UNITED STATES OF AMERICA

    FOOD AND DRUG ADMINISTRATION

    CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

    * * *

    CIRCULATORY SYSTEM DEVICES PANEL

    * * *

    MEETING

    * * *

    THURSDAY,

    NOVEMBER 20, 2003

\* \* \*

The Panel met in the Grand Ballroom of the Gaithersburg Hilton
Washington D.C./North, 620 Perry Parkway, Gaithersburg, Maryland, at
9:00 a.m., Dr. Warren K. Laskey, Chairman, presiding.

[PRESENT]{.underline}:

WARREN K. LASKEY, M.D. Chairman

SALIM AZIZ, M.D. Voting Member

JOHN W. HIRSHFELD, M.D. Consultant

ALLEN A. HUGHES, Ph.D. Consumer Representative

[PRESENT]{.underline}:

WILLIAM MAISEL, M.D., M.P.H. Voting Member

SHARON-LISE T. NORMAND, Ph.D. Voting Member

DOUGLAS A. MORRISON, M.D. Consultant

MICHAEL MORTON

JUDAH Z. WEINBERGER, M.D., Ph.D.

CHRISTOPHER J. WHITE, M.D.

CLYDE YANCY, M.D.

GERETTA WOOD Executive Secretary

[SPONSOR REPRESENTATIVES]{.underline}:

JAMES BARRY

WILLIAM KRAMER, Ph.D.

DENNIS OCWIEJA

RICHARD CHIACCHIERINI, Ph.D.

JEFFREY POPMA, M.D.

ERIC ROWINSKY, M.D.

MARY E. RUSSELL, M.D., F.A.C.C.

ROBERT SCHWARTZ, M.D.

GREGG W. STONE, M.D., F.A.C.C.

NEIL WEISSMAN, M.D.

GREG WILSON, M.D.

[FDA REPRESENTATIVES]{.underline}:

ASHLEY BOAM

JENNIFER GOODE

STEPHEN L. HILBERT, M.D., Ph.D.

HENG LI, Ph.D.

JOHN STUHLMULLER, M.D.

BRAM ZUCKERMAN, M.D.

[C O N T E N T S]{.underline}

[PAGE]{.underline}

Conflict of Interest Statement 5

Introductions 8

Open Public Session:

Kevin McKim 11

[P030025: TAXUS Express2 Paclitaxel-eluting]{.underline}

[Coronary Stent Systems]{.underline}:

Sponsor\'s Presentation:

Dennis Ocwieja 15

Mary E. Russell, M.D. 20, 84

Gregg W. Stone, M.D. 45

FDA Presentation:

Jennifer Goode 129

Stephen Hilbert, M.D., Ph.D. 140

John Stuhlmuller, M.d. 147

Heng Li, Ph.D. 156

Committee Reviewers:

Christopher J. White, M.D. 172

Judah Z. Weinberger, M.D., Ph.D. 185

Questions to the Committee 234

Open Public Session:

Jim Gustafson 289

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

(9:02 a.m.)

CHAIRMAN LASKEY: This being the magic hour, I\'d like to call this
meeting to order.

The topic today that the Circulatory System Device Panel will consider,
the discussion of the pre-market application for the Boston Scientific
Corporation, TAXUS Express2 Paclitaxel-eluting coronary stent systems,
P030025.

I\'d like to ask the Executive Secretary to read the conflict of
interest statement

MS. WOOD: The following announcement addresses conflict of interest
issues associated with this meeting and is made part of the record to
preclude even the appearance of an impropriety.

To determine if any conflict existed, the agency reviewed the submitted
agenda for this meeting and all financial interests reported by the
committee participants. The conflict of interest statutes prohibit
special government employees from participating in matters that could
affect their or their employer\'s financial interest.

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

Therefore, waivers have been granted for Drs. William Maisel and Judah
Weinberger for their interest in firms that could be affected by the
panel\'s recommendations. Dr. Maisel\'s waiver involves a grant to his
institution for the sponsor\'s product study in which he had no
involvement and for which funding to the institution was less than
\$100,001 per year.

Dr. Weinberger\'s waiver involves stockholdings in competitors in which
one value is between \$5,001 and \$25,000, and the other value is
between \$25,001 and \$50,000.

The waivers allow these individuals 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 Drs. Weinberger, John Hirshfeld,
Douglas Morrison and Clyde Yancy. These panelists reported past or
current interests involving firms at issue, but in matters that are not
related to today\'s agenda. The agency has determined, therefore that
they 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
products they may wish to comment upon.

CHAIRMAN LASKEY: If I can have the panels introduce themselves, please,
beginning on my right.

DR. ZUCKERMAN: Bram Zuckerman, Director, FDA Division of Cardiovascular
Devices.

DR. HIRSHFELD: John Hirshfeld. I\'m at the University of Pennsylvania
School of Medicine.

DR. WHITE: Chris White. I\'m from New Orleans, Louisiana.

DR. SOMBERG: Hi. John Somberg, Rush Presbyterian, St. Luke\'s Medical
Center, Chicago.

DR. NORMAND: I\'m Sharon-Lise Normand, statistician, Harvard University.

MS. WOOD: Geretta Wood, Executive Secretary.

CHAIRMAN LASKEY: Warren Laskey, Uniformed Services University and
National Naval Medical Center.

DR. MORRISON: Doug Morrison, Tucson VA, University of Arizona.

DR. YANCY: Clyde Yancy, UT- Southwestern, Dallas.

DR. WEINBERGER: Judah Weinberger, Columbia University, New York.

DR. MAISEL: William Maisel, Brigham & Women\'s Hospital in Boston.

DR. HUGHES: Allen Hughes, George Mason University, consumer
representative.

MR. MORTON: Michael Morton. I\'m the industry representative. I\'m
employed by CarboMedics.

CHAIRMAN LASKEY: And, Ms. Wood, if you could read the voting status
statement, please.

MS. WOOD: Pursuant to the authority granted under the Medical Devices
Advisory Committee charter, dated October the 27th, 1990, and as amended
August the 18th, 1999, I appointed the following individuals as voting
members of the Circulatory System Devices Panel for this meeting on
November 20, 2003:

John W. Hirshfeld, M.D.

Douglas A. Morrison, M.C.

John C. Somberg, M.D.

Judah Z. Weinberger, M.D., Ph.D.

Clyde Yancy, M.D.

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.

This is signed by David W. Feigal, Jr., M.D., M.P.H, Director, Center
for Devices and Radiological Health, and it\'s dated November 17th,
2003.

CHAIRMAN LASKEY: Prior to the open public hearing portion this morning,
I\'d like to read the following statement.

Both the Food and Drug Administration and the public believe in a
transparent process for information gathering and decision making. To
insure such transparency at the open public hearing session of the
Advisory Committee meeting, FDA believes that it is important to
understand the context of an individual\'s presentation.

For this reason FDA encourages you, the open public hearing speaker, at
the beginning of your written or oral statement to advise the committee
of any financial relationship that you may have with the sponsor, its
product, and if know, its direct competitors.

For example, this financial information may include the sponsor\'s
payment of your travel, lodging or other expenses in connection with
your attendance at this meeting. Likewise, FDA encourages you at the
beginning of your statement to advise the committee if you do not have
any such financial relationships.

If you choose not to address this issue of financial relationships at
the beginning of your statement, it will not preclude you from speaking.

I\'d like to now open the open public hearing portion this morning and
invite Kevin McKim to speak before us.

MR. McKIM: Good morning. Thank you.

First of all, in regards to your first question, I have no financial
reimbursement from either Boston Scientific nor their competition.

I am here this morning to introduce the Metricath system, which is a new
and novel product on the market, which offers quick, accurate, and cost
effective measurement in arterial stent sizing.

There\'s been a great deal of research that has demonstrated that
guidance stent implantation offers better clinical outcomes for
patients. There\'s less risk or possibility of complications, while
there is less possibility or reduced rates of restenosis and at the same
time there is actually an increase in the average diameter or
cross-sectional area of the stents that are implanted

As well, there\'s a number of studies, such as the stress study, that
demonstrated that angiography alone is oftentimes not sufficient to be
able to assess stent apposition and to know whether or not stent are
accurately placed within the arteries.

And this, we believe, is particularly true with the drug eluting stents,
that accurate and proper sizing of the arteries will allow the
physicians to select appropriately sized stents.

Additionally, it will allow them to insure that the stents are, in fact,
fully expanded and apposed against the artery wall, and this has been
mentioned in reports from both the manufacturers of the stents, as well
as the FDA.

So very quickly, what is the Metricath system? The Metricath is a
catheter based technology, and very simply the way it works is a low
pressure balloon that conforms to the shape and the size of the artery
that is being measured or to the inside diameter of the stent after it
has been deployed, and from the information that\'s gathered from the
balloon, it\'s very easy for us to quickly and accurately determine both
the cross-sectional area and also the average diameter of the stent.

So this allows us a method of (a) insuring that appropriate size stents
are being chosen, and also afterwards to insure that the stents are, in
fact, fully expanded and apposed against the artery wall.

And a few of the benefits of the system are, one, that it is very
accurate. We have evidence to show that we are equivalent to IVUS, much
more accurate than angiography alone, and more importantly, it doesn\'t
require image interpretation, and it is given simple, objective
measurement results.

Second, it is very simple. It offers very significant both technical and
operational advantages over other systems that are currently available.

Thirdly, it\'s very cost effective. So we\'re offering some significant
cost savings compared to competition.

And finally, it is a very safe product that operates at only one-third
of an atmosphere and at the pressures that it\'s operating at, we do
have some research to demonstrate that there is no damage or change to
the artery wall whatsoever.

So in conclusion, we believe that sizing, in fact, is critical for drug
eluting stents; that you offer better clinical outcomes. At the same
time, there is a much lower risk of complications, lower risk of
perforations, lower risk of restenosis, and this is especially true with
the drug eluting stents, where proper sizing and full apposition is
absolutely critical for them to work effectively. And these are all
benefits that can be achieved with the use of the MetriCath system.

And for more information, we do have a Web site,
[www.angiometrix.com]{.underline}.

Thank you very much.

CHAIRMAN LASKEY: Thank you, sir.

Is there anyone else in the audience who wishes to address the panel on
today\'s topic or any other topic?

(No response.)

CHAIRMAN LASKEY: If not, I\'d like to close this open public hearing
portion and move on to the highlight of the day, the sponsor\'s
presentation.

MS. WOOD: I would just remind the speakers to introduce yourselves and
state your relationship to the company or the competitors.

MR. OCWIEJA: Mr. Chairman, members of the panel, consultants, at first
I\'d like to thank you for the opportunity to come before you today and
present data and information relative to the TAXUS Express2
Paclitaxel-eluting coronary stent system.

I am Dennis Ocwieja. I am Senior Vice President, Regulatory Affairs and
Quality with Boston Scientific Corporation. There will be two other
presenters today: Mary Russell, M.D., Medical Director, Vice President,
Cardiovascular Clinical Sciences, Boston Scientific Corporation; and
Gregg Stone, M.D., Vice Chairman, Director of Cardiovascular Research
and Education, Cardiac Research Foundation, Lenox Hill Heart and
Vascular Institute, and a principal investigator for our TAXUS-4
clinical study.

We also have with us a number of expert consultants. Let me read their
names to you and what area of expertise we expect them to be able to
help us in.

Dr. Black, Hugh Black and Associates, Toxicology.

Dr. Chiaccierini, RPC Consulting, statistical.

Dr. Stephen Ellis, Cleveland Clinic, co-PI on the TAXUS-4 study.

Dr. William Kramer, Kramer Consulting, pharmacologist.

Dr. Jeffrey Popma, Harvard Clinical Research Institute, Angiographic
Core Lab.

Dr. Eric Rowinsky, Institute for Drug Development and Cancer Research,
oncologist.

Dr. Robert Schwartz, Minnesota Cardiovascular Research Institute,
preclinical.

Dr. Neil Weissman, MedStar Research Institute, our IVUS Core Lab.

And Dr. Greg Wilson, Hospital for Sick Children, Toronto, pathologist.

Our agenda for today is as follows. After this brief introduction that I
will be presenting to you, I\'ll also discuss our proposed indication
for the TAXUS stent.

I\'ll then turn the floor over to Dr. Russell, who will talk to you
about our TAXUS technology, the TAXUS preclinical program, and clinical
development program.

Dr. Stone will then come and give you information relative to the
TAXUS-4 pivotal U.S. trial.

Dr. Russell will come back and present conclusions, and then the three
of us will be available to take questions from the panel and direct them
to our expert consultants as necessary.

Why are we here today? The rationale for drug eluting stents.

Since restenosis is a major limitation, we\'re saying 800,000, and we
have indications that maybe as much as a million coronary stenting
procedures are performed annually, and 20 to 30 percent of the patients
receiving a bare metal stent develop angiographic restenosis with half
or approximately 100,000 of the patients requiring repeat intervention,
either PCI or CABG.

The TAXUS stent technology was developed to reduce restenosis and the
need for repeat reintervention.

We\'re looking at a proposed indication for the TAXUS stent in our
product labeling that reads as follows: \"TAXUS Express2
Paclitaxel-Eluting Coronary Stent Systems,\" both \"(Monorail and
Over-the-Wire) are indicated for improving luminal diameter and reducing
restenosis for the treatment of [de novo]{.underline} lesions less than
or equal to 28 millimeter in length in native coronary arteries, greater
than or equal to 2.5 to less than or equal to 3.75 millimeter in
diameter.\"

In addition, while we\'re talking about labeling, there was an oversight
that we made perhaps, and certainly a question that was addressed to the
panel member relative to antiplatelet labeling recommendations, and
we\'re proposing recommendations for the DFU that Clopidogrel be
recommended at a 300 milligram loading dose prior to implant, a 75
milligram dose per day for six months, and that aspirin also be provided
to the patient prior to implant and used indefinitely thereafter.

We are looking for a proposed stent matrix for approval of the product
that includes stents from 2.5 to 3.5 millimeter in diameter and eight
millimeters to 32 millimeters in length. The shortest stents, the eight
and 12 millimeter length stents are intended to be used as in the
clinical study for multiple stent procedures to optimize angiographic
outcomes.

At this point I\'d like to turn it over to Dr. Russell to get into the
technology overview.

DR. RUSSELL: Thank you very much.

Let\'s begin with the TAXUS technology overview. There\'s three
components: the drug, the polymer, and the stent. The drug we\'ve
selected is Paclitaxel. It\'s located on the stent at one micrograms per
millimeter squared per stent surface area.

Paclitaxel is the active agent used for chemotherapeutic purposes.
Paclitaxel is the active agent in Taxol used for chemotherapeutic
purposes. It binds to beta tubulin shown here in yellow, disrupts the
dimerization of tubulin, and hence interrupts microtubulin dependent
activities, including, but not limited to, signal transduction, cell
activation and migration, inflammatory cell chemotaxis, cell
proliferation, growth factor release, and matrix organization.

There are contrasting use of Paclitaxel. There\'s the anti-neoplastic
use contrasted against the anti-restenotic use. For anti-neoplastic
purposes, Taxol incorporates Paclitaxel in a Cremophor to solubilize it
for intravenous administration for systemic therapy. This systemic
therapy is targeted at malignant, actively dividing cells. A single dose
would involve about 300 milligrams for an average human being and a
cumulative dose cycle involving four cycles would be about 1,200
milligrams.

In contrast, for anti-restenotic purposes, Paclitaxel is coated onto the
TAXUS stent. This is done through a polymer, provides local vascular
dosing, targeted at activated vascular cells in the post implant period.

A single 32 millimeter stent has 209 microgram loaded on it. Four
stents, should they be required, would have a total of 0.8 milligrams.
If all of the dose were released from the four stents, which is
improbable as I\'ll show you on subsequent slides, there would be a
1,400-fold lower Paclitaxel exposure with the anti-restenotic use than
anti-neoplastic systemic exposure.

The second critical component of our technology is the polymer. It\'s
termed Translute. Polymer based delivery was specifically selected
because it provides local, targeted, short-term drug delivery, controls
release of the drug from the polymer, provides homogeneous drug coverage
along the length of the stent, retains the drug on the stent during
handling, and hence prevents drug loss during the implant procedure,
nonuniform drug distribution, and then uncontrolled release.

Translute is a proprietary polymer. It\'s a hydrocarbon based elastomer
specifically selected because of its processing capability and the
performance of uniform coding over the stent struts. It\'s highly
biostable and standardized testing and as I\'ll show you, it\'s vascular
compatible.

Procine stent implant studies evaluating mortality, morphologic and
quantitative morphometric parameters were performed to establish that
the Translute only coated stents are comparable to bare control stents
at Day 28, 90 and 180 days.

Additional studies evaluating polymer stability testing were performed
on canine graphs out to two years. Polymer coating integrity was
maintained long term without evidence of flaking, cracking or
delamination. There was no particulate generation, and there was no
polymer degradation [in vitro]{.underline} or [in vivo]{.underline}.

Molecular weight profiles are stable by sizing analysis using a
polydispersity index, and these findings are true for TAXUS stents
implanted in the porcine model and then explanted for evaluation at up
to 180 days. This allows us to conclude that the Translute polymer is
vascular and biostable, and durable [in vitro]{.underline} as well as
[in vivo]{.underline}.

I\'d like to now cover the TAXUS release kinetics, first touching on the
characteristics of a polymer matrix delivery system, and then reviewing
[in vitro]{.underline}, [in vivo]{.underline}, and systemic release
characteristics.

The Translute Paclitaxel polymer system follows the model of a matrix
drug delivery system. There\'s low drug loading in the polymer. It
provides for uniform or homogeneous drug distribution throughout the
polymer matrix by phasic release, as I\'ll show you, and the release of
very low concentrations of Paclitaxel over a short period of time,
depending on the formulation.

The characteristics of our low Paclitaxel dose loading on the TAXUS step
are depicted in this cartoon. There\'s a biphasic release mediated by an
early burst phase in the zero to two-day period. This is due to
dissolution mediated release of Paclitaxel from the surface of the
coated stent.

It\'s followed by a sustained slow release phase, two to ten days, where
the drug diffuses through channels in the subsurface shown here in
yellow to the surface, and then finally there\'s a plateau phase after
30 days where drug is sequestered within the polymer matrix without
pathways to the external environment in the so-called bulk phase shown
here in pale green.

This depicts [in vitro]{.underline} release from the TAXUS stents,
Paclitaxel release shown here. You see the early burst phase, zero to
two days, followed by the sustained slow release phase, two to ten days.

We have two dose formulations under active investigation, the slow
release formulation the subject of this PMA and the moderate release
formulation that produces three times higher initial release.

They both have a dose density of one microgram per millimeter squared,
but they\'re distinguished because there\'s a lower Paclitaxel polymer
ration in the slow release formulation compared to the higher moderate
release formulation. This results in sparser drug distribution depicted
here in the cartoon for the slower compared to the denser for the
moderate release.

Hence, to achieve the one microgram per millimeter squared, the coating
thickness is larger in the slow release than it is in the moderate
release.

This results in differential [in vivo]{.underline} release kinetics,
with 7.5 percent of the total loaded drug released in the first 30 days
for the slow release formula contrasted with 21.9 percent release for
the moderate release formulation. This leaves a residual 92.5 percent of
the total loaded drug retained on the stent after 30 days for the slow
release formulation compared to 78.1 percent for the moderate release
formulation.

This depicts cumulative [in vivo]{.underline} release in the rabbit
iliac model as shown here. The slow release in yellow has less release
than the moderate release in green. There\'s a plateau after 30 days,
and the moderate release formulation has been our focus for preclinical
studies because of its higher release.

The slow release has been the focus of our clinical studies focused on
efficacy.

We\'ve examined the stability of the retained Paclitaxel in this bulk
phase, performing studies aimed at identifying the maximum release
conditions. Physiologic conditions shown here, including phosphate
buffered ceiling with various additives, such as surfactants,
cyclodextrins, proteins including albumen, lipids, and whole blood, do
not alter the release level.

However, non-physiologic conditions, including 100 percent solvents, low
pH and high temperature, are required to reach the FDA benchmark of
greater than 80 percent release.

Under these extreme conditions, the polymer\'s physical characteristics
are destroyed as measured by increased tack force and increased
swelling, and these non-physiologic conditions are impossible to reach
in living human beings.

We\'ve also examined drug release after intentional coating disruptions.
For example, we\'ve used scalpels to abrade 50 percent of the abluminal
surface of the slow release stent, and you can see an abraded strike
here with the elastomeric polymer adherent.

And then we\'ve gone on to measure [in vitro]{.underline} the amount
released contrasting the abraded with the controlled stents. You can see
there\'s a small increase in release to 1.8 percent for the abraded
compared to 1.2 percent for the controlled stents, indicative of stable,
low level release even with artificial abrasion.

Systemic Paclitaxel measures were evaluated in studies simulating higher
Paclitaxel release, specifically serum levels were measured in porcine
stent implant models after exposure to maximum doses likely to be
present in humans.

We used the moderate release formulation, which releases more than the
slow release formulation; studied overlapping stents and higher dose
densities up to four micrograms. We developed a high sensitivity liquid
chromatography tandem mass spec assay that has a lower limit of
quantitation of 0.03 nanograms per mL and a lower limit of detection of
0.006 nanograms per mL.

In these studies, one of 247 samples, a pig that received two moderate
release overlapping stents had a level of 0.048 nanograms per mL, just
over the detection limit, immediately post implant in one of the
specimens that was measured.

The other 246 out of 247 samples have no Paclitaxel detectable. Hence,
to conclude with respect to the TAXUS technology, we have a vascular
compatible elastomeric polymer. It produces biphasic, low level release
in the targeted 30-day period. After mechanical challenge, release
remains low and stable. Retained drug is sequestered in the bulk and has
no measurable release under physiologic conditions. And we have no
detectable systemic Paclitaxel release with a high sensitivity assay.

With respect to our preclinical safety program, it is an extensive
program that has involved more than 12 studies, more than 250 swine, 800
stents, and gone out to 360 days. It is a program that has evolved from
polymer only studies to a focus on both moderate release and slow
release studies.

The majority of our studies have focused on the moderate release
formulation because of the higher amount released in the early ten-day
period.

We perform both overlapping stent and dose density studies to establish
the safety of the moderate release formulation and, as important, to
provide a safety margin for the slow release formulation.

For the slow release formulation, we\'ve looked at overlapping stents,
and then we\'ve looked at the histologic profiles over time with an
alternative antiplatelet regimen, ticlopidine.

For preclinical safety parameters, there\'s been consistency across the
moderate release, as well as the slow release studies. Out of 127 pigs,
there were two that were categorized as cardiac morality. However, one
was a super renal abdominal laceration, and the other was an air
embolism, during implant.

So there were effectively no TAXUS related cardiac mortality. There were
no miocardial infarctions as graded histologically, and there were not
stent thromboses in all 340 stents evaluated.

Hence, the pre-clinical safety pattern correlates to the clinical safety
pattern. We focused on early histologic safety parameters, have been
able to demonstrate surface passivation by day 28 for moderate release
stents using endothelial cell coverage. It is complete by day 28 for all
single layer, moderate release stents, for all slow release stents.

It\'s complete by 90 days for the moderate release overlapping stent
layers. There\'s resolution of microthrombi and surface fibrin.
Assessment of microthrombi demonstrated that it was statistically
equivalent in the control and the TAXUS groups at all time points. There
were rare microthrombi as depicted here and shown here at high power
with no evidence of gross thrombi.

And importantly, there was neointimal coverage on all struts with an
early, neointimal organization pattern.

Our early histology correlated with our preclinical safety patterns.

With respect to late histologic safety, we\'re demonstrated that it is
maintained out to 360 days for the moderate release formulation,
demonstrating a mature neointima shown here as a compacted, thin,
fibrocellular layer, indicative of a quiescent response. Vessel
stability has been demonstrated using morphometric measures of EEL,
which are equivalent to control and demonstrating a stable stent to IEL
relationship.

And then finally, there are no aneurisms. There is medial cell loss , as
I\'ll show you, but it\'s replaced by structural fibrous tissue. There
was no incomplete stent apposition. Vessel wall integrity was
maintained, and there were no aneurismal changes.

Hence, the late and sensitive histologic analysis supports long-term
safety.

We\'ve explored safety in overlapping stent models, looking at the
moderate release formulation out to 180 days and 132 stents. The
advantage of this model is that one could compare the proximal single
and distal single strut layers with the overlapping two strut layer
regions. Endothelial cell coverage was present by day 28 for the single
layers, by day 90 for the overlap layers. There was stable neointemal
and vessel structure out to 180 days, and there was healing in the
overlap zone where there was a double strut and theoretically a double
Paclitaxel dose.

Hence safety has been shown for overlapping stents using the moderate
release formulation.

We\'ve looked at histology patterns over time, again, with the moderate
release formulation from 28 out to 360 days. Endothelialization is
complete as to the presence and maturation of the neointima and then the
maintenance of vessel structure as measured morphometrically, indicating
healing over time with the moderate release dose.

We characterized the observation of para-strut amorphous material, which
is present in control and Paclitaxel eluting stents. It\'s shown here as
an acellular fibrin rich area immediately adjacent to the stents with a
connective tissue component. There\'s more in the moderate release than
the slow release, than the control.

It involves less than five percent of the vessel wall in the slow
release. It\'s not inflammatory in that there\'s a paucity of white
cells. It\'s sequestered within a maturing neointima in all cases, and
importantly, there is no associated luminal thrombus, erosion or vessel
wall necrosis.

If we look at the para-strut amorphous material over time, we see that
it resorbs and heals with a moderate release stent. At day 28, it
localizes to the struts. It\'s most apparent at this time, but highly
variable in size. There\'s less in the slow release than the moderate
release. There\'s associated early medial cell loss, and it\'s
sequestered within the neointima.

Between day 90 and 180, there\'s cellular in-growth adjacent to the
struts due to smooth muscle cell and white cell accumulation. The PAM
zones themselves decrease in size and intensity. They\'re not
inflammatory during this resolution phase, and there\'s a maturation of
the neointimal covering with stable medial and adventitial regions.

By 360 days, there\'s resorption of the PAM, fibrous in-growth, clearly
healing at the implant site and stable vessel and neointima.

We\'ve concluded that the early Paclitaxel burst release does not
inhibit the later healing pattern.

With respect to strut associated medial changes for the moderate
release, between the struts we have a normal media and a moral
neointima. Adjacent to the struts for both control and the TAXUS program
there is compression; there is medial cell loss, more apparent in the
TAXUS than in the control.

However, this is followed by fibrous replacement and stable vessel
morphometry, and we\'ve demonstrated that vessel stability is
maintained.

With respect to calcium deposits, shown here are the worst case
scenario. Calcium deposits are present in both control and moderate
release. they\'re scarce in both groups. An indicator of healed prior
focal necrosis in response to implant injury, they tend to be larger in
the control and strut based. They\'re more frequent in the TAXUS group,
but have a more diffuse pattern, as shown here by the black staining.

They\'re variable, but small in size, typically less than 50 microns,
and they are sequestered, inert, and stable over time.

So to summarize our preclinical histologic findings, we have healthy
endothelial cells and strut coverage by day 28 for the slow release
stent. There is early medial changes followed by fibrous replacement.

Neointima forms around, over and between the struts. There are small
areas of an inert para-strut amorphous material that resorb
progressively through 360 days, and we\'re left with an artery that\'s
pacified, has generated a stable neointima, and is structurally intact.

With respect to the potential concern raised by FDA, histologic
observations of PAM, medial loss, calcification did not develop into
higher risk of stent thrombosis, aneurisms, incomplete apposition, or
dissection, in long-term assessments, both preclinically and clinically,
with and without overlapping stents.

Safety has been established for the slow released TAXUS Express in that
there were no safety events with progressive healing patterns
demonstrated histologically. Safety demonstrated for overlapping
moderately stents and an acceptable safety margin established for the
slow release based on the safety of the moderate release.

I\'d now like to focus briefly on the TAXUS clinical development
program. This has involved six randomized trials with an anticipated
3,400 patients by the end of 2003. We\'ve evaluated both the slow and
moderate release formulations, and we\'ve progressed from low to higher
risk lesions, as I\'ll show you.

The program has as its foundation TAXUS I, a feasibility study on slow
release; TAXUS II, an international study looking at both slow release
and moderate release; and then a single arm in stent stenosis registry
using slow release.

The focus of our program and the focus of today\'s presentation is the
U.S. IDE pivotal TAXUS IV study using the slow release formulation to be
presented shortly by Dr. Stone. The program has expanded to include the
randomized studies, TAXUS V, a [de novo]{.underline} stent study
involving smaller reference vessel diameters and longer lesions; TAXUS V
in-stent restenosis randomized against brachytherapy; and TAXUS VI, a
European long lesion study on the moderate release formulation.

In addition to that, we have two active registries, WISDOM and MILESTONE
II. In terms of the clinical development program, the foundation, as I
just mentioned was TAXUS I through III that used the mere stent
platform. Since then we have focused on the Express stent platform in
TAXUS IV through V-ISR.

We\'ve moved from work horse stent diameters of three and three-five to
TAXUS IV, where we used a two-five stent in addition, and then more
recently TAXUS V with a stent diameter of 2.25 as well as 4.0.

Lesion lengths have increased from the focal ten to 12 in the foundation
studies to up to 28 in TAXUS IV and up to 46 in TAXUS V and V-ISR.

We\'ve moved from single lesion stenting studies to multiple lesion
overlapping stent studies in the forms of TAXUS V and VI, and we\'ve
moved from allowing single vessel stenting procedures to multiple vessel
stenting procedures to mimic the real world practice.

We\'ve studied the slow release in six studies and the moderate release
in two studies.

TAXUS I was a feasibility study focused on the TAXUS slow release
formulation. We evaluated standard risk de novo lesions. It was
randomized one to one. IVUS was used post placement and in follow-up in
all patients. This was targeted at improving our sensitivity and picking
up vascular changes both for safety and efficacy assessments. It was
double blind and the core labs remain blind to date. It was initiated in
September of 2000, enrolled 61 patients, 31 of them receiving the slow
release stent. Clopidogrel was protocol mandated for six months, as it
is in all of our studies, and we are evaluating those patients out to
five years.

The baseline demographic and lesion characteristics were well matched
with a reference vessel diameter of 2.9 and a lesion length of 11.3
millimeters. At six months there were concordant and significant QCA and
IVUS improvements of greater than 50 percent. Binary restenosis was zero
percent without evidence of any edge restenosis, and at 12 months the
MACE was three percent in the TAXUS group versus ten percent in the bare
metal control, and we are now in the middle of our third year of
follow-up.

This slide depicts the TAXUS I target revascularization rate with
control shown here in gray, with ten percent TLR at 24 months. TAXUS has
not had a single target lesion revascularization out to 24 months.

TAXUS II is our international slow and moderate release study. It\'s
focused on standard risk de novo lesions. Again, randomized one to one;
again, double blind; again, the core labs remained blind. It used IVUS
post placement and in follow-up in all patients and remains the largest
IVUS database in the drug eluting stent arena.

