Contains Nonbinding Recommendations 
Factors to Consider When Making 
Benefit-Risk Determinations in 
Medical Device Premarket Approval 
and De Novo Classifications 
Guidance for Industry and 
Food and Drug Administration Staff 
Document issued on August 30, 2019. 
Document originally issued on March 28, 2012. 
This document supersedes Factors to Consider When Making Benefit-Risk 
Determinations in Medical Device Premarket Approvals and De Novo 
Classifications issued August 24, 2016. 
For questions about this document concerning devices regulated by CDRH, contact the Office of 
Policy at 301-796-5441.  For questions about this document concerning CBER-regulated devices, 
contact the Office of Communication, Outreach and Development (OCOD) by calling 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 
2  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-2011-D-0577. 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 include the document 
number 1772 and the complete title of the guidance in the request. 
 
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., 
WO71, Room 3128, Silver Spring, MD 20903, or by calling 1-800-835-4709 or 240-402-8010, 
by email, ocod@fda.hhs.gov, or from the Internet at  
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-
biologics/biologics-guidances.  
 
  3  Contains Nonbinding Recommendations 
 
 
 
 
Table of Contents 
 
I.  Introduction ........................................................................................................................... 5 
II.  Scope ..................................................................................................................................... 5 
III.  Background ........................................................................................................................... 6 
A.  The Statutory Standard for Safety and Effectiveness .................................................... 6 
B.  Types of Scientific Evidence ......................................................................................... 7 
C.  Benefit-Risk Determinations.......................................................................................... 8 
IV.  Factors FDA Considers in Making Benefit-Risk Determinations ......................................... 9 
A.  Assessment of the Benefits of Devices .......................................................................... 9 
B.  Assessment of the Risks of Devices ............................................................................ 10 
C.  Additional Factors in the Assessment of the Probable Benefits and Risks of Devices 11 
V.  Examples of Benefit-Risk Determinations .......................................................................... 15 
A.  Hypothetical Examples ................................................................................................ 15 
B.  Examples Based on Actual FDA Benefit-Risk Determinations .................................. 22 
Appendix A ................................................................................................................................. 24 
Intersection of this Guidance with ISO 14971 ........................................................................ 24 
Appendix B ................................................................................................................................. 25 
Worksheet for Benefit-Risk Assessment ................................................................................ 25 
Benefit-Risk Assessment Summary ........................................................................................ 34 
Appendix C ................................................................................................................................. 35 
Worksheets for Hypothetical Examples.................................................................................. 35 
Worksheet for Hypothetical Example 1 .............................................................................. 36 
Worksheet for Hypothetical Example 2 .............................................................................. 46 
Worksheet for Hypothetical Example 3 .............................................................................. 56 
Worksheet for Hypothetical Example 4 .............................................................................. 66 
 
  4  Contains Nonbinding Recommendations 
 
 
Factors to Consider When Making 
Benefit-Risk Determinations in 
Medical Device Premarket 
Approval and De Novo 
Classifications 
 
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 
 
FDA has developed this guidance document to provide greater clarity for FDA reviewers 
and industry regarding the principal factors FDA considers when making benefit-risk 
determinations during the premarket review process for certain medical devices.  FDA 
believes that the uniform application of the factors listed in this guidance document will 
improve the predictability, consistency, and transparency of the premarket review process. 
 
FDA's guidance documents, including this one, do not establish legally enforceable 
responsibilities.  Instead, guidance documents describe the Agency's 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.  Scope 
 
This guidance document explains the principal factors that FDA considers when making 
benefit-risk determinations in the premarket review of certain medical devices. The 
processes discussed in this guidance are applicable to devices subject to premarket 
 
  5  Contains Nonbinding Recommendations 
 
approval (PMA) applications or De Novo classification requests.  This guidance applies to 
both diagnostic and therapeutic devices.  The concepts discussed in this guidance are 
applicable to the medical device development process from design to market.  As such, the 
benefit-risk factors set out herein should be considered during the design, non-clinical 
testing, Pre-Submission, and Investigational Device Exemption (IDE) phases as well as in 
assembling and assessing PMA applications or De Novo requests.  Although guidance is 
not binding, the concepts and factors described herein generally explain how benefit-risk 
determinations are made by FDA during the premarket review process.  The intersection of 
this Guidance with ISO 14971 is discussed in Appendix A  . 
 
III.  Background 
A.  The Statutory Standard for Safety and Effectiveness 
 
Under section 513(a) of the Federal Food, Drug & Cosmetic Act (the FD&C Act), FDA 
determines whether PMA applications provide a reasonable assurance of safety and 
effectiveness 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.1 To aid in this process, PMA sponsors submit valid scientific evidence, 
including one or more clinical investigations where appropriate, which FDA reviews to 
determine whether the device will have the effect it purports or is represented to have 
under the conditions of use prescribed, recommended, or suggested in the labeling of the 
device.2  FDA staff review the data submitted as part of the PMA application and 
determine  based on a number of factors  if the data support the claims made by the 
sponsor concerning clinically significant results from the device, i.e., intended use and 
indications for use, and if the data analysis demonstrates that the probable3 benefits of the 
                                                           
1 In addition to section 513(a), the criteria for establishing safety and effectiveness of a device are set forth in 
21 CFR 860.7.  Subsection (b)(1) notes, In determining the safety and effectiveness of a device ... the 
Commissioner and the classification panels will consider the following, among other relevant factors ...The 
probable benefit to health from the use of the device weighed against any probable injury or illness from such 
use. (21 CFR 860.7(b)). To make this determination, the agency relies upon only valid scientific evidence. 
(21 CFR 860.7(c)(1)). Valid scientific evidence is defined as evidence from well-controlled investigations, 
partially controlled studies, studies and objective trials without matched controls, well-documented case 
histories conducted by qualified experts, and reports of significant human experience with a marketed device, 
from which it can fairly and responsibly be concluded by qualified experts that there is reasonable assurance 
of the safety and effectiveness of a device under its conditions of use. (21 CFR 860.7(c)(2)). A reasonable 
assurance of safety occurs when it can be determined, based upon valid scientific evidence, that the probable 
benefits ... outweigh any probable risks, and can be demonstrated by establishing the absence of 
unreasonable risk of illness or injury associated with the use of the device for its intended uses and conditions 
of use. (21 CFR 860.7(d)(1)). Similarly, a reasonable assurance of effectiveness occurs when it can be 
determined, based upon valid scientific evidence ... the use of the device for its intended uses ... will provide 
clinically significant results. (21 CFR 860.7(e)(1)). The evidence of which is demonstrated principally 
through well-controlled investigations (see 21 CFR 860.7(e)(2)), as defined in 21 CFR 860.7(f). 
2 Section 513(a)(3)(A) of the FD&C Act. 
3 In general, probable and probability in this guidance have the same connotation as in 21 CFR 
860.7(b)(3), i.e. they refer to the likelihood of the patient experiencing a benefit or risk. Hypothesis testing, 
formal concepts of probability and predictive probability, likelihood, etc., typically are critical elements in the 
assessment of probable benefit and risk.  FDA does not intend for the use of the term probable benefit in 
this guidance to refer to the regulatory context for Humanitarian Device Exemptions (HDE) under section 
520(m) of the FD&C Act, and FDAs implementing HDE regulations. 
 
  6  Contains Nonbinding Recommendations 
 
device outweigh its probable risks.  A balanced consideration of probable benefits and 
probable risks is an essential part of FDAs determination that there are reasonable 
assurances of safety and effectiveness.4  Other considerations include that the device is 
being manufactured in accordance with FDAs quality system requirements.5 
 
Similarly, in accordance with section 513(f)(2) of the FD&C Act, sponsors of devices that 
have been determined to be not substantially equivalent (NSE) through the 510(k) 
program or if a person believes their device is appropriate for classification into Class I or 
Class II and determines, based on currently available information, there is no legally 
marketed predicate device, may be eligible to submit a De Novo request requesting FDA 
to make a risk-based classification determination for the device under section 513(a)(1) of 
the FD&C Act.6   Because devices classified under this pathway (De Novo devices) are 
low to moderate risk devices, they may not need to confer as substantial a benefit to 
patients7 in order to have a favorable benefit-risk profile.  Devices granted marketing 
authority under De Novo requests should be sufficiently understood to explain all the risks 
and benefits of the device such that all risks can be appropriately mitigated through the 
application of general and/or special controls to provide reasonable assurance of safety 
and effectiveness.  Further, devices classified under De Novo requests may serve as 
predicates for future devices which can be appropriately regulated through the 510(k) 
program; therefore, FDA carefully considers the benefit-risk profile of these devices in the 
determination that there is reasonable assurance of safety and effectiveness. 
 
B.  Types of Scientific Evidence 
 
Medical devices can be evaluated using clinical and non-clinical testing methods. Clinical 
testing methods for medical devices can include, when appropriate, 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, reports of significant human experience, and 
testing on clinically derived human specimens (DNA, tissue, organ and cadaver studies).8   
Non-clinical testing methods can encompass an array of methods including performance 
testing for product safety/reliability/characterization, human factors and usability 
engineering testing under simulated conditions of use, animal and cell-based studies, and 
computer simulations.  These tests characterize mechanical, electrical and chemical 
properties of the devices including but not limited to 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, 
including cell lines.  The information obtained from any clinical and/or non-clinical testing 
is taken into account during the premarket review process and FDAs benefit-risk 
determination. 
                                                           
4 Equally important is FDAs determination of effectiveness. See footnote 1. 
5 See 21 CFR Part 820. 
6 See FDA guidance De Novo Classification Process (Evaluation of Automatic Class III Designation) 
available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/de-novo-classification-
process-evaluation-automatic-class-iii-designation.  
7 In general, for the purposes of this guidance, the use of the term patient refers to an individual who is 
under medical care or treatment and is not a subject, and the use of the term subject refers to an individual 
who participates in a clinical investigation. 
8 See 21 CFR 860.7. 
 
  7  Contains Nonbinding Recommendations 
 
 
Although a great deal of emphasis is placed on the importance of clinical data in 
demonstrating the safety and effectiveness of a medical device, non-clinical data also can 
be critical to understanding a devices safety and effectiveness. Medical devices often have 
attributes that cannot be tested using clinical methods alone and that play a major role in 
the safety or effectiveness of the device. 
 
Both clinical and non-clinical testing methods may be used to assess the probability or 
severity of a given risk, and/or the success of risk mitigation. For example, in the case of 
some implants, the most robust long-term evidence comes from engineering tests that are 
able to challenge the device under worst-case conditions, test the device to failure, and 
simulate many years of use.  In contrast, clinical studies are usually limited in duration of 
follow-up, and, as a result, may be less informative with respect to the long-term 
performance of the device. In this case, the results of engineering testing may 
significantly influence FDA's benefit-risk determination independent of the clinical 
findings. 
 
Both clinical and non-clinical data can play a role in FDAs benefit-risk determinations, 
and the factors discussed in this guidance are informed by both types of data. 
 
FDA relies on valid scientific evidence in making risk and benefit determinations, 
including the critical issue of identifying probable risks and probable benefits in the 
first place. In general, a probable risk and a probable benefit do not include theoretical 
risks and benefits, and instead are ones whose existence and characteristics are supported 
by valid scientific evidence. Generally, isolated case reports, random experience, reports 
lacking sufficient details to permit scientific evaluation, and unsubstantiated opinions are 
not regarded as valid scientific evidence to show safety or effectiveness. However, such 
information may be considered in identifying a device that has questionable safety and 
effectiveness.9 
 
C.  Benefit-Risk Determinations 
 
The factors FDA considers as part of the benefit-risk determination are explained in detail 
below. We also give examples of how the factors interrelate and how they may affect 
FDAs decisions. By providing greater clarity about FDAs decision-making process, we 
hope to improve the predictability, consistency, and transparency of the review process for 
applicable devices. 
 
We have also included a worksheet that reviewers will use in making benefit-risk 
determinations as part of the premarket review process.  The worksheet is attached as 
Appendix B in this guidance, and examples of how reviewers might use the worksheet are 
attached as Appendix C.  By documenting reviewers thought processes as part of the 
administrative record and, in certain cases, the publicly available summary of our 
decision,10 sponsors will have a better idea of the basis for FDAs favorable decisions and 
                                                           
9 21 CFR 860.7(c)(2). 
10 See https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm.    
 
