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DHHS/FDA/CDRH

DHHS/FDA/CDRH. Circulatory Support Devices Panel. Boston Scientific Corporation TAXUS ™ Express 2 ™ Paclitaxel-Eluting Coronary Stent System P030025 November 20, 2003. DHHS/FDA/CDRH. Overview of Presentation. FDA Review Team Product Description Non-clinical Evaluation

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DHHS/FDA/CDRH

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  1. DHHS/FDA/CDRH

  2. Circulatory Support Devices Panel Boston Scientific Corporation TAXUS™ Express2™ Paclitaxel-Eluting Coronary Stent System P030025 November 20, 2003 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 CDRHJennifer Goode, BS, Biomedical Engineer Stephen Hilbert, MD, PhD, Experimental Pathologist John Stuhlmuller, MD, Clinician Heng Li, PhD, Statistician Raju Kammula, DVM, PhD, Toxicologist Lee Schroeder, PhD, Lead Polymer Chemist Carolyn Vaughan, BS, Mechanical Engineer Lisa Kennell, BS, Microbiologist Steve Wood, PhD, Molecular Biologist Walter Scott, PhD, Patient Labeling Kent Berthold, Manufacturing Hesha Duggirala, PhD, Epidemiologist Sybil Wellstood, PhD, Bioresearch Monitoring DHHS/FDA/CDRH

  5. FDA Review Team CDERNallaperumal Chidambaram, PhD, Chemist Angelica Dorantes, PhD, Pharmacokineticist Belay Tesfamariam, PhD, Toxicologist DHHS/FDA/CDRH

  6. Regulatory History • PMA (P030025) filed on June 19, 2003 • Major Deficiency Letter sent to applicant on September 15, 2003 • Applicant began submitting responses on September 30, 2003 • Interactions continue to resolve outstanding non-clinical issues DHHS/FDA/CDRH

  7. Product Description • Combination Product • Express™ balloon-expandable 316L SS stent • Elective: 3.0 to 5.0mm Ø & up to 18 mm in length • Approved September 11, 2002 NOTE: Does not include an indication for “reducing restenosis” • Catheter delivery systems • Express2™ OTW • Express2™ Monorail NOTE: Slightly different design from the Express™ delivery systems used in TAXUS IV trial DHHS/FDA/CDRH

  8. Product Description • Polymer coating • Translute Non-erodible polymer • Drug substance • Paclitaxel – FDA approved • Leveraged initial drug safety data from Drug Master File (Indena S.p.A.) DHHS/FDA/CDRH

  9. Product Description • TAXUS SR • Proposed product to be marketed • 1 g/mm2 slow release formulation • Used in animal trials and TAXUS I, II, and IV • TAXUS MR • 1 g/mm2 moderate release formulation • Used in animal trials and TAXUS II DHHS/FDA/CDRH

  10. Proposed TAXUS™ Stent Matrix & Nominal Drug Dosage Sizes used in TAXUS IV study Nominal polymer dosages (same across all stent diameters) DHHS/FDA/CDRH

  11. 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

  12. Major OutstandingNon-Clinical Issues • Animal study results • Stability/Shelf life • Finalizing protocols and QC specifications with sponsor • Adequate product has been set aside for testing DHHS/FDA/CDRH

  13. Proposed Indications for Use The TAXUS™ Express2™ Paclitaxel-Eluting Coronary Stent Systems (Monorail and Over-the-Wire) are indicated for improving luminal diameter and reducing restenosis for the treatment of de novo lesions < 28 mm in length in native coronary arteries > 2.5 to < 3.75 mm in diameter. DHHS/FDA/CDRH

  14. Non-Clinical In Vivo Studies Stephen L Hilbert MD, PhD Cardiac Support and Prosthetic Devices Branch Center for Devices & Radiological Health DHHS/FDA/CDRH

  15. Animal Model Justification • Normal swine • Comparable vascular and cardiac anatomy • Vessel diameters suitable for the delivery and deployment of the clinical version of the device • Allows for comparison to historical data DHHS/FDA/CDRH

  16. Non-Clinical In Vivo StudiesSpecific Aims • Device handling characteristics • Safety • Device-tissue responses • General healing response • Device-related pathology • Device-specific findings DHHS/FDA/CDRH

  17. Non-Clinical In Vivo StudiesExperimental Design • Deployment to all three coronary arteries • Dual antiplatelet regimen (ASA + clopidogrel) • 72 hours before implantation through implant duration • Targeted artery-to-balloon ratio • 1:1 to 1:1.2 • Implant duration • 28 to 360 days DHHS/FDA/CDRH

