**P030047 Lead Reviewer Memo**

**[History/Background/Overview]{.underline}**

The Cordis PRECISE Nitinol Stent and the Angioguard XP Emboli Capture
Device have been under clinical investigation since 1998. There have
been many modifications made to the device design, the materials of
construction, the sizes and configurations to be offered, and even the
name of the device. When the study was first proposed, the device was
called the S.M.A.R.T. stent, but the name changed when the profile was
modified. The most significant changes have been the addition of the
Angioguard as part of the pivotal study, the lowering of the device
profile, and the recent transition from an over-the-wire technology to a
rapid exchange design.

In the clinical section, all stent designs have been pooled, and
analyses presented to justify such pooling. The sponsor tested each
design on the bench, and some changes were also validated in an animal
model. There was no clinical use of the rapid exchange configuration,
but FDA agreed to consider marketing clearance of the rapid exchange
technology without clinical testing since the working ends (the filter
and the stent) have not been changed.

Initially, the sponsor proposed a randomized study, with registry arms
for stenting and surgery for patients whom the surgeon,
interventionalist and neurologist all agreed could not be randomized.
Correction/clarification: the surgeon, interventionalist, and
neurologist team determined if patients met entry criteria; the team did
not determine if a patient was entered into the registry. Entry into
stent registry occurred if the surgeon felt a patient was too high-risk
for surgery. Entry into CEA registry occurred if the interventionalist
felt a patient was inappropriate for stenting. This design is outlined
in SAPPHIRE protocol and report, and was clarified during a telephone
call to Cordis from FDA on March 22, 2004 (B. Zuckerman to J. Martin).
The sponsor was unable to complete the randomized study, mostly due to
competing studies, and because the stent registry arm filled up (i.e.,
physicians were no longer willing to randomize patients). Some of these
competing studies involved competitor devices, but many involved the
Cordis devices. While Cordis did not monitor, fund or sponsor these
single-investigator studies, they were facilitated by Cordis. For the
most part, these single investigators used the Cordis-supplied
feasibility (non-randomized) protocol drafted by Cordis, and the Cordis
case report forms and consent form, to do their studies. (In order to
open a study, each investigator-sponsor needed a letter of authorization
from Cordis to cross reference the Cordis file for the manufacturing
information and non-clinical testing). Some of these single
investigators opened their own studies after being investigators in the
Cordis trial, and others did not participate in the Cordis trial. Cordis
has asked that we clarify this memo to state that the study was stopped
due to slow enrollment, which was considered an administrative reason.
Furthermore, they asked that we state that "Although there were
competitor trials, none involved Cordis devices. SAPPHIRE centers did
not initiate their investigator-sponsored IDE studies until enrollment
in SAPPHIRE was complete." However, this is not FDA' s perception of the
situation; we stand by our initial statements on this issue.

The PMA is a compilation of data from the Cordis-sponsored IDE
(consisting of data from the 261 patient feasibility non-randomized
study, the 334 patient randomized pivotal study, the 406 patients
enrolled into the stent registry arm and the 7 patients enrolled into
the surgical registry arm), and most (but not all) of the
single-investigator IDEs, as well as data from non-U.S. Cordis-sponsored
study (CASCADE). The CASCADE and the single-investigator studies only
include 30-day data, whereas the feasibility and SAPPHIRE studies have
data to beyond one year. The table on page 4 of this memo summarizes the
data from each study, so you can see it at a glance. Although the
sponsor updated their rate table in an amendment to the PMA, they only
included data for patients having 2 year case report forms; those with
events who did not have a 2-year report form were omitted from the
tables. These tables were omitted from the Panel Pack, as they were
incomplete. The survival curves were left in, however.

In addition after the Panel Pack was submitted, but prior to mailing it
out, the sponsor provided more details regarding the reasons for
entering patients into the registry group rather than the randomized
cohort, details about patients who were adjudicated in or out, and
detailed reasons why the randomized study was terminated, which are in
the Panel Pack, under the section labeled "Addendum".

There were several people on the review team who helped to review
information in this PMA, including the following:

-   Lead Clinical Reviewer Dr. Ronald Weintraub,

-   Additional clinical oversight from Drs. Paul Chandeysson and Wolf
    Sapirstein

-   Statistical reviewer Heng Li

-   Engineering reviewers Deanna Busick, Vivianne Holt, and Terry Woods

-   Microbiological, biocompatibility and animal reviewer Lisa Kennell

-   Many others have reviewed the patient labeling, manufacturing, and
    oversaw inspections of the company and some of the hospital source
    data.

Based on input and reviews performed to date of the non-clinical
information in the file, there are a few minor remaining questions that
must be resolved relating to the non-clinical data. The sponsor did not
agree with this statement as FDA had not indicated that there were
issues remaining. The phrasing should have been that the FDA continues
to review some aspects of the non-clinical information as of this
writing. Substantive reviews of these data are not included in the
submission, but the sponsor's summary provided in the Summary of Safety
and Effectiveness provides adequate detail for your needs. If you are
interested in having a copy of the complete reviews from the FDA team
member, they can be provided upon request.

Regarding issues pending from the clinical and statistical reviews, a
few issues remain and the sponsor's response is pending. Some of the
clinical concerns have been included for discussion at the Panel meeting
as questions to the panel.

Outstanding issues as of this writing include the following:

1.  The sponsor has been asked to perform an observational study using a
    propensity score analysis of the randomized patients and the stent
    registry. As of this writing, this analysis has not been done. The
    sponsor disagreed with this statement, and in fact it is incorrect
    and should have been updated. Cordis had submitted a propensity
    score analysis, but it may not have been optimized with regard to
    the covariates chosen. If it is submitted, the results will be
    forwarded to you as an amendment to this Panel Pack. The summary of
    the results were, in fact, included in the Panel Pack, under the tab
    labeled "ADDENDUM." The sponsor was asked to provide detailed
    computational steps for the confidence interval used for the claim
    of non-inferiority, which is based on the parameter θ (theta) and a
    confidence interval for this parameter. Correction: this information
    was provided to the statistician.

2.  The statistician asked for the baseline data for patients offered
    the option of entering CEA registry but who did not enter, and those
    offered the option of the stent registry who did not enter. Again, I
    neglected to update this memo; the sponsor responded that they were
    not aware of patients in this category.

3.  We asked for more details about the events that were discrepant
    between the sites and the CEC (i.e. events that were either added in
    or adjudicated out). This information arrived late, and was added at
    the end of the FDA review memos under the tab labeled "ADDENDUM.".

**[Device Description]{.underline}**

The PRECISE is a self-expanding nitinol stent, available in 5.5F and 6F
delivery systems. The geometry of the stent struts can be described as a
fine ziz-zag mesh. The stent is laser-cut from nitinol tubing into
zig-zag rings, with links between the rings. The 5.5F stent is cut from
0.060" OD tubing, and the 6F stent is cut from 0.072" OD tubing. All
stent sizes within each family are cut using the same pattern and
dimensions; final stent size is achieved by expanding the stent on an
appropriately sized mandrel and heat-treating it to set its shape. Stent
length is determined by the number of zig-zag rings; longer stents have
more rings.

The 5.5F PRECISE stent is available in straight sizes of 5, 6, 7, and 8
mm diameter, each with available lengths of 20, 30, and 40 mm. A tapered
version is also available, measuring 6-8 mm in diameter and 30 mm in
length.

The 6F PRECISE stent is available in straight sizes of 9 and 10 mm
diameter, each with available lengths of 20, 30, and 40 mm. Two tapered
versions are also available, measuring 7-9 and 7-10 mm in diameter and
30 mm in length.

