Contains Nonbinding Recommendations 
Benefit-Risk Factors to Consider 
When Determining Substantial 
Equivalence in Premarket 
Notifications (510(k)) with Different 
Technological Characteristics 
Guidance for Industry and 
Food and Drug Administration Staff
 
Document issued on September 25, 2018. 
The draft of this document was issued on July 15, 2014. 
For questions about this document regarding CDRH-regulated devices, contact the Premarket 
Notification (510(k)) Section at 301-796-5640 or 510k_Program@fda.hhs.gov. 
For questions about this document regarding CBER-regulated devices, contact the Office of 
Communication, Outreach and Development (OCOD) by calling 1-800-835-4709 or 240-402-
8010. 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Devices and Radiological Health 
Center for Biologics Evaluation and Research    Contains Nonbinding Recommendations 
Preface 
Public Comment 
You may submit electronic comments and suggestions at any time for Agency consideration to 
https://www.regulations.gov. Submit written comments to Dockets Management Staff, Food and 
Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 20852. Identify 
all comments with the docket number FDA-2014-D-0900. Comments may not be acted upon by 
the Agency until the document is next revised or updated. 
Additional Copies 
CDRH 
Additional copies are available from the Internet. You may also send an e-mail request to CDRH-
Guidance@fda.hhs.gov to receive a copy of the guidance. Please use the document number 1818 
to identify the guidance you are requesting. 
 
CBER 
Additional copies are available from the Center for Biologics Evaluation and Research (CBER), 
Office of Communication, Outreach and Development (OCOD), 10903 New Hampshire Ave., 
Building 71, Room 3128, Silver Spring, MD 20993, or by calling 1-800-835-4709 or 240-402-
8010, or by e-mail, ocod@fda.hhs.gov, or from the Internet at 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guid
ances/default.htm. 
    Contains Nonbinding Recommendations 
 
Table of Contents 
I.  Introduction ..............................................................................................................................4 
II.  Background ..............................................................................................................................5 
A.  The Statutory Standard for Substantial Equivalence ...........................................................5 
B.  Performance Data.................................................................................................................7 
III.  Scope ........................................................................................................................................8 
IV.  Benefit and Risk Factors ........................................................................................................10 
A.  Assessment of the Benefits of Devices ..............................................................................12 
(1)  Magnitude of the Benefit(s) .......................................................................................13 
(2)  Probability of the Patient Experiencing One or More Benefit(s) ..............................13 
(3)  Duration of Effect(s) ..................................................................................................14 
B.  Assessment of the Risks of Devices ..................................................................................14 
(1)  Severity, Types, Number, and Rates of Harmful Events ...........................................14 
(2)  Probability of a Harmful Event ..................................................................................15 
(3)  Probability of the Patient Experiencing One or More Harmful Event(s) ..................15 
(4)  Duration of Harmful Events (i.e., How Long the Adverse Consequences Last) .......15 
(5)  Risk from False-Positive or False-Negative Results for Diagnostic Devices............15 
C.  Additional Factors in the Assessment of the Benefits and Risks of Devices ....................16 
(1)  Uncertainty .................................................................................................................16 
(2)  Characterization of the Disease/Condition ................................................................16 
(3)  Innovative Technology ..............................................................................................16 
(4)  Patient Tolerance for Risk and Perspective on Benefit .............................................16 
(5)  Benefit for the Health-Care Professional, Patient, or Caregiver ................................17 
(6)  Risk Mitigation ..........................................................................................................17 
(7)  Postmarket Data .........................................................................................................18 
V.  Examples of Benefit-Risk Evaluation ....................................................................................19 
A.  Example 1: Change in Device Design ...............................................................................19 
B.  Example 2: Change in Technology and Possible Change in Principle of Operation.........20 
C.  Example 3: New Device with Higher Risk of Malfunction ...............................................21 
D.  Example 4: Material Differences Resulting in Different Device Performance .................23 
E.  Example 5: Different Principle of Operation Used to Achieve Same Therapeutic 
Outcome .............................................................................................................................24 
F.  Example 6: Comparative Testing Resulting in Substantially Different Results ................25  Contains Nonbinding Recommendations 
Benefit-Risk Factors to Consider When 
Determining Substantial Equivalence in 
Premarket Notifications (510(k)) With 
Different Technological Characteristics 
Guidance for Industry and 
Food and Drug Administration Staff
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic. It does not establish any rights for any person and is not binding on FDA 
or the public. You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff or 
Office responsible for this guidance as listed on the title page. 
I.  Introduction 
A submitter of a premarket notification submission (510(k)) must demonstrate to the Food and Drug 
Administration (FDA) that the new device is substantially equivalent (SE)1 to a legally 
marketed predicate device.2 This guidance is intended to help 510(k) submitters demonstrate 
substantial equivalence. This guidance does not add new regulatory requirements for submitters, it 
does not change the 510(k) premarket review standard nor does it create extra or new burdens on 
what has traditionally been submitted in 510(k)s. FDA developed this guidance to improve the 
predictability, consistency, and transparency of the 510(k) premarket review process. Furthermore, 
this document is intended to serve as an aid for evaluating the benefit-risk profile of a new device in 
comparison to the predicate device.  
The benefit-risk profile of a new device does not need to be identical to the predicate device for it to 
be SE to the predicate device. This document is intended to provide guidance when the benefit-risk 
profile of a new device is different from that of the predicate device. More specifically, FDA 
believes this document can be helpful in situations 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. In these situations, a benefit-risk assessment should be conducted 
comparing the benefits and risks of a new device to a predicate device. Such assessments may aid in 
                                                 
1 In this guidance, SE also refers to substantial equivalence. 
2 See section 513(i) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C.  360c(i)). 
 
4  Contains Nonbinding Recommendations 
the SE evaluation by assessing whether the new device is as safe and effective as the predicate 
device. 
This guidance and associated recommendations for evaluating benefit-risk factors in the context of 
SE are consistent with the FDA guidance The 510(k) Program: Evaluating Substantial Equivalence 
in Premarket Notifications [510(k)]3 (hereinafter, 510(k) Program Guidance), and least 
burdensome provisions in the FD&C Act and relevant FDA guidance. 
FDA recognizes and anticipates that the Agency and industry may need up to 60 days to perform 
activities to operationalize the policies within the guidance. If a benefit-risk assessment as outlined 
in this guidance is not included in a 510(k) submission received by FDA before or up to 60 days 
after the publication of this guidance, FDA staff does not generally intend to request such 
information during the review of a 510(k) submission. FDA does, however, intend to review any 
such information, if submitted.  
FDAs guidance documents, including this one, do not establish legally enforceable responsibilities. 
Instead, guidance documents describe the Agencys current thinking on a topic and should be 
viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The 
use of the word should in Agency guidance documents means that something is suggested or 
recommended but not required. 
II.  Background 
A.  The Statutory Standard for Substantial Equivalence 
Submitters seeking device clearance must demonstrate to FDA in their 510(k) submission that the 
new device is SE to a predicate device. For this guidance, a new device means a device 
within the meaning of section 201(h) of the FD&C Act (21 U.S.C.  321(h)) that is not legally 
marketed. It can be either a completely new device or a modification of a legally marketed device 
that requires a new 510(k) under 21 CFR 807.81. A predicate device is a device that (1) was 
legally marketed prior to May 28, 1976 (preamendments device)4, and for which a premarket 
approval (PMA) application is not required; or (2) has been classified or reclassified into class I or 
II;5 or (3) has been found SE through the 510(k) premarket review process. For more information 
on the process required to demonstrate SE, refer to the 510(k) Program Guidance.  
The standard for a determination of SE in a 510(k) premarket review is set out in section 
513(i)(1)(A) of the FD&C Act (21 U.S.C.  360c(i)(1)(A)), which states: 
For purposes of determinations of substantial equivalence under subsection (f) and 
section 520(l), the term substantially equivalent or substantial equivalence means, 
with respect to a device being compared to a predicate device, that the device has the 
                                                 
