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Benefit-Risk Factors to Consider 

When Determining Substantial Equivalence in 

Premarket Notifications [510(k)] with Different 

Technological Characteristics

Ifeanyi Uwemedimo, PhD

Biomedical Engineer/Device Determination Policy Analyst

Office of Regulatory Programs (ORP)/Division 1

Center for Devices and Radiological Health
3

Objective

WHAT

• Purpose and policy in the final guidance

WHO

• Who performs a benefit-risk assessment

• How the guidance can be applied to help guide benefit-risk assessment in 

a 510(k)

• Factors to consider when conducting a benefit-risk assessment in a 

510(k)

HOW

WHEN

• When a benefit-risk assessment is recommended in a 510(k)

The objective is to understand the following:
4

Background Guidance History

• Draft Guidance issued on July 15, 2014

• Nine groups/individuals submitted 96 comments 

o Medical device manufacturers

o Trade organizations

o Patient and consumer advocacy groups

o Public citizens

• Revisions to the draft guidance fell into one of the three (3) categories:

Clarified that the 

guidance does not 

change the current 

510(k) process or SE 

standard

Clarified that benefitrisk assessment does 

not imply submission 

of clinical data 

Clarified what is 

expected in a 510(k) 

benefit-risk 

assessment
5

How To Use A Guidance Document

Guidance is not binding on FDA or the public

Final guidance 

Represent the current thinking of 

the FDA on a particular topic. 

Draft guidance 

Intended for input and not for 

implementation

Alternative approach from policy outlined in a guidance document should be 

documented with appropriate justification and supervisory concurrence.
6

Final Guidance Overview

• This guidance outlines the policy for evaluating substantial equivalence in a 510(k) when 

the benefit-risk profile of a new device is different from that of the predicate device based 

on performance data.

Scope

• An increase in risk and increase or equivalent benefit (↑/↑=) or

• A decrease in benefit and a decrease or equivalent risk (↓/↓=) when comparing a new 

device to a predicate device. 

Situations When Benefit-Risk Assessment is Recommended

•Valid scientific evidence is used to establish the probable benefits and risks of a device 

compared to a predicate device. Valid scientific evidence can include both non-clinical 

and/or clinical performance data. 

Performance Data in 510(k)

•Guidance outlines factors to consider when comparing the benefit-risk profile of a new 

device and a predicate device to determine substantial equivalence such as magnitude of 

benefit, severity of risk, probability and uncertainty. 

Benefit Risk (B-R) Factors to Consider

•Guidance includes examples scenarios which walk through whether a benefit-risk 

assessment is recommended, and if so, factors for consideration and how the benefit-risk 

assessment informed the SE determination.

Example Section
7

Implementation of 510(k) Benefit Risk Guidance

This guidance does not change the 510(k) premarket review standard or create extra 

burden on a submitter to provide additional performance data from what has 

traditionally been expected for 510(k)s.

510(k) Benefit-Risk Guidance:

• Serves as an aid for evaluating benefit-risk factors to determine substantial 

equivalence (SE) in a 510(k)

• Provide guidance specifically in situations when the benefit-risk profile of a new 

device is different from that of the predicate device

• Provides additional clarification on factors that FDA takes into consideration when 

evaluating the benefit-risk profile of a new device when compared to a predicate 

device

• Improves the predictability, consistency, and transparency of the 510(k) premarket 

review process
8

Benefit Risk Assessment in a 510(k)

New Device 

Benefits/Risks

Valid Scientific Evidence

Predicate Device 

Benefits/Risks

The benefit-risk framework for a 510(k) is fundamentally different from the benefit-risk (B-R) 

framework for other premarket submissions because a comparison is made between the 

benefit-risk profile of the new and predicate device in order to determine substantial 

equivalence.

510(k) B-R Assessment

Comparison of B-R profile

Valid scientific evidence (VSE) is used to establish the probable benefits and risks of a 

device. VSE can include both non-clinical and/or clinical performance data. These types of 

performance data are evaluated by FDA during premarket review.

NOTE: Clinical data is not common in 510(k)s.

Benefits

Risks

Valid Scientific Evidence

PMA/De Novo B-R Assessment

Independent assessment

Benefits

Risks

Valid Scientific Evidence

IDE B-R Assessment

Independent & Investigational 
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Policy - Benefit Risk Profile Comparison

• Differences in benefit-risk profiles does not 

automatically result in a Not Substantially 

Equivalent (NSE) decision. 

