1
DHHS/FDA/CDRH
FDA Summary
CYPHER™ Sirolimus-Eluting
Coronary Stent System
Cordis Corporation
PMA Application: P020026
2 October 22, 2002
DHHS/FDA/CDRH
Overview of Presentation
• FDA Review Team
• Product Description
• Non-clinical Evaluation
• Clinical & Statistical Evaluation
• Panel Questions
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DHHS/FDA/CDRH
FDA Review Team
CDRH Jonette Foy, PhD, Lead Reviewer
John Hyde, MD, PhD, Lead Clinician
Donald Jensen, DVM, MS
Neal Muni, MD, MSPH
Murty Ponnapalli, PhD, Statistician
Doyle Gantt, MS
Scott McNamee, PhD
John Glass, MPH, MLA, Compliance
Rodney Allnutt, Bioresearch Monitoring
CDER Xiao-Hong Chen, PhD
Patrick Marroum, PhD
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Belay Tesfamariam, PhD
DHHS/FDA/CDRH
Regulatory History
• PMA Modular Shell – M020005
• M1 – Quality Systems & Manufacturing
Controls
• M1/A1 – Chemistry, Manufacturing &
Controls (CMC)
• M2 – Non-clinical Testing (bench, animal,
biocompatibility, etc.) & Interim Clinical
Summary of SIRIUS study (N = 400) &
Final Report for RAVEL study (N = 238)
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DHHS/FDA/CDRH
Regulatory History
• PMA (P020026) filed on June 28, 2002
• All modules were still open & review
continued as part of PMA application
• Major Deficiency Letter sent to applicant
on September 18, 2002
• Applicant submitted response to Agency
on October 21, 2002
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DHHS/FDA/CDRH
Product Description
• Combination Product
• Bx Velocity™ balloon-expandable 316L SS stent
• Elective: 3.0 to 5.0mm Ø & 8 to 33 mm in length
• Approved February 1, 2001
• AC/TAC: 2.25 to 4.0mm Ø & 8 to 33 mm in length
• Approved May 11, 2000
• Catheter delivery systems
• Raptor™ OTW (used during SIRIUS study)
• RaptorRail™ RX
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DHHS/FDA/CDRH
Product Description (cont)
• Polymer coating
• Layered mixture of non-erodible polymers
• Drug-free topcoat to influence drug release
kinetics
• Drug substance
• Sirolimus – FDA approved
• Leveraged initial drug safety data from NDA
(Wyeth Pharmaceuticals)
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DHHS/FDA/CDRH
Proposed Cypher™ Sirolimus-Eluting
CSS Matrix & Nominal Drug Dosage
Stent Stent Length
Diameter 8 mm 13 mm 18 mm 23 mm 28 mm 33 mm
(mm)
2.25 71 g 111 g 150 g 190 g 229 g 268 g
208 g 790 g
2.5 71 g 111 g 150 g 190 g 229 g 268 g
2.75 71 g 111 g 150 g 190 g 229 g 268 g
3.0 71 g 111 g 150 g 190 g 229 g 268 g
3.5 83 g 129 g 175 g 221 g 268 g 314 g
520 g
4.0 83 g 129 g 175 g 221 g 268 g 314 g
4.5 105 g 164 g 223 g 281 g 340 g 399 g
5.0 164 g 223 g 281 g 340 g 399 g
488 g 1184 g
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Sizes used in SIRIUS & RAVEL studies
Nominal polymer dosages DHHS/FDA/CDRH
Non-clinical Evaluation
• Pharmacology/Toxicity Testing
• In vivo (Animal) Testing
• ISO 10993 Biocompatibility of stent + polymer only
• Stent/Delivery System Integrity Testing
• Shelf Life/Stability
• Coating Integrity
• Sterility & Package Integrity Testing
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DHHS/FDA/CDRH
Major Outstanding Non-clinical Issues
• In vitro elution methodology
• Characterization of product tested clinically
• Validate consistency in manufactured product
• Establish stability
• Stability/Shelf life
• Modification to coating process
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DHHS/FDA/CDRH
Proposed Indications for Use
The Cypher™ Sirolimus-Eluting Coronary
Stent System is indicated for improving
coronary luminal diameter in patients with
symptomatic ischemic disease due to discrete
de novo lesions (length 30 mm) in native
coronary arteries with a reference vessel
diameter of 2.25 mm to 5.0 mm.
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DHHS/FDA/CDRH
Clinical & Statistical Summary
John Hyde, Ph.D., M.D.