The Angioguard XP is a 0.014" guidewire with a filter basket near the
distal end. It functions as both an interventional guidewire and a
distal embolic protection device during carotid procedures. The filter
basket consists of a thin, porous membrane supported by a nitinol
skeleton and is designed to trap and capture emboli. After the filter
(inside a deployment sheath) is advanced to the proper position within
the vessel, the deployment sheath is removed from the guidewire. The
filter basket opens like an umbrella, and the guidewire is used to
facilitate positioning of other interventional devices (e.g., stents or
balloons). When the interventional procedure is complete, a capture
sheath is advanced over the wire to close the filter by collapsing the
proximal struts of the basket (the actual filter element is not captured
inside the sheath). The capture sheath is locked to the guidewire, and
the entire assembly is withdrawn from the patient.

The ANGIOGUARD XP is available in two wire stiffnesses: Medium Support
and Extra Support. Both are available in filter basket sizes of 4, 5, 6,
7, and 8 mm diameter and 300 mm length. The Extra Support version is
also available in a 180 mm length. The sponsor provided
clarification/revisions to the original spreadsheet created by FDA. The
sponsor stated the following: "The FDA's spreadsheet provided a summary
of all studies included in Cordis' PMA; however, in some areas, the data
differed from what Cordis presented. In the ITT columns, FDA changed the
denominator to 167 for lesion success, procedure success, stent success,
and ANGIOGUARD success. For these variables, Cordis utilized considered
"Attempt to treat" to accurately assess the performance of the stent and
ANGIOGUARD devices. Device performance cannot be assessed if it is not
attempted. For all other variables, the strict intent-to-treat
definition was utilized. In addition, Feasibility Study data were
presented as "Without ANGIOGUARD". The Feasibility Study was conducted
both with and without ANGIOGUARD (as reported in the clinical report).
Therefore, Cordis modified the table to indicate combined results,
results without ANGIOGUARD, and results with ANGIOGUARD. Also, in the
Site-Sponsored Studies, TLR data were not available, but TVR data were.
We corrected that section accordingly. We also added in the "N" for the
investigator- sponsored studies in the heading.

Also, Cordis is not clear whether the data FDA entered in the table for
"Death/Ipsilateral Stroke" represents a combination of death and
ipsilateral stroke, or death due to ipsilateral stroke. As well, we are
not clear on how these data were determined."

Safety and Effectiveness Measures to One Year (unless noted)

<table style="width:100%;">
<colgroup>
<col style="width: 27%" />
<col style="width: 14%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 13%" />
<col style="width: 0%" />
<col style="width: 14%" />
<col style="width: 0%" />
<col style="width: 14%" />
<col style="width: 15%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2">Parameter</td>
<td colspan="8">Randomized Pivotal Study</td>
<td rowspan="2"><p>Stent Registry</p>
<p>(N=406)</p></td>
</tr>
<tr class="even">
<td><p>ITT Stent</p>
<p>(N=167)</p></td>
<td colspan="3"><p>Evaluable Stent</p>
<p>(N=159)</p></td>
<td colspan="2"><p>ITT CEA</p>
<p>(N=167)</p></td>
<td colspan="2"><p>Evaluable CEA</p>
<p>(N=151)</p></td>
</tr>
<tr class="odd">
<td colspan="10"><strong>Safety Measures</strong></td>
</tr>
<tr class="even">
<td>MAE (30 day death, stroke, MI, and death and ipsilateral stroke
&gt;30 days to 12 months)</td>
<td colspan="3">12.0% (20/167)</td>
<td>11.9% (19/159)</td>
<td colspan="2">19.2% (32/167)</td>
<td colspan="2">19.9% (30/151)</td>
<td>15.8% (64/406)</td>
</tr>
<tr class="odd">
<td>MAE (without non-neurologic deaths 31-360 days)</td>
<td colspan="3">6.0% (10/167)</td>
<td>5.7% (9/159)</td>
<td colspan="2">12.6% (21/167)</td>
<td colspan="2">12.6% (19/151)</td>
<td>10.3% (42/406)</td>
</tr>
<tr class="even">
<td>MAE (without MIs to 30 days and without non-neurologic death 31-360
days)</td>
<td colspan="3">5.4% (9/167)</td>
<td>5.0% (8/159)</td>
<td colspan="2">7.8% (13/167)</td>
<td colspan="2">7.3% (11/151)</td>
<td>9.4% (38/406)</td>
</tr>
<tr class="odd">
<td>Death/ipsilateral stroke</td>
<td colspan="3">11.4% (19/167)</td>
<td>10.7% (17/159)</td>
<td colspan="2">17.4% (29/167)</td>
<td colspan="2">17.9% (27/151)</td>
<td>17.2% (70/406)</td>
</tr>
<tr class="even">
<td>Death</td>
<td colspan="3">7.2% (12/167)</td>
<td>6.9% (11/159)</td>
<td colspan="2">12.6% (21/167)</td>
<td colspan="2">12.6% (19/151)</td>
<td>10.1% (41/406)</td>
</tr>
<tr class="odd">
<td>Any stroke/TIA</td>
<td colspan="3">12.6% (21/167)</td>
<td>12.6% (20/159)</td>
<td colspan="2">10.2% (17/167)</td>
<td colspan="2">10.6% (16/151)</td>
<td>16.0% (65/406)</td>
</tr>
<tr class="even">
<td><p>Stroke</p>
<p>Major ipsilateral</p>
<p>Minor ipsilateral</p>
<p>Non-ipsilateral</p></td>
<td colspan="3"><p>6.6% (11/167)</p>
<p>0.6% (1/167)</p>
<p>3.6% (6/167)</p>
<p>3.6% (4/167)</p></td>
<td><p>5.7% (9/159)</p>
<p>0% (0/159)</p>
<p>3.8% (6/159)</p>
<p>2.5% (4/159)</p></td>
<td colspan="2"><p>3.4% (14/167)</p>
<p>3.0% (5/167)</p>
<p>1.8% (3/167)</p>
<p>3.6% (6/167)</p></td>
<td colspan="2"><p>7.3% (11/151)</p>
<p>3.3% (5/151)</p>
<p>2.0% (3/151)</p>
<p>2.6% (4/151)</p></td>
<td><p>9.1% (37/406)</p>
<p>3.2% (13/406)</p>
<p>3.9% (16/406)</p>
<p>2.2% (9/406)</p></td>
</tr>
<tr class="odd">
<td>TIA</td>
<td colspan="3">6.6% (11/167)</td>
<td>6.9% (11/159)</td>
<td colspan="2">3.0% (5/167)</td>
<td colspan="2">3.3% (5/151)</td>
<td>6.9% (28/406)</td>
</tr>
<tr class="even">
<td><p>MI</p>
<p>Q wave</p>
<p>Non-Q-wave</p></td>
<td colspan="3"><p>3.0% (5/167)</p>
<p>0% (o/167)</p>
<p>3.0% (5/167)</p></td>
<td><p>2.5% (4/159)</p>
<p>0% (0/159)</p>
<p>2.5% (4/159)</p></td>
<td colspan="2"><p>7.2% (12/167)</p>
<p>1.2% (2/167)</p>
<p>6.0% (10/167)</p></td>
<td colspan="2"><p>7.9% (12/151)</p>
<p>1.3% (2/151)</p>
<p>6.6% (10/151)</p></td>
<td><p>2.7% (11/406)</p>
<p>0.5% (2/406)</p>
<p>2.2% (9/406)</p></td>
</tr>
<tr class="odd">
<td colspan="10"><strong>Effectiveness Measures</strong></td>
</tr>
<tr class="even">
<td>Lesion success (residual stenosis &lt;30%)</td>
<td colspan="2">98.1% (145/158)</td>
<td colspan="3">91.8% (145/158)</td>
<td colspan="2">N/A</td>
<td>N/A</td>
<td>90.4% (368/407)</td>
</tr>
<tr class="odd">
<td>Procedure success</td>
<td colspan="2">88.1% (140/159)</td>
<td colspan="3">88.6% (140/158)</td>
<td colspan="2">N/A</td>
<td>N/A</td>
<td>87.9% (355/404)</td>
</tr>
<tr class="even">
<td>Device (stent) success</td>
<td colspan="2">91.2% (145/159)</td>
<td colspan="3">91.2% (145/159)</td>
<td colspan="2">N/A</td>
<td>N/A</td>
<td>89.6% 363/405)</td>
</tr>
<tr class="odd">
<td>Angioguard success</td>
<td colspan="2">95.6% (152/159)</td>
<td colspan="3">95.6% (152/159)</td>
<td colspan="2">N/A</td>
<td>N/A</td>
<td>91.6% (372/406)</td>
</tr>
<tr class="even">
<td>Presence of trapped material</td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="2">N/A</td>
<td>N/A</td>
<td>56.0% (220/393)</td>
</tr>
<tr class="odd">
<td><p>Target Lesion Revascularization</p>
<p>Surgery</p>
<p>PTA</p></td>
<td colspan="2"><p>0.6% (1/167)</p>
<p>0.6% (1/167)</p>
<p>0% (0/167)</p></td>
<td colspan="3"><p>0.6% (1/159)</p>
<p>0.6% (1/159)</p>
<p>0% (0/159)</p></td>
<td colspan="2"><p>3.6% (6/167)</p>
<p>0.6% (1/167)</p>
<p>3.0% (5/167)</p></td>
<td><p>4.0% (6/151)</p>
<p>0.7% (1/151)</p>
<p>3.3% (5/151)</p></td>
<td><p>0.7% (3/406)</p>
<p>0% (0/406)</p>
<p>0.7% (3/406)</p></td>
</tr>
<tr class="even">
<td><p>Target Vessel Revascularization</p>
<p>Surgery</p>
<p>PTA</p></td>
<td colspan="2"><p>0% (0/167)</p>
<p>0% (0/167)</p>
<p>0% (0/167)</p></td>
<td colspan="3"><p>0% (0/159)</p>
<p>0% (0/159)</p>
<p>0% (0/159)</p></td>
<td colspan="2"><p>0% (0/167)</p>
<p>0% (0/167)</p>
<p>0% (0/167)</p></td>
<td><p>0% (0/151)</p>
<p>0% (0/151)</p>
<p>0% (0/151)</p></td>
<td>0%</td>
</tr>
<tr class="odd">
<td>Stent thrombosis</td>
<td colspan="2">0% (0/167)</td>
<td colspan="3">0% (0/159)</td>
<td colspan="2"></td>
<td></td>
<td>0.7% (3/406)</td>
</tr>
<tr class="even">
<td>Major bleeding</td>
<td colspan="2">9.0% (15/167)</td>
<td colspan="3">9.4% (15/159)</td>
<td colspan="2">10.2% (17/167)</td>
<td>11.3% (17/151)</td>
<td>13.3% (54/406)</td>
</tr>
<tr class="odd">
<td>Severe hypotension</td>
<td colspan="2">17.4% (29/167)</td>
<td colspan="3">18.2% (29/159)</td>
<td colspan="2">3.0% (5/167)</td>
<td>3.3% (5/151)</td>
<td>15.5% (63/406)</td>
</tr>
<tr class="even">
<td>Bradycardia/asystole</td>
<td colspan="2">8.4% (14/167)</td>
<td colspan="3">8.8% (14/159)</td>
<td colspan="2">3.0% (5/167)</td>
<td>2.6% (4/151)</td>
<td>3.4% (14/406)</td>
</tr>
<tr class="odd">
<td>Cranial nerve injury</td>
<td colspan="2">0% (0/167)</td>
<td colspan="3">0% (0/159)</td>
<td colspan="2">4.8% (8/167)</td>
<td>5.3% (8/151)</td>
<td>0% (0/406)</td>
</tr>
</tbody>
</table>

