exposure of the aorta,
the hostile abdomen, the patient who has had multiple operations or
anastomy, all adversely effect the results following operation. And
perhaps most importantly, the experience of the surgeon and the
institution have an effect on mortality.

This is, obviously, led many to ask is there another way? Is there a way
to achieve the same thing in a less invasive manner, a less morbid
manner, a less lethal manner but once again, an equally effective manner
or look at another way, is there a way to replace this instrument pan
\-- this happens to be a setup from an open case of mine to resect an
aneurysm \-- with the same device delivered through a sheath? And that
leads us to the topic of today, which is endovascular repair.

This is a 3-D rendering of an aneurysm. The concept of endovascular
repair is to gain access to the sac remotely through a femoral artery,
to attach the device to the aorta here, here and here with stents and
barbs rather than sutures, to preserve limb blood flow but yet to
protect the sac from arterial pressure with the ultimate goal of
protecting the patient against rupture.

Because rupture is such an infrequent endpoint after endovascular
repair, there are a number of surrogate endpoints that are discussed
later on this morning. And these are endoleak, migration and change in
aneurysm size.

I\'d like to define endoleak for you. Endoleak means that blood is
somehow getting into the sac despite the presence of the device. In the
type 1 endoleak blood gets into the sac from one of the deployment
sites, either proximately or distally.

This is an arteriogram showing a patient with an endograft in place.
This is the left iliac artery and one can see that there\'s
extravasation of dye back into the sac. Type 1 endoleak is bad.

This is type II endoleak. Type II endoleak can be called branch endoleak
where blood flows into the sac from one of the collateral vessels. In
this diagram the collateral vessel happens to be inferior mesenteric
artery. And in this angiogram the collateral leak is a lumbar vessel.
There\'s a catheter going up, this is a lumbar artery and you can see
contrast material in the sac of the aneurysm. If you look carefully you
can see the stent architecture.

It\'s not clear what the impact of type II endoleak is. It\'s clearly
dependent on what happens to the sac size.

Type III endoleak can come from either a module or disconnect, which two
parts of the graft separate and blood gets into the sac, or from a
fabric tear.

This is a CT scan showing a type III endoleak from a modular disconnect.
This is a commercially available device that\'s seen in the CT scan. And
the limbs have separated. The pink represents the endoleak. This
represents the sac.

This is a CT scan showing an aneurysm before treatment. This is the
treatment at 6 months and the CT scan. And here it shows the two limbs
with contrast the sac, without contrast a very good result.

At 18 months, however, this graft has migrated. And on the CT scan there
is now contrast in the sac. The migration has caused a type 1 endoleak.
Graft migration can cause a type I endoleak and is bad.

Surrogate endpoints at 12 months for the currently approved device is
here. The occluder and the ancure device and the AneuRx device. And
I\'ve listed endoleak and migration. And the panel can see that there is
a significant incidence at 12 months of endoleak and all three, and some
movement migration similarly in all 3 grafts.

Change in aneurysm size is varied with the 3 commercially available
devices. Shrinkage clearly represents a reversal of the natural history
of the aneurysm and is intuitively good. Dilation, on the other hand, is
the natural history of the aneurysmal process and is clearly bad.
Stability in size, which can happen, is unclear as to the outcome.

So from an aortic surgeon\'s perspective aneurysms continue to be a
major health issue in the United States. Conventional repair is
associated with considerable morbidity and mortality. It is likely
underestimated when only data from high volume centers are considered. A
less invasive, less morbid repair using a stent rather than a suture
attachment and delivered remotely through the femoral artery holds great
promise.

With that, I\'d like to introduce to you Dr. Timothy Chuter, who will
discuss the design of the Zenith Endograft.

Thank you for your attention.

DR. CHUTER: Good morning. My name is Tim Chuter. I\'m an associate
professor and Director of Endovascular Surgery at UCSF. I\'m a paid
consultant for a number of stent graft companies, including Cook. And I
receive royalties from a number of stent graft companies, including
Cook. Cook paid my expenses to be here today.

The antecedents of the Zenith device were present within Cook since 1983
when Cesare Gianturco developed the Z-stent. In the mid-1980s there
followed the early versions of stent grafts, and in the early 1990s the
first bifurcated stent graft both in animal and clinical use.

Work on stent grafts began in Perth in 1993. There followed a rapid
period of evolution during which the lessons of experience were
incorporated into stent graft design, culminating in 1997 with the
development and release of the Zenith stent graft, which has many of the
features of the current device, including the proximal fixation stent,
the bifurcated three-piece configuration, a long dilator and other
things that I\'ll discuss in detail.

The only changes to have been made from 1997 until the beginning of the
U.S. study were some minor changes in the length and spacing of the
stents to improve the flexibility and durability of the device. There
were no changes made during the period of enrollment of the U.S. pivotal
study. And the only change to have been made since then is a doubling of
the suture attachment between the proximal fixation stent and the rest
of the stent graft.

Since 1997 when the device first became commercially available abroad, a
total of in excess of 10,000 cases have been performed and followed in a
variety of registries. These registries were not designed to serve for
the FDA approval process, and we\'ll not focus on them here today. But
it is difficult to ignore such a large experience and such a long
follow-up.

The primary prothesis has three components. An aortic main body and two
iliac leg extensions. All three are constructed from conventional woven
surgical polyester, and all three are supported throughout their length
by a series of stainless steel Z-stents. The Z-stents at the proximal
and distal attachment sites are inside the graft, otherwise the Z-stents
are outside the graft.

In addition, there are a number of ancillary components designed to deal
with unanticipated contingencies. For example, the proximal cuff is used
when the proximal end of the main body is not as high as one would like.
The distal extender is used when the distal end, the legs are not as
long as one would like. The aorto-iliac converter is used when one of
the legs cannot be deployed, it then directs all the blood flow down the
other leg and is used in conjunction with the femoral-femoral bypass and
a contralateral common iliac occluder to prevent retrograde flow into
the aneurysm.

Perhaps the most characteristic element of this design is the uncovered
proximal stent that reaches above the renal arteries into the most
stable segment of the entire aorta, hence anchors the device in position
through 10 or 12 caudally directed barbs. These barbs deploy passively
and are dragged into the wall of the aorta by small degrees of initial
caudal migration, where they arrest that process.

There are a series of gold markers around the proximal margin of the
graft. You see one here and here.

There is a check-shaped marker at the distal end contralateral device
orifice to assist in location and orientation and a series of markers in
the same orientation on all of the stents to help in fluoroscopically
guided orientation.

The proximal uncovered stent sits within it\'s own little cap, and is
secured there by this safety or trigger wire.

The cap is attached proximally to this long tapered Coons dilator, both
of them are attached distally to a cannula that runs throughout the
device and emerges from the outer end.

Similarly, the distal end of the device, the ipsilateral side, is
attached to a gray shaft. The gray shaft actually runs up outside this
cannula. The wire runs through the graft shaft and both of the wires are
independently controlled by these rings on the outside.

The central cannula and the gray shaft are connected only at this pinch
vise which when released allows the two to be moved one relative to the
other.

In this stage of partial deployment, the device can be moved and
reoriented by small amounts achieved precisely by in placement.

The main body of the device is available in 5 different lengths, the
goal being to achieve a long body/short limbed configuration and to
bring this contralateral iliac orifice as close as possible to the
orifice of the iliac artery.

There are also a wide range of body diameters from 22 through 32
millimeters and 2 millimeter increments.

The smaller three diameters are delivered through an 18-French sheath.
The larger three diameters are delivered through a 20-French sheath.

The iliac legs come in a range of lengths and diameters also. The
smaller three are intended to be used for extension to the external
iliac artery, and for that reason they have a wider range of lengths
extending from 37 to 122 millimeters. The larger sizes, 14 millimeters
through 24 millimeters, are available in a range of lengths 37 through
88 millimeters. The smaller devices are delivered through a 14-French
sheath. The larger devices are delivered through a 16-French sheath.

The sizing and delivery system size of the ancillary components
correspond to those of the primary components. For example, the aortic
cuff is available in a range of the same sizes with the same size
delivery systems. The iliac extender is available in a range of 9
diameters, same size delivery systems. The aortic iliac extender has
only 3 sizes, but they cover the same span and, again, the same sizes of
delivery systems.

This animation shows the deployment sequence in the infra-renal arterial
is the renal arteries is the aneurysm is the iliac. And you can see
through the right iliac artery the introduction of guidewire into the
proximal aorta. And that is followed by the tip of the delivery system
and the sheath. The sheath is then withdrawn allowing partial deployment
of the stent graft and a release of the contralateral stent that is then
catheterized. The cap of the device to advanced and the proximal stent
to be deployed.

And the second delivery system is then inserted for deployment of this
extension. The delivery system is removed. And this sheath is pulled
back to allow the stent graft to be fully deployed, whereupon the cap
can be retrieved.

A final delivery system allows insertion of a third component in the
iliac extension. Then the entire stent graft is balloon dilated to
assure a full apposition between the extent graft and its attachment
sites, and also between the separate components of the stent graft.

So to summarize the characteristic features of this device, it has a
flexible modular design and a wide range of diameters to allow one to
treat the wide range of distorted anatomies that one finds in patients
with aneurysm, many of whom cannot be treated with the currently
available devices.

It has a tractable delivery system to traverse the iliac arteries that
are commonly torturous in patients with aneurysm disease. A controlled
multi-stage deployment to allow for precise placement. A wide range of
body lengths to allow for a long body short length configuration. And to
reduce the distance between this orifice and the iliac artery for easy
catheterization.

There is barb-enhanced suprarenal fixation to resist the forces of blood
flow and prevent distal migration. Full thickness conventional surgical
woven polyester for durability. And a full stent support throughout its
length to minimize the risk of kinking and twisting.

And with that, I\'m going to hand you over to Neal Fearnot, who will
discuss the design of the pivotal U.S. study.

DR. FEARNOT: Thank you, Dr. Chuter.

Good morning, ladies and gentlemen. My name is Neal Fearnot, I\'m the
President of MED Institute of Cook company. And it\'s my pleasure to
present study design.

The principle focus of today\'s presentation will be the U.S. pivotal
study with 12 month results and a 24 month update.

When we present data in support of the integrity of the device, the
pivotal study results will be augmented with global experience in 10,000
cases to bring a more comprehensive and long term perspective. Because
of the limitations in time, my discussion of study design will refer
only to the U.S. pivotal study.

The objective of the U.S. pivotal study is to demonstrate the safety and
effectiveness of the Zenith AAA Endovascular Graft in patients with
aortic, aorto-iliac and iliac aneurysms meeting the inclusion/exclusion
criteria.

A priori knowledge was available and the background information included
prior studies of AAA disease, other endograft clinical studies,
predicate and custom Cook endografts, non-U.S. clinical experience and
extensive data from the Australasian study of the Zenith device.

During the design of this study we recognized that randomization is
preferable, however we were also aware that randomization was abandoned
in a previous endograft approval study. So in agreement with FDA, this
study was a nonrandomized concurrently controlled design similar to that
of all previous endograft approval studies.

The two principal study groups involved 280 patients with like
pathophysiology, 200 of which were treated with the Zenith Endovascular
Graft and 80 of which were treated with open surgical repair. In
addition to the 2 principal study groups, there was a group of 52
roll-in patients which allowed physicians to gain experience with the
device before enrollment in the pivotal study. This is consistent with
Dr. Green\'s comment that physician experience may effect outcome.

While the two principal study groups involved patients with standard
pathophysiology, the study design included a high risk group for
patients who were at higher risk for open surgical repair. There were
100 patients in this group. This group provides safety and effectiveness
data for this patient cohort.

All of the study groups had data available at 30 days and 12 months,
which are the basis of this study.

There were supplemental study groups which included a female registry,
recognizing the lower incidence of AAA disease in females and wanting to
augment the accrual of women in this study.

Compassionate use and emergency use applications were outside the
protocol for this study.

Following completion of the enrollment in the pivotal study, a continued
access for this device was made available through two additional study
groups.

We attempted to optimize the group comparability with the following
steps: We establishment equivalent general entry criteria; we
established equivalent medical entry criteria.

The anatomical differences were expected because of the limitations of
all endografts in terms of anatomy. This was addressed by, first,
studying the between group differences and, secondly, was adjusted for
possible bias using covariate and propensity score analysis.

Finally, we used centralized management and analysis. Centralized
management involved national proctors which trained investigational
sites before pivotal study enrollment. All patients were prescreened
reviewing the anatomical criteria and the device sizing. Monitors
performed on-site review of adverse events and protocol compliance with
over 330 on-site visits.

The sponsor, obviously, supplied devices, funding and internal
management.

An independent imaging core laboratory analyzed the angiograms, KUBs,
CTs and duplex ultrasounds.

An independent data safety monitoring board reviewed safety data during
the clinical study based on standard procedures having 8 meetings during
the trial period. And independent clinical events committee determined
if the clinical events were pertinent to the study and related to AAA
repair.

There were five study hypotheses. These study hypotheses involved the
standard risk patients receiving either the Zenith or surgical repair.
The primary hypotheses was based on 30 day morbidity. Secondary
hypotheses involved equivalent 30 day survival, equivalent 12 months
survival, equivalent 12 month treatment success and superior clinical
utility in terms of in-hospital recovery.

The primary hypotheses was based on morbidity index. Based on prior
publications that identified the morbidities that are associated with
AAA disease and its repair, either surgical or endovascular, we
developed a morbidity index with 31 measures in seven categories.
They\'re listed here and the panel pack.

Secondary hypotheses involved survival. Mortality before 30 days was
always considered procedure related. Morbidity after 30 days was
adjudicated as not AAA related, AAA related and if AAA related,
procedure related, technique related or device related.

Survival was analyzed with Kaplan-Meier estimate and Blackwelder
equivalence with a delta of .075.

Success measures were defined as follows: Technical success was defined
as a patent graft following deployment or prosthetic implantation.
Procedural success was defined at 30 days as technical success with no
major complications, patent graft in an endovascular, no type I or III
endoleak. Treatment success at 12 months, which was the basis of one of
the study hypotheses, was designed basically as procedure success
extended to 12 months with no aneurysm growth greater than 5
millimeters.

Major complications precluding success are listed on this graft and in
the panel pack. These are the more severe measures in the morbidity
index related to AAA repair.

Clinical utility involved recovery measures, such as duration of ICU
stay, days to ambulation, resumption of oral fluids, resumption of
normal diet, resumption of normal bowel function and length of stay.
Other clinical measures included rupture, conversion, secondary
interventions including all AAA procedures subsequent to the initial
operation, procedural time, anesthesia, blood products, quality of life,
a renal assessment, radiographic assessment of device function and
device integrity.

There are a few important definition from those of other studies, and
I\'d like to point those out at this time.

Radiologic migration was defined as radiographically observed, ategrade
or retrograde movement greater than 5 millimeters relative to the renal
arteries in comparison to the first post-op CT. This may differ from the
endovascular reporting standard which uses 10 millimeters, as well as
the 10 millimeters used in some other studies. We choose a more strict
criteria in this case.

Serum creatinine elevation was utilizing two different criteria. Greater
than 30 degree rise from pre-procedure baseline and an absolute level
greater than 2 milligrams per deciliter.

So in summary, the study design involved a concurrently controlled study
with five hypotheses: 30 day morbidity; 30 day survival; 12 month
survival; 12 month treatment success and clinical utility including
in-hospital recovery. Other measures which will be presented to you
today will include aneurysm size changes, endoleaks, secondary
interventions, renal assessment, migrations, major complications
including rupture and conversion and device integrity.

This study was performed at 15 investigational sites. And on behalf of
Cook and its worldwide employees, we wanted to acknowledge the dedicated
efforts of the investigators and their staffs in providing the results
that you\'re about to see.

At this time I\'d like to introduce Dr. Roy Greenberg to the podium. He
is the national principal investigator of this study, and he will be
discussing the clinical results.

Thank you.

DR. GREENBERG: Good morning. My name is Roy Greenberg. I am a vascular
surgeon from Cleveland Clinic and a paid consultant by Cook, who also
paid my expenses to be here.

I have the privilege of presenting the clinical results of this trial.
I\'ve broken this presentation down into three different components. The
first component will be the principle results, which include the U.S.
phase 2 trial through 12 months. We will then provide you with the 24
months clinical update. And then as Dr. Fearnot was saying, the global
assessment of device integrity data, any data that we have from the
worldwide experience with this device.

The enrollment period began in January of 2000 and completed in 2001.
The two pivotal groups are illustrated on the left portion of this slide
and included 200 standard risk endovascular patients and 80 standard
risk surgical patients. An additional 100 high risk and 52 roll-in
patients were accrued.

The demographics of the pivotal groups of this study are depicted here.
You can see there was a slightly greater age in the Zenith standard risk
patients and slightly higher weight in the Zenith standard risk patients
in contrast to their surgical controls. The other variables were
similar.

Pre-existing co-morbidities were evaluated in a number of different
categories. Of interest, there are three significant differences between
the two pivotal groups, and those are depicted on this slide.
Hypertension, tobacco use and excessive alcohol use were all more
prevalent in the surgical arms of the story.

Several anatomic parameters were assessed and critical differences are
depicted on this slide. The surgical standard risk group had a shorter
proximal neck, a more irregular neck, a slightly larger aneurysm size
and a higher prevalence of aorta iliac aneurysm.

The study hypotheses were evaluated at the following endpoints: reduced
30 day morbidity, equivalent 30 day survival, 12 month survival, 12
month treatment success and superior clinical utility.

With respect to morbidity, we elected to present this in two different
formats. The first format involves an assessment of freedom from any
morbidity in both of the groups. The probability of freedom from
morbidity was greater in the endovascular group than in the surgical
group. Similarly, a morbidity score based off the morbidity index
scoring system was tabulated and noted to be lower in the standard risk
group in comparison to the surgical group.

A propensity analysis was conducted and confirmed the results. Thus, the
primary hypothesis for reduced 30 day morbidity was met. This is a
Kaplan-Meier illustration of the freedom from morbidity through 30 days
of the standard risk group per endovascular and the surgical standard
risk group.

If we break down the morbidity into its constitute categories, you can
see there were four areas where there were significant differences.
These included cardiac, pulmonary, renal and vascular all in favor of
the endovascular arm.

The secondary hypotheses for survival were evaluated at 30 days and at
12 months. This table shows you the accurate mortality or the mortality
within 30 days, 0.5 percent in the standard risk group and 2.5 percent
in the surgical group with no difference.

The zero to 12 month mortality was 0.5 that was AAA related in the
standard risk group and 3.8 in the surgical group. Again, for no
difference.

The all cause mortality was 3.5 percent in the standard risk group, 3.8
percent in the surgical group. Again, for no difference and this was
confirmed by propensity analysis.

The secondary hypotheses for equivalent 30 day survival and 12 month
survival were met.

This Kaplan-Meier curve demonstrates the survival and on an expanded
axis view you can see the surgical standard risk group and the Zenith
standard risk group behave in a similar manner.

The AAA related specific survival are depicted here and in the expanded
axis you can see the surgical standard risk group and the Zenith
standard risk group are quite similar.

Several success measures were also identified. Technical success, which
was defined as a patent graft following implant following successful
deployment of the graft or prosthetic implantation in an open surgical
procedure was achieved to a high level in both categories. Only one
technical failure was noted in the Zenith endovascular group, and this
was a patient who had a calcified aorta iliac femoral system. There was
difficulty advancing the device. The arteriotomy was closed and the
patient was not converted at that time.

The surgical standard risk technical failure involved a patient who died
from intraoperative hemorrhage during the procedure.

Procedural success at 30 days was defined previously. Patient assessed
for procedural success included those patients who suffered a major
complication within 30 days, or those patients who survived the 30 days
and had CT scans that were valuable for a patent graft and the presence
or absence of a type I or III endoleak.

Procedural success was high in both study arms. As you can see, 95
percent of the standard risk group and 88 percent in the surgical group.

Treatment success was similarly assessed at 12 months. Patients assessed
for treatment success included those patients who suffered any major
complication within 12 months or those that survived the 12 months and
had a CT scan valuable for a patent graft, type 1 or III endoleak and CT
scans available to demonstrate aneurysm diameter size change.

Treatment success was noted to be high in both treatment groups. 89
percent in the standard risk group, 85 percent in the surgical group
with no statistical difference, thus the secondary hypotheses of
equivalent 12 months treatment success was met.

The secondary hypotheses for clinical utility was also evaluated.
Recovery with respect to in-hospital recovery was assessed with respect
to the length of stay in the intensive care unit, the days to recovery
of ambulation and oral fluid or normal diet intake, the days to normal
bowel function and the overall length of hospital stay. As you can see,
the endovascular group faired better than the surgical group in all of
these categories, and the secondary hypotheses of superior clinical
utility was met.

Several procedural measures were also evaluated. The overall time of the
procedure, both with respect to anesthesia and procedural time, the
estimated blood loss and the use of blood blank products.

The anesthesia time, procedural time, estimated blood loss and use of
blood bank products were lower in the endovascular group than the
surgical group.

A quality of life questionnaire was distributed and this slide depicts
the previous chart results from that where there was a perceived
perception of improved function in the standard risk endovascular group
and in the surgical group.

In conclusion from the study hypotheses, all of the hypotheses were met.
Compared to the surgical control patients, the Zenith patients had a
reduced 30 day morbidity, equivalent 30 days survival, equivalent 12
month survival, equivalent 12 month treatment success and superior
clinical utility.

Additional measures were also evaluated. These included change in
aneurysm size, endoleaks, secondary interventions, renal function,
migration, conversion to open repair, aneurysm rupture and device
integrity.

This slide demonstrates the aneurysm size over time in both the standard
risk group in gold and the high risk group in blue. You can see the
aneurysm decreases over the course of the 12 months of the study in both
study arms.

An absolute size criteria change of 5 millimeters was described, and
this slide represents the percentage of patients that had a decreasing
aneurysm size versus an increasing aneurysm size. Two-thirds of the
patients treated with the Zenith Endovascular Graft had a increasing
aneurysm size, one-third remained the same. Only 3 patients had an
increasing aneurysm size. These three patients are listed here. As you
can see, each of them had an explanation. One patient had a distal type
1 endoleak that was later treated. And two patients had subclinical
graft infections that were both later explanted.

Endoleaks were evaluated with respect to the occurrence within 30 days
and at 12 months. The overall endoleak rate was approximately 17 percent
within 30 days and the majority of these were type II endoleaks.

Over the 12 month intervening segment the incidence of endoleaks
decreased to 7.4 percent and, again, the majority was constituted by
type II endoleaks.

Secondary interventions were performed in both arms throughout the
procedure, however there was a statistically higher incidence of
secondary interventions in the standard risk arm in comparison to the
surgical group.

This slide demonstrates the secondary interventions that were performed.
As you can see, there were 5 renal interventions performed, 5 coil
embolizations for type II endoleak and no type II endoleak treatment was
left to the discretion of the investigators. There were 3 procedures
done for limb issues, two femoral-femoral bypasses and one placement of
a commercially available stent.

Of note, there was one limb thrombosis that did not undergo a secondary
intervention as the patient did not develop symptoms.

There were six patients treated for type 1 endoleaks, and one patient
treated for a type III endoleak, and this patient was noted to have a
leak from the joint, the modular joint. And this was treated with an
iliac leg extension.

Impaired intra-inguinal blood flow was treated in a single patient with
a femoral-tibial bypass.

This slide depicts the relative percentage or breakdown of secondary
interventions that were performed. And as you can see, the vast majority
of these were done for endoleaks, of which 3.5 percent of the 6 percent
were protocol as we elected to treat all type I and III endoleaks.

We took a specific look at the renal function and anatomy over time due
to the presence of the suprarenal stent. Renal function was analyzed in
several different manners. The three manners are depicted here on this
slide, which included a rise in serum creatinine greater than 30 percent
over a baseline level, the development of renal insufficiency to any
level that exceeded 2.0 milligrams per deciliter, and any patients that
required dialysis, be it humo or peritoneal.

There were no differences between these groups in any of these
categories. Of note, the relative incidence of renal dysfunction was
quite low. The 25 patients in the standard risk group were broken down,
and of those 25 patients 12 of them had creatinine levels that were less
than 1.4 milligrams per deciliter.

Specific anatomic renal events were evaluated in a cumulative manner, so
these numbers represent the cumulative detection of these occurrences.
And renal arteries were detected in two standard risk patient and one
surgical patient for no difference between the two groups.

Infarcts were detected in three standard risk patients and one surgical
patient for no difference between the two groups.

Migration was analyzed very carefully, and it was defined as greater
than 5 millimeters of movement with respect to the native arterial
vasculature. It was then categorized into two sections; one section
included those migrations that had clinical sequelae or required a
secondary intervention and those patients that did not have any clinical
sequelae from the migration or require secondary intervention.

As you can see, there were no patients that suffered migration in the
study arms that had clinical sequelae or required secondary
intervention. However, there were a total of 6 patients for 2.5 percent
in the endovascular standard risk and 2.8 percent in the high risk
groups that did have migration greater than 5 millimeters, none of which
required an intervention or sequelae.

Of note, there were no migrations grater than 10 millimeters during the
12 month study interval.

These six patients are depicted here with the distance of the migration
as defined by the core lab here. All of the migration occurred in a
caudal direction. There were no cranial migrations. There were no
endoleaks associated with these migrations. And there were no secondary
interventions performed in these patients.

