Bioabsorbable DES and Biodegradable Polymers – FDA View Andrew Farb, M.D. Interventional Cardiology Devices Branch Division of Cardiovascular Devices U.S. FDA/CDRH WORKSHOP WITH THE FDA CRT 2011 Washington, DC March 1, 2011

Andrew Fab, MD No disclosures

Components of a DES System Combination Product Stent Delivery System Drug Eluting Stent Therapeutic Agent Coating Technology

FDA’s Approach to All DES Regulatory submissions Investigational Device Exemption (IDE) Significant risk Class III products Required to conduct clinical trial in the US Premarket Approval Application (PMA) Comprehensive review of bench testing, animal studies, and all clinical data Establish a reasonable assurance of safety and effectiveness Manufacturing inspection prior to approval

Additional Considerations for Degradable Polymer Coatings on Permanent Stents Testing paradigm for bench, animal, biocompatibility, and clinical evaluations guided by The degradation profile (mechanism and time course) The degradation products and what are their biologic activities

Characterization of Bioabsorbable Stents (BAS) Fundamental questions that guide testing What is the mechanism of biodegradation? What are the degradation products and what are their biologic activities? How does the proposed BAS balance the need for mechanical integrity with the potential advantages of degradation over time? As a functional mechanical scaffold, how long is long enough?

Preclinical Testing Objectives Complete characterization of the finished sterilized product Coating/drug loading characteristics – drug and carrier content, coating integrity In vitro/in vivo elution of both coating and stent substrate Methods and specifications to allow stability testing Adequate bench & animal studies to assess safety prior to human trials Discuss test methods with FDA

BAS Bench Testing Standard tests such as stent and coating durability less relevant vs. non-BAS Test mechanical properties in a physiologically relevant environment Conduct mechanical tests at multiple time points to fully characterize the impact of degradation on mechanical integrity Characterize degradation products and amount/type of particulates, which can still pose a risk even though degradation is intentional Testing of degradation products for biocompatibility may be appropriate

Animal Studies Implant duration evaluation to capture critical safety and potential effectiveness parameters Early – when BAS is still intact During degradation Post-complete degradation Assess whether absence of rigid scaffold leads to adverse arterial remodeling & edge effects Evaluate potential toxicity of degradation products

Clinical Trials Feasibility/FIM trial(s) Pivotal trial Initial assessment of device performance and safety and effectiveness Pivotal trial RCT recommended for initial marketing approval Superiority or non-inferiority to approved DES Primary endpoint: Target lesion failure at 12 months Composite of cardiac death, target vessel MI and TLR Frequency & duration of patient follow-up reflects degradation profile To adequately capture outcomes before, during, and after stent degradation

BAS Clinical Program Considerations Need adequate number of patients to detect uncommon but clinically important safety events Not all patients need to be part of a randomized trial Can use multiple trials (both US and OUS) Discuss OUS trials with FDA – design, events definitions & adjudication, long-term follow-up Assess rates of stent thrombosis over time Assess DAPT use and duration following BAS implantation Post-approval study - Real world use beyond label Pooling of post-market data with pre-market data to increase precision around point estimates of CV death, MI, & ST

Clinical Imaging and Functional Assessment Follow-up imaging to confirm absorption QCA & IVUS/OCT to address effects of loss of rigid scaffold on restenosis In-stent & in-segment MLD, vessel area, lumen area, late lumen loss & %diameter stenosis Neointimal area and volume in-stent & in-segment Stent area (late recoil) & remodeling Vasomotion Plaque modification

Are BAS the Next Stage in the PCI Innovation Continuum? POBA Bare metal stents Permanent polymer DES Thinner strut Permanent polymer DES Biodegradable polymer DES/Non-polymer DES Bioabsorbable DES

The Potential Advantages Of BAS Coronary targets Improved healing profile Reduced inflammatory response to permanent foreign body and polymer Shorter duration DAPT Lower stent thrombosis rates Improved arterial “health” Restoration of normal vasomotion – Functional endothelium Adaptive chronic positive remodeling & lumen enlargement Beneficial plaque modification

The Potential Advantages Of BAS Coronary targets (continued) Opportunities for assessment with non-invasive imaging Side branch access after stent absorption Opportunities for repeat coronary treatment without rigid scaffold Non-coronary targets Pediatric interventions that can allow for vessel growth Aortic coarctation Branch pulmonary arterial stenosis

BAS Are Truly Innovative Devices, But … What is their optimal role in PCI? Workhorse device Niche lesion device Will innovative promise translate into clinical benefit? Are vasomotion and plaque modification clinically relevant surrogates? Can we safely shorten thienopyridine treatment duration? Clinical trials challenge Current era of single digit TLF rates at 1 year for non-complex lesions/patients with approved DES

Challenges in Characterization of Biodegradable Stents Biodegradable polymers and bioabsorbable stents add multiple levels of complexity to FDA review FDA welcomes discussions with sponsors regarding novel DES programs