+----------+-----------+---------+---------+---+-------------+---+-----------+
| Fea      |           |         | Invest  | C |             |   |           |
| sibility |           |         | igator- | A |             |   |           |
| Study    |           |         | Sponsor | S |             |   |           |
|          |           |         | Studies | C |             |   |           |
|          |           |         | (no     | A |             |   |           |
|          |           |         | n-adjud | D |             |   |           |
|          |           |         | icated, | E |             |   |           |
|          |           |         | **30    | O |             |   |           |
|          |           |         | day     | U |             |   |           |
|          |           |         | only**) | S |             |   |           |
|          |           |         |         | S |             |   |           |
|          |           |         | (N=490) | t |             |   |           |
|          |           |         |         | u |             |   |           |
|          |           |         |         | d |             |   |           |
|          |           |         |         | y |             |   |           |
|          |           |         |         | * |             |   |           |
|          |           |         |         | * |             |   |           |
|          |           |         |         | ( |             |   |           |
|          |           |         |         | 3 |             |   |           |
|          |           |         |         | 0 |             |   |           |
|          |           |         |         | d |             |   |           |
|          |           |         |         | a |             |   |           |
|          |           |         |         | y |             |   |           |
|          |           |         |         | o |             |   |           |
|          |           |         |         | n |             |   |           |
|          |           |         |         | l |             |   |           |
|          |           |         |         | y |             |   |           |
|          |           |         |         | ) |             |   |           |
|          |           |         |         | * |             |   |           |
|          |           |         |         | * |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| Fea      | **Without | **With  |         | * |             | W |           |
| sibility | Ang       | Angio   |         | * |             | i |           |
| Study    | ioguard** | guard** |         | W |             | t |           |
|          |           |         |         | i |             | h |           |
| Total    | **        | **(     |         | t |             | A |           |
| (N=261)  | (N=176)** | N=85)** |         | h |             | n |           |
|          |           |         |         | o |             | g |           |
|          |           |         |         | u |             | i |           |
|          |           |         |         | t |             | o |           |
|          |           |         |         | A |             | g |           |
|          |           |         |         | n |             | u |           |
|          |           |         |         | g |             | a |           |
|          |           |         |         | i |             | r |           |
|          |           |         |         | o |             | d |           |
|          |           |         |         | g |             |   |           |
|          |           |         |         | u |             | ( |           |
|          |           |         |         | a |             | N |           |
|          |           |         |         | r |             | = |           |
|          |           |         |         | d |             | 3 |           |
|          |           |         |         | * |             | 1 |           |
|          |           |         |         | * |             | ) |           |
|          |           |         |         |   |             |   |           |
|          |           |         |         | ( |             |   |           |
|          |           |         |         | N |             |   |           |
|          |           |         |         | = |             |   |           |
|          |           |         |         | 9 |             |   |           |
|          |           |         |         | 0 |             |   |           |
|          |           |         |         | ) |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| **Safety |           |         |         |   |             |   |           |
| Me       |           |         |         |   |             |   |           |
| asures** |           |         |         |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 10.7%    | 12.5%     | 7.1%    | 4.3%    |   |             |   |           |
| (28/261) | (22/176)  | (6/85)  | (       |   |             |   |           |
|          |           |         | 21/490) |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
|          |           |         |         |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
|          |           |         |         |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| \%       |           |         |         |   |             |   |           |
| (/261)   |           |         |         |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 3.8%     | 4.0%      | 3.5%    | 0.6%    |   | 0% (0/90)   |   | 0% (0/31) |
| (10/261) | (7/176)   | (3/85)  | (3/490) |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 14.6%    |           |         |         |   | 18.9%       |   | 3.2%      |
| (38/261) |           |         |         |   | (17/90)     |   | (1/31)    |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 8.4%     | 2.3%      | 0%      | 2.6     |   | 10% (9/90)  |   | 3.2%      |
| (22/261) | (4/176)   | (0/85)  | (       |   |             |   | (1/31)    |
|          |           |         | 13/490) |   | 2% (2/90)   |   |           |
| 1.5%     | 6.3%      | 3.5%    |         |   |             |   | 0% (0/31) |
| (4/261)  | (11/176)  | (3/85)  |         |   | 6% (6/90)   |   |           |
|          |           |         |         |   |             |   | 3% (1/31) |
| 5.5%     |           |         |         |   | 1.1% (1/90) |   |           |
| (14/261) |           |         |         |   |             |   | 0% (0/31) |
|          |           |         |         |   |             |   |           |
| 1.5%     |           |         |         |   |             |   |           |
| (4/261)  |           |         |         |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 6.1%     |           |         | 1.6%    |   | 8.9% (8/90, |   | 0 (0/31)  |
| (16/261) |           |         | (8/490) |   | 7           |   |           |
|          |           |         |         |   | i           |   |           |
|          |           |         |         |   | psilateral) |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 1.5%     |           |         | 1.4%    |   |             |   |           |
| (4/261)  |           |         | (7/490) |   |             |   |           |
|          |           |         |         |   |             |   |           |
| 0%       |           |         | 0.2%    |   |             |   |           |
| (0/261)  |           |         | (1/490) |   |             |   |           |
|          |           |         |         |   |             |   |           |
| 1.5%     |           |         | 1.2%    |   |             |   |           |
| (4/261)  |           |         | (6/490) |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| **Effec  |           |         |         |   |             |   |           |
| tiveness |           |         |         |   |             |   |           |
| Me       |           |         |         |   |             |   |           |
| asures** |           |         |         |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 95.8%    | 96.6%     | 94.0%   | 94.7%   |   |             |   |           |
| (        | (170/176) | (79/84) | (4      |   |             |   |           |
| 249/260) |           |         | 14/437) |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 90.4%    | 89.8%     | 91.7%   | 93.8%   |   |             |   |           |
| (        | (158/176) | (77/84) | (4      |   |             |   |           |
| 235/260) |           |         | 08/435) |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 92.3%    | 94.3%     | 88.1%   | 94.3%   |   |             |   |           |
| (        | (166/176) | (74/84) | (4      |   |             |   |           |
| 240/260) |           |         | 10/435) |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 86.7%    | N/A       | 86.7%   | 95.7%   |   |             |   |           |
| (78/90)  |           | (78/90) | (4      |   |             |   |           |
|          |           |         | 40/460) |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 53.8%    | N/A       | 58.3%   |         |   |             |   |           |
| (42/78)  |           | (42/78) |         |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 98.5%    | 97.5%     | 100%    |         |   |             |   |           |
| free     | Free from | Free    |         |   |             |   |           |
| from TLR | TLR       | from    |         |   |             |   |           |
|          |           | TLR     |         |   |             |   |           |
| 1.1%     |           |         |         |   |             |   |           |
| (3/261)  |           |         |         |   |             |   |           |
|          |           |         |         |   |             |   |           |
| 0.4%     |           |         |         |   |             |   |           |
| (1/261)  |           |         |         |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 0%       | 0%        | 0%      | 0.2%    |   |             |   |           |
| (0/261)  | (0/176)   | (0/85)  | (1/490) |   |             |   |           |
|          |           |         | (30-day |   |             |   |           |
| 0%       | 0%        | 0%      | rate)   |   |             |   |           |
| (0/261)  | (0/176)   | (0/85)  |         |   |             |   |           |
|          |           |         |         |   |             |   |           |
| 0%       | 0%        | 0%      |         |   |             |   |           |
| 0/261)   | (0/176)   | (0/85)  |         |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 0.4%     |           |         | 0.6%    |   |             |   |           |
| (1/261)  |           |         | (3/490) |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 6.5%     | 8.0%      | 3.5%    | 2.4%    |   |             |   |           |
| (17/261) | (14/176)  | (3/85)  | (       |   |             |   |           |
|          |           |         | 12/490) |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 10.7%    |           |         | 10.4%   |   |             |   |           |
| (28/261) |           |         | (       |   |             |   |           |
|          |           |         | 51/490) |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 3.8%     |           |         | Not     |   |             |   |           |
| (10/261) |           |         | given   |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+
| 0%       | 0%        | 0%      | Not     |   |             |   |           |
| (0/261)  | (0/176)   | (0/85)  | given   |   |             |   |           |
+----------+-----------+---------+---------+---+-------------+---+-----------+

