# DRAFT - Questions for Discussion 

### Circulatory System Devices Panel

**TAXUS™ Paclitaxel-Eluting Coronary Stent System**

**P030025**

**November 20, 2003**

#### Evaluation of Safety and Effectiveness

The sponsor has conducted a multi-center, double-blinded, randomized,
clinical investigation, referred to as the TAXUS IV Trial (N = 1326 at
76 sites; 12 subjects "deregistered") with the TAXUS™ Express^2^™
Paclitaxel-Eluting Coronary Stent System (CSS) in the following patient
population:

> patients with *de novo* native coronary artery lesions
> [\>]{.underline} 10 mm and 28mm in length and 2.5mm and 3.75mm in
> diameter (by visual estimate).

The stent sizes available for implantation in the TAXUS IV \[slow
release (SR) formulation\] study were the 2.5mm, 3.0mm and 3.5mm
diameter stents in lengths of 16 mm, 24 mm, and 32 mm, which meant that
the nominal drug dosage per stent ranged from 108g to 209g. The average
vessel diameter in the study was 3.05 mm ± 0.35 mm (for the TAXUS™ stent
arm) and the average stented lesion length was 21.79 mm ± 7.79 mm (for
the TAXUS™ stent arm). The control (uncoated Express™ stent) device is
approved for use in *de novo* lesions with diameters 3.0mm to 5.0mm.

For this PMA application, the sponsor is requesting approval for use in
the following patient population with the stent sizes designated in
Table 1:

> patients with *de novo* native coronary artery lesions (length 28mm)
> and reference vessel diameters ranging from 2.5mm to 3.75mm.

**[Evaluation of Safety]{.underline}**

The pathology findings from the animal studies submitted in the
application noted endothelial coverage of the stent, no structural
deterioration of the coronary artery wall, and an absence of thrombus,
which correspond with the clinical findings from TAXUS I, II and IV.
However, the animal studies also revealed marked histologic changes in
the media (i.e., smooth muscle cell loss, ingrowth of fibrous tissue,
neovascularization, dystrophic calcification) in the vessel wall. In
addition, parastrut amorphous material or "PAM" (also identified as
"drug effect," strut fibrin, and thrombus within the study reports) was
noted. These findings were more pronounced in the MR formulation versus
the SR formulation that is proposed for commercialization. The degree of
response appeared to correlate with increasing dose, with the least
response occurring in the animals implanted with the SR formulation.

These findings were present at all time points, including 180 and 360
days, but appeared to be resolving over time, and did not result in
structural deterioration of the coronary wall.

Although FDA generally recommends that long-term animal studies include
follow up to 180 days, it is unknown how findings present at this time
point would correlate with the human clinical experience because healing
progresses at a faster rate in the nonatherosclerotic swine model.

> **1. Does the combination of 9 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?**

The potential for interactions with several drugs has been described in
the Taxol® Directions for Use. Interactions with other drugs might be
expected based on known drug metabolism.

> **2a. Are the clinical studies presented adequate to address concerns
> about possible adverse effects from interactions with drugs typically
> administered to the target patient population?**
>
> **2b. 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:**
>
> **i. with anti-neoplastic agents**
>
> (E.g., cardiac toxicities have been noted when doxorubicin HCl is
> combined with paclitaxel; however, from the literature, FDA is unaware
> of any reports to date of paclitaxel-eluting stents enhancing
> doxorubicin HCl cardiac toxicity.)
>
> **ii. with chemotherapeutic agents, where a hypersensitivity reaction
> could be induced**

The safety endpoints evaluated in the TAXUS IV (SR formulation) study
included:

  ----------------------------- -------------- --------------- -------------
  **Safety endpoint\***         **TAXUS™       **Express™      **p-value**
                                Stent**        Stent**         

  MACE to 270 days              8.5% (56/662)  15.0% (98/652)  0.0002\*\*

  Stent thrombosis to 30 days   0.3% (2/662)   0.6% (4/652)    0.4487

  Stent thrombosis to 270 days  0.6% (4/662)   0.8% (5/652)    0.7513
  ----------------------------- -------------- --------------- -------------

\* Rates presented as number of patients with events per number of
patients in analysis.

\*\*statistically significant

  --------------------------------------------------------------------------
  **Incomplete Apposition**\*   **TAXUS™       **Express™      **p-value**
                                Stent**        Stent**         
  ----------------------------- -------------- --------------- -------------
  Post procedure                11.6% (13/112) 6.4% (7/109)    0.2415

  To 270 days                   4.0% (4/99)    3.0% (3/100)    0.7209

  Paired Data                                                  

  Resolved                      6.4% (6/94)    5.4% (5/93)     1.0000

  Persistent                    3.2% (3/94)    1.1% (1/93)     0.6210

  Late Acquired                 1.1% (1/94)    2.2% (2/93)     0.6210
  --------------------------------------------------------------------------

\*Rates are presented as number of patients with incomplete apposition
per number of patients with IVUS at the relevant timepoint.

