Bram Zuckerman, MD, FACC Director, FDA Division of Cardiovascular Devices

1. Cardiovascular Device Development and Approval: An FDA Division of Cardiovascular Devices Perspective Bram Zuckerman, MD, FACC Director, FDA Division of Cardiovascular Devices Office of Device Evaluation Center for Devices and Radiological Health

2. Disclosure Statement of Financial Interest All TCT 2018 faculty disclosures are listed online and on the App. I, Bram Zuckerman, MD, 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 in the context of the subject of this presentation.

3. FDA and Public Health “The ultimate measures of the FDA’s success should reflect its fundamental goals and go beyond such intermediate measures as the number of facilities inspected or drugs approved.”

4. What does Major League Baseball have to do with US Device Approval? • Complex and challenging endeavors – significant resource and time commitment • Know the fundamental principles (pitching, defense, and advancing runners) • Money expended doesn’t necessarily correlate with a winning team or World Series Championship – Develop a sound strategy

5. Medical Device Classes: Class I General Controls Most exempt from premarket submission Class II Special Controls Premarket Notification [510(k)] Class III Premarket Approval Require Premarket Application [PMA] Additional Classification: De Novo Device "types" that have never been marketed in the U.S., but whose safety profile and technology are now reasonably well understood Humanitarian Device Exemption (HDE) Devices for orphan diseases intended to benefit patients in diagnosis and/or treatment of disease or condition affecting or manifested in fewer than 8,000 patients per year in the United States Risk-Based Paradigm

6. PMA • Higher risk devices • Establish reasonable assurance of safety and effectiveness • Bench - Animal - Human • Similar to new drug approval process

7. FDA Device Approval: Critical Issues 1. Pre-clinical Testing • Are bench and animal studies acceptable? 2. Pivotal Trial – • Design: Minimize bias and confounding • Design: Use sample size reestimation or Bayesian design to get sample size right • 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? 3. Manufacturing • Can device be built safely for commercial distribution? 4. Is the Device Label truthful and accurate?

8. FDA Device Approval: Manufacturing Posted on FDA Voice (June 16, 2014) By: Jeffrey Shuren, M.D., J.D. CDRH Center Director • “We approved the Sapien XT THV despite observing certain quality system violations during a recent inspection at the Edwards manufacturing facility where the Sapien XT delivery systems and accessories are made. Quality system requirements govern the design, manufacture, and distribution of devices, and we conduct such inspections to assure that devices are safe and effective. When violations occur, according to federal law, we cannot approve a company’s medical device—unless, we allow deviation from quality system requirements through what is known as a “variance.”

9. Analysis of Pivotal Device Trials • Statistical significance is different from clinical significance • There is no perfect device surrogate – • CDRH deals routinely with partial device surrogates • Understand their limitations • Role of predictive modeling for hard endpoints • Composite endpoints have limitations – • A combined endpoint needs to retain its interpretability • The basic unit of analysis is the patient and not the device • Advisory panels offer advice to the FDA in an open and transparent environment • Totality of data in a device trial should indicate a beneficial risk/benefit ratio

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

11. Key Points to Consider to Connect the Dots • Anticipate device and technique iteration – How will these realitiess be factored into the device development program? • Develop an integrated pre/post-market program – What is the appropriate balance and what are reasonable post-market goals and expectations? • Consider developing a more integrated global device strategy to avoid wasting resources and duplication of effort

12. Connecting the Dots (continued) • Early communication with FDA and CMS is key • Parallel Review is one option • Requesting a sponsor/FDA/CMS meeting is another option • Investigate US EFS program through FDA and MDIC interactions • Investigate simplified seamless trial design through • FDA and MDIC • NEST • CDCRN • Heart Failure Collaboratory

13. Conclusion • Complex and challenging technology • No shortcuts • Start working with the FDA early in the process • Innovation not at the expense of safety and effectiveness

14. Striking the Right Balance Between Pre- and Postmarket Evaluation • Use appropriate amount of pre-market data to make primary decisions about approvability of new devices (safety, effectiveness) • Use postmarket data 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.

15. Research Conducted Outside the US (OUS) • OUS clinical data can be used to support approval of devices in the US • Generalizability of OUS study results to the patient population in the US is a key issue. • Sponsor must address factors such as demographics, standard of care, protocol employed • Clinical studies should be conducted in compliance with applicable standards and with adequate human subject protection to ensure data quality • Good Clinical Practices (GCPs) – see International Conference on Harmonisation (ICH) E6 guideline • A global clinical trial may be a useful alternative to consider