1 DHHS/FDA/CDRH

2 FDA Summary CYPHER™ Sirolimus-Eluting Coronary Stent System Cordis Corporation PMA Application: P October 22, 2002 DHHS/FDA/CDRH

3 Overview of Presentation FDA Review Team Product Description Non-clinical Evaluation Clinical & Statistical Evaluation Panel Questions DHHS/FDA/CDRH

4 FDA Review Team DHHS/FDA/CDRH CDRHJonette 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 CDERXiao-Hong Chen, PhD Patrick Marroum, PhD Belay Tesfamariam, PhD

5 Regulatory History PMA Modular Shell – M 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

6 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

7 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 DHHS/FDA/CDRH

8 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

9 Proposed Cypher™ Sirolimus-Eluting CSS Matrix & Nominal Drug Dosage DHHS/FDA/CDRH Stent Diameter (mm) Stent Length 8 mm13 mm18 mm23 mm28 mm33 mm  g 208  g 111  g150  g190  g229  g268  g 790  g  g111  g150  g190  g229  g268  g  g111  g150  g190  g229  g268  g  g111  g150  g190  g229  g268  g  g129  g175  g 520  g 221  g268  g314  g  g129  g175  g221  g268  g314  g  g164  g223  g281  g340  g399  g  g 488  g 223  g281  g340  g399  g 1184  g Sizes used in SIRIUS & RAVEL studies Nominal polymer dosages

10 Non-clinical Evaluation DHHS/FDA/CDRH Pharmacology/Toxicity Testing In vivo (Animal) Testing ISO Biocompatibility of stent + polymer only Stent/Delivery System Integrity Testing Shelf Life/Stability Coating Integrity Sterility & Package Integrity Testing

11 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

12 Proposed Indications for Use DHHS/FDA/CDRH 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.

Clinical & Statistical Summary John Hyde, Ph.D., M.D. Interventional Cardiology Devices Branch Center for Devices & Radiological Health DHHS/FDA/CDRH

14 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

15 Efficacy Issues Randomization / Blinding Both Used A-B Scheme Envelopes used in RAVEL Quality of Blinding Unknown ~4% “Deregistration” in SIRIUS DHHS/FDA/CDRH

16 Efficacy Issues (cont) Influence of Angiography on Target Vessel Failure (TVF) Effect of Lesion Length Effect of Vessel Diameter DHHS/FDA/CDRH

17 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

18 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

19 Other Issues MACE Definition Excluded TVR that was not TLR MACE is % 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

21 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

22 SIRIUS: Freedom from TVF

23 RAVEL: Freedom from TVF

24 SIRIUS Primary Analysis: Target Vessel Failure (TVF) Cypher™ N = 533 Control N = 525 p 9 Months8.9%21.4% < ½ Months 6.0%13.1% <.001 DHHS/FDA/CDRH

25 SIRIUS: TVF for QCA RVD > 3.0 mm Cypher™ N = 161 Control N = 180 p 9 Months 5.0%16.9% < ½ Months 4.3%10.6% <.031 DHHS/FDA/CDRH

Lesion Length DHHS/FDA/CDRH

27 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

28 DHHS/FDA/CDRH

29 DHHS/FDA/CDRH

30 DHHS/FDA/CDRH

31 9-Month TVF in Lesion Length Subgroups Length Subgroup Total NCypher™Controlp > %43%.091 > %33%.008 > %24%.048 > %19%.190 All10589%21%.001 DHHS/FDA/CDRH

Vessel Diameter DHHS/FDA/CDRH

33 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

34

35

36

Late Malapposition DHHS/FDA/CDRH

38 Late Malapposition Seen in both RAVEL and SIRIUS No apparent clinical correlate Follow-up adequate? DHHS/FDA/CDRH

39 SIRIUS: Extent of IVUS F/U Cypher™Control Assigned to IVUS subset Baseline Qual. Studies Month Qual. Studies Both Base & F/U Qual DHHS/FDA/CDRH

40 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% DHHS/FDA/CDRH

41 RAVEL: Malapposition Cypher™Control Malapposition at Follow-up (~6 months) 21%4% DHHS/FDA/CDRH

42 Current Extent of Follow-up SIRIUS (N=1058): > 9 Months RAVEL (N=238): > 1 Year FIM (N=45): > 2 Years DHHS/FDA/CDRH

43 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

45 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

46 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 ( ), 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

47 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 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

49 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

50 Estimated MACE Probabilities from Hierarchical Model ARMTRIAL Prob. (MACE) Treatment Cypher™ 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

51 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) DHHS/FDA/CDRH

52 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% DHHS/FDA/CDRH

53 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 DHHS/FDA/CDRH

54 Panel Questions CYPHER™ Sirolimus-Eluting Coronary Stent System P DHHS/FDA/CDRH

55 Evaluation of Safety 1.The safety endpoints evaluated in the SIRIUS study included: Do the data submitted on the Cypher™ product provide adequate assurance of safety? Safety EndpointCypher™ Product Bare Bx Velocity™ Stent MACE to 270 days7.1% (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

56 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 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

57 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

58 Evaluation of Safety 2.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

59 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

60 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. DHHS/FDA/CDRH

61 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

62 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. DHHS/FDA/CDRH

63 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 about possible systemic adverse drug effects? DHHS/FDA/CDRH

64 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? DHHS/FDA/CDRH

65 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. DHHS/FDA/CDRH

66 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. DHHS/FDA/CDRH

67 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. DHHS/FDA/CDRH

68 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? DHHS/FDA/CDRH

69 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? DHHS/FDA/CDRH

70 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). DHHS/FDA/CDRH

71 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

72 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. DHHS/FDA/CDRH

73 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

74 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

75 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

76 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

77 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. DHHS/FDA/CDRH

78 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? DHHS/FDA/CDRH

79 DHHS/FDA/CDRH