  18. Non-Clinical In Vivo StudiesExperimental Design • Stent platforms evaluated • Bare metal stent • Polymer - coated metal stent • Polymer - drug coated metal stent • Drug dose density - 1 ug/mm2 • MR formulation • SR formulation DHHS/FDA/CDRH

  19. Non-Clinical In Vivo StudiesGraded Pathology Assessment • Mural thrombus • Endothelialization • Neointima • Luminal narrowing • Para-strut amorphous material (PAM) • Medial remodeling • IEL disruption • EEL disruption • Inflammatory response DHHS/FDA/CDRH

  20. Non-Clinical In Vivo StudiesMorphometric Measurements • Luminal area • IEL area • EEL area • Neointimal area • Lumen equivalent diameter • Intimal thickness • Medial area • Stent profile • % stenosis DHHS/FDA/CDRH

  21. Non-Clinical In Vivo Studies Applicable to Safety for This PMA • Bare metal stent • Polymer - coated metal stent • Polymer - drug coated metal stent • Safety Margin • MR - 1 ug/mm2 • Overlapping Stents • MR - 1 ug/mm2 • SR - 1 ug/mm2 DHHS/FDA/CDRH

  22. Non-Clinical In Vivo Studies Study Observations • Similarities in findings across stent platforms • Neointimal formation • Endothelialization • No mural thrombosis • Inflammatory response DHHS/FDA/CDRH

  23. Non-Clinical In Vivo Studies Study Observations • Similarities in findings across stent platforms • Medial remodeling • In-growth of fibrous tissue • Loss of smooth muscle cells • Morphometric measurements • Stable EEL and luminal areas • Reflect medial remodeling DHHS/FDA/CDRH

  24. Non-Clinical In Vivo Studies Study Observations • Differences in findings across stent platforms • Qualitative differences • Medial remodeling • PAM • Dystrophic calcification DHHS/FDA/CDRH

  25. Non-Clinical In Vivo Studies Study Observations • Differences in findings across stent platforms • Magnitude of differences associated with: • Release formulation • MR > SR > polymer, bare metal • Segmental Analysis • Overlapping > Non-overlapping DHHS/FDA/CDRH

  26. Non-Clinical In Vivo Studies Summary • Device handling characteristics satisfactory • Device-tissue response is satisfactory • Neointimal formation • Endothelialization • No mural thrombus DHHS/FDA/CDRH

  27. Non-Clinical In Vivo Studies Summary • Device-related pathology • Medial remodeling • PAM appears to be resolving with time through 360 days • Microscopic dystrophic calcification is variably present • Vessel wall remains structurally intact DHHS/FDA/CDRH

  28. Advisory Panel Question Does the combination of 9 month clinical data from the pivotal TAXUS IV (SR formulation) study and the adjunctive data from TAXUS I (SR formulation) and TAXUS II (SR and MR formulations) adequately address the potential concerns raised by the animal studies? DHHS/FDA/CDRH

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

  30. Clinical Studies • Pivotal Study • TAXUS IV • Supporting Studies • TAXUS I • TAXUS II • TAXUS V • Peri-Approval Study DHHS/FDA/CDRH

  31. Clinical Studies • Pivotal Study • TAXUS IV • Supporting Studies • TAXUS I • TAXUS II • TAXUS V • Peri-Approval Study DHHS/FDA/CDRH

  32. TAXUS IVStudy Design • Prospective, multicenter and blinded • 1:1 randomization to TAXUS™ stent (SR formulation) or EXPRESS™ stent • Stratified Randomization • 6 month post-procedure antiplatelet regimen DHHS/FDA/CDRH

  33. TAXUS IVStudy Design Stent Length (mm) Stent diameter (mm) 2.50 3.00 3.50 16 24 32 Single Stent Use Small diameters (< 3.0 mm) Long lesions (32 mm stent) Large diameters Not available Multiple Stent Use Provisional overlapping for bail-out stenting DHHS/FDA/CDRH

  34. TAXUS IVPatient Outcome Assessment • Effectiveness • Target Vessel Revascularization at 9 months • Safety • MACE • Stent Thrombosis • Vessel wall structure DHHS/FDA/CDRH

  35. TAXUS IV Patient Outcome Assessment Primary Effectiveness Endpoint TAXUS™ Control Difference [95% C.I.] p-value TVR 4.7% (31/662) 12.0%(78/652) -7.3%[-10.2%, -4.3%] 0.0001

