TAVR: Similarities and Differences in the US and Japan Jodi J. Akin, RN, MS Vice President, Global Clinical Affairs Transcatheter Heart Valve Therapy Edwards Lifesciences, LLC Thank you Martina and Maryann. It is an honor to present here today at The Nurse’s Symposium at TCT. TCT 2011 | San Francisco | November 7, 2011

Jodi Akin, RN, MS Employee: Edwards Life Sciences

Pre Market Approval Application FDA Review Process of Class III Medical Devices The Center for Devices and Radiological Health (CDRH) is the branch of the United States Food and Drug Administration (FDA) responsible for the premarket approval of all medical devices, as well as overseeing the manufacturing, performance and safety of these devices. Three Classes of Controls: Class I Class II Class III-support or sustain human life, substantial importance in sustaining human health, or which present a potential unreasonable risk of illness or injury In 1976when the US Congress passed the Medical Device Amendments to the Food, Drug and Cosmetic Act, it established an organization within the FDA known as the Center for Devices and Radiological Health (CDRH) The Center has a two-fold mission to both protect and promote the public health when it comes to the use of medical technologies.

Japan Regulatory Classification of Risk Requirements Class I General medical devices    → Extremely low risk to the human body          e.g., X-ray film Approval of the product is not required, but marketing notification is necessary. Class II Controlled medical devices designated by the Minister of Health, Labour and Welfare , for which applicable certification standards are specified by the Minister    → Low risk to the human body          e.g., MRI, digestive catheters Certification by a registered certification body is required. Class III Specially controlled medical devices    → Medium risk to the human body          e.g., artificial bones, dialyzer The Minister's approval for the product is required. Class IV Specially controlled medical devices    → Highly invasive to patients. High risk 　　　 to the human body          e.g., pacemaker, artificial heart valves

Universal language: Key Medical Device Trial Objectives Assessment of risk: Is the device safe? Assessment of performance: Does the device work as intended? Assessment of benefit: what is the intended clinical benefit and can it be demonstrated?

Pre Market Approval Application FDA Review Process of Class III Medical Devices PMA submission includes: device description and indications for use alternative practices or procedures marketing history manufacturing information reference to any performance standard results of non-clinical testing results of (human) clinical investigations proposed labeling for the device Premarket Approval (PMA) - 21 CFR Part 814 Product requiring PMAs are Class III devices are high risk devices that pose a significant risk of illness or injury, or devices found not substantially equivalent to Class I and II predicate through the 510(k) process. The PMA process is more involved and includes the submission of clinical data to support claims made for the device.

Imperatives of a PMA Population: Definable, criteria-driven Product: Addresses unmet need Protocol: Multiple critical objectives Partners: Engaged, relevant Process: Good Clinical Trial Conduct Proof: Interpretable, defensible

Three eras of clinical trials for new technology platforms FDA Level of Evidence: Three eras of clinical trials for new technology platforms Unprecedented controls: TAVR versus SAVR TAVR versus Best Medical Management After a first generation is approved for commercial use: Subsequent generations compared to previous generations Substantial long term clinical data has been established and accepted: Single arm trials against consensus objective performance criteria

Japan PMDA ICH-E5 guidelines “Ethnic Factors in the Acceptability of Foreign Clinical Data” Utilizing foreign clinical trial data in a new drug application what is called “Bridging” has been accepted in Japan, and post-marketing data in USA and EU have been taken into consideration in review for regulatory approval where necessary. Pharmaceutical and Food Safety Bureau, Ministry of Health and Welfare, dated August 11, 1998),

First Generation Trial design TAVR-US Collaboration with FDA, Investigators, Harmonized as much as possible with global trials Trial Design ASSESSMENT: High Risk AVR Candidate 3105 Total Patients Screened Symptomatic Severe Aortic Stenosis High Risk TA ASSESSMENT: Transfemoral Access TAVI Trans femoral Surgical AVR High Risk TF Primary Endpoint: All Cause Mortality (1 yr) (Non-inferiority) 1:1 Randomization VS Standard Therapy (usually BAV) Not In Study Primary Endpoint: All Cause Mortality over length of trial (Superiority) Total = 1057 patients 2 Parallel Trials: Individually Powered High Risk n= 699 Inoperable n=358

PREVAIL Japan: Second generation Edwards TAVR Edwards SAPIEN XT THV NovaFlex Delivery System Ascendra2 Delivery System Designed to Restore proper hemodynamics Maintain valve performance, and Respect anatomical structures of the heart Reliable valve placement Controlled arch navigation Smooth crossing of the native valve Percutaneous access Single-handed use Improved visualization during valve deployment Limited movement at the access site Lower-profile apical access Design Informed by SAPIEN experience

The PARTNER II Trial Study Design Symptomatic Severe Aortic Stenosis ASSESSMENT: Operability 2 Parallel Trials: Individually Powered Operable Inoperable Transapical ASSESSMENT: Transfemoral Access tAVR Trans femoral Surgical AVR Transfemoral Primary Endpoint: Addresses safety and efectiveness apical Randomization VS tAVR SAPIEN XT ASSESSMENT: Access Non TF? Nested Registry- subgroups tAVR SAPIEN Primary Endpoint: Addresses safety and efectiveness TF? Randomization VS the N’s for each arm as well as the total to match the data that was sent earlier. 13

PREVAIL Japan: Trial Design With a lot of groundwork laid: Prospective single arm trial Shorter term composite endpoint Informed by worldwide clinical data Access decision heart team approach Endpoints address safety, performance and clinical benefit

Unique Infrastructure Needs? Trials need to be adapted to population and global product lifecycle Fundamentally for “Good Clinical Trial Practice” (GCP), no

Trial Infrastructure: Same or Different? Collaboration with PMDA, Investigators, Harmonized with global trials Trial Design Partnered principal investigators, representing the disciplines Trial Leadership CEC DSMB Safety Oversight Echo, ECG Core laboratory 100% source document verification Monitoring Electronic data capture, rigorous oversight Clinical Data Management

Harmonization Endpoint Definitions Academic Guidelines Regulatory Guidelines CEC Charters VARC Clear, ascertainable, benchmarked

Common Processes Manufacturing Review Quality System Inspection Audit Preparation of Summary of Safety and Effectiveness Data Nonclinical Studies: Microbiological, Toxicological, Immunological, Biocompatibility, Shelf Life, Animal, Engineering (Stress, Wear, Fatigue, etc.) Clinical Studies Panel Decision Final Labeling Approval Order Pre IDE Conduct of clinical trial Analysis and submission BIMO Advisory Committee Final Review

Interaction and Consideration of Key Stakeholders Professional Collaboration Intra and Inter-site Trial Conduct Worldclass DSMB, Corelabs Advisors Regulatory Agencies US and OUS Healthcare Economics Reimbursement Publication Predictors Management Echo Methods

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