3 https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM284443. 
4 See Preamendments Status at 
https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/MedicalDeviceQualityandCompliance/ucm37955
2.htm. 
5 Section 513 of the FD&C Act (21 U.S.C.  360c) establishes three device classes (class I, class II, and class III) and 
sets forth device reclassification procedures. 
5  Contains Nonbinding Recommendations 
same intended use as the predicate device and that the Secretary by order has found 
that the device 
(i) has the same technological characteristics as the predicate device, or  
(ii)(I) has different technological characteristics and the information submitted that 
the device is substantially equivalent to the predicate device contains information, 
including appropriate clinical or scientific data if deemed necessary by the Secretary 
or a person accredited under section 523, that demonstrates that the device is as safe 
and effective as a legally marketed device, and (II) does not raise different questions 
of safety and effectiveness than the predicate device. 
Therefore, in order to find a new device SE to a predicate device, FDA must first find that the 
devices have the same intended use. FDA must then determine that the devices have the same 
technological characteristics, or that any difference in technological characteristics does not raise 
different questions of safety and effectiveness and that the device is as safe and effective as the 
predicate device. Different technological characteristics is defined in section 513(i)(1)(B) of the 
FD&C Act (21 U.S.C.  360c(i)(1)(B)), which states: 
...the term different technological characteristics means, with respect to a device 
being compared to a predicate device, that there is a significant change in the 
materials, design, energy source, or other features of the device from those of the 
predicate device. 
If FDA determines that there are differences in the technological characteristics, between the new 
device and the predicate device, and that the different technological characteristics raise different 
questions of safety and effectiveness, FDA will determine that the new device is NSE to the 
predicate device. For more information on the critical decision-making points in the 510(k) 
premarket review process, refer to the 510(k) decision-making flowchart in Appendix A of the 
510(k) Program Guidance (see adapted flowchart in Figure 1). 
If FDA determines that the different technological characteristics do not raise different questions of 
safety and effectiveness, FDA will subsequently evaluate differences in the technological 
characteristics between the new device and the predicate device to determine impact on safety and 
effectiveness (i.e., whether the new device is as safe and effective as the predicate device). If a 
submitter made modifications to its own FDA-cleared device and submitted a new 510(k), FDA will 
evaluate the modifications and the information submitted to determine whether the modified device 
is still as safe and effective as the predicate device. In this situation, FDAs review focuses on the 
assessment of the modifications to device safety and effectiveness.  
Under section 513(a)(2) of the FD&C Act (21 U.S.C.  360c(a)(2)), FDA determines the safety 
and effectiveness of a device by weighing any probable benefit to health from the use of the 
device against any probable risk of injury or illness from such use, among other relevant factors.6 
                                                 
6 The criteria for establishing safety and effectiveness of a device are set forth in 21 CFR 860.7. Subsection (b) notes, 
[i]n determining the safety and effectiveness of a device...the Commissioner and the classification panels will consider 
 
6  Contains Nonbinding Recommendations 
This guidance is consistent with the 510(k) Program Guidance and provides additional clarification 
on factors that FDA takes into consideration when evaluating the benefit-risk profile of a new 
device in comparison to a predicate device. As previously mentioned, this document provides 
guidance on when the submitter and FDA identifies a decrease in benefit and/or increase in risk 
between the new device and the predicate device. 
B.  Performance Data 
When FDA is reviewing a 510(k) for a new device that has different technological characteristics 
than the predicate device, performance data may be warranted to assess whether the new device is 
as safe and effective as the predicate device. The type and quantity of performance data that may 
be needed to support a determination of SE depends upon the new device.7 Valid scientific evidence 
may be generated from both non-clinical and clinical performance data. These types of performance 
data are evaluated by FDA during the premarket review process and can provide information 
relating to the benefit and risk factors discussed in this guidance. 
Non-clinical testing can encompass an array of methods including, but not limited to, performance 
testing for product safety, reliability, characterization, human factors, usability, mechanical testing 
under simulated conditions, animal studies,8 cell-based studies, and computer simulations. These 
tests characterize properties of the devices including, but not limited to, precision, reproducibility, 
linearity, wear, tensile strength, compression, flow rate, burst pressure, biocompatibility, toxicity, 
electromagnetic compatibility (EMC), sterility, stability/shelf-life data, software validation, and 
testing of synthetic samples.  
Clinical data is not typically included in 510(k)s to demonstrate SE. However, when appropriate, 
valid scientific evidence can include randomized clinical trials in the appropriate target population, 
well-controlled investigations, partially controlled studies, studies and objective trials without 
matched controls, well-documented case histories conducted by qualified experts, certain reports of 
significant human experience, and testing on clinically derived human specimens (DNA, tissue, 
organ and cadaver studies).9 Valid scientific evidence generated from clinical and/or non-clinical 
testing can be considered during FDAs review of the benefit-risk assessment. 
When evaluating and comparing the benefits and risks of a new device to a predicate device, FDA 
evaluates the probable or probability of such risks and benefits. The use of the terms probable 
and probability in this guidance have the same connotation as in 21 CFR 860.7(b)(3), i.e., they 
refer to the probable benefit to patient health from the use of the device weighed against any 
probable injury or illness from such use. Hypothesis testing, formal concepts of probability and 
predictive probability, likelihood, etc. are typically important elements in the assessment of 
                                                 