  8  Contains Nonbinding Recommendations 
 
gain a greater understanding of what factors were considered as part of an approval or a 
down-classification decision through the De Novo process.  However, because the 
weighting of the factors for a type of device may change over time  such as a device no 
longer being a first-of-a-kind or the only available treatment as new therapies are approved 
 the benefit-risk determination for a specific device at one point in time may no longer 
represent the proper weighting of the factors for the same or similar type of device in the 
future. 
 
IV.  Factors FDA Considers in Making Benefit-Risk 
Determinations 
 
 
The factors described below are considered within the intended use of the device, 
including the target population. These sections are not intended to provide device- 
specific data requirements for the assessment of the factors or methods by which 
inferences will be drawn from the data. 
 
A.  Assessment of the Benefits of Devices 
 
 
Extent of the probable benefit(s):  FDA assesses information provided in a PMA 
application or De Novo request concerning the extent of the probable benefit(s) by taking 
into account the following factors individually and in the aggregate: 
 
-  The type of benefit(s)  examples include but are not limited to the devices impact 
on clinical management, patient health, and patient satisfaction in the target 
population, such as significantly improving patient management and quality of life, 
reducing the probability of death, aiding improvement of patient function, reducing 
the probability of loss of function, and providing relief from symptoms. These 
endpoints denoting clinical benefit are usually measured directly, but in some cases 
may be demonstrated by use of validated surrogate endpoints. For diagnostics, a 
benefit may be assessed according to the public health impact of a particular device, 
due to its ability to identify a specific disease and therefore prevent its spread, 
predict future disease onset, provide earlier diagnosis of diseases, or identify 
patients more likely to respond to a given therapy. 
 
-  The magnitude of the benefit(s)  we often assess benefit along a scale or 
according to specific endpoints or criteria (types of benefits), or by evaluating 
whether a pre-identified health threshold was achieved. The change in participants 
condition or clinical management as measured on that scale, or as determined by an 
improvement or worsening of the endpoint, is what allows us to determine the 
magnitude of the benefit in participants. Variation in the magnitude of the benefit 
across a population may also be considered. 
 
-  The 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 well predicted. The data may show 
 
  9  Contains Nonbinding Recommendations 
 
that a benefit may be experienced only by a small portion of patients in the target 
population, or, on the other hand, that a benefit 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, we consider magnitude and probability 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. For example, a large 
benefit, even if experienced by a small population, may be significant enough to 
outweigh risks, whereas a small benefit may not, unless experienced by a large 
population of participants. 
 
-  The duration of effect(s) (i.e., how long the benefit can be expected to last for the 
patient)  some treatments are curative, whereas, some may need to be repeated 
frequently over the patients lifetime. To the extent that it is known, the duration of 
a treatments 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 
 
Extent  of  the  probable  risk(s)/harm(s):    FDA  assesses  the  extent  of  the  probable 
risk(s)/harm(s) by taking into account the following factors individually and in the aggregate: 
 
-  Severity, types, number and rates11 of harmful events associated with the use 
of the device:12 
 
Device-related serious adverse events  those events that may have been 
o 
or were attributed to the use of the device and produce an injury or illness 
that is life-threatening, results in permanent impairment or damage to the 
body, or requires medical or surgical intervention to prevent permanent 
harm to the body.13 
 
Device-related non-serious adverse events  those events that may have 
o 
been or were attributed to the use of the device and that do not meet the 
criteria for classification as a device-related serious adverse event. 
 
Procedure-related complications  harms to the patient that would not be 
o 
included under serious or non-serious adverse events, and that do not 
                                                           
11 For purposes of this guidance, rates means the number of harmful events per patient or number of harmful 
events per unit of time. 
12 We have listed each type of harm individually for the purpose of clarifying which of the more commonly 
recognized harms FDA would consider in benefit-risk assessments.  In making benefit-risk assessments, FDA 
does not consider each type of harm individually, but rather looks at the totality of the harmful events 
associated with the device. 
13 See 21 CFR 803.3. 
 
  10  Contains Nonbinding Recommendations 
 
directly result from use of the device.  For example, anesthetic-related 
complications associated with the implantation of a device.  Similarly, 
FDA would factor risks associated with the collection of human biological 
materials into the benefit-risk determination.14 
 
-  Probability of a harmful event  the proportion of the intended population that 
would be expected to experience a harmful event.  FDA would factor whether an 
event occurs once or repeatedly into the measurement of probability. 
 
-  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 
would consider the severity of the harm along with its duration. 
 
-  Risk from false-positive or false-negative results for diagnostics  if a diagnostic 
device gives a false-positive result, the patient might, for example, receive an 
unnecessary treatment and incur all the risks that accompany that treatment, or 
might be incorrectly diagnosed with a serious disease. If a diagnostic device gives a 
false-negative result, the patient might not receive an effective treatment (thereby 
missing out on the benefits that treatment would confer), or might not be diagnosed 
with the correct disease or condition. The risks associated with false-positives and 
false-negatives can be multifold, but are considered by FDA in light of probable 
risks. 
 
We also consider the number of different types of harmful events that may result from 
using the device and the severity of their aggregate effect. When multiple harmful events 
occur at once, they 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 can be substantial. 
 
C.  Additional Factors in the Assessment of the Probable 
Benefits and Risks of Devices 
 
 
Uncertainty  there is never 100% certainty when determining reasonable assurance of 
safety and effectiveness of a device. However, the degree of certainty of the benefits and 
risks of a device is a factor we consider when making benefit-risk determinations.15 
Factors such as poor design or poor conduct of clinical trials, or inadequate analysis of data, 
can render the outcomes of the study unreliable. Additionally, for certain device types, it is 
sometimes difficult to distinguish between a real effect and a placebo effect in the absence 
of a trial design that is capable of masking investigators and participants. Furthermore, the 
                                                           
14 These considerations affect the risk profile of in vitro diagnostic devices when the biological material is 
collected via an invasive procedure for the purpose of performing the diagnostic test. 
15 See FDA guidance Consideration of Uncertainty in Making Benefit-Risk Determinations in Medical 
Device Premarket Approvals, De Novo Classifications, and Humanitarian Device Exemptions available at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/consideration-uncertainty-
making-benefit-risk-determinations-medical-device-premarket-approvals-de.  
 
  11  Contains Nonbinding Recommendations 
 
repeatability of the study results, the validation of the analytical approach, and the results of 
other similar studies and whether the study is the first of its kind or a standalone 
investigation can all influence the level of certainty. In addition, the generalizability of the 
trial results to the intended treatment and user population is important. For example, if the 
device requires in-depth user training or specialization, the results of the clinical study may 
not be generalizable to a wider physician population. Likewise, if the device is intended to 
diagnose a disease in a subpopulation, it may not be useful in the general population. In 
general, it is important to consider the degree to which a clinical trial population is 
representative of the intended marketing or target population. 
 
Patient-centric assessments and patient-reported outcomes (PROs)  We recognize 
that patient-centric metrics such as validated health-related quality of life measures and 
other Patient-Reported Outcomes (PROs) (e.g., scales or scores indicating patients 
experience of pain or function) can be helpful for patients and health care practitioners 
when discussing treatment options and decisions, and may be used to demonstrate benefit 
for purposes of product approval.  These types of metrics allow the physician to better 
quantify the impact of the device on the patients well-being and help the patient make a 
more informed decision.  
 
Characterization of the disease  the treated or diagnosed condition, its clinical 
manifestation, how it affects the patients who have it, how and whether a diagnosed 
condition is treated, and the conditions natural history and progression (i.e., does it get 
progressively better or worse for the patient and at what expected rate) are all important 
factors that FDA considers when characterizing disease and determining benefits and risks. 
 
Patient perspectives  if the risks are identifiable and definable, risk tolerance will vary 
among patients, and this will affect individual patient decisions as to whether the risks are 
acceptable in exchange for a probable benefit. When making a benefit-risk determination at 
the time of approval or De Novo classification, FDA recognizes that patient perspectives 
on benefits and risks may reveal reasonable patients who are willing to tolerate a very high 
level of risk to achieve a probable benefit, especially if that benefit results in an 
improvement in quality of life. Rather than one-sided evaluations, patient preference 
assessments should take into account both the patients willingness and unwillingness to 
use a device or tolerate risk in exchange for probable benefit, and/or evaluate how patients 
view trade-offs between benefits and risks of various treatment options.   
 
Patient preference studies can provide insight on how patients value benefits in comparison 
to risk. Patient preference information is defined as the qualitative or quantitative 
assessment of the relative desirability or acceptability to patients of specified alternatives 
or choices among outcomes or other attributes that differ among alternative health 
interventions.16  FDA may also consider the preferences of care-partners (e.g., parents) 
and healthcare professionals to the extent they are relevant in the benefit-risk assessments 
for a particular device subject to review in a PMA, HDE application, or De Novo request. 
 
                                                           
16 Adapted from: Medical Device Innovation Consortium. A framework for incorporating information on 
patient preferences regarding benefit and risk into regulatory assessments of new medical technology. 2015. 
(http://mdic.org/wp-content/uploads/2015/05/MDIC_PCBR_Framework_Proof5_Web.pdf). 
 
  12  Contains Nonbinding Recommendations 
 
For more information regarding patient preference studies, consult FDA Guidance: Patient 
Preference Information  Voluntary Submission, Review in PMAs, HDE Applications, and 
De Novo Requests, and Inclusion in Decision Summaries and Device Labeling.17 
 
How data concerning patient risk tolerance and other patient-centered metrics are 
developed will vary depending on a number of factors, including the nature of the disease 
or condition and the availability of existing treatments, as well as the risks and benefits they 
present. FDA encourages any sponsor that is considering developing such data to have 
early interaction with the appropriate FDA review division.18 
 
When assessing such data in a PMA application or De Novo request, FDA realizes that 
some patients are willing to take on a very high risk to achieve a small benefit, whereas 
others are more risk averse. Therefore, FDA would consider evidence relating to patients 
perspective of what constitutes a meaningful benefit when determining if the device is 
effective, as some set of patients may value a benefit more than others. It should also be 
noted that if, for a certain device, the probable risks outweigh the probable benefits for all 
reasonable patients, FDA would consider use of such a device to be inherently 
unreasonable.19 
 
Patient preference information may demonstrate that most, if not all, of the patient 
population with a specific disease or condition consider the benefit-risk tradeoffs 
acceptable. Different factors can influence patient perspective on benefits and risks, 
including: 
 
-  Severity of disease or condition  patients suffering from very severe diseases 
(i.e., those that are life-threatening) may tolerate more risk for devices used in 
treatment. For diagnostic devices, individuals might be more averse to the risk of a 
false negative result concerning a severe disease. 
 
-  Disease chronicity  some patients with chronic diseases who have adapted to their 
illness and minimized its interference with their daily lives may tolerate less risk 
and require risky devices to deliver a greater treatment benefit, whereas other 
patients who have suffered from a debilitating chronic illness over a long period of 
time may tolerate higher risk to gain less benefit. 
 
-  Availability of alternative treatment/diagnostic options (also see below)  if there 
are no other treatment/diagnostic options available, patients may tolerate more risk 
for even a small amount of benefit. 
 
Availability of alternative treatments or diagnostics  when making benefit-risk 
determinations, FDA considers whether other treatments or diagnostics, including non- 
                                                           
17 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-
preference-information-voluntary-submission-review-premarket-approval-applications.  
18 See FDA guidance Requests for Feedback and Meetings for Medical Device Submissions: The Q-
Submission Program available at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/requests-feedback-and-meetings-medical-device-submissions-q-submission-program. 
19 For the purposes of this guidance unreasonable risk refers to a risk that no set of reasonable patients 
would be willing to endure to achieve a probable benefit. 
 