It has as its primary endpoint percent net volume obstruction by IVUS,
was initiated in June 2001, enrolled 536 patients at 38 international
centers into two cohorts, the TAXUS slow release cohort with its own
control, with DMC clearance to move into the taxus moderate release
cohort with its own control.

Clopidogrel, again, mandated for six months and follow-up for five
years. Well matched demographic and lesion characteristics with a
reference vessel diameter of 2.8, a lesion length of 10.4, and for both
the slow release and the moderate release the primary endpoint was met.

There were also significant improvements in six month QCA and IVUS
parameters, as well as edge parameters and ongoing benefit demonstrated
at 12 months for TLR, TVR and MACE.

This study is now ending its second year of follow-up.

This slide depicts the TAXUS II target lesion revascularization
responses. As you can see, at six months there was significant
improvements between control and the slow release, as well as the
moderate release group. At 12 months these benefits were sustained with
a TLR rate of 14.4 percent in the control, 4.7 percent in slow release,
and 3.8 percent in moderate release, indicating stable and preserved
target lesion revascularization out to 12 months.

Systemic Paclitaxel levels have been measured in TAXUS I through III.
Blood levels were quantitated by a commercial lab with a lower limit of
quantitation of ten nanograms per mL. All 2,188 samples had no
measurable Paclitaxel.

With respect to the issue of potential systemic drug interactions,
particularly with the pharmacotherapy common in coronary artery disease,
patients that you\'re familiar with, the antiplatelet regimens,
anti-coagulations, statins, and other cardiovascular meds, there has
been no precedent for interruption of these meds with Paclitaxel,
despite systemic Paclitaxel\'s infusions for oncology patients with
levels up to 3,650 nanograms per mL and a vast clinical experience since
approval of Paclitaxel in 1992.

This is to be contrasted with the plasma levels with the TAXUS stent
that are below the lower limit of quantitation of the commercial assay,
ten nanograms per mL. Hence, it is unlikely that metabolism or clearance
of pharmacotherapy common in coronary artery disease patients will be
affected by the TAXUS stents or vice versa, given the contrast in these
plasma levels.

With respect to the issue of potential hypersensitivity reactions, the
principal culprit for Taxol associated hypersensitivity is the
Cremophor, a poly-ethoxylated castor oil that\'s used to solubilize
Paclitaxel and other agents. It generates a histaminic response.

In the oncology arena, this can be minimized by protracting the infusion
over a 24-hour period and using lower systemic Taxol dosing.

Probably most important for our technology, we do not use the Cremophor
on the TAXUS stent system. We solubilize the Paclitaxel with our
polymer, and then, of course, as I\'ve just shown you, plasma levels
with the TAXUS set are below level of detection.

Hence, we believe hypersensitivity reactions are unlikely with the TAXUS
stent.

To summarize, TAXUS I and TAXUS II serve as a foundation. They studied
the standard risk, focal, de novo lesions; demonstrate improved efficacy
with concordant benefits clinically and by QCA and IVUS, and durable
patterns out to two years.

The safety profile we believe is acceptable. There\'s improved MACE. No
measurable systemic Paclitaxel levels, no vessel enlargement, aneurisms
or dissections in spite of intensive IVUS analysis, demonstrating
structural stability post implant.

These TAXUS I and II findings support the TAXUS IV findings that you\'re
about to hear about from Dr. Stone.

And it is now my pleasure to introduce Dr. Stone, the principle
investigator of the TAXUS IV study.

Thank you very much.

DR. STONE: Thank you.

Good morning. It\'s my pleasure to present to you the pivotal data from
the TAXUS IV trail in the United States.

In the way of disclosure, I\'m a consultant for Boston Scientific. I\'ve
also served as consultant for several of Boston Scientific\'s
competitors, including Guident and Medtronic. I hold an equity position
in a subsidiary company, which was purchased by Boston Scientific, which
I liquidated before the study was complete, and finally the
not-for-profit organization that I work for, the Cardiovascular Research
Foundation, which also puts on the annual TCT meeting, has received
either research or educational grants from most of the companies that
produce both devices and pharmacology products related to interventional
cardiology.

The TAXUS IV pivotal trial of the TAXUS slow release stent was a study
that enrolled 1,326 patients undergoing elective stenting at 73 United
States sites. For enrollment in this trial, the patient had to have a
single lesion, which was de novo, that is, never before treated,
coverable by a single stent.

The reference vessel diameter had to be between 2.5 and 3.75 millimeters
by visual assessment, and to cover these vessel diameters, we had stent
diameters present of 2.5, 3.0, and 3.5 millimeters.

The lesions length had to be visually estimated by the operator to be
between ten and 28 millimeters, and we had stent length available of 16,
24, and 32 millimeters, and we had a full matrix of diameters and
stents, except there were no 32 millimeter long, 2.5 millimeter stents.

In order to insure that several of the very important variables that can
affect restenosis were equally distributed in the two groups, the
randomization was stratified by the presence of medically treated
diabetes and by visually assessed vessel diameter, either less than or
greater than three millimeters.

Patients were pre-treated with aspirin, 325 milligrams, and given a
Clopidogrel of 300 milligram loading dose, and then were randomized one
to one before predilitation to either the one microgram per millimeter
squared slow rate release Paclitaxel-eluting Express TAXUS stent or an
identical appearing uncoated Express stent.

I think it\'s an important point to note that the stents were absolutely
indistinguishable, and the stents and patients were randomized by serial
number. So to date we still don\'t know which stent was put in which
patient, and the study is being completely blinded through the five-year
follow-up period.

Patients were treated after stent implantation with Clopidogrel for six
months. Clinical follow-up was planned at one, four, and nine months,
and yearly for five years with the primary endpoint of the study being
clinical at nine months.

Angiographic follow-up was planned in a subset in nine months of 732
patients, and intravascular ultrasound follow-up was planned in a subset
of 268 patients.

Before we get more into the trial, I\'d like to go over a few of the
definitions that are used to understand the safety and efficacy of this
device.

The principal endpoint of the study was target vessel revascularization,
and the two most important determinants of efficacy of drug eluting
stent are both target vessel and target lesion revascularization called
TVR and TLR.

TVR and TLR refer to ischemia driven, repeat, percutaneous coronary
intervention or bypass surgery of the target vessel or the target
lesion, respectively. And so to be able to meet the definition of a
repeat procedure that counts as a TLR or TVR, a separate independent
clinical events committee, which was blinded, of course, to
randomization assignment, had to say that there was significant
restenosis either at the lesion or at the edges of the lesion.

So it included the entire analysis segment that we\'ll talk about later
with angiography, and they had to state that there was ischemia that was
driving that repeat intervention or that there was a severe diameter
stenosis present by angiography.

Target vessel failure was defined as either cardiac death, target vessel
revascularization or myocardial infarction, which was adjudicated by the
clinical events committee as being related to the target vessel. If it
wasn\'t clear whether or not and event was related to the target vessel
or not, it was adjudicated as being target vessel failure.

Major adverse cardiac events were more encompassing relating cardiac
death, myocardial infarction, or target vessel revascularization whether
or not related to the target vessel.

And finally, stent thrombosis, of course, is an important indicator of
safety, and we used a very sensitive determinant of stent thrombosis
being either angiographic, that is, vessel renarrowing occlusion with
the presence of thrombus or without the presence of angiography, any
death within the first 30 days without an obvious clause, such as
pneumonia or sepsis, was adjudicated as being due to stent thrombosis
even without angiographic confirmation, and any acute myocardial
infarction without angiographic confirmation was also adjudicated as
stent thrombosis.

Of the 1,326 randomized patients, the analysis plan prespecified that
the evaluable population would be those patients in whom a study stent
was attempted to be placed. Whether or not it was actually placed or
not, those patients are still in the evaluable population.

There were a total of 12 patients, a very small percentage in which for
a variety of reasons no study stents were attempted to be placed. Either
the patient withdrew on the table or there were no study stents
available or there was a left main or a wire dissection when those
stents were implanted, and again, by analysis plan, we for statistical
purposes de-register those patients.

However, these patients were followed for the full nine-month period in
ongoing, and while we\'ll be presenting the data today from the 1,314
patient evaluable study population for the analysis plan, we also have
generated data which is in your panel packs for the complete 1,326
patients, and there are no significant changes in any of the
conclusions.

Of the 1,314 patients, they were equally assigned, again, 662 to the
TAXUS group and 652 to the control group, and nine-month follow-up was
complete in 97 percent of the patients.

Now, of these 1,326 patients, we had originally planned a cohort of
1,172 patients, but we had prespecified to FDA that we would enroll at
least 200 patients, receiving 2,400 millimeter stents and have follow-up
on them, and 200 patients with 32 millimeter stents.

The 32 millimeter stents became available late within the clinical
trial. The clinical trial enrolled actually faster than we had
anticipated, and thus, as was prespecified in the protocol, we expanded
the enrollment in an additional 154 patients to include enrollment of
additional 32 millimeter patients into the study, which brought us up to
1,326.

Looking at the 1,314 evaluable patients, you can see that they have the
pretty much typical characteristics of populations that undergo
percutaneous coronary intervention. Approximately 28 percent of the
patients were women.

Important to note about a quarter of the patients had diabetes, and
eight percent were insulin requiring diabetics, mostly Type II
diabetics.

And, again, the majority had hypertension, hyperlipidemia, with
significant numbers of current smokers, prior myocardial infarction, and
unstable angina, and there was equal representation of all the major
baseline demographic characteristics between the control groups and the
TAXUS groups.

The lesions that were treated were in the left anterior descending
artery in approximately 40 percent of the cases, the right coronary
artery in about 32 percent of the cases, and the circumflex artery in
about 28 percent of the cases. So the vessel distribution of the lesions
were similar between the two groups.

By quantitative coronary angiography, the reference vessels were 2.75
millimeters in diameter in both groups, so moderately small vessels. The
minimal luminal diameters in diameter stenoses were what we\'ve come to
to expect by QCA in trials of this type, and the lesion lengths were
moderately long at 13.4 millimeters, with a standard deviation of 6.3
millimeters, meaning we had short lesions, moderate length lesions, and
long lesions, and there were no differences in the baseline QCA lesion
characteristics between the control groups and the TAXUS group.

This somewhat busy slide shows the procedural details within the trial.
Glycoprotein IIb/IIIa inhibitors were used in about 57 percent of the
patients, IVUS within a quarter.

We allowed percutaneous coronary intervention of non-target vessels
prior to randomization and for randomization to continue, this had to be
a successful, uncomplicated PCI of the non-target vessel. So this made
this a higher risk population than in other drug eluting stent studies,
but it made much more of a real world study.

And about 20 percent of the patients had a second lesion in a non-target
vessel which was treated with a stent or FDA approved stents.

Stents were deployed at 15 atmospheres, and as you can see the
balloon-to-artery ratios were about 1.2 to one, and the stent-to-lesion
length ratio is about 1.6. There were no differences in any of the
procedural characteristics between the control groups and the TAXUS
groups.

The mean number of stents implanted per patient were about 1.1 in both
groups. So this was a single lesion, single stent study. However, as
always, there are some times when an operator would choose a stent which
is a little short for the lesion, and there are other times where there
would be an edge dissection where a second stent had to be implanted.

As you can see, most of the time, about 98 percent of the time, as
prespecified by the protocol, there was an appropriate size study stent
that was available, and of course, if the patient randomized to the
TAXUS stent, the IVRS system would give them a new serial number for
another TAXUS stent, and similarly if it was bare metal stent.

Non-study stents were used in about two percent of patients, and this
typically occurred when the right size taxus stent is not available. The
data, of course, that we\'ll show you will be intention to treat, which
would include all of these stents, both study stents and non-study
stents.

So thus, the vast majority of patients received one study stent. You can
see a smaller percentage of patients with two study stents, and a very
small number that had three study stents.

This is the matrix of the stent sizes that were actually implanted. You
see the control group and the TAXUS group, 16 millimeter stents, 24
millimeter stents, and 32 millimeter stents. These are absolute numbers
broken down by in the brown, 2.5 millimeter diameter; in the orange,
three millimeter diameter; and in the yellow, 3.5 millimeter diameter.

Approximately 60 percent of the stents implanted were the 16 millimeter
stents, and about 20 percent were the 24 millimeter stents, and 20
percent were the 32 millimeter stents. And there was good representation
of both small stents, intermediate stents and large stents, and as you
can see again, there were no 32 millimeter/2.5 millimeter stents in this
trial.

Aspirin was, of course, prespecified in all patients throughout the
follow-up period, and thienopyridines, Plavix being the first choice for
six months, both pre-load and then for six months.

If you look at the aspirin scale here, this shows usage pre-procedure,
post one month, four months, and nine months, and the scale here is very
expanded, 90 percent to 100 percent, and most patients certainly before
the procedure were on aspirin. There were a few patients who developed
reactions that may have been due to aspirin, and because they were also
on Clopidogrel, the physician stopped them, but approximately 98 to 99
percent of patients were taking aspirin at most points of the study.

If you look at thienopyridine use, the vast majority of which was
Clopidogrel, you could see it was extremely high, near 100 percent, both
at baseline and lost procedure, and at one month and at four months it
was still approximately 99 percent, 98 percent. The drug was allowed to
be stopped at six months, and at nine months there was still about 45
percent of patients that were still taking Clopidogrel.

The primary endpoint of the trial was target vessel revascularization at
nine months, and going forward now, I\'ll be showing you bar graphs
which will show the control stent in red and the TAXUS stent in green.
Target revascularization at nine months occurred in 12 percent of the
control treated patients, and this was reduced approximately 61 percent,
to 4.7 percent in the TAXUS treated patients.

Now, the target vessel revascularization consists of actually restenosis
of the target lesion which could be at the lesion itself or at the
edges, and that is best represented by the clinical variable of target
lesion revascularization.

LTR is actually the best clinical surrogate for drug eluting stent
efficacy, and TLR was reduced from 11.3 percent in the control group to
three percent with the TAXUS stent group, a relative 73 percent
reduction, and you can see the confidence interval here.

The difference from TLR to TVR is other events that could occur even
from side branches or new lesions that develop four or six centimeters
away from the drug eluting stent that, of course, we don\'t expect a
drug eluting stent to be able to either prevent or treat, and there were
a few such events in both groups that weren\'t statistically
significant.

When one looks at the reduction in target vessel revascularization,
it\'s important to note that it was caused by both a reduction in repeat
percutaneous coronary intervention and repeat bypass surgery. I think
this is significant. To my knowledge, it\'s the first time I\'ve seen
one stent compared to another where there\'s actually a reduction in the
need for, of course, a much more invasive bypass surgery because of
using one stent versus the other.

This was highly statistically significant. It\'s about a 69 percent
reduction.

Thus, summarizing the clinical events, the primary endpoint, nine month
target vessel revascularization, that was met as evidenced by a 61
percent reduction in the TAXUS group versus control, and there was a 73
percent reduction in the nine-month target lesion revascularization
rate, again, which is the best clinical surrogate for efficacy of a drug
eluting stent.

Let\'s now go to the QCA and IVUS analyses to learn more about the
efficacy and safety of these devices. Of the 1,314 patient sin the
study, the nine-month angiographic cohort was prespecified actually pre
and post specified \-- I\'ll describe that in a minute \-- as 732
patients.

There were actually 536 patients from the original 1,172 patient cohort
for which angiography was prespecified. These patients signed a consent
form up front for follow-up angiography.

Now, in addition, because we wanted to get further evidence of efficacy
and safety of these additional 32 millimeter stents, and these patients
were for the most part enrolled after the follow-up angiography cohort
was closed, we submitted a protocol amendment and received permission to
get additional follow-up in an additional 196 patients in the 32
millimeter cohort. This brought the total to 732 millimeters.

Now, these patients had not originally signed a consent form for
follow-up angiography. So these patients had to be recontacted and asked
if they would again participate in the follow-up angiographic phase.

Overall, nine month angiographic follow-up was completed in 76.4
percent. This included 82.5 percent of the original cohort, who you had
agreed up front that they were going to come back for follow-up
angiography, and approximately 60 percent of the patients who were
contacted in a post hoc pattern to ask them if they would come back with
32 millimeter stents for follow-up angiography.

When one looks at the baseline characteristics of the angiographic
subset versus those not in the angiographic subset, you can see that the
age, gender, and the presence of diabetes mellitus, which is, of course,
an important determinant of restenosis, was similar in both groups.

When one looks at the two most important quantitative coronary
angiographic determinants of restenosis, that is, vessel size and lesion
length, you could see that the vessel size was similar in the patients
prespecified and not prespecified for angiographic follow-up.

Because, however, we enriched the angiographic subset with more of these
32 millimeter long lesions, there was an overall lesion length of 14.4
millimeters in those patients prespecified for angiographic subset
versus 12.1 percent in those not prespecified. So we would expect,
again, a somewhat higher restenosis rate because of longer lesions in
this group.

When one looks now at the patients in the angiographic subset broken
down by the control and the TAXUS groups, you can see similar reference
vessel diameter, similar minimal luminal diameter and diameter stenosis,
and the lesion length was 14.4 millimeters in both groups.

Now, to show you the analysis methodology, which is used at the Core
Laboratory, we break down the stented segment into the stent itself,
which goes from the edge to the edge of the stent, which one can see by
angiography, and then there\'s five millimeters on both sides of the
stent, the proximal and the distal edge, which is also analyzed.

So we will refer to \"in-stent\" measures, which goes from edge to edge.
We will refer to the proximal edge and the distal edge, and then we will
also refer to the entire analysis segment.

When we talked about target lesion or vascularization, that was due to
events over the entire analysis segment, and of course, any event
occurring over this area will relate to restenosis, clinical restenosis
for the patient.

Looking in stent is actually a very pure way to look at the efficacy of
a drug eluting stent, but looking overall at the analysis segment shows
the efficacy of the stent, the drug itself, how it diffuses at the
edges, takes into account balloon overhang issues and edge trauma
issues, et cetera, and again, this is what affects clinical restenosis.

This is the cumulative frequency distribution curves for the TAXUS stent
in green and the control stent in red. So to orient you here, this is an
increasing percentile of patients with this value of percent diameter
stenosis both at pre and at post and then at follow-up.

You can see it pre. If you go here to the 50th percentile, this how you
measure the mean percent diameter stenosis at pre. Immediate post you
can see it is reduced significantly, and the pre and the post measures
are identical for the TAXUS and control stents.

At follow-up, you can see that the diameter stenosis increases
significantly in the control stent and it increases to a much lesser
degree in the TAXUS stent. You can actually see that the TAXUS stent for
any level of measurement has a very nice, small amount of tissue growth
or neointima covering the stent, but much less than the control stent.

Thus, when one looks at the binary restenosis rates at nine months,
which, of course, has stood the test of time as being the single
angiographic parameter that most predicts clinical restenosis or the
need for repeat procedures. You can see in stent, again, looking at the
potency of the drug just in the stent, restenosis was reduced from 24.4
percent to 5.5 percent, and then looking at the more important analysis
segment, restenosis was reduced from 26.6 percent to 7.9 percent. So a
relative 73 percent reduction and 70 percent reduction, of course, both
highly statistically significant.

When one looks at the mean percent diameter stenosis, this is the entire
analysis segment, and while you can see there\'s a marked reduction in
the mean percent diameter stenosis within the stent, you can also see a
positive effect at both edges. Both at the proximal edge and at the
distal edge, the mean percent diameter stenosis is smaller with the
TAXUS stent than it is with the control stent showing some drug efficacy
and system efficacy in those locations.

This slide shows the late loss at nine months. Late loss is actually the
amount of tissue that regrows by quantitative coronary angiography after
the immediate post implantation result. You can see the overall late
loss over the analysis segment was .61 millimeters in the control stent,
and that was reduced to .23 millimeters.

When one breaks it down into three independent sections, you can see
within the stent there was a reduction in late loss from .92 to .39
millimeters, and there was also a significant reduction in late loss
both at the proximal edge and at the distal edge, mirroring what we
showed you for the mean percent diameter stenosis measurements.

The Mehran classification looks at patients who do restenose to see how
long and severe the restenosis is, and it is broken down into four
patterns either focal restenosis, diffuse restenosis along the length of
the stent but maintained within the margins of the stent, proliferative
restenosis, which is diffuse, but also extends outside the stent and
then total occlusion.

One can see that when restenosis does occur with the TAXUS stent, a
major difference compared to the controlled stent is that it is almost
always focal. There\'s a marked reduction in the combination of diffuse
and proliferative patterns of instant restenosis.

So, again, these focal restenoses are much easier for interventional
cardiologists to deal with, which I think is probably the major reason
why bypass surgery was lessened in the TAXUS stent group.

There was a small incidence of total occlusions in both groups, and
there was no significant increase in the TAXUS group.

We can learn a lot of the patterns of neointimal hyperplasia from
looking at intravascular ultrasound. There were 268 patients that were
prespecified for follow-up intravascular ultrasound. This was completed
in 199 patients, or 74.2 percent of the patients. A very rigorous,
precise requirements for the technical adequacy of intravascular
ultrasound was required to be able to do detailed volumetric analysis.

As a result 38 patients were excluded. So 161 patients comprised the
IVUS follow-up analysis, broken down in to 80 control patients and 81
TAXUS patients.

When one looks here at the results, again, in the control in red and the
TAXUS in green, looking at the vessel volume, this is the actual vessel
itself. One can see a similar vessel volume in the TAXUS in the
controlled stent. One can see that the stent itself was the exact same
size. The main difference that we saw was that the lumens were larger in
the TAXUS group compared to the control group.

The reason the lumens were larger, of course, given the stent size was
the exact same, was that the amount of neointimal volume was decreased.
So this is a volumetric analysis now, and looking at the millimeter
cubed of neointimal volume, this was reduced from 41 to a mean of 18
with the TAXUS stent, and looking perhaps at what has become accepted as
the best IVUS indicator of drug eluting stent efficacy, the percent
in-stent net volume obstruction over the length of the stent, this was
reduced from 29 percent tissue accumulation within the controlled stent
to 12 percent tissue accumulation within the TAXUS stent.

I think it is actually important to point out that this is not zero or
one percent, but there is some neointima covering the metallic stent
struts. It\'s just significantly less than what one would see with a
bare metal stent.

Thus, the QCA IVUS summary supports that in-stent and analysis segment
binary restenosis rates were reduced by 77 percent and 70 percent,
respectively in the TAXUS group compared to the bare metal stent group.

There was lower late lumen loss and a greater mean diameter stenosis at
the edges, as well as in stent. All of the QCA variables were
significantly improved in TAXUS and all of the IVUS variables were also
significantly improved with the TAXUS stent compared to the bare metal
control, and the IVUS improvements were consistent with the QCA results.

Now, let\'s move to some of the safety outcomes and what we\'ll look at
overall now, taking clinical angiographic and IVUS parameters is looking
at major adverse cardiac events, stent thrombosis, incomplete
apposition, aneurisms, and other non-MACE serious adverse events.

This slide shows the overall MACE rates in the trial. There was no
difference in cardiac death between the two groups, and there was no
difference in myocardial infarction within the two groups, and what we
have learned is that stents compared to PTCA and drug eluting stents
compared to non-drug eluting stents don\'t change the rates of death or
myocardial infarction.

What they do do is reduce restenosis as evidenced by the reduction in
TLR and TVR, which I showed you before. As a result, a composite MACE
rates adjudicated to being due to the target vessel were reduced from
14.4 percent to 7.6 percent, an approximate 50 percent reduction, and
the overall MACE rates related to any target vessel were reduced from 15
percent to 8.5 percent, both highly statistically significant
reductions.

This slide shows the subacute thrombosis rates, and as I mentioned, we
tried very diligently in a very sensitive manner to look for all
episodes that might be related and adjudicated to subacute thrombosis.

In hospital, there were very few subacute thromboses. There was two in
the control arm and one in the TAXUS arm. Out to 30 days there was two
and two, and from 31 to 180 days, there was one and two. So overall \--
and there were none, very importantly, from 180 to 270 days. This is the
period after which the Plavix was stopped. There was zero percent
subacute thrombosis in both groups.

When one sums all of this up, the overall incidence of stent thrombosis
was very low in this study in both arms. Even using the sensitive
definition, .8 percent, or five patients, in the control group; .6
percent, or four patients, in the TAXUS group, which was not
statistically significantly different.

Looking at incomplete apposition, and this is an IVUS analysis, you can
see that after the procedure, there was statistically no difference in
the stents that just by operators happen to be placed slightly and
completely opposed to the vessel wall. Numerically this appears like it
might have been slightly more by chance in the TAXUS group than the
control group.

However, what\'s more important is that over the nine-month period, the
gaps get filled in, and there was no difference in the overall late
acquired incomplete apposition being very low in both groups.

Now, when one does a paired analysis, when you have an incomplete
apposition immediately after the procedure, it can either resolve; it
can be persistent. What we\'re most concerned about with drug eluting
stents is there can be late acquired incomplete apposition, and that is
the incomplete apposition was not there at the end of the procedure, but
it develops over time possibly as a response to the drug effect causing
the vessel to grow in an etatic (phonetic) or aneurismal fashion.

And one can see the most feared type of incomplete apposition, late
acquired apposition was present in 2.2 percent of control patients and
1.1 percent of TAXUS patients. There was no correlation within the study
of incomplete apposition with MACE or safety events. So this does not
seem to be much of a concern with the TAXUS stent.

When one looks at aneurisms, we use quantitative coronary angiography to
have a very sensitive definition of aneurisms. Aneurism was defined as
being any growth within the lesion 20 percent or greater than the
reference vessel diameter. So 1.2 to one ration, which is very, very
sensitive. Our average stent, that balloon ration was 1.2 to one.

And as you can see immediately post procedure, aneurisms were called by
the core laboratory in a very small number of patients, no difference
between the two groups, as one would expect, and in a nine month
follow-up, there were two aneurisms in both groups, and again, you can
do the same sort of paired analysis, and the type that we would most
worry about is the late acquired aneurism, and as you can see, there was
one late acquired aneurism with a bare metal stent and zero late
acquired aneurisms with the TAXUS stent, and it was very difficult to
relate aneurisms with events at all. There was only one event in any
patient with an aneurism. So this also does not seem to be a safety
concern.

We looked at site reported serious hypersensitivity reactions. They were
mild reactions and may have been due to hypersensitivity according to
the site and about three percent of patients in both groups, but these
were mild and easily resolved. Looking at serious adverse events due to
hypersensitivity reactions, there was only one patient that had a
purported drug hypersensitivity reaction. This happened to be in a TAXUS
patient. It\'s the same patient up to 30 days. There were no additional
patients from 30 to 270 days.

This was a patient who had an allergic reaction, which was a rash and a
headache that the site physician felt was due mostly likely to
clopidogrel, and this resolved after discontinuation of the clopidogrel.

There was one other patient in a TAXUS patient that had a nonspecified
hypersensitivity reaction, again, occurring within 30 days. This was an
allergic reaction with a swollen tongue and shortness of breath, which
was felt to be due by the site to either an iron supplement or an ACE
inhibitor and the patient completely recovered after discontinuing those
medications.

Thus, looking at the safety data, comparing the TAXUS stent to the
control bare metal stent, the nine month overall major adverse cardiac
event rate was reduced by 43 percent; target vessel failure a little bit
greater. Stent thrombosis rates were rare and comparable, less than one
percent at both groups, the TAXUS and bare metal stent group. There were
reportedly no stent thromboses reported after six months, after the
protocol mandated clopidogrel was discontinued. The incomplete
apposition rate was low and comparable through nine months. Aneurisms
even using extremely sensitive definition were rare and comparable
through nine months. There were importantly no increase in either late
acquired incomplete apposition or later aneurisms, and hypersensitive
reactions were extremely infrequent, comparable to control, and seemed
to be related to study medications.

Finally, I want to show you some of the important subgroup analyses, and
these were all prespecified analyses within the protocol. This shows you
the main subset analyses for target lesion revascularization, thus
looking at efficacy, and what you see here are the main parameters which
tend to affect restenosis.

The most important three are the diabetic status of the patient, the
reference vessel diameter, and the lesion length, and in some studies
LAD versus non-LAD vessel has been related to restenosis.

You can see here the relative risk reduction in favor of TAXUS compared
to control for reduction in clinical target lesion or vascularization,
with a confidence intervals in yellow and the line of unity in one. And
as you can see, there\'s an approximate 70 to 75 percent reduction in
target lesion revascularization at nine months independent of all these
different parameters.

Of course, you will note here, and I\'ll get to some of this in upcoming
slides, but the rates are significantly higher, for example, in much
longer lesions compare to much shorter lesions, and as a result, the
absolute degree of benefit is greater in the more complex lesions, but
the relevant degree of benefit extends across all subgroups that were
examined.

Now, when one does what becomes standard as a Kalon-Ho diagram, and that
is it looks at the interaction between lesion length and vessel
diameter, the longer and longer the lesion and the smaller and smaller
the vessel by quantitative coronary arteriography, you\'ll see the
clinical restenosis rates as well as the angiographic restenosis rates
rise exponentially, and that\'s what we saw here.

This shows you with longer lesions and smaller vessels broken down by
tertials (phonetic) here into these nine separate groups that in general
with the bare metal stent you can see restenosis rates significantly
increased, and this is, again, clinical restenosis, the need for repeat
procedures adjudicated on the basis of angiographic restenosis.

You can see in the TAXUS group there is a significant and in some cases
marked reduction in all subgroups regardless of lesion length,
regardless of vessel size. It certainly on an absolute measure is
greatest in the most complex lesions, but even in the more simple
lesions to treat by bare metal stents within the confines of this study,
there\'s a reduction in target lesion or vascularization with all lesion
lengths and vessel diameters.

This is the exact same slide, but now looking at angiographic restenosis
along the entire analysis segment, and one can see again about a 70
percent to 75 percent reduction in angiographic restenosis, which is
consistent across diabetic status, LAD, non-LAD, small and large
vessels, and short and long lesions. And I\'ll show you some of these
specifically in slides coming up.

This looks at a function of angiographic restenosis, and the analysis
segment is a function of reference vessel diameter, and one can see with
bare metal stents as the reference vessel diameter decreases, the
angiographic restenosis rate almost linearally increases along this
scale, along with the TAXUS stent though, you can see there was a
significant reduction in angiographic restenosis which did not quite
reach statistical significance in the smaller group, although there\'s
still the same trend here for an approximate 65 percent reduction in
angiographic restenosis.

You can see the marked benefit especially in these small vessels.

Similarly, when one looks at lesion length broken up into approximate
tertiles (phonetic), less than ten, ten to 20, and greater than 20, you
can see that as the lesion lengths increase in length, the angiographic
restenosis rates increase at least linearally, and you can see here
significant reductions even with the short focal lesions with the TAXUS
stent, with the intermediate lesions, and with the longer lesions
greater than 20. And these patters were also exactly replicated when one
looked at the stent diameters, either 2.5, 3.0, or 3.5 TAXUS stent, or
when one looked at the length of stents, 16, 24, and 32 millimeter
stents.