**Clinical Review, Ronald M. Weintraub, M.D.**

**[Patient Population:]{.underline}**

Eligible patients classified as "high risk" on the basis of anatomic
and/or clinical neurologic criteria.

> [Anatomic:]{.underline} \>80% atherosclerotic stenosis of the common
> or internal carotid artery by ultrasound or angiogram
>
> [Neurologic/clinical:]{.underline} One or more TIAs, or one or more
> completed strokes, together with a \>50% of the internal or common
> carotid artery

[Both]{.underline} symptomatic and asymptomatic patients must also have
had one or more characteristics or comorbid conditions that were
considered to place them at high risk for carotid endarterectomy (CEA):
CHF, cardiac surgery within 6 weeks, recent MI, synchronous carotid and
coronary artery disease (CAD) requiring intervention, severe pulmonary
disease, contralateral carotid occlusion, contralateral laryngeal palsy,
recurrent post-CEA stenosis, post irradiation, abnormal stress test,
among others.

[Exclusionary Criteria]{.underline} included anatomic inaccessibility,
reference segmental diameter \<4mm or other anatomic contraindications,
acute neurologic ischemia or stroke within previous 24 hours, pertinent
allergies, history of coagulopathy.

**[Study Design:]{.underline}**

*Prospective, multi-center, randomized group sequential study by
Intention-to-Treat (ITT)*

-   Open, operative carotid endarterectomy

-   Carotid angioplasty and application of Cordis PRECISETM or PRECISETM
    RX Nitinol Stent System, with distal protection system

*Non-Randomized Registry*

-   A registry included those patients who met the inclusion criteria
    but were determined by the surgeon, interventionalist, and
    neurologist at each study site to be at too high a risk for carotid
    endarterectomy and therefore inappropriate for randomization. Again,
    the same clarification is needed here. The surgeon,
    interventionalist, and neurologist team determined if patients met
    entry criteria; the team did not determine if a patient was entered
    into the registry. Entry into stent registry occurred if the surgeon
    felt a patient was too high-risk for surgery. Entry into CEA
    registry occurred if the interventionalist felt a patient was
    inappropriate for stenting. This design is outlined in SAPPHIRE
    protocol and report, and was clarified during a telephone call to
    Cordis from FDA on March 22, 2004 (B. Zuckerman to J. Martin).

**[Primary Endpoints and Sample Size:]{.underline}**

[Primary Safety endpoint]{.underline} is a composite of major adverse
events (MAE) including death, any stroke, and/or myocardial infarction
at 30 days post procedure, and death and/or ipsilateral stroke between
30 (the sponsor corrected this to be 31 days) days and 12 months
post-procedure.

[Measure of Treatment Effectiveness:]{.underline} Safety and efficacy of
the stent system arm is determined by its superiority or non-inferiority
compared with the CEA arm. The 30-day MAE event rate for high-risk CEA
was estimated from previous CEA v.medical management randomized trials
(ACAS, NASCET, ECST) to be between 6% and 12%.

