# Presentation: 219923

## DHHS/FDA/CDRH

## FDA Summary

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

- DHHS/FDA/CDRH

## Overview of Presentation

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

- DHHS/FDA/CDRH

## FDA Review Team

- DHHS/FDA/CDRH

**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
- 	Belay Tesfamariam, PhD

## 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)**

- 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**

- DHHS/FDA/CDRH

## Product Description

**Combination Product**
**Bx Velocity****TM 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**
- RaptorTM OTW (used during SIRIUS study)
- RaptorRailTM RX

- 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)

- DHHS/FDA/CDRH

## Proposed CypherTM Sirolimus-Eluting CSS Matrix & Nominal Drug Dosage

- DHHS/FDA/CDRH

| Stent Diameter (mm) | Stent Length |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | 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**

## Non-clinical Evaluation

- DHHS/FDA/CDRH

**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**

## Major Outstanding Non-clinical Issues

- DHHS/FDA/CDRH

***In vitro***** elution methodology**
- Characterization of product tested clinically
- Validate consistency in manufactured product
- Establish stability
**Stability/Shelf life**
**Modification to coating process**

## Proposed Indications for Use

** **

- DHHS/FDA/CDRH

**The Cypher****TM 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.  **

## 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)**

- DHHS/FDA/CDRH

## Efficacy Issues

**Randomization / Blinding**
- Both Used A-B Scheme
- Envelopes used in RAVEL
- Quality of Blinding Unknown
- ~4% “Deregistration” in SIRIUS

- DHHS/FDA/CDRH

## Efficacy Issues (cont)

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

- DHHS/FDA/CDRH

## Efficacy Issues (cont)

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

- DHHS/FDA/CDRH

## Safety Issues

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

- DHHS/FDA/CDRH

**Notes:**
Potential drug issues with longer length, larger diameter stents?

## 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%

- DHHS/FDA/CDRH

## Influence of Angiographyon Target Vessel Failure (TVF)

** **

- DHHS/FDA/CDRH

## 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) **

- DHHS/FDA/CDRH

## SIRIUS: Freedom from TVF

## RAVEL: Freedom from TVF

## SIRIUS Primary Analysis:Target Vessel Failure (TVF)

|  | CypherTM
N = 533 | ControlN = 525 | p |
| --- | --- | --- | --- |
| 9 Months | 8.9% | 21.4% | <.001 |
| 7 1⁄2 Months | 6.0% | 13.1% | <.001 |

- DHHS/FDA/CDRH

## SIRIUS: TVF forQCA RVD > 3.0 mm

|  | CypherTM
N = 161 | ControlN = 180 | p |
| --- | --- | --- | --- |
| 9 Months | 5.0% | 16.9% | <.001 |
| 7 1⁄2 Months | 4.3% | 10.6% | <.031 |

- DHHS/FDA/CDRH

## Lesion Length

** **

- DHHS/FDA/CDRH

## 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**

- DHHS/FDA/CDRH

## DHHS/FDA/CDRH

- DHHS/FDA/CDRH

- DHHS/FDA/CDRH

## 9-Month TVF inLesion Length Subgroups

| Length Subgroup | TotalN | CypherTM | Control | p |
| --- | --- | --- | --- | --- |
| > 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 |

- 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)**

- DHHS/FDA/CDRH

## Late Malapposition

** **

- DHHS/FDA/CDRH

## Late Malapposition

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

- DHHS/FDA/CDRH

## SIRIUS: Extent of IVUS F/U

|  | CypherTM | 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 |

- DHHS/FDA/CDRH

## SIRIUS: Malapposition

|  | CypherTM | 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% |

- DHHS/FDA/CDRH

## RAVEL: Malapposition

|  | CypherTM | Control  |
| --- | --- | --- |
| Malapposition at Follow-up (~6 months) | 21% | 4% |

- DHHS/FDA/CDRH

## Current Extent of Follow-up

**SIRIUS (N=1058):  **_**>**_** 9 Months**
**RAVEL (N=238):  **_**>**_** 1 Year**
**FIM (N=45):  **_**>**_** 2 Years**

- 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**

- 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

- DHHS/FDA/CDRH

## Summary of Design and Analysis of Substudy

- DEVICE: CypherTM 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 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)

- DHHS/FDA/CDRH

## 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***

- 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

- DHHS/FDA/CDRH

## Estimated MACE Probabilities from Hierarchical Model

| ARM | TRIAL | Prob.
(MACE) |
| --- | --- | --- |
| Treatment | CypherTM product (370 patients) | 7.6% |
| Historical
Controls | Posterior mean of controls | 24.4% |
|  |          Benestent I (120 patients) | 33.6% |
|  |          Benestent II (201 patients) | 24.4% |
|  |          Stress (108 patients) | 23.2% |

- DHHS/FDA/CDRH

## Summary from Bayesian Hierarchical Model

- The probability of MACE with the CypherTM 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 CypherTM product than with balloon angioplasty (posterior mean of controls)

- 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 CypherTM MACE rate is better than balloon angioplasty remains greater 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 CypherTM product MACE rate is better than balloon angioplasty
- Analysis is relatively insensitive to effects of unmeasured covariates

- DHHS/FDA/CDRH

## Panel Questions

**CYPHER****TM Sirolimus-Eluting **
**Coronary Stent System**
**P020026**

- DHHS/FDA/CDRH

## Evaluation of Safety

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

| Safety Endpoint | CypherTM Product | Bare Bx VelocityTM 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) |

- DHHS/FDA/CDRH

## 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. **
**	**

- 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 ****	****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.**

- DHHS/FDA/CDRH

## 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. **
**	**

- 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 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.**

- DHHS/FDA/CDRH

## Evaluation of Safety

**In the SIRIUS study, the Cypher****TM 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 CypherTM 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.**
**	**

- 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?**

- DHHS/FDA/CDRH

## 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****TM product.**

- DHHS/FDA/CDRH

## 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?**

- DHHS/FDA/CDRH

## 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****TM group and 21.0% (110/525) for the Bx VelocityTM control group.**
**	**
**	****Does the evidence presented on ****the Cypher****TM product provide reasonable assurance of effectiveness at 270 days?**

- DHHS/FDA/CDRH

## 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****TM 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.**
**	**

- 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****TM product.**

- DHHS/FDA/CDRH

## 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.****  **
**	**
**	**

- 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 CypherTM 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?**

- DHHS/FDA/CDRH

## 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?**

- DHHS/FDA/CDRH

## 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).  **

- 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?**

- DHHS/FDA/CDRH

## 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.  **
**	**
**	**

- 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?**

- 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.**

- 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.**

- 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.**

- DHHS/FDA/CDRH

## Post-Market Evaluation

**The Panel Package included the available 9-month data for the Cypher****TM 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.  **
**	**

- DHHS/FDA/CDRH

## Post-Market Evaluation

**	****a.****	****Please discuss long-term adverse effects that may ****	****be associated with implantation of the Cypher****TM ****	****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****TM 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?****	**

- DHHS/FDA/CDRH

## DHHS/FDA/CDRH