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Global Experience with Peripheral DCBs/Stent Studies: C.R. Bard George Papandreou, Ph.D. Vice President of Quality and Regulatory Affairs Lutonix / C.R. Bard Inc. <George Papandreou, Ph.D.> Disclosure: • I am an employee of C.R. Bard, Inc. • Bard and Advancing Lives and the Delivery of Health Care are trademarks Care are trademarks and/or registered trademarks of C. R. Bard, Inc. or an C. R. Bard, Inc. or an affiliate. All other trademarks are the property of their are the property of their respective owners. Copyright © 2017 C. R. Bard, Inc. © 2017 C. R. Bard, Inc. All rights reserved. Treatment of the PAD Patient Wires Drug Coated Balloons Sheaths Stents PTA Catheters Clinical Studies to Support PMA Products Feasibility Studies- Pivotal Studies • Probe of safety and effectiveness • Randomized against standard of care Labeling Expansion Studies • Extend device indication Post Market Studies Continued safety assurance Clinical Trial Evolution Endpoints Patients Late Lumen Loss Primary Patency Stringent inclusion/exclusion TLR Real world Patients in RCTs vs. Real-World Studies REACH1 LEVANT 22 LTX Global3 Resilient4 Age 69 67.8 68.2 68 Male 63.7% 61.1% 67.9% 70.9% BMI >30% 29.8% 34.8% 24.7% - Diabetes 43.9% 43.4% 39.5% 38.1% Hypertension 81.7% 83.2% 84.9% 83.6% Hyperlipidemia 72.1% 83.6% 70.0% 79.9% Previous CAD 53.4% 43.7% 35.6% 56.0% Previous MI 31.7% 19.9% - 20.1% Renal Failure - 3.3% 13.3% - 1 - - - 3.0% 2 - 29.4% 20.6% 35.8% 3 - 62.7% 66.9% 61.2% 4 - 7.3% 7.4% 5 - - 1.6% Rutherford Class 1-Steg et al., JAMA 2007, 297(11), 1197 2-Rosenfield et al. N. Engl J Med 2015, 373(2), 145. 3-Thieme, TCT 2015 4- Laird et al., Circ. Cardiovasc. Interv. 2010, 3, 267-276. Patients in RCTs vs. Real-World Studies LEVANT 21 LTX Global 2 Resilient3 ETAP4 6.27 + 4.14 10.12 + 8.42 7.05 + 4.43 4.13 + 3.10 SFA SFA SFA Popliteal Total Occlusions 20.6% 31.2% 17.0% 32.8% Calcification 59.2% 50.2% 35.3% - Lesion Length (cm) Lesion Location Real-world studies include a broader patient population than RCTs 1-Rosenfield et al. N. Engl J Med 2015, 373(2), 145. 2-Thieme, TCT 2015 3- Laird et al., Circ. Cardiovasc. Interv. 2010, 3, 267276. 4- Rastan, et al. Circulation 2013, 127, 2535. Lutonix® 035 DCB Indications and Clinical Trials Indicated for percutaneous transluminal angioplasty, after appropriate vessel preparation, of de novo, restenotic, or in-stent restenotic lesions up to 300mm in length in native superficial femoral or popliteal arteries with reference vessel diameters of 4-7mm. Balloon length 40-150mm Balloon diameter 4.0 – 7.0mm Lesion length Less than 15cm Less than 30 cm Studies Levant 2 Global Registry ISR US Study Long Lesion EU Study “Please consult product labels and inserts for any indications, contraindications, hazards, warnings, precautions, and directions for use.” Lutonix ® 035 Feasibility Studies • LEVANT 1 feasibility study was performed to confirm safety and drug effect of the Lutonix DCB. • Randomized study results supported CE Mark (2011). Study Name LEVANT 1 Treatment SFA Study Type Randomized, Europe Subjects 101 total 49 – DCB 52 - POBA Primary Endpoint Primary endpoint: Angiographic late lumen loss at 6 months. Lutonix ® 035 Pivotal and Label Expansion Studies • Randomized IDE study with superior effectiveness and non-inferior safety was required for FDA approval. • Japan requires additional in-country study to confirm the pivotal study results. • Registry designs generally acceptable for label expansion: • Randomized study design in post-approval environment may not be enrollable. Study Name Pivotal IDE Studies LEVANT 2 Treatment Study Type Subjects SFA Randomized, US & Europe 476 total 316 – DCB 160 – POBA Lutonix Long Lesion Study (≥ 14 cm) SFA ISR Study SFA Registry, Europe 118 - DCB SFA LEVANT Japan SFA Randomized → Registry, US Randomized, Japan Primary Endpoint Effectiveness: Primary Patency at 12 months. Safety: Composite safety at 12 months. Label Expansion Studies Effectiveness: Primary Patency at 12 months. Safety: Composite safety at 12 months. Ongoing (127 planned) Effectiveness: Primary Patency at 12 months. Safety: Composite safety at 12 months. 109 Total Effectiveness: Primary Patency at 6 months. 71 – DCB Safety: Composite safety at 6 months. 