  13  Contains Nonbinding Recommendations 
 
device therapies, have been approved or cleared for the intended condition and patient 
population.  When considering other therapies, FDA takes into account how effective they 
are; what known risks they pose; how they are used in current medical practice; their 
benefit-risk profiles; and how well available alternatives address the needs of patients and 
providers.  For a device with a known benefit and a probability of high risk that treats a 
condition for which no alternative treatments are available, FDA would consider the risk to 
the patient of having no treatment if a device were not approved.  For example, if a new 
device has a very small significant benefit and there is significant uncertainty about that 
benefit, we may still approve the product if there are no available alternative treatments and 
the probable benefits outweigh the probable risks. 
 
Risk mitigation  the use of mitigations, when appropriate, can minimize the probability 
of a harmful event occurring and improve the benefit-risk profile. The most common form 
of risk mitigation is to include appropriate information within labeling (e.g., warnings, 
precautions, etc.), or to restrict the indication to a more limited use. Some harms can be 
mitigated through other forms of risk communication, including training and patient 
labeling. For in vitro diagnostics, risks may be mitigated by the use of complementary 
diagnostic tests. 
 
Postmarket data  the use of devices in a real world setting can provide a greater 
understanding of their risks and benefits.  FDA may consider the collection of postmarket 
data as a way to clarify the magnitude and effect of mitigations or as a way to develop 
additional information regarding benefits or risks for certain device types or in specific 
patient populations when making a benefit-risk determination.  FDA has the authority to 
require post-approval studies for PMA devices and postmarket surveillance for PMA and 
De Novo devices.20  In addition, pursuant to section 513(a)(3)(C) of the FD&C Act, in 
certain cases, such as if a device is likely to be denied approval due to uncertainty about its 
effectiveness, FDA will consider whether postmarket data collection or other conditions 
might be structured so as to permit approval subject to those conditions.21 
 
These types of studies or other data that come to light after the device is used in the real- 
world setting may alter the benefit-risk profiles of certain devices, especially if new risks 
are identified, or if the information can be used to confirm that certain risks have been 
mitigated, to identify which patients are most likely to suffer adverse events, or to identify 
more specifically how different groups of patients will respond. 
 
Novel technology addressing unmet medical need  in assessing benefit and risk, FDA 
considers whether a device represents or incorporates breakthrough technologies and 
addresses an unmet medical need. A device may address unmet medical need by providing 
a clinically meaningful advantage over existing technologies, providing a greater clinically 
                                                           
20 21 CFR 814.82 states that FDA may impose postapproval requirements in a PMA approval order or by 
regulation at the time of approval of the PMA or by regulation subsequent to approval. In addition, under 
section 522 of the FD&C Act, and FDAs implementing regulations at 21 CFR Part 822, FDA may order 
postmarket surveillance for certain Class II or Class III devices. 
21 See FDA Guidance The Least Burdensome Provisions: Concept and Principles: Guidance for Industry and 
FDA Staff available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/least-
burdensome-provisions-concept-and-principles.  
 
  14  Contains Nonbinding Recommendations 
 
meaningful benefit than existing therapy, posing less risk than existing therapy, or 
providing a treatment or means of diagnosis where no alternative is available. 
 
It is not unusual for novel devices that address an unmet medical need to have relatively 
small probable benefits, and FDA may determine the novel device to be reasonably safe 
and effective even though the sponsor demonstrates a relatively small probable benefit. In 
addition, the development of innovative technology may provide additional future benefits 
to patients.  With subsequent iterations of the device its benefit-risk profile may change 
(e.g., the benefits may increase or the risks may be reduced), the expected level of safety 
and effectiveness may change, and later versions may offer significant advantages over the 
initial device.  In these circumstances, in order to facilitate patient access to new devices 
important for public health and to encourage innovation, we may tolerate greater 
uncertainty in an assessment of benefit or risk than for most established technologies, 
particularly when providers and patients have limited alternatives available. 
 
V.  Examples of Benefit-Risk Determinations 
 
The examples below are hypothetical or simplified and are only offered for illustrative 
purposes.  The decisions described in these examples are not predictive of future FDA 
decisions, rather they are hypothetical outcomes and are only intended to demonstrate how 
FDA considers the factors described in this guidance when making benefit-risk 
determinations.  Similar scenarios or devices may result in different approval outcomes 
depending on the individual performance characteristics of a particular device and the 
population for which it is indicated. 
 
A description of how FDA would consider these examples in the context of the reviewer 
worksheet is included in Appendix C. 
 
A.  Hypothetical Examples 
 
 
Example 1 
 
An implantable device is developed to treat a severe, chronic condition for patients who 
have failed all other treatment options. 
 
The device is studied in a pivotal clinical trial with a design where all participants are 
implanted with the device, but the device is only turned on in half of them.  After 
completion of the trial, inactive devices can be turned on. The primary endpoint for the trial 
is the magnitude of the benefit, i.e., the trial is designed to measure how well the device 
reduces the subjects symptoms as compared to the current standard of care. 
 
The results of the pivotal clinical trial revealed the following: 
 
Benefits: Based on the clinical study, it is inferred that the probability that a patient will 
experience a substantial benefit when the device is implanted is 75%.  The trial was 
considered to have met its primary endpoint.  As a general matter, patients with this disease 
 
  15  Contains Nonbinding Recommendations 
 
who are able to maintain good mobility tend to have a longer life expectancy. 
 
However, the duration of the benefit cannot be determined because the subjects in the study 
were only followed for one year. 
 
Risks: The study showed that there is a very low probability of occurrence (less than 
3%) of harmful events after device implantation.  However, all implanted devices that 
require a surgical procedure carry with them their own set of risks.  In this case it is known 
from the literature that the implantation of this device is not routine and there is a 
1% chance of death from surgery.  In addition, permanent implants pose additional risks, 
namely, they typically remain with the patient for life and may be difficult to remove. Even 
in cases where the device is deactivated, it remains implanted and a risk of device fracture, 
mechanical failure, or an adverse biological response to the device remains (the probability 
is less than 3%). 
 
Additional Factors: 
Uncertainty:  It is difficult to discern the mechanism of action by which subjects 
symptoms improved and whether the surgery may have contributed to such improvement. 
Because the trial ended after one year, it is difficult to determine the duration of the benefit 
beyond one year. There is only a 75% chance that a patient will experience total success 
when implanted with the device. 
 
Patient Perspectives:  The sponsor provided data showing that most patients are willing to 
take the risk of having the device implanted even for a 75% probability of benefit because 
the alternative treatment options do not work for them and their symptoms are severe. 
 
Risk Mitigation:  The surgery to implant and explant (if necessary) the device is risky, but 
the risks can be mitigated by requiring the device to be implanted by a specially trained 
surgeon. 
 
Approval/Non-Approval Considerations:  The probability that a patient will experience 
a benefit is relatively high (approximately 75%, if the clinical trial results hold for the 
intended use population).  In this particular case, FDA does not have the option to limit 
the use of the device to only those patients who are most likely to experience a benefit 
because the covariates that determine the subgroup of patients who would definitely 
experience the benefit are unknown.  In addition, this type of permanently implantable 
device poses significant risks and there is some remaining uncertainty associated with the 
trial results.  However, for those patients in the target population who will experience a 
benefit, symptom relief and improvement in quality of life is impressive and some patients 
have expressed a willingness to tolerate the risks as a trade-off for obtaining such benefits.  
In addition, the risks, although substantial, could be somewhat mitigated through limiting 
the device use to clinicians with specialized training.  Finally, the device treats a severe and 
chronic disease for which there are few, if any, alternative treatments. Therefore, FDA is 
likely to approve the device. 
 
Example 2 
 
 
  16  Contains Nonbinding Recommendations 
 
A novel device that replaces a patients memory is developed to treat Alzheimers disease, 
dementia, and other memory disorders. The device is designed to be 
permanently implanted and the patient must undergo a brain resection for the device to 
work properly. The device functions by downloading all of a patients memories onto a 
computer chip. Once the device is implanted, any residual memory the patient retained is 
no longer accessible to the patient. 
 
Benefits:  A clinical trial of the device showed significant improvement in subjects who 
were in the early stages of dementia and minimal improvement in subjects who were in 
more advanced stages. Subjects who received implanted devices when the majority of their 
memory was intact experienced the greatest benefit and their overall quality of life was 
enhanced. Since the trial design accounted for two subgroups, subjects at the early stage of 
the disease and subjects at advanced stages of the disease, it can be inferred that, if the 
device is marketed, the patient population in early stages of the disease is likely to 
experience significant improvement, whereas the patient population in advanced stages is 
likely to experience only minimal improvement. 
 
Risks:  The surgery to implant the device is highly risky and is usually only performed by 
specially trained neurosurgeons. Even with these procedural restrictions, it is known 
from previous studies and literature that there is an 8% risk of serious adverse events from 
the surgery alone. In addition, the clinical study showed that adverse events include partial 
paralysis, loss of vision, loss of motor skills, vertigo, and insomnia (predictive probability 
of 1%). Non-serious adverse events include temporary personality shifts, mood swings, and 
slurred speech (predictive probability shown in the study was 5%). 
 
Additional Factors: 
Uncertainty:  The number of subjects eligible and willing to enroll in the trial was small, 
but the data were robust, and the trial was well-designed and conducted. The results of the 
trial are generalizable. The study showed that the subjects likely to experience the best 
results are the ones at early stages of memory loss. 
 
Patient Perspectives:  Because of the serious effect on patients quality of life from 
diseases like Alzheimers, other forms of dementia, and other conditions that are associated 
with severe memory loss, as well as the progressive nature of Alzheimers, some patients 
with these conditions, and their care-partners, often have a very high tolerance for risk, 
even a risk of serious adverse events, in exchange for a probable improvement of the 
disease symptoms, and for alleviating the burden that they anticipate they will place on 
family members during the later stages of the disease. Other patients, such as those at older 
ages, may be less willing to tolerate such risks.  
 
Patients who are at more advanced stages of their illness and experiencing more severe 
symptoms are less likely to benefit from the device. Furthermore, their tolerance for risk is 
difficult to assess due to their advanced disease. 
 
Availability of Alternative Treatments or Diagnostics:  There are currently no alternative 
treatments available. 
 
 
  17  Contains Nonbinding Recommendations 
 
Risk Mitigation:  The risks associated with this device are great.  The risks associated with 
implantation and explantation (if necessary) can be somewhat mitigated by limiting use to 
surgeons who have undergone special training, but the risks associated with personality 
changes cannot be mitigated or predicted.  The risks can also be mitigated by indicating the 
device for patients at earlier stages of the disease who are more likely to benefit, and 
explaining in the labeling using data from the clinical trial that individuals experiencing 
more severe symptoms are less likely to benefit from the device. 
 
Novel Technology      Addressing        Unmet Medical      Need:  There is no other similar technology 
available.  It is possible that future improvements of the device may allow treatment of 
many other conditions that affect cognitive function.  Moreover, there are no other 
treatments that provide the level of benefit that this device confers on the target population. 
 
Approval/Non-Approval Considerations:  The device will confer a substantial benefit 
for a defined and predictable subgroup of patients and a minimal benefit for another 
defined and predictable subgroup.  Even though the clinical trial was small, the quality of 
the data was good and the resulting confidence intervals are narrow.  The uncertainty about 
results is the usual uncertainty resulting from drawing inferences from a sample in the 
study to the population in the market.  The risks associated with the device are great and 
can be partially mitigated by training the physicians who implant/explant (if necessary) the 
device.  And, because patients experience the greatest benefit when the device is implanted 
earlier, they must expose themselves to the risks for a longer period of time in order to reap 
the greatest benefit; therefore, the patients who stand to benefit most also take on the 
greatest amount of risk.  The sponsor provided data showing that many patients who suffer 
from memory disorders are willing to try novel approaches that have significant risk, in 
order to preserve their memories and quality of life.  The fact that there are no alternative 
treatments for this condition is another important consideration. Even though the device-
related risks are high, they are tolerable to some patients because of the probable benefits 
they offer, and the progressive nature of the untreated condition.  Furthermore, the risks are 
known and quantifiable.  Therefore, this device, although it poses substantial risk, may be 
approvable based on all of these considerations taken in sum.  The decision as to whether 
or not to implant the device in a particular patient is a matter of patient preference (perhaps 
with the involvement of a legally authorized representative) and medical judgment.  After 
full consideration of the likelihood of, and timeframe for, progression of disease and the 
predictability of future impairment without intervention, FDA is likely to approve the 
device as long as the labeling prominently addresses the 8% serious adverse event rate and 
would provide through conditions of approval that only highly trained physicians will be 
able to implant the device. 
 