Conversion to open repair was analyzed in all of the endovascular study
groups. There were two conversions to open repair in the standard risk
group and one in the high risk group. Of note, there were no acute
conversions in the first 30 days of the procedure.

Freedom from conversion to open repair is depicted here, and on the
expanded axis here. And you can see there are no differences between
these two groups.

Specific details with respect to the conversions are listed here. The
conversions were viewed as either elective or urgent, and the single
elective conversion in the standard risk group was within 48 days for a
persistent endoleak. This was a type 1 endoleak, and so we elected to
treat this.

There were two urgent conversions to open repair. One was the
development of a remote aortic aneurysm, and this patient was converted
successful at 112 days where the proximal portion of the graft was
explanted and the distal anastomosis of the open repair was sewn to the
distal portion of the graft.

A single AAA rupture occurred at 222 days, and I\'ll provide you with
the details of those in a moment.

This was the only rupture that was detected, it was in the high risk
group and it occurred at 222 days. There were no ruptures in the
standard risk group and no ruptures in the roll-in group.

The details of the rupture are depicted here. As you can see, I\'m going
to draw your attention to the right common iliac artery, which is
relative short and tortuous. Following the procedure the endograft is in
place, there is no type 1 endoleak, but the amount of sealing and
fixation within the right limb is quite short, as you can see on this CT
scan and from this angiogram. This is rally attributed at this point
retrospectively to a technical failure in terms of achieving an adequate
fixation in seal distal, however over the course of the ensuing 6 months
the patient did well. The aneurysm size decreased from 6 centimeters
post-procedure to 4.6 centimeters at 6 months.

Three weeks after her 6 month follow-up visit a rupture was noted. This
was patient presented with left flank pain, and this rupture was
detected on the CT scan. The patient was converted to an open repair. As
you can see from this diagram, the proximal fixation of the graft was in
place and was not removed. The graft was transected and an aorta-iliac
bypass was constructed. This rupture potentially could have been treated
with a endovascular approach.

The lessons we learned from this rupture aneurysm involved the fact that
monitoring a fixation is very critical, and the leg length at the
initial time of the procedure must be sufficient to provide effective
distal fixation and seal.

The pivotal study conclusions were as follows: All the hypotheses were
met; the conversion rates were low; there were no pari-operative
conversions; aneurysms size decreased in two-thirds of the patients at
12 months; remain stable in one-third of the patients at that point;
aneurysm growth was limited to only 3 patients with extraordinary
circumstances; the endoleak rate was low; suprarenal fixation was not
associated with increased renal complications; migration rate was
extremely low with no clinical sequelae in any cases, and only one
rupture occurred and the patient was successfully converted.

I will now present the 12 month pivotal study update.

The all cause mortality Kaplan-Meier curves are depicted here. Of note,
the surgical group was not followed beyond 12 months, so these grafts
have the standard risk group and the high risk groups. The behavior of
these grafts is similar to the behavior that we would expect with any
aneurysm study.

Specific AAA related survival is depicted here. As you can see, the
standard risk group and the high risk group both enjoyed relatively good
triple AAA related survival.

The trend in decreasing aneurysm size continued between 12 and 24 months
in both of the study arms. More specifically, applying the absolute
criteria of 5 millimeter of changes, over three-quarters of the patients
had a decreasing aneurysm size at 24 months, less than one-quarter had
an unchanged aneurysm, and one 2 patients had an increasing aneurysm
size at 24 months.

These two patients are listed here. One was previously noted with a type
1 endoleak that was later treated. And the other patient had a type II
endoleak that was treated with an IMA coil embolization on day 751.

This slide demonstrates the overall picture of what happens to the
aneurysm size with respect to percentage of patients over time. As you
can see, there\'s a progressive number of patients at each time point
that have a decreasing aneurysm size.

Endoleaks were also evaluated at 24 months and the observation of
decreasing incidents of endoleaks was confirmed with an approximate 5
percent of the patients having endoleaks at the 24 month time period.
Again, the majority of them type II endoleaks of note at 24 months.
There were no proximal type I, no distal type I and no type III
endoleaks.

An update on the migration patients revealed that none of the patients
had developed endoleaks. There were no secondary interventions
performed. And all of the patients remained alive and well at 24 months
follow-up.

In terms of conversion to open repair, there were two additional
conversions to open repair between 12 and 24 months. One was in the
standard risk endovascular group and one was in the high risk
endovascular group.

The freedom from conversion to open repair, Kaplan-Meier curve is
depicted here with an expanded axis view. It showed relatively high
probability of freedom from conversion to open repair in all of the
endovascular groups.

There were no additional aneurysm ruptures between the 12 and 24 time
points. And therefore, the 24 month conclusions corroborate the
principle U.S. pivotal study conclusions to 12 months. The migrations
observed at 12 months, all less than 10 millimeters, remain stable. The
incidence of endoleaks continue to decrease. The aneurysms continue to
decrease in size. And no additional ruptures occurred.

I\'m now going to turn attention to the device integrity information.
And device integrity was evaluated initially with preclinical testing.
And the preclinical testing identified several specific areas to be
assessed in clinical evaluation. These includes corrosion, stent
fracture, arm separation, suprarenal stent separation from the main body
of the device and graft material wear. Of particular interest these were
defined in terms of three different categories of evaluation.

First, the rigorous preclinical testing was designed to detect potential
failure modes. Specific tests were performed to assess each component of
the device. And the test conditions were intended to test the device to
failure.

Clinical radiographic assessments of the devices at all the study points
included contrast and noncontrast CT imaging as well as four-view
abdominal flat-plate radiography.

Explants were evaluated by a variety of techniques, including light
microscopy, x-ray examination and surface electron microscopy.

There was a multitude of diverse sources of information contributing to
our global device experience. And the more specific details of these
with respect to the years of follow-up in the various studies are
depicted here. However, these studies were not necessarily designed for
FDA approval and consequently some of the data that will be presented
here is anecdotal.

Over 10,000 cases worldwide have been performed with this endovascular
graft, and of those we have 26 explants that we\'ve analyzed.

There were 6 explants in the U.S. pivotal trial, one in a physician
sponsored IDE within the United States, one in a Canadian series, and 18
in the European series. Explants were evaluated for stent fracture, barb
separation, suture breaks and graft wear. There were no suture breaks
and there was no graft wear in any of the explants. Two stent fractures
and a single barb separation were noted in this explant cohort.

Additional observations of the explants were conducted with respect to
corrosion of the stent wire, barb-wire, cannula, gold markers and the
solder. There was no corrosion noted on the stent wire, barb-wire,
cannula or gold markers, and the solder was noted to have corrosion in
all of the explants.

We divided the device integrity into two different categories, that
effecting the proximal integrity system and that effecting the remainder
of the graft.

The proximal integrity system was then divided into barb separation,
separation of the top suprarenal stent with the main body of the device
and its fractures within the fixation or the sealing stent of the
device. There were no fixation or sealing stent fractures in any of the
radiographic evaluations in all of the patients in the series.

There were a total of 5 separations of the suprarenal stent from the
main body; four in the Australasian study and one partial separation in
the U.S. pivotal trial. A second partial separation is under
investigation.

There were 6 patients with barb separations in the U.S. study, 4 in
physician sponsored IDEs in the United States, 16 in the European series
and 7 in the Australasian study. It\'s important to note that in this
worldwide conglomerate experience the proximal fixation system has
somewhat an evolutionary history. The initial barbs were attached at the
apex in association with hooks at the base. And these were modified to
obtain a staggered and multiple configuration along the suprarenal
stent.

Additionally, the initial attachment of the barbs was conducted only
with a solder at the top portion of the Z-stent. And this was changed to
a wrapped wire configuration with the solder prior to any accrual of
patients within the U.S. pivotal trial.

The only change subsequent to all of the patient enrollment in the U.S.
trial was the single suture attachment from the top stent to the main
body to the double suture attachment from the top stent to the main
body.

So, again, the device integrity of the barb design is important because
it\'s somewhat redundant. The wire wrap is then reenforced with solder.
The multiplicity of the design and the staggered design allows more even
distribution of force. And the multiplicity of the barbs shows you with
respect to the design standards of the device, you need to have more
than four barbs remaining in that prothesis to meet those design
standards. So there\'s redundancy in the number of barbs. The staggered
barb design distributes circumferentially and longitudinally in the
suprarenal aorta. The single and double barb separations, which were
noted in the U.S. clinical trial at a very low incidence of 2 percent,
were not associated with any adverse clinical sequelae or requiring
intervention. Re-intervention may be required in the rare instance of
multiple barb separations that is associated with migration and periodic
imaging allows proper monitoring of the proximal fixation system.

Corrosion methods were also specifically addressed at the preclinical
testing level and the corrosion test that was used was an aggressive 57
degree C seawater accelerated corrosion test. The 12 times acceleration
factor was achieved by temperature and ionic acceleration, and this was
confirmed by electrochemical galvanic coupling current. And the test
model was validated by human explant data.

The stent, barb wire, cannula, gold markers and solder were evaluated at
the one, three, six and 12 year time equivalent using light microcopy.

The results of the pre-clinical corrosion tested predicted no corrosion
of the stent wire, barb wire, cannula or gold markers. It predicted
solder loss not anticipated to be greater than 50 percent at 10 years.

The 12 year mean attachment strength at 12 years was still five times
greater than the design standards of the device, and the long term
solder joint design criteria were met.

Clinically no device failures or adverse events due to corrosion have
ever been reported.

On the explant data no appreciable corrosion of the stent wire, barb
wire, cannula or gold markers were noted. And solder loss was comparable
to that predicted by pre-clinical testing.

The suprarenal stent attachment suture that we\'ve been talking about
had involved a one suture mechanism prior to accrual of patients in the
U.S. pivotal study, and subsequent to completion of the U.S. pivotal
study accrual was changed to a double suture. This had the effect of
improving the mean tensile strength by 41 percent. It increased the
fatigue life nearly seven fold. There were no failures after simulated
use of ten years. It demonstrated equivalent deployability.

The change was instituted in August of 2002 and devices that are
currently being distributed contain the double suture attachment.

We divided these device integrity issues into two different categories;
those that were incidentally noted on radiography and those that we feel
were significant. And by significant, they had some clinical sequelae or
required any secondary intervention.

This slide is representative of the incidental cases. As you can see, or
maybe if you can\'t see, this barb fracture or separation here, which
occurred in 6 patients in the U.S. study and 31 cases in the worldwide
experience.

This slide is representative of a partial detachment of the suprarenal
stent as noted in the U.S. study. There was only one case in the U.S.
study confirmed, and there\'s one case under investigation. In addition
to those cases, there\'s been four cases reported worldwide.

In addition to this, it is possible for the device to migrate in the
setting of multiple barb fractures, and there\'s been three cases
reported worldwide of that incidence.

Treatment for these events is typically done in an endovascular manner
and in the case of a suprarenal stent attachment, the treatment that\'s
advocated from the worldwide population includes a placement of a
proximal extension with a redundant suprarenal stent to reenforce the
fixation of the graft.

Device integrity of the graft body was also evaluated. Again, there were
no instances of graft wear and no instances of body suture. There were a
total of 12 body stent fractures in the worldwide experience; 11 in
Europe and one in the physician sponsored IDE in the United States. None
of these fractures of the body were associated with adverse sequelae,
nor did any of them require adjunctive procedures.

This diagram is illustrated of the change that occurred in response to
these factors. The initial stent above the main body was 22 millimeters
long and the fractures were observed in the mid-strut region. Ten of the
11 fractures in Europe were located in this position.

The change that occurred in 1998 was that this 22 millimeter stent was
replaced with two 14 millimeter stents conferring additional flexibility
in that region of the graft, and only two cases since 1998 of stent
fractures in those regions have been reported, both of them have been
apex fractures.

So in conclusion, all of the study hypotheses were met in the U.S.
pivotal trial. Data have been collected to support the safety and
effectiveness of the Zenith Endovascular Graft. Clinical sequelae from
compromised device integrity are rarely seen. Global experience with
over 10,000 devices is favorable, and demonstrates the incidence of
compromised device integrity is low.

Device modification and physician training have further reduced the risk
of device failure. And periodic imaging necessary for the proper
identification of device integrity issues and to treat any potential
complications in a timely fashion.

I will now introduce Mr. David Biggs, whose the Director of Advance
Technology Management, who will discuss labeling, training and
post-market surveillance.

Thank you.

MR. BIGGS: Good morning. My name is David Biggs. I\'m the Director of
Advanced Technology Management for Cook, Incorporated.

The concluding portion of our presentation today addresses labeling, our
training and post-market surveillance for the Zenith AAA Endovascular
Graft.

Draft labeling has been prepared and submitted for review, including
instructions for use, the product box labels and a patient booklets.
Recommendations from the panel and the FDA will be incorporated into our
final labeling.

Cook is committed to physician training. We intend to conduct a training
program which will include a physician training course taught by
experienced Zenith investigators and comprised of didactic sessions,
hands on deployment, observation of a live case and a reference manual
and other educational materials to be distributed.

After completing the physician training course, physicians will be
provided a secondary sizing review and clinical specialist technical
support until they are qualified in the use of the Zenith device.

The physician training course will be a two session. The first day will
review U.S. pivotal study results, patient selection and sizing and
deployment procedures. The second day will cover more advanced topics
such as keys to success, use of ancillary devices and troubleshooting.
Because of the importance of procedural planning and device sizing,
physicians will also be given additional planning and sizing simulations
for independent study. These simulations will include images from
multiple cases and the conclusions of experts against which to access
themselves.

We plan a controlled release with the initial sales going to those 15
investigative sites who participated in the U.S. pivotal study with
experienced physicians as the primary operators. We also plan subsequent
releases to those sites with qualified physicians who have completed the
physician training program which will be required for those not having
prior experience with Zenith.

Attendance at the physician training programs will be prioritized based
on the extent of prior experience with the Zenith device, extent of any
prior AAA stent grafts, extent of prior endovascular experience and
total AAA endovascular case volume.

We plan an annual clinical and imaging follow-up through 5 years for all
Zenith patients enrolled in the pivotal clinical study, as well as those
patients enrolled in the female registry at each investigative site upon
IRB approval.

Clinical updates will be provided to all physician users at least
annually, including rates of aneurysm rupture, conversion, aneurysm
related death, all cause mortality, endoleak, aneurysm enlargement,
protheses migration, patency and device integrity.

In summary, the discussion today included treatment options for
abdominal aortic aneurysms, features of the Zenith AAA Endovascular
Graft, a description of the design of the U.S. pivotal clinical trial,
results of the U.S. pivotal trial, a review of the global assessment of
the device integrity and an overview of our planned post-market
activities.

Lastly, it is our conclusion that these data provide valid scientific
evidence supporting the termination of reasonable assurance and safety
and effectiveness of the Zenith AAA Endovascular Graft for the repair of
abdominally aortic, aorto-iliac and iliac aneurysms.

A considerable effort has been dedicated to the evaluation and
assessment of the Zenith device demonstrating Cook\'s commitment to the
treatment of AAA disease.

This concludes our presentation for the day.

Thank you very much for your time and attention.

CHAIRMAN LASKEY: Thank you very much.

Before we begin the FDA\'s presentation, we\'ll let you folks come up
for air. That was a breathtaking presentation. Thank you.

Are there any burning questions from the panel for any of the
presenters. Again, recall that we\'ll have more opportunity to query
them this afternoon, but are there any major outstanding glaring point?

I had one. For Dr. Greenberg. Could you just go over the number screened
and the numbers enrolled just to give us a handle on the generalized
ability of these results. You would up with 200 in the pivotal trial.
But how many were screened? How many before you go to the 200?

DR. GREENBERG: You\'re asking specifically about screening logs at the
institutions that we\'re enrolling patients?

CHAIRMAN LASKEY: Correct. How many did you have to sort through before
you got your 200 patients?

DR. GREENBERG: I\'m not 100 percent certain as to how many patients were
on the screening logs. We can find that out for you.

CHAIRMAN LASKEY: Okay. I\'ll bring that up this afternoon.

If not, then we\'re again ahead of schedule. Congratulations

DR. NORMAND: So I just wanted to ask something about the \-- and I
don\'t know maybe this could wait until later in the day. But people are
seeing a propensity score analyses, and I just want to find out a little
more about that in terms of the actual analyses that were done.

DR. FEARNOT: I\'d be glad to address that.

The propensity score analysis is, I\'m sure you understand, is an
approach developed by Rubin in the last 2 decades and others that
handled data from various control arms that were not identical in terms
of a demographic and other parameters. And it is one method of
simulating what might have happened given that the trial was randomized.

What we did in this case was we identified the major parameters in
demographics in patient co-morbidities and in anatomic differences. We
took that large risk and we developed from that a propensity score for
the patients in the standard list and the surgical arms.

Once this propensity score or these covariates were identified, we then
developed this score from those covariates that were significant so each
patient had a score.

After we had the score for each patient, we reanalyzed the results using
multi-variate \-- just a regression with that score as a co-variate or
one of the factors. And we also looked at Mantel-Haenszel results.

Both of those two approaches for each of the parameters we looked at
resulted in the same statistical outcome as our unadjusted result. That
gave us a lot of confidence that the potential differences between the
standard risk and the surgical group were not significant in the
determination of the statistical outcome for any of those variates.

DR. NORMAND: Okay. Thanks.

CHAIRMAN LASKEY: Sorry. Dr. Aziz.

DR. AZIZ: Looking at the data that was presented, about 46 percent of
the patients had general anesthesia during implantation. What were the
criteria that was used for sort of putting patients under the general
anesthesia versus doing it with GA?

DR. GREENBERG: There were no criteria defined for what type of
anesthesia each patient should undergo. It was really left to the
discretion of the treating physician and protocol of whatever center
they were enrolled at.

CHAIRMAN LASKEY: All right. Let\'s forge on here, and let\'s begin with
the FDA\'s presentation, please.

MS. ABEL: I\'d love to.

Good morning. I\'m Dorothy Abel, and I\'m the co-lead reviewer on this
PM with Doyle Gantt. We\'re members of the Circulatory Devices Branch of
the Division of Cardiovascular Devices.

In order to ensure that we have appropriate expertise to evaluate all
the information provided in the PMA, we do have review teams, and
there\'s a listing of the review teams for you here.

Paul Chandeysson and Gary Kamer will be presenting some summaries of
their reviews following me.

As Dr. Chuter had described to you, we\'re actually looking at an entire
product line here, that there are several different components involved
with this device. And so it\'s a little bit unique in terms of all the
various implants and their associated delivery catheters that are go
with the different implants.

The unique aspects of this PMA is that this device utilizes suprarenal
fixation, whereas other approved endovascular grafts are implanted
infrarenal. There are various configurations as well as multi-sizes in
the product line. In all there are 94 components.

The deliver is indicated for isolated iliac aneurysms, that is in
addition to the abdominal aortic aneurysms with and without iliac
involvement as the other approved products are labeled for.

There have been device integrity identified in preclinical and clinical
evaluations, and that\'s been a lot of the focus of our review of the
device.

I won\'t be describing in detail any of the clinical information.
You\'ve already seen that from Dr. Greenberg, but I do want to
acknowledge that the majority of our review was focused on the 30 day
and the 12 month clinical study results from the U.S. But there are
additional clinical studies that, though we have heard from the sponsor,
weren\'t actually studies conducted to demonstrate safety and
effectiveness for the U.S. approval process, it certainly does give us a
lot of additional information in support of the product. The
Australasian study that has 291 patients at 16 clinical centers in
Australia and New Zealand. There\'s the additional 24 month follow-up
study from the U.S. pivotal study that you\'ve heard about. The
continued access study, currently has 193 standard risk patients
enrolled, 143 high risk patients enrolled. There have been 15 additional
female standard risk patients enrolled. And there are 14 patients that
were treated under the compassionate use and emergency use provisions.

The worldwide marketing experience has included additional follow-up on
170 patients who initially were treated under the Australasian study.
And some of that follow-up is out to 6 years.

The Eurostar Registry at the time of the PMA submission had 828 patients
treated at 45 clinical centers in Europe. The number has since increased
to somewhere around 928.

There\'s also the Australian Safety and Efficacy Registry of the New
Interventional Procedures-Surgical Registry, and that is a post-market
registry that involved the treatment of 515 patients conducted by the
Australian government.

The synopsis of our clinical review is that all clarification and
additional information requested during our review has been provided and
the review process continues. The company will continue to follow
patients out to 5 years, and they will be providing results from that
follow-up to physicians and FDA on a yearly basis.

Data are not available for treatment of isolated iliac aneurysms,
however, we believe this indication could still be considered.

No studies have been designed to compare the effect of suprarenal versus
infrarenal fixation on renal function. However, the data that are
available do not demonstrate a concern. And there\'s a large amount of
clinical data available for this device.

The clinical and statistical reviews of this PMA have been provided to
the panel, and Dr. Chandeysoon and Mr. Kamer will present additional
information.

The preclinical review summary, basically the review of the
biocompatiblity in vivo animal studies, manufacturing and sterilization
information, including packaging and shelf life, have been completed and
there are not outstanding issues regarding these parts of the PMA.
Additional information regarding the preclinical in vitro studies for
the device modification you saw with the additional sutures has been
received and the review process is ongoing.

A lot of our review did focus on the device integrity issues. And in
order to fully characterize the potential for problems with device
integrity over time and any associated clinical implications, we asked
the sponsor to clearly describe and analyze all available data related
to device integrity. This included bench testing, animal data, clinical
data and explant analyses to evaluate corrosion, stent fracture, barb
separation, suture breaks and graft material wear.

The sponsor\'s presentations have appropriately described the
information available to assess device integrity. The descriptions and
analyses regarding device integrity have also been provided to the
panel.

There have been no clinical sequelae associated with corrosion, stent
fracture, and single-barb and double-barb separations. There is a
potential for solder loss due to corrosion, however, the lose in solder
is not anticipated to be greater than 50 percent over ten years, and
there is a redundancy in the design intended to provide additional
protection from migration as a result of barb slippage due to solder
loss.

Stents are not expected to fracture under normal conditions when the
device is used is used in accordance with the IFU. Barb separations are
an anticipated event for this device, however, the barb design is
considered by the sponsor to be adequate under normal clinical
conditions and there is a redundancy in design intended to provide
additional protection from migration as a result of barb separation.

Suture breaks resulting in suprarenal stent detachment have been
reported in five cases worldwide and the device has been modified in an
attempt to address this issue.

Graft material wear has not been observed to be a clinical problem.

Appropriate patient selection may reduce the risk of device integrity,
problems.

And finally, period imaging follow-up is necessary for identification of
device integrity issues and any potentially associated complications to
allow for timely intervention to avoid serious clinical sequelae.

There have been design changes that have taken place over time, as Dr.
Chuter described. The flexibility in the bifurcated region has been
increased to reduce the likelihood of stent fracture. The number,
positioning and method of attachment to the stent of the barbs on the
suprarenal stent have been modified to reduce the likelihood of
migration.

Stents are now attached to the outside of the graft instead of the
inside to reduce graft wear and to make a smooth inner lumen.

And finally, and this has taken place since they finished enrollment in
the pivotal study, the number of sutures holding the components of the
device together have been increased to minimize the potential for
separation of the suprarenal stent. And this is being evaluated with
preclinical evaluation. We have not asked that any additional clinical
information be provided to look at this change.

In review, there is extensive clinical information available for the
Zenith Endovascular Graft. The reports of device integrity observations
are complete. Although some devices will have integrity problems after
implantation, adequate information has been provided to define the risk
and to allow for a determination regarding safety and effectiveness.

In conclusion, all FDA requests for additional information have been
satisfied. The issues identified by the review team as warranting
discussion are outlined in the questions for the panel.

Thank you.

Dr. Chandeysson will now present his full review of the clinical review.

DR. CHANDEYSSON: Good morning.

My name is Paul Chandeysson, and I\'m the FDA clinical reviewer for the
pre-market approval application for the Cook endovascular graft.

This submission is supported by clinical data from two prospective
clinical studies sponsored by Cook and from two independent patient
registries.

The primary data set is from the U.S. study sponsored by Cook and
conducted under IDE. It is a controlled clinical trial which enrolled
432 patients at 15 centers in the United States. A total of 352 patients
were treated with the Cook endovascular graft for aortic-iliac
aneurysms. Fifty-two patients were enrolled during a phase one roll-in
study for the training of the implantation teams. Two hundred standard
surgical risk patients and 100 high surgical risk patients were treated
in the pivotal phase two. An additional 80 patients were treated
surgically as a control during phase two.

These control patients met the general inclusion criteria for the
standard risk patients, but their vascular anatomy was not suitable for
endovascular treatment.

Patient follow-up at one and 6 months, and annually after implantation.
One year follow-up date have been submitted and patient follow-up is
continuing.

The required sample size for this clinical study was based on the
primary hypotheses that the morbidity index in the standard risk
patients treated with the Cook endovascular graft is less than in
patients treated surgically. The morbidity index is a composite endpoint
calculated at one month follow-up from 31 types of adverse events in
seven organ system categories.

Secondary equivalence hypotheses for patients survival at 30 days and at
one year, and treatment success at one year were also stated. Treatment
success requires continued procedure success and no aneurysm enlargement
beyond 5 millimeters. A secondary superiority hypotheses was also stated
for clinical utility endpoint, such as blood usage and hospital stay
times.