Interventional Cardiology Devices Branch
Center for Devices & Radiological Health
DHHS/FDA/CDRH
Supporting Clinical Data
• SIRIUS (N=1058)
• Strongly positive clinical 1° endpoint
• RAVEL (N=238)
• Strongly positive angiography 1° endpoint
• Supporting clinical
• PK (N=19)
• FIM (First-in-Man) (N=45)
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DHHS/FDA/CDRH
Efficacy Issues
• Randomization / Blinding
• Both Used A-B Scheme
• Envelopes used in RAVEL
• Quality of Blinding Unknown
• ~4% “Deregistration” in SIRIUS
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DHHS/FDA/CDRH
Efficacy Issues (cont)
• Influence of Angiography on
Target Vessel Failure (TVF)
• Effect of Lesion Length
• Effect of Vessel Diameter
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DHHS/FDA/CDRH
Efficacy Issues (cont)
• Effectiveness for Vessel Diameters
3.0 mm
Cypher™ Control p
N = 161 N = 180
9 Months 5.0% 16.9% 25 51 18% 43% .091
> 20 151 14% 33% .008
> 18 211 13% 24% .048
> 16 307 13% 19% .190
All 1058 9% 21% .001
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DHHS/FDA/CDRH
Vessel Diameter
DHHS/FDA/CDRH
Reference Vessel Diameter
• SIRIUS target range 2.5 – 3.5 mm
• 80% of cases were 2.2 – 3.4 mm
• Issue: Confidence in extrapolation to
large vessels (small vessels is separate
issue)
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DHHS/FDA/CDRH
Logistic Linear Regression Model for
Binary Restenosis vs. QCA RVD
50%
Control Cypher
Binary Restenosis
40%
30%
20%
10%
0%
2.0 2.5 3.0 3.5 4.0
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QCA RVD (mm)
Logistic Quadratic Regression Model for
9-Month TVF vs. QCA Vessel Diameter
35%
Control Cypher
30%
9-Month TVF Rate
25%
20%
15%
10%
5% 80% of Cases
Target Range
0%
2.0 2.5 3.0 3.5 4.0
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QCA Reference Vessel Diameter (mm)
Logistic Quadratic Regression Model for
7 1/2-Month TVF vs. QCA Vessel Diameter
35%
Control Cypher
7 1/2-Month TVF Rate
30%
25%
20%
15%
10%
5% 80% of Cases
Target Range
0%
2.0 2.5 3.0 3.5 4.0
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QCA Reference Vessel Diameter (mm)
Late Malapposition
DHHS/FDA/CDRH
Late Malapposition
• Seen in both RAVEL and SIRIUS
• No apparent clinical correlate
• Follow-up adequate?
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DHHS/FDA/CDRH
SIRIUS: Extent of IVUS F/U
Cypher™ Control
Assigned to IVUS subset 132 122
Baseline Qual. Studies 105-106 93-95
8-Month Qual. Studies 96-99 71-76
Both Base & F/U Qual. 72 55
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DHHS/FDA/CDRH
SIRIUS: Malapposition
Cypher™ Control
Rate at Baseline 14% 15%
Rate at Follow-up (~8 mo) 19% 9%
Baseline vs. Follow-up
Preserved 8% 11%
Healed 8% 5%
Late 10% 0%
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DHHS/FDA/CDRH
RAVEL: Malapposition
Cypher™ Control
Malapposition at
Follow-up (~6 months)
