1. 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 | San Francisco | November 7, 2011

2. Jodi Akin, RN, MS
Employee: Edwards Life Sciences

3. 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.

4. 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

5. 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?

6. 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.

7. 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

8. 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

9. 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),

10. 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

11. 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

12. 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

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

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

15. 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

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

17. 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

18. 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

19. Thank You