The sponsor presented data comparing the demographic factors and
co-morbidities of the patients in the various treatment groups. They
performed a statistical comparison between the standard risk
endovascular group and the surgical control group. Statistically
significant differences in wage, weight and the proportion of patients
with hypertension, alcohol abuse and smoking were found. On average, the
patients in the surgical control group were younger and weighed less
than the patients in the standard risk endovascular group. But the
surgical group had a higher percentage of patients with hypertension,
alcohol abuse and smoking.

The proportion of women patients was also higher in the surgical control
group, but the difference was not statistically significant. Nor the
differences in the demographic factors or the co-morbidities were found
to be statistically significant.

The number of patient deaths is shown as early deaths within 30 days,
late deaths after 30 days but within one year, and total deaths within
one year. The number of patients in the standard risk group is 199
because one patient could not be treated with the endovascular device.
The numbers in parentheses are the percent of the number of patients in
each treatment group.

The one early patient death in the roll-in group was due to an autopsy
confirmed MI sustained by an 80 year old with a history of coronary
artery disease. The MI occurred about 16 hours after an uneventful
implantation procedure.

The one early patient death in the standard risk endovascular group
occurred to a 71 year old man with extensive history of cardiac disease
who died at home, 28 days after the procedure. According to the
investigative site and the death certificate, the death was due to
atherosclerotic heart disease, but no autopsy was done.

The two early deaths in the surgical control group include a 68 year old
man who died of hemorrhage during the procedure and a 65 year old man
who died of mesenteric ischemia 24 hours after the procedure.

The two patient in the high risk endovascular group include a 66 year
old man who died on day 7 after having undergone an emergency
hemicolectomy for ischemic colitis. The other early death in the high
risk patient group occurred 11 days after the procedure and was due to
an MI and pulmonary embolus.

The numbers of late patient death in the roll-in and standard
endovascular group are much larger than the one late death in the
surgical control group. However, the clinical events committee found
that none of the five late patient deaths in the roll-in group and none
of the six late patient deaths in the standard risk group were related
to the endovascular procedure. On the other hand, the one late patient
death in the surgical group occurred from surgical complications 51 days
after the initial surgery.

Three of the late patient deaths in the high risk group were found to be
related to the procedure, including one patient who died do to rupture
of the suprarenal abdominal aorta and two patients who died in renal
failure resulting from the implantation procedure. While the renal
failure was not the immediate cause of death, the committee felt that
the renal failure began a chain of events which eventually resulted in
death.

The patient survival at 30 days and one year in the standard risk
endovascular arm of the study appears to be at least equivalent to the
patient survival in the surgical control arm. This fulfills two of the
secondary hypotheses of the study.

Adverse event data are presented in terms of the morbidity index and by
organ system category. The morbidity index is a composite endpoint
calculated at one month of follow-up with 31 types of adverse events in
the 7 organ systems shown.

The sponsor calculated that the difference in the morbidity index
between the standard risk endovascular patients and the surgical control
patients is statistically significant. Therefore the primary hypotheses
of the study was fulfilled. Sponsor also calculated that the differences
in the rates of cardiovascular, pulmonary, renal and vascular adverse
events were also statistically significant and favor the endovascular
treatment. The rate of renal complications in the standard risk
endovascular group is less than in the surgical control group,
suggesting that the suprarenal fixation of the endovascular does not
adversely effect the renal function of the patients.

The trend of the rates in bowel, wound and neurological adverse events
also favored the endovascular treatment. However, the differences were
not statistically significant.

The effectiveness data for the endovascular patients includes
implantation success rate, the rates of endoleak, aneurysm rupture,
surgical conversion and other secondary procedures. Loss of patency and
aneurysm growth by more than five millimeters. All but one of the 352
endovascular patients were successfully implanted with the device
resulting in a successful implantation rate o 99.7 percent.

Most of the endovascular leaks which persisted to 12 months were due to
retrograde blood flow in branch arteries of aneurysm. One aneurysm in a
high surgical risk patient ruptured at 222 days after the procedure due
to a distal endoleak. The patient survived conversion to surgical
treatment.

Two standard surgical risk patients were converted to surgery, one for a
persistent endoleak, one for rupture of a suprarenal aortic aneurysm.
Other adjunctive procedures were done in a total of 36 patients. The
majority of these were done to treat persistent endoleaks, but some
procedures were done to treat loss of patency in the leg portions of the
endovascular graft.

Only 3 patients were found to have aneurysms which increased by size of
more than 5 millimeter at one year.

Treatment success at one year evaluated as continued procedure success
with no aneurysm enlargement beyond 5 millimeters was found to be 89
percent in the standard risk endovascular group compared to 85 percent
in the surgical control group. Although they are not complete for all
patients, the available data indicate that treatment success at one year
was at least equivalent to surgery fulfilling another secondary
hypotheses of the study.

The sponsor also compared various clinical utility endpoints such as
blood usage and hospital stay times between the standard endovascular
group and the surgical treatment arm. They found these endpoints favored
the endovascular treatment and the differences were reported to be
statistically significant. This fulfills another secondary hypotheses of
this study.

The other prospective clinical study sponsored by Cook was conducted at
16 clinical centers in Australia and New Zealand. It was a prospective
single arm study of 290 patients with aneurysms of the abdominal aorta
with or without involvement of the iliac arteries. One patient with an
isolated aneurysm of the iliac artery was also included. The average age
of the patients was 75 years and the majority of the patients were ASA
Class 3.

The patients were followed at 6 weeks, 6 months and annually after the
implantation procedure. Follow-up was reported through June of 1999 when
some of the patients were beyond 3 years of follow-up. Imaging data were
primarily CT data.

The implantation was successful in all but 4 patients who were converted
to open surgical treatment. This results in an implantation success rate
of 98.6 percent. Three of the four conversions to surgery were due to
difficulty in gaining access to the arterial system, the fourth was due
to difficulty in recovering the delivery device.

Six patients died within 30 days of the procedure. There were four
cardiac deaths, one stroke and one patient died of a ruptured aneurysm
on post-operative day 6. The patient had been thrombocytopenic during
and after the procedure and the endovascular apparently never
effectively excluded the aneurysm.

Two other aneurysms ruptured. One aneurysm ruptured at 850 days and was
fatal. The other was successfully treated with an aortal iliac
endovascular graft about 3 years after the initial treatment.

There were three late conversions to surgery, one due to persistent
endoleak and two to migration of the device. The device was redesigned
to increase the number of barbs as a result of the migrations.

The Center for Health Services Research of the Department of Public
Health of Western Australia has followed 170 of the 291 patients who
were enrolled in the Australasian study. As of July, 2001, 98 patients
have been followed through the two to three year post-operative period.
Thirty-eight patients through 3 to 4 years. Nineteen patients through 4
to 5 patients. And 6 patients through 5 to 6 years. The results were
reported to the sponsor.

Three fatal aneurysm ruptures were reported, two in the 2 to 3 year
interval and one in the 3 to 4 interval. Three patients underwent late
conversion to surgery, two in the 2 to 3 year interval and one in the 4
to 5 year interval.

A statistical analysis of the survival from death due to rupture of the
aneurysm was compared to the survival from death due to any cause. The
results have been presented in survival curves extending out to 5 years
after implantation. The freedom from death due to aneurysm rupture was
95 percent at 5 years. The freedom from death due to any cause was 50
percent in this cohort of patients.

Although no error bars are shown on the survival curves, the analysis
indicates that the endovascular treatment reduces the chance of death
due to the aneurysm to a small fraction of the chance of death due to
other causes.

Data from the Eurostar Data Registry Center in Eindhoven, the
Netherlands was summarized and procedure and follow-up results for 828
patients treated in Europe with the Cook Endovascular Graft were
submitted. The registry excluded patients with high artery aneurysm. The
majority of the patients were ASA Class 2, Class 3 and 21 percent were
considered unfit for open surgical treatment. Follow-up data to 3 years
were included.

The implantation procedure was not completed in 12 patients. Of these, 5
patients were converted to open surgery. Two were treated with
extra-anatomic bypass and 5 were treated in other ways. Unresolved
stenosis of the graft at implant occurred in an additional five
patients. Counting these 17 patients are implantation failures, the
implant success rate was 97.7 percent.

Thirteen of the patients died before discharge. One patient is reported
to have suffered a rupture of the aneurysm at 12 months. None of the
patients were reported to have undergone late conversion to open
surgical treatments, but 6 patients underwent an extra-anatomic bypass
procedure of some kind.

Additional follow-up data are being collected on the patients who were
treated with the Cook Endovascular Graft under the IDE. Additional
patients are being enrolled and treatment under continuous access
supplement to the IDE.

A registry study of 50 women patients treated with the device is being
conducted under the IDEA. Additional patients treated with the device
are being entered into the Eurostar Registry and data from separate
registries of patients treated with the device in France and Australia
are being submitted.

Two prospective clinical studies and two independent patient registries
provide a large amount of clinical data. A fairly large number of
patients have been treated. Longer term follow-up of some of the
patients is available, and some high surgical risk patients are
included. The data indicate the treatment of abdominal aortic aneurysm
with the Cook Zenith Endovascular Graft offers a high rate of successful
implantation and lower operative mortality.

All of the study hypotheses were met.

Rupture of the aneurysm after treatment is fairly rare, but the
possibility of rupture is not eliminated. Continued follow-up with the
patients is necessary, probably for the life of the patient. Additional
endovascular treatment maybe be necessary during follow-up and
conversion to open surgical treatment is needed in some cases.

Suprarenal fixation of the Cook Zenith Endovascular Graft did not appear
to cause an excess of renal failure.

Mr. Kamer will now discuss is statistical review.

MR. KAMER: Good morning. I\'m Gary Kamer. I\'m the statistician for the
Food and Drug Administration who reviewed this original submission.

At the time of the review of the first PMA review, we noticed of course
the effectiveness of the device had been shown throughout with
significant P values. All of the endpoints that were pre-specified were
met. However, there seemed to be some problem \-- two problems we
noticed. One was the clinical study design.

Now, we did agree to the clinical study design. But this particular \--
the reason I wanted to bring this up is this clinical study design did
result in the need for some additional analysis, which I\'ll discuss
more so why that occurred.

Secondly, the excess all-cause late mortality, 31 to 365 days, which was
not a predetermined clinical endpoint. The two endpoints for zero to 30
days and then zero to 1 year. But we did notice that there was an excess
with this.

The clinical study design, first of all, was a nonrandomized study. A
study that requires treatment and control patients to be anatomically
different. This could have been avoided. It would have taken longer to
run a study, but there are positive and negatives that I would to
present here.

Also, treatment arm comparability issues, of course, arise from this.

The results indicated excess all-cause late mortality for treatment
patients. For the standard risk graft patients, 6 of 199, the 3 percent
of the patients died. With the control patients it was 1 out of 80, 1.3
percent. Now, these numbers were originally a little higher than this
for standard risk, and that\'s what caught my attention particularly.
They were, I think at one point, listed as 10 out of 199. But those were
later found to be after one year, following one year, I believe. I may
be wrong with that. I think that\'s \-- they differently \-- it was
changed to six.

Odds ratio for this is 2.456. The difference is \-- the point estimate
for difference is 1.77 percent with a 95 percent two-tailed confidence
in that we\'re going for a minus 5.85 to 9.27 percent.

The mortality concerns we had were, of course, that they all-cause late
mortality endpoint showed a numerically greater mortality rate than the
standard risk graft patients in a study that was not powered to detect
this. Again, it was not significant, but it was larger.

Also that was combined with numerically high mortality rates for roll-in
and high risk graft patients. So we thought of how to look at this, and
there are three ways that you can adjust for possible difference in the
treatment groups. One is by in a state that it\'s nonrandomized in
particular. One is a patient-by-patient clinical evaluation of mortality
risk factors. And I think that has been done by Paul Chandeysson.

Covariate analysis including logistical regression. The sponsor did
provide some of this in their initial submissions. And they did not \--
the analysis did not seem to really show too much of a difference
between treatment groups nor \-- so the impact was questionable. So we
\-- I requested a propensity score analysis, which I hope might be able
to be a little more sensitive and illustrate whether or not there was a
difference between the two treatment groups. And this would be based on
characteristics, primarily.

So the propensity score analysis \-- first of all, propensity score is
the conditional probability of a patient receiving the active treatment
in this case, rather than the control, given the collection of observed
covariates.

The purpose of the propensity score analysis is to attempt to
simultaneously balance many covariates in the two treatment groups of a
nonrandomized study, thus trying to reduce bias.

Specifically, the propensity score model was built by the sponsor using
backward stepwise regression, a procedure which is often used. The
resulting \-- and this was run apparently or developed at least by
2/7/03 model utilized ten variables and a constant term. Two hundred and
seventy patients were to have been grouped into five quintiles, that
would be 54 per quintile, based on the propensity score.

A Mantel-Haenszel chi-square test was used to test for treatment
differences along with apparently a regression model also, I believe.

The propensity score analysis on the 2/7/03 propensity score analysis
suggest that an imbalance of covariates between the two treatment groups
may contribute somewhat to the excess all-cause late mortality. However,
we noticed in that analysis that 37 patients were missing and the type
of analysis that was used, either one of the two analysis, would
themselves fail to adjust appropriately for these missing patients. They
do not consider censoring at all.

So in speaking with the sponsor concerning this issue, I received today
a new propensity score analysis, which I can\'t comment on completely. I
don\'t \-- from what I could tell, there were no tremendous differences
or differences that were quantitative rather than qualitative. They did
not \-- I don\'t think we were speaking of qualitative differences to
begin with. We just had some nervousness about \-- I did about the
mortality rates that were not significantly different.

But still we have 21 additional patients with 12 months survival were
reported and analyzed in this new analysis. Still 16 were excluded from
the Mantel-Haenszel test and the other test due to no device being
implanted to begin with in one patient, explant withdrawal lost to
follow-up, etcetera.

The upshot of this is that I\'m not sure, first of all, how far back the
analysis \-- the other analysis we\'ve seen go. Due they include these
21 patients, etcetera? So this could invalidate some of the previous
statistical analysis involving by number the proportions, if these
patients weren\'t censored, weren\'t in this. And, of course, the
propensity score analysis it does effect.

The propensity score analysis should address both censored data and
non-inferiority design issues where appropriate. This is another issue,
too, the non-inferiority hypothesis. Now I\'m not sure how you would do
this. Obviously, I don\'t think it\'s going to be that trivial. It may
also be something that again will be quantitative more than qualitative.
I don\'t think it will have a huge impact, but for correctness,
appropriateness of doing this method, I believe it has to do that. Which
would mean some type of a \--whatever method it has to deal with
censored data. And also has to deal with inferiority hypotheses and
Mantel-Haenszel. Neither method used actually does that.

In summary, given the need for conducting \-- I think there was a need
for it, appropriately, less than optimally designed study, the property
use of propensity score analysis may provide study results adjusted for
measured covariates.

Neither clinical evaluation, standard covariate analysis nor propensity
score analysis is capable of adjusting for non-measured covariates or
the existence of an anatomical difference between the treatment groups;
a properly-designed randomized study would have been necessary to
accomplish this.

A proper propensity score analysis should be considered along with the
patient-by-patient clinical evaluation and covariate analysis in
assessing the safety and effectiveness of this device.

These analysis should be evaluated in terms of their providing similar
results, their limitations and their comprehensiveness. The analysis
provided by the sponsor should be revised if we\'re talking about using
it, the numbers being correct, to reflect the hypotheses being tested
and the censored nature of the data.

Thank you very much.

CHAIRMAN LASKEY: Mr. Kamer, I just have a question. Your last series of
points are obviously a bit distressing and confusing for me, and
probably for the other panel members.

Can you give us your best guesstimate either in a Bayesian sense or just
a practical sense how likely it is that a 70 percent of production in
the endpoint, which drives this study and its attractiveness, how likely
is that to go away given all of the caveats?

MR. KAMER: Well, I believe that probably the best \-- you\'re talking
now about the concern for the mortality. And I believe the best
procedure from what I\'ve seen to get at what really happened is
probably the clinical. I think the statistical serves a purpose, should
go the same direction of propensity score analysis. I was concerned
about covariate \-- the analysis of covariate was not really showing \--
or covariates were not really showing a difference between the two
groups. So we felt we\'d try to \-- I don\'t believe this is going to
impact greatly. But for purposes of doing it appropriately and correctly
is what we\'re doing.

CHAIRMAN LASKEY: Do panelists have any questions for the agency
presenters?

DR. FERGUSON: Dr. Ferguson.

As a panel member, I need some clarification because it\'s my sense that
we were supposed to judge the performance of the graft on the basis of
the American study. And I\'d really like to be informed as to why all of
the data from the foreign lands has been included. Not that it\'s not
important data, but is that part of our \-- are we supposed to take that
into account as we make the judgments? That\'s for the FDA?

DR. ZUCKERMAN: I think your primary analysis should rely on the PMA
American data. The additional data should be looked upon as adjunctive
data supplying adjunctive safety information, etcetera. But both the
sponsor and FDA indicated the adjunctive nature of that data and the way
that it should be consequently looked at.

MS. ABEL: Dorothy Abel.

I\'d just like to add that I think the reason we had some additional
focus on the data outside the pivotal study was to look at device
integrity. And we felt that it was important to look at the potential
implants, that there may any information on, to try to really focus on
that issue.

So, I think probably the information is just supportive with respect to
other rates in terms of the technical success and that sort of thing.
But it just gives us more data points for that particular issue.

CHAIRMAN LASKEY: Panelists have any other questions? Yes?

DR. MAISEL: Was there any subgroup analysis performed, perhaps by the
propensity score, to look at the excess mortality in the roll-in group
compared to the standard risk group?

I realize you did the analysis to look at the devise versus the standard
surgical. Is there an explanation for the excess mortality in the
roll-in group?

CHAIRMAN LASKEY: Actually, the question was put to the agency, but if
they want to respond and then \--

MR. KAMER: We did not do the propensity score analysis. It was presented
to us by the sponsor. It was requested. So you\'ll have to ask that
question of them to get the answer. But we have not received any, and we
would expect, of course anticipate those two \-- you were speaking of
high risk and which, the standard risk?

DR. MAISEL: The roll-in versus the standard risk?

MR. KAMER: Oh, the roll-in versus standard risk. You might expect a
difference there. But that might be due to things that are \-- the very
fact that they are in roll-in patients rather than the other
characteristics at baseline.

But, do you have any \-- if you wish to?

CHAIRMAN LASKEY: We\'re a tad out of sequence here. If you\'d like to
answer that now or you may come back to it this afternoon. But go right
ahead, please.

DR. FEARNOT: In assessing the mortality in the roll-in group, it\'s
important to recognize that the roll-in group included both patients
with standard pathophysiology as well as patients with high risk
pathophysiology. So it would be expected that the mortality rate in that
group would be somewhere in between the standard risk group and the high
risk group, which it was.

I think that\'s the mortality rates in both the standard risk group and
the high risk group are close to what would be expected. And the roll-in
because it\'s a mix between the two, is also in between those as
expected. There are no surprises in terms of those numbers.

CHAIRMAN LASKEY: I would just remind everyone, this is the point where
the statisticians appropriately weigh in and caution us against doing
these sort of post hoc subgroup analyses for really small events. So I
think all of this should be taken in stride, including the mortality
issue needs to be discussed further. But as pointed out, it was not any
component of an endpoint.

We are in the unenviable or enviable position of being way ahead of
schedule. We can either break for lunch or we can proceed with the lead
reviewers presenting their reviews. What does the panel prefer?

Too early for lunch. I second that. And the audience? We need a break.

How about a ten minute break. It\'s now 11:20. We\'ll resume at 11:30
and we\'ll have one or perhaps two of the presenters. Thank you.

(Whereupon, at 11:24 a.m. a recess until 11:40 a.m.)

CHAIRMAN LASKEY: Okay. Thank you for your flexibility. And we\'ll
continue on with the lead reviewers presentations, beginning with \-- or
reviews beginning with Dr. Comerota. Tony?

DR. COMEROTA: Thank you, Warren.

I\'ve had the privilege to review the volumes of material that was
supplied to the panel members by the FDA, which included the submission
from Cook, Incorporated. And I had an in depth report prepared. However,
the presentations by Dr. Greenberg and by Dr. Chandeysoon, as well as
Dorothy Abel and the statistician were complete. They were to the point
and many of the comments that I had prepared would be redundant in
reviewing the information.

So within the past 30 minutes I\'ve revised my comments for the panel.
And I\'ve decided to, in a stepwise fashion, address the issues that
were posed to us as panel members and posed to me as a reviewer to
address. So I\'m going to take these in stepwise fashion and integrate
some of the information that has been presented and has been provided in
the reports to answer these important questions.

First of all, we were asked to evaluate the clinical study results
relative to the safety endpoints and do these clinical study results
provide a reasonable assurance of safety in the intended population for
which they\'re proposed?

And, obviously, mortality data play into that answer. There\'s 432
patients, as has been summarized from 15 centers, 80 patients in a
surgical arm and 351 patients who actually received the device in the
United States as part of this pivotal trial. And we\'ve seen the
mortality rates, we\'ve seen the death rates at 30 days, .5 percent in
the Zenith standard risk endovascular graft, 2.5 percent in the standard
surgical group. Looking at the Zenith high risk group, the mortality was
2 percent at 30 days and in the Zenith roll-in group, 1.9 percent.

And if we look at all-cause mortality at one year, there was no
significant difference, although the issue of increased late deaths in
the endovascular group was appropriately raised.

So I think the answer to the first question is yes, the clinical study
did confirm that there is reasonable assurance of safety in the intended
population for which it is to be used.

And then, of course, safety issues aside, then there is effectiveness or
efficacy in that same population. And if we look at efficacy, there are
a number of issues involved. There the definitions for technical
success, there were the definitions of procedural success and then there
was the definition of treatment success at 12 months. And they\'re
clearly defined in the information. They were defined previously by the
presenters very nicely, and I won\'t review those definitions. But as
has been observed, the treatment success in the standard risk of the
Zenith group, the 9.5 percent treatment success in the surgical group
was 99 percent, and then the treatment success in the high risk group
and the roll-in group for the Zenith Endo Graft was a 100 percent in
each group.

And as we drop down to procedural success, there\'s 95 percent in the
standard risk group, 86 percent in the high risk Zenith group and 91
percent in the roll-in group compared to 88 percent in the surgical
group.

And if we look at overall treatment success at 12 months, 89 percent in
the standard risk group, 70 percent in the high risk Zenith group and 87
percent in the roll-in compared to 85 percent in the surgical risk
group.

So looking at technical success, procedural success, overall treatment
success and then if we look at the absence of aneurysm rupture, you can
see aneurysm rupture was exceptionally rare, and look at shrinkage of
aneurysm. If one is to think that that might be good, and there\'s some
question as to whether significant shrinkage is actually good, at least
with some grafts. But if we look at shrinkage of aneurysm which occurred
in a majority of the patients, the answer to that question is yes, this
endograft does provide reasonable assurance of effectiveness as defined
by the hypotheses in the study.

But then the concern of suprarenal fixation rises and we were asked to
comment on whether suprarenal fixation offered safety and effectiveness
for this specific design. And, of course, looking into the specific
issues of renal failure in patients who have had endografts, those
patients moving on to dialysis, those patients moving on to renal artery
occlusion, one sees that the numbers of the patients suffering those
complications in the endograft population were small. 1.4 percent of the
endografted patients suffered a renal infarction compared to 1.3 percent
in the surgical group. Those patients having suffering progressive renal
dysfunction requiring dialysis was observed in 1.3 percent in the
surgical patients and 1.7 percent in the endografted patients. However,
in fairness, one needs to appreciate that in the standard risk endograft
population, only .5 percent of the patients went on to dialysis.

Five of the 6 endografted patients that ultimately required dialysis
were in the high risk group. And two of those patients, their baseline
creatinine exceeded 4 at the time of initial treatment. So I think that
the answer to the question of whether suprarenal fixation for this
endograft is safe and is effective, I think the answer to that question
is yes, it is safe and effective. And the clinical data and the clinical
follow-up support that conclusion.

Another question is whether we can provide or whether the data provides
reasonable assurance of the safety and effectiveness of the components
of the device. And the way I arrive at the answer to that question is to
look at the number of type III endoleaks that occur once the device is
successfully implanted and whether there were any clinical sequelae
device failure unto itself. And there were no type III endoleaks. And
there was no serious clinical sequelae of graft failure, per se. So I
think the answer to that question is yes, there is reasonable clinical
assurance of the safety of the efficacy of the components.

And then we needed to address the observations of the benchtop
mechanical stress/strain studies and the issues of corrosion, barb
separation, stent fracture, suture breaks and graft material wear and
tear.

Interestingly, on the in vivo testing there was a description of full
thickness abrasion. Well, full thickness abrasion to me means a hole in
the graft. And a hole in the graft was reported in 90 percent of the
grafts that were studied on the benchtop model. Ninety percent meaning
27 of 30. And these were tear-like abrasions, basically 3 to 10
millimeters in length. They were longitudinal in nature. And, obviously,
this raises a good deal of concern. However, when one looks at the
clinical data involved in the patients in the relatively large number of
patients involved in the study, and in the absence of type III
endoleaks, it raises the question in my mind as whether the benchtop
mechanical stress/strain studies are these in vitro studies are actually
a greater stress on the graft than would be experienced by this material
after it\'s implanted in a human.

