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

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.

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.

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

PMDA - Medical Device Review

Innovative Device Trials Evolution of Populations Studied ERA 1 ERA 2 ERA 3 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

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

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

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

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

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)

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

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

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

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!!

Thank You! John Laschinger, MD john.laschinger@fda.hhs.gov

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

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.

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

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

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.

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

PMDA - Medical Device Review 26

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

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)

Japan – USA Regulatory Synergies Harmonization by Doing (HBD)

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

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

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

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

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!

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

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?

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)

Evolution of Patient Populations Studied ERA 1 ERA 2 ERA 3 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

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