Finally, the diabetic subgroup is very important, and here you can see
is the overall angiographic restenosis in the patients without diabetes,
showing a marked and significant reduction. In the overall diabetics, if
anything, the relative reduction is even greater, and a marked reduction
from 34 and a half percent to 6.4 percent, and in our most difficult
group to treat, the insulin dependent diabetics, you can see with the
bare metal stent the restenosis rates go up from 24.4 in no diabetics to
42.9 in insulin dependent diabetics, but the angiographic restenosis
rates with the TAXUS stent were approximately level in this study.

There are certainly relatively small numbers of patients in the insulin
dependent diabetic group. So we can\'t make firm conclusions, but at
least with this very large, approximately 80 percent reduction showing
the treatment effect, I think this is highly likely to be very
significant.

There was a lot of question raised based on an earlier clinical trial of
looking at Paclitaxel using a nonpolymeric based system, that there may
be a significant interaction between glycoprotein IIb/III inhibitor use,
and so we wanted to put this to rest and looked at patients who had
IIb/III inhibitors versus those who did not have glycoprotein IIb/III
inhibitors, and there was no difference in either clinical or
angiographic efficacy on the basis of using IIb/III inhibitors.

And finally, while this trial was a single lesion, single stent study,
as I showed you, approximately ten percent of the patients had multiple
stents implanted, and that\'s important to be able to implant multiple
stents. These were for the most part study stents when required. You can
see there were a total of 45 patients who had multiple study stents in
this trial, including 20 patients who had a 16 plus a 16; 13 patients, a
16 plus a 24 millimeter long stent; 11 patients, a 16 plus a 32; and one
patient had three study stents.

When one looks here at the TAXUS improvement in patients with multiple
study stents, with a single study stent you could see the reduction in
clinical restenosis, and we are gratified to see that while the numbers
are relatively small, there was no instance of clinical restenosis or
target lesion revascularization in any of the patients in the TAXUS
group that had multiple study stents implanted, and similarly, while the
angiographic numbers are even smaller, only 15 patients in the TAXUS
group, there was no instance of angiographic restenosis in TAXUS
patients who had multiple stents.

You can see with bare metal stents, even with the small numbers, you put
in more stents for, you know, complications or for longer lesions; the
restenosis rates go up, but there does not seem to be at least with
these small numbers increase to the TAXUS group.

Thus the conclusions from the pivotal TAXUS IV trial were that the
nine-month results demonstrate safety of the slow release TAXUS stent
with no increased risk of stent thrombosis and no increased risk of
aneurism formation, late total occlusions or incomplete stent
apposition, and a reduced overall risk of both major adverse cardiac
events and target vessel failure.

There was a reduction in 70 percent and 77 percent, respectively, for
analysis segment and in-stent angiographic restenosis and 61 percent and
73 percent, respectively, for TVR and TLR, resulting in lower rates of
bypass graft surgery and repeat percutaneous coronary intervention.

Thus, I think the clinical results mirror the preclinical results that
are shown to you.

And finally, effectiveness was demonstrated in this large pivotal trial
across a wide range of complex patients and lesions, including small
vessels, long lesions, and patients with diabetes.

Thank you very much.

DR. RUSSELL: Thanks, Gregg.

And now a few concluding remarks.

Clinical safety for the TAXUS slow release stent has been evaluated in
three randomized control trials involving more than 1,900 patients.
Clinical safety profiles were comparable to control with low rates of
stent thrombosis, myocardial infarction, incomplete apposition,
aneurism, and other adverse effects.

Boston Scientific has a commitment to the ongoing tracking of safety
events, in particular stent thrombosis. Here is our most recent records,
as of November 14th, 2003. We track these results in our preapproval
studies, post approval studies, and also in customer reporting.

You\'ve heard about the results from our completed studies where TAXUS
is unblinded from control, and there were eight out of 987 TAXUS
patients that had a reported stent thrombosis. In the ongoing studies,
TAXUS IV, V, ISR, and TAXUS VI, there have been 13 reports of stent
thrombosis out of 1,747 patients. That, of course, includes the control
and the TAXUS group.

Of note, one patient had a periprocedural stent thrombosis complicated
by two recurrent stent thromboses. So that accounts for three of the
stent thromboses in the 13.

In our post approval studies, we have programs that are sponsored by
Boston Scientific. That includes the WISDOM and MILESTONE II registries.
There have been 11 reports out of 3,072 patients that have received the
TAXUS stent.

And then we have investigator sponsored initiatives where we have
personal communication as of this week of the latest stent thrombosis
events, and there are seven out of a total of 932 patients.

With respect to customer reporting, there have been eight reported stent
thromboses out of more than 69,000 units sold. So the total number of
individual stent thromboses reported includes 47 out of more than 75,000
stents implanted or sold for a percentage of 0.06 percent.

The majority of these stent thromboses which we carefully tracked occur
in the periprocedural period. The ones that have occurred subsequent to
that have been examined in detail and often have extenuating
circumstances associated with them.

We\'re committed to ongoing tracking of long-term safety. It\'s evident
in our preapproval trial programs. We have follow-up out to five years,
and we\'ve implemented dynamic safety reporting. This was done in our
trials, typically Web-based systems where we can track the events with
ongoing reporting in a relatively frequent basis to FDA.

We\'re committed to post approval surveillance registries, including
transitional registries, such as WISDOM and MILESTONE II that were
specifically set up to track such events and our proposed ARRIVE U.S.
periapproval registry.

ARRIVE stands for TAXUS periapproval registry. It\'s a U.S. Web-based,
two phased program, multi-center and focused on safety surveillance to
capture real world safety profiles. The principal investigators are Dr.
John Lasalle and Dr. David Cox.

There are two phases, a preapproval phase. We have a submission in for
an expanded access registry as part of our IDE, and then Phase 2 will
involve post approval, including 2,000 patients in 50 community type
centers, reflecting the real world use of drug eluting stents.

We\'re focused on consecutive patient enrollment per participating
physician, and that would be any use of a TAXUS stent.

We will be tracking TAXUS stent related thromboses MI, reinterventions,
death and other events, and using an independent committee to classify
these events. This will allow us to have dynamic updates of both
enrollment and safety status.

You\'ve heard about the effectiveness of the TAXUS slow release stent
from Dr. Stone in the form of TAXUS IV, further supported by TAXUS I and
II in more than 1,900 patients that have been evaluated. We\'ve
demonstrated TAXUS superiority compared to control with concordant
improvements in clinical outcomes, QCA and IVUS endpoints.

Taken together, the taxus data demonstrates safety and effectiveness for
the TAXUS slow release stent, and we believe that the benefit of the
TAXUS slow release stent out weighs any potential risks.

Thank you very much.

CHAIRMAN LASKEY: Thank you for a most comprehensive presentation, and
congratulations on completing ahead of schedule. That, of course, leaves
more time for the panel to ask pertinent questions prior to our break.

So, again, I\'ll remind the panel that they will have another
opportunity to query, but right now are there any questions from panel
members to the sponsor on matters presented in the last hour? Starting
with Dr. White.

DR. WHITE: Thank you.

Dr. Russell and Gregg, a very nice presentation.

I want to ask a question focused on the histology because I\'m just a
little confused, and I don\'t know whether you have the same panel
packet I have, but I\'m looking at in our packets called the \"Summary
of FDA Review Memos,\" and I referring to page 13 in that section where
there\'s a summary of some pathology.

And it says RVF 01-049, and ten there\'s several other as we go through,
and they summarize histology, and in virtually every one of the
histologic reports it says that at 28 days the endothelialization is
partially complete.

And you said several times in the presentation that at 28 days it was
complete, and I haven\'t been able to find any data in the submission
that says that that\'s true. So I\'m wondering why the disparity.

DR. RUSSELL: Well, I\'m going to refer this question to our study
pathologist, as well as our study preclinical expert, Drs. Wilson and
Schwartz. Part of this has to do with the use of statistics. So we used
statistics to analyze differences between control and TAXUS stents for
ordinate grading scales, and when one compares across multiple programs
with ordinate scales, it can be difficult to determine if there\'s a
difference.

But I think Dr. Schwartz and Dr. Wilson.

DR. WILSON: So I\'m Dr. Greg Wilson.

In terms of disclosure, I\'m a paid consultant to Boston Scientific
Corporation. I have never and do not now hold stock or stock options in
the company, either directly or through family members or related
entities.

Now, I\'m the pathologist who developed the histological grading systems
for the preclinical animal studies. I authored some of the pathology
reports on those studies, and more importantly, I have reviewed all of
the pathology on all of the preclinical animals studies, including
looking through over 4,000 glass slides with mounted histological
preparations.

The question you asked about the endothelialization really comes out of
a modification that was made in our grading system. Initially the
grading system was simply complete or incomplete, and complete initially
was interpreted to really truly be absolutely complete, that is, 99, 100
percent endothelialization as assessed on histology.

Now, when you look at a histology slide as distinct from looking at
scanning electron microscopy, and there was some scanning electron
microscopy done in the studies as well on some of the explanted stents,
but when you are grading endothelialization based on histology, you\'re
basically looking for the nuclei of the endothelial cells on the lumenal
surface. The endothelial cells are very thin, tenuous cytoplasms. So, in
essence, you\'re really looking at the numbers and how close the nuclei
are to each other for the endothelial cells.

And so the result of this is that there is a bit of uncertainty in terms
of actually saying whether there is truly 100 percent
endothelialization.

Now, as these animal studies progressed, we modified the grading system
to have three categories: less than 75 percent, 75 percent to 90
percent, and over 90 percent endothelialization. And when we looked at
the data in that way, at 28 days with the drug at both the slow release
and moderate formulations compared to control was equivalent. That is
always over 90 percent endothelialization as reflected in that grading,
and I\'ll comment that for the controls, just for the drug, there would
be instances where it would be hard to tell whether it was, you know, 99
percent, 95 percent.

There was scanning electron microscopy done on a number of stents that
were explanted. It\'s not possible to do the scanning EM and the
histology on the same stents because, of course, this histology is
destructive. You have to cut through the stents.

But on those stents that were submitted for scanning EM, which has the
advantage that you\'re looking at an on fast preparation, you\'re
looking at the entire flow surface, and so that you can make really a
better evaluation of endothelialization and be more confident about
whether it\'s really complete. We found there was equivalence between
the control, the slow release and the moderate release at 28 days, and
subsequently, and indeed, the endothelialization was remarkably
complete.

I can\'t say absolutely perfect in every specimen, but certainly no
detectable differences between control and the drug.

So I\'m afraid the material, I think, that you\'ve received reflects the
sort of earliest just complete, not incomplete grading.

DR. RUSSELL: Thanks, Greg.

Next question?

CHAIRMAN LASKEY: Chris? Dr. Somberg.

DR. SOMBERG: I appreciate the difficulty. I just think that the
presentation \-- I mean, one of the concerns about the stents that
we\'re all listening to and obviously the presentation takes pains to
point out is that there is healing and that there\'s intimal thickening
and the IVUS and everything else shows that. So I don\'t have any doubt
about that.

I just think it bothers me when the data is not congruous. I mean, the
data that we\'re given to review says that there\'s not complete
endothelialization, and the presentation says there is. I understand
that the pathology is not black and white, but maybe the presentation
could have reflected that a little bit better just to be clear.

DR. SOMBERG: John Somberg.

I have a couple of questions. The first one for Dr. Russell is dose
consideration both for the SR and the MR. I would imagine, as with the
pharmaceutic, you would have looked at a number of different doses with
the polymer and then try to establish a minimal or a borderline.

Are we at that borderline with the SR and the MR formulations or are we
far beyond that? There\'s no mention of any sort of dose studies, and
this matter was sort of magic polymer on the stent and it works, but I
just wondered where are we along the minimal effective concentration
gradient.

DR. RUSSELL: Yes, that\'s an excellent question. What we discovered in
the early foundations of our program is the importance of preclinical
models, and perhaps I can get Dr. Schwartz to comment on this following
my brief comments.

And we are very confident about the reproducibility of our preclinical
implant model for safety evaluations, but our model produces a very thin
neointima, which was inadequate for efficacy evaluations.

So our dosing decision was made by establishing formulations that were
clearly safe by detailed histologic analysis, and efficacy is being
studied in the actual human atherosclerotic disease milieu, so to say.

Rob.

DR. SCHWARTZ: Thank you.

My name is Rob Schwartz. I\'m from the Minneapolis Heart Institute
Foundation. My conflicts of interest, I own no stock, no options in
Boston Scientific or any subsidiary. My laboratory receives research
grants from Boston Scientific as well as from all of the other major
competitors. I am a paid consultant, but the funds go to my laboratory
and not to me personally.

Boston Scientific did reimburse my air fare and hotel here. I have
received honoraria for talks about Paclitaxel and stents in the past
that have been personal, but I also receive honoraria and give talks for
all of the other major competitors.

Concerning the issue of animal models, a terrific question. In terms of
safety, there are several things that are important. Preclinical safety
represents animal death. I think that we all know, those of us who do
preclinical work, that if a stent or a technology put into the coronary
artery is not safe, the animal typically dies in the case of a pig
within 12 to 24 hours.

It was rather remarkable in this study. I find that there were zero
stent related deaths. Typically in the guidelines that we published and
are working out with FDA, in fact, typical mortality is ten percent, but
there were no mortalities in this.

So I think in terms of safety during the endothelial question, regarding
the neointima, I think we\'re very comfortable that there is a great
deal of safety in a preclinical/clinical context.

From there, as we move to your questions about dose and about the effect
of the dose on the tissue itself, what appears to me to be key is
cellularity. Is the media intact? Are the medial cells killed?

There was a little bit of cell dropout in the media of these vessels,
but not much. The majority of the media was preserved and certainly the
media in between stents looked quite normal.

The endothelium, as we heard, was virtually intact, mostly intact. We
know very well that as little as ten to 15 percent of a vessel
endothelialized can function as a normal vessel. So from an endothelial
standpoint, from a medial standpoint, the doses that were chosen, the
doses that were used, I think, panned out very well in a cellular
context. In fact, that translated into a preclinical safety context,
animal death, and, indeed, as you heard from Dr. Stone, these safety
issues were not issues, were not concerns all the way up to the
1900-plus patients who have received these stents in the TAXUS trial
series.

DR. SOMBERG: But essentially you\'re saying you do not know on what
point of the dose response curve this formulation is in terms of the
minimal effective concentration.

DR. SCHWARTZ: We don\'t know the low end. We do know the high end. As a
result of a recommendation, we did do a safety margin study with doses
between four and ten times as high. In the highest dose, ten times we,
indeed, did find medial cell dropout at that point. There was perhaps
more neointima at those levels, but this was the purpose of the study,
was, in fact, to find more the higher dose rather than the lower dose.

I think, again, the safety issues \--

DR. SOMBERG: Some place between that range you might have had a greater
reduction in restenosis or no change from what you have or you could
have used half this dose in the polymer and still gotten a prevention of
restenosis.

DR. SCHWARTZ: That is true. Hard to answer that question. We, again,
know the safety end and the high. We do not know the efficacy end on the
low, at least from the preclinical, bearing in mind, once again, that
the preclinical is not a good efficacy model at this point.

DR. RUSSELL: And what may not be reflected in your briefing document is
the foundation for the studies that were presented. So the program was
founded based on evaluation of six different polymers to identify the
one that was the most vascular compatible, the one that could retain and
release the drug at the low level, which was our design principle, and
then there are a number of variables that could be explored with this
technology.

So one can change the dose density. One can change the formulation, one
can change the coating thickness, and we did a series of early studies
looking at various combinations of other formulations and other doses
that did not have the extensive preclinical analysis that I reviewed
earlier to come to our decision to focus on the one microgram per
millimeter dose squared dose density, and on the slow and moderate
release formulations where we decided to delve deep into the
histopathology so that we could at least understand overdose density
with the same formulation and over time.

And these studies are quite painstaking. If you\'re looking at animal
studies out to 360 days and the histologic analysis, Dr. Wilson looked
at thousands and thousands of sections to establish that these two
formulations with this one dose that we selected had a safe profile that
was reasonable to pursue, proof of concept in the TAXUS program.

So that\'s the history behind our dosing rationale.

DR. SOMBERG: You led into my second question to you, Dr. Russell, and
that was really why. I\'m a little confused on the issue. There\'s an SR
and MR formulations. What is the company\'s, I guess, plan? Are we going
to have two different formulations? Are we going to try to get different
indications for that?

You know, you\'ve presented very nice information about the difference
in release characteristics, but I\'m a little confused on how clinicians
are going to make use of that pharmacologic information.

DR. RUSSELL: Yes, I can understand and appreciate that question. TAXUS
II was designed to compare based on very sensitive IVUS assessment the
difference between the slow and moderate release formulations, and as I
mentioned but did not elaborate on, the IVUS findings were very similar
between the slow release and moderate release program.

And I must point out that the study was not powered to show a difference
between the slow release and moderate release formulation, but
nonetheless the percent net volume obstruction was nearly identical at
six months.

We spent some time analyzing this, and our conclusion was one possible
explanation was that we had reached the threshold, the dosing threshold,
with the slow release formulation and there was no additional benefit
for the three times higher release with the moderate release formulation
in this standard low risk lesion set.

And so we actively pursued TAXUS VI, which is a higher risk lesion
subset, longer lesions, has more diabetic patients in it for a European
study and are awaiting the moderate release results from this higher
risk lesion subset to make a decision about whether the moderate release
formulation is of added value to the slow release formulation in more
complex lesions

DR. SOMBERG: Another question I had and it relates, I think, to the
preclinical models: is there a plan to continue beyond 24 months? Taken
with the stent is going to be there forever and there\'s about 80
percent retention of the active agent there, we know things last for a
while and then all of a sudden the device fails at some point or a
polymer may change its release characteristics.

Do we have any idea if that will occur and how long are we going to
follow that out?

DR. STONE: Well, the patients are being followed for five years. So
yearly for five years in all of the TAXUS trials. So at least, you know,
to that extent and that duration, you know, will have good clinical
follow-up.

You know, we expect that since the stents will be by then, you know, by
six months, if not a year, completely endothelialized with a neointima
separating the stent struts from both the blood vessel and whenever
there\'s neointima growing on one side, it grows on the other side. We
expect the stent struts, the polymer and whatever Paclitaxel is left to
be pretty much sequestered.

But I think just in case there\'s any problem, that\'s one of the
reasons why the patients are being followed out to five years.

DR. SOMBERG: I appreciate that. I just would think you could also have a
parallel animal evaluation of this since it has been said that it\'s
sensitive to the potential toxic adverse effects.

DR. SCHWARTZ: I might add that preliminary discussions, in fact, with
Dr. Zuckerman, as an interest, these are ongoing in relationship to
putting a study together to evaluate just that, to understand the
relationship between short/long-term animal data with the clinical data.

So these are under discussions at present.

DR. RUSSELL: Yeah, and we do have one group of animals that could be
sacrificed at 24 months. There\'s some debate about whether we should
sacrifice them at 24 months or let them go to 36 months, and I think the
ideal time point for that group of animals is something that I\'d
appreciate feedback on because it\'s quite a debate.

DR. SOMBERG: And two questions I just have for Dr. Stone, if I may just
to finish that up, that came directly from your presentation.

One is I was struck by the small number of diabetics. There was about
eight or nine percent in the population and probably because of a bias,
but maybe you could comment on that, and what severity of diabetes.

You know, you said insulin dependent, but that can be a variability
here, and also the additional follow-up. There\'s one cut point chose,
nine months. Is there any other follow-up planned?

DR. STONE: Well, there were about 25 percent diabetics in the study. So
actually there was a pretty good representation of diabetics. Probably
in our clinical practice we see with all comers much more complex
disease that was in TAXUS IV even, probably about 30 percent diabetics.
So it was pretty representative with 25 percent diabetics. About eight
percent of them were insulin requiring diabetics, and I think that\'s
also a reasonable representation that we see in most studies.

European trials, for example, tend to have much fewer diabetics than was
represented in TAXUS IV.

Regarding the second question was about extended follow-up. Since you
asked, and I understand that since you asked I\'m allowed to talk about
it, we now have the 12-month TAXUS IV data, and the curves continue to
spread between showing extra clinical efficacy. Maybe I can show you one
or two quick slides.

This actually shows the events now that have occurred between nine and
12 months in the TAXUS IV cohort, and particularly striking to me is
that first you can see there was one cardiac death and seven myocardial
infarctions in the control patients and no deaths from myocardial
infarctions in TAXUS patients.

And this incremental reduction in myocardial infarction between nine and
12 months was actually significant at the .007 level.

In addition, you can see if you look at TLR, again, the best clinical
surrogate of drug eluting stent efficacy, there were 26 additional TLR
events between nine and 12 months in the control group and only nine in
the TAXUS group. So four percent versus 1.4 percent.

So overall the difference, therefore, in TLR and TVR, in MACE and in
target vessel failure continues to spread favoring the TAXUS stent. And
it\'s not surprising that there\'s a difference in duration of when we
see patients come back for TLR or TVR compared to angiographic
restenosis.

We\'ve known for years for the most part most angiographic restenosis
occurs between three and six months or is complete between three and six
months, but it takes patients longer. They have symptoms for a couple of
months and then they have to schedule an appointment with their doctor,
and then they finally get referred for a repeat angiogram. Maybe they
have a stress test.

So there\'s a delay which can be anywhere from three to six months
between restenosis and clinical events. Thus, if you look here at the
overall event rates here, 12 month MACE and target vessel failure,
there\'s no difference in cardiac death. If anything, there\'s a weak
numerical trend now overall from zero to 12 months favoring myocardial
infarctions, less in the TAXUS group, a big difference in TLR, a big
difference in TVR, and again, a bigger reduction in MACE and target
vessel failure than we\'re seeing just at nine months.

And finally, I think this curve kind of shows the change in efficacy
very nicely. This is target vessel revascularization from zero to nine
months, with an 8.2 percent delta by actuarial statistics, and now when
you carry it out to 12 months, there\'s actually a ten percent
difference in target vessel revascularization.

So all of the evidence that we have so far is that the incremental
benefit continues to increase in the patients who receive the TAXUS
stent.

DR. NORMAND: I have a clarification of the slides, and it sort of
carries over to many of the presentations.

DR. STONE: Sure.

DR. NORMAND: I notice the sample size is always 652 and six whatever the
number is, and is that in 12 months you really have follow-up on
everybody?

I don\'t want to look at the Kaplan-Meier. I want to look at your \--

DR. STONE: No, it was about 97 percent. In fact, it\'s a little bit
higher at 12 months than it was at nine months, but it\'s about 97
percent at both time periods. This curve, of course, takes into account
the different time effects.

DR. NORMAND: But the other one?

DR. STONE: Yeah, the other ones, a true denominator would be
approximately 97 percent of those numbers for each time period.

DR. NORMAND: No both groups?

DR. STONE: In both groups, and I put those on the first slide.

DR. NORMAND: So the percentage that you\'re showing are really the
percentages of the true numbers or they\'re the percentage of the
numbers at the beginning?

DR. STONE: Those are the percentages of the patients with follow-up.

DR. NORMAND: So the percentages reflect the different denominators.

DR. STONE: That\'s correct.

DR. NORMAND: And hence your P values reflect the fact that you have
different denominators.

DR. STONE: Exactly.

DR. NORMAND: Thank you.

Ten more questions? Dr. Morrison.

DR. MORRISON: I\'m trying to understand the difference between the slow
and moderate release, and perhaps this is just ignorance of polymer
chemistry. So I apologize for that, but it looks to me on your diagrams
that it\'s the same dose density. What differs is the coating thickness,
and in either case you\'re left with a majority of the drug behind.

Is that the case? And I think Dr. Somberg\'s question was directed at
the notion of is this truly inert because there\'s an endothelial layer.

Are you concerned about the fact that there\'s \-- with the slow release
what we\'re discussing today primarily, it\'s less than a tenth of the
dose that\'s actually been delivered and sure about what\'s going to
happen with what\'s left behind is my first question.

The second is wouldn\'t it make more intuitive sense to try and get it
out and get it in action the first 30 days and get rid of it so that
it\'s not left behind to cause problems 12, 36, 48 months down the line?

DR. RUSSELL: With respect to your first question, we did perform a
series of studies looking at the retained drug, as I mentioned, and what
circumstances would be required to get the retained drug to come out,
and as you may recall from those slides, it took fairly extreme
conditions that are not really consistent with living human beings to
get the sequestered drug out, and that was in stents that really were
not implanted and healed as they typically are in humans.

And then, of course, we developed sensitive assays to see if we could
determine whether there was any measurable Paclitaxel, and we were not
able to do that, and hence, we turned our focus to the preclinical
studies that allow us to use histologic assessments to see if there was
any evidence of Paclitaxel activity even though we could not measure it.

And what we discovered was that healing progressed in spite of the
presence of the retained Paclitaxel and achieved many of our design
objectives.

With respect to your original question about the polymer chemistry and
the release kinetics, I would like to refer that question to Dr. Kramer.

DR. KRAMER: My name is Phil Kramer. I\'m a paid consultant to Boston
Scientific. I have no other financial interest in that company or in any
of their competitors, and as far as I know, I\'ve never done any
consulting for any of their competitors.

To answer your question, basically I think you just have to appreciate
what happens with this coating. There\'s really three layers as Dr.
Russell described earlier. There\'s the surface layer, which is sort of
here. There\'s the immediate subsurface, and then there\'s the bulk.

And essentially what happens with either the moderate or the slow
release is that particles that are on the surface or drug molecules that
are on the surface, which is sort of these purple dots, those are
released first essentially by dissolving or by dissolution, and that
opens up a channel so that particles that are in the immediate
subsurface now have a pathway to get out, and so they diffuse to the
surface and then dissolve just as the original surface molecules
dissolve.

Everything else is left in the bulk, really has no pathway to get out.
It\'s surrounded by polymer, and it\'s basically locked in place.
There\'s no way unless you were to do very extreme, nonphysiologic
destruction of the polymer to get out.

The difference between the moderate release and the slow release is the
thickness of the coating, and in the moderate release, there\'s a
greater percentage of the load that is either on the surface or in the
immediate subsurface because it\'s essentially a thinner coating with
the same amount of drug in it, and so you have a higher initial release
because there\'s more on the surface and a greater overall release
because there\'s more in the subsurface.

But either way, you still have the majority left behind in the bulk.

CHAIRMAN LASKEY: Can I just ask a follow-up on that while you\'re there?
This is such a remarkably efficient and effective drug where really
eight to nine percent of what\'s applied can do the job. Yet are these
\-- just tell me about the variability and the measure here of the
cumulative [in vivo]{.underline} release kinetics. It\'s not a flat
eight to nine. There\'s some variability around there.

Are those error bars or SD bars or what am I looking at to see where
those amounts released might be more than eight percent and could
conceivably be more toxic?

DR. KRAMER: Well, those are standard deviation bars. On the figure that
Dr. Russell presented during her presentation, those are standard
deviations.

So there is variability, and the other thing that you have to realize is
that that is measured by the percent released is measured indirectly by
measuring the percent that remains because you explant the stent and
then basically destroy the coating and measure what\'s left.

And so because of that process, the process of explanting, removing
tissue, et cetera, that\'s attached to the stent, there is more
variability in that.

DR. RUSSELL: Yes. It\'s a fairly labor intensive and awkward model to
use in the long term. The longer the stents have been implanted, the
more imbedded and compacted the neointima is, as well as the adventitial
response. So we actually have to extract the stent physically and then
digest off the tissue in order to do these measures.

So you can imagine there is a moderate amount of variability with that
process.

CHAIRMAN LASKEY: I understand that, but therein lies the existence or
death of the neointima. So that\'s just the clinician\'s standpoint.

Dr. Yancy and then Dr. Weinberger.

DR. YANCY: Thank you.

I, too, want to commend Dr. Stone for a very nice presentation and a
well executed study.

My two questions, and I\'d like one follow-up afterwards, comes from the
perspective of what I do, which is dealing with LV dysfunction and heart
failure. Most of our clinical trials are very heavily inclined towards
clinical events, hospitalizations, relief of symptoms.

It would seem to me, reviewing the data that we had available, that in
fact, these patients presented for elective stenting primarily because
of an event or a reasonable clinical indication. I appreciate the MACE
data, but I don\'t see additional data regarding clinical events or the
relief thereof after implantation, especially with your nine month and
now 12 month data.

I was a little bit concerned, looking at the nine month data because
death and MI were virtually indistinguishable between bare metal and
drug eluting stent. The 12 month data you\'ve just demonstrated are much
more gratifying in that regard.

I\'m wondering what your perspective is on clinical events and whether
or not the registries that Dr. Russell owns would, in fact, include
clinical events.

So that is the first point about the clinical events outside of death
and MI.

The second question refers to something I commented on during the
presentations, but which was in the preceding data, and that is the
exclusion apparently of patients with fairly extensive LV dysfunction.
Again, the rationale for that and what you think the applicability of
this technology might be in that specific higher risk.

So let me ask you to address those two questions, and then I\'d like to
follow up with one very clinical question.

DR. STONE: Well, thank you for the kind comments.

I think when one looks at what you expect a drug eluting stent to do,
it\'s really the same thing you expect a bare metal stent to do or the
same thing you expect a balloon angioplasty catheter to do, and that is
you are treating one very focal stenosis in a coronary artery.

When one looks at the propensity for patients to die or to develop
congestive heart failure or ventricular arrhythmias, I think it\'s a
function of multiple different features.

Certainly if a vessel goes on to close an infarct, but it\'s obviously a
function of overall left ventricular function, ventricular irritability,
and inducibility for ventricular arrhythmias, valvular disease, systemic
factors such as hypertension and renal disease, et cetera.

What we\'ve learned over decades now of doing the angioplasty versus
surgery studies and now angioplasty versus stent and now stent versus
drug eluting stent is that the drug eluting stent we hope will reduce
restenosis at that focal site. We hope we can do that safely without
hurting the patient, therefore reduce recurrent angina, reduce
hospitalization, reduce recurrent ischemia, reduce repeat percutaneous
and bypass procedures.

Now, to the extent \-- and this kind of answers the second question at
the same time \-- to the extent that in a patient with severe left
ventricular dysfunction, and patients were excluded for an LVF of less
than 25 percent in this study, but to the extent that patients with
severe LVF who continue to have to have recurrent procedures are always
at risk in any of the procedures we do for them and are always at risk
when a vessel renarrows, you would think if anything, this device would
probably have some incremental benefit in those patients.

But I wouldn\'t expect it to a priori nor did we see a statistically
significant effect on death or myocardial infarction, which one is a
function of what\'s happening at the lesion and the MIs, but also
vulnerable plaque and new lesions that appear elsewhere. This device is
not going to affect new lesions elsewhere or the progression of trivial
stenoses to acute vessel closure.

So I think we saw exactly what I would have expected us to see, and I
think it\'s important for people to realize this device is not a panacea
for heart disease. It\'s treating a very focal stenosis, so relieving
ischemia, and then hopefully it will not recur.

DR. YANCY: Let me follow up with the one clinical question. Given the
data which appear to be fairly robust, what do you think the remaining
indication is for the bare metal stent?