I don\'t know the answer to that question. I\'m not a mechanical
engineer. But logic might dictate that it is a more severe stress/strain
model on this graft material because in the explanted devices, not only
in this country but also from the additional data from other studies, it
fails to document this high degree of device erosion or abrasion.

So, I think that the clinical effects observed do not match the concern
that at least was raised in my mind from the benchtop stress/strain
models.

And then we were asked to comment upon whether the indications for the
graft use in this patient population were appropriate and whether it was
appropriate to include treatment of isolated iliac artery aneurysms. And
it raises a number of questions. And then we were asked also to comment
on any additional issues that we had.

And so I\'m going to combine these last three issues into a number of
comments.

One was these patients were entered who had 4 centimeter abdominal
aortic aneurysms and larger. We know from actual history studies, we
know from prospective randomized trials that have been published of late
that there is no survival benefit in the management of patients treated
operatively who have small aortic aneurysms. However, we choose to
define small less than 5 centimeters or less than 5? centimeters.

To date there have been no data published demonstrating that
endografting improves survival over surgical care. I have a great
concern that many patients may well be treated with small aneurysms who
will not enjoy the benefit of improved survival, but yet run the risk of
potential complications from management, not only from endografting but
from surgical care as long as we continue to include small aneurysms in
prospective studies such as this without making appropriate provisions.
So that\'s a generic comments.

If we step back, on one of the assumptions coming into this trial, was
that the mortality, the complication rate and the mortality in surgical
patients was not related to the anatomy, but rather related to
associated medical comorbidities. And I would take issue with that
assumption. I\'m not sure that it\'s correct.

I would suggest that the anatomy of the aneurysm may well have an impact
on the surgical complication rate and may well have an impact on
operative mortality.

In this trial, 19 percent of the patients who were operated upon had
super renal clamping. That\'s far in excess of most clinical series of
the surgical management of infrarenal abdominal aortic aneurysms or
abdominally aortic aneurysms where generally about 5 percent of the
patients require infrarenal clamping.

So this is anatomy biased surgical group, and I wonder if the sponsors
have information regarding the complication rate, the operative
morbidity and the mortality rate in those patients who had suprarenal
clamping versus infrarenal clamping to support the assumption that the
anatomy did not come into play in terms of the associated morbidity,
mortality. But I think it might.

And if the information is not readily available, albeit a very small
group of patients, 80, it would be an interesting look.

The need to follow patients longer than 12 months is important. The need
to follow patients longer than 24 months is important. We\'ve seen that
in the small number of patients who have been followed for up to 4
years, the rupture rate of endografts in that group of patients at 3 to
4 years is somewhere between 3 and 5 percent. This does not occur with
patients who have been operated upon. So I think long term follow-up is
important. Therefore, late imaging of these grafts in an ongoing fashion
is important. And in the series late imaging at 24 months fell to about
60 to 65 percent of the patients entered into the trial, the patients
who were available for imaging at the 24 month time period. So we\'re
missing a great deal of patients. And if we\'re facing a graft migration
rate that\'s increasing over time, and if we\'re facing an increasing
rupture rate over time, the importance of long term follow-up then is
underscored by the observational data which we have.

We also know from other clinical experiences, other endograft experience
as we\'re following patients out to 3 years and more, if the patient has
the endograft inserted at 3 years and more, the risk of migration in
selected series is up to 20 percent at 3 years. And we know from the
presentations that this may increase the risk of a type I endoleak. So
therefore, the emphasis on long term follow-up is important.

Basically those are my comments.

I think that the important issues that were asked of this clinical trial
were met, the primary hypotheses and the secondary hypotheses tested
were met. The data were objectively and concisely presented. The safety
appears firm in early observation. And the effectiveness appears firm in
early observation.

We do wonder if the increased late mortality, that is 30 days and
beyond, compared to the surgical group is real and the need to follow
the surgical patients beyond 12 months then is underscored. Because if
those lines continue to separate but we don\'t know what those lines are
in the surgical group, we\'re going to miss the opportunity to test
them.

Thank you, Mr. Chairman.

CHAIRMAN LASKEY: Thanks, Tony.

Did you want to specifically formulate a question for the sponsor or was
your whole presentation comment plus question? Do you want them to come
to the table and answer your query as to the suprarenal clamping issue
or \--

DR. COMEROTA: If those data are available, it would be good to have that
information. If it\'s available. I realize that we may be putting you on
the spot. But someone like Roy Greenberg, I would expect would have that
data at his fingertips.

DR. GREEN: I would defer that question.

Thank you. I\'d like to address the issue that Dr. Comerota raises,
because as reading the results of the operative arm, one might get the
impression that there was a significant bias against open repair because
of the shift of the clamp site to patients who have shorter necks. And
therefore, adversely impact the results of open repair.

So if I could have slide 32, please, of the backups.

I think it\'s very important to recognize a couple of things. That the
clamping position chosen by anatomy and surgeon \-- the clamping
position was chosen by surgical preference. And if you look at the list
of surgical investigators, many of them have at one point in their
career been under my influence. And I, as you know, have written quite a
bit about the safety of suprarenal clamping when done in an elective
setting. And there are ample data to show that the danger of open repair
is often related to disease in the infrarenal and perirenal neck that
can be avoided by putting the clamp up higher.

So I believe, and I think many of the surgical investigators believe,
that there really is no morbidity/mortality difference in clamp site.
But we looked at those data to assure the panel that that was in fact
the case.

Can I have the next slide, please.

If you separate out the infrarenal and suprarenal clamp patients, as
we\'ve done in these columns, and look at 30 day mortality, aneurysm
related mortality for zero to 12 months and all-cause mortality, one
clearly sees that there were no adverse events in the suprarenal group.
All the events happen to be in the infrarenal group.

Can I have the next slide, please.

If you look at freedom from morbidity, and in this analysis we actually
took out the patients that had suprarenal clamps, that the freedom from
morbidity remains highly significantly significant in benefit of the
Zenith standard risk group. Total freedom from morbidity, 80 percent, 65
percent.

And then if we look at the morbidity score adjusted for patients only
who had standard operation with infrarenal clamping, there remains a
benefit to the Zenith standard risk group.

The last slide, please.

Much of the size difference that you\'re seeing relates to a simple fact
of design of the trial. If one elected to operate on a patient with a
larger aneurysm, and I think most of us who are dealing with aneurysms
larger than 7 centimeters would want that patient operated on promptly,
the problem with enrolling a patient in the endograft arm was that it
was a 6 week process. And so I think there was a drift to the larger
diameter aneurysm because of that very fact of patient safety.

Thank you.

CHAIRMAN LASKEY: All right.

DR. COMEROTA: Believe it or not, I didn\'t even Dick was going to be
here this afternoon. I didn\'t set him up. This was just an honest
question.

CHAIRMAN LASKEY: You might want to stay there. Dr. Roberts wants to
precede her review with a question.

DR. ROBERTS: Yes. I don\'t know that this is the way \-- I know which is
better for me to ask a similar question that was going to be part of my
review or to go through my review and then ask it, but I think since
you\'re up there, I\'ll go ahead and ask it.

One of the questions that I have, though, is that my understanding, and
grant that I\'m only an interventional radiologist, but my understanding
is is that suprarenal clamping there\'s at least some increased
potential for embolization into the kidneys. You know, I\'m assuming
that you put ties or something around to try and protect them. But at
least my understanding is there\'s at least some increased risk of that.

Now, when I look at the morbidities that are here in terms of renal
risk, it seems to be considerably higher in the surgical group. My
question was going to be can \-- have you at all separated out those
patients in the surgical group that had an increase renal problems and
is there any association \-- I grant it\'s only, I guess, 8 patients.
I\'m not really sure about how this is broken down, whether it\'s eight
events or eight patients, but I\'m assuming it\'s eight patients. Do you
have any idea how many of those were suprarenal versus infrarenal?

DR. GREEN: Well, first, can I challenge your assumption?

DR. ROBERTS: Okay. That\'s fine.

DR. GREEN: I think the sole reason in this patient population to use a
suprarenal clamp is to prevent the very event you\'re talking about by
clamping a disease perirenal aorta whether it\'s above or below the
renal artery, in the proximity to atherosclerotic disease, clearly one
risks the athero-embolic phenomenon. And so the choice of clamp position
is to select a normal segment of aorta. And when one does that, the
results are comparable. The important thing is to select the normal site
on the aorta to clamp.

There were o renal events related to the clamp site in the trial.

DR. ROBERTS: So all of the events were when it was clamped infrarenally
or they were divided between the two, or \--

DR. GREEN: I think I\'m going to let Roy deal with that issue, because
there\'ll be a slide for it.

DR. ROBERTS: Okay. The other question, maybe because it\'s kind of
related, is do you have a feeling for the patients that underwent
surgery, were most of them because of a short neck or because of iliac
disease that prevented \-- was felt to probably prevent the placement of
the device?

DR. GREEN: Are you talking now about the\--

DR. ROBERTS: Of the surgical group.

DR. GREEN: Of the surgical group why a person would opt for surgery?

DR. ROBERTS: Yes. Why \--

DR. GREEN: In this particular trial?

DR. ROBERTS: Yes, because my understanding is that all of these patients
that were in the surgical group were patients who had an anatomic reason
that they weren\'t candidates for the graft. Is that right? The
endograft? And if so, what was the reason?

DR. GREEN: It many cases it was preference of the surgeon, preference of
the patient. Time, as I said. Anatomy was one. But one entry criteria.

DR. ROBERTS: Okay. All right. I guess that wasn\'t clear, because it
sounded like anatomy was supposed to be the major criteria.

DR. GREEN: It was a criterion.

DR. ROBERTS: I see.

DR. COMEROTA: Dick, before you leave, you showed on the last slide that
the operated patients had many more larger aneurysms than the
endografted patients had many more smaller aneurysms. And there\'s any
number of series that have documented associated morbidity with size.
And you probably have another slide to follow this \--

DR. GREEN: I actually don\'t, Tony.

DR. COMEROTA: You don\'t? But what about that potential bias that the
patients with the larger aneurysms may have greater morbidity compared
to patients with smaller aneurysms?

DR. GREEN: There clearly are studies to suggest that. However, it\'s
another thing that I personally don\'t believe and we could not find any
correlation in this trial related to size.

CHAIRMAN LASKEY: Dr. Roberts, do you want to do your \--

DR. ROBERTS: Sure. Sure. If you have some information \--

DR. GREENBERG: Well, just as a point of clarification with respect to
the suprarenal versus infrarenal, there was one patient who was treated
with the suprarenal clamp who developed a renal artery occlusion later
on. But there no other renal events associated with the suprarenal or
\--

DR. ROBERTS: And do you have a feeling \-- because again I would have to
run through this to find it, but my understanding is that the reason \--
I mean it\'s written, at least \-- I don\'t know \-- but it was \-- that
this was supposed to be for anatomic differences.

DR. GREENBERG: Yes, you\'re correct in your interpretation of the
protocol. However, you have to realize when you define anatomic
differences, there are several subjective variables.

DR. ROBERTS: Okay.

DR. GREENBERG: Such as iliac tortuosity.

DR. ROBERTS: Right.

DR. GREENBERG: Or the ability to deliver a device.

DR. ROBERTS: Right.

DR. GREENBERG: Or successfully achieve a fixation and seal.

So these subjective things become, for lack of a better word, the
gestalt of the treating physician. And consequently it\'s really left up
to a decision between the patient and the physician. But the protocol is
correct. You are correct in your interpretation of the protocol.

DR. ROBERTS: Okay. The reason I think is it probably becomes a little
bit important in that it maybe gives us an idea of, someone asked
earlier, if you have the logs as to the people that didn\'t get included
into the trial. I was just thinking, it might give us some information
in terms of were most of these because they were short necks or were
they because there was tortuosity or stenosis in the iliacs that would
preclude that and, you know, that may be important in terms of the
labeling to let people know you need to pay attention to those
particular aspects.

DR. GREENBERG: Yes. We do have an anatomic breakdown of the different
groups in terms of surgery versus standard risk. And also the size.

Can you put up 160.

I mean so much of this is subjective and there were a lot of differences
between the groups. However, the overlap between the different groups
were all significant as well, which allowed for the propensity analysis
to correct for things like aneurysm size.

But just to not divert from the last slide that Dr. Green showed, these
are the endovascular aneurysm sizes that you can see there\'s really a
large percentage of the aneurysms, the vast majority of these aneurysms
were over 5 centimeter in all of the endovascular arms, which I think is
important. So it wasn\'t simply a size criterion in that nature.

DR. COMEROTA: Roy, were there patients who were operated upon during the
time of this trial that were not included in the surgical group?

DR. GREENBERG: You mean the institution centers?

DR. COMEROTA: In the participating centers?

DR. GREENBERG: The criteria \-- you know, I\'m not 100 percent sure
about that. Because I\'m sure that there were aneurysm patients operated
on during the course of the trial on patients where they wouldn\'t
consent to be a surgical control. They didn\'t want to participate in
research.

Our criteria for the surgical control patients were that they came back
for follow-up at 30 days with a CT scan and at one year for a CT scan.
And I know personally I had a number of patients who didn\'t want to do
that, being surgical control.

So the short answer to your question is yes, but the reason for that is
not, I think, because of a preference in terms of operating technique.

DR. ROBERTS: Sorry.

Well, I am going to continue being very brief.

First of all, I would like to thank the FDA and the sponsors, but
particularly the FDA for putting together a very nice panel pack. I
think, you know, having participated in this now for \-- I think this is
the fourth one of these, it gets better and better. And I think that the
comments get shorter and shorter. Obviously, we\'re making progress
here.

I will do the same thing, and most of what I have to say I think has
also been said. And so I\'ll be probably even briefer than Tony was in
terms of my comments on this. And I will also just go through the FDA
questions and make my comments with regards to those issues.

I think in terms of the safety, my feeling is is that the information
that\'s been presented would led me to believe that this has in fact
been shown to be safe with the extent of what we know about these
endografts and the need for close follow-up of these patients. And I
think the appropriateness of picking the right patients to undergo this
procedure. So I think in terms of that it has been shown to have a
reasonable assurance of safety.

I will say in terms of the statistical comments with regards to the
mortality, I think that there\'s, quite frankly, such a small number
that it\'s very difficult for me to figure out what the statistics mean
on this. And it seems to me that some of this going back and trying to
remassage the data probably doesn\'t get us very far. And I think if we
look at the actual events and the actual patients, I think that gives us
a much better idea.

There, obviously, as you go through this group of patients, these are
very sick people, a lot of them. And many of them are dying from lung
cancer or prostate cancer, something else that is not associated with
the aneurysm. So I think in terms of the safety, by in large, I think it
looks like the data that\'s been presented would support that.

In terms of the effectiveness, I certainly agree with the previous
presenter that this looks like it\'s effective. Again, I think we need
to continue to have good follow-up on these patients because I think
that we don\'t know as well as we should, although the one thing that is
I think sort of comforting in the fact that we do have these Australian
figures. And I really support that data being brought in, because I
think at least it gives us some longer term data which is not easily
available in the United States. And from the Australian information and
the Eurostar data, at least it gives us some idea of the longer term
device safety and effectiveness.

In terms of the suprarenal fixation, it seems like it\'s okay. This is
certainly one of the things that I was looking at, and I\'m sure that
the agency was looking at, was because of the uniqueness of this graft
which does, I think, allow us perhaps to treat patients more
effectively, it was whether or not there was going to be a problem with
this. My concern had been, I think a little bit allayed now, that
perhaps the larger number of patients that had a problem in the surgical
group might have been secondary to the clamping or something else going
on in the surgical group which actually made it look like the graft
group was doing better because the surgical group looked worse. But
perhaps that not important. And, again, a small number of patients. So
it makes it hard to know for sure.

The other question with regards to the modular components, I think that
there certainly are a large number of components. It sounds like they
work together reasonably well. I suspect that we\'re going \-- you know,
that\'s something that we\'re going to sort out as we get more of these
devices placed. And I think that one of the things that the sponsor
perhaps needs to be very careful about doing is to educate people well
in terms of which components to use where and when. And that may help
with this.

I do think that the large number of components will, in fact, allow
better treatment of patients because you\'ll be able to make them more
compatible to each person\'s anatomy. So I think actually there may be
some real benefits in terms of that.

I don\'t really have much to say in terms of the device integrity. I
think that the issue of whether or not the bench testing is actually
worse on these caps then putting them in the patient may, in fact, be
something that we need to think about. Again, I think that the longer
terms data would suggest that, by in large, this looks like it\'s a
minimal problem. But, again, would deserve careful follow-up.

In terms of the labeling, I would certainly agree was one of my comments
that I don\'t know that having in the labeling treating an abdominally
aortic aneurysm of 4 centimeters is really appropriate. First of all,
there\'s not very much data on those patients. There\'s only a few
patients that fall into that group. And I think that really the standard
treatment is 54 centimeters. And until we have data that shows that in
some kind of a study that 4 centimeter aneurysms need to be treated,
that goes against the data that there is.

I think that I would be not inclined to allow it for something less than
5 centimeters.

In terms of the iliac aneurysm, that\'s a real problem. And I\'d like to
know how many iliac aneurysm \-- isolated iliac aneurysms were treated.
As far as I could find there was only one. Is there more? I guess I\'ll
ask that question right off the bat. Because I didn\'t see that we had
any data on that.

DR. GREENBERG: Yes, there\'s one isolated iliac aneurysm in the pivotal
trial. Two in continued access. And I think the incidence was around 26
percent of aorta iliac aneurysms.

DR. ROBERTS: Well, aortic iliac aneurysms are, to me, a little bit
different. To say that we\'re going to have this indication for use for
a person with an isolated iliac aneurysm, I don\'t honestly think we
have data to support that. I\'m not saying that this wouldn\'t be a good
way to treat it, it may be. But I\'m not sure that we\'ve got the data
to say that.

The other thing that I really am concerned about is the business of the
MRI exams. I don\'t know how to get around that. I mean, certainly
there\'s plenty of warnings in all of the labeling and in the patient
brochure regarding the use of MRI. But I worry a little bit about this.
There\'s a lot of people. A lot of these people that are going to get
these devices are people that have atherosclerotic disease involving
their carotids, and are going to end up with the need for evaluation of
those carotids. And I saw that at least one patient had an MRI, I
assume, without any bad things happening to that patient. I assume it
wasn\'t the one where the barbs all came apart. But I don\'t know how to
get around this, but I wonder if it would be worth at some point trying
to do some animal testing to see whether really in vivo this really
makes a difference. Because I suspect there are going to be a number of
patients that end up in the MRI unit, whether or not they are supposed
to be there or not. And not to have their aortas studied, but to have
another part of their body studied. And I think it would be good to get
some information on that.

The other thing I would suggest in the labeling is that there be some
kind of a suggestive follow-up imaging scheme to alert physicians about
what would be an appropriate way to follow these patients up. It\'s very
vague in there. And I think that one of the things that I\'m very
concerned about is that patients and physicians don\'t recognize the
importance of following these patients up. And that\'s something that I
would like to see.

The patient brochure I thought was quite good. But one of the things
that somehow \-- and there certainly is a statement in there about the
fact that these patients should realize that they need to be followed
up, that it\'s very important. But I would almost like to see that
stressed a little bit more. And certainly in the labeling have some kind
of suggested follow-up scheme perhaps put in there.

And finally, in terms of the training, the one thing that I didn\'t see
in there that there was going to be any kind of proctoring in a real
time, you know, with the person whose putting these in. Certainly the
people who have been putting them in won\'t be needing to do that. But I
think for the newer people there is the training program, but then that
could be considerably different than doing it on your own. And
particularly if there are people, and there may not be, but if there are
individuals who have not put in any of the other types of grafts, I
think it\'s something we ought to consider whether or not there\'d be
some kind of proctoring for those.

And then I think the post-market study look like it\'s pretty
appropriate. And I think congruent with what some of the other grafts
are undergoing.

And so those are my comments.

CHAIRMAN LASKEY: Thanks very much, Anne.

It\'s 12:20. I suggest we break for lunch and we resume at 1:20 for the
remainder of the panel\'s queries.

I want to thank everybody again for their conciseness and clarity.

(Whereupon, at 12:22 p.m. the panel was adjourned to reconvene this same
day at 1:25 p.m.)

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

1:25 p.m.

CHAIRMAN LASKEY: All right. Welcome back.

I\'d like to call us back to order. Thank you for your promptness. And
so far so good with the schedule. We\'re doing very, very well.

And I\'d like to resume the afternoon session by having the other panel
members query the sponsor.

Let\'s start with Dr. Nicholas.

DR. NICHOLAS: I have several questions for the sponsors.

Some of them have been addressed, but there\'s two specifically
regarding the indications and that in the protocol you indicated the
issue of angulation of both the neck and the stents, the uncovered
stent. And that\'s not listed as one of your indications, yet it was
listed as part of the protocol. Do you still support that as being a
consideration or did that not turn out to be a factor in the success of
the stenting procedure? That was one.

The observation about aneurysms less than 5.5 centimeters not
benefitting, as to best we know right now, is again a concern about \--
in that case about the labeling.

The third question I have is related to the converter and occluder. Is
there any more data that you have available to you that isn\'t in the
material that we received. Because it seems they weren\'t used very
often in the pivotal study to really give it an evaluation that we could
be comfortable with.

And then my final one is one probably of ignorance. In the treatment of
isolated iliac aneurysms are you installing the entire graft or a
segment of the graft?

Thank you.

CHAIRMAN LASKEY: So do you wish that they approach the podium and
answer?

DR. NICHOLAS: If they would, please.

CHAIRMAN LASKEY: Whoever is comfortable with the question here. Yes, if
you could just approach the podium and respond in sequence.

DR. NORMAND: Can they sit at the table?

CHAIRMAN LASKEY: Apparently they can\'t.

DR. GREENBERG: Okay. Sorry. We\'re all a little confused about protocol
here.

With respect to angulation, I think we agree with you and there will be
some limitation of angulation probably that matches the study protocol
and the labeling, which seems like a reasonable thing.

Our intention with small aneurysms was not to advocate the treatment of
small aneurysm, nor was the study designed to determine which patients\'
aneurysms should be treated in. Instead, we left this decision to the
treating physicians. And a small aneurysm in one person is not
necessarily small in other person. And in our desire to approve women
and so forth, they have a much higher rupture rate with small aneurysms
according to the two randomized \-- the one randomized trial that really
looked at a significant number of women. So we did not want to eliminate
those patients. Still, the vast majority of our aneurysms were greater
than 5 centimeters, as we showed earlier.

The isolated iliac artery issue is an issue where we put the entire
graft in. It\'s not a single part of the graft, it\'s the entire graft.
And that\'s really because in an isolated iliac aneurysm usually
there\'s not a lot of proximal neck of good healthy common iliac artery.
So we\'re actually treating it in an identical way to an aortic aneurysm
by putting a bifurcated graft in with two limbs that cover the iliac
arteries.

And Dr. Chuter is going to answer the question regarding additional data
on the ancillary components.

DR. CHUTER: Thank you.

They selected me to answer this one because I think I\'m the only person
who used an occluder in the study.

The reason I\'m asking for slide 130 is that it describes the use of
devices and the numbers of devices that have been used outside the
United States. And there is a reasonably extensive use of this
component, partly because more are able to \-- uni-iliac versions are
used.

Just on a general level, though, you know the features that this
component has many often shared the fabric, the stent, many aspects of
the delivery are shared with other devices. So you can, perhaps,
extrapolate some of the experience from the other devices.

All right. If you look down the column on the right here, you have a
worldwide total of devices used. And as we mentioned earlier, there\'s
in excess of 10,000 total devices. Of the those the occluder was used in
390 and the aorta uni-iliac converter used in 790. And you might wonder
how could you use a converter without occluder. Well, some of those
patients probably had already occluded iliac arteries or those iliac
arteries were occluded by other means.

But I think that you can see that there\'s a fairly extensive use of
that device.

DR. NICHOLAS: I have one other question for the sponsors. Regarding
access site morbidity, was there any unique problems with either
reconstructions necessary or infection beyond other access for other
endografts?

DR. GREENBERG: You\'re referring to issues specific to the ilio-femoral
vessels during excess?

DR. NICHOLAS: Yes.

DR. GREENBERG: The incidence of access site complication was extremely
low. And I think that\'s manifest by two factors. One is that in the
pivotal study arm there were only four \-- there were only actual three
interventions done for iliac problems. Two occlusions and one with a
stent. I don\'t think any of those interventions pertain to any
dissection or whatnot on the iliac vessel. And there was probably one
complication that was directly related to the access site, which is the
single patient that underwent fem-tib bypass after the procedure. I
think it was around 10 days after the procedure they underwent a fem-tib
bypass for lower extremities. But other than that, the ABIs were
followed and remained unchanged during that 12 month period.

CHAIRMAN LASKEY: Thank you.

Tom?

DR. FERGUSON: First, let me congratulate the individuals from Cook and
also from the FDA. I think this has been an absolutely superb, superbly
presented device.

And I only have one question which relates, I guess, to my ignorance.
There are 106 components as I read in our material that comprise what a
surgeon can have available for placing these devices. I guess my
question relates to are there that many different sizes and different
configurations to prevent endoleaks or does the endoleak rate have any
relationship to this? Because I can envision if this gets out for
general use, that perhaps an individual, a surgeon is not going to have
a full panoply of devices available, number of devices available and he
might use one that\'s not accurately sized to what you would consider
proper? Is that a reasonable question? Probably not.

