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

2. 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

3. 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)

4. 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

5. 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”

6. 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

7. 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

8. 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)

9. 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

10. 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

11. 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

12. 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

13. 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

14. Summary Please review and comment on the new HVGD
Follow Federal Register Instructions (FDA-2009-D-0559)
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

15. 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)

16. 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, WO
Silver Spring MD