DR. STONE: It\'s a great question. I think there are certainly many
subsets that weren\'t studied in TAXUS IV, that were excluded, that we
don\'t yet have safety and efficacy data for with drug eluting stents,
very small vessels, very long lesions, in-stent restenogic (phonetic)
lesions, thrombotic lesions, acute myocardial infarction, chronic total
occlusions, brachytherapy failures.

In fact, in some regard, the universe of patients we don\'t have the
answer for is probably as large as the ones that we do have the answer
for now, and that\'s why, you know, we\'re strong believers that outside
of carefully controlled research settings these devices should be used
on label as evaluated within large pivotal trials such as this.

DR. WEINBERGER: I just want to echo the congratulations of the other
members to Gregg and to the whole team.

I would like to focus on something that hasn\'t been spoken about quite
as clearly, and that is some of the more minor complications that were
recognized and reported by the investigators, namely incidents of CVAs
and hematological dyscrasias.

Now, these are minor and we tend not to think of them as cardiovascular
events, but given that we\'re putting a new pharmacologically active
component into the blood stream, I think that I\'d like to understand a
little bit more about sort of the trend at least in what was reported as
hematological dyscrasias. There was access in the TAXUS group. There
were about ten patients with hematological dyscrasias, and there was
excess of CVAs.

Now, each one by itself doesn\'t lead to statistical significance, but
whether or not that represents a common pathophysiological mechanism or
not is something I\'d like to hear from the investigators.

DR. STONE: Well, I think the first point is that when one looks at these
SAEs which were all operator reported, there was no statistical
significance between the two groups. I mean, they were small. They were
infrequent in both groups.

And then the second issue is: is there an underlying pathophysiologic
relationship between some that look numerically like they might be going
in the wrong direction.

I think it\'s important to note that for each one that looked like it
might be going in the wrong direction we can show you another SAE that
looked like it was going in the right direction with less SAEs with the
TAXUS stent, and I think whenever one looks at so many different
subgroups, first of all, you have to really use a Bonferroni correction
to get a significant P value, which would probably bring you down with
the hundreds of SAEs that have been looked at down to about a .001 P
value or less.

Regardless, there\'s no real pathophysiologic relationship that I know
of between stent implantation and stroke. I don\'t think we think that
thrombi and emboli are forming on the stent and then embolizing to the
carotid circulation, and again, I have to think from just for no other
reason than not being able to at all possibly explain Paclitaxel
relationship to stroke, especially given the fact that there is no
systemic detectable levels, that that\'s just, you know, one of those
things, small, infrequent events, not statistically significant.

Now, hematologic dyscrasias, of course, we could be more worried about
from any, quote, oncologic agent. The P value is not statistically
significantly different. There\'s no systemic levels. We don\'t think
there should be any systemic accumulation in the bone marrow that might
affect the hematologic parameters, and again, it was not a statistically
significant P value; just one of those things that happened, which
looking at multiple subgroups, you do expect to see some.

There are other things that Paclitaxel could theoretically do, you know,
like rash and whatnot that we saw, if anything, being less in the
Paclitaxel group.

DR. WEINBERGER: I would just as a comment add that we shouldn\'t glibly
expect that we\'re just looking at Paclitaxel effect. It could also be
the polymer itself, and we don\'t have a huge experience with this
intravascular polymer, I imagine.

And then the second also fairly brief question \--

DR. RUSSELL: Maybe I could further elaborate on Dr. Stone\'s comments
here. We actually looked at the individual reports for those ten events.
Five or six of them were, in fact, formal CVAs. The remainder were TIAs
that resolved. Of the five, two of them were related. One of them
occurred in a patient who against the protocol had a history of
recurrent CVAs, and the second one was in a patient that actually had a
stroke post knee replacement surgery.

So that\'s fairly antidotal, two out of the five, but that is the
breakdown, and we did look at that closely.

In terms of the hematologic dyscrasias, a scary word, I would have to
say, that reflects how the coating was done for the serious adverse
events in our trial. We used the standard Med DRA coating dictionary,
and when we examined the verbatim terms that were classified as
hematologic dyscrasia, the majority of them were bruising and rashes.

DR. SOMBERG: What was that word? I didn\'t hear.

DR. RUSSELL: Bruising, bruising and rashes.

And we have the, you know, superimposed complexity, let\'s say, of the
plavix.

DR. WEINBERGER: And the angiographic subset, was that pulled out at
random? In other words, were people randomly chosen to be angiographic
subset candidates, or was that some operators volunteered to be the
angiographic subset operators?

DR. STONE: There was a consecutive series of patients at all sites.

DR. WEINBERGER: In all sites. Okay. So I would imagine that since we\'re
talking about when we define TLR in the study, that we\'re talking about
clinically driven TLR. If you looked at TLR rates in the nonangiographic
patients, they should be the same as in the angiographic patient.

DR. STONE: Well, we always expect, of course, to see somewhat of an
oculus stenotic reflex, and that is that patients who come back for
follow-up angiography sometimes will be feeling perfectly well, but
you\'ll see a moderate stenosis, and you\'re right there and the
operator feels it\'s in the best interest to dilate that patient.
That\'s been well described to us since the Benastent II (phonetic)
trial.

We carefully adjudicated events so that you had to have either confirmed
ischemia or a least quantitative coronary angiographic diameter stenosis
greater than 70 percent, which correlates to an operator seeing I think
it\'s 85 or 90 percent, to adjudicate it as a TLR.

When we looked at the TLR rates in the angiographic subset, it was 3.8
percent. In the non-angiographic subset, it was 2.8 percent. So we had a
very minimal ocular stenotic reflex in this trial. So I think the
results are generalizable.

CHAIRMAN LASKEY: We have time for one more. Dr. Somberg, did you have
one final before the break?

DR. SOMBERG: I\'d like to bring back the polymer chemist, if I could,
and just get a little bit more information on the material and the
studies that have been done on the material\'s integrity over time and
what that period might be.

MR. BARRY: Hi. I\'m Jim Barry. I\'m the Vice President of the corporate
R&D group at Boston Scientific.

So with a low drug to polymer ratio like the TAXUS technology, we would
very much expect that we could see some drug retention. We\'ve been very
sensitive to that. So we\'ve done some very extensive testing. [In
vitro]{.underline} we\'ve done accelerated fatigue out to ten years, and
we see no difference between control and TAXUS stents.

We\'ve done tensile testing. We\'ve seen on change in mechanical
properties. We\'ve looked [in vivo]{.underline} both at six months and
at two years for polymer degradation, and we saw none between those that
were implanted in the polymer that was not.

So I think we\'ve done pretty extensive studies there as well.

DR. SOMBERG: What about [in vitro]{.underline} degradation?

MR. BERRY: We have not done [in vitro]{.underline} degradation. Again,
the polymer is very, very biostable and couldn\'t really degrade there.
So that\'s why we did it [in vivo]{.underline} as well. Much more
realistic.

CHAIRMAN LASKEY: Thank you.

I have 11:30. We should take a 15 minute break and be back at 11:45, and
then we\'ll have the FDA presentation.

Thank you again.

(Whereupon, the foregoing matter went off the record at 11:27 a.m. and
went back on the record at 11:47 a.m.)

CHAIRMAN LASKEY: As much as I\'m warmed by the collegiality and
conviviality, we have the rest of the day to get through. If we can
resume with the FDA presentation, please.

MS. GOODE: Good morning, ladies and gentlemen of the panel. I want to
thank you for agreeing to participate with this panel deliberation on
the TAXUS PMA application.

My name is Jennifer Goode, and I\'m a biomedical engineer in the
Division of Cardiovascular Devices at the Food and Drug Administration.
I\'m the lead reviewer for FDA, for Boston Scientific\'s premarket
approval application for the TAXUS Express2 Paclitaxel eluting coronary
stent system, PMA No. P030025.

As panel participants, you\'re being asked to discuss and make
recommendations on the applicant\'s PMA submission. Your discussion on
the clinical study results and labeling recommendations will be taken
into consideration by FDA in the evaluation of the application.

Finally, you will be asked to vote on the approvability of the
application.

The FDA presentation will identify for you the FDA review team members
and their expertise, briefly describe the product, summarize the
nonclinical testing that was conducted, summarize the clinical and
statistical evaluation of the TAXUS product, and identify the FDA
questions for the panel.

The expertise required to review this product was quite extensive, and
this slide identifies for you the names of the individuals in the Center
for Devices and Radiologic Health that provided reviews for us.

I\'d like to thank all of these individuals for their work on this
project, and in addition, I\'d like to identify for you the three
members of the review team who will be speaking this morning after I do.

First, Dr. Stephen Hilbert, the lead animal study reviewer from the
Office of Device Evaluation, will describe the issues identified in the
FDA review of the animal data.

Then Dr. John Stuhlmuller, a medical officer from the Office of Device
and Evaluation, will describe the issues identified in the FDA clinical
review.

And finally, Dr. Heng Li, a mathematical statistician from the Office of
Surveillance and Biometrics, will describe for you the issues identified
in the FDA statistical review of the clinical data.

I also want to thank our colleagues from the Center for Drug Evaluation
and Research for their immensely valuable assistance on this project,
and their names and expertise are identified for you here.

This PMA application was submitted to the agency on June 19th, 2003, and
was assigned a PMA file number P030025.

The agency issued the applicant a major deficiency letter on September
15th, 2003. This letter requested additional information from the
applicant that was deemed necessary to complete the review of the
application.

The applicant submitted a response to the agency\'s letter on September
30th, 2003, to address the specific animal study, clinical and
statistical issues that would be the subject of the panel review today.

By November 5th, the sponsor had responded to all of these deficiencies
in FDA\'s letter of September 15th, and this additional information is
currently under review by FDA.

The agency and the applicant are working interactively to resolve these
outstanding nonclinical and manufacturing issues.

As defined by Title 21 of the Code of Federal Regulations, Part 3, the
TAXUS expressed two Paclitaxel eluting coronary stent system is a
combination product because it is comprised of two regulated components,
a device and a drug. The device component consists of the Express
balloon expandable 316L stainless steel coronary stent, and the delivery
catheter.

The bare metal Express stent is currently marketed for improving
coronary luminal diameter in patients with symptomatic ischemic disease
associated with stenotic lesions in native coronary arteries less than
or equal to 18 millimeters in length with reference to vessel diameters
from 3.0 to 5.0 millimeters, and this stent was approved through
P020009.

It\'s important to note that the label for the bare metal Express stent
does not include a claim for reducing restenosis, as does the proposed
TAXUS stent. The Express stent is approved on both of the proposed
delivery systems, the Express2 over the wire and the Express2 monorail
delivery systems.

While the proposed Express2 delivery systems were not used in the TAXUS
IV trial, the differences are minor and are not expected to affect
clinical performance.

To make the TAXUS product, the Express stent is coated with a
non-erodible drug polymer coating. The drug substance used in this
product is Paclitaxel. Under the trade name Taxol, a Bristol-Myers
Squibb product, Paclitaxel in injectable form was approved by FDA in
December 1992 for the treatment of cancer.

For this stent, a generic form of Paclitaxel is being provided by a
company called Indena S.p.A., and drug safety information has been
provided by this manufacturer in an FDA drug master file.

Paclitaxel has not, however, been approved for the treat treatment of
restenosis or for use in coronary arteries.

In developing safety information for this product, the sponsor studied
various formulations consisting of different amounts of polymer and drug
that have a range of release characteristics. TAXUS SR is the product
being proposed for market and is a slow release formulation with a dose
per unit area of one microgram per millimeter squared.

This product was studied in the animal trials as well as in the TAXUS I,
TAXUS II, and TAXUS IV clinical trials. TAXUS MR also has a dose per
unit area of one microgram per millimeter squared. However, the drug
releases more quickly in this formulation, providing some information on
the safety from an overdoes perspective. This product was used in the
animal trials, as well as in the TAXUS II clinical trial.

For this PMA application, the applicant is requesting approval for
stents ranging in length from eight to 32 millimeters and in diameters
from 2.5 to 3.5 millimeters as outlined in this table.

For the 2.5 to 3.5 millimeter diameter stents, the stent is crimped on
various size deliver catheter balloons. Because the identical stent
component is used for the entire 2.5 to 3.5 millimeter diameter range,
the total drug and polymer per stent are a function of the stent length
irrespective of stent diameter.

Please also note that the proposed indications for use include vessel
diameters to a maximum of 3.75 millimeters. The agency is evaluating the
acceptability of expansion of the stent to 3.75 millimeters from results
of bench testing. In addition, use of the product in this fashion was
evaluated in the clinical studies and no safety concerns were noted.

Based on the dose density of one microgram per millimeter squared of
metal surface area, the total nominal dosage of Paclitaxel ranges from a
minimum of 50 micrograms to a maximum of 209 micrograms for the
currently proposed matrix of stent sizes as shown on this slide.

The total nominal dosage of polymer content ranges from a minimum of 519
micrograms to a maximum of 2,170 micrograms for the currently proposed
matrix of stent sizes and is shown in orange.

As denoted in yellow on this slide, please note that the TAXUS IV study
was conducted using the 2.5, 3.0, and 3.5 millimeter stent diameters in
lengths of 16, 24, and 32 millimeters. Although approval has been
requested for a wider range of stent lengths, the sizes evaluated in the
TAXUS IV study allow for adequate assessment of safety and effectiveness
because the amounts of drug substance in polymer are the same or less
than the stents implanted in the clinical study.

The sponsor conducted pharmacology studies and [in vivo]{.underline}
release studies to assess the elution kinetics and toxicity of the TAXUS
product. [In vivo]{.underline} animal testing has been conducted to
assess the acute and long-term safety of the proposed stent for the
clinically intended dosage and with an overdosage of drug and polymer.

The detailed arterial histopathology and histomorphometry provide
important information that cannot be obtained through human clinical
trial experience, and Dr. Hilbert will outline FDA\'s assessment of this
information for you.

Biocompatibility testing in accordance with ISO 10993 was conducted on
polymer coated stents, or coupons, without the inclusion of the drug
substance. Since the applicant did not conduct biocompatibility testing
on the finished product with drug substance according to ISO 10993,
chronic [in vivo]{.underline} animal testing has been used to evaluate
the biocompatibility of the finished product.

Bench testing has been performed to evaluate the mechanical integrity
and function of the TAXUS product. FDA is working actively with the
sponsor to finalize the stability protocols and specifications prior to
assigning an expiration date for the product.

The sponsor has indicated that they have set aside adequate commercial
product per ICH guidelines for conduction of stability testing. This
product will be stability tested once protocols and specifications are
finalized with the agency.

The applicant has performed drug content, elution, degradation impurity,
residual solvent, and particulate testing to assess the coating
integrity of the finished TAXUS products. Sterilization validation and
package integrity testing have also been conducted.

With the exception of information on the [in vivo]{.underline} animal
testing, FDA has not yet completed the review of the recent responses to
questions regarding the nonclinical testing. However, no data have been
presented to indicate a safety concern in the clinical setting regarding
mechanical device failure or malfunction.

There are two major outstanding nonclinical issues, one of which is
important for your consideration today. First, Dr. Hilbert will outline
for you results from the animal studies, and FDA would like your input
on whether the clinical data adequately addresses any concerns that
might be raised by these animal study findings.

Second, as noted on my last slide, FDA is working interactively with the
sponsor to finalize protocols and quality control specifications for
product stability testing and adequate product has been set aside to
conduct this testing.

As you heard earlier from Boston Scientific, the applicant has proposed
the following indications for use for the TAXUS Express2
Paclitaxel-eluting coronary stent system for improving luminal diameter
and reducing restenosis for the treatment of [de novo]{.underline}
lesions less than or equal to 28 millimeters in length in native
coronary arteries from 2.5 to 3.75 millimeters in diameter.

At this time I\'d like to introduce Dr. Stephen Hilbert.

DR. HILBERT: I\'m Steve Hilbert, and I\'m an experimental pathologist
and served as the pathology reviewer for the preclinical [in
vivo]{.underline} studies that were provided in this submission.

This first slide provides the animal justification for the use of normal
swine. Comparable vascular and cardiac anatomy were present. Vessel
diameter suitable for the delivery and the deployment of the clinical
version of the device, and this model certainly allows for comparisons
of findings to, you know, historical data.

I focused my review in the following areas. Looking at handling
characteristics, meaning, you know, delivery and deployment safety, and
then within the safety areas, I focused on tissue or \-- sorry \--
device tissue responses, you know, addressing general healing
characteristics, device related pathology, again focusing on device
specific findings.

The experimental design of this series of studies consisted of
deployment in all three coronary arteries, dual antiplatelet treatments
using ASA and clopidogrel. These treatments started 72 hours before the
implantation and were continued through the duration of the study.

The target artery to the balloon ratio is one to one to one to 1.2. The
duration of implant ranged from 28 days to 90, 180, and 360 days.

The very stent platforms evaluated in this series of studies consisted
of a bare metal stent, polymer coated metal stent, polymer drug coated
stent, and the drug dose density was one microgram per millimeter
squared, using two formulations, the moderate release and the slow
release formulation.

The sponsor is accommodated or is commended for the extensive data set
that was provided, as well as the high quality of the studies that were
conducted by both the animal study investigators and the study
pathologists.

The following graded pathology endpoints were used: neural thrombus,
endothelialization, neointima, luminal area or \-- sorry \-- luminal
narrowing, a para-strut amorphous material which will be referred to as
PAM, medial alterations, IEL or internal elastical lamina disruption,
EEL, external elastic lamina disruption, and inflammatory response.

The studies also included morphometric measurements, luminal area, IEL
area, EEL area, neointimal area, luminal equivalent diameter, intimal
thickness, medial area, stent profile, and percent stenosis.

You know, I\'ve estimated that greater than 400 stents have been
implanted in over 200 swine and the various safety studies that are
directly applicable to this marketing application, which resulted in,
you know, well over 1,000 sections being evaluated in this series of
safety studies.

The sponsor has presented this morning micrographs illustrating the
findings of these studies. I will briefly summarize my observations by
grouping the findings into similar and different categories, comparing
the various stent platforms.

And the next series of slides really go through some of the criteria of
the different studies that were used for the safety studies. There were
studies focusing on the bare metal stent, on the polymer coated metal
stent, again the polymer drug coated stent and metal stent, a safety
margin study that included the moderate release formulation of one
microgram per millimeter squared, and then there was an overlapping
stent study using both the moderate release as well as the slow release
product at one microgram per millimeter squared.

And, you know, there were similarities as I mentioned across all of
these stent platforms, and the similarities were in the areas of
neointimal formation, endothelialization, no neural thrombus or
thrombosis, and inflammatory response.

And continuing on with the similarities, medial remodeling is
demonstrated by ingrowth of fibrous tissue and morphometric measurements
which demonstrated a stable EEL and luminal area, again reflecting
medial remodeling.

And differences across the stent platforms, there were some qualitative
differences that were observed focusing on medial smooth muscle cell
loss and PAM.

And there were also some differences across the platforms that were
noticed in trends that were associated with the release formulation,
with the moderate release, the slow release as compared to the polymer
and the bare metal stent.

And then we also looked at the segmental analysis, looking at
overlapping versus non-overlapping stents.

So the handling characteristics which I mentioned were looking to
deployment and, you know, delivery of the device so that we\'re
satisfactory. The tissue responses were satisfactory from the standpoint
of neointimal formation, endothelialization, medial modeling and
inflammatory response.

There were some device related pathology findings which really require,
you know, additional discussion at this time. You know, medial smooth
muscle cell loss was related to the exposure to the arterial wall to
Paclitaxel. Medial smooth muscle cell loss was most apparent in the
28-day explants. By 90 days, remodeling by fibrous tissue, in growth was
apparent in the media, and that continued through the study time periods
and was complete at 360 days.

PAM was resolving with time through 360 days, and microscopic dystrophic
calcification is variably present, occurring more frequently in the
polymer drug coated stents. Microscopic regions of dystrophic
calcification and polymer drug coated stents were reducing in size
through the 360-day period. The long-term significance of the presence
of PAM in microscopic regions of dystrophic calcification are certainly
unknown.

The vessel wall remains structurally intact as demonstrated by
histologic findings, and EEO and luminal area. As within any animal
model, the extension of these clinical findings to [in vivo]{.underline}
findings in the general patient population really should not be made for
the following reasons:

Accelerator rates of healing are seen in various animal models,
typically used in the evaluation of cardiovascular devices.

Neointimal formation, endothelialization, and medial remodeling findings
in nonclinical [in vivo]{.underline} studies may not reflect similar
rates of healing in humans.

Lastly, variations in device tissue responses and device related
pathology between individuals are always a concern, although a large
number of animals and stents have been examined in the series of
studies, the sample size is small in comparison to the expected clinical
use of the coronary artery stent.

For these reasons, FDA would like the panel to consider the following
question: does the combination of nine-month clinical data from the
TAXUS IV slow release study and the supporting data from the TAXUS I and
the TAXUS II, which was slow release and moderate release, adequately
address the issues raised by the animal data.

Thank you.

DR. STUHLMULLER: Good morning. My name is John Stuhlmuller, and I\'m a
medical officer in the Interventional Cardiology Devices Branch in the
Division of Cardiovascular Devices. I\'m going to provide a brief
overview of the clinical information contained in the PMA.

In their PMA application, the sponsors provided data for the following
clinical studies that are applicable to the evaluation of safety and
effectiveness of the TAXUS stent for the proposed intended use: TAXUS I,
TAXUS II, TAXUS IV, and TAXUS V.

Data from the TAXUS IV study is considered the pivotal data set. Data
from the TAXUS I, TAXUS II, and TAXUS V studies are considered
supporting data sets.

In addition, I will outline the sponsor\'s proposal for the
peri-approval study.

At this time I would like to highlight the findings of the TAXUS IV
study. The TAXUS IV study is a domestic, prospective, multi-center, and
blinded one-to-one randomization of the TAXUS drug eluting stent to a
bare metal control stent, the Express stent, in patients with de novo
coronary artery lesions.

Randomization was stratified by clinical site, reference vessel
diameter, and the presence or absence of medically treated diabetes. The
intent of the stratified randomization was to insure that an adequate
number of patients were enrolled in the various cohorts to allow
assessment of whether a treatment effect was noted that would affect the
poolability of the data.

The study was not adequately powered to reach any specific conclusions
regarding safety and effectiveness or to support a specific marketing
claim into subgroups such as medically treated diabetes.

At the time of randomization, a designation was also made as to whether
the patient would complete angiographic and/or IVUS follow-up. A
six-month combination post procedure antiplatelet regimen of aspirin and
clopidogrel or ticlopidine was utilized.

The table on this slide interpolates the stent matrix and lesion
characteristics. Three stent diameters and three stent lengths were used
in the TAXUS IV study. Reference vessel diameters of three millimeter or
less were considered small, and long lesions were characterized by the
use of the 32 millimeter stent. The bold lines delineate the
characterization of lesion length and vessel diameter.

Multiple stents were used for bailout stenting only. Where necessary, a
16 millimeter stent was used for provisional overlapping. Forty-four
patients in this study received multiple taxus stents.

Target vessel revascularization, TVR, at nine months is the principal
effectiveness outcome measure. MACE, stent thrombosis and vessel wall
structure are the principal safety outcome measures.

The TVR rate is 4.7 in the TAXUS arm and 12.0 in the control arm at nine
months. The absolute reduction in TVR is 7.3 percent and the relative
reduction is 61 percent. The difference in TVR is due to reduction in
the number of target lesion revascularizations in the TAXUS arm versus
the control arm.

Differences in the rates of death or myocardial infarction in the TAXUS
arm versus the control arm are reflected in the secondary composite
clinical endpoint of target vessel failure.

The MACE rate is 8.5 percent in the TAXUS arm and 15.0 percent in the
control arm at nine months. The absolute reduction in MACE is 6.5
percent and the relative reduction is 43 percent.

The stent thrombosis rate at 30 days is 0.3 percent in the TAXUS arm and
0.6 in the control arm. There were no cases of in-hospital stent
thrombosis in the TAXUS arm.

The stent thrombosis rate at 270 days is 0.6 percent in the TAXUS arm
and 0.8 percent in the control arm.

The incomplete stent apposition rate is 11.6 in the TAXUS arm and 6.4
percent in the control arm post procedure. The incomplete stent
apposition rate is four percent in the taxus arm and three percent in
the control arm at 270 days.

Incomplete stent apposition resolved in the majority of cases from post
procedure to 270 days. The late acquired incomplete stent apposition
rate is 1.1 percent in the TAXUS arm and 2.2 percent in the control arm.
Otherwise the vessel wall remains structurally intact.

At this time I would like to highlight the findings of the TAXUS I
study. The TAXUS I study is a prospective, multi-center and blinded
study completed at three centers in Germany using a near stent platform.
The primary study endpoints are MACE at 30 days and angiographic
restenosis at six months. Follow-up through two years has been
completed. This includes clinical angiographic and IVUS evaluation in
those patients in the TAXUS arm who agreed to complete this evaluation.

In terms of effectiveness, a persistent drug effect is maintained
through two years by angiography and IVUS measurements in those patients
in the TAXUS arm who completed the angiographic and IVUS follow-up.

In terms of safety, the angiographic and IVUS measurements demonstrate
that the wall remains structurally intact. No safety issues are noted.

At this time I would like to highlight the findings in the TAXUS II
study. The TAXUS II study consisted of two separate studies, meaning the
TAXUS II SR cohort and the TAXUS II MR cohort.

The TAXUS II SR cohort evaluated the slow release formulation on the
near stent platform. The TAXUS II MR cohort evaluated the moderate
release formulation on the near stent platform.

Both cohorts are prospective, randomized, multi-center, blinded studies
completed outside the United States. The TAXUS II SR cohort enrolled 267
patients at 28 centers in 12 countries. The TAXUS II MR cohort enrolled
270 patients at 28 centers in 12 countries.

The primary study endpoints were MACE and angiographic restenosis at six
months. Follow-up through one year has been completed.

In terms of effectiveness for the TAXUS II SR cohort, clinical benefit
is assessed by clinical event rates as maintained at one year. In terms
of safety, the vessel wall remains structurally intact in the TAXUS arm
compared to the control arm by angiography and IVUS at six months. No
safety issues are noted.

In terms of effectiveness for the TAXUS II MR cohort, clinical benefit
is assessed by clinical event rates as maintained at one year.

In terms of safety, the vessel wall remains structurally intact in the
TAXUS arm compared to the control arm by angiography in IVUS at six
months. No safety issues are noted.

In terms of comparing the results of the TAXUS II SR cohort and the
TAXUS II MR cohort, similar clinical benefit is seen at one year. In
terms of safety, similar vessel wall measurements by angiography and
IVUS are seen at six months for both groups. thus, the TAXUS II MR
cohort provides preliminary clinical evidence of the safety margin for
the SR formulation. No safety issues are noted.

At this time I would like to highlight the preliminary findings of the
TAXUS V study. The TAXUS V study is a domestic, prospective,
multi-center and blinded, one-to-one randomized comparison to the TAXUS
drug eluting stent to a bare metal, uncoated Express stent in patients
with de novo coronary artery lesions. A broader range of lesions with
smaller diameters and longer lesion lengths are being evaluated compared
to those evaluated in the TAXUS IV study.

In addition, overlapping stents are being used as the primary treatment
versus being limited to provisional bailout stenting. Patient enrollment
in several prespecified subgroups is ongoing.

The study remains blinded at this time. Thirty-day follow-up on 1,080 of
1,103 patients enrolled through November 12th, 2003, has been provided
by the sponsor in its safety update to FDA. A total of 122 MACE events
have been recorded.

Ten episodes of stent thrombosis in eight patients have been recorded.
Stent thrombosis has been characterized as acute in three episodes,
subacute in six episodes and late in one episode.

No safety issues are noted with the broader range of stent use at this
time.

At this time I would like to highlight the proposed peri-approval study.
The proposed enrollment would be 2,000 patients. The study would be
conducted in two phases. Phase I would enroll up to 500 patients under
continued access protocol utilizing the IDE expanded access provisions.
This will allow assessment of the format and function of a Web based
registry.

Phase 2 would enroll up to 1,500 patients as a post approval Web based
registry. The intent of the two-phase design would allow a smooth and
efficient transition between pre and post approval.

The total sample size is appropriate for detecting low rates of adverse
events. For example, with the proposed sample size of 2,000, an adverse
event that occurs at a rate of one percent can be detected with an upper
95 percent limit of 1.4 percent.

At this time I would like to summarize the results of the TAXUS studies.
The TAXUS IV study is considered the pivotal study by the sponsor. In
terms of effectiveness, clinical benefit is demonstrated at nine months.
In terms of safety, the vessel wall is structurally intact at nine
months. No safety issues are noted.

The TAXUS I study is a supporting study. Clinical benefit is maintained
through two years. The vessel wall remains structurally intact at two
years. No safety issues are noted.

The TAXUS II study is also a supporting study. Similar clinical benefit
is maintained through one year for both cohorts. Similar vessel wall
measurements are seen in both groups at six months. No safety issues are
noted.

The TAXUS V study is a supporting study at this time that is evaluating
an extended lesion range in that treated in TAXUS IV study. The study
provides preliminary evidence of safety for a broader range of use in
greater than 1,000 patients.

The proposed peri-approval study will enroll 2,000 patients in two
phases pre and post approval. The proposal is satisfactory from FDA\'s
perspective.

At this time I would like to introduce Heng Li from the Department of
Biostatistics.

DR. LI: My name is Heng Li. I\'m the FDA mathematical statistician for
this PMA submission.

In the next three slides I will provide a few comments, some main
features of the pivotal clinical trial design conduct and analysis.

The pivotal clinical trial, the TAXUS IV trial is a multi-center,
randomized, controlled, double blind study for safety and effectiveness.
Pretreatment variables are very well balanced between the two randomized
arms, indicating that the randomization has been successful.

Twelve patients were de-registered from the trial after being
randomized. Those 12 patients were not included in sponsor\'s analysis.

It\'s not a good statistical practice to routinely exclude deregistered
patients from analysis without considering the reasons for
de-registration.

In this specific case, since the study is double blind, the number of
de-registered patients is small and evenly distributed across the two
randomized arms. The analysis excluding de-registered patients is
considered by FDA as acceptable.

This is not the first instance in which an analysis excluding
de-registered patients was considered to be acceptable by FDA.

Among the patients who are not de-registered, those are patients who
were included in the analysis. Reportedly there were quantified
deviations. For example, reportedly there are deviations from treatment
protocol, and apparently not every patient has been followed all the way
to nine months.

Those protocol deviations are not very extensive. Differing approaches
to handling those protocol deviations in data analysis do not change the
statistical significance of the statistical test preplanned for the
primary endpoint.

The sponsor performed subgroup analysis for this PMA. Here a subgroup
refers to subset of patients, such as males, females, those with
diabetes, those without diabetes.

The subgroup analyses, as reported, have not identified safety issues.
Generally speaking, statistical inference, foremost statistical
inference associated with subgroup analyses usually is complicated by
the need to account for issues such as multiplicity and is limited by
insufficient power due to small sample sizes.

Here multiplicity is a general term referring to the phenomena such as
inflation of Type 1 error due to too many statistical testing.

