Regulatory Challenges for Bioasorbable Stent Approval Andrew Farb, M.D. Interventional Cardiology Devices Branch Division of Cardiovascular Devices U.S. FDA/CDRH andrew.farb@fda.hhs.gov BIOABSORBABLE STENT SYMPOSIUM CRT 2011 Washington, DC February 28, 2011

Andrew Farb, 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 Including Bioabsorbable (Bioresorbable) Stents 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

Current Expectation: Drug-Eluting Bioabsorbable Stents (BAS) Drug may be studied Evaluated on another approved DES E.g., sirolimus, paclitaxel, zotarolimus, everolimus Studied for a different indication Currently being studied under an investigational new drug (IND) application

Drug on a DES Drug substances may be unstudied Never tested in humans in the US Defined as “NME” – New Molecular Entity Drugs that are analogs of studied drugs are considered to be NME’s -Limus analogs (e.g., biolimus A9)

Requirements for a New Drug Substance on a DES Safety data required prior to human exposure to DES Same data required as in “Phase I IND” for drug development See DES Draft Guidance http://www.fda.gov/cdrh/ode/guidance/6255.pdf

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 Bioabsorbable DES

Characterization of 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

Animal Studies Implant duration evaluation to capture critical safety and potential effectiveness parameters Early, when the 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

Animal Studies Safety and effectiveness characterization Neointimal growth & inflammatory responses Thrombus deposition & re-endothelialization Remodeling: Stent and proximal & distal edges Safety margin overlap/overdose studies Assessment of downstream myocardial pathology Evaluate embolization due to bulk degradation Optional: Vasomotor function & use of disease models

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 Longer-term follow-up to capture events 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 labeled indication Pooling of post-market data with pre-market data to increase precision around point estimates of CV death, MI, & ST

Other Important Clinical Assessments Procedural results Device handling: Tracking, deliverability, crossing, deployment, acute recoil, balloon deflation, catheter withdrawal, post-dilatation Device success: Achievement of an acceptable post-deployment angio result with the test device alone Is radial force adequate? Clinical success: Device success without in-hospital MACE Evaluate BAS visibility during imaging Assess frequency of geographic miss Ability to accurately deploy overlapping stents in bailout situations

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 Mal-apposition & stent fracture Vasomotion Plaque modification

BAS Are Truly Innovative Devices, But … What is their optimal role in PCI? Workhorse device vs. niche patient/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 BAS add multiple levels of complexity to FDA review Discussions with FDA early in new BAS program development highly recommended DES Draft Guidance document http://www.fda.gov/cdrh/ode/guidance/6255.pdf