the following, among other relevant factors... (3) 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)). For additional information on FDAs safety 
and effectiveness review, see 21 CFR 860.7(d) and (e).  
7 See 21 CFR 860.7(c)(2). 
8 FDA supports the principles of the 3Rs, to reduce, refine, and replace animal use in testing when feasible. We 
encourage sponsors to consult with us if it they wish to use a non-animal testing method they believe is suitable, 
adequate, validated, and feasible. We will consider if such an alternative method could be assessed for equivalency to an 
animal test method. 
9 See 21 CFR 860.7(c)(2). 
7  Contains Nonbinding Recommendations 
probable benefit and risk. In general, a probable risk and a probable benefit do not include 
purely theoretical risks and benefits, but rather those that are supported by valid scientific evidence. 
FDA does not intend for the use of the term probable benefit in this guidance to refer to the 
regulatory term as used for the approval requirements for Humanitarian Device Exemptions (HDE) 
under section 520(m) of the FD&C Act (21 U.S.C.  360j(m)), and FDAs implementing HDE 
regulations. 
III.  Scope 
The 510(k) premarket review standard (i.e., SE of a new device when compared to a predicate 
device) does not require a new device to be identical to a predicate device. Under section 513(i) of 
the FD&C Act (21 U.S.C.  360c(i)), FDA may determine that a new device is SE to a predicate 
device if, among other things, it has the same intended use. Differences in the indications for use, 
such as the population for which a device is intended or the disease a device is intended to treat, 
may not necessarily result in a new intended use.10 In other words, FDA may find a new device with 
indications for use or technological characteristics that are different from those of the predicate 
device SE to a predicate device. Likewise, the benefit-risk profile of a new device does not need to 
be identical to be found SE to the predicate device. 
This guidance document focuses on the steps of the 510(k) premarket review process after FDA 
finds that the intended use of the new device and predicate device are the same and have different 
technological characteristics that do not raise different questions of safety and effectiveness. 
Specifically, the guidance focuses on the step where FDA evaluates whether the new device is as 
safe and effective as the predicate device. As shown in the decision-making flowchart in Figure 1, 
this guidance focuses on the review steps after FDA has answered Yes to Decisions #1 and #2, and 
No to Decisions #3 and #4. (Note that the flowchart was adapted from Appendix A of the 510(k) 
Program Guidance.)  
At this point in the review process, FDA determines whether the new device is as safe and 
effective as the predicate device by looking at the submitted performance data among other things. 
During the review, if FDA identifies 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, a benefit-risk assessment may be beneficial to aid in the evaluation of SE or NSE. Figure 1 
highlights steps in the decision-making process where consideration of a benefit-risk assessment 
may be informative when reviewing a 510(k). 
                                                 
10 [T]he term intended use means the general purpose of the device or its function, and encompasses the indications for 
use. The indications for use generally describe the disease or condition that will diagnose, treat, prevent, cure or 
mitigate, including a description of the patient population for which the device is intended. The indications include all 
the labeled patient uses of the device. As it relates to medical devices, the indications for use statement is a factor in 
determining a devices intended use; however, a change indications for use that requires submission of a new 510(k) 
does not necessarily mean that the device has a new intended use (such that the device would not be substantially 
equivalent under section 513(i) of the FD&C Act). See the FDA guidance, Deciding When to Submit a 510(k) for a 
Change to an Existing Device 
(https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM514737) (internal 
citations omitted).  
8  Contains Nonbinding Recommendations 
Benefit-risk factors are often considered when making a determination of SE or NSE for a new 
device that has the same intended use as the predicate device and different technological 
characteristics that do not raise different questions of safety and effectiveness. Some benefit and 
risk factors that FDA may consider are described below. Not all of the factors listed in this guidance 
will be applicable to each 510(k). Section V of this guidance provides examples of how these 
factors could be considered during a 510(k) premarket review. 
Identify the new  Determine what questions of safety 
device and the  and effectiveness the different 
predicate device technological characteristics raise. 
Decision 1 Decision 4
Is the predicate  Do the different technological 
device legally  NO NSE NSE YES characteristics of the devices raise 
different questions of safety and 
marketed? effectiveness? 
YES NO
Review all labeling and assure that  Review the proposed scientific 
it is consistent with IFU  methods for evaluating new/ 
statements.  different characteristics effects on 
safety and effectiveness. 
Decision 2
Do the devices have  Decision 5a
the same intended  NO NSE NSE NO Area ctcheep mtaebtlhe?o ds  This guidance document is 
use? applicable when a new device has the 
same intended use as the predicate 
device, and different technological 
YES YES characteristics do not raise different 
questions of safety and effectiveness.  As 
Review design, materials, energy  discussed in Sections III and IV, FDA 
source and other features of the  believes this document would be most 
Evaluate performance data
devices  helpful in situations 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.
Decision 3 Decision5b
Do the devices have the  Does the data 
NO NSE NO
same technological  demonstrate SE?
characteristics?
YES YES
SE SE
Figure 1: Decision-making flowchart (adapted from 510(k) Program Guidance) showing steps in 
the process when inclusion of a benefit-risk assessment could be helpful.
9  Contains Nonbinding Recommendations 
IV.  Benefit and Risk Factors 
The benefit-risk framework for 510(k) premarket reviews is fundamentally different from the 
benefit-risk framework that applies to devices in PMA or De Novo review. More specifically, in 
510(k) premarket review, the benefit-risk profile of the new device is determined in the context 
of a comparison to the benefit-risk profile of a predicate device. Thus, during the 510(k) 
premarket review for a new device, it is important to understand the benefit-risk profile of the 
predicate device and previously cleared devices within the same type.11 FDA may also consider 
whether prior evaluation of the benefit-risk profile for the same or similar device type is 
appropriate and still applicable based on postmarket and current real-world data.  
As previously mentioned, the benefit-risk profile of a new device does not need to be identical to 
be as safe and effective as the predicate device. This section focuses on some of the factors that 
are taken into consideration when comparing the benefit-risk profile of a new device and 
predicate device to determine whether the new device is as safe and effective as the predicate 
device. An evaluation of these factors is important when there is 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. In these situations, the factors in this guidance should be 
applied to help FDA determine if SE has been demonstrated. A benefit-risk assessment is not 
recommended for the majority of 510(k)s to support a determination of SE, including situations 
where there is an increase or equivalent benefit and a decrease or equivalent risk, when 
comparing a new device to the predicate device. 
FDA may also consider the value that health-care professionals and patients place on the 
benefits. FDA understands that health-care professionals, who utilize devices in the treatment or 
diagnosis of patients with a disease or condition, may have developed their own insights into the 
benefits of the treatments that may vary from that of regulators. For more information on patient 
preference information (PPI) and patient-reported outcomes (PROs), refer to the FDA guidance 
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 Labeling12 (hereinafter, PPI Guidance). 
When comparing the benefits and risks of a new device to a predicate device, there might be 
variability in the type or extent of benefits and/or risks. For that reason, FDA evaluates the 
differences between the benefits and risks of a new device to a predicate device, along with 
additional factors identified in Section IV.C. FDA evaluates the aggregate benefits, which 
includes, but is not limited to, consideration of the type, magnitude, probability, and duration of 
benefits. Likewise, FDA also evaluates the aggregate risks and considerations include, but are 
not limited to the severity, types, number, rates, and probability of risks. 
                                                 