Example 3 
 
A sponsor claims that its new in vitro diagnostic device (IVD), a serum-based test, can 
differentiate patients with BI-RADS 4 mammography results into two groups, namely 
patients with a low probability of having cancer for whom the physician may recommend 
waiting a few months for additional testing, thus avoiding the morbidity associated with a 
biopsy, and all other BI-RADS 4 patients for whom a biopsy would be recommended as 
currently occurs under standard of care.  The proposed intended use is: 
 
  18  Contains Nonbinding Recommendations 
 
 
The in vitro diagnostic test measures 10 peptide analytes and yields a single qualitative 
result.  The test is intended for females 40 years or older following mammography of a 
breast lesion with a BI-RADS of 4 result to aid physicians in the decision to recommend a 
breast biopsy. 
 
Negative test result (Low Risk): immediate biopsy is not recommended, wait a few months 
for further tests. 
 
Positive test result (High Risk): immediate biopsy is recommended. 
 
Results from a clinical study in the intended use population (with biopsy results for all 
subjects) are: 
 
 
    Biopsy   
    Malignancy  Benign   
Test  Positive  97  75  172 
Negative  3  225  228 
    100  300  400 
Sensitivity=97% (97/100) with 95% two-sided CI: 91.5% to 99.0% Specificity=75% 
(225/300) with 95% two-sided CI: 69.8% to 79.6% Prevalence=25% (100/400) 
NPV=98.7% (225/228) PPV=56.4% (97/172) 
 
Benefits: The main benefit from use of the device is avoiding morbidity associated with 
an immediate biopsy for the 57% (228/400) of subjects whose test results indicate a low 
probability of having breast cancer. 
 
Risks:  Among test-negative subjects, the observed (from immediate biopsy) prevalence of 
cancer is 1.3% (3/228 = 1-NPV).  The main risk from use of the device is in failing to 
biopsy some BI-RADS 4 patients who have biopsy-detectible breast cancer, thus delaying 
their diagnosis and treatment.  Concerning this risk, the sponsor asserts that a clinically 
acceptable prevalence for cancer among non-biopsied BI-RADS 4 subjects is 2% or 
lower, because: a) BI-RADS 3 patients are usually counseled not to have an immediate 
biopsy (waiting a few months, instead, for further evaluation), and b) the expected 
prevalence of breast cancer among BI-RADS 3 patients is 2%.  The benefit-risk odds 
measurable from the clinical study is 75 (225/3), and the observed risk for non-biopsied 
BI-RADS 4 subjects is lower than the expected risk in BI-RADS 3 patients. 
 
Additional Factors: 
Uncertainty:  There are the usual uncertainties tied to statistical confidence intervals 
surrounding observed study results. 
 
The benefit-risk odds are not weighted for the clinical impact of avoiding biopsy morbidity 
compared to the clinical impact of missing a biopsy-detectible cancer.  That is, the type of 
benefit is not necessarily commensurate with the type of risk. 
 
 
  19  Contains Nonbinding Recommendations 
 
There is no assurance that the clinical impact of breast cancers missed among patients with 
BI-RADS 4 mammography results is equivalent to the clinical impact of breast cancers 
among patients who have BI-RADS 3 results.  Hence, there is uncertainty about the extent 
of the probable risk(s)/harm(s). 
 
Test-negative BI-RADS 4 patients, who do not undergo biopsy, will receive no 
histopathological assessment of benign disease that is present. 
 
Patient Perspectives:  Patients tolerance for delayed diagnosis and treatment of breast 
cancer typically is low. This needs to be weighed against the value that patients place on 
avoiding biopsy-related morbidity. 
 
Availability of alternative treatments or diagnostics: There are no other in vitro diagnostic 
devices cleared or approved for the new tests intended use. 
 
Risk mitigation: All women with negative test results will have follow-up visits for further 
evaluation and testing. 
 
Approval/Non-Approval Considerations:  The kinds and probabilities of benefits and 
risks are reasonably defined. A clinical practice reference for acceptable risk is put forth, to 
which the tests performance characteristics are aligned. Weighting of the different kinds 
of benefits versus risks is not directly addressed, and additional information is needed to 
establish whether the trade-offs are acceptable. Given that the benefits are uncertain and 
the risk (for a very small number of patients) could be substantial, FDA might determine 
that this device is not approvable, but would likely take it to an advisory panel prior to 
making a decision. 
 
Example 4  De Novo 
 
A new standalone therapeutic device is developed to provide enhanced stability for more 
invasive, higher-risk implanted devices, which could otherwise affix themselves without 
support.  The device can be used to support a primary device at the time of implantation, or 
can be added to an already-implanted device that is malfunctioning. 
 
The device is studied in a prospective, multi-center, single-arm clinical study of over 200 
subjects. The primary endpoint for the trial is the magnitude of the benefit, i.e., the trial is 
designed to measure how well the device prevents movement and malfunction of the 
primary device as compared to when it is implanted without the benefit of enhanced 
stability. 
 
The results of the pivotal clinical trial revealed the following: 
 
Benefits: Through one year of follow-up, no subject experienced device movement and 
only two subjects experienced complications related to the device malfunctioning.  This is 
a significant improvement over primary device performance when implanted alone and 
gives a very high predictive probability that a patient receiving the device will not 
experience device movement. 
 
  20  Contains Nonbinding Recommendations 
 
 
Risks: Through one year of follow-up, there were no fractures of any primary device and 
only a handful of malfunctions of the support system, none of which lead to serious 
adverse events.  The risks of failure of the support system are not high because even if the 
support system fails, it is unlikely to lead to an overall failure of the primary device. 
 
Even though all implanted devices that require a surgical procedure carry with them their 
own set of risks (e.g., 1% chance of death from surgery), this device is implanted along 
with the primary device and consequently does not require an additional surgery to 
implant.  Or, if it is placed to enhance the performance of a malfunctioning primary device, 
it is put in during a surgery that would have otherwise been performed to fix the 
malfunctioning primary device.  Therefore, the data suggest that adding the support device 
during surgery does not appear to increase the risk to the patient. 
 
FDA determined that the support device poses low-to-moderate risk, the risks associated 
with its use are well-defined and understood, and the risks can be mitigated by general and 
special controls, which would provide reasonable assurance of the safety and effectiveness 
of the device.  As a consequence, the support device is appropriate for the De Novo 
pathway. 
 
Additional Factors: 
Uncertainty:  The results of the pivotal clinical trial are limited to one-year of follow-up. 
For a permanent, implantable device, longer follow-up times can reduce uncertainty 
regarding the long-term safety and effectiveness of the device. 
 
Patient Perspectives:  Patients who receive the support device either are already 
undergoing a surgery and implantation of the primary device or have had complications 
with an existing device that the support device can be used to correct non-surgically.  The 
results of the pivotal clinical trial indicate that future patients stand to benefit from greater 
stability of the primary device as a result of the use of the support device; therefore, most 
patients stated they would accept the probable benefits of the device given the probable 
risks. 
 
Risk Mitigation:  For this De Novo, FDA established special controls to mitigate the risks 
associated with the device and make it appropriate to be classified under Class II.  For this 
device, FDA required demonstration of biocompatibility, sterility, safety and effectiveness 
data (including clinical performance data, durability, compatibility, migration, resistance, 
corrosion resistance, and delivery and deployment); evaluation of the MR-compatibility of 
the device; validation of electromagnetic compatibility of device; limiting of the device to 
prescription use; and clear instructions in the labeling regarding the safe and effective use 
of the device. Since this device does not require an additional surgery to be implanted, the 
surgical risk is not an issue. 
 
Novel Technology Addressing Unmet Medical Need:  This device is the first system that 
can access and repair a failed or problematic primary device, providing surgeons with a 
minimally-invasive option for re-affixing devices that are not properly positioned or that 
have migrated, or those that are at risk of such complications. 
 
  21  Contains Nonbinding Recommendations 
 
 
Approval/Non-Approval Considerations:  The clinical trial results provide assurance of 
at least one year of clinical effectiveness of the device.  Furthermore, it is important to 
consider that the device merely supports and supplements the effectiveness of another 
device and its failure would not significantly affect the performance of the primary 
device.  The device does not pose risks that would rise to the level of a Class III device. 
Any safety concerns regarding device failure can be readily addressed through special 
controls related to appropriate testing and labeling.  Given the device benefits, the ability 
to mitigate risks through special controls, and the fact that this device is not life- 
supporting or life-sustaining, FDA would be likely to grant a De Novo request to classify 
this device into Class II. 
 
B.  Examples Based on Actual FDA Benefit-Risk 
Determinations 
 
 
  A device to treat a very rare cancer was tested in a clinical trial that demonstrated 
o
with some uncertainty that the device performed as well as standard treatment, but 
not better.  However, use of the device did not have harmful effects as severe as 
those associated with the standard anti- cancer treatment, and neither treatment was 
curative.  The cancer was rapidly progressive and terminal, so the participants had 
very little time to live after they were diagnosed.  FDA approved this device 
because it gave patients access to a treatment that appeared to be equivalent to the 
standard of care (with some uncertainty remaining), but that did not cause the same 
severity of side effects. 
  A permanently implanted cardiovascular monitoring device is intended to diagnose 
o
heart failure.  The device is studied, and the study shows that its use reduces the 
number of days the subject is hospitalized for heart failure by about three.  
However, the implantation procedure for the device requires that the patient be 
hospitalized for two days. There are similar devices on the market that provide a 
similar level of benefit as this device that do not require an implantation procedure.  
FDA determined that the benefit of saving one day of hospitalization does not 
outweigh the risk of complication from the surgery needed to implant the device 
and found the device to be not approvable. 
  A permanent birth control device can be placed in a womans reproductive system 
o
through the vagina using a specialized delivery catheter. This device is a permanent 
implant and is not intended to be removed. Explantation of the device would require 
surgery. Clinical data show that the device is effective in preventing pregnancy over 
a two-year period in women and the safety data show a low incidence of adverse 
clinical events. However, study results also show that there are several cases where 
the physician had difficulty correctly placing the device. In addition, the device was 
noted to be fractured on a follow-up x-ray in a few study subjects. Given the 
uncertainty of the long-term impact of the device, the possibility of device fracture 
(which was not predicted in any of the bench and animal testing), and the safety and 
effectiveness of alternative therapies, FDA deemed the device to be not approvable 
for the intended patient population. 
  An implanted device offers a unique design feature in comparison to the standard of 
o
 
  22  Contains Nonbinding Recommendations 
 
care used to treat similar conditions.  While the current standard of care works very 
well, it has limitations associated with hindering the mobility of the patient; in 
contrast, the novel implanted device does not affect patient mobility.  Based upon the 
effectiveness  data  from  the  clinical  study,  the  device  demonstrates  that  it  has 
significantly improved functional outcomes in comparison to the current standard of 
care. However, from a safety perspective, the device did present different adverse 
events that were different from those of the current standard of care.  The risks can 
be appropriately mitigated with training of surgical professionals as well as through 
proper labeling.  In the event the implant was to fail over time, the clinician could 
also resort to the current standard of care.  In this situation, despite the different 
adverse events, the probable benefits outweighed the risks and FDA approved the 
device. 
 
  23  Contains Nonbinding Recommendations 
 
Appendix A 
 
Intersection of this Guidance with ISO 14971 
 
ISO 14971 provides medical device manufacturers with a framework to systematically 
manage the risks to people, property and the environment associated with the use of 
medical devices.  Specifically, the standard describes a process through which the medical 
device manufacturer can identify hazards associated with a medical device, estimate and 
evaluate the risks associated with these hazards, control these risks, and monitor the 
effectiveness of those controls throughout the products lifecycle.22 Implementing this 
standard requires the user to make decisions on the acceptability of individual risks, and 
overall residual risk for a medical device throughout its lifecycle. 
 