21% 4%
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DHHS/FDA/CDRH
Current Extent of Follow-up
• SIRIUS (N=1058): > 9 Months
• RAVEL (N=238): > 1 Year
• FIM (N=45): > 2 Years
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DHHS/FDA/CDRH
Clinical Conclusions
• Overall there is evidence of safety and
effectiveness
• Extension to diameters outside 2.5 – 3.5 mm
range is less definitive
• Extension to long lesions is less definitive
• IVUS suggests abnormal remodeling, no
clinical impact seen yet
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DHHS/FDA/CDRH
De novo Small Vessel Substudy
R. Murty Ponnapalli, Ph.D.
CDRH Division of Biostatistics
Cardiovascular & Ophthalmics Team
DHHS/FDA/CDRH
Statistical Evidence for Effectiveness
• Vessel diameter > 3.0 mm
• Randomized, bare stent control
• Statistical issues covered earlier
• Vessel diameter < 3.0 mm
• 3 historical PTCA control studies
• Bayesian analysis
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DHHS/FDA/CDRH
Summary of Design and
Analysis of Substudy
• DEVICE: Cypher™ Sirolimus-eluting stent
• SUBSTUDY POPULATION: 370 patients,
RVD < 3 mm
• CONTROL: Balloon angioplasty in three historical
studies (1993-1996), 429 patients
• PRIMARY EFFECTIVENESS: Major adverse cardiac
event rate (MACE) at 9 months post-procedure
• STATISTICAL ANALYSIS: Bayesian hierarchical
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model with non-informative priors for the parameters
DHHS/FDA/CDRH
Pre-planned Subgroup Analysis
• Sponsor and FDA agreed to the use of Bayesian
methods with a historical control in this subgroup
• No FDA approved bare stent for de novo lesions in
vessels < 3mm in diameter
• Control comprised of (balloon angioplasty) data from
three previous trials by the sponsor
• Bayesian methods used to
• Combine the three controls in an appropriate way
(accounting for variability between studies)
• Compare MACE rates using logistic regression
(adjusting for important covariates)
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DHHS/FDA/CDRH
Bayesian Statistics
Scientifically valid way of combining prior
information & comparing it with current data
1. Assign prior probabilities to parameter values (e.g.,
effects in logistic regression model)
2. Update to posterior probabilities after observing
data
3. Base inferences on the posterior distribution
DHHS/FDA/CDRH
Hierarchical Model
• Bayesian method for comparing the MACE rate
in the SIRIUS study with MACE rates in several
historical studies
• Combines information from control studies,
taking variability of studies into account
• Logistic regression of MACE rates
• Covariates: RVD, lesion length, diabetes, LAD,
gender, MLD
• Assuming that prior studies are a sample from a
larger population (after covariate adjustment)
• Used “non-informative” priors for the parameters
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DHHS/FDA/CDRH
Estimated MACE Probabilities from
Hierarchical Model
Prob.
ARM TRIAL
(MACE)
Treatment Cypher™ product (370 patients) 7.6%
Posterior mean of controls 24.4%
Historical Benestent I (120 patients) 33.6%
Controls Benestent II (201 patients) 24.4%
Stress (108 patients) 23.2%
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DHHS/FDA/CDRH
Summary from Bayesian
Hierarchical Model
• The probability of MACE with the Cypher™
product is considerably less than with balloon
angioplasty in any one of the historical studies
• Posterior probability 98% that the MACE rate is
less with Cypher™ product than with balloon
angioplasty (posterior mean of controls)
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DHHS/FDA/CDRH
Sensitivity Analysis
• No randomization in the small vessel substudy
• Statistical conclusions could be sensitive to a
variable which is not taken into account in the
logistic model
• Sponsor undertook an analysis of the
sensitivity to an unmeasured covariate with an
effect on MACE
• Unless the confounding is excessive AND the
confounder has a large effect on MACE, the
probability that the Cypher™ MACE rate is
better than balloon angioplasty remains greater
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than 92%
DHHS/FDA/CDRH
Summary of Small Vessel Substudy
• Pre-planned subgroup analysis (since no
approved control)
• Pre-specified and appropriate Bayesian analysis
plan
• Posterior probability 98% that Cypher™ product
MACE rate is better than balloon angioplasty
• Analysis is relatively insensitive to effects of
unmeasured covariates
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DHHS/FDA/CDRH
Panel Questions
CYPHER™ Sirolimus-Eluting
Coronary Stent System
P020026
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DHHS/FDA/CDRH
Evaluation of Safety
1. The safety endpoints evaluated in the SIRIUS study
included:
Safety Endpoint Cypher™ Bare Bx
Product Velocity™ Stent
MACE to 270 days 7.1% (38/533) 18.9% (99/525)
Stent thrombosis to 0.2% (1/533) 0.2% (1/525)
30 days
Late thrombosis to 0.2% (1/533) 0.6% (3/525)
270 days
Do the data submitted on the Cypher™ product
provide adequate assurance of safety?
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DHHS/FDA/CDRH
Evaluation of Safety
2. The applicant has requested approval for a range of
stent diameters and lengths that corresponds to a
nominal drug dosage as high as 399g. The animal
studies conducted by the applicant on dosages
higher than 180g were limited to 30-day follow-up.
The SIRIUS study only evaluated 15 subjects who
received stents with a total nominal drug dosage
greater than 350g.
