Regulatory Challenges for Biodegradable Scaffold Approval Andrew Farb, M.D. Interventional Cardiology Devices Branch Division of Cardiovascular Devices U.S. FDA/CDRH andrew.farb@fda.hhs.gov BIOABSORBABLE SCAFFOLDING SYMPOSIUM CRT 2012 Washington, DC February 6, 2012

Andrew Farb, MD I have no real or apparent conflicts of interest to report.

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

FDA’s Approach to All DES Including Biodegradable (Bioabsorbable) Scaffolds (Stents) Regulatory submissions Investigational Device Exemption (IDE) Significant risk Class III products Required to conduct clinical studies 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

Drug Component of a Drug-Eluting Biodegradable Scaffolds (BDS) 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 Component of a Drug-Eluting Biodegradable Scaffolds (BDS) Drug 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data are required prior to human exposure via a DES Same data required as in “Phase I IND” for drug development See DES Draft Guidance http://www.fda.gov/cdrh/ode/guidance/6255.pdf

Characterization of BDS 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 BDS balance the need for mechanical integrity with the potential advantages of degradation over time? As a functional mechanical scaffold, how long is long enough?

Nonclinical 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

BDS Bench Testing Characterize the degradation profile including weight loss and mass loss Standard tests should be conducted with special caveats: Test mechanical properties in a physiologically relevant environment at multiple time points to fully characterize the impact of degradation on mechanical integrity Time points for long-term testing are determined by expected BDS performance Structural fatigue through time point of complete tissue coverage Chronic particulates through time point of significant mass loss Acceleration of mechanical loading should be synchronized with accelerated degradation

Animal Studies Duration of studies and tissue evaluation methods adequate to capture critical safety and potential effectiveness parameters Early, when the BDS 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

Feasibility/FIH Clinical Studies Provide initial insights into BDS performance and safety and effectiveness BDS visibility, deliverability & early fracture Need for quantitative imaging (QCA, IVUS, OCT) for optimal sizing Performance in bailout situations Device and procedural success rates Follow-up imaging Acceptable clinical and imaging data in feasibility study used to justify a larger pivotal trial

Pivotal Trial “More-comers” inclusion/exclusion criteria 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 Alpha set at 0.025 for non-inferiority study Longer-term follow-up of pivotal trial subjects to capture events post-complete BDS degradation

Separate Imaging Study Particularly important if BDS or investigational plan modified after FIH/feasibility studies Mechanistic imaging information Assess neointimal growth & negative remodeling Relevant imaging time points to assess scaffold absorption Optional value-added investigations Restoration of normal vasomotion Marker of functional endothelium Markers of plaque stabilization (beneficial plaque modification) Late adaptive positive remodeling

BDS Clinical Program Considerations for Regulatory Review 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 non-US) Discuss non-US trials with FDA – design, events definitions & adjudication, long-term follow-up Assess rates of stent thrombosis over time Assess DAPT use and duration following BDS implantation

Post-Approval Study Real world use beyond labeled indication Nested registries for additional indications Potential opportunity to evaluate shorter duration of post-PCI P2Y12 receptor inhibitor use if supported by available scientific evidence

The Future of BDS What is their optimal role in PCI? Workhorse device vs. niche patient/lesion device? Will innovative promise translate into clinical benefit? Can we safely shorten P2Y12 receptor inhibitor treatment duration? Are vasomotion and plaque modification clinically relevant surrogates? Challenging to conduct a successful pivotal randomized trial Currently, TLF rates at 1 year are in the single digits for non-complex lesions/patients with approved DES

Conclusion Bioabsorbable drug-eluting scaffolds add multiple levels of complexity to FDA review Discussions with FDA early in new BDS program development highly recommended DES Draft Guidance document http://www.fda.gov/cdrh/ode/guidance/6255.pdf