ISO 14971 is an FDA-recognized standard, and assuring conformity with this standard may 
help device manufacturers meet the design validation requirements specified in the Design 
Controls section of Part 820 of FDAs regulations governing quality systems.23 Part of the 
premarket review process is an evaluation (direct and/or indirect) of a medical device 
manufacturers risk management decisions as they pertain to the requirements to market a 
device in the United States.24   The medical device manufacturers risk management 
decisions that are directly and/or indirectly evaluated include those pertaining to risk 
estimation, risk evaluation, risk acceptability, risk control measures, and overall residual 
risk. Good documentation of risk management decisions by manufacturers helps to 
streamline the premarket review process for both FDA and manufacturers. At some point, 
after the manufacturer has completed its risk management activities associated with the 
design phase of product development, the premarket submission process with FDA is 
initiated, and the benefit-risk assessment takes on a different shape, which is the primary 
focus of this guidance. This guidance discusses the considerations FDA makes when 
assessing the benefit-risk profile of a device that has been designed to deliver the most 
benefit for the least amount of risk and to provide a reasonable assurance of safety and 
effectiveness. 
 
 
                                                           
22 ANSI/AAMI/ISO 14971:2007 Medical devices  Application of risk management to medical devices, p xi. 
23 Design controls are described in 21 CFR 820.30. 
24 Additionally, the manufacturer can engage FDA during the pre-submission stage regarding their proposed 
risk management decisions related to clinical study design, biocompatibility testing, non-clinical animal 
testing, bench testing, etc., and receive preliminary feedback on the adequacy of the decisions probability for 
generating information that will establish whether the device meets the requirements to be marketed in the 
United States. 
 
 
  24  Contains Nonbinding Recommendations 
 
Appendix B 
 
Worksheet for Benefit-Risk Assessment 
 
Instructions for FDA Staff: You should make your recommendation regarding the benefit-risk assessment 
based on the totality of the evidence. The benefit-risk assessment is part of the decision whether to 
approve the application, but it does not include an assessment of all applicable requirements for approval. 
An indication from these tools that the benefits outweigh the risks does not mean that the application 
satisfies other applicable requirements for a PMA application or a De Novo request. 
 
The following questions are intended as a sequential method to help weigh various factors as part of the 
benefit-risk assessment. As such, the questions are intended to help identify and explain which factors and 
considerations are critical in making a benefit-risk assessment for a particular device. However, the 
questions are not intended to suggest that considerations other than those listed in the completed 
worksheet are irrelevant. This checklist should be used when non-clinical and/or clinical evidence has 
been submitted in the form of valid scientific evidence. 
 
Consider questions 1-8 for the proposed Indications for Use, until you reach a recommendation either that 
the benefits outweigh the risks or to move to question 9, which prompts you to consider a modified 
Indications for Use.  When considering an acceptable, modified Indications for Use, interact with the 
sponsor to reach agreement on a modified Indications for Use. However, as reflected under question 1, if 
the evidence does not support a finding of benefit under the proposed Indications for Use (or narrowed 
Indications for Use), or evidence does not support a finding of benefit for the proposed Indications for 
Use and agreement on a modified Indications for Use is not achievable or applicable, the application 
would not be approvable or grantable. 
 
   
  25  Contains Nonbinding Recommendations 
 
Assessment of Benefit 
 
1.  Is there any evidence of clinical benefit?   
Is a clinical benefit demonstrated for the device for this indication (e.g., from any one or more 
of the primary and/or secondary datasets or from associated real-world evidence)? Benefit 
may be considered in terms of how a patient feels, functions, survives, or an acceptable 
surrogate outcome.  This information may be collected using validated tools such as quality 
of life questionnaires.  Benefit may also be considered in terms of convenience in managing 
or diagnosing a disease or condition.  Benefit should be considered based on the assessment 
of the data, whether or not the results are statistically significant.  Select any of the following 
that demonstrate benefit, and then answer the question in the box below. 
      
 
 A favorable change in at least 1 clinical assessment that is equal to or greater than seen 

in the control group 
 A favorable change in at least 1 clinical assessment that meets a predetermined 

performance goal 
 A favorable change in at least 1 clinical assessment that meets or surpasses a 

minimally important clinical difference 
 A favorable change in at least 1 clinical assessment that is equal to or greater than 

changes seen with other available modalities for the disease or condition 
 A favorable change in at least 1 clinical assessment that would be meaningful to 

patients considering the severity, chronicity, etc., of the condition, taking into 
consideration patient-reported outcomes and health-related quality of life 
 A favorable change in non-clinical data or modeling that is deemed to be predictive of 

clinical outcomes 
 A favorable clinical performance characteristic (e.g., sensitivity/PPA,25 

specificity/NPA26, etc.) for screening, diagnosis, prognosis, monitoring or 
treatment selection  
 Acceptable performance characteristics for analytical validation of the device 

 Other(s): 

 None 

      
Q1: Is there any evidence of clinical benefit? 
     
 YES  Continue to Question 2 

 NO  Move to Question 9 

   
                                                           
25 PPA: Positive Percent Agreement 
26 NPA: Negative Percent Agreement 
  26  Contains Nonbinding Recommendations 
 
 
2.  What is the extent of uncertainty for the benefits? 
Recognizing that some extent of uncertainty always exists, select the sources of uncertainty, 
if applicable, in the data that affect your assessment of the clinical benefit. Consider sources 
of uncertainty related to clinical and/or analytical performance characteristics (e.g., 
sensitivity, specificity, accuracy, precision, reproducibility, as applicable). Select any of the 
following that demonstrate sources of uncertainty for the benefits, and then answer the 
question in the box below. 
 Inconsistent or conflicting results between studies 

 Wide confidence intervals surrounding the point estimate(s) and/or odds ratio(s)) 

 A significantly underpowered study with statistical insignificance in outcome 

measure(s)  
 High subject or specimen loss-to-follow-up at critical assessment point(s) 

 Large amount of missing data at critical assessment time(s) +/- imputation 

 Significant number of major protocol deviations 

 Impact of confounding interventions or physiological factors 

 Inconsistent user experience or user experience not representative of likely real-world 

user 
 Unclear correlation between non-clinical data, pre-selected enriched data, or computer 

modeling and clinical performance  
 Surrogate endpoint has not been demonstrated to correlate with a clinical outcome 

 Real-World Evidence (RWE) is not relevant or reliable for the purposes of the 

proposed analysis 
 Inspectional findings 

 Study design or results lead to lack of generalizability for the intended use population 

or specific clinical subpopulations. 
 Physiological or clinically meaningful range of the diagnostic output is unknown, or 

generalizability of proposed clinical cut-off is unknown 
 Imperfect comparator method used to calculate performance characteristics 

 Other(s): 

 None 

 
Q2: What is the extent of uncertainty for the benefits? 
   
 Low  Continue to Question 3 

 Med  Continue to Question 3 

 High  Continue to Question 3 

 
 
 
 
 
 
 
  27  Contains Nonbinding Recommendations 
 
Summary of the Assessment of Benefit 
For the Proposed Indications for Use: 
Considering responses to Q1 and Q2, enter summary of the Assessment of Benefit for the proposed 
Indications for Use.  Include a description of your assessment of the extent of benefit, considering the 
type, magnitude, and probability of benefit(s); and the duration of effects.  Include a description of the 
impact of uncertainty on your Assessment of Benefit.  If no benefit is identified, briefly explain why. 
 
Assessment of Risk
 
3.  Are known/probable risks more than minimal?  
Select any of the following elements that demonstrate sources of known/probable risks that are 
more than minimal, then answer the question in the box below. 
 
 Adverse events (AEs) or outcomes related to the device itself 

 AEs or outcomes related to the use of the device or procedure to use the device 

 AEs or outcomes related to anesthesia or sedation to use the device 

 AEs or outcomes due to subsequent tests/treatments needed (e.g., radiation from CT scans) 

 AEs or outcomes, not seen in the study/data, but probable based on class effect or events 

known to occur with similar technologies 
 False positive/false negative/failed to provide a result for diagnostics 

 Treatment or diagnostic intended to be used as a standalone rather than an adjunctive use 

 Other(s):  

 None 

 
Q3: Are known/probable risks more than minimal? 
  
  YES  Continue to Question 4 

  NO  Continue to Question 4 

 
 
4.  What is the extent of uncertainty for the risks?  
Recognizing that some extent of uncertainty always exists, select the sources of uncertainty, if 
applicable, in the data regarding the adverse events/outcomes or risks. Select any of the following 
that demonstrate sources of uncertainty for the risks, and then answer the question in the box 
below. 
 
 Insufficient patient numbers to detect serious events or false positives/false negatives  

 Insufficient duration of follow-up to detect delayed/late events 

 Lack of data on repeated exposure to the device/use 

 Inconsistent or conflicting results between studies 

 Proper evaluations not performed as part of the study protocol to adequately detect certain AEs 

 Poor or inconsistent adverse event definitions and documentation 

 Events likely confounded by, and attributed to, other comorbidities or treatment modalities 

  28  Contains Nonbinding Recommendations 
 
 High subject loss-to-follow-up at critical assessment point(s) 

 Large amount of missing data at critical assessment time(s) +/- imputation 

 Significant number of major protocol deviations 

 Inconsistent user experience or user experience not representative of likely real-world user 

 Concerns related to performance characteristics (e.g., sensitivity/PPA, specificity/NPA)  

 Imperfect comparator method used to calculate performance characteristics 

 Other(s):  

 None 

 
Q4: What is the extent of uncertainty for the risks? 
  
 Low  Continue to Question 5 

 Med  Continue to Question 5 

 High  Continue to Question 5 

 
Summary of the Assessment of Risk 
If you answered No to Question 3 but High to Question 4, please explain here. 
 
For the Proposed Indications for Use: 
Enter summary of the Assessment of Risk for the proposed Indications for Use. Include a description of 
your assessment of the extent of risk, considering the severity, types, number and rates of harmful events 
associated with use of the device; probability of a harmful event; duration of harmful events; and risk 
from false-positive or false-negative results for diagnostics. Include a description of the impact of 
uncertainty on your Assessment of Risk. 
 
 
   
  29  Contains Nonbinding Recommendations 
 
Assessment of Benefit-Risk
 
Instructions for FDA staff: Provide a recommendation based on the totality of the evidence. As noted 
above, the benefit-risk assessment is part of the decision regarding whether to approve a PMA application 
or grant a De Novo request but is not an assessment of all applicable requirements. 
To approve a PMA application or grant a De Novo request, FDA must find, among other things, that there 
is a reasonable assurance of safety and effectiveness for the device.  FDA determines whether there is a 
reasonable assurance of safety and effectiveness by weighing any benefit to health from the use of the 
device against any risk of injury or illness for such use, among other relevant factors. To grant a De Novo 
request, FDA must find that general controls or general and special controls provide a reasonable 
assurance of safety and effectiveness for the device. 
If you answer yes for any Q5-8, explain your rationale for how the benefits outweigh the risks.  You 
should also consider and recommend actions that would enhance the benefit-risk profile of the device, 
such as modifications to the proposed labeling, which may include additional appropriate warnings and 
precautions, instructions for use, or presentation of data, to help ensure the product labeling is transparent 
with respect to the benefits and risks.  
If you answer unable to conclude for Q5-8, please provide the information that you believe would be 
needed to support a determination that the benefits outweigh the risks for the Indications for Use under 
consideration in the summary text boxes and also proceed to Q9. 
 
Q5: Do the Benefits outweigh the Risks, considering the assessment of Benefit 
and Risk and the extent of uncertainty identified above? 
  
 Yes  the benefits outweigh the risks such that, for this device, additional 

consideration of relevant factors would not change that determination  
 Unable to conclude that benefits outweigh the risks  further discussion and 

consideration of relevant factors is appropriate  Continue to Q6  
 
Summary of the Assessment of Benefit-Risk 
For the Proposed Indications for Use: 
Summarize the clinical benefit(s) that have been demonstrated for the proposed Indications for Use and 
your assessment of how Benefit(s) compare to Risk(s).  Include a description of how uncertainty 
regarding Benefit(s) and Risk(s) affects your assessment. 
 