DR. CHUTER: I think it\'s a reasonable question. The answer is that the
devices aren\'t intended to sit on the shelf and it\'s not intended that
one surgeon would have an inventory of devices that he could use under
any circumstances. That inventory would have to be huge, as you
suggested.

If we could just have up the slide, I think number 17 would illustrate
the point.

There are a wide variety of arterial dimensions in patients who have
aneurysm disease. And that is one \-- I should say this, but it\'s one
of the problems with the currently available devices is that they
provide a very limited range of sizes.

If you look here at the pre-procedure neck diameters in the endovascular
group, which is this group here, you see they extend over quite a wide
range.

Now studies both in Europe and in this country have suggested that the
rate of type I endo leak, that is endoleak around the top end of the
stent graft, is related to the degree of oversizing. And naturally you
can see a line that comes down and goes to a minimum level up to 20
percent oversizing. In this study we required 10 to 15 percent. But you
wouldn\'t even be able to do that with the currently available devices
in a large number of these patients.

In fact, 65 percent of the devices used in this study just the proximal
component were 28 millimeters and larger. So you do need to have a wide
range of sizes if you\'re going to achieve optimal sizing. And we could
look at the other aspects of this. But it\'s these anatomic variables
change independently, which is one of the advantages of the modular
approach is that you can vary them independently. But to do that, you
need to have a wide range.

DR. FERGUSON: Thank you. That\'s all.

CHAIRMAN LASKEY: Dr. Maisel?

DR. MAISEL: Thank you.

I just have a couple of questions. The first regards reinstrumentation
of the iliac artery and the aorta. Are there any counter indications or
issues regarding other procedures that might need to be performed in
these patients, such as cardiac catheterization with passing wires or
regaining vascular access?

My second question, in the instruction for use it\'s mentioned, I think
appropriately, that patients should be regularly monitored following
implantation of the graft. Specifically how often do you think the
patient should be evaluated and by what means do you think should be
used for this evaluation?

And then the third question just regards a clarification on the
training. It\'s mentioned that physicians will have \"hands on\" use of
the graft at their training session. Will this be as a primary operator
during implantation?

DR. GREENBERG: There really no contraindications to reintervention
through the graft. So if you need to do a cardiac catheterization or
what have you subsequently, it\'s been done in a number of patients. I
couldn\'t tell you exactly how many, but it\'s never been reported to us
as a problem.

With respect to the follow-up algorithm, that\'s a very good question
and we\'re probably not prepared to answer that for all endograft
patients. However, what we can tell you is that our recommendations with
respect to the follow-up algorithm are the same as those in the study
protocol, which would be a minimum of one CT scan within the first 30
days, post-discharge or pre-discharge, 30 days, 6 months, one year and
then annually thereafter unless there\'s evidence to suggest that
something else is going on or something concerning is happening, such as
the presence of an endoleak or any device integrity issue that may
compromise the result.

Was there another question?

DR. MAISEL: The training issue regarding the hands on experience.

DR. GREENBERG: Yes. During the training course we expect that the
physicians that are being trained would each deploy a minimum of one
device.

DR. MAISEL: Thank you.

CHAIRMAN LASKEY: Dr. Normand?

DR. NORMAND: Thank you. And I also want to congratulate the sponsor as
well as the FDA for a very well presented information.

I have three general questions. And the first question relates to the
multi-centeredness. This is a prospective observational multi-center
study. And we heard from the sponsors at the beginning that there is a
physician effect; that physicians matter, and there was some role in the
training. So I was compelled by the fact that, indeed, there was, and so
I wanted to get some clarification regarding the poolability of the
information across the centers. And specifically where you powered to
test for the poolability of that?

The second question relates to the balance of the observables in the
surgical and treated group, let me refer to them that way. We saw from
the slides that there were some observed differences between the two
groups. Part of the time I want to say it looks like the surgical group
is sicker and part of the time I want to say maybe they\'re not. The
treated groups were older, yet the surgical group had more
comorbidities. So one could hypothesize which direction that would weigh
things, but it\'s difficult to hypothesize.

So I wanted to get some sense from you in terms of your propensity score
analysis. Obviously, I know what a propensity score analysis is, and
there are many ways to conduct a propensity score analysis. And I feel
that there wasn\'t enough information, at least in terms of what I read
and moreover what I saw today, to: (a) determine whether or not from
your propensity score analysis that the observables were at least
balanced and there are standard procedures to look at whether they\'ve
not been balanced or not. And that would be really incumbent to see
that. And that relates as well as to whether or not if they\'re
balanced, you could wipe out or you could change signs in terms of your
primary endpoint as well.

So the information you did present us had to do with some differences
and some not nondifference as the secondary and the primary endpoint.
However, when there are observed differences and if you haven\'t
convinced people that you\'ve balanced on those observed differences,
you can actually switch effects. And so I just wanted to get more
information regarding exactly how the propensity score analysis is done;
weighted, stratified, matched, balancing things such as that.

And the final point I wanted to bring forth, and it\'s probably related
both to the FDA as well as to the sponsor, you included patients. They
were selected on observables. I had misunderstood the materials, and I
regret that in terms of I thought the anatomy restriction was really a
hard one, but it sounds like there was some subjectivity included into
that group that went to the surgical side. And so there are a lot of
things that now we\'re seeing that, unfortunately, they\'re not balanced
and then you rightfully did a propensity score analysis, you did another
analysis to try and adjust for those observed confounders. But my
question then as put forth to you, is do you actually have enough power
with \-- because I assume, and please correct me if I\'m wrong, but your
sample size was not based on an adjusted analysis. It was based probably
on a two sample test and not an adjusted analysis.

So did you have enough power to conduct your statistical tests after
observing the fact that they were differences, at least observed
differences and you had to subsequently adjust for those observed
differences?

Thank you.

DR. FEARNOT: Your first question was about poolability and the fact that
there\'s a multi-center trial, that are physician effects. In this
multi-center study these physicians were, as you might expect,
experienced physicians in endovascular and interventional procedures.
And so there wasn\'t an observed effect between the centers.

There was poolability analysis done, the study was evaluated in terms of
outcomes. Was there any observed differences, you know,
center-to-center? As you know, that\'s somewhat complicated by the fact
that the enrollment at each center is not the same and in some centers
there were few patients and in other centers there were more.

But considering that, in the inferences drawn from the study, the
poolability criteria that we set were met, doesn\'t mean there weren\'t
differences of various types. But in the way we set up the statistics to
evaluate poolability, those in fact were met.

The balance of observables, use of a propensity score, you\'re correct.
There were a number of different observables, obviously, that at the
beginning of the study we recognized would be different. These are the
anatomical criteria. And so those we knew would not be balanced. And we
tried to use the concept that medical risk or the pathophysiology would
be the basis of making the groups reasonably comparable.

You\'ve also pointed out correctly that despite having the
pathophysiologic criteria equal, we did end up with some differences,
such as age and weight and they played in the favor of the \-- you know,
like they were older and weighed more in the standard or standard risk
group. And so your comments are accurate in stating that some of the
variables were on one side, others were on the other side. It was for
that reason that we put all of those variables that differed in the
propensity analysis.

We did not do a specific test to look at scoring, the scoring balance.
It was reasonable, but we didn\'t do that.

We did try to make sure that there was in fact patients for both groups
in each of the strata, as you expect in a propensity score analysis. And
there was significant overlap in all of these variables to allow that.
Every one of the variables we looked at had substantial overlap, even
though there were statistical differences.

And with regard to the fact that some of the variables in anatomical
measurements were softer than others, that\'s true. The main ones,
however, were hard. Those are aneurysm size that was measured by the
independent core lab with quite a rigorous protocol. The softer ones
such as thrombus and shape are not as important in this cohort as the
hard anatomical diameters.

So in the propensity score analysis you see the largest effects in terms
of the hard numbers of diameter \-- in terms of diameter, neck diameter
and aneurysm diameter. So those drive the effects, if you will. For that
reason we were not concerned about the softer ones and the variabilities
that be associated with observational determinations.

Let me try to address the power calculation for the propensity score
analysis. You are correct, we did not power the study for an adjusted
outcome. What we did do, though, is after we looked at the adjusted
outcome, we looked at the significance of those values before and after
adjustment. And in the cases of the superiority measures, they were, if
you will, so significant greater than .001 in both cases of morbidity
and in the case of clinical utility, that we felt like it wasn\'t on the
borderline.

When we finished the propensity analysis, those results were also quite
significant. So you\'d have to ask the question what\'s the probability
of it switching sides. And it was our impression that because they were
so significant, that the probability of switching sides or having a
major effect or miss something small was very low. And that\'s why we
had confidence in the propensity score analysis even though it wasn\'t
powered at the beginning of the study for that adjusted analysis.

The propensity score analysis was requested by the FDA after the
protocol was put in place and approved by everyone. So while it wasn\'t
powered for that prospectively, I think the results still are
reasonable.

Did I answer your questions?

DR. NORMAND: Well, except for the \-- I guess the secondly finding where
you found no difference in the mortality between the two groups.

DR. FEARNOT: Yes.

DR. NORMAND: So that\'s a null result. So my concern really is so there
were two issues. One is for our primary endpoint you\'re indicating that
the adjusted analysis, you still get the same results?

DR. FEARNOT: Right.

DR. NORMAND: And so the question about power also relates to the result
where you found no difference.

DR. FEARNOT: Right.

DR. NORMAND: And so the question, it begs the question did you have
enough power to actually find a difference there? And it\'s not a fair
question to ask you right now. I mean, it\'s not an easy population to
do. But one thing you may want to think about, or I would think about,
is did you actually have enough power to do an adjusted analysis to find
a difference for that secondary?

DR. FEARNOT: Right. As you know, when we used Blackwelder that ends up
with a significance. And both the unadjusted and the adjusted
Blackwelder results were similar. So both of them that were significant
in terms of the Blackwelder and therefore, you know, the inference is
that they\'re equivalent.

So I think in that sense since we did achieve a significant effect in
the Blackwelder equation, I\'m not sure the power is, you know, as
important as if you were to be looking at trying to prove the null
hypotheses and asking what the beta was, if you know what I mean?

DR. NORMAND: Yes.

DR. FEARNOT: It make sense?

DR. NORMAND: Yes, I guess sort of.

And then I\'ll just have one more comment just to speed along.

Just the one other thing I think you didn\'t answer had to do with \--
and I\'m sorry, it\'s the last one \-- has to do with the type of
analysis you conducted for the propensity score. Was it a progression,
was it a stratified, was it a weighed and all of these matter in terms
of stratified analysis.

I am doubting whether or not you had enough of events in those tables to
see anything, but it\'s only now if you could just elaborate in terms of
the actual analysis?

DR. FEARNOT: I\'d be absolutely pleased to.

The parameters were equally weighted in the morbidity index. And they
were equally weighted because the morbidity index is not a validated
index, if you will, and so there\'s not a database from which to set
correct weighting that everyone would agree with.

There is history behind the use of these indices.

DR. NORMAND: Well, I think maybe I didn\'t \-- I wasn\'t clear on that
question. I\'m sorry.

DR. FEARNOT: Okay.

DR. NORMAND: I was actually referring to the propensity score analysis
when you actually get the estimated propensity for each patient in the
sample, then you use that propensity score to do an adjusted analysis in
one of several ways.

DR. FEARNOT: Right.

DR. NORMAND: One way to do is to do weight analysis. So I was actually
talking about you did your propensity score analysis.

DR. FEARNOT: Oh, I see.

DR. NORMAND: I completely understand your \-- I\'m sorry. I wasn\'t
clear.

DR. FEARNOT: We took the scoring and we did have the five subclasses.

DR. NORMAND: Stratified?

DR. FEARNOT: Yes.

DR. NORMAND: And you had events in each of those tables?

DR. FEARNOT: Yes, we did.

DR. NORMAND: Okay.

DR. FEARNOT: All tables had events on both groups.

DR. NORMAND: Okay. Thank you.

CHAIRMAN LASKEY: A few quick questions here.

There probably should be a minimum time limit for reinstrumenting the
aorta, so you might want to come up with your best guess for a day, a
week, several weeks for recross to follow-up on Bill\'s question about
catheter instrumentation of things above the diaphragm. I mean, was is
it safe to go back through there? Probably not a day later, but maybe a
week later. These are patients that are likely to need interventions
above the diaphragm, too.

DR. CHUTER: My main concern with reinstrumentation of these devices is
that the potential for hematogenous spread of infection. And I think
that we don\'t know what the time course of that risk is. I think as
time goes by, it probably lessens as a pseudo-interim gets laid time and
you can see that kind of pseudo-interim on the CT scans. But really the
studies have not been done and the events that we\'re trying to prevent
are rare even in the absence of antibiotic prophylaxis. So it\'s hard to
give an answer there.

As regards the dangers of reinstrumenting one of these devices, by in
large, stents are on the outside. Any instrument that passes into the
device is meeting graft material and relatively smooth surface. It
probably would be possible to pass a guidewire through the wall of this
device. But it also is possible to pass a guidewire through the wall of
an artery. I don\'t think there\'s any particular risk associated there.
And I don\'t think there\'s a risk of displacement.

Anybody whose ever put these devices in the wrong place will find out
difficult they are to move once they\'re placed.

So I wouldn\'t necessarily put a reinstrumentation limit on it.

The other aspect is, of course, the access. Most of these procedures are
performed through surgically exposed arteries. And that\'s not a place
you would want to puncture at least for several weeks until some healing
has gone by. And we perhaps should develop some recommendation there.

I think most of these patients who undergo reintervention undergo them
in the hands of a cardiologist, and many of those are getting
reintervened through their upper extremities. And I think that probably
would be my recommendation in the early post-operative period.

CHAIRMAN LASKEY: I would agree with you, but the majority of my
colleagues in my profession would not. People do prefer the leg and
Judkins transfemoral, so that\'s why the question.

In terms of touching up your result with balloon inflation of the stent
graft at the end, if this is a self-expanding stent why do it? What bang
for your buck are you getting? And is there a potential hazard to the
touch up?

DR. CHUTER: I guess as with most things, it\'s a risk benefit. I think
the risk is relatively low. If you pass one of these balloons, and
they\'re fairly large caliber balloons, back into the device and hit a
fold in the fabric or an acute angulation, or whatever else, the first
thing that happens is that the shaft of the balloon buckles and the
sheath pops out of the groin and it\'s not complete. It\'s not that you
move the device. That is not the risk factor.

I have never encountered a situation in which balloon inflation has
caused a major problem, actually, in terms of the placement of the
device. So I think the risk is relatively low.

So then what is the benefit? Well, the first benefit is that the stents
themselves are self-expanding, but that doesn\'t necessarily mean that
all the folds in the fabric are flattened and the apposition to the
surrounding vessels is perfect. And I think the balloon has a role to
play there, particularly in the junctions between components. So
although there is graft fabric to graft fabric of these component
junctions, I think it is enhanced by balloon inflation.

I don\'t think they play a big role in preventing kinking or anything
else, but that the theoretical advantage of an implantation.

And the last one, I don\'t know if this was intentional, but when you
blow the first balloon inflation is performed up at the level of the
proximal stent, the uncovered stent. And the idea is that as the balloon
is being inflated there, if you have any thrombus in the neck, it\'s
being squeezed like toothpaste down into the aneurysm rather than
squeezed like toothpaste up into the renal arteries. So the first
inflation is done up at that level.

And when the balloon is inflated, you can see it bobbing up and down in
the flow stream as it gets hit with the hit arterial pulse, it\'s almost
like a little pile driver sending the barbs into the wall. So although I
describe them as passively deployed, they\'re being deployed by the
force on that balloon. So I think there are advantages to be gained,
yes. And it\'s time consuming, but I do it. I believe it\'s worthwhile.

CHAIRMAN LASKEY: And one final, just please help me understand this
morbidity end point scoring. You have an estimate which is half of the
standard deviation for both the standard risk and the surgical risk, a
lot of scatter. I mean, how did you come up with this number? I just \--
I\'m not quite sure I understand .26 events. That\'s per patient? It\'s
less than one event per patient in each arm and I would have expected at
least an event, if not two in some of the arms. I\'m not sure what this
number is or how you got it, or whether you just added up events and
divided by the end. Just tell me how you got .26 and .92?

DR. GREENBERG: The mean morbidity score?

CHAIRMAN LASKEY: Yes.

DR. GREENBERG: The mean morbidity score was calculated off the index.
And we can put that slide up. The slide with all the variables in the
index, which essentially everything was weighted equally and given a
one. And so each patient accumulated a total of events that occurred to
that patient.

CHAIRMAN LASKEY: That\'s my question. Are these numbers that you have in
table 3.4.6-4, are these events or patients?

DR. GREENBERG: Yes, events.

DR. FEARNOT: The score, if I can drive you through a calculation. First
of all, let me say that most of the patient with endovascular \-- well,
80 percent of the patients with endovascular devices and 57 percent of
the patients with surgical had no events. So those people had zero
events, zero scores.

The rest of those may have had one or two events, three events. So if
you take for the score for each patient, it would be a certain number of
events out of 31 measures. So if they had one event, it would be one out
of 31; that would be their individual score. And then you average those
scores across patients, if you will.

So what it says is that if you take the number of events, there is for
instance in the endovascular .26 events per patient on the average for
endovascular. There is .93 events per patient on the average for
surgical patients.

I know it\'s a mathematical calculation, but \--

CHAIRMAN LASKEY: Well, it\'s arithmetic, so I\'m following you.

DR. FEARNOT: Okay.

CHAIRMAN LASKEY: Okay.

DR. FEARNOT: Does that answer?

CHAIRMAN LASKEY: It\'s still confusing, because what\'s the unit of
analysis? Is it the patient or is it the event and is it the number of
patients that you\'re comparing in the two arms or is it the number of
events in the two arms?

DR. FEARNOT: It\'s the number of events per 31 events averaged across
patients. And the more meaningful clinical measure I think is the number
of patients without any events at all. And they match up with each
other.

CHAIRMAN LASKEY: Generally because of the correlation within patients,
you need to adjust for your \-- when you do the comparisons. Because if
you\'re comparing events which you\'re correlating within patients,
events exceeds the number of patients, then this is somewhat misleading.

DR. FEARNOT: The way the hypotheses was set up prospectively was that we
would look at the proportion of events per patient. All right. We\'ve
asked what percentage of these events happened in a patient. So is it
four out of 31. So these were proportions of events within the index.

And then we looked at patients in the endovascular versus surgical in
terms of the ratio of proportions of events.

It\'s rather mathematical, but \--

CHAIRMAN LASKEY: Yes, I\'m with you. I\'m just \-- I was somewhat
skeptical when I see standard deviations that are so wide. There\'s a
lot of scatter here. And it\'s an invalidated measure. And one just
wonders about those things, that\'s all.

The estimate is pretty rough.

DR. FEARNOT: Yes, I would agree. The significance is pretty high on the
other side. So, you know \--

CHAIRMAN LASKEY: Thank you.

Dr. Kato?

DR. KATO: Thank you.

I\'d like to congratulate also the FDA as well as the sponsor for a
great set of presentations today.

I\'d like to share in Dr. Nicholas\' comments about keeping the
indication for aneurysm intervention around 5 centimeters, but possibly
for those smaller patients using an index of, let\'s say, twice the
normal size of their aorta as an indication for intervention.

My question has to do with the training and certification process.
Clearly based on the types of reviewers that you had reviewing your
clinical studies, you had interventional radiology, vascular surgery,
interventional cardiology which implies that the types of physicians
that will be \-- that your target market is being directed encompasses a
very wide range of people, and it probably even include general surgeons
who are just trained in vascular surgery but don\'t have a vascular
board certification.

So I\'d like to hear a little bit more about an explanation of what that
certification process entails. Does it have an expiration date? Will you
have to be recertified in order to continue putting in these devices, or
do you have to be certified at all to get approval to put in these
devices? Will the certification be accessible from credentially agencies
such as hospital medical staff offices in order to figure out whether or
not if somebody is allowed to do this procedure?

DR. FEARNOT: Let me start off and clarify a few things, and we\'ll have
someone address the more clinical issues.

The training program, obviously, is supported by the company and it\'s
our intent to do whatever we can to convey the information about the
device. I don\'t know that it\'s appropriate for a company to exactly
certify a physician in their ability, but what we can do is qualify them
that they have completed the course.

And in the course we\'ve taken all of the lessons learned from this
clinical experience, not only in the U.S. but internationally, and tried
to incorporate that information into the training program.

As far as physicians having to get certification, there is a comment in
the instructions for use that physicians in order to use this device
need to have interventional training, and that\'s not the interventional
training put on by the company. But they need to be permitted to do
interventional procedures by their local institutions. And so that\'s
addressed in the broader sense of interventional.

DR. KATO: Well, I mean I agree with your comment about qualifying versus
certifying.

DR. FEARNOT: Right.

DR. KATO: However, in your documents you say specifically that
\"CAUTION: Physicians performing the Zenith AAA Endovascular Graft
procedure must be trained in vascular interventional procedures.\"

DR. FEARNOT: Right.

DR. KATO: \"And/or required to have successfully completed additional
training,\" which I agree, \"and certification in the use of the Zenith
AAA Endovascular Graft system.\" So the word certification is in there,
so that\'s why I was \--

DR. FEARNOT: Okay. Maybe we should take that out.

DR. KATO: Just wanted to ask.

DR. FEARNOT: I think that\'s an excellent point. Your point\'s well
taken.

Are you clear on the training program?

DR. KATO: Oh, I\'m very clear on the training program.

DR. FEARNOT: That\'s a very good point. Thank you.

DR. KATO: The other question I had, my last question, is regarding the
complaint handling system. Obviously, as we\'ve discussed today, the
people who undergo \-- the patients who undergo these procedures are
going to have to be followed for a period of time, maybe indefinitely.
One concern is that there must be a reporting system in place so that,
you know, one day if there is, you know, God forbid a graft problem,
that we don\'t hear from the sponsor, you know, \"Well, oops, we had an
operational issue within the company and the message never got through
to us and sorry we\'re late, but all of these people have had
injuries.\" So I\'d like to have a comment about that.

DR. FEARNOT: I think your concern is shared by the company also. The
company does have a complaint processing system, and more actively we,
as you know, have the post-market surveillance in this as well as
international feedback from these other institutions such as those in
Australia and in Europe that actually have more history than we will
have. And that was the basis of gathering the information you saw on the
worldwide experience. So you can see the types of information we gather.

And there are rare cases, there\'s one from here and one from there,
does offer for instance an early warning, if you will, of potential
things to look into and ask the questions are there any other concerns.
And fortunately we don\'t have major concerns with that data so far.

We will continue that. We will continue to gather the information on
this product process internationally in a coordinated way to identify if
there are any concerns, and address them as soon as we can.

DR. KATO: Well, I guess my question was how high up within your
organization does this responsibility go to make sure that this data
which, you know, is really for all of our benefit, not only the
physicians but the patients as well, to learn about problems experienced
by other people. But where does that responsibility lie within the
company in that, you know, to make sure that this is done and complied
with?

DR. FEARNOT: This is real simple. All the way to the top. And we have
everyone at the top of this organization knowledgeable about what\'s
happening. Good question.

CHAIRMAN LASKEY: Dr. Aziz?

DR. AZIZ: Let me also echo the excellent presentation both by the FDA
and the company.

I have a few questions. This concept of a high risk patient, what
exactly do you mean by that? I think it maybe is in the panel, but I
wasn\'t quite able to figure that out. I mean, how are you defining
those patients?

DR. GREENBERG: Okay. Well, while we\'re waiting for it, I\'ll try to
answer it from memory.

We really try to divide the patients into low physiologic risk and high
physiologic risk with respect to their risk of undergoing an open
surgical repair. So we took several studies that have looked at specific
outcome analysis of open surgical repair and broke the patients down in
that regard. So things like age, elevated baseline creatinine, ejection
fraction less than 20 percent, pulmonary function of an FEV 1 less than
1 liter or home oxygen; those sorts of things were all brought up. These
are the list of patients of criteria that patients had to meet to become
high risk patients.

DR. AZIZ: So these are largely comorbid sort of complications rather
than anatomical high risk apart from the significant iliac stenosis?

DR. GREENBERG: Correct.

DR. AZIZ: Okay. I see. Thank you.

In a patient who has the device placed, how soon after this do you think
he or she could have, if they needed an intra-aortic balloon assist
device, that you could use that? Or let\'s say if they have to go for
cardiac surgery, how soon would you say that would be a safe period to
wait for?

DR. GREENBERG: That\'s a very difficult question. Not because of the
access issue, because now we\'re going to put a balloon device into the
aorta.

I\'ve had one patient where we\'ve put an intra-aortic balloon device
in, not in this trial, of an endograft in shortly after the
intervention, probably 2 days or so. And I think you need to make sure
that the balloon portion of the intra-aortic balloon device is up above
any of the stent. And then I think you do what you can, because that\'s
obviously a critical situation.

DR. AZIZ: So would there be a time period, would you say don\'t do it
within 6 weeks, or 2 weeks? And then obviously if you have to do it,
you\'ve got to do it.