• FDA determines whether the differences 

impacts SE.

• Guidance is intended to provide direction when 

the benefit-risk profile of a new device is 

different from that of the predicate device. 

• Guidance specifies two situations when a 

benefit-risk assessment is appropriate. See 

quadrants 1 and 3 in the table. 

FDA understands that there might be variability in the benefit-risk profile comparison. 

New Device Predicate Device

Benefit

Risk

Benefit

Risk
10

Policy

Table serves as a guide for when benefit-risk assessment is recommended in a 510(k). This table 

should be used with the guiding principles provided in the rest of the guidance.

INCREASE IN RISK DECREASE /EQUIVALENT RISK

INCREASE/ EQUIVALENT 

BENEFIT

Conducting a benefit-risk assessment is 

recommended.

FDA evaluates the nature of the increased risk and 

considers whether additional measures may help to 

mitigate the increased risk. FDA will generally not 

deem a new device SE to a predicate when the 

increased risk cannot be mitigated and is not 

accompanied by an increase in benefit.

Conducting a benefit-risk assessment is likely not 

recommended to determine whether the new device 

is “as safe and effective” as the predicate device.

FDA will generally determine the new device SE to the 

predicate device when there is increase/equivalent benefit 

and decreased/equivalent risk.

DECREASE IN BENEFIT

Conducting a benefit-risk assessment is likely not 

recommended to determine whether the new 

device is “as safe and effective” as the predicate 

device.

FDA will generally determine the new device NSE to 

the predicate device when there is a decrease in 

benefit and an increase in risk.

Conducting a benefit-risk assessment is 

recommended.

If the aggregate benefit of a new device is decreased in and 

the risk level is decreased, FDA may determine the new 

device to be SE if the differences do not impact whether 

the new device is at least “as safe and effective”. However, 

if there is a decrease in benefit without a decrease in risk, 

FDA would likely find a device NSE to the predicate 

especially if the benefit-risk assessment confirms that the 

new device is not “as safe and effective” as the predicate 

device.

1 2

4 3
11

When during a 510(k) review can benefit-risk 

assessment be conducted?

After it is determined...

• That the predicate device is 

legally marketed 

• The intended use of the new 

and predicate device are the 

same. 

• Differences in technological 

characteristics do not raise 

different questions of safety 

and effectiveness. 

[Cross reference SE guidance* 

containing the decision making 

flowchart.]

*The 510(k) Program: Evaluating Substantial See Figure 1 in 510(k) Benefit-Risk Guidance

Equivalence in Premarket Notifications 

[510(k)] 

:
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Factors to Consider When Assessing Benefit Risk

• FDA considers the following factors 

when assessing the extent of the 

probable benefit(s): 

o Type of benefit(s) 

o Magnitude

o Probability that the patient will 

experience one or more 

benefit(s) 

o Duration of effect(s)

• FDA considers the following factors 

when assessing the extent of 

probable risk(s): 

o Type of risk

o Severity

o Rate

o Probability of harmful event

o Probability that the patient will 

experience one or more harmful 

events

o Duration of harmful event(s)

o Risk from false-positive or false 

negative results for diagnostic 

devices

BENEFIT RISK

FDA evaluates the aggregate benefits and aggregate risks of a new device and compares it 

to that of a predicate device. 
13

Additional Factors to Consider When Assessing Benefit-Risk

• Uncertainty. FDA considers the extent of uncertainty of a benefit or risk. Uncertainty may arise 

from quality of valid scientific evidence. (Example: Less than optimal bench testing, inadequate 

data analysis, poor study design, etc.)

• Disease Condition. Consideration of the clinical manifestation of disease/condition, how it’s 

treated and how it affects the patient.

• Innovative Technology. Consideration for whether a new device has technological improvements 

that are important for public health.

• Patient Tolerance for Risk & Perspective. Consideration of how the patient tolerates risk and 

perceives benefit. Risk tolerance varies amongst patients.

• Benefit for the Health Care Professional, Patient or Caregiver. FDA recognizes that there are 

tools that positively affect patient management.

• Risk Mitigation. Use of mitigation strategies could minimize probability of a harmful event. 