11 See the FDA guidance, Medical Device Classification Product Codes 
(https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm285317.htm). 
12 https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM446680. 
10 
  Contains Nonbinding Recommendations 
The benefit-risk assessment should identify and compare the differences in technological 
characteristics and how that could impact the new devices benefit-risk profile when compared to 
the predicate device.  
Despite differences in the benefit-risk profile, in some circumstances the new device may be 
determined to be SE to the predicate device. As a part of our determination, FDA could also 
consider whether mitigation strategies, such as labeling revisions, could be implemented to 
address differences in the benefit-risk profile between a new device and a predicate device. 
Generally, if there is an increase in risk or decrease in benefit, FDA will likely find the new 
device NSE to the predicate device. See Section V of this guidance for examples of how FDA 
evaluates and considers benefits and risks during the review of a 510(k). 
Both non-clinical and clinical data can play a role in FDAs benefit-risk determinations, and the 
factors discussed in this guidance may be informed by either type of data. In addition, both 
clinical and non-clinical testing can be used to assess the benefits and risks of a new device and 
can be used to assess the impact of risk mitigation measures. For information on the types of 
performance data that FDA can consider during the 510(k) premarket review, refer to Section F 
of the 510(k) Program Guidance. 
A summary of the benefit-risk assessment can be included as part of the 510(k) summary 
consistent with 21 C.F.R. 807.92(b)(3). For more information on factors that are considered 
when assessing benefit, refer to Section IV.A below. For more information on factors that are 
considered when assessing risk, refer to Section IV.B below. 
Below is an explanation of certain scenarios where a benefit-risk assessment could be useful. 
Table 1 provides a guide for certain benefit and risk outcomes when the inclusion of a benefit-
risk assessment in a 510(k) may be recommended. However, neither the table nor the benefit-risk 
outcomes explained below are intended to be decisional and instead represent the Agencys 
recommendation for when a benefit-risk assessment may or may not be helpful to include in a 
510(k). This table should be used in conjunction with the guiding principles provided elsewhere 
in this guidance and not in isolation. 
Decreased Benefit and Decreased/Equivalent Risk 
If the aggregate benefit of a new device is decreased in comparison to the predicate and the risk 
level is decreased in comparison to that of the predicate device, FDA may determine the new 
device to be SE if the differences do not affect whether the new device is as safe and effective 
as the predicate device. 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. 
Equivalent/Increased Benefit and Increased Risk 
FDA evaluates the nature of increased risk and degree of risk (e.g., severity, type, rate) in 
comparison to the predicate device to determine if the difference impacts whether the new device 
is as safe and effective as the predicate device. FDA may also consider whether additional 
11 
  Contains Nonbinding Recommendations 
measures may help to mitigate the increase in risk. If there is an increase in aggregate risk and 
there is an increase in benefit associated with the new device as compared to the predicate 
device, FDA may determine the new device to be SE if the device is as safe and effective as 
the predicate. FDA will generally not find a new device SE to the predicate device when an 
increase in risk cannot be mitigated and is not accompanied by increased or equivalent benefit.  
Table 1. Situations when a benefit-risk assessment could be recommended or not recommended 
as part of the evaluation of SE. [Note: This table should be used with the guiding principles 
provided in the rest of the guidance.] 
  INCREASE IN RISK  DECREASE/EQUIVALENT RISK 
T  Conducting a benefit-risk assessment is  Conducting a benefit-risk assessment as 
N
E recommended.*  described in this guidance is likely not 
L
A   recommended to determine whether the new 
V
I T  The factors in this guidance should be used  device is as safe and effective as the predicate 
QU FI to assess the benefits and risks as part of the  device. 
E
E/ E EN e valuation of substantial equivalence.   
S B FDA will generally determine the new device SE 
A
E to the predicate device when there is 
R
C increase/equivalent benefit and 
N
I decreased/equivalent risk. 
Conducting a benefit-risk assessment as  Conducting a benefit-risk assessment is 
T 
I described in this guidance is likely not  recommended.* 
F
E
recommended to determine whether the   
N
E new device is as safe and effective as  The factors in this guidance should be used to 
B
N  the predicate device.  assess the benefits and risks as part of the 
E I   evaluation of substantial equivalence. 
S  
A FDA will generally determine the new 
E
R device NSE to the predicate device when 
C
E there is a decrease in benefit and an increase 
D
in risk. 
*FDA recommends conducting a benefit-risk assessment to determine if the new device is as safe and effective as 
the predicate device despite these differences. A summary of the benefit-risk assessment should be included in the 
510(k) summary, when such information was important to FDAs determination that the new device is as safe, as 
effective, and performs as well as or better than the predicate device, consistent with 807.92(b)(3).  
A.  Assessment of the Benefits of Devices 
Examples of possible device benefit(s) include, but are not limited to: 
  Reduction in treatment time to achieve same effect; 
  Improvement of mechanical properties to reduce probable likelihood of adverse events 
or to improve handling; 
  Reduction of variability in device output; 
  Improvements in clinical management, probability of survival, other aspects of patient 
health status (e.g., effect on patient management and quality of life, improvement of 
12 
  Contains Nonbinding Recommendations 
patient function, prevention of loss of function, relief from symptoms), and patient 
satisfaction in the target population, which may be measured with the use of PROs; and 
  For diagnostic devices specifically, benefit(s) in reference to the nature of the public 
health impact, could be based on a number of factors including: 
  Identification of a specific disease; 
o
  Provision of diagnosis at different stages of a disease; 
o
  Prediction of future disease onset; 
o
  Improvement of patient workflow; 
o
  Increase in efficiency or examination; 
o
  Provision of reproducible and quantifiable results contributing to the optimization 
o
of therapy and treatment; and 
  Improvement of patient outcome (e.g., well-being, health status, safety of 
o
patients) by facilitating fewer missed diagnoses (or the right diagnosis the first 
time, hence the correct treatment plan) and/or identification of patients likely to 
respond to a given therapy and therefore enable treatment of the disease or 
reduce/prevent its spread, which can often be measured through the use of PROs. 
 
