Structural Heart Disease and Devices in Japan and USA FDA View: Balancing Safety and Effectiveness John Laschinger, MD Food and Drug Administration, Center for Devices and Radiological Health, Office of Device Evaluation, Division of Cardiovascular Devices

Disclosure Statement of Financial Interest I DO NOT have a financial interest, arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest. John Laschinger, M.D.

Innovative Device Development Regulatory Perspective Striking a Balance Investigator, Sponsor and public enthusiasm for innovative CV devices Critical evaluation of Safety and Effectiveness in well controlled clinical trials The regulatory process for development of Innovative Class III devices is built upon a base of responsible innovation. In this process, the need for critical evaluation of safety and effectiveness in well controlled clinical trials will always outweigh pressures that exist due to enthusiasm for adoption of innovative medical devices Responsible Development

Safety And Effectiveness “There is reasonable assurance that a device is safe when it can be determined based on valid scientific evidence that the probable benefits to health from use of the device for its intended uses and conditions of use, when accompanied by adequate directions and warnings against unsafe use, outweigh the probable risks.” “There is reasonable assurance that a device is effective when it can be determined, based upon valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warnings against unsafe use, will provide clinically significant results.”

Class III Medical Devices : The Pre-Market Application(PMA) Establish reasonable assurance of safety and effectiveness 2 STEP PROCESS Preclinical: Bench and Animal Testing Clinical: Human Trials

Pre-Clinical Assessment: Device Design and Safety Bench Tests Mechanical Engineering Durability, structural and hydrodynamic performance Animal Studies Proof of concept Mode of Action Computational Modeling Biocompatibility Toxicity Sterilization Manufacturing Device Design, Risk Assessment & Mitigation Test Device Pilot & OUS Study Clinical Data Sufficient Safety for Pivotal Study

Clinical Assessment Pivotal IDE Trial Clinical Assessment of Device Demonstrate Safety & Effectiveness Results are Clinically Significant Clinical Benefit outweighs Risks Appropriate Clinical Trial Design Conduct Analysis If the inclusion criteria include good risk patients as well as high risk patients, then results have to be better Risk/benefit – will depend on more than meeting endpoints Standard non-inferiority with a large delta won’t support labeling Comment on roll in patients Causes of trial bias in unblinded trials

Structural Heart Disease: Trial Design Considerations Defining Subjects – Intended use and Conditions of Use Condition being treated Risk of Population being studied STS risk prediction Heart Team Approach - Inoperability Access Options Vary within devices – peripheral vs. direct Vary with comparator – percutaneous vs. surgery Balancing Adverse Events Major Bleeding, Vascular Complications Assessment and Definition of neurological events Safety and effectiveness endpoints Appropriate choice Duration of Follow-up

Structural Heart Disease: Trial Conduct Considerations Protocol Driven Adherence to Inclusion/Exclusion Criteria Pre-defined AE’s Tests and Follow-up within windows Minimize missing data Site Selection and Monitoring Core Laboratories for key data CEC Adjudication DSMB

Structural Heart Disease: Trial Analysis Considerations Pre-specified Statistical Analysis Plan (SAP) Appropriate Hypothesis Appropriate statistical methodology Defined Analysis Population Intention to treat (ITT) As treated (AT) Per Protocol (PP) Minimize Bias Minimize Missing Data

Safety: Benefits Outweigh the Risks Device Approval Meeting Endpoints Risks Harmful events Number Severity Type Probability Duration Benefits Clinically Meaningful Benefits Type & Magnitude Probability Durable over relevant duration Reproducible & generalizable Disease Characteristics Available Rx options

Effectiveness: Device provides Clinically Significant Results Higher Procedure Risk WORSE More Procedure Benefit Control 95% C.I. BETTER Less Procedure Benefit Lower Procedure Risk

Effectiveness: Device provides Clinically Significant Results Higher Procedure Risk Inoperable Patients *Optimal Medical Therapy More Procedure Benefit Controls* Less Procedure Benefit High Risk Patients *Standard Open Operation Lower Procedure Risk

Transcatheter Valve: Published Results Higher Procedure Risk IB Inoperable Patients vs. Optimal Medical Therapy More Procedure Benefit IA High Risk Patients vs. Standard Open Operation Controls* Less Procedure Benefit Lower Procedure Risk

Transcatheter Valve Pivotal Trial Evolution: Are There Limits? Higher Procedure Risk IB Inoperable Patients vs. Optimal Medical Therapy More Procedure Benefit IA High Risk Patients vs. Standard Open Operation Controls* Less Procedure Benefit Intermediate Risk Patients vs. Standard Open Operation Lower Procedure Risk