DR. GREENBERG: I would just be reluctant to put a time criteria on that
only because when somebody needs an intra-aortic balloon pump, they\'re
pretty far down on the chain of things that we can do.

DR. AZIZ: Well, what about if they had to go for cardiac surgery? Would
you, say if you had a patient with a AAA and also had bad coronary
artery disease, and he was a high risk and you wanted to put one of
these in before you did the CABG, would you like \-- should there be a
certain period of delay?

DR. GREENBERG: Well, this actually a very frequent occurrence in our
institution. Not because our endograft patients require cardiac surgery,
but because patients who are going to undergo transplant that have
aneurysms are required to have an endograft prior to the transplant. And
so that typically happens one to two weeks before the transplant. And
the only reason that the cardiac surgeons have given us for that is that
post-transplant they\'re on such high doses of pressors they\'re
concerned about the aneurysm rupturing.

So we know that it\'s in current practice to undergo cardiac surgery
quite quickly after endograft placement.

DR. AZIZ: And if somebody was on Coumadin at the time, let\'s say
because they had a mechanical valve for some other reason, before you
put the endograft in, I presume you take them off, but you can\'t take
them off Coumadin, but I mean how do you handle that sort of patient?

DR. GREENBERG: Well, I can tell you in my particular practice it depends
on the reason that they\'re on Coumadin for. So if, for example,
they\'re on Coumadin for atrial fibrillation, I may have them stop the
Coumadin 5 days beforehand and then have the procedure. But if they\'re
on Coumadin because they have an aortic prosthetic valve, then I would
admit them, heparinize, then reverse the Coumadin with either the
vitamin K or FFV, depending on the circumstances.

In my practice, I don\'t operate \-- put an endograft in patients that
have INRs greater than 2 or 2?.

DR. AZIZ: Let me ask you while you\'re up there another question. The
question of bowel ischemia in patients that have AAAs both related to
surgery, you know, they obviously talk about the IMA being of \-- of
sort of playing a role. And somebody who has, let\'s say, a higher risk
of getting bowel ischemia, let\'s say if they had had a colectomy and
the Senator had had the colectomy I\'m told, where when you put these
grafts clearly the IMA I\'m sure you\'re occluding that. Is this
something we should worry about or \-- I mean, how would you tackle that
sort of patient?

DR. GREENBERG: Well, in the occlusion criteria, defined as the lack of
indispensable IMA, how we define an indispensable IMA is the subject of
a lot of debate. However, I can tell you with the advent of endovascular
treatment of aneurysms our perception of the IMA has probably done a 180
degree turn.

Where we used to be worried about low flow in the IMA, now we\'re
worried about high flow in the IMA because that would create an
endoleak.

DR. AZIZ: Yes.

DR. GREENBERG: But really the incidence of valve ischemia across all the
endograft trials has been less than one percent, and it\'s extremely
low. And it\'s really had to select which patients would do that.

I agree with you that a patient who has had a colectomy in the past may
be at a higher risk, but it\'s really hard to quantify that.

DR. AZIZ: Okay. Let me just take you to one of the case, actually. Well,
this is a case who ended up having a thoracic early dissection. You
might know this case. I think patient 038008. Essentially it was a 82
year old lady who had a 4.1 centimeter aneurysm who had the stent graft
place properly, but then shortly thereafter had a thoracic aortic
dissection. Is there any peculiar or odd about that or that we should
know about, or that would prevent that sort of catastrophe happening?

DR. GREENBERG: Yes. I think that when we \-- I have seen in my own
experience outside of experience with this trial, three cases of
thoracic dissection following endograft placement, all of them have
related to wire manipulations in the arch of the aorta and not to the
endograft in and of itself.

So these cases I\'ve been able to see where the entry tear is, which is
far remote from the infrarenal protheses, and this relates to training
and instructing people that when they\'re manipulating wires in the
thoracic aorta, particularly the arch, they need to do this under
visualization and when they\'re placing a stiff guidewire there, they do
it through a catheter and not directly.

DR. AZIZ: And if you do see that in the descending thoracic aorta, what
would you advise me done then? Because if you detect it, let\'s say,
with the leakage of dye, I mean should that be further standard or how
would you \-- what should be done?

DR. GREENBERG: I would elect to treat dissections in the presence of
something that\'s pressing me to treat them. So, in other words, if the
true lumen was so compressed the patient was going to develop visceral
or lower extremity ischemia, or if the dissection extended into any of
the branch vessels. Actually I think a stent graft is somewhat
protective in the setting of a dissection for preventing its
propagation. But it very much depends on the circumstance.

DR. AZIZ: I thank you.

CHAIRMAN LASKEY: Our Executive Secretary will now read the FDA questions

EXECUTIVE SECRETARY WOOD: I\'ll give the FDA reviewers just a little bit
of time to bring those questions up on the projector.

I will read each question, and then the panel members may respond.

The first question relates to safety. There was a primary safety
hypothesis and additional analyses to evaluate the safety of the Zenith
Endovascular Graft as follows:

(a): The primary evaluation of safety in the clinical study was based
upon the incidence of adverse events and factors related to morbidity
within 30 days and were assessed as a composite morbidity score that
included 31 specific measures in seven categories: cardiovascular,
pulmonary, renal, bowel, wound, neurologic and vascular.

(b): Technical success included a successfully deployed graft, with
angiographic patency. Procedural success at 30 days and treatment
success 12 months were evaluated, incorporating patency, type I and III
endoleak, aneurysm enlargement, i.e., for treatment success, and serious
adverse events or major complications in their definition. Safety was
also assessed i terms of the incidence of patient mortality at 30 days
and 12 months, with the need for secondary interventions and conversions
to open surgical repair, effects on renal function and device integrity
evaluated over 12 months.

Please comment on whether the results of the clinical study with the
above mentioned safety endpoints provide reasonable assurance of safety
in the intended population.

CHAIRMAN LASKEY: All right. It\'s my role in life to take the lead here,
so I\'ll try and articulate the consensus and like thereof of the
Committee. And please chime in.

In terms of the safety \-- the primary safety endpoint, I think both
reviewers made it clear that that criteria was met, and that therefore
the study did meet its primary endpoint. However, there are some ongoing
concerns with respect to the composite morbidity score. And perhaps Dr.
Normand, do you want to articulate a little bit further?

DR. NORMAND: So, yes, I just want to have a clarification. Because it\'s
key to understanding this.

Is the morbidity \-- why are you dividing by 31? Is it because people
have differential exposure to the possible things? So I may be eligible
for 20 of those measures and I might have had 10 of those 20, let\'s
say, where as somebody else might be eligible for all 31? No. So the
division by 31 is sort of \-- it\'s a nuisance. You don\'t even need to
do it, right? So it\'s a straight count. The dividing by 31 is \-- I
don\'t know why you did it, but for some reason you were talking about
dividing by 31. But everybody has an equal chance for all of the \-- not
an equal chance \-- so then that\'s \--

CHAIRMAN LASKEY: So therefore are we in agreement that they\'ve met
their stated primary hypothesis? It is safe? Okay.

With respect to subparagraph (b) technical success, I didn\'t hear any
ongoing concerns with respect to either the various definitions or
meeting the criteria established by those definitions. There is,
however, some concern albeit it was not a prespecified endpoint about
the catch up, if you will, in mortality between 30 days and 12 months.
The numbers are small, the concern exists, but do we all agree that from
the data in front of us they have certainly met their stated secondary
endpoint hypothesis with respect to 30 day and 12 month mortality? Okay.

Next?

EXECUTIVE SECRETARY WOOD: The next question relates to effectiveness.
There were two secondary effectiveness hypotheses and additional
analyses to evaluate the effectiveness of the Zenith Endovascular Graft,
as follows:

\(a\) Twelve-month treatment success and clinical utility provided the
basis for the effectiveness hypotheses.

\(b\) Additional evidence of device effectiveness is available from
study evaluation of technical success, procedural success, and shrinkage
of aneurysms, and absence of aneurysm rupture and clinically significant
device migration. An evaluation of aneurysm related death also provides
evidence of the effectiveness of the endovascular treatment.

Please comment on whether the results of the clinical study with the
above mentioned endpoints provide reasonable assurance of effectiveness
in the intended population.

CHAIRMAN LASKEY: I think it\'s fair to say that the panel would or is in
agreement with respect to meeting the various secondary endpoints, but
we also agree to a person that 12 months is not an adequate period of
time to certainly look at long term treatment success. That longer
duration follow-up is requisite, which as I hear it, it\'s built into
the surveillance registry.

Are there any other opinions on whether the secondary endpoints were
met?

EXECUTIVE SECRETARY WOOD: The third question. A unique aspect of this
device is the suprarenal fixation. Please comment on whether the results
of the clinical study are adequate to provide reasonable assurance of
the safety and effectiveness of this specific features of the Zenith
Endovascular Graft.

CHAIRMAN LASKEY: Well, group, I think it\'s fair to say that there\'s
not enough data on suprarenal fixation in this study. So, therefore,
that \--

DR. COMEROTA: Warren, I think that \--

DR. ROBERTS: My understanding is all of the patients had suprarenal
fixation.

DR. COMEROTA: Right.

DR. ROBERTS: Is that correct? Yes.

DR. COMEROTA: It\'s a suprarenal fixation device.

DR. ROBERTS: Right.

DR. COMEROTA: So it\'s not a matter of whether suprarenal aneurysms were
being cared for. The aneurysms were infrarenal, but the attachment
extended above the renal arteries. So I think that all of the patients
had that.

CHAIRMAN LASKEY: I stand corrected. So since all the patients had
suprarenal fixation, that would be reasonable pursuant to the safety and
effectiveness? That answers that question.

DR. ZUCKERMAN: Let\'s just clarify that, Warren. So we are referring to
the patients in the device group who all had suprarenal fixation. The
panel was presented with the follow-up renal function data, and there\'s
consensus among the panel members that it\'s adequate to show that
suprarenal fixation for this device is fine.

CHAIRMAN LASKEY: Well, it\'s safe. I mean, there is a finite rate, as I
read it, of post-procedural renal insufficiency, is that \-- but it\'s
acceptable?

DR. COMEROTA: Well, in the standard risk group, renal insufficiency
leading to dialysis occurred in .5 percent. And it was equivalent in the
surgical group versus the overall group of patients having an endograft,
both were under 2 percent at 12 months. So I think the data do
demonstrate safety.

CHAIRMAN LASKEY: Okay. The only other question I would have in that vein
is in patients with preexisting renal insufficiency, is there some
reason to be concerned about patients with preexisting renal
insufficiency and the placement of this device across the kidneys? Was
there not some increased rate, new patients with baseline elevated
creatinines? Should we be concerned with?

DR. COMEROTA: The issue there is that they face a relatively high risk
of progressive renal dysfunction and need for dialysis if they\'re
offered routine operative repair. And, of course, if there are any data
carving out that subset of patients, it would be interesting to see. But
I rather suspect those numbers would be quite small.

DR. FERGUSON: The issue to me is are there any data that have been
presented in the group that would indicate a higher propensity to have
renal complications, whatever the preexisting status of the patient is.
And I could find none. So I would have to say that I don\'t see any
increased risk from the use of the suprarenal fixation. That would be my
opinion.

CHAIRMAN LASKEY: I think the panel agrees.

EXECUTIVE SECRETARY WOOD: Question number four. Another unique aspect of
this device is that there are 94 modular components, i.e., 30 bodies, 42
legs, 6 body extenders, 9 leg extenders, 4 occluders, 3 converters that
may be used in the treatment of patients. Section 3.4.3 of the Clinical
Summary identifies the components used in the U.S. phase II study.
Please comment on whether the clinical data provided are adequate to
provide reasonable assurance of the safety and effectiveness of the
components of the device that fall outside of the size range or
configurations, i.e., the converter and occluder components, of those
used in the study.

CHAIRMAN LASKEY: Well, what I heard was that the modular features of
this device are a major attraction of it that it provides increased
access to the wide spectrum of disease in these patients. So therefore,
having 94 components is a plus for the operator to have increased
flexibility of procedure choice. So I don\'t \-- I think that as
presented, although not every single subset was included in the study,
in which every single modular component was used, I think what we\'ve
seen is a very safe and effective application of this modular device.

Did we want to follow-up on the converter occluder component of this? No
concerns? Yes?

DR. HUGHES: Yes. Allen Hughes, consumer representative.

And with regards to the number of components and I guess the device
itself, I have one point of clarification I\'d like. That is, whether
the device in total as well as all the components, are they all
manufactured at one facility of Cook or are we talking about multiple
facilities where they are manufactured?

DR. FEARNOT: That\'s a good question. They are all manufactured by the
same group.

DR. HUGHES: One facility?

DR. FEARNOT: There are a number of facilities around the world that
manufacture these. But the facilities, each facility that is in
manufacturing of this graft, manufactures the full selection of these
products.

Does that answer your question?

DR. HUGHES: Yes. I think so. That\'s fine.

And then a follow-up on that. I was trying to see if I could save these
until the very end, but it seems to me that this is the appropriate
point.

In looking through the material that has been given to us, and thinking
about the number of components and issues of compatibility or mechanical
integration of these various components, is there anywhere that you\'ve
done a failure modes and effects analysis or fault tree analysis as part
of the design process? I mean, I couldn\'t get a good sense of that from
the material. And I\'m just wondering \-- and it may be more of a
question that\'s appropriate to the FDA, you know, staff whether or not
that\'s a requirement or not.

But you know what I mean by failure modes and effects, fault tree?

DR. FEARNOT: Absolutely.

DR. HUGHES: Yes. Okay.

CHAIRMAN LASKEY: I think we\'re out of the realm of this particular
question. So feel free to answer it, but we need to get back on track.

DR. FEARNOT: I will answer it yes.

DR. HUGHES: I\'m sorry.

CHAIRMAN LASKEY: That\'s all right. It\'s just that the question the
agency needs an answer to is whether the clinical data are adequate to
provide reasonable assurance when applied to situation in which all
modular components were used. And I think the committee has said yes.

DR. ZUCKERMAN: Well, Warren, can we just explain the last sentence,
i.e., the converter and occluder? I\'m not sure that came through as
what we\'re asking.

MS. ABEL: Yes, I just want to provide a little bit of clarification.

For other devices, although we\'ve had other devices that have been
modular where you would take different things off the shelf to make a
device, that\'s something we\'ve dealt with before. This is actually
more of a bailout device, the converter and the occluder. And we\'ve had
other manufacturers where they\'ve had completely separate studies of
the uni-iliac devices, and those aren\'t bailout devices. But it\'s a
different situation. And it kind of gets to the point that you were
making. We could be concerned about the fact that now you\'ve got a
bifurcated device implanted. You\'re going to put in this converter
device inside the existing device, and we don\'t have clinical data in
the U.S. study and, you know, we have some limited information from the
worldwide experience. And is it appropriate, given that this is a device
to treat a problem, to go ahead and give clearance even though we don\'t
have that type of data?

CHAIRMAN LASKEY: Maybe, Tony, you want to \--

DR. COMEROTA: It\'s a very interesting question. It\'s a difficult
question. And I don\'t know that I\'m in a position to answer that.

If I take the position of a physician who is treating a patient and we
now have a technique to manage a difficult problem, and we\'re using
that technique. And then something happens that we can\'t do the entire
procedure the way it\'s planned. And like you said, this is a bailout
option that can continue to offer a safe option for treatment, although
we\'re not reconstructing both iliac clamps the way we intended to. But
we can still avoid a major abdominal operation, perhaps, in a high risk
patient who wouldn\'t do well with the major abdominal operation.

So from my perspective, a physician\'s perspective, I would like \-- and
I have accepted this, and I\'ve agreed that it should be part of part
and parcel of our approval. If you were to ask me are there data to
support my opinion aside from my being a physician taking care of these
patients, I don\'t think we\'ve seen data to support that approach. So
I\'m qualifying my response, but I think it\'s in the best interest of
our patients to accept this as a bailout option.

DR. ROBERTS: Well, and I think that at least granted it\'s not been done
much in the U.S., and part of that may be secondary to the fact of the
trial where when you start looking at this with the European data and
perhaps with some of the registry data, that in fact this is being done
occasionally. Maybe not in a huge number, but is needed. It seems to me
that it probably is reasonable to \-- I mean, we at least have some data
that it seems to be okay. And I would probably leave that \-- say that
it\'s a reasonable thing to have for the agency to approve that
particular part of the components. Because we know that they also sort
of work together, and so this should be part of that.

So I would agree with the idea that it should be available.

EXECUTIVE SECRETARY WOOD: The next question relates to device integrity.
Based on non-clinical engineering bench studies, clinical observations
within and outside of the US and analyses performed on explanted
devices, there have been a number of mechanical integrity issues
identified with the endovascular graft components of the Zenith
Endovascular Graft. These issues include the potential for corrosion,
barb separation, stent fracture, suture breaks, and graft material wear.
The information available regarding each issue and the probability and
potential clinical effects of these potential problems are discussed in
Appendix D of the Clinical Summary. while these clinical observations
may be associated with additional interventions in some patients, there
haver been o adverse events attributed to any of these issues in the
U.S. There have, however, been cases outside of the U.S. where
structural failure, for example, barb separation, associated with other
factors such as neck dilatation in absence of adequate patient follow-up
have lead to serious clinical sequelae, for example aneurysm rupture.

Please comment on the significance of these observations. In addition,
please comment on the information in the labeling, such as patient
section and follow-up recommendations, needed to reduce the potential
for these observations to occur and to minimize associated adverse
clinical effects in patients treated with this device.

CHAIRMAN LASKEY: Well, I think we\'ve seen that in the pivotal trial
here in the States there were no adverse events attributed to these
issues. I\'m not sure we have access to enough information from the
non-U.S. database to speak to the sequelae of these other events. What
they do point out in my mind, however, is the absolute necessity of
patient follow-up, which of course will be emphasized and put in bold
letters in the booklet for the patient. Without that: (a) there\'s no
data on which to make a decision as to whether these mechanical failures
are at all clinically significant or whether it\'s just the lack of
follow-up and other features conferred by absent follow-up that lead to
these disasters. So, we just don\'t have enough data to speak to that.

But clearly what comes through is the necessity of follow-up.

DR. KATO: Do we also have a need to have that put specifically those
issues identified in the patient booklet as well as the package insert
in this device?

CHAIRMAN LASKEY: You mean these instances or the follow-up?

DR. KATO: Well, clearly the follow-up I believe is mentioned.

CHAIRMAN LASKEY: Yes.

DR. KATO: But for example, you know, well I guess specifically the
sentence these issues include the potential for corrosion barb
separation, stent fractures, suture breaks and graft material wear which
have been associated with, you know, serious clinical sequelae or
rupture. At least some type of, you know, precaution addressed both to
the patients and the physicians of the need for \-- not only to be aware
of this, the patient also has to have \-- has to assume some
responsibility for \-- to know about that problem in order to always
obtain an annual follow-up.

DR. FERGUSON: Warren?

CHAIRMAN LASKEY: Well, yes. Let me just ask the agency that question.
Where do we draw the line between anecdote and data and where do we need
to be definitive? We hate to hang the sponsor out to dry based on
anecdote without additional information.

DR. COMEROTA: And perhaps in answering that, if I can extend that
question. If we were evaluating a drug \-- a medication and we had
animal data suggesting certain toxicity but no such data in humans, how
is that handled by the agency?

DR. ZUCKERMAN: Okay. Ms. Abel is going to begin by answering that
question, and then I\'ll add.

MS. ABEL: I think there are times where we\'ve got a suspected problem
that\'s shown up in an animal study or in preclinical testing that we
may include a caution that although this hasn\'t been observed in the
clinical study, this is something that has been seen in the animal
studies if we truly believe that it could be predictive of the clinical
outcome.

Now, on the other hand, if we have something that showed up that has
shown up in the preclinical testing and we have additional clinical data
to suggest that it was a false/positive, like we\'ve mentioned several
times in the conversation today about the bench testing being pretty
aggressive, then I don\'t think that there\'s a need to include it.

But we do have actual cases that have been presented to the agency with
respect to some of these failures. It\'s not anecdotal information. We
actually have the data. We have some of the doctors in the room that
have observed these things. So, there are some areas that will occur
with this device, and I think it\'s reasonable to say that you should be
looking for barb separation and the potential problems that could occur
if you do have the separations and, you know, how you should be managing
those patients that have that sort of problem, just as an example.

I\'m not trying to tell you what your answer should be, but I just \--
you know, this isn\'t just anecdotal. We have actually have cases.

Now, I think that there are some where we don\'t have clinical cases and
in our presentation we mentioned, for example, that there weren\'t any
graft wear observations in the analysis. I\'m trying to find my list.
Corrosion has definitely been seen in the analysis, hasn\'t been
associated with any failures. But certainly you would want to be looking
for whether you continued to have fixation, you know, and that could be
or it could not be related to the corrosion.

I already mentioned barb separation, stent fracture, clearly is
something that needs to be looked for any under \-- and the suture
breaks. I think it\'s been shown that the device needed to be modified
to improve the potential for that, that they were to provide all the
information on those 5 cases. And I think it\'s reasonable to continue
to look for that problem, because we don\'t have clinical data to
demonstrate that the problem has been solved.

So, if that helps.

DR. ZUCKERMAN: So in summary, Warren, one approach that the agency takes
is certainly we don\'t want to hang anyone\'s hat out to dry, but on the
other hand we do want to have a reasonably truthful labeling. So some of
that information potentially could go in the adverse events section of
the current label, as well as looking at section 8 of the IFU, which is
the patient counseling information which does indicate some concerns
about late term follow-up. But that could be beefed up also,
potentially.

DR. ROBERTS: I think it might be worth in the patient brochure to have
something in there that\'s sort of a little bit of educational, but
that\'s \-- you know, that you have a device in you that, you know, is
going to be in for a long time and there may be some structural problems
with it. And that\'s why, you know, close follow-up, you know, is
important, or something like that. So that they understand that it\'s
not just, you know, to get a CT scan, but there really are things that
we\'re looking for.

MR. MORTON: Mr. Laskey, just one point I\'d make that I agree, that that
might be very appropriate in patient labeling. But perhaps we could also
comment that these failures have been found in devices of this type to
differentiate from a specific design issue here.

DR. FERGUSON: Warren, a question.

CHAIRMAN LASKEY: Yes, sir.

DR. FERGUSON: I had a question about the first paragraph under number 5
that relates to what we\'ve been talking about. And correct me if I\'m
wrong here, but I thought that some of the failures that have been
mentioned in this paragraph had been altered by design changes before we
started the U.S. study. Am I wrong on that? You see specifically it says
that there have been structural failures, barb separations associated
with other factors, etcetera, etcetera. And I know that they added, you
know, they reconfigured the proximal by changing to 12 rather than 4.
And the question I\'m asking is when was that done and does it impact on
this?

MS. ABEL: There certainly were more barbs separations that occurred with
the previous design before they added the additional barbs and did some
of the other changes to the suprarenal stent. But the failures that were
reported most recently have been with the final product, final design
that we\'re discussing today.

DR. FERGUSON: Okay. Thank you.

CHAIRMAN LASKEY: I think we\'re obligated to report that rate, though. I
think it\'s not enough just to alarm the patient by saying you have
something with lots of moving parts that can come apart. In think in
fairness to everyone we need to cite what the best estimate is for these
failure rates. They\'re very low, as I take it. And the clinical
significance is perhaps even lower, but it would be best to put this in
a positive light rather than negative light.

DR. COMEROTA: With the proviso that the observation period is short and
any mechanical stress is likely to incur an increase in frequency the
longer the device is in.

So, just need to balance.

CHAIRMAN LASKEY: Okay.

DR. ZUCKERMAN: Dr. Laskey, can you just try to summarize then what parts
of the labeling and patient information you would change to reflect
those comments?

CHAIRMAN LASKEY: That in the \-- since you\'re reporting the results of
the trial in the pivotal U.S. trial there have been no adverse events
attributed to barb separation, stent fractures, suture breaks or graft
material where over an integral of, whatever your study interval is, 12
months. There have, however, been reports of such mechanical failures.
And there I would put a rate best guess for point whatever percent of
barb separation and etcetera that may have clinical significance in the
outpatient follow-up or something. Something like that. It\'s a bit
softer on the edges, but also makes the point.

DR. ZUCKERMAN: I agree with that.

CHAIRMAN LASKEY: Does that help?

DR. ZUCKERMAN: Yes.

CHAIRMAN LASKEY: All right.

EXECUTIVE SECRETARY WOOD: The next questions relates to labeling. One
aspect of the pre-market evaluation of a new product is the review of
its labeling. The labeling must indicate which patients are appropriate
for treatment, identify potential adverse events with the use of the
device, and explain how the product should be used to maximize clinical
benefit and minimize adverse events. If you recommend approval of the
device, please address the following questions regarding product label.

\(a\) The indication for use for this device is as follows:

The Zenith AAA Endovascular Graft would be H&L-B one-Shot Introduction
System and ancillary components is indicated by the endovascular
treatment of patients with abdominal aortic, aorto iliac or iliac
aneurysms having morphology suitable for endovascular repair, including:

Adequate iliac/femoral access greater than or equal to 7.5 millimeters
non-aneurysmal infrarenal neck length of at least 15 millimeters; neck
diameter measured outer wall to outer wall of no grater than 28
millimeters and no less than 18 millimeters; iliac artery distal
fixation site grater than 10 millimeters in length and no greater than
20 millimeters in diameter, measured outer wall to outer wall; one of
the following: An abdominal aortic aneurysm with a diameter greater than
or equal to 4 centimeters; an iliac aneurysm with diameter greater than
or equal to 3.5 centimeter; aortic, aorto-iliac, or iliac aneurysm with
a history of growth greater than or equal to 0.5 centimeters pear hear.