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DHHS/FDA/CDRH
Evaluation of Safety
a. Given the limited preclinical and clinical
information outlined above, please comment
on whether there is adequate evidence to
support the use of stent diameters and lengths
(i.e., 4.5mm and 5.0mm diameter with a 33mm
length) with a nominal drug dosage greater than
350g.
b. If not, what additional studies or information
would be necessary to support the safety of stents
with a nominal drug dosage greater than 350g.
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DHHS/FDA/CDRH
Evaluation of Safety
2. Additionally, the nominal amount of total polymer
ranges from 208g to 1,184 g for the currently
requested range of stent sizes. The animal studies
conducted by the applicant on polymer dosages
higher than 500g were limited to 28-day follow-up.
The nominal total polymer amounts tested in the
SIRIUS study ranged from 208g to 520g.
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DHHS/FDA/CDRH
Evaluation of Safety
c. Please comment on whether there is adequate
evidence to support the use of stent diameters
and lengths (i.e., 6-cell and 7-cell stents in lengths of
23, 28 and 33mm and 9-cell stents in lengths of 18,
23, 28 and 33mm) with a nominal polymer dosage
greater than 520g.
d. If not, what additional studies or information
would be necessary to support the safety of stents
with a nominal polymer dosage greater than
520g.
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DHHS/FDA/CDRH
Evaluation of Safety
3. In the SIRIUS study, the Cypher™ group had a
19% rate of incomplete apposition at follow-up
versus 9% for the control. This included a 10% rate
of late incomplete apposition for the Cypher™
versus 0% for the control. In the RAVEL study, the
rate of late incomplete apposition was 21% versus
4% for the control.
There was no obvious clinical correlation between
late appositions and adverse events.
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DHHS/FDA/CDRH
Evaluation of Safety
a. Please comment on whether additional
information is necessary to evaluate the
significance of the late stent malapposition found
in the clinical studies?
b. Is there any specific targeted follow-up, additional
clinical investigations, animal studies, or bench
testing that should be requested to contribute
important information regarding this clinical
finding?
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DHHS/FDA/CDRH
Evaluation of Safety
4. In the RAVEL study, subjects received ASA for 6
months and clopidogrel or ticlopodine for 2 months.
In the SIRIUS study, subjects received ASA for 9
months and clopidogrel or ticlopodine for 3 months.
Please discuss your recommendations for the
antiplatelet therapy for patients receiving the
Cypher™ product.
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DHHS/FDA/CDRH
Evaluation of Safety
5. The potential for interactions with several drugs has
been evaluated as described in the Rapamune®
labeling. Interactions with other drugs might be
expected based on known metabolism by CYP3A4.
a. Please comment on whether the application
adequately addresses drug interactions that are
likely to be important or of interest. If not, what
other information or studies should be
requested?
b. Has follow-up been adequate to address concerns
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about possible systemic adverse drug effects?
DHHS/FDA/CDRH
Evaluation of Effectiveness
6. The primary effectiveness endpoint for the SIRIUS
study was target vessel failure (TVF) at 9 months
(270 days). Rates of TVF at 270 days were 8.6%
(46/533) for the Cypher™ group and 21.0%
(110/525) for the Bx Velocity™ control group.
Does the evidence presented on the Cypher™
product provide reasonable assurance of
effectiveness at 270 days?
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DHHS/FDA/CDRH
Evaluation of Effectiveness
7. Prolonged inflammation and notably increased
restenosis were observed when polymer-coated, but
drug-free stents were implanted in swine. In swine
implanted with Cypher™ product (i.e., coated with both
drug and polymer), this effect was not observed at one
month post-implant, but was observed at both three and
six months post-implant.
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DHHS/FDA/CDRH
Evaluation of Effectiveness
Given the non-parallel timelines of healing between
juvenile normal pigs and atherosclerotic older patients,
do these findings raise significant concerns about the
ability of the clinical follow-up to address the possibility
of a similar delayed occurrence of neointimal
hyperplasia?
If so, please comment on whether additional testing or
follow-up (pre-or post-approval) is necessary to support
the effectiveness of the Cypher™ product.
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DHHS/FDA/CDRH
Evaluation of Effectiveness
8. The temporal relationship between scheduled
angiography and revascularization, and analysis of
the subgroup that did not have angiography, suggest
that angiographic outcomes may have influenced the
clinical outcomes in a way that differentially affected
the control group.