6.  Do the Benefits outweigh the Risks, when taking into account the following additional 
considerations? Select relevant considerations, and then answer the question in the box below. 
 Understanding of patient willingness or unwillingness to accept a large extent of uncertainty in 

the benefits and/or risks 
 Available patient preference information (PPI) showing patient willingness or unwillingness to 

  30  Contains Nonbinding Recommendations 
 
accept the risks in exchange for the benefits. In circumstances where it is not feasible to 
obtain PPI (e.g., some pediatric or impaired patient population), care-partner perspectives 
may be considered.  
 Understanding of care-partner perspectives on the benefits and risks for a device intended to 

provide benefit to the care-partner (e.g., ease of care) 
 Understanding of healthcare professional perspectives on the benefits and risks for a device 

intended to provide benefit to the healthcare professional (e.g., reduction of radiation 
exposure) 
 Available qualitative or quantitative PPI on the relative desirability or acceptability to patients 

of outcomes or other attributes that differ among alternative health interventions 
 Understanding how the size of the patient population impacts feasibility of conducting large 

trials and affects public health need for both rare and common diseases or conditions 
 Understanding that the device represents novel technology for which the current device 

technology is different 
 Ability to manage or diagnose the condition and consideration of natural history of disease 

progression in the absence of the intervention or diagnostic information with the device 
under review 
 No legally marketed alternative medical product or medical intervention exists, or the device 

offers advantages over existing alternatives 
 The device fills an unmet medical need or niche for more effective treatment or diagnosis of 

life-threatening or irreversibly debilitating human disease/conditions 
 The device avoids serious harms associated with currently available therapies for the disease or 

condition 
 The adverse events associated with use of the device are reversible 

 Type of intervention required to address the harmful event (e.g., medication, surgery) 

 The study is a first of a kind (robustness of the analysis) 

 Tipping point and/or worst-case sensitivity analysis continuing to show clinical benefit 

 Understanding of mechanistic plausibility and/or class effect (e.g., familiarity with similar 

technology) 
 Other(s):  

 None 

 
Q6: Do the Benefits outweigh the Risks, when taking into account additional 
relevant considerations? 
 
 Yes  the benefits outweigh the risks such that, for this device, additional 

consideration of relevant factors would not change that determination 
 Unable to conclude that benefits outweigh the risks  further discussion and 

consideration of risk mitigation measures is appropriate  Continue to Q7 
 
Summary of the Assessment of Benefit-Risk, taking into account additional relevant considerations 
For the Proposed Indications for Use: 
Summarize the clinical benefit(s) that have been demonstrated for the proposed Indications for Use and 
your assessment of how Benefit(s) compare to Risk(s).  Include a description of how available alternative 
modalities, including their benefits and risks, affect your assessment.  Include a description of how 
uncertainty regarding Benefit(s) and Risk(s) affects your assessment.  Include a description of how patient 
  31  Contains Nonbinding Recommendations 
 
perspectives affected your assessment. 
 
7.  Can the risks be mitigated, so that Benefits outweigh the Risks? Consider if the Benefits 
outweigh the Risks if risk mitigation strategies are incorporated to lower the probability of 
a harmful event occurring and improve the benefit-risk profile of the device.  Select relevant 
considerations, and then answer the question in the box below. 
 
 Additional descriptions of known and probable benefits and risks in physician and patient 

labeling including appropriate Contraindications, Warnings, and Precautions and 
description of the clinical events 
 Additional warnings noting limitations of safety information (e.g., The safety of the use of 

this device in [situation] has not been evaluated.) 
 Labeling the device Prescription Only 

Training: 
 Limitation to caregivers with certain qualifications or clinical training 

 Limit to users with a minimum set of qualifications and/or training 

 Physician/user training program 

Other: 
 Device tracking 

 Other(s):  

 None 

 
Q7: Can the risks be mitigated, so that Benefits outweigh the Risks? 
 
 Yes  the benefits outweigh the risks such that, for this device, additional 

consideration of relevant factors would not change that determination  
 Unable to conclude that benefits outweigh the risks  further discussion and 

consideration of postmarket actions is appropriate  Continue to Q8 
 
Summary of the Assessment of Benefit-Risk, considering risk mitigation strategies 
For the Proposed Indications for Use: 
Summarize the clinical benefit(s) that have been demonstrated for the proposed Indications for Use and 
your assessment of how Benefit(s) compare to Risks. Include a description of how available alternative 
modalities, including their benefits and risks, affect your assessment. Include a description of how 
uncertainty regarding Benefit(s) and Risks affects your assessment.  Include a description of how patient 
perspectives affected your assessment. 
 
 
8.  Do the Benefits outweigh the Risks considering the use of postmarket actions?  Select 
appropriate postmarket action(s), and then answer the question in the box below. 
  
 Collection of additional and/or confirmatory non-clinical performance data in the postmarket 

space (e.g., post-approval study, postmarket surveillance) 
 Collection of additional and/or confirmatory clinical data in the postmarket space (e.g., post-

approval study, postmarket surveillance) 
  32  Contains Nonbinding Recommendations 
 
If either non-clinical or clinical performance data collections in the postmarket space are 
checked, consider: 
 The feasibility of postmarket data collection and likelihood that postmarket data 

collection will be completed within a reasonable timeframe  
 Whether it would be appropriate for labeling to include description of postmarket data 

collection and its purpose 
 Other(s):  

 None 

 
Q8: Do the Benefits outweigh the Risks considering the use of postmarket actions? 
  
 Yes  The benefits outweigh the risks   

 Unable to conclude that benefits outweigh the risks  Continue to Q9 

 
Summary of the Assessment of Benefit-Risk, considering postmarket actions 
For the Proposed Indications for Use: 
Summarize the benefit(s) that have been demonstrated for the proposed Indications for Use and your 
assessment of how Benefit(s) compare to Risks. Include a description of how available alternative 
modalities, including their benefits and risks, affect your assessment. Include a description of how 
uncertainty regarding benefit(s) and risks affects your assessment. Include a description of how patient 
perspectives affected your assessment. 
 
 
Q9: Is there any evidence of clinical benefit for a modified Indications for Use? 
  
 Yes  Return to Q1 and proceed with modified Indications for Use 

 No   Do not approve/grant 

 
 
 
  33  Contains Nonbinding Recommendations 
 
Benefit-Risk Assessment Summary 
 
Based on the totality of the data  Proposed Indications for Use  
Device Name:  
PMA/De Novo Number:    
 Interim    Final 
 
Considering benefit in terms of 
  Type    Patient perspective (or 
  Magnitude  care-partner and/or 
Assessment of Benefit    Probability  healthcare professional 
  Duration of effects  perspectives, if 
applicable) 
  Other 
 YES  Q2  
1. Is there any evidence of clinical  
 NO  Do not approve/grant for proposed Indications for Use; proceed 
benefit?  
to Q9 
2. What is the extent of uncertainty for   High   Med  Low 
  
the Benefits?   Continue to Q3 
Considering risk in terms of    Patient perspective (or 
  Severity, types, number and rates of  care-partner and/or 
harmful events  healthcare professional 
Assessment of Risk    Probability of a harmful event  perspectives, if 
  Duration of harmful events  applicable) 
  Risks from false-positive or false-
negative results  
3. Are known/probable risks more than   YES  Q4  

minimal?   NO  Q4 

4. What is the extent of uncertainty for   High   Med  Low 
  
the risks?   Continue to Q5 
Assessment of Benefit-Risk 
 YES  Worksheet complete  
5. Do the Benefits outweigh the Risks?  
 Unable to conclude that benefits outweigh the risks  Q6 

6. Do the Benefits outweigh the Risks, 
 YES  Worksheet complete  
taking into account additional  
 Unable to conclude that benefits outweigh the risks  Q7 
considerations?  
7. Can the risks be mitigated, so that   YES  Worksheet complete  

Benefits outweigh the Risks?   Unable to conclude that benefits outweigh the risks  Q8 

8. Do the Benefits outweigh the Risks 
 YES  Worksheet complete 
considering the use of postmarket  
 Unable to conclude that benefits outweigh the risks  Q9 
actions?  
9. Is there any evidence of clinical 
 YES  Return to Q1 and proceed with modified Indications for Use 
benefit for a modified Indications for  
 NO  Do not approve/grant 
Use?  
 
 
 
  34  Contains Nonbinding Recommendations 
 
Appendix C 
 
 
Worksheets for Hypothetical Examples 
  35  Contains Nonbinding Recommendations 
 
Worksheet for Hypothetical Example 1 
 
Instructions for FDA staff: You should make your recommendation regarding the benefit-risk assessment 
based on the totality of the evidence. The benefit-risk assessment is part of the decision whether to 
approve the application, but it does not include an assessment of all applicable requirements for approval. 
An indication from these tools that the benefits outweigh the probable risks does not mean that the 
application satisfies other applicable requirements for a PMA application or a De Novo request. 
 
The following questions are intended as a sequential method to help weigh various factors as part of the 
benefit-risk assessment. As such, the questions are intended to help identify and explain which factors and 
considerations are critical in making a benefit-risk assessment for a particular device. However, the 
questions are not intended to suggest that considerations other than those listed in the completed 
worksheet are irrelevant. This checklist should be used when non-clinical and/or clinical evidence has 
been submitted in the form of valid scientific evidence. 
 
Consider questions 1-8 for the proposed Indications for Use, until you reach a recommendation either that 
the benefits outweigh the risks or to move to question 9, which prompts you to consider a modified 
Indications for Use.  When considering an acceptable, modified Indications for Use, interact with the 
sponsor to reach agreement on a modified Indications for Use. However, as reflected under question 1, if 
the evidence does not support a finding of benefit under the proposed Indications for Use (or narrowed 
Indications for Use), or evidence does not support a finding of benefit for the proposed Indications for 
Use and agreement on a modified Indications for Use is not achievable or applicable, the application 
would not be approvable or grantable. 
 
 
  36  Contains Nonbinding Recommendations 
 
Assessment of Benefit 
 
1.  Is there any evidence of clinical benefit?   
Is a clinical benefit demonstrated for the device for this indication (e.g., from any one or more 
of the primary and/or secondary datasets or from associated real-world evidence)? Benefit 
may be considered in terms of how a patient feels, functions, survives, or an acceptable 
surrogate outcome.  This information may be collected using validated tools such as quality 
of life questionnaires.  Benefit may also be considered in terms of convenience in managing 
or diagnosing a disease or condition.  Benefit should be considered based on the assessment 
of the data, whether or not the results are statistically significant.  Select any of the following 
that demonstrate benefit, and then answer the question in the box below. 
      
 A favorable change in at least 1 clinical assessment that is equal to or greater than seen 

in the control group 
 A favorable change in at least 1 clinical assessment that meets a predetermined 

performance goal 
 A favorable change in at least 1 clinical assessment that meets or surpasses a 

minimally important clinical difference 
 A favorable change in at least 1 clinical assessment that is equal to or greater than 

changes seen with other available modalities for the disease or condition 
 A favorable change in at least 1 clinical assessment that would be meaningful to 

patients considering the severity, chronicity, etc., of the condition, taking into 
consideration patient-reported outcomes and health-related quality of life 
Other: 
 A favorable change in non-clinical data or modeling that is deemed to be predictive of 

clinical outcomes 
 A favorable clinical performance characteristic (e.g., sensitivity/PPA,27 

specificity/NPA28, etc.) for screening, diagnosis, prognosis, monitoring or 
treatment selection  
 Acceptable performance characteristics for analytical validation of the device 

 Other(s): Improved mobility. Longer life expectancy. 

 None 

      
Q1: Is there any evidence of clinical benefit? 
     