Such issues, such as multiplicity, issues such as multiplicity is
usually intractable for unplanned analysis. Therefore, unplanned
subgroup analysis can perhaps never be considered as reliable from a
statistical perspective.

This concludes the statistical summary.

CHAIRMAN LASKEY: Thank you, people.

Does the panel have any questions for any of the FDA presenters?

Dr. Hirshfeld, do you?

DR. HIRSHFELD: Yes. This is a question for Jennifer Goode and maybe BSC
and can also answer this.

I note that the design of this device is that it actually provides a
twofold variation in delivered drug dose if you normalize dose per unit
vessel area because you\'re delivering the same dose of drug to a two
and a half millimeter vessel as you are to a three and a half millimeter
vessel so that the actual dose delivered if you normalize it to vessel
area varies over a factor of two.

And I wondered whether this issue had been addressed in the original
design planning and whether, you know, we could see any effect of this
in the larger vessel sizes.

MS. BOAM: I\'m Ashley Boam. I\'m the Branch Chief for this product. I\'m
sure Boston Scientific can speak to this in more detail.

In terms of some of the [in vivo]{.underline} studies that were done and
animal studies, a wide range of stent sizes were evaluated so that this
type of effect could be looked for.

DR. STONE: You know, the Paclitaxel is a very lipophilic agent, and we
think there\'s a different way of looking at this issue. Rather than the
dose actually being double, what happens when you put the same stent
size in the smaller vessel is that the metal surface area coverage of
the vessel is actually greater. The stent struts are closer together.

So I think there\'s actually greater drug distribution over any given
vessel area, and actually when you look at the relative efficacy of the
device going from larger vessels to smaller vessels, we actually saw
less late loss in the smaller vessels treated with the Paclitaxel stent
compared to the control stent.

We\'ve never seen that before with the bare metal stent. The amount of
late loss is always pretty independent of vessel size. With the
Paclitaxel stent it tended to be smaller, and of course, this is just a
hypothesis at this point, but it may be because the stent struts were
relatively closer together. We saw no safety concerns in any of the
subsets.

DR. HIRSHFELD: It might be for future development that it may be that
the dose at the two and a half millimeter level is actually better than
the dose at the 3.5 millimeter level.

DR. STONE: That is possible.

CHAIRMAN LASKEY: Chris.

DR. WHITE: I\'d like to ask Ms. Goode in her submission or the questions
on page 7 for the FDA, summary of FDA review information, she makes a
comment that the sufficient information to support the claim of
cytostatic versus cytotoxic effect has not been submitted to FDA for
review.

Does she think that\'s an important issue?

MS. GOODE: The labeling that Boston Scientific provided for your review
included that claim. We\'ve talked to Boston Scientific about the fact
that we don\'t believe they provided data to us in the PMA application
that supports that claim. They can speak to the fact that they have been
collecting additional data, and I believe may play to address that at a
future time.

But I wanted to bring it to your attention in the FDA review in the
panel pack because we have not yet agreed that we\'ve seen sufficient
data to support that claim.

DR. RUSSELL: We removed that claim from our DFU until we gather
substantially more data to support it.

MS. GOODE: I guess I should just make one clarification. We had talked
to Boston Scientific about this, and it was in two places in the label,
and they removed it from one place, and it may have been an oversight
not to remove it from the second place, and that\'s why in the FDA
review memo I brought it to your attention. So that may have been an
oversight.

CHAIRMAN LASKEY: Only if it\'s a statistical question. Sharon.

DR. NORMAND: I can\'t ask a clinical question?

(Laughter.)

DR. NORMAND: It will be a statistical question.

I just wanted to ask the FDA reviewer. You said there were protocol
deviations, and I can sort of guess what some are, but I was wondering
if you could just broadly say what those protocol deviations were.

DR. LI: Oh, the protocol deviations are inferred from the fact that a
protocol analysis was provided by the sponsor, as well as analysis that
does not address protocol deviation.

So from that fact I know that there are protocol deviations.

DR. NORMAND: Okay. So it wasn\'t like anything. It was just really the
fact of the analytic procedure that they adopted. That\'s the way
you\'re characterizing protocol deviations.

DR. LI: I believe that a protocol deviation is defined in this PMA as
target lesion without not being treated with study stents, but I would
like to confirm this with the sponsor.

DR. NORMAND: Okay. Thank you.

DR. STUHLMULLER: I\'d like to add one clarification. I mean, from a
clinical perspective, part of that comes down to, you know, if you have
a two week or 30-day window to complete follow-up in and somebody comes
in at day 31 versus day 30, well, that counts, you know, in terms of
bean counting as a protocol deviation, but from a practical perspective
it doesn\'t affect the interpretation of the data, or if somebody is
supposed to take a medication for six months and they take it for four
months for some reason, that could potentially also be interpreted as a
protocol deviation. And that\'s part of what we were referring to.

Dr. Russell might want to address that as well.

DR. RUSSELL: We did extensive monitoring in this study. The
investigators were cited if there were any deviations whatsoever from
any of the follow-up windows, including testing such as cholesterol.

Investigators were cited for having protocol deviations if they did not
inflate the balloon to the specified amount listed in the protocol. So
in our analysis of the protocol deviations, there were few of them that
had any effect on the outcomes. We provided FDA with analyses of per
protocol.

All randomized patients, including the 12 de-registered patients,
patients that received only single stents, patients that received
multiple stents. We provided FDA with extents of analyses and the
findings were replicated irregardless of the analysis.

With respect to the 12 patients that were deregistered, those patients
were deregistered because there was no attempt ever to even place a
stent. Patients that had an attempt and failed were included in our
analysis.

I hope that addresses the questions.

CHAIRMAN LASKEY: Dr. Maisel.

DR. MAISEL: This is a question for Ms. Goode.

On page 7 of the FDA review, it mentions that the sponsor had been asked
to provide additional information regarding the carcinogenic potential
of the entire stent, including the polymer, manufacturer additives, et
cetera. Was that additional information provided? And what was the
result?

MS. GOODE: That information has been provided to the FDA. The review is
not yet complete on that. So we don\'t expect that there would have been
a problem, but I haven\'t conferred with my consultants.

CHAIRMAN LASKEY: One question to Dr. Stuhlmuller and perhaps the
statistician. This certainly was an interesting study from the
standpoint of it being a clinical endpoint rather than an angiographic
endpoint for the restenosis. That being the case and clinical endpoints
being driven by the patient population, if I read the pack right, about
50 percent of these patients were asymptomatic at the time of the
procedure, and I wonder how that might affect rates and certainly
differences between the two arms if that were to change in some more
real world fashion, for example.

DR. STUHLMULLER: Just in terms of clarification, let me make sure we all
understanding what we\'re all talking about. Can you identify the table
specifically?

CHAIRMAN LASKEY: Yeah. The clinical study report, report Table 7,
Baseline Demos and Clinical Characteristics. This is page 68 in Volume
2. If you just look down to the \-- it\'s actually the top angina class,
none. It\'s 48.9 percent versus 48 percent.

I just struck me as being quite unusual for, first of all, an
interventional trial, but secondly, a trial driven by a clinical
endpoint to have such a rich population of patients without angina and
then to use angina as the driver for the endpoint.

DR. STUHLMULLER: Yeah, my interpretation of that table is if you add up
the unstable and the silent ischemia is that comes out to be 48.9, and
it took me a while. You know, it took several times for me when I went
through that table to understand that, and I think perhaps it would be
reasonable to ask Dr. Russell to clarify that, as to whether my
interpretation is correct.

CHAIRMAN LASKEY: I\'m misreading that. That\'s supposed to add up to 100
percent?

DR. STUHLMULLER: Yes.

CHAIRMAN LASKEY: Very confusing.

DR. RUSSELL: I believe that Dr. Stuhlmuller has addressed the question.
Those were the patients with stable angina only and the breakdown of
stable angina. So the patients that had none fell into either silent
ischemia or unstable angina.

CHAIRMAN LASKEY: But they were in a minority.

DR. RUSSELL: Yes.

CHAIRMAN LASKEY: Okay. Thank you.

DR. RUSSELL: The inclusion criteria mandated that they have either
stable angina, unstable angina, or silent ischemia.

CHAIRMAN LASKEY: Any other questions for the \-- oh, Dr. White.

DR. WHITE: I\'m sorry. I just wanted to ask a short of one of Dr.
Russell.

The Express2 stent, the FDA says that the Express2 stent is a minor
change. Express2, I suppose, is the delivery system. Why did you not use
that delivery system for the trial?

DR. RUSSELL: We were optimizing the minor modifications at the time of
the IDE submission and so \--

DR. WHITE: So it wasn\'t available before the trial. Because it makes it
seem like it\'s an approved platform for the express stent; is that
correct?

DR. RUSSELL: It\'s been subsequently approved for the Express.

DR. WHITE: I see. It seemed to me like it was available and you chose
not to use it as a delivery platform and now have changed your mind.
that\'s not true.

DR. RUSSELL: That\'s correct. It\'s an evolving scenario.

CHAIRMAN LASKEY: Well, then we\'re at that critical point where we can
now break for lunch. So may I suggest that we adjourn for one hour?

I have 12:40. If we can call ourselves to order at 1:40, I would
appreciate that. Thank you all.

(Whereupon, at 12:36 p.m., the meeting was recessed for lunch, to
reconvene at 1:40 p.m., the same day.)

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

(1:49 p.m.)

CHAIRMAN LASKEY: If we can resume, that would be much appreciated.

Okay. I\'d like to call us back to order and lead off the afternoon with
the open committee discussion and have Drs. White and Weinberger,
respectively, give their reviews and ask questions of the sponsor.

Dr. White.

DR. WHITE: Thank you.

I guess I will reference the submission panel that I\'m talking from. Do
you have that available?

I\'d like to start on page 4 of the safety and effectiveness part of the
document. Page 4, where it says \"contraindications,\" the last of the
bullets say \"known allergy to stainless steel.\" And I\'m asking a
question because my reading of other products, usually that sentence
says \"known allergy to nickel.\"

And is that what you normally say? Is that what you say in your other
stents? Is that what it says for the Express or is the specific mention
of allergy to stainless steel what you\'re trying to call attention to
or is it more the nickel component of the stainless steel that you want
to raise awareness about.

Because my understanding is it was the nickel allergy that was of
concern.

DR. RUSSELL: I agree with you, Dr. White. I\'m not sure if this language
was FDA mandated, but I would be happy to \--

DR. WHITE: We should just be consistent with what you\'ve done for your
other stainless steel stents, and when I\'ve read them, it has always
been a nickel allergy, not a stainless steel.

DR. RUSSELL: I guess ours says stainless steel.

DR. WHITE: Fair enough. That\'s fine. I just wanted to raise that
question.

And then on the next page, page 5, under precautions number one, general
precautions, the final bullet says that \"antiplatelet therapy is
recommended for a period of six months post procedure.\"

And I think this morning in your presentation, and I would suggest I
think you acknowledged this this morning in your presentation, but I
would like to see you specify that you really want people taking plavix
or ticlopidine for six months with their aspirin; that you not just say
\"antiplatelet therapy.\" I think you really do want to ask for a dye.

DR. RUSSELL: Absolutely.

DR. WHITE: All right. On the next page, page 6, you talk boulesion and
vessel characteristics, and other than the fact that on the fourth
bullet there\'s a typo, you said \"overflow\" and I think you mean
\"outflow.\" That\'s not important.

But the next bullet down says, \"Patients with tortuous vessels in the
region of the obstruction.\" What are you trying to communicate to the
physician when you say \"tortuosity\"?

I know that in the inclusion criteria of the trial you ask for 60
degrees. Do you want to be more specific or less specific than the trial
criteria for the IFU?

DR. RUSSELL: I\'m looking at FDA because we complied with the language
that we used in our protocol. We could be more specific?

DR. ZUCKERMAN: Dr. Whit, you\'re referring to the summary of safety and
effectiveness.

DR. WHITE: Right.

DR. ZUCKERMAN: Which if the product is approved would appear on our Web
site and would be the FDA document that summarizes the data for a PMA
submission. We can certainly make it a more accurate and truthful
document.

Are you questioning the sponsor and FDA regarding the actual intended
labeling, which is a little bit different? It is in a section
\"instructions for use.\" Maybe you want to refer to that section if you
look at how the clinical trial is described.

DR. WHITE: I think that as a physician who \-- you know, if you ever
want to look at the label, I think tortuosity is \-- every vessel has
got some tortuosity. So I think you want to make sure that you are
giving a reasonable estimate. If 60 degree tortuosity was what the trial
used and you can expect those results and that success, then probably
being consistent in the IFU for the physician reader would make sense
rather than being more general.

The next thing, I\'d like to jump to the patient guide. I have a booklet
in here that has a colored label called patient guide, and on page 11 of
the patient guide, the second question, it says, \"Can I walk through a
metal detector with a stent?\"

(Laughter.)

DR. WHITE: And the answer is of course you can, but your reasoning I
think isn\'t correct, and that is that you said here that you have a
nonmagnetic and I believe stainless steel is ferromagnetic. Nitenol
stents (phonetic) are nonmagnetic, but isn\'t stainless steel magnetic?

You\'re saying no. It\'s not ferromagnetic? I didn\'t know that. So
stainless steel is not or 516 or whatever it is you\'re making? No, I
didn\'t know that. All right. There you go. You taught me something.

DR. RUSSELL: I believe that that is a residual hangover, Dr. White, from
the labeling on all of our other stents.

DR. WHITE: Well, I guess I always thought that the stainless steel stuff
was ferromagnetic and was an issue, and the Nitentol stents were not. I
thought that was the difference between those stents, but I guess
that\'s not true.

I would like to see in the patient\'s guide some emphasis about the need
to continue to take their plavix and the risk of thrombosis. I think the
newspapers in the last couple of months have raised everyone\'s
awareness to a probably inappropriate degree over the risk of subacute
stent thrombosis, and I think the one thing we can do is instruct
patients of the need to continue plavix. Occasionally I think patients
inadvertently stop their medicine without thinking that it\'s that
important or it\'s expensive or whatever the reason.

So perhaps in the patient instruction booklet there would be some
emphasis about the importance of taking the medicine and if you must
stop, contact your doctor, and that would be something they could take
away from the encounter.

I wanted to compliment Boston Scientific and Gregg and Steve on the
conduct of this trial. I think that we were talking about how
disciplined and how nice this was done. It is nice.

The one fly in the whole ointment is the IVUS data, where only 66
percent of the data was actually interpretable, and I mean, the way that
you cite investigators for noncompliance, and I get cited every day for
other Boston trials, I can\'t believe people were sending you IVUS data
that wasn\'t interpretable and not getting feedback to fix it.

I mean, how could only two thirds of the data that went to the IVUS lab
end up being interpretable unless it was stacking up somewhere and not
being read until the end of the trial?

DR. RUSSELL: I\'m going to have Dr. Weissman answer that question, but
it is one of the complexities of paired IVUS analysis.

DR. WEISSMAN: I\'m Neil Weissman. I\'m a cardiologist from Washington
Hospital Center. I directed the Core Lab.

In terms of conflicts, I\'m a full-time, salaried employee of MedStar
Research Institute. Boston Scientific gave a grant to MedStar Research
Institute to do this. No stock or anything like that.

If you look at the compliance with the IVUS, it actually was very good.
It\'s about 75 percent, which is pretty typical for U.S. multi-center
studies. What you\'re looking at is how many patients had full, 3D
volumetric analysis. In order to have that, they had to have every
single millimeter throughout the stent visualized and the interface was
visualized.

DR. WHITE: But let me just stop you because it does say 2D, two
dimensional analysis. In the next sentence it\'s 53 percent for 3D.

DR. WEISSMAN: Okay, but the cutoffs even with 2D, okay, we would go
through. If you were missing part of it, okay, and you could still do
2D, you know, on some, you wouldn\'t go on to 3D. So I guess there is
differential.

I think the things to look at is the characteristics between the
patients that did and did not have IVUS, and if you look at the patient
characteristics, the lesion characteristic, angiographic and so forth,
they\'re the same

The other thing that we set up to alleviate bias is that we present IVUS
sites. So at those IVUS sites, everyone had to have IVUS consecutively.
So I agree with you. You know, it could have been better, but I think
that we still did a good job, and if you look at the IVUS cohort, they
are very representative.

DR. WHITE: Were you given feedback to the operators that they were
giving you unusable data?

DR. WEISSMAN: Yeah, we gave them friendly feedback forms usually within
about two weeks of the time.

DR. WHITE: So they\'d get unfriendly feedback.

(Laughter.)

DR. WHITE: While I\'ve got you here, do you have access to these tables?

DR. WEISSMAN: I can get them, I\'m sure.

DR. WHITE: I have a question about Table No. 34. I\'m sorry. Table No.
35. It\'s on page 93 of 145. The title of the table is \"Incomplete
Apposition Determined by IVUS.\"

My question is that the denominator used in the table is an n of 112,
and the denominator in the rest of the IVUS tables are all in the 80s.
So how did you get 112 evaluable patients for that endpoint and not for
the other endpoints?

DR. WEISSMAN: Yeah, again, I think when you look at the difference
between qualitative and quantitative measures, I think that we\'re
talking about quantitative measures, the low ones, but you could still
have qualitative measures.

DR. WHITE: Okay. Fair enough.

I\'d like to switch to Volume 2 for just a minute. In Volume 2, I\'m
looking at the protocol amendments, and this is page 14 of 83. Number
14, one of the exclusion criteria with the patient taking colchicine, is
that important? Why was that?

DR. RUSSELL: That was set up originally because colchicine also can
affect mycrotubulus. Obviously the number of patients receiving
colchicine in modern medicine is relatively small.

DR. WHITE: I that going to end up in the IFU or as a contraindication?

DR. RUSSELL: I think it should be debated.

DR. WHITE: Can you tell me why you didn\'t include the most important
lesions in the LAD that I want to treat with this stent, which are the
osteolesions? Why can I not treat an osetolesion now with a TAXUS stent,
an osteo LAD lesion? Why did you not include osteolesions in this trial?

DR. RUSSELL: Well, osteolesions are routinely excluded from early phase
programs, originally, I think, because they were perceived to be of
higher risk. As interventional cardiologists have gotten more
technically savvy, I think that concern has gone away, and in fact, it
is one of the things that we are looking at modifying in our standard
inclusion criteria.

DR. WHITE: I was going to say that I don\'t think you\'re including
osteos in TAXUS V, are you, Gregg? And you might want to consider
modifying that.

DR. STONE: Yeah, I mean, there\'s always the concern in a controlled
trial about implanting a stent within the left main coronary when
you\'re dealing with an osteo, and especially when you have a narrow,
you know, angle between that. That can lead to a complicated situation.

So you try to do these trials to avoid those what could become outlier
situations and very rare complications that could skew the data one way
or the other. So for that reason, most studies have excluded osteos, but
I agree. It\'s not in TAXUS V either, and it\'s just a reality of doing
clinical trials, the same way we exclude definite angiographic thrombus
and heavy calcification and other situations. It\'s difficult.

DR. WHITE: I would say that I think now more than ever in our clinical
practices we\'re being driven by the evidence base, and that driving
away from the evidence base is risky and dangerous, and many of us are
afraid to do that, and so we really do depend on the trial data to
justify our practices.

So I think it pushes us even more important to test the lesion subsets
that are going to become clinically important to us.

When you say \"osteolesions,\" would that also then apply to a right
coronary osteolesion?

DR. STONE: Yeah, they were excluded.

DR. WHITE: I mean, you could exclude the left main stuff by the
bifurcational nature of the lesion, but it still would \-- now I guess
when I have subacute thrombosis and I put a TAXUS stent in a right
coronary osteo and a plaintiff attorney says, \"Dr. White, didn\'t you
participate in the panel that said that that wasn\'t a good place to put
that stent?\" it puts us in a difficult spot.

DR. STONE: No, I understand, and a lot of these complex types of
lesions, I mean, bifurcations we probably do more than any other type of
lesion subset that weren\'t included here. Ultimately we need registry
studies and then follow-up carefully controlled studies to examine those
lesions.

DR. WHITE: That\'s all I have. Thank you.

CHAIRMAN LASKEY: Thank you.

We\'ll go to Dr. Weinberger and then resume around the table.

Judah.

DR. WEINBERGER: I think Chris covered a number of things I was
interested in, but I\'d like to just go back to the issue of MRI. In the
proposed instructions for use, it says, \"Do not perform magnetic
resonance imaging scan on patient post implantation until the stent has
been completely endothelialized (30 days) to minimize the potential for
migration.\"

So my question and comment is, number one, if this is non-ferromagnetic,
do you care about the patient having an MRI the next day?

And if it\'s not \-- okay, and if it is ferromagnetic, are you so
assured by the animals studies that it\'s completely endothelialized at
30 days that you\'re comfortable that that\'s the situation in humans?

DR. RUSSELL: It has been my contention with my staff that this should
not be included in the DFU, that there is substantial literature to
justify the safety of MRIs after patients have been stented, and I have
been instructed that it is included in all DFUs and needs to be there.

So I would be happy, delighted to follow the panel\'s recommendation and
work with FDA on that particular issue.

(Laughter.)

DR. WEINBERGER: Okay.

(Laughter.)

DR. WEINBERGER: All right. Question/comment No. 2. There was a
relatively small number of patients that got two stents in TAXUS IV.
Certainly that was an unintentional event, and that was not
prespecified. In any case, the instructions for use are not silent about
that. They say that use of more than two TAXUS stents has not been fully
evaluated, implying that the use of two TAXUS stents has been fully
evaluated.

And I don\'t know whether or not that can clearly be stated from your
study.

DR. RUSSELL: I believe that it should read the use of two stents has not
been evaluated. I mean, it has not been evaluated. That was our
intention.

DR. WEINBERGER: You correct that because it then goes on to say, \"When
multiple stents are required, resulting in stent-to-stent contact, stent
materials should be of similar composition to avoid the possibility of
dissimilar metal corrosion.\"

So my question is: is there any data to support that contention either,
or is that just a theoretical issue?

DR. RUSSELL: Yeah, I had exactly the same discussion with my staff when
the DFU was developed, and I believe that is a theoretical concern.

DR. ZUCKERMAN: Dr. Weinberger, we can have Ms. Boam clarify why we have
that standard language in.

(Laughter.)

MS. BOAM: That\'s standard language that goes into IFUs for both drug
eluting and bare metal stents because there are now stents of multiple
materials available in the market. Unless the company has actually done
testing to evaluate the potential, for example, for galvanic corrosion
because of the mix of metals.

DR. WEINBERGER: But I assume that\'s never been seen [in
vivo]{.underline} in any animal study; is that right, or it has never
been tested?

DR. RUSSELL: We\'ve only tested two similar stents in our studies. We\'d
be happy to work with FDA on clarifying that language.

DR. WEINBERGER: Okay, and I would just add my overall congratulations to
Boston Scientific on providing some very clear information about this
particular stent device.

CHAIRMAN LASKEY: Is that it?

DR. WEINBERGER: Yeah.

CHAIRMAN LASKEY: Thank you.

It actually may come up because there are some non-316L stents coming
down the pike. So dissimilar metals in an aqueous environment is not a
good situation.

Dr. Hirshfeld.

DR. HIRSHFELD: One question relating to the physician instructions for
use. Unless I missed it, I don\'t believe there\'s anything in there
that describes the maximum diameter to which the stent is approved to be
inflated or if there is, I looked for it and couldn\'t find it, which
would mean it\'s probably not displayed prominently enough to enable us
to find it.

And I was wondering. I\'m sure this data has already been determined for
the Express stent, and I think that should be available.

DR. RUSSELL: We\'d be happy to include that. It is provided with the
Express stent. So we\'ll just make sure that it\'s supplied in this DFU
as well.

DR. HIRSHFELD: Yeah, because your language right now that\'s in there
says to use an appropriate sized balloon, but it doesn\'t tell you what
the upper limit of appropriate is.

DR. RUSSELL: We\'ll work with FDA to get the proper language on that.

CHAIRMAN LASKEY: Dr. Somberg.

DR. SOMBERG: Well, I, too, want to congratulate the company on a very
excellent presentation and very good database that they have presented.

With that said, I do have some concerns, one being, as I mentioned
earlier, the dose, and I\'m going to congratulate you and take you,
whoever chose that dose, to Las Vegas next time I go \--

(Laughter.)

DR. SOMBERG: \-- because it takes a certain amount of, oh, courage to
embark upon these types of large clinical studies with really minimal
assurity (phonetic) that you\'re going to choose the right dose. And
having the MR versus the SR really is another issue, and that\'s the
rapidity of release early on, which doesn\'t have to do with a
cumulative dose release.

So I think we have a polymer here that is retaining most of the
material, 80 or 90 percent. When you take it out, you might lose ten
percent, maybe even higher, and you have a potential for an adversity
down the road. So I would strongly suggest that you\'re going to get
this data earlier from animal studies. If you can carry out the animal
studies for a prolonged period of time [in vivo]{.underline} and study
the reliability of the material over time.

So I think that\'s necessary, but not a reason to deny the public the
benefits here.

There are two other areas I have concern about, and that is stent-stent
interactions and drug interactions. The first is a stent-stent
interaction, which is in part a stent-drug interaction, and that is that
it\'s well known in the pharmacologic literature that sirumulous
(phonetic) inhibits Paclitaxel\'s activity.

So I think if you had a situation where you didn\'t deliver your stent
and they only have one Paclitaxel stent and then they had a sirumulous
stent and they mixed them and they put them next to each other, I think
you would have a problem since sirumulous may very well inhibit. Let\'s
say you wanted that minimal concentration effect curve, and it inhibited
it. You could really undo it so that you could have, you know, \$10,000
worth of stents, and it would have zero benefit.

So I think that should be noted in the material that there is a
potential drug-drug interaction from the sirumulous to the Paclitaxel.

Now, there\'s a whole complexity here because it said in the literature
that the eluting substance really just has a local effect, and I do
agree, and the systemic effects are not very much, but that local effect
does go beyond just the stent because it occurs to both of your edges,
and you do have an edge effect, as well, which takes in that whole area
that you\'re considering.

And I think systemic effects of drugs that interact with the Paclitaxel
is something to note. So there are some drugs that may be inhibitory and
there are some drugs that may be facilitory and really don\'t have
knowledge on that. So I think that has to be looked into.

The commonest drug used in this population is a torvastatin, and the
torvastatin, you know, it\'s not a hepatic effect. It\'s not through
your 2C8 or the other polymorphisms, but it\'s a direct effect on the
action of Paclitaxel.

So I think you have to mention that, and I actually think, you know, if
you get a large enough study you find better results than those who are
on a torvastatin.

Also, dicumerol is a rather frequently used compound there, and that
potentiates the Paclitaxel effect, and then there is the COX-2
inhibitors, which has an action there as well. So I think these things
have to be noted for clinicians, and I did not see in your database an
analysis of, you know, people on, people off. I\'m not sure the database
is at this time large enough to look at that. But these may be
confounding factors and certainly should be noted.

With those said, I want to again congratulate you on this very nice
study and presentation.

CHAIRMAN LASKEY: Dr. Aziz, do you have it within you?

DR. RUSSELL: Dr. Aziz, do you mind if I ask Dr. Rowinsky to address the
concerns about drug interaction? Dr. Rowinsky is an oncologist deeply
involved in the Taxol program who may be able to provide us with some
insight.

DR. ROWINSKY: Thank you, Dr. Russell.

Good afternoon. I\'m Eric Rowinsky. I\'m a medical oncologist and
clinical pharmacologist and Director of the Institute for Drug
Development in San Antonio.

I\'m a paid consultant for Boston Science. I do own stock. I do not have
any options. I do perform studies as a clinical investigator with
competitors and potential competitors.

I\'ve worked with Taxol since the initial studies in 1984 and was
involved with its approval in the first oncologic indication in 1992,
and have been very much involved in clinical research first with this
agent since its approval.

At this point, there really are no consistent evidence of drug-drug
interactions reported with Taxol. It is metabolized by Cyp3A4 and 2C8
very extensively and very efficiently. It is only a weak inhibitor of
those two Cyp systems, and there has been extensive [in
vitro]{.underline} work with multiple types of metabolic systems,
including all of the Cyp enzymes.

The KI for those two enzyme systems which are most relevant as far as
inhibitory effects far exceed the concentrations that we even achieve in
oncology patients which are several orders of magnitude higher.

The only interactions than would be relevant in this population, the
only interactions that have been reported thus far are interactions with
respect to inducing agents, such as anti-convulsants on the metabolism
of Taxol, which I don\'t really believe is relevant here.

Thank you.

DR. SOMBERG: Well, I\'d just like to follow up for a moment. I\'m not
talking about the hepatic polymorphism systems, but for instance, a
torvastatin has been reported to potentiate the effect of Paclitaxel
locally.

So what I\'m saying is if you have a systemic concentration of a
torvastatin and you have a local effect of the Paclitaxel, could you not
potentiate that effect, potentiate in terms of its efficacy, which is
good, but also potentially potentiate it in terms of further inhibition
of the phenomena that may lead to weakening of the imbedding and all of
that sort of stuff.

So that\'s really my concern. Do you share in those local effect
considerations?

DR. ROWINSKY: No, I don\'t think the evidence is in, but I think that
there are some, for example, studies now of systemic rapamycin which is
being developed as a chemotherapeutic in Taxol and in combinations, and
I think that will actually give us some lead as far as the ability of
these agents to augment the other in various tissues, but I believe that
won\'t answer your question that deserves to be answered.

CHAIRMAN LASKEY: Salim.

DR. AZIZ: I\'ve got to whisper because I\'ve got laryngitis.

Dr. Russell, the focal calcification that that you see in the animals,
do you have any explanation for that?

DR. RUSSELL: The calcification, the focal calcification? We believe and
have a fair database that with implant injury you can have small areas
of necrosis, focal necrosis in the regions where the stents are, so to
be part of the healing response to that focal necrosis.

DR. AZIZ: Do we have any data from any patients that died and your
autopsy studies?

DR. RUSSELL: We have no stents from any patients that have died that
have received TAXUS. We did receive one stent from a patient that died,
and unfortunately that was a control stent.

We did look at calcification scoring by the Core Labs before and after
to see if there was any correlation, and we were not able to identify
one.

DR. AZIZ: And just a matter of theoretical interest, do you have any
animal data with a stent intravenous system?

DR. RUSSELL: I don\'t believe we do.

DR. AZIZ: Okay. Thank you.

DR. NORMAND: I have a few technical questions for clarification.

First of all, I wanted to ask both the procedures for randomization. You
didn\'t mention this. I\'m just presuming it. I assume you randomized
within center.

DR. RUSSELL: Yes.

DR. NORMAND: It didn\'t exactly work out that way the whole time, but it
looked like, in fact, that\'s what you had done.

DR. RUSSELL: We used an interactive voice randomization system.

DR. NORMAND: And the other thing I wanted to get some clarification on
is the procedures for blinding. You indicated it was double blinded. I
wanted to get some sense of it wasn\'t in the panel packet, the
description. You did mention. I think Dr. Stone earlier today indicated
that the stents looked identical. So presumably the interventionist
doesn\'t know what it is.