[Sample Size (Intention-to-Treat, i.e., all randomized consented
subjects)]{.underline}

-   CEA Arm: 167 patients

-   Stent Arm: 167 Patients

-   Stent Registry: 406 patients

-   CEA Registry: 7 patients

[Sample size ("Evaluable" Patients, i.e. randomized subjects who
actually received treatment to which they were randomized)]{.underline}

-   CEA Arm: 151 patients

-   Stent Arm: 159 patients

[Number of Centers:]{.underline} 29 American (USA) study centers

**[Major Secondary Endpoints]{.underline}**

[Secondary Safety endpoints]{.underline} include:

-   Successful stent deployment

-   Successful filter deployment

-   Endovascular access complications

-   Surgical site complications

-   Patency (\<50% stenosis) by ultrasound (US) within 48 hours, and 6,
    12, 24 and 36 months post procedure

-   Independent neurologic assessment at the same time intervals as
    above

-   Composite MAE at the same time intervals

**[Analysis of Results]{.underline}**

Analysis was performed two ways: using an intent to treat (ITT) and an
"evaluable" basis for the denominator. The ITT group consisted of all
consented and randomized subjects, whereas the "evaluable" group had a
subset of those who included only subjects who actually received the
treatment in which they were randomized.

**[Patient Characteristics]{.underline}**

["Evaluable" patients or patients withdrawn for reasons other than not
receiving randomized treatment]{.underline}

There were 24 of 334 patients that were randomized but never received
therapy. Of these, 16 had been randomized to CEA, and 8 to stent. One
patient who suffered acute hypertension and stroke during arterial
puncture and whose procedure was terminated before stent insertion,
though not included in the "randomized evaluable" patients, was
appropriately reported as a MAE (death) in the larger 167-patient ITT
arm. Twenty-one patients were withdrawn after randomization, either
because of patient request or failure to fulfill I/E criteria upon
review.

The following patients might arguably have been reported as MAEs in an
ITT series:

> Pt \# 4, suffered a stroke after randomization to stent upon admission
> to hospital.
>
> Pt \# 10, was randomized to CEA, not performed. Although referred then
> for stent, pt. died 3 days later, before stent could be implanted.

The sponsor clarified that these subjects were, in fact, included in the
ITT analysis; therefore, FDA rescinds this statement.

[Patient Characteristics and Comorbid conditions]{.underline}

Patients randomized by ITT to either CEA or Stent were compared by
patient characteristics and comorbid conditions: demographics, medical
history, risk factors, Charlson Comorbidity Index, and high risk
characteristics. These comparisons were made between the arms of the
entire cohort (167 v. 167), and also between those of each arm that were
considered "symptomatic" (50 stent v. 46 CEA). Only one comparison (2
high risk characteristics, within the symptomatic patients) reached
statistical significance (p = 0.04): CEA: 23.8% v. stent: 8.0%.

[Baseline Carotid Artery Characteristics]{.underline}

Baseline, procedural, and post-procedure angiographic characteristics of
the stent cohort are described in several Tables (7-9, pp2-179-181,
Vol.2), but I could not find equivalent baseline descriptors in the CEA
cohort. The sponsor clarified that CEA patients did not undergo
angiography as this is not normal practice for this surgical procedure.
Therefore, no such data was collected and reported. FDA amends this
language as follows: The CEA preoperative angiography results were not
obvious, and there were no early CEA postoperative ultrasound data.

**[Results: Primary Endpoints]{.underline}**

[Cumulative Percentage of MAE at 30 days (ITT Group):]{.underline}

Stent arm: 8/167, 4.8 % +/- 1.7%

CEA arm: 16/167, 9.8% +/- 2.4%

Eliminating 14 of the 16 patients randomized but withdrawn from
treatment (See above), would

yield:

For the stent arm: 9/152, 5.9%

For the CEA arm: 17/146, 11.7%

[Cumulative Percentage of MAE at 360 Days Among **Evaluable**
Patients]{.underline}

Censoring MAE events as adjudicated by the Independent Clinical Events
Committee reveals a statistical difference between the two groups: The
event rate for Stent is 12.2% +/- 2.6%. That for CEA is 20.1% +/- 3.4%.
The curves diverge (Figure 9, PMA Vol 2, p 2-382), and

P=0.048 (Log-Rank), and p=0.045 (Wilcoxon).

[Non-Inferiority at 360 Days (ITT Group):]{.underline}

MAE (Death, MI, Stroke): Stent Arm: 20/167, 12.0% CEA Arm: 32/167, 19.2%

> Difference: (95% C.I): -7.2% (-14.9%, 0.6%)
>
> Theta: 0.50764 95% C.I. (-0.03620, 1.05149)

**[Major Secondary Endpoints]{.underline}**

[Failure of Stent or Filter Delivery]{.underline}

There were eight patients in whom failure of stent delivery was
encountered. Although seven of these patients ultimately had successful
stent delivery at the index procedure, one required CEA. There were 8
additional patients in whom difficulty was encountered in either passing
or retrieving the angioguard protection device. Among these 16 patients,
7 were found to have 50-70% stenoses either immediately post-procedure,
or by US at the first re-evaluation.

[Endovascular Access or Surgical Site Complications]{.underline}

These were few in number in both stent and CEA arms. These are not
described in detail.

Stent access site complications: 2 major vascular requiring
intervention, 6 hematomas, 4 pseudoaneurysms, 1 A-V fistula, 1 infection
for a total complication rate of 8%.

CEA surgical site complications: 1 major vascular, 3 hematomas, 7
cranial nerve injuries (usually hypoglossal), 1 infection, for a total
complication rate of 7%.

[Patency by Ultrasound at 48 hours, and 6, 12, 24, and 36
months]{.underline}

Post-procedure residual stenosis or restenosis, as measured by peak
velocity (PSV) and end diastolic velocity (EDV) showed no difference
between the treatment arms. At 6 months, however, both PSV and EDV were
higher in the CEA arm (p=0.03 and 0.01, respectively). At one year PSV
was still higher in the CEA group (p=0.03), though the difference in PDV
did not reach statistical significance. Two and three-year results are
not included in the original PMA.

[Neurologic follow-up at one year]{.underline}

Of 26 patients not seen for follow-up at one year, 4 had expired, 11 had
withdrawn or refused follow-up, 3 were too ill to return and 6 were lost
to follow up. Review of the Excel spread sheets shows generally good
compliance.

**[Review of Deficiencies (amendments to the PMA)]{.underline}**

**[Significant Deficiency]{.underline}**

*FDA Question: For demonstration of reasonable assurance of safety and
efficacy, it is critical to show a sustained benefit (\> one year) of
your device. In fact, your protocol stipulates\...that patients will be
followed for three years. A substantial number of patients from your
feasibility study, randomized trial, high-risk registry, and OUS CASCADE
study are presently beyond the one-year time point. Therefore, please
provide detailed longer-term data (\> one year) for these cohorts in
order to demonstrate sustained safety and efficacy.*

Summary of response: Of the 121 patients entered into the [CASCADE
study]{.underline}, 68 were followed for 12 months. The sponsor states
that four further strokes occurred between the one and 6-month
intervals. There were no further TIAs. There were two other deaths, not
considered device-related, that occurred during this interval. The
sponsor states that there were no further strokes between 6 and 12
months. Neurologic examinations were not complete. There were 112
performed at discharge, 94 at one month, 98 at six months, and 68 at one
year. The sponsor states that "No further follow-up was required for the
CASCADE study".

The sponsor supplied MAE data for those patients in the randomized stent
and CEA arms of the SAPPHIRE trial followed for two years, for the
SAPPHIRE stent registry to two years, and the feasibility study out to
three years.