 YES  Continue to Question 2 

 NO  Move to Question 9 

   
                                                           
27 PPA: Positive Percent Agreement 
28 NPA: Negative Percent Agreement 
  37  Contains Nonbinding Recommendations 
 
 
2.  What is the extent of uncertainty for the benefits? 
Recognizing that some extent of uncertainty always exists, select the sources of uncertainty, 
if applicable, in the data that affect your assessment of the clinical benefit. Consider sources 
of uncertainty related to clinical and/or analytical performance characteristics (e.g., 
sensitivity, specificity, accuracy, precision, reproducibility, as applicable). Select any of the 
following that demonstrate sources of uncertainty for the benefits, and then answer the 
question in the box below. 
 Inconsistent or conflicting results between studies 

 Wide confidence intervals surrounding the point estimate(s) and/or odds ratio(s)) 

 A significantly underpowered study with statistical insignificance in outcome 

measure(s)  
 High subject or specimen loss-to-follow-up at critical assessment point(s) 

 Large amount of missing data at critical assessment time(s) +/- imputation 

 Significant number of major protocol deviations 

 Impact of confounding interventions or physiological factors 

 Inconsistent user experience or user experience not representative of likely real-world 

user 
 Unclear correlation between non-clinical data, pre-selected enriched data, or computer 

modeling and clinical performance  
 Surrogate endpoint has not yet been demonstrated to correlate with a clinical outcome 

 Real-World Evidence (RWE) is not relevant or reliable for the purposes of the 

proposed analysis 
 Inspectional findings 

 Study design or results lead to lack of generalizability for the intended use population 

or specific clinical subpopulations. 
 Physiological or clinically meaningful range of the diagnostic output is unknown, or 

generalizability of proposed clinical cut-off is unknown 
 Imperfect comparator method used to calculate performance characteristics 

 Other(s): The duration of benefit is unclear. 

 None 

 
Q2: What is the extent of uncertainty for the benefits? 
   
 Low  Continue to Question 3 

 Med  Continue to Question 3 

 High  Continue to Question 3 

 
 
Summary of the Assessment of Benefit 
For the Proposed Indications for Use: 
The probability that a patient will experience a substantial benefit in terms of reduction in symptoms 
when the device is implanted is 75%.  The data also support improved mobility, which is anticipated to 
  38  Contains Nonbinding Recommendations 
 
lead to longer life expectancy.  The patients who experience the benefit value it substantially. Patients 
also value the opportunity to achieve the benefit.  The study was well designed and conducted.  Follow-up 
was only 1 year and there was missing data, but sensitivity analyses were conducted, and the results are 
relatively robust. 
 
Assessment of Risk
 
3.  Are known/probable risks more than minimal?  
Select any of the following elements that demonstrate sources of known/probable risks that are 
more than minimal, then answer the question in the box below. 
 
 Adverse events (AEs) or outcomes related to the device itself 

 AEs or outcomes related to the use of the device or procedure to use the device 

 AEs or outcomes related to anesthesia or sedation to use the device 

 AEs or outcomes due to subsequent tests/treatments needed (e.g., radiation from CT scans) 

 AEs or outcomes, not seen in the study/data, but probable based on class effect or events 

known to occur with similar technologies 
 False positive/false negative/failed to provide a result for diagnostics 

 Treatment or diagnostic intended to be used as a standalone rather than an adjunctive use 

 Other(s): 

 None 

 
Q3: Are known/probable risks more than minimal? 
  
  YES  Continue to Question 4 

  NO  Continue to Question 4 

 
 
4.  What is the extent of uncertainty for the risks?  
Recognizing that some extent of uncertainty always exists, select the sources of uncertainty, if 
applicable, in the data regarding the adverse events/outcomes or risks. Select any of the following 
that demonstrate sources of uncertainty for the risks, and then answer the question in the box 
below. 
 
 Insufficient patient numbers to detect serious events or false positives/false negatives  

 Insufficient duration of follow-up to detect delayed/late events 

 Lack of data on repeated exposure to the device/use 

 Inconsistent or conflicting results between studies 

 Proper evaluations not performed as part of the study protocol to adequately detect certain AEs 

 Poor or inconsistent adverse event definitions and documentation 

 Events likely confounded by, and attributed to, other comorbidities or treatment modalities 

 High subject loss-to-follow-up at critical assessment point(s) 

 Large amount of missing data at critical assessment time(s) +/- imputation 

  39  Contains Nonbinding Recommendations 
 
 Significant number of major protocol deviations 

 Inconsistent user experience or user experience not representative of likely real-world user 

 Concerns related to performance characteristics (e.g., sensitivity/PPA, specificity/NPA)  

 Imperfect comparator method used to calculate performance characteristics 

 Other(s): No information is provided regarding removal of the permanent implant. If 

necessary, removal would be difficult. 
 None 

 
Q4: What is the extent of uncertainty for the risks? 
  
 Low  Continue to Question 5 

 Med  Continue to Question 5 

 High  Continue to Question 5 

 
Summary of the Assessment of Risk 
If you answered No to Question 3 but High to Question 4, please explain here. 
 
For the Proposed Indications for Use: 
Known risks are those typically associated with permanent, implantable devices and include device 
fracture, mechanical failure or adverse biological response (less than 3% chance). However, all implanted 
devices that require a surgical procedure carry with them their own set of risks. In this case it is known 
from the literature that the implantation of this device is not routine and there is a 1% chance of death 
from surgery.  The device-related adverse events last as long as the device remains implanted but are 
expected to be reversed by removing the device.  However, no information about device removal is 
provided, and if necessary, removal is expected to be difficult. 
 
   
  40  Contains Nonbinding Recommendations 
 
Assessment of Benefit-Risk
 
Instructions for FDA staff: Provide a recommendation based on the totality of the evidence. As noted 
above, the benefit-risk assessment is part of the decision regarding whether to approve a PMA application 
or grant a De Novo request but is not an assessment of all applicable requirements. 
To approve a PMA application or grant a De Novo request, FDA must find, among other things, that there 
is a reasonable assurance of safety and effectiveness for the device.  FDA determines whether there is a 
reasonable assurance of safety and effectiveness by weighing any benefit to health from the use of the 
device against any risk of injury or illness for such use, among other relevant factors. To grant a De Novo 
request, FDA must find that general controls or general and special controls provide a reasonable 
assurance of safety and effectiveness for the device. 
If you answer yes for any Q5-8, explain your rationale for how the benefits outweigh the risks.  You 
should also consider and recommend actions that would enhance the benefit-risk profile of the device, 
such as modifications to the proposed labeling, which may include additional appropriate warnings and 
precautions, instructions for use, or presentation of data, to help ensure the product labeling is transparent 
with respect to the benefits and risks.  
If you answer unable to conclude for Q5-8, please provide the information that you believe would be 
needed to support a determination that the benefits outweigh the risks for the Indications for Use under 
consideration in the summary text boxes and also proceed to Q9. 
Q5: Do the Benefits outweigh the Risks, considering the assessment of Benefit 
and Risk and the extent of uncertainty identified above? 
  
 Yes  the benefits outweigh the risks such that, for this device, additional 

consideration of relevant factors would not change that determination  
 Unable to conclude that benefits outweigh the risks  further discussion and 

consideration of relevant factors is appropriate  Continue to Q6  
 
Summary of the Assessment of Benefit-Risk 
For the Proposed Indications for Use: 
The probability that a patient will experience a benefit is relatively high (approximately 75%, if the 
clinical trial results hold for the intended use population). In this particular case, FDA does not have the 
option to limit the use of the device to only those patients who are most likely to experience a benefit 
because the covariates that determine the subgroup of patients who would definitely experience the 
benefit are unknown. In addition, this type of permanently implantable device poses significant risks and 
there is a fair amount of remaining uncertainty associated with the trial results, especially around the lack 
of information regarding device removal. 
 
6.  Do the Benefits outweigh the Risks, when taking into account the following additional 
considerations? Select relevant considerations, and then answer the question in the box below. 
  41  Contains Nonbinding Recommendations 
 
 Understanding of patient willingness or unwillingness to accept a large extent of uncertainty in 

the benefits and/or risks 
 Available patient preference information (PPI) showing patient willingness or unwillingness to 

accept the risks in exchange for the benefits. In circumstances where it is not feasible to 
obtain PPI (e.g., some pediatric or impaired patient populations), care-partner perspectives 
may be considered. 
 Understanding of care-partner perspectives on the benefits and risks for a device intended to 

provide benefit to the care-partner (e.g., ease of care) 
 Understanding of healthcare professional perspectives on the benefits and risks for a device 

intended to provide benefit to the healthcare professional (e.g., reduction of radiation 
exposure) 
 Available qualitative or quantitative PPI on the relative desirability or acceptability to patients 

of outcomes or other attributes that differ among alternative health interventions 
 Understanding how the size of the patient population impacts feasibility of conducting large 

trials and affects public health need for both rare and common diseases or conditions 
 Understanding that the device represents novel technology for which the current device 

technology is different 
 Ability to manage or diagnose the condition and consideration of natural history of disease 

progression in the absence of the intervention or diagnostic information with the device 
under review 
 No legally marketed alternative medical product or medical intervention exists, or the device 

offers advantages over existing alternatives 
 The device fills an unmet medical need or niche for more effective treatment or diagnosis of 

life-threatening or irreversibly debilitating human disease/conditions 
 The device avoids serious harm associated with available therapies for the disease or condition 

 The adverse events associated with use of the device are reversible 

 Type of intervention required to address the harmful event (e.g., medication, surgery) 

 The study is a first of a kind (robustness of the analysis) 

 Tipping point and/or worst-case sensitivity analysis continuing to show clinical benefit 

 Understanding of mechanistic plausibility and/or class effect (e.g., familiarity with similar 

technology) 
 Other(s):  

 None 

 
Q6: Do the Benefits outweigh the Risks, when taking into account additional 
relevant considerations? 
 
 Yes  the benefits outweigh the risks such that, for this device, additional 

consideration of relevant factors would not change that determination  
 Unable to conclude that benefits outweigh the risks  further discussion and 

consideration of risk mitigation measures is appropriate  Continue to Q7 
 
Summary of the Assessment of Benefit-Risk, taking into account additional relevant considerations 
For the Proposed Indications for Use: 
For those patients in the target population who will experience a benefit, symptom relief and 
improvement in quality of life is impressive and some patients have expressed a willingness to tolerate the 
  42  Contains Nonbinding Recommendations 
 
risks as a trade-off for obtaining such benefits. Further, the device treats a severe and chronic disease for 
which alternative treatments have been exhausted. However, it remains unclear which patients will 
benefit and further mitigation of the risks of the device are needed in order to achieve a favorable benefit-
risk assessment. 
 
7.  Can the risks be mitigated, so that Benefits outweigh the Risks? Consider if the Benefits 
outweigh the Risks if risk mitigation strategies are incorporated to lower the probability of 
a harmful event occurring and improve the benefit-risk profile of the device.  Select relevant 
considerations, and then answer the question in the box below. 
 
 Additional descriptions of known and probable benefits and risks in physician and patient 

labeling including appropriate Contraindications, Warnings, and Precautions and 
description of the clinical events 
 Additional warnings noting limitations of safety information (e.g., The safety of the use of 

this device in [situation] has not been evaluated.) 
 Labeling the device Prescription Only 

Training: 
 Limitation to caregivers with certain qualifications or clinical training 

 Limit to users with a minimum set of qualifications and/or training 

 Physician/user training program 

Other: 
 Device tracking 

 Other(s):  

 None 

 
Q7: Can the risks be mitigated, so that Benefits outweigh the Risks? 
 
 Yes  the benefits outweigh the risks such that, for this device, additional 

consideration of relevant factors would not change that determination 
 Unable to conclude that benefits outweigh the risks  further discussion and 

consideration of postmarket actions is appropriate  Continue to Q8 
 
Summary of the Assessment of Benefit-Risk, considering risk mitigation strategies 
For the Proposed Indications for Use: 
The risks, although substantial, could be further mitigated through limiting the device use to clinicians 
with specialized training. With that additional risk mitigation, the benefits provided by the device 
outweigh the risks. 
           
8.  Do the Benefits outweigh the Risks considering the use of postmarket actions?  Select 
appropriate postmarket action(s), and then answer the question in the box below. 
  
 Collection of additional and/or confirmatory non-clinical performance data in the postmarket 

space 
 Collection of additional and/or confirmatory clinical data in the postmarket space (e.g., post-

approval study, postmarket surveillance) 
  43  Contains Nonbinding Recommendations 
 
If either non-clinical or clinical performance data collections in the postmarket space are 
checked, consider: 
 The feasibility of postmarket data collection and likelihood that postmarket data 

collection will be completed within a reasonable timeframe  
 Whether it would be appropriate for labeling to include description of postmarket data 

collection and its purpose 
 Other(s):  

 None 

 
Q8: Do the Benefits outweigh the Risks considering the use of postmarket actions? 
 
