1. Collaborative Program: Is It Ready for Valve Studies?
John Laschinger, MD
FDA, CDRH, ODE, DCD, ICDB

2. Disclosure Statement of Financial Interest
I DO NOT have a financial interest, arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest.

3. FDA and PMDA Mission Statements
FDA: “Protecting the public health by assuring that … medical devices intended for human use are safe and effective. Advancing the public health by helping to speed product innovations”.
PMDA: “Our obligation is to protect the public health by assuring safety, efficacy and quality of pharmaceuticals and medical devices…monitoring of their post-marketing safety…providing relief services for adverse health effects.

4. FDA- Medical Device Reviews of Innovative Devices
Higher risk devices - PMA
Establish reasonable assurance of safety and effectiveness
Bench - Animal - Human
Similar to new drug approval process

5. PMDA - Medical Device Review

6. Innovative Device Trials Evolution of Populations Studied
ERA ERA ERA ERA 4
INOPERABLE
STANDARD OP PATIENT
HIGH RISK OPERATIVE
Treat a Different Disease (add AI)
Modify
Device
“TOO WELL”
Era 1 : First person to eat an egg must have been starving

7. Clinical Trial Considerations for Innovative Devices
Risk Assessment Determines the Patient Population to be Studied
Determining level of operative risk is subjective
Combination of STS risk predictor and surgeon assessment
Valid Comparator
Control group depends on therapy patient would receive if they were not enrolled in the study
Separate Trials
Implantation approach and/or
Disease etiology
Collaboration and Similar expertise
Cardiologists and Cardiac Surgeons

8. Population Studied Determines Trial Design
Inoperable
Device
Optimal
Medical Rx
Operable
Device
Standard
Operation

9. Innovative Device Trials Selection of Study Population
Selection of Study Population determines:
Patients enrolled (inclusion/exclusion criteria)
Control Group - How the patient would be
treated today in a center of excellence if
the new device were not used
Clinically relevant endpoints – Death, stroke, etc
Timing of endpoints – duration of follow-up
Statistical design (superiority, non-inferiority)
Risk/benefit determination
Labeling/marketing/reimbursement

10. Innovative Devices Key Features of Market Entry Trials
Study population identified with appropriate comparator
Team approach (Cardiologist and CV Surgeons)
Clinically relevant hypotheses
Sample size justification
Clear definition(s) of success
Clinically relevant endpoints
Appropriate for device, study population and era
Easily interpretable with clear definitions
Objective evaluation methods and appropriate data collection tools
Independent CEC, DSMB and Core Labs
Protocols US and OUS – same (ideal) or complementary

11. Primary Hypothesis Considerations
Less Invasive First Generation Percutaneous Intervention
Less effective (size of delta)
Trade superiority for safety (? clinically important)
Risk/benefit tradeoff is difficult to define
Later Stage - Standard Trial Design
Effectiveness (most often superiority)
Safety (commonly non-inferiority)

12. Percutaneous Valve Trial Design “One Size Does Not Fit All”
Type of device and intended use (Era) Determines
Patient population (if low risk are included, bar is higher)
Hypotheses
Clinical trial design
Population/Era Determines Comparator
Device vs. OMM
Device vs. Device
Device vs. Standard Surgical Therapy
Recognize causes of bias in unblinded trials
Design
Analysis
Need for randomization?
Device vs. Performance Goal
If the inclusion criteria include good risk patients as well as high risk patients, then results have to be better
Risk/benefit – will depend on more than meeting endpoints
Standard non-inferiority with a large delta won’t support labeling
Comment on roll in patients
Causes of trial bias in unblinded trials

13. FDA Device Approval Percutaneous Valves
Evaluation of Percutaneous Valve devices:
Pre-Clinical Studies
Bench
Animal
OUS clinical trials
Pivotal Trial
Design: Minimize bias and confounding
Execution: Minimize amount of missing data
Analysis: Rule out chance (prospective endpoints, hypotheses)
Clinically meaningful results:
Clearly demonstrated?
Durable over a clinically relevant time period?
Labeling is truthful and accurate
Risk/Benefit balance is favorable vs. current therapy
Accept MR as a clinical surrogate
Can you vs should you
SAFETY AND EFFECTIVENESS

14. Innovative Devices Need for World Wide Follow-up
Percutaneous Valve Device Trials:
Unknown long term durability and safety
Relative performance vs. standard operative therapy
Unknown long term effects on:
heart failure progression
residual perivalvular/valvular regurgitation
ventricular reverse remodeling with or without residual regurgitation
the ability to do subsequent valve repair or replacement
Minimum follow-up of 5-10 years may be required

15. Regulatory Synergies USA and Japan
FDA – PMDA
Similarities > Differences
Similar Missions
Similar processes
Similar trial design requirements
Both Emphasize
Promotion of Innovative Technology
Total Product Lifecycle
Collaborative Program
ready for
study of Percutaneous Valves!
Let’s do it!!

16. Thank You!
John Laschinger, MD

19. Innovative Devices Later Stage Trials
Expectations for Lower Risk Populations
Endpoint evaluation time likely longer
May need co-primary endpoint or powered secondary endpoints with specific statistical plan for secondary endpoints defining “success”
Possible EPs – survival, hemodynamics, echo dimensions, LV mass, function (VO2, 6MWT), aortic/mitral insufficiency, QOL

20. Innovative Device Evaluation Pre- and Post-market Evaluation
Pre-market data – used to make primary decisions about approvability of new devices (safety, effectiveness)
Post-market data used to
supplement our understanding about device and operator performance
identify device malfunctions and take corrective action as necessary
modify pre-market expectations for next generation devices.