[For the SAPPHIRE randomized arms]{.underline}, 2-year data are
presented in two ways. In the first, if an event (even death) occurred
in a patient without a 2-year contact, it did [not]{.underline} appear
in the rate table. In the other, since events may have been recorded on
patients that did not have a 2-year contact, the sponsor provided data
on the entire patient populations. For the randomized arms, the MAE
rates are 19.2% (stent) v. 26.7% (CEA), and death rates are 14.4%
(stent) v. 20.9% (CEA). The differences did not reach statistical
difference.

Similarly, for the SAPPHIRE randomized arms, cumulative ipsilateral
stroke rates at 2 years were 5.9% (stent) v. 5.8% (CEA), and the MI
rates were 6.0% (stent) v. 8.7% (CEA), with no statistical difference
between groups.

With respect to restenosis at 2 years (for those patients having US
studies), the stent restenosis rate was 13/75=17.3% v. 6/45=13.3% for
CEA (p=NS).

[In the SAPPHIRE Stent Registry,]{.underline} the cumulative MAE rate
was 26.4% at two years.

The restenosis rate among those patients examined at two years was
47/138, or 34.1%.

[For the feasibility study]{.underline} patients followed for three
years, the MAE rate was 21.8% and 13.9%, depending on the method of
calculation (see above). The sponsor was confused by these numbers. In
fact, upon re-review, these represent MAE and death, respectively, at
1080 days.

2 Year Adverse Events Rates

  -------------------- --------------- ----------------- -----------------
  **STUDY ARM**        **MAE**         **IPSILAT         **RESTENOSIS**
                                       STROKE**          

  **RANDOM STENT**     19.2%           5.9%              38.7% (IVS)

  **RANDOM CEA**       26.7%           5.8%              26.6% (IVS)

  **REGISTRY STENT**   26.4%           9.3%              34.1% (IVS)

  **FEASIBILITY        16.8%           8.7%              22.7% (IVS)
  STENT**                                                
  -------------------- --------------- ----------------- -----------------

**[Minor Deficiencies (FDA questions in italics)]{.underline}**

*#1) For the randomized cohort line listing\...please include (the
information with respect to previous surgery or de novo stenting), and
stratify the analysis by de novo and post-endarterectomy subjects for
those receiving a stent.*

The sponsor supplied the requested information. There were 127 patients
with *de novo* stenosis, and 37 who had post-endarterectomy stenosis.
Cumulative MAE at one year were 17/127=13.7% and 3/37=8.2%,
respectively. The cohorts were also compared with respect to lesion
success, procedure success, in-vessel and in-stent stenosis at 360 days,
major and minor ipsilateral stroke at 360 days, and major bleeding.
Though some of the numbers are small, there were no statistical
differences between cohorts.

*#2) Please supply the same analysis as in #1 above to the cohort of
feasibility subjects*

The sponsor supplied the requested data. There were 194 patients who
received stents for *de novo* lesions, and 59 who received stents for
post-endarterectomy lesions. MAE rates at 360 days for *de novo* and
post-endarterectomy lesions were 21/194= 10.8% and 5/59=8.5%,
respectively. As in the previous comparisons there were no statistical
differences between groups with respect to death, major or minor
ipsilateral strokes or bleeding complications at 360 days.

*#3) Please stratify patients with respect to anatomic versus co-morbid
risk factors for both the pivotal and feasibility cohorts.*

The sponsor states that insufficient data for the requested analysis had
been collected for the feasibility study.

The patients in the randomized arms were stratified by anatomic and
medical (co-morbid) criteria. There were few statistical differences
between group. When stratified anatomically, there were more patients
with history of cardiac arrhythmias in the surgical group (8/35=22.9%)
than in the stent arm (1/36=2.8%), p=0.01. There were more patients with
previous CABG in the stent group (18/39=46.2%) than in the surgical
group (8/35=22.9%), p=0.05. Of particular interest, there was no
difference between arms with respect to previous CEA. When classified by
medical high risk, there were no statistical differences between groups.

There were significant differences in MAE at 360 days when patients were
stratified by anatomic and medical criteria. The anatomic high-risk
patients had an MAE rate of 10.3% for stented patients, and 5.6% for CEA
patients, whereas patients stratified by medical high risk
co-morbidities had rates of 14.5% and 23.1% for stented and CEA
patients, respectively. The differences were accounted for largely by a
higher death and coronary atherosclerosis deaths.

*#4) Please provide an interpretation of the data collected on patients
in the stent and CEA registries in terms of how they could be utilized
to provide evidence for the safety and effectiveness of the stent
relative to CEA.*

Only 7 patients were entered into the CEA arm of the registry. The
sponsor states, with reason, that the number is too small for meaningful
interpretation. The sponsor also states that the 406 patients in the
stent arm of the registry "included those patients who met the criteria
for SAPPHIRE, but were determined by the surgeon at each site to be at
too high risk for carotid endarterectomy, and therefore inappropriate
for randomization". The sponsor documents 5 clinical characteristics
that were statistically more prevalent in the stent registry than in the
randomized CEA cohort: angina class CC III or IV, prior CEA, Previous
CEA with recurrent stenosis, history of stroke, and patients with 2 risk
factors. The sponsor compared the MAE rate for this presumably higher
risk group of patients (15.8%) with that of the randomized CEA cohort
(19.2%) and found no statistical difference (p=0.33).

#5) Adequate data should be provided for all stent models and sizes that
you intend to market. The 5mm size was not represented in any cohort,
and other sizes had minimal representation. Please provide data for this
size.

The sponsor provides data for all stent sizes. Of a total 896 stents
implanted, only 4 were of 5mm. At the larger end, only 2 were 7-10mm
tapered.

**[Commentary]{.underline}**

[Primary Endpoint]{.underline}

The rate of MAE in stented patients at 360 days (12.2% +/-2.6) was lower
than that of CEA (20.1% +/-3.4%), almost reaching statistical
significance (p=0.053).

[Secondary Endpoints]{.underline}

Initial failure to deliver the stent or difficulty in delivering or
retrieving the protection device led to a high incidence (approximately
50%) of post procedure high-grade stenosis. The sponsor wanted to add
the following clarification: Device success in the Sapphire protocol was
defined as an achievement of \<30% diameter stenosis by **angiography**
post-revascularization procedure. For patients that had an initial
failure to deliver the stent, or difficulty retrieving the protection
device, the post procedure diameter stenosis was \<30% in all but one
patient (Patient 34 -- Failed to deliver stent and converted to CEA).
Regarding the comments from the Ultrasound Core lab that appear in the
narratives for those patients: Peak systolic velocities are often mildly
to moderately increased during the early post-revascularization period
(prior to reaching hemodynamic baseline). Early in the conduct of the
trial, those increases in velocity were interpreted as an increase in
diameter stenosis. This was discovered as longer term follow up showed
velocities in those same patients had stabilized. There were relatively
few complications related to either the surgical or vascular access
sites. There was a steady, but significant restenosis rate with time in
both stent and CEA arms, though there was no significant difference
between arms. Neurologic follow up was reasonably complete.

[Response to Deficiencies]{.underline}

The sponsor has supplied data to one-year and two-year follow-up for the
randomized arms, and for the stent registry arm. Three-year data was
presented for the feasibility arm. Data for the CASCADE study was not
available beyond one year. There were no differences between randomized
stent and CEA arms with respect to MAE or restenosis at two years.
Nevertheless, the two-year MAE and ipsilateral stroke rates are
substantial in both randomized arms, as well as the registry stent arm:

\*Total In-Vessel Stenosis

For the Feasibility cohort, the 3-year MAE rate was 13.9% +/-2.9% or
21.8% +/-3.5%, depending on the censoring method (See Amendment #2, Dec.
30, 2003, p6.)

There are no statistically significant differences between compared
groups. Even among those groups not directly compared there is a
noticeable similarity.