(Example: Labeling) 

• Post-Market Data. Post-market data could provide understanding of benefits and risks of similar 

device types.

Uncertainty

Patient 

Tolerance & 

Perspective

PostMarket 

Data 

Disease 

Condition

Innovative 

Technology

Risk 

Mitigation

Benefit for 

healthcare 

professional, 

patient or 

caregiver
14

 Submitter: 

• If the benefit-risk profile comparison falls in quadrants 1 or 3, the submitter can include 

a benefit-risk assessment in a 510(k) submission, but it is not required.

 FDA: 

• If the benefit-risk profile comparison falls in quadrants 1 or 3, the Lead Reviewer 

performs a benefit risk assessment.

• If there is not sufficient information in the submission, the Lead Reviewer can request 

summary benefit-risk information from the submitter to help complete the benefit-risk 

assessment. 

Who Performs a Benefit Risk Assessment?
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Example Deficiency

Based on the information provided in your submission, it is not clear how the differences in benefits and risks of 

your device, when compared to the predicate device, impact substantial equivalence (SE). Thus, to help us 

understand the benefit-risk profile of your device in comparison to the predicate device, please provide the 

following:

a. The benefits of your device (type of benefit, magnitude, probability of the patient experiencing one or 

more benefit, duration of effect(s))

b. The risks associated with use of your device (type of risk, severity, rate, probability, duration)

c. Summary of any additional factors to be taken into consideration (e.g., uncertainty, risk mitigation, postmarket data, innovative technology, patient perspective)

d. Conclusionon whether the benefits associated with use of your device outweighs the risks in comparison 

to the predicate device

This information will help us conduct a benefit-risk assessment and inform our substantial equivalence (SE) 

decision. In your response, we recommend that you consider the factors outlined in the guidance “BenefitRisk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications (510(k)) with 

Different Technological Characteristics”

(https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM404773). 

Please note that a summary of how the benefit-risk assessment was used to support SE should be included 

in your 510(k) Summary consistent with 21CFR 807.92(b)(3). 

If there is not sufficient information in the submission to complete the benefit-risk 

assessment, the Lead Reviewer can request for additional information.
16

Example 1 

Scenario: The manufacturer of a male condom, fabricated from 

synthetic material, claimed SE to a natural rubber latex condom. 

The only technological difference between the two devices was 

the material, i.e., synthetic versus natural rubber latex. There was 

concern that the new material may not perform as well as the 

natural rubber latex material and could result in breakage or 

slippage during sexual intercourse. These risks can be evaluated 

in a clinical study comparing the performance of the synthetic 

condom to a cleared natural rubber latex condom. The device 

manufacturer sought to demonstrate non-inferiority to natural 

rubber latex condoms using a primary endpoint evaluating 

clinical failure (i.e., slippage and breakage) during sexual 

intercourse. Based on the clinical study, the primary endpoint for 

clinical failure was met; however, the slippage rate for the new 

device was slightly higher than that of natural rubber latex 

condoms.

Is a benefit-risk assessment 

recommended?

Yes. A benefit-risk assessment is 

recommended to assess the increase 

in risk and increase in benefit. 

Training Examples are from the Final 510(k) Benefit-Risk Guidance:

Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications (510(k)) with 

Different Technological Characteristics
17

Benefits: 

• The new device, condom fabricated from synthetic material, provides another option for 

contraception and prophylaxis, which is particularly beneficial for users and their partners 

who are allergic to natural rubber latex.

Risks: 

• The clinical study showed that the occurrence of slippage was slightly higher. Increase in 

slippage increases the risk of undesired pregnancy and/or transmission of sexuallytransmitted infections (STIs). 

Additional Factors:

• Risk Mitigation: To mitigate the risk associated with the slightly higher slippage rate a 

warning was placed on all labeling stating that the device should only be used if the user 

has an allergy to natural rubber latex. 

Example 1 continued... 
18

Example 1 continued... 

SE Analysis:

• The new device provides another contraception and prophylaxis option, which is 

particularly beneficial for patients and their partners who are allergic to natural rubber 

latex. 

• However, as compared to the predicate device, the new device may have the potential 

for increased slippage during sexual intercourse, resulting in an increased risk of 

undesired pregnancy and transmission of STIs. 

• This risk between the new device and the predicate device is partially mitigated by 

warnings on the labeling. 