21. Innovative Device Trials Relevant Clinical Endpoints
Clinical Endpoints Must Be:
Clearly defined
Supportive of each other
Clinically relevant
Easily interpretable (difficult with composites)
Minimally affected by trial bias
Appropriate for
Device being studied
Patient Population being studied
Trial era

23. Regulatory Synergies in Device Innovation
Japan – USA
Regulatory Synergies in Device Innovation
John Laschinger, MD
FDA, CDRH, ODE, DCD, ICDB

24. Mission Statements
FDA: “Protecting the public health by assuring that … medical devices intended for human use are safe and effective. Advancing the public health by helping to speed product innovations”.
PMDA: “Our obligation is to protect the public health by assuring safety, efficacy and quality of pharmaceuticals and medical devices…monitoring of their post-marketing safety…providing relief services for adverse health effects.

25. FDA- Medical Device Reviews of Innovative Devices
Higher risk devices
Establish reasonable assurance of safety and effectiveness
Bench - Animal - Human
Similar to new drug approval process

26. PMDA - Medical Device Review26

27. Japan – USA Regulatory Synergies Harmonization by Doing (HBD)
What is the HBD Initiative
Pilot project
launched in December 2003
seeks regulatory convergence between FDA and MHLW-PMDA
premarket review of device cardiovascular technology
Utilize parallel development, application submissions and review of actual medical device projects
Objective - eliminate redundancies, added costs, and time delays inherent in sequential trials

28. Japan – USA Regulatory Synergies Harmonization by Doing (HBD)
Participants
FDA and the Center for Devices and Radiological Health (CDRH)
Japan’s Ministry of Health Labour and Welfare (MHLW) and its review agency, the Pharmaceutical Medical Devices Agency (PMDA)
Duke Clinical Research Institute (DCRI) and Japanese Academic Community (JAG)
Japanese and US Medical Device Industry and trade Associations (JFMDA and ADVA MED)

29. Japan – USA Regulatory Synergies Harmonization by Doing (HBD)

30. Japan – USA Regulatory Synergies Harmonization by Doing (HBD)
Purpose
International effort to develop global clinical trials and address regulatory barriers that may be impediments to timely device approvals
Cooperative effort to move both Japan and the U.S. toward international regulatory harmonization

31. Japan – USA Regulatory Synergies Harmonization by Doing (HBD)
Intent of the HBD Initiative
The intent of HBD is not simply to create guidance and discuss policy but to:
Develop common protocols for investigational clinical studies
Allow safe and effective "breakthrough" cardiovascular technologies to benefit patients worldwide

32. Japan – USA Regulatory Synergies Harmonization by Doing (HBD)
Benefits the HBD Initiative
More robust clinical trials
Improved clinical research infrastructure
Better clinical trial data
Identify and develop synergies between regulators
Facilitate early market availability -Innovation
Decrease lag time between U.S. and Japan
Foster collaboration - regulators, regulated industry, clinical researchers, patients and academia
International postmarket clinical studies and patient registries

33. Japan – USA Regulatory Synergies Harmonization by Doing (HBD)
Ultimate Goal of HBD Initiative
Reduce the amount of time it takes for a new therapy to be available that has been demonstrated to be reasonably safe and effective using global, harmonized protocols conducted in patients worldwide
Facilitate convergence of the regulatory processes between Japan and the United States.
Future expansion to other medical devices and regulatory bodies

36. Preparing for U.S. Clinical Studies
Preclinical Testing Requirements
Based on risk assessment
Most common reason for disapproval
Importance of boundary conditions
Animal Studies
GLP
Acute/chronic studies
Contact FDA before you start your study
Leveraging OUS Clinical Data
In theory, could be used to satisfy feasibility, pivotal or post-approval study requirements
Usually can NOT replace engineering/animal testing requirements
Dependent on patient population, protocol, treatment strategies, adequacy of follow-up
Pre-IDE Process – Come early, come often!

37. Pre-IDE Submission
Detailed device description
Specific indication for use
Failure Modes and Effects Analysis (FMEA) or Failure Modes, Effects and Criticality Analysis (FMECA)
Proposed protocols for:
Bench tests
Animal studies
Clinical study
Summary of any OUS clinical data
Specific questions for FDA to consider
Please provide protocols to FDA via Pre-IDE PRIOR to implementation to ensure applicability and adequacy of testing

38. FDA Device Approval: Critical Issues
Pre-Clinical Testing
Are bench and animal studies acceptable?
Manufacturing
Can device be built safely for commercial distribution?
Pivotal Trial
Design: Minimize bias and confounding
Execution: Minimize amount of missing data
Analysis: Rule out chance (i.e., several prospectively chosen, clinically relevant hypotheses with plan for alpha allocation)
Have clinically meaningful results been clearly demonstrated?
Is the Device Label truthful and accurate?

39. Treatment of Controls During Trials (Avoid Treatment Bias)
If control is OMM, need same contact with medical team and same excellent care
If control is surgery, need excellent surgeons to match excellent interventional cardiologists
Metric for surgeon ability (?STS quality score)

40. Evolution of Patient Populations Studied
ERA ERA ERA ERA 4
INOPERABLE
“TOO WELL”
STANDARD OP PATIENT
HIGH RISK OPERATIVE
Treat a Different Disease (add AI)
Modify
Device
Era 1 : First person to eat an egg must have been starving

41. The Total Product Life Cycle
Regulation of device technologies requires a
total product life cycle approach
HHS/FDA/CDRH