39 – POBA Lutonix ® 035 Post Market Studies • Post-market study types: o Mandated post-approval studies o Company initiated ‘real-world’ registry studies. • Post approval studies show continued safety and effectiveness over a larger population/longer time points. • ‘Real-world’ studies provide additional supportive information for safety and effectiveness with ‘standard of care’ follow-ups. Study Name LEVANT 2 Safety Registry Global SFA Real-World Registry BARD LifeStent & Lutonix DCB for Treatment of Long Lesions SAFE DCB US RealWorld Registry SFA Treatment Study Type Registry, US & Europe Subjects 657 - DCB SFA Registry, Europe 691 - DCB SFA – Pre, PostDilatation of BMS Registry, Europe 149 - DCB SFA Registry, US 1006 - DCB Primary Endpoint Primary endpoint: Rate of unanticipated device- or drug- related adverse events over long-term. Effectiveness: Freedom from TLR at 6 months. Safety: Freedom at 30 days from VIVA safety endpoint. Effectiveness: Primary Patency at 12 months. Safety: Freedom at 30 days from VIVA safety endpoint. Effectiveness: Freedom from TLR at 12 months. Safety: Composite safety at 12 months. LifeStent Indications and Clinical Trials Intended to improve luminal diameter in the treatment of symptomatic de novo or restenotic lesions up to 240mm in length in the native SFA and popliteal artery with RVD 4.0-6.5mm Stent length 20-160mm 20-200mm Stent diameter 6-7mm 5-7mm Studies Resilient- SFA SOLO (200mm) ETAP- Popliteal Reality (5mm) Retrospective review in the treatment of long lesions “Please consult product labels and inserts for any indications, contraindications, hazards, warnings, precautions, and directions for use.” LifeStent Feasibility and Randomized Studies • RESILIENT 1 feasibility study was performed to assess peri-procedural safety and 6 month effectiveness. • Randomized clinical trials supported indications in the SFA and popliteal arteries Study Name RESILIENT 1 SFA Treatment Study Type Registry, EU Subjects 20 – stent Primary Endpoint Safety: Adverse Events (death, stroke, MI, dsital embolization, surgical revascularization, thrombosis, transfusion or renal failure) at 30 days Effeciveness: primary patency at 6 months Study Name RESILIENT 2 SFA Treatment Study Type Randomized, US (22 centers) & Europe (2 centers) Randomized EU (9 centers) Subjects 206 total 134 – stent 72 – POBA 246-total 119-stent 127-POBA Primary Endpoint Effectiveness: Freedom from TLR at 6 months. Safety: 30 day mortality ETAP Popliteal Effectiveness: Primary patency at 12 months LifeStent Label Expansion Studies • LifeStent label expansion studies extended stent diameter (5mm) and length (200mm), as well as lesion length treatment (240mm) • LifeStent safety and effectiveness had to be confirmed in Japan Study Name Treatment Study Type Subjects Primary Endpoint Retrospective analysis of SFA -240mm lesion Retrospective analysis patients from length RESILIENT and observational studies 285-Stent Acute safety: 30d safety vs VIVA OPG Long-term safety: Freedom from death and amputation at 12 months Effectiveness: Primary patency at 12 months for lesions at 50mm, 100mm, 160mm and 240mm. REALITY SFA- 5mm stent Registry, Europe (1 center) 3--Stent LifeStent Solo 200mm SFA – 200mm stent Registry, Europe (7 centers) 76-Stent RELIABLE SFA and prox. popliteal Registry, Japan, 77- Stent Effectiveness: successful deployment Safety: Freedom at 30 days from death, amputation TVR and/or TLR. Acute safety: Freedom from death, amputation, TLR and/or TVR at 30 days Long-term safety: Freedom from TLR at 30 days and 12 months Acute Effectiveness: Primary patency at 12 months. Long-term effectiveness: Primary patency at 12 months Target limb failure (device and/or procedure related death, amputation, TVR and TLR) at 12 months LifeStent Post Market Studies • LifeStent post-approval study was part of the VQI PVI Registry Study Name LifeStent post-approval study Treatment SFA and popliteal Study Type Registry, US Subjects 74- Stent Primary Endpoint Primary endpoint: freedom from MAE, TLR, TVR, acute lesion success, primary patency, primary assisted patency, secondary patency, sustained clinical success, sustained hemodynamic success, limb ischemia, ABI, stent fracture through 2 years Conclusions • Pivotal, label expansion and post-approval studies were necessary for FDA approval of Bard DCBs and stents. • In-country studies were required for Japan approvals • Indication expansion can be supported by registry studies with appropriate clinical endpoints. LUTONIX® 035 INDICATIONS FOR USE The Lutonix 035 Drug Coated Balloon PTA catheter is indicated for percutaneous transluminal angioplasty, after pre-dilatation, of de novo or restenotic lesions up to 300 mm in length in native superficial femoral or popliteal arteries with reference vessel diameters of 4-7mm. BARD® LIFESTENT® Vascular Stent System INDICATIONS FOR USE The LIFESTENT® Vascular Stent System is intended to improve luminal diameter in the treatment of symptomatic de novo or restenotic lesions up to 240 mm in length in the native superficial femoral artery (SFA) and popliteal artery with reference vessel diameters ranging from 4.0 - 6.5 mm.