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™ Express2™
Paclitaxel-Eluting Coronary Stent System (CSS) in the following patient
population:
patients with de novo native coronary artery lesions > 10 mm and £ 28mm in length and ³ 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 108mg to 209mg. 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 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
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™
Stent |
Express™
Stent |
p-value |
|
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™ Stent |
Express™ Stent |
p-value |
|
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 SR formulation (n=31) |
TAXUS II SR Cohort (n =131) |
TAXUS
II MR Cohort (n =135) |
|
Time point of analysis |
2
years |
12
months |
12
months |
|
MACE |
3.0% (1/31) |
10.9% (14/129) |
9.9% (13/131) |
|
Stent
Thrombosis to 30 days |
0% (0/31) |
0.8% (1/131) |
0.0% (0/135) |
|
Stent
Thrombosis (through
time-point of analysis) |
0% (0/31) |
1.5% (2/131) |
0.7% (1/135) |
* “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
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?
The proposed labeling
currently states in Section 2, Indications:
The TAXUS™ Express2™
Paclitaxel-Eluting Coronary Stent System is indicated for improving luminal
diameter and reducing restenosis for the treatment of de novo lesions < 28mm in length in native coronary
arteries > 2.5 to ≤ 3.75mm in diameter.
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™ Express2™
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.