But could you just say a little bit more about the double blinding
procedures?

DR. RUSSELL: Certainly. We began by investing in a process that allowed
us to serialize the stents. So they were packaged under identical
conditions. Then they were serialized. The serialization numbers were
used by the interactive voice randomization system to conduct the
randomization.

And the reason we consider it \-- I\'ve been told I inappropriately said
this \-- triple blind is because the investigators are blind; the
patients are blind; all of the core labs remain blind, and all of the
study staff working on the study remain blind.

DR. NORMAND: Well, it\'s a beautifully designed study. There\'s no doubt
about that.

I wanted to get a clarification on we\'ve heard two different
interpretations of intention to treat which I find amusing, but I guess
what I wanted to get a sense of, it\'s 12 people, you know, but in terms
of the 12 people, I\'m still confused as to why your Boston, the
sponsors, doesn\'t believe that they were part of anything and, hence,
you really did use intention to treat principles.

DR. RUSSELL: This decision was a decision that we made prospectively in
partnership with FDA. Our study randomized patients before they had
predilitation, which is fairly unusual in the interventional cardiology
world. We did that at the request of our investigators to facilitate the
conduct of the procedure.

Normally, we would have waited till there was successful dilatation, and
then we would have known that the chances of implanting a stent were
high, but we made this decision at the request of the investigators.

So we had a number of patients where there was failure of the wire to
actually cross the lesion and failure to dilate, which led to the need
to revascularize with alternative means because of complications.

DR. NORMAND: Okay, but they had been randomized in theory, but never
made it subsequently. So they actually had been randomized to two
different \-- okay.

DR. RUSSELL: Yes.

DR. NORMAND: So I think in that technical sense you really didn\'t do an
intention to treat analysis. It doesn\'t matter, I think, because of the
numbers, but I would hate to describe anything as the intention to treat
when it really isn\'t intention to treat, but I think most statistical
people would feel that, in fact, those 12 people are important.

I have some clarifications I would like about the missing data again,
and this is actually kind of important, and it relates to some of, well,
almost all of the tables I saw presented today, and I still think I may
be misunderstanding, but I checked the numbers again, and I think all of
the percentages are based on full numbers, six, six, two and six, five,
two.

So you could go and look through your packages and you\'ll see that in
various tables where the numbers are presented you are assuming as if
you have complete follow-up on all of the individuals.

Now, someone help tell me that I\'m wrong on that because I just don\'t
understand it, and again, I think you said 97 percent are complete,
which is, you know, a pretty high number, but nevertheless, for example,
if I look at page 78 of 145 \-- I don\'t know how to describe these to
you \-- Volume 1, nonclinical and clinical testing summary, and I\'m
just pulling out one of the tables. We could go through several more
tables, but so if you look down at the numbers, all of the denominators
are exactly the same.

So six, six, two, and six \-- I can\'t see. I\'ve got to hold it far
away from me to see this \-- but six, six, two and six, five, two, it
looks like you have the same denominators all the time, and that\'s true
for all of your descriptive tables.

Hence, my inference is that indeed even though you did have loss to
follow-up, you included them as if they were in there. So I think when I
asked earlier, the answer was that they were taken out, but could
somebody help me with that?

CHAIRMAN LASKEY: You\'re looking at me?

(Laughter.)

DR. RUSSELL: We\'re looking at the tables ourselves

DR. NORMAND: I mean, it\'s fairly simple if you look on page \--

DR. RUSSELL: Yes.

DR. NORMAND: It all is divided by six, six, two and six, five, two, and
surely it looks like you\'ve used that. I can\'t imagine \-- that\'s a
pretty big typo.

And it\'s the same thing in many of the other slides that I viewed.
There\'s a lot of them. So I hate to go through all of them, but again,
I don\'t want you to sort of have to look at every single table, but it
seems to me with the numbers that are missing, I\'d just like to get a
sense of where, indeed, it looks like you\'re assuming you\'ve got
complete cases for the six, five, two and the six, six, two.

The 30-day may be 100 percent, but my understanding is at 270 days you
did have some loss to follow-up. It\'s not a great big loss to
follow-up, and I\'m understanding you assume the censoring was
uninformative, and that\'s why you did your cost model.

I\'m rambling. I\'m waiting for you to tell me something and I\'ll be
quite.

DR. RUSSELL: Right, and that\'s pretty much what my statisticians have
just told me.

DR. NORMAND: I rambled a lot, but that, in fact, everybody was included.

DR. RUSSELL: That all of the people that were included at the 30-day
window, that was the denominator used subsequent.

DR. NORMAND: So you proceeded as if you had information on everybody
forward in time.

DR. RUSSELL: That\'s what my statisticians have said.

DR. NORMAND: Okay. So I think that\'s in contradiction to the earlier
answer I had in the morning, just so I understand that.

Now, with that said, I understand that the \-- and I\'m sorry. I have to
move this far away. I need to get different glasses or something, but at
the nine month \-- it raises two separate issues to me. One is the
follow-up issue in terms of how many observations you had in order to
make your comparisons, and I see on the table I\'m looking at that, you
know, certainly for the major endpoints, you had like 96, 97 percent.

So I\'m not so concerned about that. It\'s just that it\'s somewhat
misleading \--

DR. RUSSELL: Yes.

DR. NORMAND: \-- in terms of the follow-up information. I\'m okay with
it because of the Kaplan-Meier analysis that I believe hopefully they
were assumed censored.

Somebody is coming up.

CHAIRMAN LASKEY: They said in the text they were censored, in their stat
analysis.

DR. CHIACCHIERINI: I\'m Dick Chiacchierini. I\'m a statistical
consultant to Boston Scientific. I\'m a paid consultant and have no
other financial relationship with the company.

Dr. Normand, you\'re absolutely right. I came to the review of the
analysis after it was done and asked the very same question and, in
fact, had there not been such complete follow-up, I would be worried
about the results.

DR. NORMAND: Okay.

DR. CHIACCHIERINI: Because in a true imputation analyses the ten
patients that were lost to follow-up between implantation and nine
months should have had an imputed value in order to use them in the
denominator. That was not done here, but it will make little relevance
to the outcome.

DR. NORMAND: Okay. Just for clarification, because as I said I asked it
earlier in the day and I realize that I think there was either a
misunderstanding how I raised the issue because my issue was correct.

The reason why I\'m raising this issue not only relates to the follow-up
for the endpoints, but also relates to the comparisons that were
presented comparing the various groups. So, again, if you\'re describing
smoking history or whatever, I\'m surprised that you had complete data
on everybody. It may have happened, but, for example, your baseline
demographics characteristics because you use this principle of always
having the same denominator, I couldn\'t tell if, in fact, for the
characteristics of your population at baseline, whether or not you were
missing any of those points, and so hence, when I looked at the
comparability, I couldn\'t figure out.

So my question is: were you also missing data describing the baseline
characteristics of the population that you presented in earlier tables?
But yet you still used the full sample size in the denominator.

DR. CHIACCHIERINI: That\'s exactly correct, but the number of patients
missing, any single observation was very small.

DR. NORMAND: So even the baseline measurements might be \--

DR. CHIACCHIERINI: Even the baseline measurements. I mean, the
monitoring was extremely well done so that the number of patients that
were missing, height, weight, or any of the medical history variables,
was so small that it would not have made a difference.

DR. NORMAND: Okay. So the reason why I raise this issue, clearly, as you
know as a statistician, but for other people, is that even though on the
available observations that they\'re not different when at least one is
reviewing the material, one would like to see whether or not information
is missing differentially between the two treatment groups.

It wasn\'t there. So I couldn\'t tell.

DR. CHIACCHIERINI: It turns out that what you\'re saying is correct
regarding the clinical data, that it did use the full denominator.

The angiographic data and the IVUS data used the data where there was an
actual number of data points.

DR. NORMAND: Okay. Thank you.

So it\'s difficult to assess balancing and comparability. If you don\'t
separate out the missing data, I can\'t see the denominator. So given
the small number that\'s missing, maybe it\'s not such a big deal, but
it\'s difficult to follow.

DR. CHIACCHIERINI: Excuse me a moment. You can do that.

DR. NORMAND: I\'m sorry.

DR. CHIACCHIERINI: There is a table on accountability very early on.

DR. NORMAND: There are 3,000 pages here or something. Okay.

DR. CHIACCHIERINI: Yes, it\'s early on in the document, particularly in
the clinical report, and it talks about it starts out with the total
number that were enrolled. It takes the 12 away and \--

DR. NORMAND: Oh, no. Yeah.

DR. CHIACCHIERINI: \-- in each one down tells you how many patients were
missing certain relevant pieces of information, and the numbers were
very small.

DR. NORMAND: Okay, but again, as a principal, typically you don\'t
report it that way.

Two more questions. Dr. Russell, I think you had said in an earlier
response to a question that was raised that there was \-- my
interpretation of your answer was that there was a lot of site
variability, that you had prefaced this with, you know, statistics was
difficult because the measurements were quite varied from site to site.
I\'m pretty sure that\'s what you said.

The reason why I\'m asking that question is I\'m wondering whether or
not in your analysis you incorporated center specific effects or was
that ignored in your statistical analysis?

DR. RUSSELL: No, we did do an analysis of pooling and then an analysis
of centers, but my reference to the variability had to do with the
preclinical results.

DR. NORMAND: Okay. So it was really isolated to that.

DR. RUSSELL: Right.

DR. NORMAND: So you actually did a test to see whether or not the data
were poolable across the 73 sites. Okay.

And I had one final question, and that has to do with your registry,
which I was looking at, and let me see where it is.

Yes, the sites that will participate in that registry, how are they
chosen?

DR. RUSSELL: We\'ve used the MEDPAR billing database to identify volume
at community centers, at centers. Then we\'ve used our analysis of
centers that are considered tertiary compared to non-tertiary centers by
dividing those that are affiliated with a teaching university, and then
we\'ve basically tried to select sites that have not participated in our
previous studies after the first ten and select sites where we believe
that they will have capacity to actually enter the data. They\'ll have
some sort of research staff or interest in getting research staff.

So that\'s how we\'ve done it.

DR. NORMAND: Okay. So it sounds like it\'s certainly a well thought
through strategy on how to select sites to follow through.

Thank you.

CHAIRMAN LASKEY: Dr. Morrison.

DR. MORRISON: Well, I\'d love to ask a very insightful question that no
one else have thought of, but I don\'t have any. So I\'d like to just
make a \--

(Laughter.)

DR. MORRISON: \-- brief comment and say that what really impressed me
first in going through these two volumes before coming here, and
secondly, in listening all day to your presentations and the FDA\'s
attempt to dissect all of the work is that you didn\'t really put
together one team to do one study. You put together multiple teams to do
a series of studies going from relatively simple anatomy and single
vessel to greater complexity.

Clearly, there are a million questions that could be asked based on the
fact that you don\'t have all of the world of data, but given what you
had, it seems to me a very impressive effort with a lot of planning at
each stage, and as I said, all I can do is echo what my colleagues have
said because, given the patients that have been studied and the way
things are presented, I think it\'s a beautiful job.

DR. YANCY: Once again, I would congratulate the sponsor and
investigators for really putting forward a very nice piece of work that
should be of some significance in the clinical arena.

Just as a matter of statement, I would reiterate my earlier comments
that it would be my desire to see a more robust clinical profile when
we\'re dealing with what we think are culprit lesions that have caused
people to present to an angiographic suite for intervention. It would
seem as if there would be an opportunity to assess the clinical impact
beyond just the major adverse cardiac events.

The specific issue that I\'d like to raise just for clarity, because it
seems as if this has been dispelled and has been addressed by both the
FDA and the company, but we came to this meeting with the understanding
that one stated concern was the loss of intimal smooth muscle cells
after exposure to the drug eluting stent, and I think in both
presentations, the sponsor and the FDA, there was a comment that this is
acknowledged to occur, but there was a quick statement that it did not
appear to be related to any significant adverse events.

I\'d like to just know a little bit more about your position on the loss
of intimal smooth muscle cells, particularly in reference to the data
regarding incomplete apposition. I\'m wondering if there is a concern
here that over a longer term exposure to the stent that we may see some
more significant disease down the road beyond just nine to 12 months
related to this loss of integrity of the vessel smooth muscle cells.

So that would be my specific concern, if you could address that, please.

DR. RUSSELL: Well, let me being with the TAXUS II IVUS analysis. We were
concerned about local drug delivery at the time that TAXUS II was
initiated, and elected to use IVUS, postulating that it was the most
sensitive way of looking at vascular responses and would allow us to
look at the media, unlike any other diagnostic modality.

We had excellent IVUS follow-up with many paired analyses, and we were
able to demonstrate with those studies that there was no significant
change within the groups for EEL. We found that reassuring. In fact, we
were able to demonstrate that the difference from baseline to follow-up
was actually increased for what we call peri-stet area. Some people call
it plaque burden.

We were heartened by that. We had postulated that if there were to be a
significant and ongoing drug effect that didn\'t heal, that there might
be thinning in that region. So the TAXUS II data argues that the initial
medial cell loss is associated with what we saw preclinically, which is
the replacement of the lost cells by what we\'re calling fibrous tissue.

And on that note, I\'d actually like Dr. Wilson to come up because we
have asked him to specifically analyze the medial cell loss and provide
his comments as the pathologist.

DR. WILSON: Unquestionably, there is more medial cell loss with the drug
eluting stents. This is in the preclinical animal studies, than with the
controls. However, in the typical case, the amount of that loss of
medial smooth muscle cells is really quite modest with the SR
formulation. It is really with the MR formulation that it is more
substantial.

Now, in all cases, and this is every slide, every stent, that medial
cell loss is accompanied by a replacement with collagen so that the
media always remains structurally intact right through to the longest
follow-up we have, one year in the pigs.

Now, it turns out that the strength and resilience of the wall of an
artery is not dependent on its cellular composition. One can actually
gently remove all of those cells by detergented enzymatic digestion and
then do mechanics on the vessel, and you will find that the strength
and, in fact, other passive mechanical properties remain the same.

So the strength of the vessel wall is not determined by the amount of
medial smooth muscle cells present, and histologically the vessel wall
is always structurally intact in all of the vessels surrounding the drug
eluting stents in the animal studies.

DR. YANCY: Thank you.

DR. RUSSELL: I\'d like to ask Dr. Schwartz to comment because his
experience with bare metal stents is extensive.

DR. SCHWARTZ: Thank you.

I think Dr. Wilson said it. It was not absence of medial cells. It was
less medial cells, and even with that, there were still fibroblasts that
were there.

I think more important physiologically, it\'s very clear in the animal
models that when you lose muscle mass in terms of smooth muscle cells
that actually stimulates new intimal hyperplasia. In fact, we saw the
opposite here, that there was less new intimal hyperplasia at the site
because of the stent.

So I think the argument can be made very strongly that, in fact, yes,
there was less, but it had little to no physiologic impact. In fact, the
effect of the drug was very positive, as we saw in the preclinical trial
as well.

So I think we have good physiologic information that despite there was
less medial cells, they were not absent. It did not seem to have any
deleterious effect at all on the vessel.

CHAIRMAN LASKEY: Bill.

DR. MAISEL: I just have a couple of questions. The first relates to the
entry criteria for the lesion. It\'s mentioned that the lesion length
was to be between ten and 28 millimeters, but fully one third or more of
the patients had a lesion length that was measured to be outside that
range.

So perhaps you could discuss the rationale for picking a minimum lesion
length of ten millimeters at the start of the trial and explain why
approximately a third of the patients did not have a lesion length that
fell within the predetermined range.

DR. RUSSELL: I think that\'s why there is a Core Lab business.
Investigators make their own assessments of lesion length and reference
vessel diameters to make the decision about inclusion of patients, and
I\'ll have Jeff come up and comment on the disparity between
investigator assessment and Core Lab assessment.

DR. POPMA: I\'m Jeff Popma. As the Director for the Angiographic Core
Laboratory for the study at the Brigham Women\'s Hospital, we did
receive research money for the performance of this study as we have done
with other competitive trials. I have done speaking talks for Boston
Scientific, as well as the other competitors on stent designs. All of my
speaking engagements have been with under the guidelines for the Harvard
Clinical Guidelines Committee for Conflicts of Interest.

Having said all of that, you\'re absolutely correct that the
investigator at the clinical site doing the angiogram usually comes up
with a different lesion length than we do in the Core Laboratory. The
reason for that is that as a clinician looking at an angiogram, we begin
to think that we want a stent from fully shoulder to shoulder, wherever
there is a luminal irregularity that we see on the angiogram.

That\'s very difficult for us to quantitate in the core laboratory, and
as a result of that, our automated algorithms us a luminal narrowing of
more than 20 percent before it begins to call the shoulder of the
lesion. Just by abligation, it is always shorter when we use a 20
percent criteria than the investigator looking at an angiogram who sees
a luminal irregularity.

And this has been a relatively consistent theme through most of the
studies, that the investigator always calls the lesion length a bit
longer than we do in the core laboratory. We want to make sure we have
reproducible measurements. So we use a fixed criteria of a 20 percent
narrowing.

That\'s how the numbers came out the way they did.

DR. MAISEL: Great. That\'s helpful.

Can you comment on the minimum lesion length for the entry criteria? Why
was ten millimeters picked?

DR. POPMA: Well, I think ten millimeters was picked because of the need
to have a good shoulder of drug eluting stent, proximal and distal. So
if our 16 millimeter stent length and a ten millimeter lesion, we were
allowed then to have a three millimeter margin proximally and distally.

One thing we have learned from the drug eluting stent trials thus far is
it\'s important to have adequate stent eluting drug outside the margins
of vessel injury as best one can do. So I think that was specifically
designed because of the stent lengths that were available.

DR. MAISEL: So the related question would be in the labeling. It\'s
mentioned that any lesion less than 28 millimeters would be acceptable,
although the trial, you know, set a parameter, a minimum parameter. Do
you think that\'s \--

DR. POPMA: Yeah, I think, you know, this is a good thing. Should we send
every film at the investigatory site that gets treated with a TAXUS
stent to the Core Laboratory for analysis before we do it?

I think we should.

(Laughter.)

DR. POPMA: But unfortunately, I don\'t think that\'s going to actually
be applicable for clinical practice. So I think what we have to do is to
rely upon what was done with the clinical protocol, which is a visual
assessment of lesion length, something that\'s treatable with a 16
millimeter stent as a minimum, and then up to 20 millimeters because of
the availability of the longer 32 millimeter stent for clinical
practice.

DR. MAISEL: Thanks.

My second question relates to the fact that you\'re seeking \-- oh, I\'m
sorry?

DR. STONE: If I can interrupt, I\'ll add one other thing, too, on that
end. In TAXUS I and II, which would support the data to this
application, they tested very short focal lesions, anything less than 15
millimeters. So visually they were often three millimeters, five
millimeters, et cetera.

So I think with that as supportive information, in addition to the fact
that many of these, quote, ten to 12 millimeter lesions were, in fact,
truly shorter lesions by any estimate of the criteria, and given the
fact that we did see benefit in all lesion lengths and vessel sizes,
then I think it\'s reasonable to include less than 28 millimeters.

The sponsor is also seeking approval for several stents that were not
used in the clinical TAXUS IV trial, and specifically I\'m interested in
comments related to the eight and the 12 millimeter stents, which were
not used at all.

Were they available for this trial? And if so, why were they not used in
over 1,300 patients? And is there any clinical data at all related to
stents this short that are drug eluting? And if not, how about non-drug
eluting?

DR. RUSSELL: The first question is that they were not available at the
time that the study was initiated.

With respect to the issue of why should they be included, we believe
that the most likely use of a second small stent would be to optimize
outcomes in the setting of dissection, and this provides a reasonable
matrix for operators to use easily to get optimum outcomes.

There were no issues identified with longer stents. So it\'s unlikely
that there would be issues identified with the smaller stents.

Do we have any data on eight and 12 millimeter stents? We have data that
we\'re collecting in our ongoing TAXUS V studies, but that is short-term
data, and now I\'m going to let Gregg speak.

(Laughter.)

DR. STONE: I think from a clinical point of view, we always want to
match the lesion as close as possible to the stent, given that we
probably do want an extra two or three millimeters, as Jeff was saying,
to be able to get into the normal reference segment.

One of the drawbacks, I think, if any, in this trial was that we didn\'t
have shorter stents available. So when we did miss the lesion length by
one or two millimeters or we did have a one or two millimeter long edge
dissection, we had to put another 16 millimeter stent in, and the
drawback of that is not only is there some relationship between every
stent and restenosis, but also you tend to cover more side branches as
you\'re putting in longer and longer length stents.

So there\'s a true clinical need to be able to have shorter lengths of
stents to be able to match the lesion needs and dissection lengths to
the stent length.

We have a lot of experience with bare metal stents with eight and 12
millimeter stents, and we know that those are appropriate in our hands
to be able to accurately place them where we need to, and so while there
isn\'t data yet, this is, I think, an extension of what a reasonable
clinical need would be, and given that the doses of both the polymer and
the drug are less or no more, that it should be safe and effective.

DR. MAISEL: Yeah, I guess I would defer to my interventional colleagues
on the panel, but I guess I harbor a little concern that the shorter
stents would result in frequent multiple stent uses if there\'s a little
area that needs just another eight or 12 millimeters of stenting. But
enough said.

I don\'t have any other questions.

CHAIRMAN LASKEY: Well, let me take it just a half a step further.
You\'re kind of encouraging people to cover dissections with this, the
availability of it, or asking for approval, and yet the vast majority of
the literature would support leaving these little edge dissections
alone, whether it\'s drug eluting or not.

So I wonder if we can dredge this a little bit further.

DR. RUSSELL: Yes, most of the circumstances when a second stent has been
put in all of the studies, TAXUS I, TAXUS II and TAXUS IV, were when the
investigator judged the dissection to be problematic for acute
procedural success. So they were not the low grade dissections.

Our focus on using a second drug eluting stent and mandating it in TAXUS
II and TAXUS IV arose from our experiences in TAXUS I and TAXUS III,
when it was mandated that if a second stent was required, it should be a
bare metal stent.

And what we discovered with that protocol mandate was restenosis
occurring in the bare metal stents when two stents had been used. So
TAXUS IV was put together to prospectively study that, and the protocol,
as you know, mandated that a second study stent should be used, and as
you saw from the small amount of multiple stenting data that we had, the
outcomes looked promising.

DR. STONE: Also, what we\'ve actually required in this protocol and most
of our other protocols was that while very small NHLBI Type A
dissections could be left and those don\'t seem to have any consequence,
anything of a dissection of greater than Type B was stented. So you know
that you\'ve got good luminal in-flow and luminal outflow without any
irregularity.

And I think, number one, that partly explains in both arms, the bare
metal stent arm and the drug stent arm, why the stent thrombosis rate
was so low because we did have complete lesion coverage with no
persistent dissections. I agree that\'s never been 100 percent proved,
but it seems like the bulk of the suggestive evidence would support
that.

In addition, there\'s also a lot of situations where you think your
lesion length is about, you know, 20 to 22 millimeters. Maybe I can get
by with a 24 millimeter stent, but I\'d rather not put in a 32
millimeter stent. So you try the 24 millimeter stent. You happen to be a
millimeter or two short and then unfortunately you do need a second
stent, and it is probably better to be able to match closer even if you
do need a second stent than to use one long stent, which will, again,
cover more side branches and be more associated with more periprocedural
myocon (phonetic) necrosis.

CHAIRMAN LASKEY: Which I guess raises the question again. Chris touched
on it, but in the IFU are you encouraging people to get full coverage
plus? Is that stated explicitly, that you need to include the lesion
plus?

Should you? Ought you?

DR. STONE: I\'ll let Dr. Russell speak to what\'s actually in the IFU.
It was a recommendation in the protocol. Did the lesion coverage go from
as near normal reference segment to as near normal reference segment as
possible, realizing that these are often diffusely diseased vessels and
that any dissection greater than or equal to Type B gets stented?

And that is certainly our standard practice, but I\'ll let Dr. Russell
speak to what\'s actually in the IFU.

DR. RUSSELL: We do not comment at this time specifically in the IFU
about coverage. We\'d be happy to work with FDA on the right language.

CHAIRMAN LASKEY: It seems to be de rigueur in the community. So maybe we
should make it official in the drug eluting stent era.

DR. RUSSELL: Works for me.

CHAIRMAN LASKEY: I just had one final question. To follow up on Bill\'s
point, less about the discordance between the Core Lab angiography, but
the CEC evaluation of the events, which of course is the primary
endpoint, you had about an 83 percent concordance. Did I read that
right?

So 17 percent of the time the investigator at the site felt that there
was a process requiring revascularization, but the CEC did not feel that
way. Is that right?

DR. RUSSELL: Yes, and that had to do most frequently with the percent
diameter stenosis criteria that the CEC uses, and occasionally due to
the absence of any symptomatology with the percent diameter stenosis
that was not very impressive.

CHAIRMAN LASKEY: Because I guess a 17 percent miss rate is not too bad,b
ut it\'s a little disturbing, but finally, did it sort out evenly in the
two arms?

DR. RUSSELL: It was even in the two arms. It\'s a pattern that\'s
actually lower than we\'ve seen in some of our other larger studies.
We\'ve seen discordance of up to 45 percent, depending on the study and
the rigor, let me say, of the CEC.

The mandate is on the monitoring staff to actually carefully review the
records and collect information about symptomatology. As Gregg will
point out, this study requested that before the angiogram at follow-up
was performed, that investigators actually fill out a form indicating if
there were symptoms or positive exercise testing and send it in ahead of
time to help the CEC in assessing whether it was ischemia driven or not.

CHAIRMAN LASKEY: Sorry. Dr. Aziz.

DR. AZIZ: Just one more pathology question. Did you look at the
vasovasorum of the vessels of the stents that were placed in animals?

DR. RUSSELL: I\'ll let Rob answer that question. It\'s one of his
favorite topics.

(Laughter.)

DR. SCHWARTZ: A superb question. We have done it now unofficially. We
actually presented it in abstract at TCT, suggesting that there is an
inhibition of near angiogenesis in the vasovasorum. It\'s currently in
preparation for manuscript, but I have a fellow working on that right
now. So there is somewhat a significant inhibition of angiogenesis of
additional vaso.

DR. AZIZ: And the PAM material, is there a lot of ex cellular matrix?
What exactly is that, PAM, the amorphous material?

DR. SCHWARTZ: Excellent question. Against our advice, we had actually
said sequestered PAM, S-PAM, which would have made it SPAM, and that was
actually deferred by Dr. Russell.

(Laughter.)

DR. SCHWARTZ: In all seriousness, the important things to know about
SPAM are really four salient points that Dr. Russell, I think, pretty
clearly outlined. First, we know what it is. It\'s essentially fibrin.
It\'s very benign in the context. There was little to no inflammation
associated with it. It goes away over time. It seems dose dependent.

It also was found in a few of the control animal sections as well. So in
that context, it has absolutely no effect as far as we can see on the
safety of the animals. It\'s really based on those four points.

DR. RUSSELL: Just to follow up on that point that Rob has covered, we
have speculated based on the paucity of white cells, which we believe is
an effect of Paclitaxel, that the clearance of fibrin is initially
delayed, and then once macrophages return, we see the resorption.

CHAIRMAN LASKEY: Thank you.

We have that precious opportunity to either be on time or perhaps even
end early. Does anybody up here want to take a break or should we
proceed with the questions?

Yes, sir. In that case, I\'m going to ask the Executive Secretary to now
read the questions, please.

MS. WOOD: Does the combination of the nine month clinical data from the
pivotal TAXUS IV SR formulation study and the adjunctive data from TAXUS
I SR formulation and TAXUS II SR and MR formulations adequately address
the potential concerns raised by the animal studies?

CHAIRMAN LASKEY: I will try and summarize the consensus of the panel on
this. As usual, please wade in if you want to clarify or disagree.

I think at the nine month clinical point, clinical endpoint, the data is
convincing. However, none of us up here are comfortable with a nine
month cutoff to establish safety concerns, certainly those raised by
animal studies. I think we would like to see longer term follow-up,
particularly given the discordance in progression in animals versus man.

Are we in agreement?

DR. ZUCKERMAN: Okay. Dr. Laskey, I think you need to clarify your
response. Does it provide reasonable assurance of safety, not absolute
assurance?

CHAIRMAN LASKEY: This is not my response. This is the collective
response, and I\'ve just surveyed the nodding of heads that we are all
in accord with safety out to nine months, but we await additional
long-term clinical data to be fully assured.

MS. WOOD: Are the clinical studies presented adequate to address
concerns about possible adverse bent from interactions with drugs
typically administered to the target patient population?

CHAIRMAN LASKEY: There is a member of the panel that feels that there
\-- and I would agree with this \-- that there are some theoretical
issues about drug-drug interaction which have not been evaluated. From a
practical standpoint, there does not appear to be any evidence of
drug-drug interactions with drugs most likely to be used in this
population.

Can we be 100 percent certain? No.

Is that fair?

MS. WOOD: Please comment on whether the clinical studies adequately
address other drug interactions that are likely to be important or of
interest. If not, what other information or studies should be provided?

Specifically, please consider the potential for the following types of
interactions, with anti-neoplastic agents, with chemotherapeutic agents
where a hypersensitivity reaction could be endused.

CHAIRMAN LASKEY: Well, do you want to summarize that?

I don\'t think we spent a great deal of time on this issue. It\'s a very
small point, and I think it\'s a very targeted, very small population,
that we shouldn\'t hang ourselves up on.

DR. SOMBERG: Well, I would say we do not have adequate information at
this time, but it shouldn\'t preclude the availability of the product,
but this should be collected from the planned studies, and I think the
panel pretty much would encourage a long-term follow-up in animal
studies as well, with potentially some activity.

Specifically, I think what the question is getting at, and which we
didn\'t discussion, was, for instance, doxorubicin, you know, the
chemotherapeutic agent, can antagonize the activity of Paclitaxel, and
we talked about some of the potentiating effects.

So I think that that\'s long term, and there are very small safety and
very small efficacy issues that can come of it, but for instance, in a
large \-- I\'m going on on this, but to make it very brief \-- in a
large registry one can develop a database. You know, who\'s on
torvastatin and who isn\'t on it? And then see if there\'s any improved
benefit or lack of benefit of the stent in that situation.

But I think that it\'s similar to the drug area where not everything is
known when something is available, and certain interactions will have to
come out, and this is certainly not with the P450 polymorphisms where
you can predict something. So we\'re going to have to be able to develop
a larger database than just 1,000 and a half patients.

DR. WEINBERGER: I\'d just like to make one comment about this. I don\'t
think that we\'re exposing patients even in the worst case scenario to
an infinite time of hypersensitivity. This drug presumably has some
finite residence time in the vessel wall, and after that, an initial
month or so. The release rates are very slow, and I don\'t think that
even on a theoretical basis we should be concerned with drug-drug
interaction when the second drug is going to be administered out of the
first couple of months after implantation. I just don\'t think that
that\'s going to be much of a likely interaction time.