Endpoints denoting clinical benefit are usually measured directly, but in some cases may be 
demonstrated by use of surrogate endpoints that are reasonably likely to predict clinical benefit.  
FDA assesses information provided in a 510(k) concerning the extent of probable benefit(s) by 
considering, among others, the following factors individually and in aggregate when making a 
comparison to the predicate device: 
(1)  Magnitude of the Benefit(s) 
Benefits are often assessed along a scale or according to specific endpoints or criteria. The 
criteria should be established based on scientific and/or clinical rationale. Variation in the 
magnitude and type of benefit across a population is considered. The magnitude of benefit for 
diagnostic devices is defined in large part by the accuracy and reproducibility of test results and 
by the expected effect of clinically applying those results. 
(2)  Probability of the Patient Experiencing One or More 
Benefit(s) 
Based on the data provided, it is sometimes possible to predict which patients may experience a 
benefit, whereas other times this cannot be accurately predicted. The data may show that a benefit 
may be experienced only by a small portion of patients in the target population or may occur 
frequently in patients throughout the target population. It is also possible that the data will show that 
different patient subgroups are likely to experience different benefits or different levels of the same 
benefit. If the subgroups can be identified, the device may be indicated for those subgroups. In some 
cases, however, the subgroups may not be identifiable. In addition, the magnitude and probability can 
be considered together when weighing benefits against risks. That is, a large benefit experienced by a 
small proportion of participants may raise different considerations than does a small benefit 
experienced by a large proportion of participants.  
13 
  Contains Nonbinding Recommendations 
(3)  Duration of Effect(s) 
This factor refers to how long the benefit can be expected to last for the patient. Some treatments 
could be curative, whereas some may need to be repeated frequently over the patients lifetime. 
To the extent that it is known, the duration of a treatment effect may directly influence how its 
benefit is defined. Treatments that must be repeated over time may introduce greater risk or the 
benefit experienced may diminish each time the treatment is repeated. 
B.  Assessment of the Risks of Devices 
Risks of devices can take many forms, including impact on: 
  Device performance (e.g., device failure and its impact on adverse events); 
  Clinical management; 
  Patient health status, often measured using PROs (e.g., negative effect on patient 
management and quality of life, decline of patient function, loss of function, worsening 
symptoms); and 
  Patient tolerability. 
FDA assesses the extent of the probable risk(s)/harm(s) by considering, among others, the 
following factors individually and in the aggregate as compared to the predicate device: 
(1)  Severity, Types, Number, and Rates of Harmful Events 
For the purpose of this guidance, rate of harmful events refers to the number of harmful events 
per patient or the number of harmful events per unit of time associated with the use of the device. 
We identify each type of harm individually for the purpose of clarifying which of the more 
commonly recognized harms FDA might consider in benefit-risk assessments. In making benefit-
risk assessments, FDA may consider each type of harm individually and in aggregate. 
  Device-related serious adverse events: These are events that may have been or were 
attributed to the use of the device and caused or contributed to a death, injury, or illness 
that is life-threatening, resulted in permanent impairment or damage to the body, or 
required medical or surgical intervention to prevent permanent harm to the body.13 
  Device-related non-serious adverse events: These are events that may have been or 
were attributed to the use of the device and do not meet the criteria for classification as a 
device-related serious adverse event. 
  Procedure-related complications: These are events that caused harm to the patient, 
would not be included under serious or non-serious adverse events, and indirectly 
resulted from use of the device. Examples include anesthetic-related complications 
associated with the implantation of a device or risks associated with the collection of 
human biological materials. The latter consideration affects the risk profile of in vitro 
                                                 
13 See generally 21 CFR 803.3(w) (defining serious injury for purposes of 21 CFR part 803). 
14 
  Contains Nonbinding Recommendations 
diagnostic devices when the biological material is collected via an invasive procedure for 
the purpose of performing the diagnostic test. 
(2)  Probability of a Harmful Event  
The probability of a harmful event is the proportion of the intended population that could be 
expected to experience a harmful event. FDA could factor whether an event occurs once or 
repeatedly into the measurement of probability. 
(3)  Probability of the Patient Experiencing One or More 
Harmful Event(s) 
Based on the data provided, it is sometimes possible to predict which patients may experience a 
harmful event, whereas other times this cannot be accurately predicted. The data may show that a 
harmful event may be experienced only by a small portion of patients in the target population or 
may occur frequently in patients throughout the target population. 
(4)  Duration of Harmful Events (i.e., How Long the Adverse 
Consequences Last) 
Some devices can cause temporary, minor harm; some devices can cause repeated, but reversible 
harm; and other devices can cause permanent, debilitating injury. FDA may also consider the 
severity of the harm along with its duration. 
(5)  Risk from False-Positive or False-Negative Results for 
Diagnostic Devices 
If a diagnostic device gives a false-positive result, the patient might, for example, receive an 
unnecessary treatment and incur the potential risks that accompany that treatment or might be 
incorrectly diagnosed with a serious disease. Additionally, the patient might not receive effective 
treatment (thereby missing out on the benefits that treatment could confer) or might not be 
diagnosed with the correct disease or condition. These risks and other risks arising from false test 
results should be considered in terms of their likelihood and severity. 
In addition to the type of risks discussed in (1) to (5) above, FDA also considers the number of 
different types of harmful events that can result from using the device and the severity of the 
aggregate effect. When multiple harmful events occur at once, they can have a greater aggregate 
effect. For example, there may be a harmful event that is considered minor when it occurs on its 
own, but when it occurs along with other harmful events, the aggregate effect on the patient may 
be substantial. 
In circumstances where clinical data are not warranted to demonstrate SE, other types of valid 
scientific evidence may be used to assess probable risks of the technological changes that address 
the considerations above (e.g., rates of failures, severity of failures, duration of harmful event, 
etc.). These include, but are not limited to, the risk analysis for the product, reports of simulated 
15 
  Contains Nonbinding Recommendations 
use tests, modeling, animal testing, and, where applicable, a review of conformance with FDA-
recognized consensus standards. 
C.  Additional Factors in the Assessment of the Benefits and 
Risks of Devices 
(1)  Uncertainty 
When determining if a new device is as safe and effective as a predicate device, we consider 
the extent of certainty of the benefits and risks of a device. In the context of this guidance, 
greater uncertainty may arise from a lower level of available evidence with regards to the 
benefit-risk profile for a new device. Factors such as less than optimal design or less than 
optimal conduct of bench testing, animal or clinical studies, or inadequate analysis of data can 
render the outcomes of the test or study less reliable or invalid, and may not provide the degree 
of information to fully understand the effects of the new technology. Additionally, for certain 
device types where clinical data are warranted to determine SE, it is important that the clinical 
study is adequately designed; failure to adequately design a clinical study can introduce 
uncertainty into the benefit-risk assessment for the device, which may not support an SE 
determination.  
(2)  Characterization of the Disease/Condition 
During review of the 510(k), FDA may consider the following: 
  the treated or diagnosed disease/condition and its clinical manifestation; 
  how the disease affects the patients who have it; and 
  how and whether a diagnosed disease/condition is treated and the conditions natural 
history and progression (i.e., does it get progressively better or worse over time for the 
patient and at what expected rate?). 
(3)  Innovative Technology 
When a new device has technological improvements that are important for public health, FDA 
may accept greater uncertainty in an assessment of benefits and risks as compared with the 
predicate device than for other established technologies in order to facilitate patient access to 
these innovative technologies, if FDAs overall assessment is sufficiently balanced by other 
factors to support a determination that the new device is as safe and effective as the predicate 
device. Innovative changes are evaluated on a case-by-case basis in terms of the degree of 
benefit. 
(4)  Patient Tolerance for Risk and Perspective on Benefit 
Risk tolerance varies among patients and affects individual patients decisions as to whether 
higher risks in the new devices technology as compared to the predicate device are acceptable in 
exchange for a higher probable benefit. When evaluating benefits and risks, FDA recognizes that 
16 
  Contains Nonbinding Recommendations 
PPI studies of risk may identify patients who are reasonably willing to accept a higher level of 
risk to achieve a higher probable benefit or an additional type of benefit (e.g., an improvement in 
quality of life stemming from greater comfort or ease of use). At the same time, other patients 
may be more risk-averse. Patient-centric assessments and PPI studies should take into account 
both the patients willingness and unwillingness to use a device or tolerate risk when evaluating 
the relative safety and effectiveness of the new device in comparison to the predicate. FDA may 
also consider evidence relating to patients perspectives on what constitutes a benefit, as some 
set of patients may value a benefit more than others. 
Assessing patient tolerance for risk and perspective on benefit via PPI studies may be an 
informative and helpful factor in evaluating the overall benefit-risk profile of a device and 
whether a new device is as safe and as effective as a predicate device. FDA recommends that any 
submitter who is considering developing or presenting studies and/or data concerning patient risk 
tolerance or perspective on benefit in their 510(k) consult the PPI Guidance. Although the PPI 
Guidance is not specific to 510(k) submissions, the concepts and recommendations in this 
guidance may be helpful for manufacturers who intend to submit PPI studies in a 510(k) as part 
of a benefit-risk assessment. 
We also recommend discussing your plans at an early stage with the appropriate FDA review 
Division using the Pre-Submission Program described in the FDA guidance Requests for 
Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with 
Food and Drug Administration Staff.14 
(5)  Benefit for the Health-Care Professional, Patient, or 
Caregiver 
FDA recognizes that certain devices, such as surgical tools that allow different techniques or 
devices that positively affect ongoing patient management, may benefit health-care professionals 
or caregivers by improving the way they care for the patients and consequently improving patient 
outcomes. Additional examples are surgical instruments with improved ergonomic design for 
ease of use or patient monitoring devices with wireless capabilities. For these devices, submitters 
may consider developing or presenting valid measurement methods and/or data concerning 
perspective on benefit for health-care professionals or caregivers. FDA recommends that any 
submitter who is considering developing or presenting valid measurement methods and/or data 
concerning perspective on benefit for health-care professionals or caregivers in their 510(k) have 
early interaction with the appropriate FDA review division. 
(6)  Risk Mitigation 
The use of mitigations, when appropriate, can minimize the probability of a harmful event 
occurring and improve the benefit-risk profile. Even if a new device has an increased risk and if 
the risk is appropriately mitigated, FDA may determine that the new device has a comparable 
benefit-risk profile to the predicate device and therefore determine that the new device is as safe 
                                                 