• Because the increase in risk, which may be partially mitigated by warnings on the 

labeling, is accompanied by an increase in benefit, the new device would likely be found 

SE.
19

Scenario: A self-contained device uses a low-level laser therapy for the 

treatment of toenail fungus (onychomycosis). The new device uses:

• A different wavelength than the predicate device 

• Wavelength produces different photo-biological effects

• Has a power level that much lower than the predicate device

• Has a constant energy delivery sequence in comparison to the 

pulsing sequence of the predicate device. 

For the treatment of onychomycosis, the purported mechanism of 

action is either a photo-biological process in which the laser 

wavelength interacts with chromophores within the fungal cells 

resulting in cell death or may involve a thermal effect on the fungal cells 

at temperatures below those required for tissue coagulation or tissue 

vaporization. 

• Due to the differences in technological characteristics and possible 

changes in principles of operation between the new device and 

predicate device, the manufacturer provided clinical data to 

compare their device to the predicate device. The device would 

have equivalent benefit as the predicate device if it had a 

comparable amount of responders. A responder is a subject whose 

toenail is effectively treated according to predefined success criteria. 

The clinical data demonstrated that the responder rate was lower 

in the group treated with the new device. However, the new 

device posed a lower risk than the predicate device because of the 

lower power level.

Is a benefit-risk assessment 

recommended?

Yes. A benefit-risk 

assessment is recommended 

to assess the decrease in risk 

and decrease in benefit. 

Example 2
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Benefits: 

The new device offers an alternative treatment modality than the predicate device. However, the 

study failed to meet the primary endpoint because it showed a lower responder rate.

Risks: 

Reduction in power in the new device offers lower risk in comparison to the predicate device due to 

the minimal side effects.

Additional Factors:

• Uncertainty: There were significant data inconsistencies regarding the manufacturer’s photographs 

and data set in comparison to the predicate device thus, raising significant concerns regarding the 

reliability of the data.

• Risk mitigation: Wearing of laser safety protective glasses to prevent accidental eye damage from 

laser exposure.

Example 2 continued... 
21

SE Analysis:

• The clinical data failed to demonstrate that the new device provided benefit for the 

majority of treated patients. 

• Although the new device imparts less risk, the benefit of the device is considerably 

smaller than the predicate device. 

• Data provided presented significant inconsistencies and was considered to be unreliable.

• Overall, due to the level of uncertainty and the relatively small benefit observed, this 

device would likely be found NSE based on lack of adequate performance data.

Example 2 continued... 
22

Key Message

• Purpose of the 510(k) Benefit-Risk Guidance 

Intended to serve as an aid for evaluating the benefit-risk profile of a new device 

especially when there are differences in the benefit-risk profile of a new device when 

compared to a predicate device. 

• Understand when a benefit-risk assessment is performed in a 510(k)

When there is:

1) an increase in risk and increase or equivalent benefit or 

2) a decrease in benefit and a decrease or equivalent risk 

when comparing a new device to a predicate device.

• The benefit risk profile of a new device does not have to be identical to that of a 

predicate device

FDA assesses the differences between the benefit-risk profile of a new device and a 

predicate device. This assessment informs the final substantial equivalence decision.
23

Resources

• Deciding When to Submit a 510(k) for a Change to an Existing Device

• The 510(k) Program: Evaluating Substantial Equivalence in Premarket 

Notifications [510(k)] 

• Patient Preference Information – Voluntary Submission, Review in Premarket 

Approval Applications, Humanitarian Device Exemption Applications, and De 

Novo Requests, and Inclusion in Decision Summaries and Device Labeling

Link to Final 510(k) Benefit-Risk Guidance:

• Benefit-Risk Factors to Consider When Determining Substantial Equivalence 

in Premarket Notifications (510(k)) with Different Technological 

Characteristics 

Link to Certain Pre-Existing Guidance Documents:
24

Questions?

Email 510(k) Program mailbox

510k_Program@fda.hhs.gov

For general questions, email the Division of Industry and 

Consumer Education: DICE@fda.hhs.gov

Slide Presentation, Transcript and Webinar Recording will be 

available at:

http://www.fda.gov/training/cdrhlearn

Under Heading: How to Study and Market Your Device; In the 

section: Premarket Notification (510k)

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