Bioresorbable Stent Clinical Study: FDA Andrew Farb, MD P F Adrian Magee MD Division of Cardiovascular Devices Center for Devices and Radiological Health (CDRH) Food and Drug Administration andrew.farb@fda.hhs.gov patrick.magee@fda.hhs.gov 10 min Sunday, February 21, 2016 4:20 PM – 4:30 PM, Room: Congressional AB Japan-US Synergies: BRS CRT 2016 Washington, DC February 22, 2016

No Conflicts of Interest

Attributes of an ‘Ideal’ Bioresorbable Stent (BRS) At least comparable to current DES in deliverability Provides adequate mechanical support for a sufficient period of time to ensure luminal patency Elute a safe and effective antiproliferative drug to inhibit neointimal growth Bioresorb safely and completely

BRS: US Regulatory Classification and Pathway for Approval Significant risk Class III devices Combination Product (comprises a regulated device and a drug) - CDER consultants participate in CDRH interactions and review Pathway Investigational Device Exemption (IDE) Required to conduct a clinical study 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 for FDA approval Manufacturing facility and site inspections prior to approval

Targeting IDE Approval Identify and justify bench & animal studies to provide adequate safety information to support the IDE Leverage clinical information (if available) Consider Early Feasibility Study Utilize the Pre-Submission process to discuss test methods with FDA to avoid wasted steps and misspent resources

Early Feasibility Study (EFS) Program CDRH priority program intended to facilitate the clinical evaluation of medical devices in the US under the IDE regulations Approval of an EFS IDE may be based on less nonclinical data than would be needed to support the initiation of a larger clinical study Device that may be early in development, typically before the design has been finalized Small number of subjects Contact for EFS program: carla.wiese@fda.hhs.gov

Initial Clinical Assessments Early Feasibility and Traditional Feasibility Studies Preliminary insights: BRS performance, safety & effectiveness In-Cath Lab Appropriate lesion selection and preparation prior to device deployment ( e.g. pre-dilatation requirements) Device, deliverability, visibility and early integrity (? fracture) Appropriate device sizing (? need/value for enhanced imaging modalities (e.g., QCA, IVUS, OCT) Need/Value/Limitations of post dilatation Performance in bailout and overlap situations Rates of device and procedure success Follow-up Mechanistic insights via follow-up imaging (e.g., late lumen loss, vessel remodeling, device absorption) Clinical event rate estimates to guide pivotal trial development

Pivotal Trial Considerations RCT recommended for initial marketing approval Demonstrate superiority or non-inferiority to an approved current generation DES For non-inferiority statistical hypothesis testing, choose and justify a clinically acceptable non-inferiority margin Adequate total sample size to detect clinically important events with adequate precision

Clinical Endpoints Primary endpoint Target lesion failure (TLF) at 12 months Composite of cardiac death, target vessel MI and ID-TLR Secondary endpoints Device and procedure success rates Individual components of composite endpoints Scaffold/stent thrombosis

Supplementary Evaluations Angiographic imaging assessments Late lumen loss, neointimal growth, binary restenosis rates, & negative remodeling BRS absorption Optional value-added investigations Vasomotion studies Restoration of normal vasomotion - marker of functional endothelium MSCT evaluation Other imaging assessments Late adaptive positive remodeling and lumen enlargement Plaque features and beneficial plaque modification Opportunities for additional labeling claims

Patient Reported Outcomes (PROs) Assessment instruments must be useable and understood by study subjects Usually included as secondary endpoints Pre-specified in clinical study protocol Requires statistical planning to control type I error Utilize an appropriate recall period Blinding critically important for PROs to avoid bias Should be supported by the other objective studies and consistent with the totality of the data http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf

Targeting PMA Approval – Non-Clinical Complete characterization of the finished sterilized product Coating/drug loading characteristics – drug and carrier content, coating integrity and uniformity In vitro and in vivo evaluation of degradation products (oligomers) evolved from both coating and stent substrate Methods and specifications to allow stability testing Discuss test methods with FDA for efficient use of resources

Targeting PMA Approval - Clinical Utilize all appropriate clinical data to demonstrate “A reasonable assurance of safety & effectiveness” Pivotal Trial Results US and non-US pivotal trial data acceptable Need to address poolability Other Non-US studies may be used to support PMA High quality studies Prespecified event definitions Methods to minimize bias Adequate subject follow-up Independent adjudication

Post-Approval Study Longer-term follow-up of pivotal trial subjects to assess rates of late events (as BRS degradation proceeds to completion) TLF composite endpoint events and individual components of the composite BRS thrombosis Newly enrolled post-market cohort Address training program and pre-market lessons learned Evaluate real world use Provide insights into BRS performance when used beyond the labeled indication Can use nested IDE studies for additional indications

Conclusion Bioresorbable drug-eluting scaffolds/stents add multiple levels of complexity to FDA review Interaction with FDA recommended for efficient device non-clinical and clinical evaluation and regulatory review

Back Up Slides

Drug Component of a Drug-Eluting BRS A Combination Product One of 3 choices: Studied drug Evaluated on another approved DES Studied for a different indication Currently being studied under an investigational new drug (IND) application Unstudied drug – New molecular entity Never tested in humans in the US (e.g., new limus analogs) Mention combination product CDER consultants participate in CDRH interactions and review

Bench Testing for BRS Standard bench tests 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 vs. a permanent platform DES may want to mention importance of fully characterizing degradation/mass loss profiles for selection of appropriate time points for testing 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 18

BRS Bench Testing Goals and Principles Characterize device degradation and mass loss profiles Test mechanical properties in a physiologically relevant environment to characterize the time-dependent effect of degradation on mechanical integrity Time points for long-term testing are determined by expected BRS performance Structural fatigue testing through the time of needed radial strength Particulate testing to the time of device tissue coverage In fatigue testing, synchronize accelerated degradation with acceleration of mechanical loading 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 Characterize in-vivo PK profile Histopath studies to describe important safety and potential effectiveness parameters Early (when BRS still intact and providing radial support) During degradation, at a time of significant mass loss Post-complete degradation Does adverse negative remodeling occur after loss of radial support? Sponsors can justify why the duration of their animal studies is adequate to support initiation of a clinical study Longer-term studies may be ongoing during clinical studies Full necropsies recommended to exclude adverse off-target effects and supplement biocompatibility bench tests

Non-Traditional Assessments Quality of life and patient reported endpoints Need to be clinically important to be of value to patients, physicians, and payers (e.g. Angina) Key requirements of patient reported outcome instruments: Reliability: Ability to yield consistent, reproducible estimates of true treatment effect Validity: Extent to which the instrument measures the concept of interest Ability to detect change and meaningful differences reliability or ability to yield consistent, reproducible estimates of true treatment effect. Content validity is the extent to which the instrument measures the concept of interest. Content validity is supported by evidence from qualitative studies that the items and domains of an instrument are appropriate and comprehensive relative to its intended measurement concept, population, and use.