Benefit-Risk Determinations in Medical Device Appendix A

Appendix A
Worksheet for Benefit-Risk Determinations

Factor	Questions to Consider	Notes
Measures for Effectiveness of Devices (the extent of the benefit)
Type of benefit(s)	What primary endpoints or surrogate endpoints were evaluated? What key secondary endpoints or surrogate endpoints were evaluated? Which endpoints or surrogate endpoints were not assessed in the trials but would have been relevant? Would their outcome change your decision?
Magnitude of the benefit(s)	For each primary and secondary endpoint or surrogate endpoints evaluated: What was the magnitude of each treatment effect? Was this magnitude clinically significant?
Probability of the patient experiencing a benefit	How did the benefits evaluated vary across sub-populations? (Note specific subpopulations, nature of difference and any known reasons for these differences.) Was there a variation in public health benefit for different populations?
Duration of effect(s)	Could you determine the duration, if relevant, of each treatment effect, including primary and secondary endpoints? If so, what was it?
Metrics for Safety of Devices (the extent of harmful events)
Severity and types of harmful events (events and consequences):
Serious adverse events	What are the serious adverse events for this product?
Non-serious adverse events	What are the non-serious adverse events for this product?
Other harms	What other harms may result from the use of this product?
Probability of a harmful event	What is the incidence of each harmful event in the study population? How much uncertainty is in that estimate? (i.e., are you concerned that the incidence of the harmful event in the study population may not represent the true incidence in the intended patient population?) How does the incidence of harmful events vary by subpopulation?
Duration of harmful events	How long does the harmful event last? Is the harmful event reversible? What type of intervention is required to address the harmful event?
Risk of false-positive or false-negative for diagnostics
Additional Factors for Weighing Benefits and Risks of Devices
Uncertainty:
Quality of the study design	How robust were the data?
Quality of the conduct of the study
Robustness of the analysis of the study results
Generalizability of results (e.g., training of MDs, learning curve)
Patient tolerance for risk	Is there any current literature that assesses patient tolerance for risk in light of different levels of perceived benefit to treat the condition in question?
Disease severity
Disease chronicity
Availability of alternative treatments or diagnostics	What other therapies are available for this condition? How effective are the alternative treatments? How does their effectiveness vary by sub-population? How well-tolerated are the alternative therapies? How does their tolerance vary by sub-population?
Risk mitigation	Could you identify ways to mitigate the risks such as using product labeling, establishing education programs, providing add-on therapy, etc?
Novelty of technology	How well is the medical need this device addresses being met by currently available therapies?

Summary of the Benefit(s)	Summary of the Risk(s)	Summary of Other Factors
Conclusions Do the probable benefits outweigh the probable risks?

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¹ In addition to §513(a), the criteria for establishing safety and effectiveness of a device are set forth in 21 CFR 860.7. Subsection (b)(1) notes, “In determining the safety and effectiveness of a device … the Commissioner and the classification panels will consider the following, among other relevant factors…The probable benefit to health from the use of the device weighed against any probable injury or illness from such use.” (21 CFR 860.7(b)).

To make this determination, “the agency relies upon only valid scientific evidence.” (21 CFR 860.7(c)(1)). Valid scientific evidence is defined as “evidence from well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts, and reports of significant human experience with a marketed device, from which it can fairly and responsibly be concluded by qualified experts that there is reasonable assurance of the safety and effectiveness of a device under its conditions of use.” (21 CFR 860.7(c)(2)).

A reasonable assurance of safety occurs when “it can be determined, based upon valid scientific evidence, that the probable benefits … outweigh any probable risks.” The evidence of which is demonstrated by establishing, “the absence of unreasonable risk of illness or injury associated with the use of the device for its intended uses and conditions of use.” (21 CFR 860.7(d)(1).

Similarly, a reasonable assurance of effectiveness occurs when “it can be determined, based upon valid scientific evidence … the use of the device for its intended uses … will provide clinically significant results.” (21 CFR 860.7(e)(1)). The evidence of which is demonstrated principally through “well-controlled investigations” (see 21 CFR 860.7(e)(2)) as defined in 21 CFR 860.7(f)

² Under §513(a)(2)(C) of the FD&C Act, FDA may weigh “any probable benefit to health from the use of the device against any probable risk of injury or illness from such use” not only in determining there is a reasonable assurance of safety and effectiveness for a device evaluated under a PMA, but also in determining substantial equivalence under §513(i).

For purposes of this guidance the term “studies” is equivalent to the term “investigations.”

³ 21 CFR 860.7(e) “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”, as demonstrated by well-controlled investigations.

⁴ 21 CFR 860.7(d) “There is reasonable assurance that a device is safe when it can be determined, based upon 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 any probable risks. The valid scientific evidence used to determine the safety of a device shall adequately demonstrate the absence of unreasonable risk of illness or injury associated with the use of the device for its intended uses and conditions of use.”

⁵ 21 CFR 803.3.