With respect to comparisons between those patients receiving stent
treatment for *de novo* versus post-CEA stenosis, there appear to be no
significant differences in results with respect to death, major or minor
ipsilateral stroke, or bleeding. This was true in both the randomized
and feasibility cohorts.

Stratification of the randomized cohorts by anatomic versus medical high
risk also demonstrated that stent implantation was not inferior to CEA,
but those patients classified as high-risk by medical comorbidities had
significantly greater rates of MAE in [both]{.underline} randomized arms
when compared with those patients classified by anatomic severity. There
was a high percentage of asymptomatic patients in **all** groups
(377/740 =51%). Of the patients receiving a stent in the randomized arm
and in the registry, 331/573=58% were asymptomatic. In the registry
alone over 2/3 of patients were asymptomatic (281/406=69%), yet the
30-day MAE event rate was 6.9%.

The sponsor employs OPC criteria derived from the NASCET trial (NEJM
1991; 325:445-453), but this study enrolled patients that were both
symptomatic (neurologically: TIA or non-disabling stroke within 120
days) and had high-grade ipsilateral carotid stenosis (75-99%).

*[Question #1]{.underline}: Please derive OPC hypothesis from ACAS study
of CEA v. medical therapy in asymptomatic patients ([JAMA]{.underline}
1995; 273:1421), or from the ECTS study severe stenosis cohort
([Lance]{.underline}t 1991; 337: 1235-43) for comparison. FDA should
clarify that the sponsor was not asked this question; we thought it
would be best left up for discussion by the Panel, and if such analyses
are deemed appropriate, we can ask for such an analysis.*

The number of stents implanted at the smallest and largest diameters is
very small. Presumably, the larger diameter is not likely to present
hemodynamic problems, but the smallest size (5mm) could be problematic.

*Question #2: Please submit such data that exist specifically for those
patients who had 5mm stents implanted, specifically MAE and ultrasound
at the specified time frames. In the absence of such data, please
consider a PMA supplement when such data become available. FDA should
clarify that we posed this question differently to the sponsor; we asked
them to provide data for this size, or a justification for including
this size. The sponsor responded that the 5mm stent was utilized in the
registry and feasibility studies in 4 patients \[4/896 (0.45%)\]. In
addition, the following points were presented as justification to
consider this size:*

> *-Although the majority of patients required stents in the 6-8mm
> diameter range, other sizes provided treatment for varying patient
> anatomies and lesion locations.*
>
> *-Reliability and PPQ testing demonstrates that 5mm stents are
> comparable to 8mm stents for radial and chronic outward force.*
>
> *-PRECISE stents have similar open area, ranging from 82.5% to 89.5%,
> are constructed of identical material, and have minimal foreshortening
> (\<10%). And, 5-8mm PRECISE stents have identical design.*

Statistician Memos (original PMA and amendments, plus answers to
statistical questions)

## Introduction

The devices under review are the PRECISE^TM^ Nitinol Stent System,
PRECISE^TM^ RX Nitinol Stent System, ANGIOGUARD^TM^ XP emboli capture
guidewire, and ANGIOGUARD^TM^ RX emboli capture guidewire, sponsored by
Cordis Corporation. The clinical study (SAPPHIRE), conducted under IDE,
has multiple components. It consists of a multicenter, prospective,
randomized clinical trial, initially designed as a group sequential
trial, in which patients are randomly assigned to treatment with carotid
endarterectomy (control group) or the investigational device system
PRECISE^TM^ Nitinol Stent System with ANGIOGUARD^TM^ XP emboli capture
guidewire (treatment group). Additionally, it also consists of a "stent
registry" and a "surgical registry". The "stent registry" is made up of
patients enrolled in the clinical study who are considered as being too
high-risk for carotid endarterectomy (CEA) and therefore not suitable
for randomization. The "surgical registry" is made up of patients
enrolled in the clinical study who are considered as being too high-risk
for stenting and therefore not suitable for randomization. There are 334
randomized patients, 167 in the treatment group and 167 in the control
group (8 patients in the treatment group and 16 patients in the control
group did not receive the assigned treatment). The randomized clinical
trial was conducted in such a way that the original group sequential
protocol was neither followed (for reasons unclear to this reviewer) nor
replaced by an alternative protocol. The sponsor asked that we amend our
review memo to include the following: On March 26, 2004, Cordis provided
FDA with a much more detailed description of why the group sequential
analysis was not conducted and it has been explained by our expert
consultants that a trial stopped for administrative reasons does not
require an alternative analysis. However, we maintain that the decision
not to follow the protocol was made much earlier than the decision to
stop the trial, that these two issues are separate, and that we still do
not understand the reason for not following the original sequential
protocol. The trial was discontinued on June 11, 2002, due to "slow
enrollment, the unwillingness of surgeons to refer patients, competing
non-randomized trials, and waning physician interest in randomizing
patients". There are 406 patients in the stent registry and 7 patients
in the surgical registry. Cordis is not aware of any patients who turned
down entry into the stent or surgical registries.

## Statistical Issues

The clinical protocol specified two primary endpoints: 1) composite of
major adverse clinical events including death, any stroke, and/or
myocardial infarction at 30 days post procedure, and 2) the same 30 day
composite of major adverse clinical events plus death and/or ipsilateral
stroke between 31 days and 12 months post-procedure (copied from page
45, Volume 2 of the PMA). The sponsor asked that we provide the
following clarification regarding their primary endpoints: It is
acknowledged by Cordis that the study endpoint was unusual in that the
components of the composite endpoint change over time. However, it is
important that we do not confuse it as 2 endpoints. The study had one
primary endpoint that consists of a composite of clinical events at 360
days. In the randomized clinical trial, the statistical hypothesis for
the primary endpoints is formulated in terms of a parameter θ, defined
by the quantity φ(t)=-log(-log(1-p~E~(t)))+log(-log(1-p~C~(t))), where
p~E~(t) and p~C~(t) are the probabilities of an adverse event
constituting the primary endpoints in the first t months in the
treatment and control groups respectively. It is assumed that
φ(1)=φ(12), and the common value is denoted by θ. The clinical protocol
specified that if a 95% confidence interval (based on data from the
randomized clinical trial) for θ includes only values greater than
-0.240, then the investigational device system used for the treatment
group can be declared as non-inferior to CEA (administered to the
control group). The 95% confidence interval for θ reported in the PMA is
\[-0.03620, 1.05149\], supporting the declaration of non-inferiority.
The sponsor was requested to submit detailed computational steps for
this confidence interval. Attached to this review memo is the document
that the sponsor has submitted so far in response to FDA's request for
detailed computational steps for the confidence interval for θ.

The randomized trial has at least two remarkable features in its design
and conduct. With regard to the study design, it does not have a set of
inclusion/exclusion criteria in the usual sense, in that patients
enrolled in the study are subjectively selected into the randomized
trial. Consequently, the patient population of which the randomized
clinical trial is representative may not have a precise, objective, and
consistent definition. With regard to the study implementation, the
original group sequential protocol was neither followed nor replaced
with an alternative protocol. On both features the sponsor was requested
to provide comments. The sponsor's comments are summarized below.

The sponsor agreed that the population used for the randomized trial may
not have a precise definition, and proposed to address this issue in the
summary of safety and effectiveness (SSE) by describing the
distributions of high-risk factors, demographic variables, and lesion
characteristics for the randomized and registry patients. At the same
time, the sponsor also argued that the results of the randomized study
may be generalized to a broad population, by claiming that many
high-risk factors have similar distributions among the randomized and
stent registry patients, that the treatment effect seems not to depend
on some of the high-risk factors, and that the event rate constituting
the primary endpoint is similar in the randomized stent arm and the
stent registry.