DR. WHITE: But are you concerned that if you\'re treating the patient
who is going to be actively treated with chemotherapy should there be
something in the IFU for the physician that raises concerns?

I mean, it\'s an unusual patient, but is there a caution?

DR. WEINBERGER: I think that that\'s what\'s being asked in this
question, whether or not we want to take a position as to whether or not
that\'s contraindicated or let\'s say that it\'s unknown.

CHAIRMAN LASKEY: Well, I don\'t think that we can say it\'s
contraindicated if there\'s no body of knowledge. So it\'s certainly
unknown.

DR. WHITE: I would think that most clinicians are not aware of the
potential potentiators or problems, and so simply providing information
of the possible issue, informing them and allowing them to ask questions
would be appropriate, I think.

DR. ZUCKERMAN: So, Dr. White, can you extend your comments? I think you
and Dr. Weinberger have understood the intent of this question. Is the
practical solution that you\'re suggesting to perhaps beef up Section
5.6 of the label which talks about potentials for drug interaction?

DR. WHITE: Yeah, that would make me happy. I don\'t see a problem at
all, but I think as a user myself, I would like to know if there was a
potential problem in a potential patient, and that information could be
provided, I think, to us, where an unknown risk, but perhaps a risk, and
just raise that awareness.

CHAIRMAN LASKEY: I guess we\'ll come back to that when we vote, but that
may be the Pandora\'s box.

Can we also be clear about what we mean by hypersensitivity? I\'m not
sure we\'re all on the same page on that one. You mean IgE mediated
events with typical IgE mediated clinical sequelae or what do you mean
by hypersensitivity?

DR. ZUCKERMAN: Not necessarily. I think this whole issue needs to be
better thought out and discussed with the sponsor.

CHAIRMAN LASKEY: As well as for ourselves if we need to. Okay.

MS. WOOD: Do the clinical data submitted from the pivotal TAXUS IV SR
formulation study, plus the data from the adjunctive TAXUS I SR
formulation and TAXUS II SR and MR formulation studies, provide
reasonable assurance of safety?

CHAIRMAN LASKEY: I\'d say the panel is universally in agreement that
there is a reasonable assurance of safety at the 270-day point, perhaps
at the 365-day point if we looked at the materials supplied to us from
the AHA presentation as well.

Beyond that we need to be very, very circumspect.

MS. WOOD: Does the clinical data at 270 days presented on the TAXUS
stent from the pivotal TAXUS IV study provide reasonable assurance of
effectiveness?

CHAIRMAN LASKEY: That I believe there\'s no question.

MS. WOOD: Does the evidence presented on the TAXUS product support the
proposed labeling indication?

CHAIRMAN LASKEY: Well, we can generate some discussion here. There were
several items that were brought up this afternoon that may or may not
lead us to consensus. The first is the short stent is the eight and 12
millimeter stents. So can we have some discussion on that?

DR. WHITE: I think everything the sponsor said and I think in that
discussion about using the shorter lengths was appropriate.

The other thing that I didn\'t hear said was that there\'s a
deliverability issue that comes with shorter stents, and there are times
when that second stent is needed that a longer, 16 or 28 millimeter
stent may be very difficult to deliver, and so the ability to use
smaller links really helps the doc in the cath lab.

And so Ii would want to give this issue the benefit of the doubt for the
smaller subsets in order to improve safety and usability in the cath lab
if there is not real concern or real evidence that there\'s a problem
with the shorter lengths. I think I would give them the benefit of the
doubt for improved cath lab safety.

I would want those. I would want those on my shelf.

CHAIRMAN LASKEY: As a clinician, I agree, but does the evidence
presented on the TAXUS products support that? We\'d have to say no, but
we\'re reacting as clinicians at this point; is that right?

DR. WHITE: I think you have to ask yourself, you know, this is the same
\-- I mean, again, it goes with the different sizes. You know, it\'s the
same stent mounted from two and a half to three and a half. So it\'s not
a different device because they\'re also asking for a diameter that
hasn\'t been tested as well, but it\'s the same device.

So to me cutting the device shorter simply means less total drug
delivery. So the whole risk here would be lower dose or maybe loss of
efficacy perhaps, but I don\'t see how it increases risk or makes it
unsafe because of a lower dose. I mean, I don\'t see any evidence of
unsafety. So I think that would be reasonable.

DR. NORMAND: Can I? I\'d like to just make the point that there\'s no
evidence presented. So just to emphasize that. As I said, there\'s no
data about that. So I just want to \-- you can guess or give good
clinical opinion, but there\'s no evidence.

CHAIRMAN LASKEY: Thank you.

DR. HIRSHFELD: I\'d just like to echo what Chris said. I think that the
shorter lengths belong in the tool box and that we would be hampering
clinicians if they didn\'t have access to the entire complement of
lengths that are requested.

CHAIRMAN LASKEY: Clinicians happy?

(Laughter.)

CHAIRMAN LASKEY: Was there another?

DR. WHITE: Let me say that this is different than if we were considering
a size that had not been tested. Let\'s say that somebody said we\'d
like to get approval for a one and a half millimeter device and that
wasn\'t tested. I would have concern about that, but I don\'t see the
fact that the data hasn\'t been presented is much less worrisome to me
in this configuration just because the length gets shorter than it would
be in a different diameter vessel.

I view it as much less of a leap of faith for these shorter lengths, and
if I was going to be writing this or if they hadn\'t asked for approval
of these, I\'d be the one telling them to cut them up, give them to me
shorter because I\'m the one who has been struggling for two hours to
get that long stent through the other one, and I want a shorter piece.

DR. ZUCKERMAN: Okay. Dr. White, we don\'t want you cutting up your
stents.

(Laughter.)

DR. ZUCKERMAN: But I think you understand the spirit of the question
here. As Dr. Normand has correctly indicated, there are no real data in
the submission, but the FDA is asking for an independent expert opinion
from expert interventional cardiologists, and I think we\'ve heard your
opinion and will act accordingly.

The second part of Question 5(a) though, perhaps the more important one,
is the addition of reducing restenosis to the indication.

DR. MORRISON: Well, as a clinician rather than a statistician, I would
like to carp about the characterization there\'s no data. I mean, we
were told that in Texas one and two by design, bare metal stents were
used for the purpose that now in TAXUS IV, the drug eluting stent, was
used, and what they noted was restenosis in the area of the bare metal
stent.

Now, that\'s not \--

PARTICIPANT: A different length.

DR. MORRISON: Yeah, but they used overlapping stents, bare metal, and
demonstrated restenosis. So we have the kind of clinical data that we
use every day to make inference. It\'s not large scale, prospective,
randomized trials, but it sounds pretty clear that you don\'t want to
tack up an edge dissection with the express stent.

And then we\'ve gone through at great length different metals,
different, you know, drugs and so forth.

So it seems to me pretty clear if you have a flow limiting edge
dissection, you don\'t want to use a bare metal stent to tack that up.
So that\'s within the spirit of labeling.

CHAIRMAN LASKEY: Well, just to clarify, those were near stents.

DR. WHITE: But I think the answer or to direct Bram\'s question is I
think there\'s no question the efficacy has been measured in restenosis
and TLR, and so I think they deserve labeling for that indication.

DR. WEINBERGER: As a practical matter, if you don\'t supply an eight
millimeter stent for the most common use, which would be a edge
dissection tack-up, what will happen is people will take a longer stent
and just get a larger amount of overlap, which I would argue is a worse
thing to do.

So I think that from a practical point of view, from a real world
clinician point of view, you have to make those shorter lengths
available.

CHAIRMAN LASKEY: Full circle. We are in agreement then.

DR. WEINBERGER: One other comment about the label, about the
indications, and that is it\'s not just that we\'re being told that the
indication includes reduction of restenosis, but there\'s a statement
that there is less restenosis, improved outcomes in nine months compared
to uncoated stents, and just in the interest of fair disclosure, I think
that you can say that there is less restenosis than Express stents, but
not all bare metal stents.

So I think that making an unqualified statement that there\'s a better
outcome at nine months compared to bare metal stents is slightly
overstating what was studied.

CHAIRMAN LASKEY: Well, it\'s easy enough to change that. It does reduce
restenosis in comparison to the bare metal stent comparator. That\'s
easy to reword.

DR. WEINBERGER: That would be fine.

DR. ZUCKERMAN: Are there any other comments on the main indication given
by the sponsor? There\'s no indication, for example, that these are
symptomatic patients, symptomatic de novo lesions?

DR. MAISEL: I did have one comment on the labeling with regard to total
occlusions and acute myocardial infarction, which is not really
mentioned anywhere. I didn\'t know if that warrants mentioning as, you
know, it clearly wasn\'t included in the trial and whether that should
be mentioned one way or the other.

DR. WEINBERGER: You know, I think that we get into trouble if we have to
try to list every exception because I think Greg listed a whole bunch of
things that were not studied. So I think that \--

CHAIRMAN LASKEY: Well, the inclusion/exclusion criteria go into the IFU.

DR. WEINBERGER: Right.

CHAIRMAN LASKEY: So it\'s clear from the get-go who\'s in and who\'s
out.

Dr. Zuckerman, your question about the patient population, again, about
symptomatic and asymptomatic?

DR. ZUCKERMAN: Yeah. Ms. Goode, can you put up the proposed indication?
This is perhaps one of the key parts of the label to get right, and
we\'ve heard several comments, but we want to get it all right.

DR. SOMBERG: Are you suggesting that there was data presented that may
have suggested that it might benefit symptoms as well as just this?

DR. ZUCKERMAN: No. If we were to summarize what has been said so far, I
think Dr. Weinberger has indicated we should be reducing restenosis
compared to the bare metal stent that was used in the trial because
other stent designs and materials will be shown in the future and may be
better than drug eluting stents.

The second point is that perhaps, well, just from a regulatory viewpoint
we want to correctly describe the patient population that this stent is
intended for, and therefore, one might consider using the word
\"symptomatic\" in front of \"de novo lesions.\" If one has, for
example, a 50 percent lesion on an angiogram where the patient is not
symptomatic with a very high work load, does one need this device or any
other interventional device?

DR. SOMBERG: You clarified the point, but it cuts both ways. If you put
the word \"symptomatic\" in, I think that\'s what our chairman was going
to do, but I don\'t want to put words in his mouth here.

But if you say \"symptomatic,\" it suggests that we\'re doing something
to benefit symptoms as well, and while there was a suggestion about the
database, I\'d be concerned. So I think the way it stands is pretty
neutral.

I\'m a little concerned about saying just the bare metal in the Express
stent because that\'s sort of surrogate for the state of the art as it
is now, and I can see somebody else saying, \"Well, if you used ours it
wouldn\'t, you know, compare,\" or whatever.

So I think, you know, the word just \"restenosis\" is with bare metal
stents at this point. If something comes along that\'s different, that
would be fine, but I think that\'s an inroad to deceit.

DR. HIRSHFELD: The statement as written has an implied comparison and
doesn\'t state what it\'s compared to. The actual data is compared to
the bare metal Express stent, and so I think the panel needs to decide
whether the bare metal Express stent is a generic reflector of all bare
metal stents or whether there may be something different about the
Express stent than other stents.

Now, in favor of considering a generic is that the actual Core Lab
restenosis rates are very similar to what we\'ve seen in many other
trials of similar lesions, and so I don\'t think it\'s to large a leap
of faith to say that the data that are presented are relatively generic
for other bare metal stents.

CHAIRMAN LASKEY: If the inclusion and exclusion criteria are going into
the IFU, I believe the inclusion criteria do use the word.

DR. SOMBERG: Symptomatic.

CHAIRMAN LASKEY: Documented stable angina or unstable angina, ischemia,
et cetera, et cetera. So it is there. Do you need to repeat it again in
the label then?

DR. ZUCKERMAN: Where are you referring to?

DR. WHITE: I think the question though, Bram is that if the indications
that are used for the trial are included in the IFU and you\'re going to
start to abstract certain words as more important, would you \-- I mean,
I don\'t know where to stop.

I mean, the problem with symptoms is that they\'re subjective, and I
don\'t think I want to. You might want to say \"appropriate for
revascularization,\" but, I mean, there\'s a whole bunch of language
that you could attach to that.

DR. MORRISON: I thought a quarter of the patients in TAXUS IV had silent
ischemia. Well, silent ischemia is asymptomatic where I come from. Is
that different from the East Coast?

(Laughter.)

CHAIRMAN LASKEY: It said on page 29, Volume 2 of 2, Section 9.2, 9.3.1,
inclusion criteria. Read number three. \"Documented stable angina CCS
Class 1, 2, 3, 4 or unstable angina with documented ischemia, brown
wall,\" et cetera, et cetera, \"or documented silent ischemia.\" That\'s
the universe.

DR. MORRISON: So ischemia is asymptomatic on the East Coast, right?

CHAIRMAN LASKEY: Does that help?

DR. ZUCKERMAN: Yes. I think you\'ve defined the patient population. And
is there a consensus as to how much of a comparison statement should be
for reducing restenosis compared to what?

MR. MORTON: Just if I could point out on the indications, when you look
at page 6 of 31, that\'s rather nicely done in two paragraphs there, and
so rather than change this paragraph, we might want to consider the way
it\'s expressed in the second paragraph.

DR. MAISEL: I think that concept that there\'s an implied \--

DR. ZUCKERMAN: Yes. I think we need to take a step back and recognize
that the agency traditionally would remove that second paragraph that
Mr. Morton is referring to.

And let me try to explain why by just reading the regulatory definition
of indications for use. It\'s a general description of the disease or
condition the device will diagnose, treat, prevent, cure or mitigate,
including a description of a patient population for which the device is
intended, and that is in the CFR.

The type statements that are found in that second paragraph would
generally go in the clinical trial section of the label to actually
describe what happened in the trial in appropriate detail.

PARTICIPANT: I think the statement regarding reducing stenosis that
there\'s an implied comparison, I\'m a little uncomfortable making the
general statement that it reduces stenosis compared to all bare metal
stents because evidence hasn\'t been presented there, and I think the
information is provided in the IFU. So I personally don\'t think we need
anything more than that.

CHAIRMAN LASKEY: But I thought we suggested just the addition of the
term\" the Express\" or the \"bare metal stent, Express stent.\" That
seemed to fit the bill.

DR. WEINBERGER: So is what you\'re saying, Bram, that there\'s a mandate
to include a description of the patient population in this one paragraph
statement under indications?

DR. ZUCKERMAN: Ideally we should in the indications for use have a
description of the intended patient population, and is this adequate is
the question here.

DR. WHITE: I think the patient population that was included in the trial
was the universe. I mean it was. It was asymptomatic ischemia. It was
stable and unstable angina, right?

DR. WEINBERGER: Well, but it boiled down to patients with some sort of
documentation of ischemia. That\'s what it boils down to.

DR. WHITE: So we could say that.

DR. WEINBERGER: Fine. That I\'m happy with. Are you happy?

(Laughter.)

DR. WHITE: Yes.

CHAIRMAN LASKEY: For the penultimate time, are we in agreement and is
the agency content with that?

DR. ZUCKERMAN: Yeah, we received enough feedback on this sentence.

CHAIRMAN LASKEY: Yeah.

MS. WOOD: Please comment on whether the labeling should specify that
multiple stents should only be used for bailout purposes, dissection,
insufficient lesion coverage, and whether in these cases the shortest
stent available, such as the eight millimeter, should be used.

CHAIRMAN LASKEY: I think to summarize the last 15, 20 minutes of
discussion, we feel that these stents should be approved, that is, the
eight and 12, approved for other reasons, for reasons of expediency and
efficiency, and just the general availability of these stents, not
necessarily for coverage of dissections for which there was not enough
documentation in this particular protocol.

MS. WOOD: Please comment on whether the labeling should address the
potential combination of the TAXUS stent with an additional drug eluting
stent in the same vessel.

CHAIRMAN LASKEY: It should.

DR. WEINBERGER: Is there any proposal as to what it would say?

MS. WOOD: Please comment on whether the label \--

CHAIRMAN LASKEY: Just a \-- I don\'t know. That wasn\'t entirely
facetious.

DR. WEINBERGER: No. It\'s a serious question.

CHAIRMAN LASKEY: That will probably come up, and I think it\'s worth
some discussion. So, Judah, you\'ll have an opportunity to suggest
language when we vote with conditions.

You\'re new to the process I know, but you\'ll have an opportunity to
suggest such language, but we need to concern ourselves not only about
drug-drug, but stent-stent interaction. So that will come up. We\'ll get
to that.

MS. WOOD: Please comment on whether the labeling recommendation for post
procedural antiplatelet regimen is appropriate and whether additional
recommendations on procedural anticoagulation regimens are warranted.

DR. WHITE: I think the sponsor agreed to add the six-month Plavix or
Ticlid. I think that needs to be specified, not just antiplatelet. I
don\'t see any reason to get into the cath lab anticoagulation issues.
There didn\'t seem to be any difference with different agents that we
used.

CHAIRMAN LASKEY: But I heard you get the sponsor to agree that the
inclusion of six months of Plavix is critical.

Sorry, John?

DR. SOMBERG: I was just going to say, I mean, I feel that way possibly,
too, but do we really \-- we have to ask ourselves do we have data to
support that. And I think we\'re reacting to the concerns that there is
a thrombogenic \--

DR. WHITE: The data you have to support it though is the trial was
conducted that way, that the investigators were all encouraged for six
months. So we\'re just basing the recommendation on the data, evidence
that we have.

If you want to get the results they got, you\'ve got to do it their way.

DR. SOMBERG: That\'s good point.

MS. WOOD: Please comment on any other aspects of the labeling, such as
the contraindications, warnings, precautions, such as use with
bracytherapy, in conjunction with other procedures, et cetera, drug
pharmacology, pharmacokinetics, or specific drug safety information,
such as use in special populations, warnings, precautions.

DR. WHITE: I mean, the answer is yes. We\'ve been talking about all of
these, and I think that we need to have \-- well, we don\'t have
information, but we have concerns. The concerns need to be raised and
listed and informed, and we may not have a lot of data about a lot of
these concerns, but I don\'t think it\'s wrong that we should raise the
issue that we have concern because it\'s potentially a difficult thing.

CHAIRMAN LASKEY: Okay. So the contraindications to the use of this stent
are? What do we all agree on as an absolute contraindication?

There\'s a history of allergy to nickel or stainless steel? What other
contraindications are there?

DR. WHITE: I don\'t see any reason not to accept the contraindications
that were used in the trial.

CHAIRMAN LASKEY: Okay. So keep that.

And as far as the warnings and precautions, obviously adjunctive or
precedent brachytherapy was an exclusion criteria. So it simply remains
good clinical sense that it\'s a warning and precaution.

DR. WHITE: Did the sponsor comment on the presence of a CYPHER stent?
Was a CYPHER stent \-- did that kick them out of TAXUS IV?

So we can say that as well.

DR. ZUCKERMAN: Dr. Laskey, in going through this section, which is
really a critical section where the FDA needs your expert panel
feedback, are you turned to the labeling section? Right now we\'re on
page 7.

CHAIRMAN LASKEY: Page 7 of?

DR. ZUCKERMAN: Of the IA instructions for use. So it\'s in Volume 1,
instructions for use.

CHAIRMAN LASKEY: Right.

DR. ZUCKERMAN: So the contraindications are listed in Section 3.

DR. WHITE: So we would want to add that a serolimus stent would also \--
the presence of a serolimus stent would be a contraindication.

DR. WEINBERGER: In that vessel. Is that right, in that vessel?

DR. SOMBERG: And we also don\'t know the interaction of several drugs
that have been talked about before. I wouldn\'t make it a
contraindication. It\'s just that we just don\'t know the interactions.

DR. WEINBERGER: That would be the drug interaction section, right?

DR. SOMBERG: Yeah.

And can I just ask a quick question? There was no comment made. Do we
know anything about radiation therapy, brachytherapy with this material?
I mean were there any patients in the clinical trials who got that?

DR. WEINBERGER: That was an exclusion.

DR. SOMBERG: That doesn\'t mean they didn\'t get it. I know many trials
that have also sorts of things that are excluded.

DR. RUSSELL: Yeah, in TAXUS II and IV combined, there have been 17
patients that have had bracytherapy used to treat instant restenosis,
and of those, not surprisingly, only three of them were in the TAXUS
group, for which there was one reported adverse event, but that was not
a MACE event.

DR. SOMBERG: Why do you say that? It was blinded, right? So they
shouldn\'t know which one. Why was there a bias towards the plain metal?
Am I \--

DR. RUSSELL: Because more patients developed restenosis in the control
group.

DR. SOMBERG: Oh, okay. Yeah, okay.

DR. RUSSELL: In our ongoing studies obviously the investigators have
been compliant. So we haven\'t had any brachytherapy use.

DR. SOMBERG: As a physician, I\'d just say list that sort of information
because it\'s most critical because if there\'s a dire \-- you know, we
don\'t know this, but if there\'s something that\'s dire, pressing, you
know, you can\'t do anything else and you want to do something, this is
the only experience we have and there\'s really a paucity of it.

CHAIRMAN LASKEY: Again, it was drawn to our attention in Section 5.3 on
page 7. It says explicitly \"safety and effectiveness of the use of
brachytherapy to treat ISR in a TAXUS Express stent has not been
established.\" So the language is there.

DR. MORRISON: Well, I think the language is there to say it\'s not known
for both CYPHER stent and brachytherapy, but I would not include that in
contraindication any more than in five \--

CHAIRMAN LASKEY: It\'s a warning. It\'s just a warning.

DR. MORRISON: Right.

DR. SOMBERG: You don\'t want to put it in the contraindications.

CHAIRMAN LASKEY: Yeah.

DR. SOMBERG: I agree with you.

DR. ZUCKERMAN: Okay, and the same principle applies to another comment
that was previously made where a panel member wanted to put a
contraindication of a CYPHER and a Boston Scientific product, and again,
given the lack of data, perhaps it\'s Section 5.6 that needs to be
expanded regarding all of the comments about potential drugs and their
interaction with this particular product that have been discussed today.

Is there any comment on that notion?

DR. YANCY: If you want to do that, it would appear that Section 5.2
might be the better spot for it because it comments on having multiple
stents with similar composition, and so perhaps if there are multiple
drug eluting stents, you can comment that they should have similar drug
profiles.

DR. SOMBERG: I must say the section on drug interactions I have a log of
problem, specifically Section 5.6, because it implies that because
there\'s such a low concentration there won\'t be a drug interaction,
but that\'s not what we\'re talking about. We\'re talking about a local
effect and then a systemic effect of a drug that might interaction in
that local phenomena, and there may actually be a major interaction
there.

So, I mean, this is a nice story, but it\'s based in I can make up
another story. It\'s not based in fact.

DR. MORRISON: Isn\'t this a little bit analogous to a legal decision
being a precedent for subsequent decisions? I mean one of the things I
can see the agency getting into is consistency as there are more and
more drug eluting stents and more and more other technologies, and if
you start setting the precedent that everything that isn\'t known is a
contraindication, that really defeats the purpose, it seems to me.

DR. SOMBERG: I don\'t want you to take my statement as a
contraindication. They\'re just warnings that we don\'t know what the
effects are and let somebody make a decision on that basis.

But as he said earlier, as Dr. White says, some people are more into the
mechanical aspects and don\'t know the potential interactions. Some
people know a lot about the interactions, but never do anything
mechanically. So that\'s why you put it in the document.

But I don\'t want it to be said as a contraindication. In fact, I agree
with you. Sirolimus and, you know, unless we have some data, it\'s not a
contraindication, but it\'s a very strong warning.

DR. ZUCKERMAN: Right. I think that would be the agency\'s perspective,
but the key issue here, as Dr. Somberg noted, is that we want to as best
as possible have truthful and accurate statements about this drug
eluting stent in the label, given that it\'s probably the best source of
information for this product.

And what I heard him say is that Section 5.6 needs to be reworked with
the sponsor.

DR. YANCY: Well, I might speak against that. I think that from a
pragmatic standpoint nothing that I saw today suggested that we were
dealing with detectable levels of the agent in the serum, and I also
think we\'ve heard evidence that animals proves that if it\'s a
logarithmic scale where there\'s drug release in the early phase and
minimal drug release late, and I think that there is enough ambiguity in
this statement to suggest what\'s unknown, that to go further, the
necessity for data then becomes upon us to say that we have hard data
that this drug-drug interaction is a real possibility.

I am comfortable with 5.6 as it\'s stated.

DR. SOMBERG: I just want to say that the systemic level of Paclitaxel
has nothing to do with the drug interaction. We\'re not talking about a
systemic level. We\'re talking about local effect and a local
interaction. So I think you have to mention that. I also feel strongly
that if this is not mentioned that I\'d like to query the company again
in going through each of their studies and asking them how many was on,
how much was on a torvastatin, how much wasn\'t, did you do an analysis
by that particular drug, did we do an analysis on the preclinical work,
and we can go through all of this step by step.

That would be demanded on a drug level, and I think this is a drug
device.

CHAIRMAN LASKEY: I\'m not so sure. I mean, that is an endless road,
number one.

Number two, this is not a study of 100,000 or a half a million or five
million people. The event rate for the toxicity there is below the
detection level. So I would tend to line up behind Dr. Yancy on this
one. I don\'t know how much you really want to beat this stone, but
there are contraindications which we seem to agree on.

There are warnings and precautions, which we would like to draw a line
somewhere at the end of that, but the list of drug-drug interactions in
patients with cardiovascular disease and their permutations is several
orders of magnitude. So I\'m not sure it\'s useful to go there unless
you have a huge population base.

I would agree with Clyde that what we have here is probably adequate
with some fine tuning, but to ask for information on every single
conceivable drug interaction with Paclitaxel is unreasonable.

John.

DR. HIRSHFELD: I think one way we might be able to address this
conundrum is to divide it into two things. The first is the potential
interaction between the Paclitaxel on the TAXUS stent and a systemic
drug, another chemotherapeutic agent that a patient might be
concomitantly receiving. We had some discussion about that today, and I
think that would be an appropriate issue to raise in the instructions
for use, just to make sure that the investigator considers that.

The second is to just merely make a statement that there is no
information available about the interaction between stents that elute
sirolimus and stents that elute Paclitaxel, and that the clinician
should be aware that this has not been studied and there\'s no
information about this and that they should take that under advisement
in selecting a product.

CHAIRMAN LASKEY: And by extension, the use of dissimilar stents. Okay.

DR. HIRSHFELD: That\'s fine.

CHAIRMAN LASKEY: We want to be helpful.

DR. NORMAND: I had a comment about the label. Are we done with the label
now or no?

CHAIRMAN LASKEY: No.

(Laughter.)

DR. NORMAND: Well, could I just make a \-- I don\'t think there\'s going
to be any discussion about it, but the tables where they report the
numbers, it\'s the issue I raised earlier about the long sample sizes
that you report in the tables. So I think they need to be fixed in the
label because you\'ve got the wrong numbers and misleading rates.

DR. ZUCKERMAN: Can you clarify also, Dr. Normand, for the primary
endpoint should that be a Kaplan-Meier estimate at nine months, given
that problem and a comparison that way?

DR. NORMAND: It doesn\'t matter because they\'re making the same
assumptions. Kaplan-Meier, I\'m assuming that they said that it\'s
censored. The censoring was uninformative, whereas I still didn\'t have
the answer to my question, but if the P value is based on the real
numbers, then it\'s the same. It\'s the same inference. It\'s just that
it\'s misleading to report the rates that are listed here because
they\'re not the rates, and so I would just clean that up.

MS. WOOD: Please discuss long-term adverse events that may be associated
with TAXUS stents and whether the proposed five-year follow-up on the
clinical trial cohorts and the proposed pre/post marketing study are
appropriate to evaluate the chronic effects of the implantation of the
TAXUS stent.

If not, what additional information should be collected? Specifically
discuss how long the patients should be followed and what endpoints and
adverse events should be measured.

CHAIRMAN LASKEY: So I think we\'re certainly comfortable with longer
term follow-up than what we have and five years is certainly practical
and should be informative if there\'s a signal there. The devil is in
the details about the clinical population in whom these stents are being
implanted, but certainly the long-term follow-up we all agree is
absolutely mandatory.

The additional information that should be collected is of the nature of
the beast. What types of patients are being procedurized and under what
circumstances is the procedure being done? In effect, how well is the
protocol being adhered to?

DR. WEINBERGER: Is the intent of this really to look at low probability
outcomes that are important to clinicians? I assume that that\'s what
you\'re really interested in in post marketing surveillance. So the
question is not just who\'s getting in and who\'s getting it, but
what\'s happening to them.

So I think that it\'s not just MACE, but it\'s MACE and some of the
lower, sort of the noisy things that appeared as possible complications.
We want to know if they pop up during the five years, and you want to
know whether people develop aneurisms. You want to know whether or not
they develop pericardial effusions. You want to know whether or not they
develop things that we were theoretically worried about that haven\'t
shown up in the first 1,000 patients, but might show up over five years
when you give more time for the clinical syndromes to develop.

DR. WHITE: Well, I think rather than to specify the issues though,
Judah, since you don\'t know what those are, I mean, in five years of
following these patients, I think that\'s an adequate amount of time to
follow these patients.

DR. WEINBERGER: I agree with that. The question is from a practical
matter, you\'re collecting data. There\'s going to be a central data
repository. There\'s going to be a form. What are they going to be
asking for?

DR. WHITE: But I don\'t think we\'re prepared to write that form for
them.

CHAIRMAN LASKEY: We\'re just discussing the need for it rather than
anything.

DR. SOMBERG: I\'m not sure if it his is implicit in this statement, but
it should be, that there has to be some sort of concomitant group that
you follow it. I think some of the industry follows their device and you
have 43 of this or 75 of that, and you don\'t have anything to compare
to, and you might see the same number in a concomitant population.

So it\'s important to, I think, follow concomitantly your bare metal
stent. Is that built into this?

MR. WHITE: You mean following a control population?

DR. SOMBERG: Well, some sort of comparator. Here it would probably be
the bare metal stent or something of that nature because, say, you got
100 people had neuropathy over five years in the Express stent and you
had 110 in the bare metal stent. What does that tell you?

But if you just had 100, you would say, \"Hey, let\'s Taxol it. It
reduces neuropathy.\"

DR. NORMAND: Yeah, I had sort of the same comments. There just wasn\'t
enough \-- I don\'t think you meant to put a lot of detail in this, but
when I looked at the proposal for the registry and sort of the
surveillance, there\'s lots of details that aren\'t here, and I had the
same reaction. It seems to me you need somebody else to follow up.

There\'s lots of questions I had in terms of what you\'re really looking
at, but I just didn\'t think that you were meant to have that much
detail here because actually it says in terms of, let\'s say, the
registry, that you\'re going to look at all of the people who have the
indication. I guess you\'re not interested in off indication.

Again, there were details here that I didn\'t think we wanted to get
into necessarily, that good suggestions could be made to help get some
more information, but again, I don\'t know how much detail you want.

