Slide Master

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FDA Summary

• CYPHER Sirolimus-Eluting
• Coronary Stent System
• Cordis Corporation
• PMA Application P020026
• October 22, 2002

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Overview of Presentation

• FDA Review Team
• Product Description
• Non-clinical Evaluation
• Clinical Statistical Evaluation
• Panel Questions

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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 Xia
o-Hong Chen, PhD Patrick Marroum, PhD Belay
Tesfamariam, PhD
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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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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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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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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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Proposed Cypher Sirolimus-Eluting CSS Matrix
Nominal Drug Dosage
Stent Diameter (mm) Stent Length Stent Length Stent Length Stent Length Stent Length Stent Length
Stent Diameter (mm) 8 mm 13 mm 18 mm 23 mm 28 mm 33 mm
2.25 71 ?g 208 ?g 111 ?g 150 ?g 190 ?g 229 ?g 268 ?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 520 ?g 221 ?g 268 ?g 314 ?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 488 ?g 223 ?g 281 ?g 340 ?g 399 ?g 1184 ?g
Sizes used in SIRIUS RAVEL studies Nominal
polymer dosages
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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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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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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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Clinical Statistical Summary

• John Hyde, Ph.D., M.D.
• Interventional Cardiology Devices Branch
• Center for Devices Radiological Health

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Supporting Clinical Data

• SIRIUS (N1058)
• Strongly positive clinical 1 endpoint
• RAVEL (N238)
• Strongly positive angiography 1 endpoint
• Supporting clinical
• PK (N19)
• FIM (First-in-Man) (N45)

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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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Efficacy Issues (cont)

• Influence of Angiography on Target Vessel Failure
  (TVF)
• Effect of Lesion Length
• Effect of Vessel Diameter

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Efficacy Issues (cont)

• Effectiveness for Vessel Diameters lt 3.0
• Control stent not approved for de novo lesions in
  that range
• Support drawn from Bayesian analysis vs.
  historical angioplasty

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Safety Issues

• Late Malapposition
• Higher Dosages with Longer Lengths Larger
  Diameter Stents
• Overlapped Segment
• Interaction with Brachytherapy Is Not Known
• Systemic toxicities

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Other Issues

• MACE Definition
• Excluded TVR that was not TLR
• MACE is 1.5-2.1 lower than TVF
• Changed Protocol-defined MI to WHO MI Definition
• Lowered rates 4-5

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Influence of Angiographyon Target Vessel Failure
(TVF)

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Influence of Angiography on TVF

• Endpoint was mostly TVR, therefore has
  discretionary component
• Influence of angiography may dilute clinical
  meaningfulness of TVF
• Events were adjudicated
• Earlier TVF might be affected less (but fewer
  events)

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SIRIUS Freedom from TVF
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RAVEL Freedom from TVF
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SIRIUS Primary AnalysisTarget Vessel Failure
(TVF)
Cypher N 533 ControlN 525 p
9 Months 8.9 21.4 lt.001
7 ½ Months 6.0 13.1 lt.001
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SIRIUS TVF forQCA RVD gt 3.0 mm
Cypher N 161 ControlN 180 p
9 Months 5.0 16.9 lt.001
7 ½ Months 4.3 10.6 lt.031
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Lesion Length

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Lesion Length

• SIRIUS target range 15 30 mm
• 80 of cases were 8 22 mm
• TVF vs. angiography
• Issue Confidence in extension to long lesions

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9-Month TVF inLesion Length Subgroups
Length Subgroup TotalN Cypher Control p
gt 25 51 18 43 .091
gt 20 151 14 33 .008
gt 18 211 13 24 .048
gt 16 307 13 19 .190
All 1058 9 21 .001
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Vessel Diameter

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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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Late Malapposition

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Late Malapposition

• Seen in both RAVEL and SIRIUS
• No apparent clinical correlate
• Follow-up adequate?

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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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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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RAVEL Malapposition
Cypher Control
Malapposition at Follow-up (6 months) 21 4
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Current Extent of Follow-up

• SIRIUS (N1058) gt 9 Months
• RAVEL (N238) gt 1 Year
• FIM (N45) gt 2 Years

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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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De novo Small Vessel Substudy

• R. Murty Ponnapalli, Ph.D.
• CDRH Division of Biostatistics
• Cardiovascular Ophthalmics Team

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Statistical Evidence for Effectiveness

• Vessel diameter gt 3.0 mm
• Randomized, bare stent control
• Statistical issues covered earlier
• Vessel diameter lt 3.0 mm
• 3 historical PTCA control studies
• Bayesian analysis

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Summary of Design and Analysis of Substudy

• DEVICE Cypher Sirolimus-eluting stent
• SUBSTUDY POPULATION 370 patients, RVD lt 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 model
  with non-informative priors for the parameters

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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 lt 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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Bayesian Statistics

• Scientifically valid way of combining prior
  information comparing it with current data
• Assign prior probabilities to parameter values
  (e.g., effects in logistic regression model)
• Update to posterior probabilities after
  observing data
• Base inferences on the posterior distribution

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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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Estimated MACE Probabilities from Hierarchical
Model
ARM TRIAL Prob. (MACE)
Treatment Cypher product (370 patients) 7.6
Historical Controls Posterior mean of controls 24.4
Historical Controls Benestent I (120 patients) 33.6
Historical Controls Benestent II (201 patients) 24.4
Historical Controls Stress (108 patients) 23.2
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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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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 than 92

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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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Panel Questions

• CYPHER Sirolimus-Eluting
• Coronary Stent System
• P020026

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Evaluation of Safety

• The safety endpoints evaluated in the SIRIUS
  study included
• Do the data submitted on the Cypher product
  provide adequate assurance of safety?

Safety Endpoint Cypher Product Bare Bx Velocity Stent
MACE to 270 days 7.1 (38/533) 18.9 (99/525)
Stent thrombosis to 30 days 0.2 (1/533) 0.2 (1/525)
Late thrombosis to 270 days 0.2 (1/533) 0.6 (3/525)
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Evaluation of Safety

• The applicant has requested approval for a range
  of stent diameters and lengths that corresponds
  to a nominal drug dosage as high as 399?g. The
  animal studies conducted by the applicant on
  dosages higher than 180?g 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 350?g.

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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 350?g.
• b. If not, what additional studies or
  information would be necessary to support the
  safety of stents with a nominal drug dosage
  greater than 350?g.

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Evaluation of Safety

• Additionally, the nominal amount of total polymer
  ranges from 208?g to 1,184 ?g for the currently
  requested range of stent sizes. The animal
  studies conducted by the applicant on polymer
  dosages higher than 500?g were limited to 28-day
  follow-up. The nominal total polymer amounts
  tested in the SIRIUS study ranged from 208?g to
  520?g.

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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 520?g.
• d. If not, what additional studies or
  information would be necessary to support the
  safety of stents with a nominal polymer dosage
  greater than 520?g.

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Evaluation of Safety

• 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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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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Evaluation of Safety

• 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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Evaluation of Safety

• 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 about possible systemic adverse drug
  effects?

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Evaluation of Effectiveness

• 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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Evaluation of Effectiveness

• 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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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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Evaluation of Effectiveness

• 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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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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Evaluation of Effectiveness

• 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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Evaluation of Effectiveness

• 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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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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Product Labeling

• 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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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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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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Product Labeling

• d. Please comment on the Operators 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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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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Post-Market Evaluation

• 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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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 measured?

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