14 https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM311176. 
17 
  Contains Nonbinding Recommendations 
and effective as the predicate device. The most common form of risk mitigation is to include 
appropriate information within labeling (e.g., warnings, precautions, contraindications). Some 
risks can be mitigated through other forms of risk communication, including training and 
professional and patient labeling. For in vitro diagnostic devices, risks may be mitigated by the 
use of complementary or supplementary diagnostic tests and/or controls or when used in 
conjunction with other available information, including clinical symptoms and family history. 
(7)  Postmarket Data 
The use of devices in a postmarket setting can provide a greater understanding of their risks and 
benefits and the risks and benefits of similar devices. When reviewing a new device and 
assessing different technological characteristics in accordance with this guidance, FDA may 
consider postmarket data (e.g., literature, recalls, registry data, medical device reports) collected 
on marketed devices of the same type. This assessment may clarify the magnitude and effect of 
mitigations and may provide additional information when evaluating benefits and risks of the 
new device in accordance with an SE determination. In some cases, postmarket information can 
be used to confirm that certain risks have been mitigated or to identify which patients are most 
likely to suffer adverse events. In addition, FDA has the authority to require postmarket 
surveillance for certain class II devices15 and may order postmarket surveillance for a new device 
that is expected to have significant use in pediatric populations as a condition to an SE 
determination.16 Postmarket surveillance for a new device that is expected to have a significant 
pediatric use can serve to complement premarket data. 
Furthermore, section 513(i)(1)(C) of the FD&C Act (21 U.S.C.  360c(i)(1)(C)) requires FDA to 
consider the use of postmarket controls in the review of 510(k)s, stating [t]o facilitate reviews 
of reports submitted to the Secretary under section 510(k), the Secretary shall consider the extent 
to which reliance on postmarket controls may expedite the classification of devices... As 
discussed in the FDA guidance The Least Burdensome Provisions of the FDA Modernization 
Act of 1997: Concept and Principles,17 reliance on postmarket controls (e.g., Quality System 
regulations, postmarket surveillance, and the Medical Device Reporting requirements) should be 
considered as a mechanism to reduce the extent of premarket data for 510(k)s, while still 
ensuring the safety and effectiveness of the device. In some cases, FDA may accept greater 
premarket uncertainty regarding a devices benefit-risk profile through greater reliance on 
postmarket controls, such as postmarket surveillance where applicable, in order to reduce the 
premarket burden for a 510(k), if FDAs overall assessment is sufficiently balanced by other 
factors to support SE and taking into account FDAs limitations with respect to requiring 
postmarket studies for 510(k)s. 
                                                 