DR. MAISEL: I think it\'s asking a great burden for them to have a
five-year controlled trial of people not getting a drug eluting stent. I
think the ball is going to be in a different place in two or three years
and maybe everyone is going to be getting drug eluting stents. I think
there has been plenty of people who have gotten stents, and there are
historical controls. I think that would be quite reasonable.

DR. NORMAND: We could argue about design issues. I could tell you how to
design it so that it would be efficient, but again, what do you want to
gain from this?

If you want to gain adverse events rates, that\'s one thing. If you want
to \-- I mean, we could think about how to make it better, but again, I
think that there\'s not enough detail here to really \--

CHAIRMAN LASKEY: Long-term adverse events, Sharon.

DR. NORMAND: Well, that\'s a pretty simple statement. So if we say
long-term adverse events, we could talk about in an absolute sense
versus a relative sense. We could talk about a design, which is it only
for the patients in which the label is written for, or do you want to
get, you know, again, detail, detail?

DR. SOMBERG: But to keep it simple, you just need some \-- and I\'m not
saying it has to be concomitant. It may be just this population followed
out plus the as they accrue in. It\'s not that one type of stent will
disappear immediately, but there\'s a great danger of just having your
product being followed and a reporting number which has no comparator.

I mean, I don\'t want to get into specifics, but that has just come out
with another stent with another problem.

DR. MAISEL: Do we have any interest in long-term pathology, such as
either autopsy or animal studies?

CHAIRMAN LASKEY: Well, we do, but I don\'t know how you enforce that
sort of thing. It\'s hard to enforce under trial conditions.

I think it would be worth hearing Dr. Zuckerman on the whole issue about
what the agency needs for post marketing surveillance so that we can
perhaps be a bit more pragmatic in terms of what we suggest.

DR. ZUCKERMAN: Good. I think the key word is pragmatic because we want
to, first of all, extend upon the point that you made, Dr. Laskey. We
have safety data out to nine months. In an idea setting we might want
safety data out to ten years, but there\'s a preapproval/post approval
balance. So both the sponsor gave you an indication of the main safety
problems they would be looking at. The agency is in general concurrence,
and in addition, the agency gave you an estimate of the precision with
which we could look at low frequency events.

I believe Ms. Goode had a slide where 2,000 patients or a one percent
event rate. Our delta is about .4 percent, and with all of that said,
we\'re looking any other practical suggestions about any other unusual
safety concerns that you would want us to look for over the next five
years.

We also have heard the point about comparing to an adequate control, but
I think the panelists should recognize that this sponsor has a large,
in-house, historical bare metal stent database that can be utilized.

Any other suggestions?

CHAIRMAN LASKEY: No one has mentioned it, but explicitly and
specifically the endpoints and adverse events should be those that we
looked at at nine months to start.

DR. ZUCKERMAN: Okay. Any other adverse events that you\'re concerned
about?

CHAIRMAN LASKEY: Well, there\'s the hematologic dyscrasia blip. I think
that needs to be looked at. Again, that\'s another one of these if you
do 50 comparisons something will show up, but because of the potential
hematologic toxicity of this agent, it makes sense to look for that in
terms of non-cardiac toxicity.

Other cardiovascular sequelae may or may not be taken up by the fold,
but certainly what Dr. Yancy has suggested, the repeat hospitalizations
as an index of either efficacy or safety is a very useful handle on how
these products are doing in the real world.

DR. ZUCKERMAN: Okay.

CHAIRMAN LASKEY: Sorry, Chris.

The Executive Secretary will now read the \--

MS. WOOD: I\'ve already done that.

CHAIRMAN LASKEY: You did that. Good. Good job.

(Laughter.)

CHAIRMAN LASKEY: Well, do you want another two minutes to add additional
comments or the end of our discussion? Dr. Zuckerman.

DR. ZUCKERMAN: The FDA has no additional comments.

CHAIRMAN LASKEY: Does the sponsor have additional comments before the
vote or questions?

MR. OCWIEJA: The sponsor would not have any other additional comments
except to again extend our thanks to you for taking the time to take a
look at our data and information and discuss it as well as you have.

Thank you.

CHAIRMAN LASKEY: Mr. Morton?

MR. MORTON: Only to echo what\'s been said before, to recognize that the
sponsor brought a well planned and well managed study and also to
acknowledge what they had presented to us for a peri and post approval
study, and to compliment the agency for concise and pertinent review.

CHAIRMAN LASKEY: Concise, as always. Thank you.

(Laughter.)

CHAIRMAN LASKEY: Dr. Hughes?

DR. HUGHES: Thank you.

I, too, would like to compliment the manufacturer, the FDA staff, and
the committee for the overall preparation of the PMA package and its
review and this dialogue.

I think I do want to say something that perhaps goes along with the last
question on post market evaluation. Actually, a question or a point of
clarification from the consumer\'s perspective in terms of the post
approval registry.

I guess in the fourth from the last or third from the last slides that
the manufacturer presented, you introduced MILESTONE II and WISDOM and
also ARRIVE as your long-term registries, and I\'m just wondering about
the relationship among those different approaches or packages.

I take it that these are, you know, specific to earlier versions of
TAXUS, and you know, the current drug eluting coronary stent, you know,
for ARRIVE, and so I\'m wondering, you know, what kind of lessons were
learned from the previous two and also maybe just a little bit about
user interface in terms of entering the data into the registry because
with this type of device where, you know, it looks like it\'s indeed a
very good, useful device, you know, safe, but we are going into
territory or treading into unchartered waters a little bit when it comes
to, you know, drug device or interactions or products, as well as how
long to go out and looking for interactions and data like that.

So I was wondering if the manufacturer could say a little bit more than
what they\'ve already said about that.

DR. RUSSELL: Yes, thank you very much for the opportunity to address
this issue.

We\'ve gained substantial experience in how to conduct trials and work
at gaining investigator compliance. Most investigators and studies sign
agreements, and we work diligently to gain their compliance, but it
requires a moderate amount of effort.

We will be following the patients five years in the studies that we have
ongoing. So that includes TAXUS IV, V, VI and V-ISR. Hence, we will have
substantial control data, and it will be useful control data because it
will be conducted under formal preapproval trial processes.

I say that as a prelude to the contrast of the issue you raised, which
is in the post approval registry world in the two programs we have,
WISDOM and MILESTONE II, are what I would term transitional programs. So
they are not the purest form of post market study, and we do request
substantial information from participants, and it\'s not even fair to
call them investigators.

However, if you are in the real world in a busy cath lab as an active
operator, it is very burdensome for you to enter the volume of
information into a Web-based system that is required in the preapproval
study.

So we have worked diligently with FDA to streamline progressively our
data collection to gather the essential information about the safety
events, but what one must remember from a post approval study is we can
tell you what was reported and we can monitor against the report, but
unlike a preapproval study, we cannot tell you what was not reported.

So I have worked actively with my staff to avoid the use of any of the
phrases that are used in the preapproval world. We are not reporting
target lesion revascularization. That requires some amount of
angiographic follow-up. It requires mandated follow-up.

We are reporting events that are reported by customers, and we are
trying to collect that in an accurate manner and monitor against that,
but the information collected is only as good as the people entering the
information in the database, and if you want real world data from real
world community physicians, we may run into a conflict here.

So we have worked very actively in designing the study to make sure we
are making it user friendly, making it an easy Web base that\'s
intuitive, looking at sites that are willing to commit to staff, but we
have had to invest huge amounts of effort to get our other post market
registries up to dynamic data collection, and so I just want the panel
to consider the practical sides of being a busy practitioner who is
using the stent in real life and the kind of data that we\'re really
practically going to be able to provide.

Along those lines, an important difference in this particular registry,
ARRIVE, from the previous registries is we mandated that participation
in the registry follow the directions for use. So that was the inclusion
criteria.

So if you had a patient and they fit the inclusion criteria, they got
enrolled in the registry, but that doesn\'t mean any patient that
received a TAXUS stent was included in that registry.

The purpose of ARRIVE as negotiated with the FDA is to collect
consecutive TAXUS stent use, which I think is a different purpose than
you may have been addressing in your earlier conversation about the real
world use of the scent and its associated safety outcomes.

And the way we have worked on the case report forms interactively with
FDA has been to add the option of reporting other events that the
implanter believes are related to the TAXUS stent and to take out some
of them for the convenience of reporting as opposed to allowing them to
enter verbatim language, which can make it very difficult to capture and
categorize events.

So just to back up, WISDOM was a transitional study, had 778 patients
about enrolled. All stents used at those sites were required to enter
data into that study, and we specifically were tracking the worrisome
events of stent, MI, death, and use patterns to see if they had shifted.

MILESTONE II is an extension of MILESTONE I. MILESTONE I was a use
registry collecting information on how the bare metal stent was used in
our European experience. We then hope to use that information as
relative control information to the use of the TAXUS express stent.

We are collecting events that are reported by sites, doing monitoring,
but as I point out, this is only of events that are reported by the
sites.

And then ARRIVE, the details are still in development, and it is really
an effort to work at a real world registry that works.

DR. HUGHES: Thank you.

That\'s all I have.

CHAIRMAN LASKEY: Thank you.

Before we proceed to the vote, I\'d like to briefly open the meeting to
the open public hearing portion again, and we have a request from Jim
Gustafson to address the panel.

MR. GUSTAFSON: Give me a minute to get set up here.

Okay. Mr. Chairman, members of the panel, my name is Jim Gustafson. I\'m
Vice President of Research and Development for Possis Medical, maker of
the AngioJet thrombectomy catheter system.

I have no financial interest in Boston Scientific or any other stent
manufacturer or developer, but I will confess to having a compelling
financial interest in Possis Medical, which goes pretty much all the way
down the line.

I\'ve asked to address the panel on the topic of resolving thrombus
prior to the use of drug eluting stints, which goes back to Question
5(e)(ii) that the panel just considered from the FDA.

Intercoronary thrombus is recognized as one of the most challenging,
complicating factors in performing percutaneous coronary interventions.
In an article published in the [American Journal of
Cardiology]{.underline} presenting the pivotal VeGAS 2 trial data for
the AngioJet catheter, Dr. Richard Kuntz, [et al]{.underline}., stated,
\"Percutaneous coronary or vein graft interventions in thrombus
containing lesions carry high risks for complications, including abrupt
closure, late reocclusion, periprocedural MI, emerging CABG, and
death.\"

And we believe thrombus is present in coronary lesions more often than
is usually appreciated. In a study published in
[Circulation]{.underline} by Dr. Chris White, [et al]{.underline}., who
just left the room, 122 angina patients were evaluated with both
angiography and angioscopy. The angiography identified thrombus in 20
percent of these patients, but angioscopy identified thrombus in 60
percent of these very same patients.

These results suggest that lesion thrombus is significantly under
diagnosed in the very kind of patients that were enrolled in the pivotal
trials for both the CYPHER and TAXUS stents.

In fact, the approved indication for the CYPHER stent states that the
safety and effectiveness of the CYPHER stent has not been established in
patients with unresolved thrombus or in AMI patients with evidence of
thrombus, and the clinical trial for the TAXUS stent had the same
exclusion. So actually as we saw today in the draft IFUs, the exact same
text is included.

We believe that unresolved thrombus presents both safety and
effectiveness concerns when considering the use of a drug eluting stent.
This animation illustrates two important safety issues.

First, that stenting in the presence of unresolved thrombus can cause a
cheese grater effect, creating many smaller thrombus particles that
could embolize downstream.

And, secondly, that unresolved thrombus in the treatment field today
creates an environment conducive to thrombus reformation in the future.

Did that animation run up on the screen? It did not. It\'s running on my
screen. Well, it starts out, but it doesn\'t run. Let\'s try that.

I apologize. We tested this at lunch time.

CHAIRMAN LASKEY: That\'s all right. We\'ve all been there.

MR. GUSTAFSON: But I\'m not sure what to do about it. Anybody who\'s
more computer savvy than I am? That should be hard. Well, you could all
gather around my screen, but I don\'t suppose that would be particularly
effective.

CHAIRMAN LASKEY: Sir, it\'s not critical that we have the video. If you
can proceed.

MR. GUSTAFSON: All right. I\'ll do.

CHAIRMAN LASKEY: Thank you.

MR. GUSTAFSON: I\'ll go on to actually the previous slide. This
animation illustrates two important effectiveness concerns: first, that
stenting over unresolved thrombus can result in undersizing the stent,
producing suboptimal stent apposition; and, second, that pinning the
thrombus between the stent struts and the vessel wall may compromise
drug delivery.

Now, this slide.

These safety and effectiveness concerns may be minimized by effectively
resolving thrombus before stenting. So what does it mean to effectively
resolve thrombus? This table shows various treatment strategies and
their effect on thrombus.

Glycoprotein 2B3A inhibitors are effective at preventing new thrombus,
but they do not have an appreciable effect on already existing thrombus.
Thrombolytics can effectively dissolve thrombus, but lytics can take
many hours and some patients cannot tolerate it.

Conventional angioplasty and stenting displaces thrombus, but as the
failed animation showed, it basically just squishes the thrombus against
the vessel wall, and that can create some additional and more serious
difficulties.

Thrombectomy will actually remove thrombus from the target lesion.

This was going to be an animation of mechanical thrombectomy performed
with the AngioJet catheter. AngioJet is an approved and proven safe and
effective treatment of intercoronary thrombus. Specifically the approve
indication states that AngioJet is intended for removing thrombus in the
treatment of patients with symptomatic coronary artery or SVG lesions in
vessels two millimeters or larger in diameter prior to balloon
angioplasty or stent placement.

And this animation was going to show that with intercoronary thrombus
removed from the lesion site, a drug eluting stent can more readily
achieve maximum desired stent expansion with full strut apposition and
more effective delivery of drug to the target lesion and the target
tissue.

And that was going to compare with this next animation that would have
shown again what you would have already seen, suboptimal strut
apposition and impeded drug delivery to the target tissue when thrombus
had not been removed before loading the stent.

Therefore, we urge the panel to consider a more explicit statement in
drug eluting stent labeling regarding the need to remove thrombus prior
to using a drug eluting stent to optimize their safe and effective use
in such patients.

Thank you.

CHAIRMAN LASKEY: Thank you.

Is there anyone else in the audience who wishes to address the panel on
today\'s topic?

(No response.)

CHAIRMAN LASKEY: If not, I\'d like to close the public hearing and ask
the sponsor one final time: do you have any additional comments?

DR. RUSSELL: We have no further comments. Thank you.

CHAIRMAN LASKEY: God bless you.

(Laughter.)

CHAIRMAN LASKEY: Ms. Wood, if you can read the voting options please.

MS. 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 premarket 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 changes or a further analysis of existing
data. Prior to voting all of the conditions should be discussed by the
panel.

Nonapprovable. 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 voting the Chair will ask each panel member to present a
brief statement outlining the reasons for their vote.

CHAIRMAN LASKEY: The panel is now prepared to vote. As Geretta said, the
recommendation of the panel may be approvable, approvable with
conditions that are to be met by the applicant, or denial of approval.

I\'d like to now ask for a motion on the PMA.

DR. WHITE: I\'d like to make a motion that the device is approvable with
the following conditions and that those pertain to the labeling issues.

CHAIRMAN LASKEY: One at a time.

DR. WHITE: One is the Plavix-Ticlid continuation for six months.

CHAIRMAN LASKEY: Yeah. Remember we need to do these one at a time. So
you are moving that the PMA be approved with the following conditions.

Okay. Is there a second of Dr. White\'s motion for approval?

MS. WOOD: You first ask for a motion on the main motion. You have to get
a second on that. then you list the conditions, and then you take a
final vote on the entire package. So right now we\'re looking for a
second on the motion for approvable with conditions.

CHAIRMAN LASKEY: Okay. Do we have a second?

(Show of hands.)

CHAIRMAN LASKEY: Do we now want to enumerate?

DR. ZUCKERMAN: We need to talk into the microphone for the
transcriptionist and the audience.

DR. WHITE: I would defer to you, Warren. Do you want to summarize what
we\'ve talked about since your mind is so much better able to capture
these things than me?

CHAIRMAN LASKEY: No, not at this hour, Chris. Thank you. But we need to
-

DR. WHITE: We\'ve talked about a lot of things in the labeling which I
think are important that we include.

CHAIRMAN LASKEY: But you need to make the motion and the condition.

MS. WOOD: We start with the first condition.

DR. WHITE: The first one would be that it be specified in the labeling
that it\'s recommended that Plavix or Ticlid with aspirin be continued
for six months.

CHAIRMAN LASKEY: Do I hear a second on this?

(Show of hands.)

CHAIRMAN LASKEY: Okay, and is there discussion?

Are we all universally in agreement on that, all right? On that first
condition of Plavix plus aspirin for six months.

I am told that we will now vote on Dr. White\'s motion to approve with
condition number one being the addition of Plavix and aspirin for six
months. All in favor, raise hands, please.

(Show of hands.)

CHAIRMAN LASKEY: It\'s unanimous.

May I have another condition for the PMA?

DR. WHITE: I\'m empty.

DR. HIRSHFELD: I could offer two. Should I offer them once or \--

CHAIRMAN LASKEY: Unfortunately we need to do it one at a time.

DR. HIRSHFELD: Okay. The second one is that the interaction \-- that
labeling should state that the interaction between the Paclitaxel
eluting stents and stents that elute other compounds has not been
established, has not been studied.

CHAIRMAN LASKEY: Do I have a second?

PARTICIPANTS: Second.

CHAIRMAN LASKEY: Discussion?

(No response.)

CHAIRMAN LASKEY: I think we\'re all in agreement. All in favor of the
second condition being the labeling to specifically reflect the
precautions or the potential interaction of the Paclitaxel and sirolimus
eluting stent? All in favor \--

MS. WOOD: Other drug eluting stents.

CHAIRMAN LASKEY: Did you say \--

DR. HIRSHFELD: I thought it should be other drug eluting stents to allow
for future contingencies.

CHAIRMAN LASKEY: Okay. All in favor?

(Show of hands.)

CHAIRMAN LASKEY: Again it\'s unanimous. You had a second? You had an
additional?

DR. HIRSHFELD: Well, I don\'t know whether \-- the other issue that I
had raised was that the labeling doesn\'t describe the maximum expansion
diameter for the stent, and I didn\'t know whether that\'s a peccadillo
or whether that needs to be officially voted on as the labeling.

CHAIRMAN LASKEY: Yes, unfortunately.

DR. HIRSHFELD: Yes, it is a peccadillo?

CHAIRMAN LASKEY: And we need to vote on it.

DR. HIRSHFELD: Okay.

CHAIRMAN LASKEY: So it needs to be included.

DR. HIRSHFELD: Well, then I would propose that the labeling has to
reflect the maximum permittable expansion diameter of the Express stent.

CHAIRMAN LASKEY: Of?

DR. HIRSHFELD: The TAXUS Express stent.

DR. WEINBERGER: Second.

CHAIRMAN LASKEY: Discussion?

(No response.)

CHAIRMAN LASKEY: Okay. We\'ll vote on this condition of the labeling to
reflect the maximum permittable stent diameter. All in favor?

(Show of hands.)

CHAIRMAN LASKEY: Unanimous again.

DR. NORMAND: Do I have to say the condition about the labeling and the
numbers in the table?

I\'d like another condition. I\'d like the numbers in the table that
report on the primary effectiveness endpoints in the denominators to be
corrected to reflect accurately the numbers.

CHAIRMAN LASKEY: So the rates in all of the tables?

DR. NORMAND: Yes. They have to be corrected everywhere.

CHAIRMAN LASKEY: That will be in the IFU.

DR. NORMAND: Yes.

CHAIRMAN LASKEY: Okay. Do we have a second?

DR. WEINBERGER: Second.

CHAIRMAN LASKEY: If there\'s no discussion, let\'s vote. All in favor?

(Show of hands.)

CHAIRMAN LASKEY: Great. Unanimous again.

Are there other conditions for us to consider to Dr. White\'s
recommendation?

DR. MORRISON: I\'d like to suggest that the labeling also state that the
interaction between this drug eluting stent and bracytherapy has not
been studied.

CHAIRMAN LASKEY: As a precaution that note is in there already, is it
not? It\'s in the IFU as a precaution.

DR. MORRISON: Is it?

CHAIRMAN LASKEY: Yes. So it\'s technically in the label.

Judah?

DR. WEINBERGER: I think that the discussion of MRI should probably be
deleted.

CHAIRMAN LASKEY: A bold move.

(Laughter.)

CHAIRMAN LASKEY: A second? We have established the fact that the Express
stent is a non-ferromagnetic stent; is that correct?

DR. WEINBERGER: That is correct.

DR. SOMBERG: Could we have discussion on that?

CHAIRMAN LASKEY: Absolutely.

DR. SOMBERG: I don\'t think it has been studied.

DR. WEINBERGER: I think it is pretty well known that if you put this
particular alloy, 316L, into a magnet that there\'s no force on the
alloy. That\'s a matter of scientific fact.

DR. SOMBERG: Has it been studied? I mean, I\'ll just be the devil\'s
advocate here.

DR. WEINBERGER: Why don\'t we have the bioengineers tell us that?

DR. SOMBERG: I\'m just saying I would caution the other panel members if
you haven\'t seen the data, I wouldn\'t endorse one person\'s statement.

DR. WEINBERGER: The problem here is that if there\'s any instruction in
there about the MRI, there is no data to say that at 30 days it is safe.
So either it\'s never safe or it\'s safe immediately.

DR. SOMBERG: I would prefer to leave this to the FDA biomaterials and
radiologic group which is expert in this area and will be able to either
mandate tests or make, you know, a generic warning that is standard for
things that are not studied because this is a medical legal issue.

CHAIRMAN LASKEY: I am happy tabling this and not making this as a
condition of approval. I think it\'s a theoretical issue as far as I\'m
concerned. I don\'t think there\'s scientific basis for it. I think all
of us have sent patients to the magnet within a couple of days, but how
does the agency feel on moving forward from here?

DR. ZUCKERMAN: I think you\'ve given some good advice, Dr. Laskey.
We\'ll work with the sponsor to see what data there are, and we\'ll
construct a statement that is appropriate for the data that the sponsor
has.

CHAIRMAN LASKEY: Okay. So let the discussion reflect that you want to
withdraw the motion?

DR. WEINBERGER: Yes, I will.

CHAIRMAN LASKEY: The motion has been withdrawn

DR. SOMBERG: I wanted to remind the Chairman of his biomaterial
compatibility that you mentioned. You might want to mention that.

DR. WEINBERGER: That\'s in there already.

DR. SOMBERG: It is? Different metals? Okay.

CHAIRMAN LASKEY: Additional conditions of approval? We only have four,
folks. Come on. We need some more.

(Laughter.)

CHAIRMAN LASKEY: Okay. We spoke during the day of the metal-metal
incompatibility. Do we want to include \--

DR. WHITE: It\'s already there.

CHAIRMAN LASKEY: You\'re there. It\'s in the biocompatibility? You metal
to metal? Fine.

DR. MAISEL: We had an extensive discussion regarding the indication
statement which I will allow you to summarize if you like, but do we
need to make any changes to that?

CHAIRMAN LASKEY: Can I paraphrase that? We need to include the use of
the term \"Express stent comparator\" in the labeling claim of reducing
restenosis compared to. Is that what you\'re driving at?

DR. MAISEL: Yes.

CHAIRMAN LASKEY: Can we have a second to that motion?

PARTICIPANT: I second.

CHAIRMAN LASKEY: Discussion and a vote. All in favor of including the
comparator?

(Show of hands.)

CHAIRMAN LASKEY: Okay. Let\'s raise hands again because not everybody is
unanimous.

(Show of hands.)

CHAIRMAN LASKEY: We have one, two, three, four, five in favor.

Those against?

(Show of hands.)

CHAIRMAN LASKEY: One, two, three, against.

PARTICIPANTS: Four.

CHAIRMAN LASKEY: I\'m sorry.

DR. ZUCKERMAN: Okay. For the record, Dr. Laskey, we need to identify
who\'s voting in favor and who\'s against this condition of approval.

CHAIRMAN LASKEY: So in favor of the condition, including the language of
the term of comparator, the bare metal stent comparator being the
express stent, Drs. Hirshfeld, White, Morrison, Weinberger and Maisel in
favor, and Drs. Somberg, Aziz, Normand and Yancy against.

DR. HIRSHFELD: Is there an opportunity to discuss this briefly?

The reason that I think this is a good motion and why I voted for it is
that the language that currently exists contains an implied comparison,
but doesn\'t state what it\'s compared to, and so I think just from a
linguistic standpoint the statement needs to be revised.

DR. SOMBERG: The reason I\'m opposed to this is that it will be said
that other bare metal stents that are existing now will not offer the
benefit or will offer benefit for a reduced restenosis while only the
Express is the one that is problematic.

I think the Express is a generic standard for bare metal stents and that
the rates are comparable from what I understand from the literature, and
therefore, I don\'t want a detail person saying, \"Well, if you use this
bare metal stent, you know, it\'s different; it\'s okay because they
limited the warning that this was better than the Express.\"

So I think it can cause confusion, and I think there is as good as
you\'re going to get that this is a controlled study against the bare
metal stent.

DR. HIRSHFELD: I agree with that, and the qualification is that the
panel really didn\'t come to agreement as to whether they felt that bare
metal stents were generic with respect to restenosis or not, and that
could be subsequently assessed, and that decision could be made
subsequently.

DR. SOMBERG: We didn\'t have data presented on that in detail, but I
think when this study was put together, it was put together as a drug
eluting stent versus bare metal, and there may be bare metal stents that
are not as good as the bare metal stent in this particular comparitor.

So I just think it\'s fraught with dangers, and we shouldn\'t get that
specific.

DR. YANCY: And I tend to agree with that. I think that by specifically
stating the Express stent we are excluding the possibility of that other
bare metal stents are as good as, better than, or not as good as, and I
am comfortable that the event rate in the reference population was
equivalent where it\'s reported for the majority of bare metal stents,
and I think that this creates a precedent that would be very difficult
to future generations of these devices.

DR. WEINBERGER: So the way you would like to put it, it would include
the possibility that the introduction of a new bare metal stent with a
different alloy would never be better than the TAXUS stent. That\'s what
you\'re saying.

DR. SOMBERG: No. I\'m just saying that we\'re not saying that the only
thing this particular intervention does is compare favorably to the
Express stent. As it now stands, I mean, if you want you can ask them to
put the data of restenosis in many restenosis trials, and it all seems
to me very, very similar.

If something comes down the line that uses a new epoxy resin and the
will be the first ones to differentiate themselves in the future from
all other bare metal stents, and they probably will do a comparator to a
drug eluting stent.

So it will not stymie anybody, but it will not give people a segue to
mislead.

CHAIRMAN LASKEY: I\'m not sure it\'s misleading, John, at all, and in
fact, it\'s just very specific. A stent is not a stent is not a stent,
and if you look at the rates of TVR with NIR, they\'re different than in
this study. So I don\'t see what the problem is, but I don\'t know where
to go from here if we\'re on the fence with a condition. I need some
legislative help.

It\'s five to four, but you need more than that?

So the condition passes. Okay.

Were there other conditions? I think we\'ve exhausted the list. Panel
members?

DR. WEINBERGER: Under indications for use we wanted to say ischemia
driven revascularization because there\'s no reference to the patient
population or \--

CHAIRMAN LASKEY: Except in the patient population in the IFU.

DR. WEINBERGER: Right, but in the indications there was a legislative
requirement to mention the patient population.

CHAIRMAN LASKEY: Is there, indeed, a legislative requirement? I don\'t
think so.

DR. ZUCKERMAN: I think we reviewed the general framework for indications
for use, but you know, are you offering this as a condition for approval
to vote on, Dr. Weinberger?

DR. WEINBERGER: Yes, I was.

DR. ZUCKERMAN: Okay.

CHAIRMAN LASKEY: All right. Well, we tend to shy away from recommending
patterns of practice. I don\'t think that\'s in our purview. I think we
need to stick to what we have before us.

DR. MAISEL: Can we be a little more vague and say patients requiring
revascularization ore percutaneous revascularization?

MR. MORTON: Could I just ask is this particular drug eluting stent that
much different than another drug eluting stent or from a bare metal
stent?

And what I\'m looking for is just kind of some continuity from device to
device so that we\'re not specifying something with this device unless
it really is different.

In other words, are we simply evolving into a matter of specificity that
may not be needed?

CHAIRMAN LASKEY: May not be needed and may be a dangerous precedent for
us. I wish we had discussed this a bit greater, but from prior years
we\'ve tended to back away from telling people what to do.

DR. WEINBERGER: Well, if people are uncomfortable, I don\'t mind leaving
it in the more detailed instructions which follow the indication
section. That would be acceptable.

CHAIRMAN LASKEY: Which is where it is. Great.

So then we have five conditions on Dr. White\'s motion for approval.
They are, number one, the addition of the Plavix and aspirin treatment
for six months; number two, for the labeling to reflect the drug-drug
interaction; number three, for the labeling to reflect the maximum
inflation diameter; number four, for the tables to reflect reality; and
number five, the inclusion of the comparator term \"bare metal Express
stent\" in the indication statement.

Will all of those voting members in favor of approval of these
conditions raise their hands?

(Show of hands.)

CHAIRMAN LASKEY: We have Drs. Hirshfeld, White, Somberg, Aziz, Normand,
Morrison, Yancy, Weinberger and Maisel, unanimous.

And finally, just a brief rendition of why you voted as you did. Dr.
Hirshfeld?

DR. HIRSHFELD: I think the clinical data for both safety and efficacy
are compelling, and the product should be on the market.

CHAIRMAN LASKEY: Chris.

DR. WHITE: I would concur with that. I agree.

CHAIRMAN LASKEY: Dr. Somberg.

DR. SOMBERG: Clinical data is compelling and while I\'m not happy with
the mention of the Express stent because I think the control group is a
generic control group, I think that\'s a minor point and will not overly
confuse the practicing physicians.

DR. AZIZ: It\'s safe and effective.

(Laughter.)

DR. NORMAND: Ditto, if you heard that. I agree with safe and effective.

DR. MORRISON: I think there\'s concordance between multiple well done
clinical trials and some extremely well done animal data, and I think we
look forward to seeing this on the market.

DR. YANCY: I agree with all that has been said. I just hope that future
iterations of this device, particularly since other companies are
represented, will bring to bear data that will be a bit more robust with
bedside clinical endpoints. I think that that\'s very much needed.

DR. WEINBERGER: And I think that clearly efficacy and safety were
demonstrated so that there was no question that this would be a valuable
addition.

DR. MAISEL: Very well conducted clinical trials with evidence of safety
and efficacy.

CHAIRMAN LASKEY: Mike or Allen, any final comments?

MR. MORTON: None from me. Thank you.

DR. HUGHES: No additional comments.

CHAIRMAN LASKEY: Well, in conclusion, I want to thank the sponsors for
an absolutely superb presentation; thank my fellow panel members for
sticking to the schedule; and this concludes the report and
recommendations of the panel on PMA P020039 \-- you gave me the wrong
script \-- this is P030025.

Thank you much. The meeting is adjourned.

(Whereupon, at 4:34 p.m., the meeting in the above-entitled matter was
concluded.)