  36. TAXUS IV Patient Outcome Assessment Safety Endpoints Safety Endpoint TAXUS Control p-value MACE to 270 days 8.5% (56/662) 15.0% (98/652) 0.0002 Stent thrombosis to 30 days 0.3% (2/662) 0.6% (4/652) 0.4487 Late thrombosis to 270 days 0.6% (4/662) 0.8% (5/652) 0.7513

  37. TAXUS IV Patient Outcome Assessment Safety Endpoints Incomplete Apposition TAXUS™ Control p-value Post Procedure 11.6% (13/112) 6.4% (7/109) 0.2415 To 270 Days 4.0% (4/99) 3.0% (3/100) 0.7209 Paired Data Resolved 6.4% (6/94) 5.4% (5/93) 1.0000 Persistent 3.2% (3/94) 1.1% (1/93) 0.6210 Late Acquired 1.1% (1/94) 2.2% (2/93) 0.6210

  38. Clinical Studies • Pivotal Study • TAXUS IV • Supporting Studies • TAXUS I • TAXUS II • TAXUS V • Peri-Approval Study DHHS/FDA/CDRH

  39. TAXUS IStudy Design • Prospective, randomized, multicenter and blinded clinical feasibility study • A total of 61 patients enrolled at 3 centers in Germany • NIRx Paclitaxel-Eluting Stent (SR formulation) • Primary study endpoints • MACE at 30 days • Angiographic restenosis at 6 months • Follow-up through 2 years completed DHHS/FDA/CDRH

  40. TAXUS IPatient Outcome Assessment • Effectiveness • Persistent drug effect is maintained through 2 years by angiography and IVUS assessments • Safety • Vessel wall remains structurally intact at 2 years • No safety issues noted DHHS/FDA/CDRH

  41. Clinical Studies • Pivotal Study • TAXUS IV • Supporting Studies • TAXUS I • TAXUS II • TAXUS V • Peri-Approval Study DHHS/FDA/CDRH

  42. TAXUS II Study Design • Prospective, randomized, OUS multicenter, and blinded • NIRx Paclitaxel-Eluting Stent • TAXUS II SR Cohort • 267 patients at 28 centers in 12 countries • TAXUS II MR Cohort • 270 patients at 28 centers in 12 countries • Primary study endpoints • MACE at 6 months • Angiographic restenosis at 6 months • Follow-up through 1 year completed DHHS/FDA/CDRH

  43. TAXUS II SR CohortPatient Outcome Assessment • Effectiveness • Clinical benefit maintained at 1 year • Safety • Vessel wall remains structurally intact in the TAXUS arm compared to control arm at 6 months • No safety issues noted DHHS/FDA/CDRH

  44. TAXUS II MR CohortPatient Outcome Assessment • Effectiveness • Clinical benefit maintained at 1 year • Safety • Vessel wall remains structurally intact in the TAXUS arm compared to control arm at 6 months • No safety issues noted DHHS/FDA/CDRH

  45. TAXUS II SR vs. TAXUS II MRPatient Outcome Assessment • Effectiveness • Similar clinical benefit at 1 year • Safety • Similar vessel wall measurements by angiography and IVUS at 6 months • TAXUS II MR provides preliminary clinical evidence of safety margin for SR formulation • No safety issues noted DHHS/FDA/CDRH

  46. Clinical Studies • Pivotal Study • TAXUS IV • Supporting Studies • TAXUS I • TAXUS II • TAXUS V • Peri-Approval Study DHHS/FDA/CDRH

  47. TAXUS V Study Design • Prospective, multicenter and blinded • 1:1 randomization to TAXUS™ (SR formulation) stent or EXPRESS™ stent • Smaller diameters and longer lesions • Single or overlapping stents DHHS/FDA/CDRH

  48. TAXUS VPatient Outcome Assessment • Study remains blinded • 30-day follow-up on 1080 of 1103 patients enrolled to date • Safety • Total of 122 MACE events • 10 episodes of stent thrombosis in 8 patients • Acute-3, subacute-6 and late-1 • No safety issues noted with broader range of stent use DHHS/FDA/CDRH

  49. Clinical Studies • Pivotal Study • TAXUS IV • Supporting Studies • TAXUS I • TAXUS II • TAXUS V • Peri-Approval Study DHHS/FDA/CDRH

  50. TAXUSPeri-Approval Study • Proposed enrollment of 2000 patients • Phase I – 500 patients • Continued Access Protocol under IDE • Assess format and function of web-based registry • Phase II – 1500 patients • Post-approval web-based registry DHHS/FDA/CDRH

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