The sponsor does not consider the deviation from the initial group
sequential protocol to be a problem for the randomized trial. In
particular, the sponsor argued that the statistical inference can be
conducted for the randomized trial as though it had had a protocol that
had pre-specified the sample size to be 334 (167 per treatment arm), the
sample size at which the trial was discontinued. A justification given
by the sponsor for this approach is that no interim analyses had been
performed (following the original group sequential protocol).

In the original PMA submission the sponsor made a straightforward
comparison between the outcomes of the patients in the stent registry
and those randomized to CEA. In the initial FDA deficiency letter for
the original PMA it was pointed out that such straightforward
comparisons are not meaningful and do not constitute an interpretation
of data; in particular, they cannot be used directly as evidence for the
safety and effectiveness of the investigational stent system relative to
CEA. In response, the sponsor stated that there are several risk factors
that are more prevalent in the stent registry than in the randomized CEA
arm, and still the primary endpoint of the rate of major adverse events
at 12 months is not significantly different between the stent registry
(15.8%) and the randomized CEA arm (19.2%). The sponsor stated: "We
believe that this comparison can be utilized to provide evidence for the
safety and effectiveness of the stent relative to CEA".

At this point, FDA reminded the sponsor that comparing the stent
registry with the randomized CEA arm is an instance of observational
study. For a comparison to be acceptable as evidence, at least an
observational study using appropriate methods needs to be completed. In
response, the sponsor proposed to conduct a propensity score analysis on
the groups of stent registry and randomized CEA arm. Upon receiving this
proposal, FDA made a few comments with regard to some options and
opportunities for the sponsor to consider. The FDA pointed out that the
propensity score analysis may be applied to the stent registry and the
entire group of randomized patients, since it was not obvious that the
sponsor had considered this option. The FDA brought to the sponsor's
attention that the fact that the entire group of randomized patients was
randomly divided into the stent and the CEA arms may be taken advantage
of to enrich the results of the proposed propensity score analysis. The
FDA also mentioned the opportunity for the sponsor to use the results of
the propensity score analysis to address the issue of generalizing the
results of the randomized trial to an objectively defined population.
Currently the response to those suggestions has not been submitted to
this reviewer.

The analysis planned in the original protocol for the stent registry is
the comparison of the rate of major adverse events consisting of death,
any stroke and/or MI on the first 30 days and death or ipsilateral
stroke to 12 months post-procedure to an objective performance criterion
(OPC). The null hypothesis is the above event rate being no lower than
the OPC plus a margin (δ) of 4%. Non-inferiority to OPC can be declared
upon rejection of the null hypothesis. The OPC was chosen to be 15% for
patients with co-morbidities and 11% for patients with unfavorable
anatomic conditions. The overall OPC, which is the weighted average of
the above two values, is 12.94% for the stent registry. With an observed
event rate of 15.8%, the null hypothesis is not rejected (p=0.2899), and
hence non-inferiority to OPC cannot be declared.

## Statistical Reviewer's Main Concerns

-   The randomized study was originally designed as a group sequential
    clinical trial, but the group sequential protocol was not followed
    and an alternative protocol had not been developed. To what extent
    would the statistical inference involving the results of the
    randomized study be affected by the fact that the original group
    sequential protocol was neither followed nor replaced by an
    alternative protocol?

-   Has the sponsor made attempts to address the issue of generalizing
    the results of the randomized trial to an objectively defined
    population through valid analyses of the SAPPHIRE trial data, and to
    what extent are those attempts successful?

## APPENDIX: The sponsor's response to the request to submit detailed computational steps for the confidence interval for θ 

**Calculation of a point estimate and confidence interval for the
treatment effect following observation of interval-censored survival
data**

The primary analysis has focused on the incidence of major adverse
events, including death, stroke, or myocardial infarction within either
one month or one year. The one-month and one-year adverse event rates
are combined by considering the data as interval-censored survival data,
with the number of patients experiencing adverse events after one month
and at the end of one year being recorded. In the analysis, the time of
the event is set to be one month for all events occurring within the
first month and one year for all events occurring within months 2 to 12.
Patients who do not have an event within the first year are considered
censored at 12 months.

If we denoting by *p~E~*(*t*) and *p~C~*(*t*) the probability of an
event in the first *t* months on the experimental and control treatments
respectively, a measure of the treatment efficacy up to time *t* is

*ϕ*(*t*) = −log(−log(1−*p~E~*(*t*))) + log(−log(1−*p~C~*(*t*))) (1)

for t equal to 1 and 12. The statistical model assumes that this
treatment difference is equal at times 1 and 12. The common value, which
will be denoted by θ, is therefore a measure of the overall treatment
difference.

If the hazards of adverse events on the experimental and control arms
are proportional, the quantity ϕ(t) is constant over time, with
exp(--ϕ(t)) equal to the hazard ratio. The assumption that ϕ(1) = ϕ(12)
is, however, considerably less restrictive than the assumption of
proportional hazards.

A method for the calculation of a point estimate and confidence interval
for θ is described by Whitehead (see Whitehead and Thomas, 1997, and
Whitehead, 1997, Section 3.5). This is based on the calculation of the
efficient score and observed Fisher's information for θ, which will be
denoted by Z and V respectively.

Suppose that n~1E~ and n~1C~ are the numbers of patients in the
experimental and control groups respectively for whom one-month data are
available, with n~1~ = n~1E~ + n~1C~, and n~2E~ and n~2C~ are the
numbers of patients in the experimental and control groups who did not
experience an adverse event during the first month and for whom 12 month
data are available, with n~2~ = n~2E~ + n~2C~. Using similar notation,
let f~1E~, f~1C~, f~2E~ and f~2C~ denote the numbers of one-month and
12-month adverse events in the experimental and control groups, with
f~1~ = f~1E~ + f~1C~ and f~2~ = f~2E~ + f~2C~. The test statistics Z and
V are then given by

*Z = q*~1~ *( n*~1*E*~ *f*~1*C*~ *-- n*~1*C*~ *f*~1*E*~*)/n*~1~ *+ q*~2~
*( n*~2*E*~ *f*~2*C*~ *-- n*~2*C*~ *f*~2*E*~*)/n*~2~ (2)

and

*V = q*~1~^2^ *(n*~1~ *-- f*~1~*) n*~1*E*~ *n*~1*C*~ */ n*~1~ *f*~1~ *+
q*~2~^2^ *(n*~2~ *-- f*~2~*) n*~2*E*~ *n*~2*C*~ */ n*~2~ *f*~2~ (3)

where q~i~ = --log(1 -- f~i~/n~i~) for i = 1,2.

For small values of θ and a large sample size, Z is normally distributed
with mean θV and variance V (see Scharfstein, Tsiatis and Robins, 1997).
An approximate maximum likelihood estimate of θ is thus given by

> ![](media/image1.wmf) = Z/V. (4)

Since, conditional on the observed value of V, this estimate is
asymptotically normally distributed with variance 1/V, an approximate
confidence interval is given by

(![](media/image2.wmf) -- 1.96 /√V, ![](media/image3.wmf) + 1.96 /√V).
(5)

It is the confidence interval (5) that has been reported, and on which
the non-inferiority claim is based.

**References**

Scharfstein, D.O., Tsiatis, A.A. and Robins, J.M. (1997) Semiparametric
efficiency and its implications on the design and analysis of
group-sequential studies. Journal of the American Statistical
Association, **92**, 1342-1350.

Whitehead, J. (1997) The Design and Analysis of Sequential Clinical
Trials. Wiley, Chichester.

Whitehead, J. and Thomas, P. (1997) A sequential trial of pain killers
in arthritis: Issues of multiple comparisons with control and of
interval-censored survival data. Journal of Biopharmaceutical
Statistics, **7**, 333-353.