New Heart Valve Guidance & FDA Expectations for Percutaneous Heart Valve Therapies Carolyn D. Vaughan FDA Lead Reviewer / Mechanical Engineer Division of Cardiovascular Devices

Outline New FDA heart valve guidance document (HVGD) Differences between old version and new HVGD How the new HVGD fits with ISO 5840 When to contact FDA Risk assessments Preclinical in vitro bench testing issues Preclinical bench differences new HVGD vs. ISO 5840 Preclinical in vivo animal study issues

New Draft Heart Valve Guidance Document (HVGD) Addresses valves constructed of prosthetic materials, biologic materials (e.g., porcine valves), or a combination of prosthetic and biologic materials Does not address Valve-repair devices (e.g., annuloplasty rings or mitral valve repair devices) Allograft heart valves or more-than-minimally-manipulated allograft valves Regulated by Center for Biologics, Evaluation and Research (CBER) Percutaneous valves will likely need different/additional testing HVGD is not in effect yet Currently posted for public comments (see Federal Register Notice FDA-2009-D-0559)

Old vs New Guidance Differences 1994 Draft New HVGD Prescriptive Risk-based Mechanical & Tissue Rigid & Flexible Shelf life – tissue samples Shelf life – includes functional testing of aged and un-aged whole valves

New HVGD & ISO 5840* HVGD was written to essentially “supplement” information in ISO 5840 cardiac valve standard ISO 5840 is FDA-Recognized Standard FDA has members on the ISO 5840 committee Some ISO 5840 testing requirements are different than the new HVGD A new ISO 5840 percutaneous heart valve addendum is currently being drafted International Organization For Standardization (ISO), ISO 5840:2005, “Cardiovascular Implants - Cardiac Valve Prostheses”

Contact FDA if… You are developing a percutaneous heart valve You are developing a NEW type of heart valve Tissue-engineered Polymer leaflet valve Other unique types These valves may need different or additional preclinical and clinical studies, depending on the specific device design, proposed indications for use, and results of risk assessment

Risk Assessment Perform risk assessment (e.g., hazard analysis, failure modes & effects analysis {FMEA}, fault tree analysis) to develop device specific studies Percutaneous valve risk assessment Risks of a misaligned, misshapen, undersized or oversized percutaneous valve deployment Risks of deploying a valve within a valve Risks of migration/embolization

In Vitro Bench Testing for Surgical Valves Material property testing Biological safety Hydrodynamic performance Structural performance Heart valve durability/accelerated wear testing (AWT) 200 million (M) cycles for flexible valves 600 M cycles for rigid valves Component fatigue 600 M cycles for rigid components (i.e. stent frame)

In Vitro Bench Testing for Percutaneous Valves Same testing as surgical valves PLUS Durability & hydrodynamics of non-cylindrical shape (misaligned, misshapen, under and oversized) Delivery system performance Valve migration/embolization Valve-in-valve placement Additional device-specific testing Establishing preclinical testing boundary conditions for percutaneous valves is very important because these are needed to perform device-specific testing

Bench Testing Differences New HVGD vs ISO 5840 Rigid Valve Durability (accelerated wear testing – AWT) HVGD: 600M cycles vs ISO 5840: 400M cycles Structural Component Fatigue Testing Dynamic Failure Mode Testing – using valves from AWT Hemodynamic Performance Verification of Bernoulli Relationship – relates to Echo machine compatibility Shelf Life Testing – includes functional testing of whole valves pre- and post-aging Corrosion Testing – both pre- and post-fatigue testing

In Vivo Animal Studies Use best practices of biomedical research, including 3R principles (Reduce, Refine, or Replace) Data submitted should be from all animals tested, not just the surviving animals’ data Perform in vivo animal testing in accordance with 21 CFR Part 58, Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies ISO 5840:2005 & ISO 10993:2006 FDA is currently preparing an animal study guidance document

In Vivo Animal Studies for Surgical Valves Acute performance Ease of handling and surgical implantation Hemodynamic performance Leaflet motion Presence of stenosis or regurgitation Chronic performance (20+ weeks) 6+ surviving animals with 2+ surviving control animals All anatomical positions reflected in Indications for Use Biological response Baseline & chronic health assessments echocardiography (Doppler) direct measurement of transvalvular pressure Device-related histology and pathology Please talk with FDA before doing animal studies

In Vivo Animal Studies for Percutaneous Valves Acute – same as surgical valves PLUS Device delivery, deployment (via percutaneous access), and handling characteristics (could make part of chronic study) Human cadaver study may be necessary Chronic (20+ weeks) – same as surgical valves PLUS Deployment of the valve Assessment of possible valve migration Please talk with FDA before doing animal studies

Summary Please review and comment on the new HVGD Follow Federal Register Instructions (FDA-2009-D-0559) http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm193096.htm If you are developing a percutaneous heart valve: Utilize ISO 5840:2005 Refer to 1994 FDA guidance regarding the usual FDA recommended 600M cycle AWT and component fatigue Please contact FDA to discuss animal studies before you start Utilize the Pre-IDE process Watch for the new HVGD as we incorporate your comments

Many Thanks! To the entire FDA Heart Valve Team Office of Device Evaluation (ODE) Office of Science and Engineering Laboratories (OSEL) Office of Surveillance and Biometrics (OSB)

Contact Info Carolyn Vaughan U.S. Food & Drug Administration Center for Devices and Radiological Health Office of Device Evaluation Division of Cardiovascular Devices 10903 New Hampshire Avenue, WO66-1230 Silver Spring MD 20993-0002 Carolyn.Vaughan@fda.hhs.gov 301-796-6338