Thank You! John Laschinger, MD john.laschinger@fda.hhs.gov

US Class III Device Pre-Market Approval Process Pre-Clinical Stage Sufficient safety - Bench testing Animal Studies Feasibility/FIM PMA Submission PMA Approval IDE submission IDE Approval Pivotal Trial Safety and Effectiveness MARKET Labeling Pre-IDE Meeting -Adequacy preclinical studies -OUS Studies -Pivotal Trial -Hypothesis generation -Protocol development -Statistical plan Post Approval Study (PAS) For Class III devices, the proces in the US is divided into 3 phases, each with separate goals – Device development occurs in the pre-clinical stage and is designed to show significant safety exists to proceed with a pivotal clinical trial. The pre-IDE and IDE stage is where Hypothesis generation occurs and where an appropriate clinical study is designed. The Pivotal clinical trial is then performed with the goal of generating quality data sufficient to demonstrate that adequate safety and effectiveness exists for introduction of the device into the market place for its intended use Valid Scientific Evidence of Safety and Effectiveness

Europe Class III Device Pre-Market Evaluation Process Notifying Body Verifies conformance Clinical evaluation Safety and Performance Pre-CE Mark Studies - Bench testing Animal Studies Feasibility/FIM Clinical Trial Safety and Effectiveness MARKET CE Mark The CE process in comparison is different in several key aspects. First, there is no uniform regulatory body. 80 for profit notifying bodies exist in 31 member states. These notifying bodies Assess conformity with the essential requirements of the relevant European Directives and Verify the clinical evaluation of safety and performance. This evaluation results in the CE Mark and introduction to market and is Performed once for entire European market. The stringency of these bodies can vary greatly, and a manufacturer may use different bodies for different devices. As a result. devices reach the market based on experience in relatively few patients, and the data provided for these evaluations is not made public. Well controlled Clinical trials for demonstration of additional safety or device effectiveness are performed post market release, are not required, and are left to the manufacturer, physicians and hospitals. To date, none have been performed for transcatheter or percutaneous valve devices Clinical Evaluation of Safety and Performance

Transcatheter Valve Pivotal Trials: Where are we? Patient Heart Team Inoperable TAVR Medical Rx BAV PG High Risk Operative Candidate Surgery Intermediate Risk for OR Surgery-MIS Validated Risk Score Clinical Assessment RCT RCT RCT RCT = Randomized Control Trial

Determining Safety and Effectiveness for Innovative Devices - PMA Pre-Clinical Studies Sufficient Safety Bench Animal Feasibility and OUS clinical trials Pivotal Trial Safety and Effectiveness Design: Minimize bias and confounding Execution: Minimize amount of missing data Analysis: Rule out chance (prospective endpoints, hypotheses) Clinically meaningful results: Clearly demonstrated Durable over a clinically relevant time period Risk/Benefit balance is favorable vs. current therapy Labeling is truthful and accurate Accept MR as a clinical surrogate Can you vs should you

Defining Surgical Risk: Use of Validated Databases Predictor Development Set External Validation Set EuroScore 19,000 (2,660 isolated valves) NO for valves STS 2002-6 591,780 394,519 STS aortic STS MVR STS MV repair STS Valve + CAB STS isolated CAB 40,375 12,737 12,743 60,997 464,928 26,916 8,492 8,495 40,664 309,952

Limitation of STS Risk Predictor: Can’t be used as a Control for single-arm studies Although validated as a predictor of acute surgical risk: Limited to 30 day data For the most part, self-reported and unaudited Study hospital(s) performance may be better or worse than the whole Uncaptured and unknown covariates (e,g., educational level, socioeconomic class, etc.) that might effect long term results Use of STS dataset and definitions - attractive for use as standardized pre and peri-operative dataset

Medical Device Approval Risk-Based Paradigm Medical Device Classes: Class I General Controls Most exempt from premarket submission Class II Special Controls Substantial Equivalence Premarket Notification [510(k)] Class III Premarket Approval Safety and Effectiveness Require Premarket Application [PMA] Additional Classification: De Novo Device "types" that have never been marketed in the U.S., but whose safety profile and technology are now reasonably well understood Humanitarian Device Exemption (HDE) Devices for orphan diseases intended to benefit patients in diagnosis and/or treatment of disease or condition affecting or manifested in fewer than 4,000 patients per year in the United States 24

The Total Product Life Cycle Regulation of device technologies requires a total product life cycle approach HHS/FDA/CDRH

Clinical Trial Considerations for Transcatheter Devices Defining the Population and Risks Traditional Paradigm Inclusion Criteria Exclusion Criteria Important Subgroups Age, Gender or Race Concomitant Disease Disease subtypes Heart Team Assessment New Paradigm Use of Validated Databases Define risk (4-8%) “real world” populations Heart Team Assessment 40 -60 criteria

“Transcatheter” Valve Replace/Repair = “Non-invasive” Valve Replace/Repair Transcatheter Valve Procedure: Stroke Crushing calcified valve Aortic manipulation Major Vascular Injury Aortic/Annular dissection Pacemaker Coronary Occlusion Perivalvular insufficiency Radiation General anesthesia Open surgical access Nephrotoxic dyes or drugs Device Risk is tied to Procedure Risk

TAVR – Critical Endpoints Mortality – early and late Stroke – early and late Vascular Injury Perivalvular Aortic Insufficiency Need for Pacemaker Hemodynamics & Function Valve Durability QoL