Safety information available from TAXUS I (SR formulation), and TAXUS II
(SR and MR formulations) included:

+---------------------------+-------------+--------------+------------+
| **Safety Endpoint\***     | **TAXUS I** | **TAXUS II** | **TAXUS    |
|                           |             |              | II**       |
|                           | SR          | SR Cohort    |            |
|                           | formulation |              | MR Cohort  |
|                           |             | (n =131)     |            |
|                           | (n=31)      |              | (n =135)   |
+---------------------------+-------------+--------------+------------+
| **Time point of           | **2 years** | **12         | **12       |
| analysis**                |             | months**     | months**   |
+---------------------------+-------------+--------------+------------+
| MACE                      | 3.0% (1/31) | 10.9%        | 9.9%       |
|                           |             | (14/129)     | (13/131)   |
+---------------------------+-------------+--------------+------------+
| Stent Thrombosis to 30    | 0% (0/31)   | 0.8% (1/131) | 0.0%       |
| days                      |             |              | (0/135)    |
+---------------------------+-------------+--------------+------------+
| Stent Thrombosis          | 0% (0/31)   | 1.5% (2/131) | 0.7%       |
|                           |             |              | (1/135)    |
| (through time-point of    |             |              |            |
| analysis)                 |             |              |            |
+---------------------------+-------------+--------------+------------+

\* "Rates" presented as number of events per number of patients in
analysis.

> **3. 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 formulations) studies, provide
> reasonable assurance of safety?**

**[Evaluation of Effectiveness]{.underline}**

The primary effective endpoint for the TAXUS IV (SR formulation) study
was target vessel revascularization (TVR) at 9 months (270 days). Rates
of TVR at 270 days were 4.7% (31/662) for the TAXUS™ group and 12.0%
(78/652) for the Express™ control group.

> **4. Does the clinical data at 270 days presented on the TAXUS™ stent
> from the pivotal TAXUS IV study provide reasonable assurance of
> effectiveness?**

**[Labeling]{.underline}**

One aspect of the pre-market evaluation of a new product is the review
of its labeling. The labeling must indicate which patients are
appropriate for treatment, identify potential adverse events with the
use of the product, and explain how the product should be used to
maximize benefits and minimize adverse effects.

The proposed labeling currently states in Section 2, Indications:

> The TAXUS™ Express^2^™ Paclitaxel-Eluting Coronary Stent System is
> indicated for improving luminal diameter and reducing restenosis for
> the treatment of *de novo* lesions [\<]{.underline} 28mm in length in
> native coronary arteries [\>]{.underline} 2.5 to ≤ 3.75mm in diameter.

The proposed indication represents a change from the bare Express^2TM^
Coronary Stent System indication because it includes the phrase
"reducing restenosis."

> **5a. Does the evidence presented on the TAXUS™ product support the
> proposed labeling indication?**

The TAXUS IV (SR formulation) clinical trial was designed to investigate
use of a single stent, with bailout stenting allowed. Out of the 652
patients treated with the TAXUS™ stent (SR formulation), only 44
patients had two stents placed, and 1 patient had 3 stents placed. All
patients receiving overlapping stents were included in the IVUS subset,
and no clinical concerns were noted for these patients.

The proposed labeling currently states in Section 5.2, Use of Multiple
Stents:

> The extent of the patient's exposure to drug and polymer is directly
> related to the number of stents implanted. Use of more than two TAXUS™
> Express^2^™ stents has not been fully evaluated. 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.
>
> **5b. Please comment on whether the labeling should specify that
> multiple stents should only be used for bailout purposes (e.g.,
> dissection, insufficient lesion coverage) and whether in these cases
> the shortest stent available (i.e., 8 mm) should be used.**
>
> **5c. 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.**

The labeling currently states in Section 5.1, General Precautions:

> Antiplatelet therapy is recommended for a period of 6 months
> post-procedure.

The labeling does not recommend any specific pre-procedural or
procedural anticoagulation regimens. The TAXUS IV (SR formulation) study
was designed to include mandatory aspirin ([\>]{.underline} 325mg p.o.
QD) at least 1 hour pre-procedure; clopidogrel (300mg p.o.) or
ticlopidine (500mg p.o.) pre-procedure (within 24 hours) or within 2
hours after the procedure; heparin or other procedural antithrombotics
(Abciximab, eptifibatide, and tirofiban were allowed); and clopidogrel
(75mg p.o. QD) or ticlopidine (250mg p.o. BID), and aspirin
([\>]{.underline} 325mg p.o. QD) for at least 6 months post-procedure.
Recent publications have addressed the risks and benefits of various
pre-procedural and procedural anticoagulation regimens and
post-procedural anti-platelet regimens.

> **5d. Please comment on whether the labeled recommendation for
> post-procedural antiplatelet regimen is appropriate, and whether
> additional recommendations on procedural anticoagulation regimens are
> warranted.**

**5e. Please comment on any other aspects of the product labeling, such
as:**

**i. Contraindications**

> **ii. Warnings/Precautions (such as use with brachytherapy,
> conjunction with other procedures, etc.)**

**iii. Drug pharmacology, pharmacokinetics or specific drug safety
information (e.g., use in special populations, warnings, precautions)**

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

The panel package included the available 9-month data for the TAXUS™
Express2™ product (SR formulation) in the TAXUS IV study. In addition,
the available data were provided for the TAXUS I (SR formulation - 2
year) and TAXUS II (SR & MR formulations - 1 year), and safety updates
were provided for all patients currently enrolled in the TAXUS series of
studies.

The applicant has proposed continued follow-up (to 5 years) on subjects
from the TAXUS series of studies. The applicant has also proposed to
collect data through two years on approximately 2000 patients implanted
with the marketed product, using an electronic database. This study will
consist of two phases. Phase 1 will consist of a pre-market continued
access study with up to 500 consecutive patients enrolled at 10 U.S.
sites. Phase 2 will be a post-market registry with 1500 consecutive
patients enrolled at 40 U.S. sites. Geographically diverse U.S.
community-based facilities representing a variety of annual implant
volumes will participate.

> **6. Please discuss long-term adverse effects that may be associated
> with TAXUS™ stents, and whether the proposed 5--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 patients should be followed, and what
> endpoints and adverse events should be measured.**