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DHHS/FDA/CDRH

DHHS/FDA/CDRH. FDA Summary. CYPHER ™ 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

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DHHS/FDA/CDRH

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  1. DHHS/FDA/CDRH

  2. FDA Summary CYPHER™ Sirolimus-Eluting Coronary Stent System Cordis Corporation PMA Application: P020026 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 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 DHHS/FDA/CDRH

  5. 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

  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 Sizes used in SIRIUS & RAVEL studies Nominal polymer dosages DHHS/FDA/CDRH

  10. 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 DHHS/FDA/CDRH

  11. 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 DHHS/FDA/CDRH

  12. 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. DHHS/FDA/CDRH

  13. 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 1.5-2.1% lower than TVF • Changed Protocol-defined MI to WHO MI Definition • Lowered rates 4-5% DHHS/FDA/CDRH

  20. Influence of Angiographyon 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) DHHS/FDA/CDRH

  25. SIRIUS: TVF forQCA RVD > 3.0 mm DHHS/FDA/CDRH

  26. 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

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  31. 9-Month TVF inLesion Length Subgroups DHHS/FDA/CDRH

  32. 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. Late Malapposition DHHS/FDA/CDRH

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

  36. SIRIUS: Extent of IVUS F/U DHHS/FDA/CDRH

  37. SIRIUS: Malapposition DHHS/FDA/CDRH

  38. RAVEL: Malapposition DHHS/FDA/CDRH

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

  40. 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

  41. De novo Small Vessel Substudy R. Murty Ponnapalli, Ph.D. CDRH Division of Biostatistics Cardiovascular & Ophthalmics Team DHHS/FDA/CDRH

  42. 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

  43. 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 model with non-informative priors for the parameters DHHS/FDA/CDRH

  44. 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

  45. Bayesian Statistics Scientifically valid way of combining prior information & comparing it with current data Assign prior probabilitiesto 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

  46. 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

  47. Estimated MACE Probabilities from Hierarchical Model DHHS/FDA/CDRH

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