Please comment on whether the indications for use adequately define the
patient population studied and for which the device will be marked.

CHAIRMAN LASKEY: These seem to be the inclusion criteria for the pivotal
U.S. trial. I guess the panel had some concerns about the cutoff at 4
centimeters, so I think we would probably suggest that that not be in
the IFU. Are we in agreement with that? That it be five?

Similarly, the data on iliac aneurysm is vanishing small, so what should
we do with that?

DR. ROBERTS: I don\'t think we have any data for that. I think that
might have to be something we look at. I think there probably needs to
be something for iliac aneurysms, but I\'m not sure that we have the
data to support it.

CHAIRMAN LASKEY: Okay.

DR. COMEROTA: I have a question, Warren.

CHAIRMAN LASKEY: Yes.

DR. COMEROTA: I think we\'re in agreement that the elective management
of an asymptomatic small aneurysm is not what the panel wishes to see,
but by the same token in women, and especially smaller women a 4?
centimeter aneurysm may be a very dangerous situation. And I don\'t
think we want to limit a physician or a company in that scenario either.

And I think we have to be cautious in our wording. Unfortunately, I\'ve
seen of very late patients in any number of institutions treated with
aneurysms less than 4 centimeters. And probably no one in this room
would concur with that, since they\'re asymptomatic.

So I think in our zeal to improve patient care, we just need to be
careful that we don\'t want to restrict appropriate use in those
patients that need it who have smaller aneurysms.

CHAIRMAN LASKEY: Well, that\'s a great point. I mean, should we index it
then to \-- you\'re leaning more towards keeping it in than jettisoning
it. But should it be so many centimeters per square meter or \--

DR. COMEROTA: If we want to mention a gender difference.

CHAIRMAN LASKEY: Okay.

DR. ZUCKERMAN: Let me just \-- I\'m sorry to suggest a general paradigms
that the agency takes regarding this difficult type of problem with a
high to assess risk benefit. And that\'s why the agency has indicated
the labels for other approved devices.

If you look, for example, at the Gore device, there\'s no indication of
a specific cutpoint. For example, the agency sometimes has indicated for
the endovascular treatment of patients with symptomatic abdominal
aortic-aortae iliac or iliac aneurysms and let the physician figure out
what the cutpoint is.

Another potential strategy is to utilize a different set of cutpoint
data as noted in the Medtronic label.

DR. KATO: Right. Well, that\'s where I came up with that twice the size
of the normal aorta.

DR. ZUCKERMAN: Right. But now \--

DR. KATO: Only as somebody else has done it that way.

DR. COMEROTA: That doesn\'t get us out of the 4 centimeter range,
because most aortas will be 4 centimeters in that ball park. So I don\'t
think that\'s going to help us.

DR. ZUCKERMAN: So, again, you know one strategy the agency uses if there
aren\'t ideal cutpoints, is just to indicate a broad general statement
such as symptomatic aneurysms. And then the clinical trial section, I
forgot. You know we actually as listed in this IVU, the indications are
there and we can describe in more detail the actual range of aneurysm
sizes treated.

DR. COMEROTA: Might I suggest as a starting point, Warren, that we
consider approval for symptomatic abdominal aortic aneurysms and then
asymptomatic aneurysms 5 centimeters or more in men and 4? centimeters
or more in women?

CHAIRMAN LASKEY: Well, that\'s out there for discussion. I like Dr.
Zuckerman\'s suggestion of just putting the ranges of aneurysm size
treated and let the physician be aware. But nowhere in this protocol do
I see a distinction between symptomatic and asymptomatic. And I would be
loath to confine this to one or the other. It\'s not specified in the
protocol. In the era of EBCTs all around, there are going to be many
asymptomatic AAAs picked up. So I don\'t know whether we should put that
language in here.

DR. COMEROTA: The intent for that, Warren, is that the smaller aneurysm,
which is symptomatic would still be considered at much higher risk for
rupture. So we would be \-- all of us would be forced into managing that
patient one way or another to take care of that aneurysm.

CHAIRMAN LASKEY: I mean, I defer to the surgeons on the panel in terms
of symptomatic versus asymptomatic.

DR. NICHOLAS: I think the symptomatic issue, obviously, we don\'t have
data on from the pivotal protocol. However, might work as another
suggestion to indicate its useful in aneurysms greater than 4
centimeters recognizing that we currently have no data to suggest its
benefit unless the patient is symptomatic until the aneurysm reaches a
higher size, whether you pick 5 or 5.5.

CHAIRMAN LASKEY: Yes. Knowing the workings of Dr. Zuckerman, I\'m not
sure that\'s helpful. But \--

DR. MAISEL: Another alternative \--

CHAIRMAN LASKEY: But I think putting the ranges of the sizes and the
range of aneurysm size treated in the trial is at least defensible.
Though I\'m not sure there\'s enough data to support that claim of 4
centimeter. I mean, it\'s a minority in this pivotal trial. I\'m not
sure whether they were symptomatic either. Do we know that?

DR. COMEROTA: I think we don\'t want to get confused as to what our
intent is here. The intent is that right now there aren\'t any data
showing that the management of a 5 centimeter aneurysm operatably is any
better than if we observed that patient until the aneurysm becomes
larger, and then intervene.

Right now there aren\'t any data demonstrating that endograft treatment
offers lower mortality than an operation. So the logical conclusion is,
there aren\'t any data showing that endograft treatment of an aneurysm
that\'s 5 centimeters in diameter is better than just watching the
aneurysm. There isn\'t any mortality. There aren\'t any mortality
benefits, and there may be a down side if there\'s a complication of the
procedure. And that\'s the logical progression, you know, of sequence.

But by the same token, in those same trials there\'s an observation in
women that women with smaller aneurysms are at higher risk for rupture,
even though they weren\'t stratified right up front, it was an
observation. So therefore, we\'re trying to protect against that,
against that situation.

CHAIRMAN LASKEY: Yes. Well, I mean, I hate to perseverate here, but do
you want to just want to say 4 centimeters in women and 5 in men, or
where do we \-- if we\'re going to have this in the IFU as a bullet,
then we need a cutpoint.

DR. COMEROTA: Well, I think all the vascular surgeons would agree that a
patient who has a symptomatic aneurysm needs to be treated. So,
therefore, a patient with a symptomatic aneurysm is fair game for
whatever treatment we have at our disposal.

CHAIRMAN LASKEY: Right.

DR. COMEROTA: The patient who has an asymptomatic aneurysm, we might
consider identifying a gender difference based upon available
information. Now whether you want to say 4 or 4?, but I think it\'s in
line with the keeping that an asymptomatic aneurysm in a woman for 4?
centimeters, we want to have a lower cutpoint, and I\'d suggest a
similar cutpoint of perhaps 5 in a man.

DR. ROBERTS: Is there any reason not to go with twice the diameter of
the normal aorta? I\'m sorry, did I miss that?

DR. COMEROTA: Well, my \-- yes. But if you look at a 1.8 millimeter
aorta, then you\'re dealing with a \-- I\'m sorry. 1.8 centimeter aorta,
then you\'re dealing with a 3.6 centimeter aneurysm, and I\'m not sure
we want to get into that.

DR. ROBERTS: Well \--

MR. MORTON: Dr. Laskey, I realize that rightfully the panel is being
concerned about what is actually approved the clinician\'s use and
trying to be very accurate there. This also, as you know, has got market
implications. And I just wonder could you take a second to ask, having
heard the discussion of the panel, if the sponsor has a suggestion for a
way to deal with this?

CHAIRMAN LASKEY: That would be out of order at the moment, with all due
respect. We\'re supposed to hash this out up here first and then \--
maybe we should move on.

Obviously, we need to think this through because this will undoubtedly
come up when we vote and we put conditions on the motion. So, we may not
resolve this right now, but I think we need to resolve this within the
next 20 minutes or so when we come to the vote. So let\'s keep thinking
about it. Several suggestions on the table.

DR. NICHOLAS: I have one other concern regarding the indication, and I
raised that in my initial discussion and the sponsor agreed that it
should be part of this. And that is the issue of angulation of the
proximal neck or the angulation between the bear stent and the graft.
And they had some specific numbers they used in the pivotal protocol
that are not listed here.

CHAIRMAN LASKEY: And, again, that would come up as we apply conditions
to the motion. So, we will incorporate your suggestion.

Okay. How about the greater than .5 centimeter per year growth? Can we
let that sit for now? Yes. Probably the one thing we do agree on.

Okay.

EXECUTIVE SECRETARY WOOD: (b) The indications for use include treatment
of iliac aneurysms, which is unique to this device as compared to the
other approved endovascular grafts. Please comment on whether this
indication is appropriate.

CHAIRMAN LASKEY: Well, again, I\'ll just defer to our primary reviewers.
It did not appear on isolated iliac aneurysms, is that correct?

DR. COMEROTA: Yes.

DR. ROBERTS: That\'s my feeling.

CHAIRMAN LASKEY: Yes.

DR. ROBERTS: Isolated ones. I think that\'s important, because obviously
if they\'re part \-- if they\'re iliac artery aneurysms as part of the
aortic aneurysm, then obviously they need to be treated.

CHAIRMAN LASKEY: C?

EXECUTIVE SECRETARY WOOD: (c) Based on the clinical investigation
experience, please comment on whether there are any additional warnings,
precautions, or contraindications that you think you should be included,
either specific to this device or from a generic standpoint for
endovascular grafts.

DR. ROBERTS: I do have a comment on this.

CHAIRMAN LASKEY: Yes, and I do. Go ahead.

DR. ROBERTS: And I brought up this MRI issue in my initial discussion,
and I was thinking about it more at lunch. And I would like to ask the
sponsor how many patients have had MRIs?

DR. CHUTER: The answer overall is we don\'t know. But I do know from my
own practice, because I came out here I performed a brief review of the
charts, and you are absolutely correct. We cannot contraindicate MRIs
because the patients will get them. And I discovered 11 patients out of
an experience of about \-- well, it was over 250 Zenith\'s implanted for
a period of over 4 years total. And all of those patients were fine.

Now, I didn\'t have follow-up CTs on all of those patients. I\'d say
there are probably 3 or 4 who have not been follow-up studies. But
clinically the patients were fine.

So I would say we have performed the experiment in an indirect way, and
that the answer is we haven\'t in that small group seen adverse effects.
I think probably what I would do, since contraindication is impractical,
I would just downgrade the thing to a warning. I would not want to see
people undergoing these things willy-nilly. I think people should \--
the physicians making decisions about this and the neurologists, or
whoever they are, should be in a position to balance the risks and
benefits and we still consider this to be a risk. So put it on there as
a warning.

DR. ROBERTS: Well, I would certainly agree that \-- I\'m very
uncomfortable with the idea that it\'s a contraindication, because I
think that\'s going to conceivably jeopardize the health of the patients
that get this device. And, you know, with some people quite frankly they
might say, \"Gees, I can\'t predict that this person\'s not going to
need an MRI for a lifesaving kind of event.\" And so does that mean I
don\'t put in this device even though I think it\'s the best one to put
in, or whatever. So that, I think, is very important.

And quite frankly, what I would like to see the sponsor do is I would
like to see the data looked at in terms of these patients and find out
how many of them really did have MRIs. Because I am sure that if you go
back and look at these patients, I\'ll bet you can find a whole bunch of
them that have had MRIs. And then I think, you know, at least that data
could be presented in terms of the question does it even need to be a
warnings, which of course also raises a lot of red flags, although
certainly not as much as a contraindication. But I really feel very
strongly that this needs to be looked at. Because I think \-- I suspect
it\'ll be a little bit like the bench testing that when you get it
implanted, it\'s a little different than when you have it on a string,
you know, floating around in a magnet or something.

DR. CHUTER: We certainly will do that. It would make a great little
paper.

CHAIRMAN LASKEY: I would just \-- it\'s not going to cost you anything
to just include some window whereby these aortas are not instrumented. I
do not share your optimism about the potential hazard of a catheter and
an interventionist on the other end of it. So there probably ought to be
some time window whereby these things are crossed with stiff liners and
sheaths and catheters.

DR. ROBERTS: You mean as a warning, maybe?

CHAIRMAN LASKEY: A precaution.

DR. ROBERTS: A precaution.

CHAIRMAN LASKEY: A caution.

DR. ROBERTS: I don\'t know. I think honestly if you\'re careful, you
can\'t \-- I don\'t see a problem. I mean, we\'ve gone through these
things just if nothing else, to repair \-- I mean, if you get a leak,
you\'ve got to go across them. I think as long as you are paying
attention and you know what you\'re doing, and you know the thing\'s in
there.

I think, you know, I\'m actually more worried like Dr. Chuter is about
infection rather than disrupting the graft. You know, I think it\'s fine
to put it in as a warning that you should be careful if you do it. But I
don\'t know what the time period would be.

CHAIRMAN LASKEY: Yes, I don\'t know either. But all those magic words:
\"If you know what you\'re doing, if you\'re capable, if you\'re skilled
\--\"

DR. ROBERTS: Well, if you\'re not, you shouldn\'t be doing that.

CHAIRMAN LASKEY: Well, but people are.

DR. COMEROTA: The reality is that once this device is in, once the graft
is in, it may be technically easier on safer on the patient than going
through the native aneurysm.

DR. ROBERTS: Yes.

DR. COMEROTA: And the disease iliac. So I wouldn\'t push that caution
very hard.

EXECUTIVE SECRETARY WOOD: (d) Please provide any additional comments you
have on the labeling.

DR. MAISEL: May I make a general comment?

I\'m a little bit troubled by the term \"clinical utility,\" which is
used. To the best of my knowledge it appears that on page 24 of the
sponsor slide set they define what the clinical utility is. And in their
patient instruction manual on page 12, they say that the endovascular
graft has \"improved clinical utility measures compared to surgical
control patients.\" And I just would be interested in other people\'s
opinion about it.

To me that implies that the aneurysm outcomes were improved. And I just
wonder if the terminology bothers anyone else?

CHAIRMAN LASKEY: Discussion?

DR. COMEROTA: It boils down to a definition, doesn\'t it?

CHAIRMAN LASKEY: As does most of this conversation, yes.

DR. COMEROTA: And at best there was equivalence, so it wasn\'t improved
if my definition is accurate.

DR. MAISEL: Well, by their definition it was improved. Their definition
of clinical utility, at least to my understanding, refers to the
recovery measures, ICU stay, hospital stay, those sorts of issues. So I
take issue more with the terminology, or at the very least I think those
things should be \-- there should be an asterisk and a description of
what they mean by \"clinical utility.\"

DR. COMEROTA: As reduced early morbidity?

DR. MAISEL: Exactly.

DR. COMEROTA: Correct?

MR. MORTON: Dr. Laskey, just a comment. Clinical utility is something
that we\'re \-- that the sponsor\'s expected to address throughout the
study. I mean, it\'s a fairly standard term. And I think what they\'ve
tried to do here is make a comparison and draw some conclusions. I would
caution not to assume that clinical utility is something that they have
concocted.

DR. MAISEL: I didn\'t mean to imply that. I just meant that definitions
differ among people, and I was concerned that a physician reading that
might misinterpret it. So just simply a clarification I think would be
adequate.

CHAIRMAN LASKEY: Yes. So the solution to this, of course, is just to put
the data out there so there\'s a little table coming here with length of
stay and transfusion and so on and so forth. That would just settle that
right there, be very useful.

DR. KATO: Well, one other thing on pages 63 through 66 of the sponsor\'s
information, I guess the booklet on the graft, shows that the graft
placement is actually infrarenal instead of suprarenal fixation. And
that may be another area where we were confused on initially.

CHAIRMAN LASKEY: Thank you, Norm. I was confused there, too, obviously.

Okay. Number seven.

EXECUTIVE SECRETARY WOOD: Please comment on the adequacy of the proposed
physician training plan as described in the panel package, Section 5 of
the Clinical Summary.

CHAIRMAN LASKEY: Well, Norm, I think you really summarized this very
distinctly and articulately. I mean, what I heard was a convincing
program on the part of the sponsor. I think it\'s adequate. We agree?

DR. KATO: Yes, I agree. I just question the use of that word
\"certification.\"

CHAIRMAN LASKEY: Yes. Okay.

DR. KATO: I think we get rid of that, you\'ll be okay.

CHAIRMAN LASKEY: Okay.

EXECUTIVE SECRETARY WOOD: The remaining question relates to the
post-market study. The sponsor is proposing to conduct a post-approval
study on the patients enrolled in the pivotal clinical study. Follow-up
on patients will be obtained in accordance with the clinical protocol
approved under the IDE for this device. Please comment on the
acceptability of this plan, as briefly described in the panel package
(Section 4.6 of the Clinical Summary.)

CHAIRMAN LASKEY: Well, we agreed a longer term clinical follow-up is
requisite. Perhaps with imaging required.

I think one question that I \-- is it clear in everybody\'s mind what
surveillance mechanism is going to be prescribed here? Is it \-- is it
that described by Dr. White? What is the registry \-- what surveillance
mechanism is actually being suggested here? Is it sending in a card to
Cook every time a stent is implanted? If you could provide us with a
little bit more information on this post-marketing study. Is it
consecutive patients? Is it a voluntary \-- how does this work?

MS. ABEL: As it\'s stated here, we\'re requiring that there\'s
additional five year follow- up on all patients enrolled in the pivotal
study. And I\'m not sure that we\'ve completely agreed whether there
would be follow-up on the roll-in patients, but certainly all patients
in the pivotal study.

The sponsor has the option of either using the Lifeline Registry to hold
that data so that information could be combined with other data from
other manufacturers for analyses, unrelated to the sponsor\'s needs and
unrelated to the FDA needs, but for research purposes.

So there would be prospective follow-up with the patients in accordance
with the same type of follow-up that was described in the IDE study.

CHAIRMAN LASKEY: But it\'s clinical? There\'s no requisite imaging?

MS. ABEL: The imaging is also specified and the IDE protocol is the
same.

CHAIRMAN LASKEY: All right. That sounds excellent then.

DR. ZUCKERMAN: One question, Dr. Laskey. Dr. Roberts has recommended
that we sponsor an agency, review the number of MRIs, scans and what if
any sequelae were there. But if there isn\'t enough information, should
this continued post- approval follow-up and post-market surveillance
also be directed at trying to obtain this MRI information is a question?

CHAIRMAN LASKEY: How do we get that?

DR. ROBERTS: Well, I mean, these patients are going to be followed. So,
I mean, I think it could just be part of the \-- you know, when they
came in for their yearly follow-up with their physicians they\'re asked,
you know, have you had an MRI. And, you know, that way at least we\'ll
know. If the physician know and they saw somebody else who ordered an
MRI and they forgot they weren\'t supposed to get one and went merrily
ahead and got it, at least we\'d have that information.

CHAIRMAN LASKEY: It\'s not the stuff of a manuscript, but is it good
enough for \--

DR. ZUCKERMAN: Continued surveillance.

CHAIRMAN LASKEY: It\'s just kind of \-- I just maybe to be more specific
in how the data\'s acquired, that\'s all. Did you get an MRI?

DR. ROBERTS: Well, I would recommend that part \-- I\'m assuming, I must
say it\'s an assumption, that there\'s a questionnaire that gets filled
out that gets sent back in to the sponsor as part of their information.
I would suggest that from now on that part of that be put have you had
an MRI examine and if so, you know, the date and the type.

CHAIRMAN LASKEY: And what part of your body?

DR. ROBERTS: Right. Yes.

CHAIRMAN LASKEY: Okay. Dr. Zuckerman, does the agency have any
additional comments or questions before the vote?

DR. ZUCKERMAN: Yes. Dorothy Abel would like to make one more comment.

MS. ABEL: I just have a suggestion with respect, trying to determine the
appropriate aneurysms to be treated for the device. And I think you\'ve
got the labeling in front of you of the different devices that we\'ve
approved. And most recently that\'s been the W.L. Gore device, it was
approved last fall. And it says patients diagnosed with infrarenal
abdominally aortic aneurysms who have appropriate anatomy as described.
So it really does leave it up to the clinician to determine whether or
not it\'s an aneurysm that should be treated. And I\'m not sure if it\'s
something that went for this specific device because I don\'t know if
it\'s any different than it would be for the other devices.

Now early on back in \'99 Medtronic did include a listing of the types
of aneurysms that were treated in their study. And I\'m not \-- you
know, I don\'t think that that\'s necessarily a problem, especially
given where their technology was at the time. But I think we have to be
careful between, you know, labeling the device and setting the criteria
for when patients should be treated.

CHAIRMAN LASKEY: Thank you.

Any other queries?

I\'d like to ask the sponsor if you have any additional comments or
questions before the vote? Thank you.

And at this point, could we hear from Mr. Morton and Mr. Hughes \-- Dr.
Hughes?

MR. MORTON: Just to echo what\'s been said before. A fantastic review by
the FDA. Good job and a good presentation by the sponsor.

CHAIRMAN LASKEY: Dr. Hughes?

DR. HUGHES: Yes, I would like to say the same thing, especially with
regards to the FDA staff. I think they\'ve done an excellent job of
ferreting out the issues. And I think that overall the panel has done a
good job of looking into all of these.

Also from a consumer\'s perspective with regards to safety and
effectiveness, and I commend the manufacturer also for the fine job that
they\'ve done.

CHAIRMAN LASKEY: Thank you.

I\'d like to just reopen the open public hearing portion of the meeting
before we move to a conclusion here. Is there anyone who wishes to
address the panel on the topic? If not, I\'ll close the open public
hearing.

And if it\'s okay with everybody here, let\'s move ahead without a break
and move to the vote. Is that all right?

Okay. Geretta, if you could please read us the voting options?

EXECUTIVE SECRETARY WOOD: The Medical Device Amendments to the Federal
Food, Drug and Cosmetic Act, as amended by the Safe Medical Devices Act
of 1990, allows the Food and Drug Administration to obtain a
recommendation from an expert advisory panel on designated medical
device pre-market approval applications (PMAs) that are filed with the
agency. The PMA must stand on its own merits and your recommendation
must be supported by safety and effectiveness data in the application or
by applicable publicly available information. Safety is defined in the
Act as reasonable assurance, based on valid scientific evidence that the
probable benefits to health under conditions on intended use, outweigh
any probable risks. Effectiveness is defined as reasonable assurance
that, in a significant portion of the population, the use of the device
for its intended uses and conditions of use when labeled will provide
clinically significant results.

Your recommendation options for the vote are as follows:

Approval - if there are no conditions attached.

Approvable with conditions - the panel may recommend that the PMA be
found approvable subject to specified conditions, such as physician or
patient education, labeling changing, or a further analysis of existing
data. Prior to voting, all of the conditions should be discussed by the
panel.

Not approvable - the panel may recommend that the PMA is not approvable
if: The data do not provide a reasonable assurance that the device is
safe, or; if a reasonable assurance has not been given that the device
is effective, under the conditions of use prescribed, recommended, or
suggested in the proposed labeling.

Following the vote, the Chair will ask each panel member to present a
brief statement outlining the reasons for their vote.

CHAIRMAN LASKEY: May I have a motion on the PMA?

DR. COMEROTA: Warren?

CHAIRMAN LASKEY: Sir?

DR. COMEROTA: I would move that the panel approve the PMA with the
condition of excluding isolated iliac artery aneurysm and the addition
\--

CHAIRMAN LASKEY: Let me stop \-- okay. Here\'s where we get into this
lovely procedural non-quagmire.

I just need to hear a motion and then we will \-- I will ask for a
second and then we will append the conditions. So, may I have a motion
on the PMA? Motion to approve with conditions?

DR. COMEROTA: I move to approve with condition.

DR. ROBERTS: I second.

CHAIRMAN LASKEY: It has been moved and seconded that the PMA is approved
with conditions.

May I have the first condition?

DR. COMEROTA: That the isolated iliac artery aneurysm be excluded from
the PMA.

CHAIRMAN LASKEY: Yes. Discussion?

Well, okay. We have the condition. Do we have a second? We\'ll just go
to that.

DR. ROBERTS: Yes.

CHAIRMAN LASKEY: Okay. Second.

So now we do have some discussion on the condition to exclude isolated
iliac aneurysms from the PMA? Any discussion? No.

Now we vote on the \-- I guess we vote on the condition starting with
\--

DR. COMEROTA: Do we discuss any other conditions or do we vote on this
condition first?

CHAIRMAN LASKEY: Yes, I think we do these one at a time.

DR. COMEROTA: Okay.

DR. ROBERTS: Vote on each condition.

CHAIRMAN LASKEY: Vote on each condition. And then we put together the
composite recommendation, and then we \-- okay.

So should we just do a show of hands here? How we doing it this week?

EXECUTIVE SECRETARY WOOD: A show of hands.

We\'ll start with Dr. Nicholas and move around the table and you state
how you\'re voting, please.

DR. NICHOLAS: I agree.

DR. FERGUSON: Agree.

DR. MAISEL: Agree.

DR. ROBERTS: Agree.

DR. NORMAND: Agree.

DR. KATO: Agree.