15 See section 522 of the FD&C Act (21 U.S.C.  360l). 
16 See section 522(a)(1)(B) of the FD&C Act (21 U.S.C.  360l(a)(1)(B)). 
17 https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM085999. 
18 
  Contains Nonbinding Recommendations 
V.  Examples of Benefit-Risk Evaluation 
The examples below are hypothetical or simplified real-world situations and are offered only for 
illustrative purposes, i.e., no example is a complete assessment of the benefit-risk issues 
associated with any actual 510(k). The decisions described in these examples are not predictive 
of future FDA decisions; rather, they are hypothetical outcomes and are intended only to 
demonstrate how FDA could consider the factors described in this guidance when evaluating 
benefits and risks during a 510(k) premarket review. Similar scenarios or devices may result in 
different clearance outcomes depending on the individual performance characteristics of a 
particular device, the population for which it is indicated, and the context. These examples are 
not intended to provide device-specific data recommendations for the assessment of the factors. 
Because this guidance document focuses on the part of the SE decision-making process 
occurring after FDA finds that the intended use of the new device and predicate device are the 
same, and that any differences in technological characteristics do not raise different questions of 
safety and effectiveness, these examples focus on the use of benefit-risk assessments after 
Decision #4 of the SE decision-making process, as described in Figure 1.  
A.  Example 1: Change in Device Design 
Scenario: A manufacturer submitted a 510(k) for a powered rongeur for use during spinal 
surgery that utilizes new designs, i.e., a different shape and a different, deeper cutting action than 
the identified predicate device. The new design presents increased risk because the new cutting 
action exposes additional anatomy of the patient to an increased risk of injury. On the other hand, 
the new design expedites the cutting process and minimizes the time needed for surgical 
procedures, and its shape allows easier access to specific anatomic regions than the available 
predicate devices. After reviewing bench testing, FDA noted that the bench testing was not 
designed to address the increased risk. The manufacturer provided performance data to 
demonstrate that the risks noted by the review team had very low incidence. The animal study 
made a direct comparison to the predicate device. The new device demonstrated shorter surgery 
time, and the results of a survey of the participating surgeons emphasized the ease of accessing 
more difficult anatomic areas compared to the predicate device, therefore reducing the likelihood 
of injury to neighboring tissue when accessing the difficult-to-reach anatomical areas in the 
patient. The device is also available in a range of sizes which also raises concerns about elevated 
risk if larger sizes than necessary are used because this resulted in higher adverse event rates in 
the animal study. 
Is a benefit-risk assessment recommended? 
Yes. A benefit-risk assessment should be conducted to assess the increase in risk and increase in 
benefit.  
Benefits: Compared to the predicate device, the new device offers surgeons an option to access 
specific anatomic areas around the spine more easily with a lower likelihood of injury to 
neighboring tissue. In some cases, surgeons may prefer to use this tool rather than the predicate 
19 
  Contains Nonbinding Recommendations 
because the new device can offer a deeper cutting action which was demonstrated in the animal 
study to shorten the duration of surgery. In addition, shorter surgery time results in less time 
under anesthesia and less exposure to risk of infection. 
Risks: The new deeper cutting action introduces higher risks of injury to the dura, arteries, veins, 
and nerve roots than the predicate device. The manufacturer provided data from an animal study 
to address the higher level of risks associated with the new deeper cutting action. The data 
provided demonstrate that the probability of harm is low; however, using the incorrect size of the 
device was found to increase risk of injury in the animal study. 
Additional Factors: 
Risk Mitigation: To address the concern of elevated risk due to using an incorrectly sized device, 
labeling is used to identify the proper size to be used based on anatomical measurements made 
before surgery. 
Benefit for the Health-Care Professional or Caregiver: The new design allows for easier use by 
the surgeons as demonstrated in the survey data provided by the manufacturer, thereby reducing 
risk of injury to the patient. 
SE Analysis: The technological differences present an increased risk of injury to the dura, 
arteries, veins, and nerve roots. The manufacturer provided animal study data to address these 
additional risks and to demonstrate that the probability of such harms is low. The manufacturers 
labeling further mitigates risk observed in the animal testing by identifying methods to help the 
surgeon choose the proper device size. Furthermore, the animal study demonstrated that the new 
device shortened the surgery time compared to the predicate device, and surveys of participating 
surgeons emphasized the benefit of easier access to specific anatomic regions around the spine, 
thereby reducing risk of injury to the patient. Although the probable risk may be slightly higher 
than that of the predicate device due to the nature of cutting, the increase was demonstrated to be 
minimal. In addition, the non-clinical performance data did demonstrate benefit from the new 
shape and cutting action in terms of shortened surgical time and easier access. Because the 
increase in risk is accompanied by an increase in benefit and the new device would likely have a 
comparable benefit-risk profile to the predicate device for the indicated patient population, this 
device would likely be found SE. 
B.  Example 2: Change in Technology and Possible Change 
in Principle of Operation 
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 
that was shown to produce different photo-biological effects, have a power level much lower 
than the predicate device, and have 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 
20 
  Contains Nonbinding Recommendations 
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 a majority of the subjects were responders, where a responder is 
a subject for whom the 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. The new device is considered to pose a lower risk than the predicate device because the 
power level of the new device is significantly lower. 
Is a benefit-risk assessment recommended? 
Yes. A benefit-risk assessment should be conducted to assess the decrease in risk and decrease in 
benefit.  
Benefits: The new device offers an alternative treatment modality than the predicate device. 
However, the study failed to meet the primary endpoint, as data did not support that the majority 
of the responders saw treatment success. 
Risks: The new device offers lower risk to the subject with a reduction of power and offers 
minimal side effects when compared to the predicate device. Other risk mitigations include the 
wearing of laser safety protective glasses to prevent accidental eye damage from laser exposure. 
Additional Factors:  
Uncertainty: The results of the clinical study raised significant concerns regarding the reliability 
of the observed benefit of the new device. The proportion of responders was lower than desired. 
In addition, there were significant data inconsistencies regarding the manufacturers photographs 
and data set in comparison to the predicate device. 
SE Analysis: Due to the differences in technological characteristics between the new device and 
predicate device, the manufacturer provided clinical data to establish SE. The clinical data failed 
to demonstrate the new device provided benefit for the majority of treated patients. In addition, 
the provided data presented significant inconsistencies and was considered not reliable. Although 
the new device imparts less risk, the benefit of the device is considerably smaller than the 
predicate device. Additionally, there is considerable uncertainty with the small benefit observed. 
Therefore, this device would likely be found NSE based on a lack of adequate performance data. 
C.  Example 3: New Device with Higher Risk of Malfunction 
Scenario: A manufacturer submitted a 510(k) for an external infusion pump that can be used in 
an ambulatory, portable setting. The device manufacturer claimed SE to a standalone external 
infusion pump which is used within the hospital setting for controlled intravenous (IV) delivery 
of fluid and medications to patients. The new device utilizes a new, compact, portable platform 
that may be used to deliver IV therapy to a patient who is in transit via ambulance or other 
transport, such as a helicopter. Unlike the predicate device, the new device operates fully on a 
battery and has a smaller, simpler user interface than the predicate device. Because the new 
21 
  Contains Nonbinding Recommendations 
device is mobile, it can serve as a medical countermeasure to provide therapy to patients as part 
of a public health response to a chemical, biological, radiological, nuclear, or high-yield 
explosive (CBRNE) event.18 
The user interface was evaluated and found to be adequate in achieving device performance 
without additional risk. However, there was concern that the new device has a higher risk of 
damage-related malfunction than the predicate device due to the ambulatory environment in 
which it is used which could result in harm to the patient due to under-infusion, over-infusion, or 
delay of therapy. To address the concern, the manufacturer performed bench studies to assess the 
durability of the device when exposed to simulated, worst-case conditions in ambulatory 
transport scenarios. This included, but was not limited to, humidity tests, temperature exposure 
tests, mechanical forces (impact, vibration, etc.), fluid ingress, pressure altitude, and occlusions. 
Bench testing results demonstrated an increased risk of calibration drift over repeated uses in 
ambulatory environments. To mitigate this risk, the manufacturer changed the labeling to instruct 
the user to perform frequent preventive maintenance. 
Is a benefit-risk assessment recommended? 
Yes. A benefit-risk assessment should be conducted to assess the increase in risk and increase in 
benefit.  
Benefits: Compared to the predicate device, the compact, portable platform of the new device 
enables the health-care professional to extend intravenous (IV) therapy from the hospital care 
setting into the mobile setting. It is important to consider that in the cramped environment of a 
transport vehicle, such as an ambulance or helicopter, the compact profile of this new devices 
design enables the health-care professional to accommodate the critical care needs of the patient 
which may include ventilator support, cardiac monitoring, and suction. In an emergency setting, 
vehicles are often modified to accommodate the transport of multiple patients. In this scenario, 
where the space for patients and health-care professionals is already constrained, the compact 
profile of durable medical equipment becomes an essential characteristic. In addition, the device 
can operate in various temperature and humidity conditions, as demonstrated by the bench data, 
thereby increasing its utility as a medical countermeasure in response to CBRNE events. 
Risks: The environments in which the new device is used introduce increased risks of damage to 
the device while it is an ambulatory setting, such as in an ambulance or helicopter. The 
manufacturer provided non-clinical testing demonstrating that calibration may drift over time 
due to the mechanical forces that the device is exposed to while in ambulatory transport. This 
calibration drift may cause the pump to deliver more or less fluid than the amount programmed 
                                                 
