1. Reasonable Assurance of Safety and Effectiveness: 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. 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

5. Demonstrating Safety Preclinical evaluation Clinical studies
Risk analysis
Computational modeling, where appropriate
Testing – mechanical, electrical, software, biocompatibility, sterility, etc.
Animal studies
Clinical studies
Ability to provide rates of expected major adverse events with sufficient precision
Adequate sample size to detect unanticipated events
Evaluation of the learning curve for optimal device usage
Complete and comprehensible instructions for use

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. 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 7

8. The Total Product Life Cycle
Regulation of device technologies requires a total product life cycle approach. 8
HHS/FDA/CDRH

9. 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. 9 9