DR. COMEROTA: Agree.

DR. AZIZ: Agree.

CHAIRMAN LASKEY: Unanimous.

May I have another condition for the PMA?

DR. COMEROTA: That the wording be included that these patients need
lifelong follow-up by their treating physician.

CHAIRMAN LASKEY: Second?

DR. NICHOLAS: Second.

CHAIRMAN LASKEY: Discussion?

DR. FERGUSON: Is that something we can make a part of a condition for
approval of a PMA? I mean \--

DR. COMEROTA: Wording indicating \--

DR. FERGUSON: That\'s up to the surgeons and the \--

DR. COMEROTA: Wording indicating the importance of lifelong follow-up.

DR. FERGUSON: Well, that\'s different from what you said.

DR. COMEROTA: I realized that the minute I said it.

Physicians may be managing these patients, they\'re not going to be
following them lifelong, but at least it\'s their responsibility to
transmit this type of important \-- the importance of this follow-up to
the patient\'s physicians in their communities who will be seeing the
patient on an ongoing basis. Because I am afraid that we will be seeing
additional problems 3 years, 4 years, 5 years from now that may not be
surfacing just yet.

EXECUTIVE SECRETARY WOOD: Dr. Comerota, for the record you restate the
motion?

DR. COMEROTA: The condition? That wording be included indicating the
importance of lifelong follow-up following endograft placement.

CHAIRMAN LASKEY: Any other discussion?

Vote?

DR. NICHOLAS: Agree.

DR. FERGUSON: Agree.

DR. MAISEL: Agree.

DR. ROBERTS: Agree.

DR. NORMAND: Agree.

DR. KATO: Agree.

DR. COMEROTA: agree.

DR. AZIZ: Agree.

CHAIRMAN LASKEY: Unanimous.

May I entertain another condition?

DR. ROBERTS: I don\'t know whether the agency feels that they need this
as a condition, but that I would think that the contraindication of MRI
be downgraded or put as a warning rather than a contraindication. And
that \-- and this is what I don\'t know if you really need, is that data
that the sponsor be encouraged to \-- or be encouraged to provide data
regarding patients who have already obtained MRIs. Does that work for
you?

DR. ZUCKERMAN: So if I were to summarize that, Dr. Roberts, it\'s: (1)
that the sponsor and agency review the current MRI data; (2) take the
MRI statement out of the contraindications, and; (3) if possible with
the available data write a better warnings statement regarding use of
that technology?

DR. ROBERTS: That sounds wonderful. Thank you.

CHAIRMAN LASKEY: Did you guys get that? Okay. Thanks.

All right. There\'s no need to restate that.

DR. ROBERTS: Do I need a second.

CHAIRMAN LASKEY: Second it. We had discussion.

EXECUTIVE SECRETARY WOOD: We didn\'t receive a second.

DR. NORMAND: I\'ll second.

CHAIRMAN LASKEY: Any other discuss on how the wording should be phrased,
crafted?

DR. NICHOLAS: Agree.

DR. FERGUSON: Agree.

CHAIRMAN LASKEY: So this is the vote now?

DR. MAISEL: Agree.

DR. ROBERTS: Agree.

DR. NORMAND: Agree.

DR. KATO: Agree.

DR. COMEROTA: Agree.

DR. AZIZ: Agree.

CHAIRMAN LASKEY: And just to be sure, this is a tripartite condition as
Bram phrased it. It was to review the current data on patients receiving
MRI. It\'s to revise the MRI contraindication down to a warning or a
precaution. And the third bullet was \--

DR. FERGUSON: I think you said if I understood you said remove it for
now, and then when you had the data to put the warning back in. Was that
not what I heard?

DR. COMEROTA: To craft the statement.

CHAIRMAN LASKEY: Could you be so kind as to just read back the three
component response that Dr. Zuckerman suggested to modify Mr. Roberts
question?

SUMMARY WRITER: Sure. (1) that the sponsor and agency review the current
MRI data; (2) take the MRI statement out of the contraindications, and;
(3) if possible with the available data write a better warnings
statement regarding use of that technology?

CHAIRMAN LASKEY: But are we clear, we are removing that contraindication
from the labeling as we speak, is that right? That\'s what we just voted
to do. Okay.

Any other conditions from Tony or Anne? Any other conditions.

DR. ROBERTS: Not from me.

CHAIRMAN LASKEY: Okay. And from anyone? May I hear another condition?

DR. KATO: I\'d like to move that where it says one of the following the
abdominal aortic aneurysm with a diameter greater than 4 centimeter and
iliac aneurysm with diameter greater than 4.5 centimeter, and
aorta-iliac or iliac aneurysm with a history of growth greater than 0.5
centimeter per year be removed. And replace with nothing.

Well, and that would make it consistent with the other \-- yes, be
replaced with appropriate anatomy if isn\'t already in there.

CHAIRMAN LASKEY: Norm, do you want just to rephrase that so I\'m clear
on how I can phrase the motion? Just remove?

DR. KATO: I would remove \--

CHAIRMAN LASKEY: That paragraph.

DR. KATO: That under indications for use where it says one of the
following, it would begin with one of the following, bullet point, an
abdominal aortic aneurysm with a diameter greater than 4 centimeter,
iliac aneurysm with diameter greater than 3.5 centimeters and aortic,
aortal-iliac, or iliac aneurysm with a history of growth greater than
0.5 centimeters per year be stricken and replaced with appropriate
anatomy. The term appropriate anatomy.

DR. ROBERTS: Well, the appropriate anatomy is above it anyway.

DR. KATO: Okay. Yes, I said if it isn\'t there already.

CHAIRMAN LASKEY: Do I have a second to strike that paragraph from the
IFU.

DR. ROBERTS: Second.

DR. MAISEL: Could you just clarify where the term \"appropriate
anatomy\" is going to be inserted, because I don\'t see it unless \--

DR. ROBERTS: Can I just suggest that what it should read is that it
should read from indication of use the Zenith AAA Endovascular Graft, so
on and so forth, is indicated for the endovascular treatment of patients
with abdominal aorta, aortic iliac, and then I would leave out the iliac
aneurysms, because that sounds like an isolated iliac aneurysm, having
morphology suitable for endovascular repair including, and then list
those. And then just drop everything from \"One of the following\"
through the \"aorta-iliac at centimeters per year.\"

CHAIRMAN LASKEY: That was my understanding. Delete that paragraph.

So we have a second. WE have a discussion.

Dr. Comerota, you happy with that?

DR. COMEROTA: Yes.

CHAIRMAN LASKEY: Great. Vote.

DR. NICHOLAS: Agree.

DR. FERGUSON: Agree.

DR. MAISEL: Agree.

DR. ROBERTS: Agree.

DR. NORMAND: Agree.

DR. KATO: Agree.

DR. COMEROTA: Agree.

DR. AZIZ: Agree.

CHAIRMAN LASKEY: Okay. Any further conditions?

DR. NICHOLAS: I\'d like to make a motion. The conditions of the
indications include the angulation criteria that we used in the protocol
in patient selection.

CHAIRMAN LASKEY: So just to use the language as specified in the
protocol, to repeat that in the IFU.

A second?

DR. ROBERTS: Second.

CHAIRMAN LASKEY: I think we\'re all in agreement. But do we need
discussion on this point?

DR. KATO: Well, I guess the question is do you want the sentence stating
that the angulation at the less than the proximal neck angulated \--
less than 60 degrees \-- is that the one?

Well I guess the question is then should one or more of the precautions
and warnings be placed into the indications?

DR. NICHOLAS: Well, I look on this as a criteria for use similar to the
neck\'s diameter or the length of a iliac landing site.

DR. KATO: Well, and I agree with that. But it\'s under the precautions
and the warning section of the label.

DR. COMEROTA: In other words, it\'s already in there.

DR. ROBERTS: But I think what he\'s saying is just make it as part of
the morphology. It\'s part of the morphology where we have the other
morphology regarding the length, the next length and that kind of thing,
it should be in there as a proximal aortic angulation less than 60
degrees.

CHAIRMAN LASKEY: So putting that in the space occupied by the paragraph
that we just deleted would be just fine?

DR. ROBERTS: Right. Yes.

CHAIRMAN LASKEY: Right?

DR. COMEROTA: Point of clarification.

CHAIRMAN LASKEY: Yes.

DR. COMEROTA: Would that change the onus of the treating physician if
this is a particular high risk patient for an operation? The angle is a
little more than stated, but moving that terminology from the warning to
the body of the recommendation, does that change the liability of the
physician, of the treating physician?

DR. ROBERTS: Well, the question is should it be done with an angulation
of \-- I mean, if you feel that that\'s the only way to treat the
patient and the patient can\'t undergo a surgical procedure and
everybody understands what the risks are, I guess you do it. But, I
mean, you know, I think that the issue is that we don\'t have any data
in here that putting it in somebody with an angulation greater than
that, that we know it\'s going to work or that there\'s going to be a
problem with it.

DR. KATO: Well, it\'s an interesting problem because it \-- one other
manufacturer has listed that as a \-- in their indications. The other
manufacturers do not.

And, you know, is this \-- you know, how tight do you make the
indications versus how tight do you make the precautions and warnings
when, you know \-- I think we all understand that this will be used in a
\"off label\" situation where the angulation is going to be probably
greater than 60 degrees in many situations.

DR. ZUCKERMAN: Right. Well, the agency doesn\'t regulate the practice of
medicine. We are obligated to adequately promote truth in the IFU, truth
in labeling. And the panel consensus, and this is where we need help,
has reflected that the key criteria are morphological criteria that, you
know, really indicate who these patients are that should be treated with
this device. And if that\'s the consensus of the panel, it\'s
appropriate potentially to have those morphological criteria in the
indications for use, the most important statement.

Again, we\'re interested in truth in labeling based on the results of
the PMA application. What an individual practicing physician then does
is based on how that physician sees a risk benefit profile for a
particular patient.

CHAIRMAN LASKEY: So we continue to have this discussion on this
particular condition. Should it supplant the paragraph that we just
voted to delete since it belongs to the other morphologic/anatomic
features?

DR. KATO: If we\'re going to put that the neck has to be less than 60
degrees angulated, then I think we\'re obligated then to also consider
the other six anatomic criteria, which are immediate suprarenal neck
angulated more than 45 degrees \-- and again these are precautions.
Proximal neck inverted funnel shape, change in neck diameter greater
than 10 percent over the defined nick line, proximal neck to the
circumferential thrombus or atheroma, indispensable inferior mesenteric
artery, inability to maintain at least one patent hypogastric artery and
then unsuitable arterial anatomy.

Those would be the other anatomic criteria that would go along with
proximal neck angulation.

DR. ZUCKERMAN: Right. But we\'re looking for a realistic concise
statement that emphasizes the most critical morphological criteria. And
you could continue to extend that list, I\'m sure, with the experts
here. So I guess the question that the agency has is there is a prior
template with the Gore device and most recently approved AAA device. Is
that template hit the mark or should there be more morphological
criteria as you\'ve suggested or even potentially less?

DR. KATO: Well, I guess I would turn that over to Dr. Comerota for some
advice.

DR. COMEROTA: I think the angulation issue is an important one, and I
would concur with the motion. I think we need to be a little bit careful
about how many details we add to the over labeling. I think cautions as
they\'re going to be listed to draw the treating physician\'s attention
to these important details is appropriate. But I\'m not sure we want to
put it up there with all the red flags as angulation is.

MR. MORTON: I had just one brief comment on this. That the indications
show up in more places than simply the IFU. The sponsors are required to
put that in other promotional literature, or whatever. And if we end up
with one that becomes actually confusing to the reader, we may be
defeating our purpose.

CHAIRMAN LASKEY: Well, I favor brevity. So may we vote on this motion?

DR. NICHOLAS: Agree.

DR. FERGUSON: Agree.

DR. MAISEL: Agree.

DR. ROBERTS: Agree.

DR. NORMAND: Agree.

DR. KATO: Agree.

DR. COMEROTA: Agree.

DR. AZIZ: Agree.

CHAIRMAN LASKEY: The question up here was what are we agreeing to?
We\'re agreeing to the inclusion of the angulation criteria in place of.

DR. COMEROTA: That\'s right.

CHAIRMAN LASKEY: It\'s easy to get lost here. All right.

Are there any other conditions that we should apply?

DR. COMEROTA: Call the question? I think we were deconditioned.

CHAIRMAN LASKEY: We\'re getting there.

DR. KATO: Is this where you take out certification?

CHAIRMAN LASKEY: Remove that.

DR. KATO: Be removed.

CHAIRMAN LASKEY: Second?

DR. ROBERTS: Second.

CHAIRMAN LASKEY: Discussion. None.

Vote on the condition to remove the word \"certification\" from the
package insert?

DR. NICHOLAS: Agree.

DR. FERGUSON: Agree.

DR. MAISEL: Agree.

DR. ROBERTS: Agree.

DR. NORMAND: Agree.

DR. KATO: Agree.

DR. COMEROTA: Agree.

DR. AZIZ: Agree.

CHAIRMAN LASKEY: Any further condition?

DR. ROBERTS: I move that we vote on approval \-- oh, I\'m sorry.

EXECUTIVE SECRETARY WOOD: That\'s already on the table.

DR. ROBERTS: Oh, that\'s already on the tale.

DR. ZUCKERMAN: Dr. Laskey, before \-- since you are asking for other
conditions, do any panel members believe that the post-approval study
should be a condition of approval as presently outlined?

DR. ROBERTS: I thought it was since it was in here.

DR. ZUCKERMAN: It\'s the \-- the template has been proposed, but it
helps sometimes if the panel is very interested in seeing that this is
actually completed, a statement by the panel may be appropriate as a
condition of approval.

DR. ROBERTS: I would like to see that done as outlined.

CHAIRMAN LASKEY: AS a condition.

DR. ROBERTS: As a condition. Yes, I sort of assumed that was part of \--

CHAIRMAN LASKEY: It is confusing. It was a given, is was part of the
presentation. So what \-- are you asking for some form to the
surveillance, or how can we help here?

DR. ROBERTS: Well, maybe it should be that the condition is that the
post-marketing study, the continuation of the group that is enrolled in
the pivotal study be continued for 5 years as outlined in the IDE.

DR. COMEROTA: Seconded.

CHAIRMAN LASKEY: Sounds great. Thank you.

Discussion?

A vote?

DR. NICHOLAS: Agree.

DR. FERGUSON: Agree.

DR. MAISEL: Agree.

DR. ROBERTS: Agree.

DR. NORMAND: Agree.

DR. KATO: Agree.

DR. COMEROTA: Agree.

DR. AZIZ: Agree.

CHAIRMAN LASKEY: It\'s through five years as stated? Okay. We\'re up to
\--

DR. KATO: One more motion that the terms \-- I guess the words \"The
issues including potential for corrosion, barb separation, stent
fracture, suture break and graft material wear\" be included in the
precautions and warnings since these potential device failures have, you
know, with a parenthesis on the very low frequency, but have led to
significant serious clinical sequelae, be added to the precautions and
warnings.

CHAIRMAN LASKEY: May have resulted in?

DR. KATO: May have resulted in, correct.

CHAIRMAN LASKEY: Is there a second?

DR. ROBERTS: Yes.

CHAIRMAN LASKEY: And so we\'re clear on the vote, and I think, Norm,
you\'ve articulated that, but the inclusion of the rates here as
reflected in the data is key?

DR. KATO: Yes.

CHAIRMAN LASKEY: That they are very low, but they should be cited?

DR. KATO: Yes.

CHAIRMAN LASKEY: Okay.

MR. MORTON: Could I ask for a clarification on that? If this is coming
from outside the pivotal study, do we really know what the rates are? In
other words, I\'m \-- maybe I missed that in the package. Do we know
what the rates are, or are we asking for something that\'s going to be
very difficult to get?

CHAIRMAN LASKEY: Well, there were no clinical events in the pivotal
study. Nevertheless, there are some \--

MR. MORTON: Let me rephrase my question. The FDA has indicated that
there have been observed events, as I understand from a marking
experience.

Okay. And my only point is are we able to know what the rates are?
Obviously, the rates would be low, but are we able to know that and are
we comfortable with putting that in the labeling?

MS. ABEL: I think there\'s the option of either having the rates or just
saying that there have been 5 cases observed worldwide, and that sort of
thing. So I think there\'s a way to describe how often it\'s been
observed without actually coming up with a percentage.

And I would suggest that the other device labeling for comparable
devices also \-- you know, when talking about long term follow ups has
specifically looked for these various things. And that may be an
appropriate place to mention these specific types of failures that could
occur.

CHAIRMAN LASKEY: I think we get into a very slippery slope there if we
start to put numbers on things. I think it\'s enough to just mention
that they may occur. I don\'t think we have a handle on the frequency.
I\'m not sure it\'s going to be defensible or fair to put any number on
that frequency, and it therefore remains of realm of anecdote.

So we\'ll just state this motion, Norm, if I can restate it to include
language to mention the potential for device failure, i.e., barb
separation, corrosion, etcetera \-- leave it at that.

DR. KATO: That\'s fine.

DR. FERGUSON: Again, I\'d like to be instructed and clarify where are
the data for this and are we again appropriating data from worldwide
experience at a time when we\'re supposed to be using our own American
study to make our decisions and so on?

DR. ROBERTS: But I think the point is that all we\'re doing is to say in
the instructions for use, that people out to be aware \-- ought to be
looking for this, whether, you know, because at least they know that
this is a potential. You know, whether it\'s the animal data or it\'s
the bench testing. I mean, we can \--

DR. COMEROTA: Well, it\'s occurred and it\'s occurred in this pivotal
trial. So we\'re not drawing conclusions from data outside the pivotal
trial.

DR. FERGUSON: But there were no adverse events that occurred from this,
that\'s my point. If you\'re going to look at only pivotal trial, then
you\'re saying watch out for all these sorts of things that might
happen. Am I wrong on that?

DR. COMEROTA: You\'re talking about mechanical failure \--

DR. FERGUSON: Which we haven\'t seen.

DR. COMEROTA: But the clinical events only go up to 12 months.

DR. ROBERTS: But we\'ve only got 2 year\'s data.

MS. ABEL: Can I just clarify something. There are different sections in
the device label, and there\'s a section that does describe the clinical
data that was used in the approval of the device and the determination
as to whether or not the device was safe and effective. Obviously, if
there\'s an approved label, we determined that it was safe and
effective. But that summarizes only the U.S. data, and that\'s where,
like you\'re saying, these observations would not be in that section.
But there\'s another section warnings and cautions where it\'s perfectly
reasonable to say some of the types of things that you could see going
wrong these deices include barb separation, suture breaks, that sort of
thing. And especially if we aren\'t putting any rates in, it\'s just \--
I mean, this is a fact. They have certainly been observed, but we\'re
not going to based on the latest discussion put any numbers in. So I
don\'t think that it would be a burden.

CHAIRMAN LASKEY: I think what would help you to know that it\'s not
going to go in the IFU section, it\'ll go in the \--

DR. FERGUSON: Yes, she clarified that.

CHAIRMAN LASKEY: Yes. Did we vote on that?

EXECUTIVE SECRETARY WOOD: No.

CHAIRMAN LASKEY: Okay.

DR. NICHOLAS: Agree.

DR. FERGUSON: Agree.

DR. MAISEL: Agree.

DR. ROBERTS: Agree.

DR. NORMAND: Agree.

DR. KATO: Agree.

DR. COMEROTA: Agree.

DR. AZIZ: Agree.

CHAIRMAN LASKEY: Unanimous again.

That\'s the eighth condition, folks.

Do we have more conditions.

DR. KATO: Can I just ask one more question? I know we just voted on the
5 year follow-up.

CHAIRMAN LASKEY: Surveillance.

DR. KATO: Five year surveillance. Some of the studies that are being
published recently are up to 9 years and they\'re showing, you know,
increasing problems even at that point. I mean, and I\'m trying to get a
feel for is \-- I guess this is my question. Is five years long enough,
and I should have brought up in the discussion. So maybe I should be
quiet. But is 5 years long enough or do we \-- or should we make it ten?
Is it relevant? We just keep it at five?

DR. COMEROTA: I thought we addressed this one of the first conditions
that \-- our recommendation to the physicians is lifelong follow-up, and
that\'s already a condition.

CHAIRMAN LASKEY: That\'s was our second condition.

DR. COMEROTA: The condition to the sponsor for the patients in the
pivotal trial is that there be detailed follow-up to 5 years of the
patients in the pivotal trial. Whereas, once this device is approved,
their recommendation to the treating physicians of the patient is that
these patients be followed lifelong.

DR. KATO: I see. Okay. So there\'s no need to add the extra 5 years on
it.

CHAIRMAN LASKEY: Any other conditions?

If not, we now move on to the main motion of approvable with conditions.
And I may need some help here. I haven\'t taken my statin dose this
morning so my pre-senile dementia may kick in, but am I reciting the
conditions?

EXECUTIVE SECRETARY WOOD: To the best of your ability.

CHAIRMAN LASKEY: Do the best that I can.

So we have a move for approval with the following conditions:

Number one, that the inclusion of patients with isolated iliac aneurysms
be excluded.

Second, that there be lifelong follow-up of patients receiving this
device.

The third is the tripartite Zuckerman/Roberts crafting of the revision
for the elimination of the contraindication to MRI to be supplanted
with, first of all, a look at the current MRI experience in the pivotal
trial and to review MRI data as it is forthcoming. And certainly to
remove the contraindication as it currently exists.

Fourth condition is to remove the paragraph in the IFU alluding to AAAs
greater than 4 centimeter iliac aneurysms greater than 3.5 centimeters,
to remove that paragraph. Jumping ahead to replace that paragraph with
the angulation data as specified in the inclusion criteria for the
protocol.

The next condition is to strike the word \"certification\" from the
patient brochure \-- the training document.

The seventh condition is to ensure the collection of surveillance data
through 5 years.

And the final condition is to note the potential for mechanical failure
of the device, including barb separation, corrosion, etcetera, etcetera
but not putting any frequencies on those events.

And probably to indicate that there were no clinical sequelae in the
U.S. trial out to 12 months.

EXECUTIVE SECRETARY WOOD: That wasn\'t part of the last condition, just
as a clarification. The condition was actually to just include a
statement about the barb fractures and the other mechanical failures.

DR. FERGUSON: Mr. Chairman, is it possible to add that in an addendum.

CHAIRMAN LASKEY: I think we should.

DR. FERGUSON: Because I continue to think that the language is
pejorative to the company if we don\'t have, you know, factual data.

CHAIRMAN LASKEY: I agree. I think we should, but I think we should
specifically note that it\'s at 12 months.

Okay. Should we redo that vote just so we\'re all happy?

DR. ROBERTS: No.

EXECUTIVE SECRETARY WOOD: Yes.

CHAIRMAN LASKEY: No. We need to. This will be quick.

EXECUTIVE SECRETARY WOOD: You need a second and a vote.

DR. ROBERTS: Second.

CHAIRMAN LASKEY: A second. Good.

No discussion? Votes?

DR. NICHOLAS: Agree.

DR. FERGUSON: Agree.

DR. MAISEL: Agree.

DR. ROBERTS: Agree.

DR. NORMAND: Agree.

DR. KATO: Agree.

DR. COMEROTA: Agree.

DR. AZIZ: Agree.

CHAIRMAN LASKEY: Agree. Unanimous.

Okay. Will all those voting members in favor of approval with these
conditions please raise their hands? We have 8 for.

Against? Zero.

(Whereupon, a final vote was taken).

CHAIRMAN LASKEY: And we\'ll just finish up here by going around the
table. Please restate your name and why you voted yes.

DR. NICHOLAS: Gary Nicholas. I think the conditions of safety and
effectiveness have been well demonstrated, and with the addition of the
conditions the device should be useful to the clinician.

DR. FERGUSON: Tom Ferguson. I essentially agree with what\'s just been
said.

DR. MAISEL: William Maisel. I agree with the presented data. It appears
to assure safety and effectiveness.

DR. ROBERTS: Anne Roberts. I agree that the data demonstrate safety and
effectiveness, and I think with the conditions it\'ll be a good device.

DR. NORMAND: Sharon-Lise Normand. I agree with the data that were
presented and also believe that the conditions are important, and it
will be good for patients.

DR. KATO: Norman Kato. I agree with the approval with conditions. I
believe this device will make a \-- is safe and will be effective. And
look forward to seeing it on the market.

DR. COMEROTA: Anthony Comerota. I think that the suprarenal fixation
offers a new option for additional patients with security. The fabric of
the device may offer some advantages in additional patients and the
increased utility of the sizes may expand the number of patients that
can be treated with the endografting technique.

DR. AZIZ: Salim Aziz. In favor because I think the efficacy and safety
of the device has been demonstrated.

CHAIRMAN LASKEY: Mr. Hughes, Mr. Morton, many final words from the
consumer standpoint, industry?

DR. HUGHES: No, nothing else.

CHAIRMAN LASKEY: For my part, I want to thank Cook for an outstanding
presentation. Very clear, very cogent. Thank you.

And to the agency for a wonderful panel pack. You made life easy.

And to fellow panelists, for getting us out of here by 4:00. That\'s
great.

This concludes the report and recommendations of the panel on PMA
P020018. The PMA for Cook Zenith AAA Endovascular Graft.

Thank you very much.

(Whereupon, at 4:02 p.m. the panel was adjourned.)