Regulatory Challenges for Biodegradable Scaffolds Approval Andrew Farb, M.D. Interventional Cardiology Devices Branch Division of Cardiovascular Devices U.S. FDA/CDRH andrew.farb@fda.hhs.gov DES Bioabsorbable and DCB Technologies CRT 2013 Washington, DC February 25, 2013

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

The Potential Advantages of Biodegradable Scaffolds (BDS) Effective revascularization without an implanted permanent intra-arterial metallic prosthesis Low thrombosis rates Shorter duration of DAPT vs. permanent platform stents Restoration of normal vasomotion Beneficial plaque modification Opportunity for non-invasive imaging assessment of patency

Fundamental Scientific Questions That Guide Nonclinical and Clinical Evaluation How does the 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 for optimal performance by a BDS?

Regulatory Approaches to the Evaluation of BDS

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 at US sites 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data are required prior to human exposure via a DES Same data required as in “Phase I IND” for drug development See DES Draft Guidance http://www.fda.gov/cdrh/ode/guidance/6255.pdf

Targeting IDE and PMA Approval To initiate an IDE study: Identify and justify bench & animal studies to provide adequate safety information to support the IDE Leverage available clinical information Include risk mitigation strategies in the clinical study protocol For PMA approval: 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 Consider benefit-risk principles Discuss test methods early with FDA to avoid wasted steps and mis-spent resources

Bench Testing All standard bench tests still apply BMS Guidance: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM071986.pdf DES Draft Guidance: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072193.pdf But with some additional considerations Test mechanical properties (e.g., radial stiffness and radial strength) in a physiologically relevant environment at multiple time points to fully characterize the impact of degradation on mechanical integrity 12

BDS Bench Testing Characterize the degradation profile including molecular weight loss and mass loss Standard tests should be conducted with caveats: Test mechanical properties in a physiologically relevant environment at time points to fully characterize the effect of degradation on mechanical integrity Time points for long-term testing are determined by expected BDS performance Structural fatigue testing through time of complete tissue coverage Particulates testing through time of significant mass loss Acceleration of mechanical loading synchronized with accelerated degradation Putting results in context Understand that stent and coating integrity should look different over time Characterize degradation products & clinical relevance of “particulates” Particulates assessment is by definition different (since 1 or more components intended to degrade) Understanding of pattern and amount of degradation (number and size distribution) is important Bolus of particles shed (e.g., at point of critical mass loss) can still represent safety concern Consider the entire story told by bench and animal observations

Animal Studies In-vivo PK profile Duration of histopath studies adequate to capture critical safety and potential effectiveness parameters Early (BDS still intact) During degradation Post-complete degradation: Does absence of rigid scaffold lead to adverse arterial remodeling & edge effects Evaluate potential toxicity of degradation products Based on acceptable results from short & medium-term studies (and outcomes consistent with degradation profile), long-term animal studies may be completed after initiation of the clinical study

Early Feasibility and Traditional Feasibility Clinical Studies Provide initial insights into BDS performance and basic safety & effectiveness, e.g.: BDS handling, visibility, deliverability & early fracture Optimal device sizing and the need for quantitative imaging (QCA, IVUS, OCT) Performance in bailout and overlap Device and procedural success rates Follow-up imaging information: late loss, remodeling Acceptable feasibility data support 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

Other Clinical Investigations Imaging cohort provides mechanistic imaging information Assess scaffold absorption Assess neointimal growth & negative remodeling Optional value-added investigations Vasomotion studies Restoration of normal vasomotion - marker of functional endothelium Plaque assessment: Plaque size stabilization & beneficial plaque modification Late adaptive positive remodeling

Targeting PMA Approval Need adequate number of subjects to detect uncommon but clinically important safety events Utilize data from all appropriate studies Not all patients need to be part of the pivotal trial Can use global approach (US and non-US subjects/studies) Discuss non-US studies with FDA as early as possible – design, event definitions & adjudication, long-term follow-up, & poolability Assess stent thrombosis rates 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

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