1. Medical Device Regulatory Essentials: 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 1 1

2. Disclosures
I have nothing to disclose 2

3. FDA’s and CDRH’s Public Health Mission
FDA’s role: To assure that drugs and devices are safe and effective for their intended uses and that labeling and packaging is truthful and informative
FDA’s Center for Devices (CDRH) is responsible for establishing a reasonable assurance of the safety and effectiveness of medical devices prior to marketing in the U.S.
Regulation is a balancing act -
Get safe and effective devices to market as quickly as possible while ensuring that devices currently on the market remain safe and effective

4. Risk-Based Paradigm Medical Device Classes: Additional Classification:
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 4,000 patients per year in the United States 4

5. Safety and Effectiveness Defined in CFR
Safety - benefits outweigh risks
“There is reasonable assurance that a device is safe when it can be determined based on valid scientific evidence that the probable benefits to health from use of the device for its intended uses and conditions of use, when accompanied by adequate directions and warnings against unsafe use, outweigh the probable risks.”
Effectiveness - results are clinically significant
“There is reasonable assurance that a device is effective when it can be determined, based upon valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warnings against unsafe use, will provide clinically significant results.”
21 CFR 860.7
What is S? Here is the language in the regs, and I will be discussing some of the caveats, but essentially safety means that the Benefits outweigh risks

6. Device Performance vs. Device Effectiveness
Focuses on device mechanism of action
For example: Enlarges arterial lumen, occludes LAA orifice
Effectiveness
Focuses on clinical outcomes
For example: Reduces repeat revascularization rates, prevents strokes
Limited role for surrogate endpoints
It is important to note the difference between device performance, a standard requirement in the EU, and effectiveness, a US requirement. Performance focuses on…

7. Pivotal Trial Essential Elements
Objective, meaningful study endpoints
Appropriate inclusion/exclusion criteria
Appropriate control group (standard of care)
Minimize bias (with blinding if possible)
Minimize missing data
Statistical analysis plan
Prespecified study hypotheses
Sample size justification based on best estimates of event rates
Control of type I error (rule out chance)
Study FDA and sponsor slides and panel transcripts

8. 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 8

9. The Total Product Life Cycle
Regulation of device technologies requires a total product life cycle approach. 9
HHS/FDA/CDRH

10. 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. 10 10

11. 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 11 11