1. Percutaneous Heart Valves: Standards and Modeling Timothy Kelley, MS
Medtronic CardioVascular

2. Conflicts/Disclosure:
Employee of Medtronic, Inc.

3. Scope ISO 5840 Cardiovascular Implants – Cardiac Valve Prostheses
Key pre-clinical in vitro evaluation requirements

4. Current State of Heart Valve Standards
Well established and comprehensive requirements exist for surgical heart valves
ISO 5840: 2005 Cardiovascular Implants – Cardiac Valve Prostheses
FDA 1994 Draft Replacement Heart Valve Guidance
Risk Management
ISO Medical devices—Application of Risk Management to Medical Devices

5. Motivation for Revised Standards
Existing standards do not address requirements for percutaneous heart valve therapies.
Given the uniqueness of these devices, appropriate device evaluation and risk mitigation guidance must be provided to manufacturers.
Standards are intended to provide a roadmap not a checklist.
It is the responsibility of the manufacturer to determine appropriate design requirements based on intended device application and risk assessment process.
Direct Flow
AorTx
Medtronic Melody
Medtronic CoreValve
Edwards Sapien
ATS 3f Entrata
Sadra Lotus

6. Revised Standards
Regulatory agencies, the scientific community and industry have been working collaboratively to define appropriate requirements/guidance for percutaneous therapies
ISO 5840 Cardiovascular implants  — Cardiac valve prostheses — Part 3: Heart valve substitutes implanted by minimally invasive techniques
Focus expanded from implant-centric to overall system

7. Pre-Clinical In Vitro Requirements Comparison Highlights
Element
Current FDA HVGD and ISO 5840
ISO 5840 Part 3 Enhancements
Scope
Aortic & mitral valve replacement
Adult population
Surgically implanted
Risk-based evaluation approach
Pulmonic & tricuspid valve replacement
Pediatric population
Minimally invasive delivery
Percutaneous delivery
Hydrodynamic Performance Assessment
Transvalvular regurg
Effective orifice area
Steady & pulsatile flow pressure drop vs. reference valve
Steady & pulsatile transvalvular regurg vs. reference valve
Flow visualization
Deployed valve shape variation
Transvalvular and paravalvular regurg
Valve Durability
5 year valve wear testing vs. reference clinical valve – round configuration, fixed diameter
Valve dynamic failure mode test
5 year valve wear testing vs. reference clinical valve – round and non-round configurations, range of intended deployed diameters
Device Structural Performance Assessment
Primary loading mode differential pressure across closed valve and associated dynamic effects
15 year minimum structural lifetime (FDA)
No minimum structural lifetime (ISO 5840)
Multiple physiologic loading modes to be considered based on the valve design and implant location
Crimping and loading effects
10 year minimum structural lifetime (ISO 5840)
Device migration resistance
System Usability (Human Factors Assessment)
Limited physician subjective evaluations
Objective, formalized usability studies
Use error analysis
Assessment of interactions between device, delivery system and users/physicians

8. Pre-Clinical In Vitro Valve Testing
Valve Hydrodynamic and Durability performance characterized and compared against reference valve and established performance requirements:
Pressure Drop, Flow Regurgitation and Leakage characterized under Steady and Pulsatile flow conditions
Transvalvular and paravalvular regurgitant volumes quantified
Accelerated Wear Testing to a minimum equivalent 5 year implant duration
Pulse duplicator images, porcine aortic valve, outflow view, 5 L/min, 100mmHg MAP, 70 bpm
Range of deployed sizes, non-circular shapes
Simulated congenital or calcified anatomies

9. Valve Frame Structural Assessment
Frame structural lifetime requirement is a minimum equivalent 10 year implant duration (400 million cycles)
Computational Modeling
Finite Element Analysis (FEA)
Increased reliance on computational methods to augment in vitro testing
Sensitivity analyses on critical variables
Modeling Challenges
Definition of Inputs to Model
Variation in anatomical implant sites as a function of disease state and target patient population
Assessment of potential variation in deployed device size and shape within target implant site
In vivo loading conditions difficult to characterize
Limited data in scientific literature
Limited resolution of current imaging modalities for quantifying loading (CT, MR, angiography)
Assessment of device loading under peak physiologic conditions
Human Aorta
RVOT Conduit

10. System Usability Assessment (Human Factors)
Demonstrate that all critical aspects of the implant procedure can be safely and reliably performed with the tools and accessories specified for the system
Potential procedural-related risks such as:
Device placement variability
Unintended effect of device on adjacent anatomical structures
Gross device embolization
Arrhythmia/heart block
Vascular complications …
Conduct formalized usability studies in accordance with the procedural flow to assess interactions between device, delivery system and users/physicians
Physician does not have direct visual or tactile access to implant site -- adequate imaging is critical. New hazards associated with delivery of valve to target implant site and deployment of valve within implant site must be addressed.
Note: Complete list of risks should be identified based on detailed risk analysis--ISO 14971

11. Additional Evaluation Methods
Existing pre-clinical tests may not fully mitigate all risks prior to a clinical study due to complexity of device/anatomical interactions
Complementary methods:
Deployment of devices into diseased cadaver hearts, perfused cadaver models and/or specialized animal models
Visible Heart® Lab
Physiological prep that recreates in vivo perfusion and flows through heart. Enables re-animation of human donor hearts with calcification and congenital physiology.
Interactions between device and anatomy can be directly visualized

12. Wrap Up
Definition of pre-clinical evaluation requirements for percutaneous valve therapies is an evolving endeavor.
Guidance documents and standards provide a roadmap, but may not cover all applicable considerations for a given design.
Strong collaboration among industry, regulatory agencies and clinical centers is crucial to determine the appropriate evaluation approaches for perctaneous heart valve therapies.