18 For information on FDAs policies for authorizing the emergency use of medical products under section 564 of 
the FD&C Act (21 U.S.C.  360bbb-3), see the FDA guidance, Emergency Use Authorization of Medical Products 
and Related Authorities (https://www.fda.gov/RegulatoryInformation/Guidances/ucm125127.htm). Section 564 of 
the FD&C Act permits the FDA Commissioner to authorize the use of an unapproved medical product or an 
unapproved use of an approved medical product during a declared emergency involving a heightened risk of attack 
on the public or U.S. military forces, or a significant potential to affect national security, provided that certain 
criteria are met. 
22 
  Contains Nonbinding Recommendations 
into the device. Testing demonstrated that the calibration drifts occurs only after repeated 
exposures to the ambulatory environment. 
Additional Factors: 
Benefit for the Health-Care Professional or Caregiver: The predicate device does not allow the 
health-care professional to extend IV therapy into the mobile setting. This new device allows 
health-care professionals to use the pump in the mobile setting to accommodate the critical care 
needs of the patient, which may include ventilator support, cardiac monitoring, and suction in an 
emergency environment. 
Risk Mitigation: The manufacturer demonstrated that increased preventive maintenance will 
reduce the risk to health associated with possible calibration drift. Therefore, the manufacturer 
changed the labeling to instruct the user to perform preventive maintenance after 100 hours of 
ambulatory use, which is more frequent than the predicate devices instructions regarding 
preventative maintenance. 
SE Analysis: Unlike the predicate device the new device is fully battery-operated, compact, and 
contains a simplified user interface so that it can be used in a mobile ambulatory setting. The 
higher risk of damage-related malfunction in the ambulatory environment could result in under-
infusion, over-infusion, or delay of therapy. The manufacturer provided non-clinical 
performance data that confirmed the durability of the device in simulated, worst-case ambulatory 
conditions. These data revealed that the device is prone to calibration drift over repeated use in 
ambulatory settings. To mitigate this risk, the manufacturer changed the labeling to instruct the 
user to perform more frequent preventative maintenance. The increased benefit of providing 
therapy to patients in transit or to a mass number of patients in a public health emergency 
outweighs the increased risk of calibration drift identified with the ambulatory platform for an 
infusion pump. Because the increase in risk, mitigated by statements in the labeling, is 
accompanied by an increase in benefit, the new device would likely have a comparable benefit-
risk profile for the indicated patient population to the predicate device, and this device would 
likely be found SE. 
D.  Example 4: Material Differences Resulting in Different 
Device Performance 
Scenario: The manufacturer of a male condom composed of synthetic material claimed SE to a 
natural rubber latex condom. The only technological difference between the two devices is 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 (predicate 
device). The new device manufacturer sought to demonstrate non-inferiority to natural rubber 
latex condoms for a primary endpoint evaluating clinical failure (slippage and breakage) during 
sexual intercourse. The manufacturer performed the clinical study, which met the primary 
endpoint, but the slippage rate was slightly higher than natural rubber latex condoms. 
23 
  Contains Nonbinding Recommendations 
Is a benefit-risk assessment recommended? 
Yes. A benefit-risk assessment should be conducted to assess the increase in risk and increase in 
benefit.  
Benefits: This device provides another option for contraception and prophylaxis, which is 
particularly beneficial for users and their partners that are allergic to natural rubber latex. 
Risks: The new material may lead to increased slippage and breakage of the condom during 
sexual intercourse, which increases the risk of undesired pregnancy and/or transmission of 
sexually-transmitted infections (STIs). The clinical study showed an equivalent rate of clinical 
failure for the synthetic condoms compared to natural rubber latex condoms; however, the 
occurrence of slippage was slightly higher. 
Additional Factors: 
Risk Mitigation: To mitigate the risk associated with the slightly higher slippage rate revealed by 
the clinical study, a warning was placed on all labeling that states that the device should be used 
only if the user has an allergy to natural rubber latex. 
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. 
E.  Example 5: Different Principle of Operation Used to 
Achieve Same Therapeutic Outcome 
Scenario: A device that exerts pressure on the mouth is used to treat obstructive sleep apnea in 
adults. In comparison to the predicate device, which is the first-line treatment for this condition, 
the new device has a different principle of operation to achieve the same intended therapeutic 
outcome. There was concern that the new principle of operation could potentially partially close 
the oral cavity, restricting the user to breathing through the nose. The bench data reveal a higher 
level of pressure exerted by the new device as compared to the predicate device, but the 
manufacturer provided bench performance data to show that the level of pressure would not hold 
the mouth closed in the event of nasal obstruction. In addition, clinical data from a 28-day study 
evaluating the ability of the device to reduce the apnea-hypopnea index (AHI) from baseline as 
compared to the predicate device was provided. The study results showed that the new device 
had a reduction in AHI, but less than that of the predicate device. The study also revealed that 
patient compliance with the device was lower than the predicate due to the higher pressure 
exerted by the device and had a higher complication rate compared to the predicate.  
24 
  Contains Nonbinding Recommendations 
Is a benefit-risk assessment recommended? 
No. A benefit-risk assessment is not recommended because there is increased risk and a 
decreased benefit. FDA will generally determine the new device NSE to the predicate device 
under these circumstances. 
F.  Example 6: Comparative Testing Resulting in 
Substantially Different Results 
Scenario: The manufacturer of a new test for measurement of prothrombin time (PT) 
international normalized ratio (INR) and coagulation factor levels produces a critical reagent 
through recombinant DNA technology, rather than as a multicomponent extract of animal tissue. 
For samples with prolonged PT, the PT results from the new test showed positive bias, compared 
to results from the predicate device. INR results from the two devices were in better agreement 
across the measurement range but included few samples with markedly elevated INR. Calibrated 
assays for fibrinogen and coagulation factors II, V, VII and X showed strong correlation between 
the new device and the predicate device, though times required for clot formation at low factor 
levels were longer with the new device than with the predicate device. Precision and inter-
day/inter-lot studies showed that results from the new device were more reproducible than are 
results from the predicate device. Studies of known PT interferents, at physiologically relevant 
concentrations, showed no unexpected effect on results from the new assay. Review of recent 
postmarket medical device reports (MDRs) for PT devices showed that the only previously 
cleared PT product incorporating a (different) recombinant DNA reagent is subject to 
interference from an antibacterial drug that has not previously been associated with PT 
interference. The mechanism of the interference (involving the recombinant reagent and another 
chemically defined assay component) is well-defined. Bench studies showed no interference with 
the new product by the antibacterial drug associated with the MDRs or by currently marketed 
members of that antibacterial drugs class. 
Is a benefit-risk assessment recommended? 
No. A benefit-risk assessment is not recommended because there is equivalent risk and an 
increased benefit. FDA will generally determine the new device SE to the predicate device under 
these circumstances. 
25