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DHHS/FDA/CDRH
Evaluation of Effectiveness
Please comment on the adequacy of the primary
endpoint (9-month TVF) for capturing the expected
clinical benefit of the Cypher™ product, in light of
the possible influence of 8-month angiography
results. Are there other ways the clinical impact
should be assessed, either for
a. evaluation of efficacy in determining the
appropriate indication, or
b. for information to be conveyed in labeling?
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DHHS/FDA/CDRH
Evaluation of Effectiveness
9. Because the control stent is not approved for de novo
stenosis in vessels of diameter less than 3.0 mm, the
applicant provided additional analyses, including a
Bayesian comparison to historical angioplasty data.
Please comment on whether adequate evidence has
been presented to demonstrate effectiveness for
stents with diameters less than 3.0 mm?
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DHHS/FDA/CDRH
Evaluation of Effectiveness
10. Univariate regression analyses of data collected in the
SIRIUS study suggest that the treatment effect may be
reduced in longer length lesions. This could be due to
either a true diminished treatment effect or a lack of
power (e.g., too few subjects) to detect a treatment
difference in subjects with longer lesions.
The applicant has performed logistic regression
analyses, but these analyses only included main effects
and did not specifically evaluate the possible interaction
between each variable (in this case, lesion length) and
the treatment effect (i.e., an analysis of treatment effect
by covariate interaction).
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DHHS/FDA/CDRH
Evaluation of Effectiveness
a. Does the data presented provide reasonable
assurance of effectiveness for the treatment of the
full requested range of lesion lengths ( 30 mm)?
b. The protocol for the SIRIUS study specified the
inclusion of subjects with reference vessel diameters
from 2.5 mm to 3.5 mm. The proposed indications
for use include reference vessel diameters of 2.25
mm as well.
Does the data presented provide reasonable
assurance of effectiveness for vessel diameters of
2.25 mm?
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DHHS/FDA/CDRH
Product Labeling
11. 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.
Please address the following questions regarding
the product labeling.
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DHHS/FDA/CDRH
Product Labeling
a. Please comment on whether the Indications for Use
statement identifies the appropriate patient
populations for treatment with this product.
1. Has the application provided reasonable assurance
of safety and efficacy for treating the full requested
range of vessel diameters (2.25 mm to 5.0 mm)?
If not the full requested range, what range of vessel
diameters should be included?
2. What length of lesions should be included in the
Indications for Use?
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DHHS/FDA/CDRH
Product Labeling
b. Please comment on the Contraindications as to
whether there are conditions under which the product
should not be used because the risk of use clearly
outweighs any possible benefit.
c. Please comment on the Warnings/Precautions sections
as to whether they adequately describe how the
product should be used to maximize benefits and
minimize adverse events.
Specifically, please comment on whether a warning or
precaution related to subsequent brachytherapy
should be included in this section.
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DHHS/FDA/CDRH
Product Labeling
d. Please comment on the Operator’s Instructions as to
whether it adequately describes how the product
should be used to maximize benefits and minimize
adverse events.
e. Please comment on what aspects of drug
pharmacology, mechanism of action,
pharmacokinetics, drug interactions, or systemic
effects should be added to the labeling to maximize
benefits and minimize adverse events.
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DHHS/FDA/CDRH
Product Labeling
f. Please comment on the remainder of the product
labeling as to whether it adequately describes how
the product should be used to maximize benefits and
minimize adverse events.
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DHHS/FDA/CDRH
Post-Market Evaluation
12. The Panel Package included the available 9-month
data for the Cypher™ product in the SIRIUS study.
In addition, the available 12-month data were
provided from the RAVEL study and the available
18- to 24-month data from the First-in-Man (FIM)
feasibility study were provided.
The applicant has proposed continued follow-up (to
5 years) on subjects from the SIRIUS, RAVEL and
the FIM studies. The applicant has also proposed to
collect data through one year on approximately
1,000 to 2,000 patients implanted with the marketed
product, using an electronic database.
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DHHS/FDA/CDRH
Post-Market Evaluation
a. Please discuss long-term adverse effects that may
be associated with implantation of the Cypher™
product including late thrombosis formation,
aneurysm formation, MI, and late stent
malapposition.
b. Based on the clinical data provided in the Panel
Package, do you believe that additional follow-up
as proposed by the applicant is appropriate to
evaluate the chronic effects of the implantation of
the Cypher™ product.
If not, what additional follow-up information
should be collected?
Specifically, how long should patients be followed
and what endpoints and adverse events should be
78 measured?
DHHS/FDA/CDRH
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DHHS/FDA/CDRH