 Yes  The benefits outweigh the risks 

 Unable to conclude that benefits outweigh the risks  Continue to Q9 

 
Summary of the Assessment of Benefit-Risk, considering postmarket actions 
For the Proposed Indications for Use: 
Summarize the benefit(s) that have been demonstrated for the proposed Indications for Use and your 
assessment of how Benefit(s) compare to Risks.  Include a description of how available alternative 
modalities, including their benefits and risks, affect your assessment.  Include a description of how 
uncertainty regarding benefit(s) and risks. 
 
 
Q9: Is there any evidence of clinical benefit for a modified Indications for Use? 
  
 Yes  Return to Q1 and proceed with modified Indications for Use 

 No   Do not approve/grant 

 
 
   
  44  Contains Nonbinding Recommendations 
 
Benefit-Risk Assessment Summary 
 
Based on the totality of the data  Proposed Indications for Use  
Device Name: Hypothetical Example 1 
To reduce symptoms for patients with condition X in patients who 
PMA/De Novo Number:  
have failed all other treatment options 
 Interim    Final 
 
Considering benefit in terms of 
  Type    Patient perspective (or care-
  Magnitude  partner and/or healthcare 
Assessment of Benefit 
  Probability  professional perspectives, if 
  Duration of effects  applicable) 
  Other 
 YES  Q2  
1. Is there any evidence of clinical  
 NO  Do not approve/grant for proposed Indications for Use; 
benefit?  
proceed to Q9 
2. What is the extent of uncertainty for   High   Med  Low 
  
the Benefits?   Continue to Q3 
Considering risk in terms of   
  Severity, types, number    Risks from false-positive or 
and rates of harmful  false-negative results  
events    Patient perspective (or care-
Assessment of Risk 
  Probability of a harmful  partner and/or healthcare 
event  professional perspectives, if 
  Duration of harmful  applicable) 
events   
3. Are known/probable risks more than   YES  Q4  

minimal?   NO  Q4 

4. What is the extent of uncertainty for   High   Med  Low 
  
the Risks?   Continue to Q5 
Assessment of Benefit-Risk 
 YES  Worksheet complete 
5. Do the Benefits outweigh the Risks?  
 Unable to conclude that benefits outweigh the risks  Q6 

6. Do the Benefits outweigh the Risks, 
 YES  Worksheet complete 
taking into account additional  
 Unable to conclude that benefits outweigh the risks  Q7 
considerations?  
7. Can the risks be mitigated, so that   YES  Worksheet complete 

Benefits outweigh the Risks?   Unable to conclude that benefits outweigh the risks  Q8 

8. Do the Benefits outweigh the Risks 
 YES  Worksheet complete 
considering the use of postmarket  
 Unable to conclude that benefits outweigh the risks  Q9 
actions?  
 YES  Return to Q1 and proceed with modified Indications for 
9. Is there any evidence of clinical benefit  
Use 
for a modified Indications for Use? 
 NO  Do not approve/grant 

  45  Contains Nonbinding Recommendations 
 
Worksheet for Hypothetical Example 2 
 
Instructions for FDA staff: You should make your recommendation regarding the benefit-risk assessment 
based on the totality of the evidence. The benefit-risk assessment is part of the decision whether to 
approve the application, but it does not include an assessment of all applicable requirements for approval. 
An indication from these tools that the benefits outweigh the risks does not mean that the application 
satisfies other applicable requirements for a PMA application or a De Novo request. 
 
The following questions are intended as a sequential method to help weigh various factors as part of the 
benefit-risk assessment. As such, the questions are intended to help identify and explain which factors and 
considerations are critical in making a benefit-risk assessment for a particular device. However, the 
questions are not intended to suggest that considerations other than those listed in the completed 
worksheet are irrelevant. This checklist should be used when non-clinical and/or clinical evidence has 
been submitted in the form of valid scientific evidence. 
 
Consider questions 1-8 for the proposed Indications for Use, until you reach a recommendation either that 
the benefits outweigh the risks or to move to question 9, which prompts you to consider a modified 
Indications for Use.  When considering an acceptable, modified Indications for Use, interact with the 
sponsor to reach agreement on a modified Indications for Use. However, as reflected under question 1, if 
the evidence does not support a finding of benefit under the proposed Indications for Use (or narrowed 
Indications for Use), or evidence does not support a finding of benefit for the proposed Indications for 
Use and agreement on a modified Indications for Use is not achievable or applicable, the application 
would not be approvable or grantable. 
 
Assessment of Benefit 
 
1.  Is there any evidence of clinical benefit?   
Is a clinical benefit demonstrated for the device for this indication (e.g., from any one or more 
of the primary and/or secondary datasets or from associated real-world evidence)? Benefit 
may be considered in terms of how a patient feels, functions, survives, or an acceptable 
surrogate outcome.  This information may be collected using validated tools such as quality 
of life questionnaires.  Benefit may also be considered in terms of convenience in managing 
or diagnosing a disease or condition.  Benefit should be considered based on the assessment 
of the data, whether or not the results are statistically significant.  Select any of the following 
that demonstrate benefit, and then answer the question in the box below. 
      
 
 A favorable change in at least 1 clinical assessment that is equal to or greater than seen 

in the control group 
 A favorable change in at least 1 clinical assessment that meets a predetermined 

performance goal 
 A favorable change in at least 1 clinical assessment that meets or surpasses a 

minimally important clinical difference 
 A favorable change in at least 1 clinical assessment that is equal to or greater than 

changes seen with other available modalities for the disease or condition 
 A favorable change in at least 1 clinical assessment that would be meaningful to 

patients considering the severity, chronicity, etc., of the condition, taking into 
consideration patient-reported outcomes and health-related quality of life 
Other: 
  46  Contains Nonbinding Recommendations 
 
 A favorable change in non-clinical data or modeling that is deemed to be predictive of 

clinical outcomes 
 A favorable clinical performance characteristic (e.g., sensitivity/PPA,29 

specificity/NPA30, etc.) for screening, diagnosis, prognosis, monitoring or 
treatment selection  
 Acceptable performance characteristics for analytical validation of the device 

 Other(s): 

 None 

      
Q1: Is there any evidence of clinical benefit? 
     
 YES  Continue to Question 2 

 NO  Move to Question 9 

   
                                                           
29 PPA: Positive Percent Agreement 
30 NPA: Negative Percent Agreement 
  47  Contains Nonbinding Recommendations 
 
 
2.  What is the extent of uncertainty for the benefits? 
Recognizing that some extent of uncertainty always exists, select the sources of uncertainty, 
if applicable, in the data that affect your assessment of the clinical benefit. Consider sources 
of uncertainty related to clinical and/or analytical performance characteristics (e.g., 
sensitivity, specificity, accuracy, precision, reproducibility, as applicable). Select any of the 
following that demonstrate sources of uncertainty for the benefits, and then answer the 
question in the box below. 
 Inconsistent or conflicting results between studies 

 Wide confidence intervals surrounding the point estimate(s) and/or odds ratio(s) 

 A significantly underpowered study with statistical insignificance in outcome 

measure(s)  
 High subject or specimen loss-to-follow-up at critical assessment point(s) 

 Large amount of missing data at critical assessment time(s) +/- imputation 

 Significant number of major protocol deviations 

 Impact of confounding interventions or physiological factors 

 Inconsistent user experience or user experience not representative of likely real-world 

user 
 Unclear correlation between non-clinical data, pre-selected enriched data, or computer 

modeling and clinical performance  
 Surrogate endpoint has not yet been demonstrated to correlate with a clinical outcome 

 Real World Evidence (RWE) is not relevant or reliable for the purposes of the 

proposed analysis 
 Inspectional findings 

 Study design or results lead to lack of generalizability for the intended use population 

or specific clinical subpopulations. 
 Physiological or clinically meaningful range of the diagnostic output is unknown, or 

generalizability of proposed clinical cut-off is unknown 
 Imperfect comparator method used to calculate performance characteristics 

 Other(s): small sample size 

 None 

 
Q2: What is the degree of uncertainty for the benefits? 
   
 Low  Continue to Question 3 

 Med  Continue to Question 3 

 High  Continue to Question 3 

 
 
Summary of the Assessment of Benefit 
For the Proposed Indications for Use: 
Patients place an enormous value on the benefit, which include memory preservation and improvement of 
quality of life.  The magnitude of benefit is large for patients in early stages of the disease; smaller for 
  48  Contains Nonbinding Recommendations 
 
patients in later stages of the disease.   
The trial was designed to study two subgroups, subjects at early stages of the disease and subjects at late 
stages of the disease. It can be inferred that benefits will be higher for patients in early stages of the 
disease and lower for patients in later stages of the disease.  While the number of subjects eligible and 
willing to enroll in the trial was small, the data were robust, and the trial was well-designed and 
conducted. The results of the trial are generalizable. 
 
Assessment of Risk
 
3.  Are known/probable risks more than minimal?  
Select any of the following elements that demonstrate sources of known/probable risks that are 
more than minimal, then answer the question in the box below. 
 
 Adverse events (AEs) or outcomes related to the device itself 

 AEs or outcomes related to the use of the device or procedure to use the device 

 AEs or outcomes related to anesthesia or sedation to use the device 

 AEs or outcomes due to subsequent tests/treatments needed (e.g., radiation from CT scans) 

 AEs or outcomes, not seen in the study/data, but probable based on class effect or events 

known to occur with similar technologies 
 False positive/false negative/failed to provide a result for diagnostics 

 Treatment or diagnostic intended to be used as a standalone rather than an adjunctive use 

 Other(s):  

 None 

 
Q3: Are known/probable risks more than minimal? 
  
  YES  Continue to Question 4 

  NO  Continue to Question 4 

 
 
4.  What is the extent of uncertainty for the risks?  
Recognizing that some extent of uncertainty always exists, select the sources of uncertainty, if 
applicable, in the data regarding the adverse events/outcomes or risks. Select any of the following 
that demonstrate sources of uncertainty for the risks, and then answer the question in the box 
below. 
 
 Insufficient patient numbers to detect serious events or false positives/false negatives  

 Insufficient duration of follow-up to detect delayed/late events 

 Lack of data on repeated exposure to the device/use 

 Inconsistent or conflicting results between studies 

 Proper evaluations not performed as part of the study protocol to adequately detect certain AEs 

 Poor or inconsistent adverse event definitions and documentation 

 Events likely confounded by, and attributed to, other comorbidities or treatment modalities 

  49  Contains Nonbinding Recommendations 
 
 High subject loss-to-follow-up at critical assessment point(s) 

 Large amount of missing data at critical assessment time(s) +/- imputation 

 Significant number of major protocol deviations 

 Inconsistent user experience or user experience not representative of likely real-world user 

 Concerns related to performance characteristics (e.g., sensitivity/PPA, specificity/NPA)  

 Imperfect comparator method used to calculate performance characteristics 

 Other(s): small sample size 

 None 

 
Q4: What is the extent of uncertainty for the risks? 
  
 Low  Continue to Question 5 

 Med  Continue to Question 5 

 High  Continue to Question 5 

 
Summary of the Assessment of Risk 
If you answered No to Question 3 but High to Question 4, please explain here. 
 
For the Proposed Indications for Use: 
The risks associated with this device are great.  The surgery to implant the device is highly risky. Serious 
adverse events include partial paralysis, loss of vision, loss of motor skills, vertigo, and insomnia.  Non-
serious adverse events include temporary personality shifts, mood swings, and slurred speech.  It is 
known from previous studies and literature that there is an 8% risk of serious adverse events from the 
surgery alone.  8% risk of death from surgery; 1% chance of a serious adverse event; and 5% chance of a 
non-serious adverse event. When considered together, these present a high risk. Patients in the early 
stages of the disease will have higher risks due to longer exposure to the device. 
 
   
  50  Contains Nonbinding Recommendations 
 
Assessment of Benefit-Risk 
Instructions for FDA staff: Provide a recommendation based on the totality of the evidence. As noted 
above, the benefit-risk assessment is part of the decision regarding whether to approve a PMA application 
or grant a De Novo request but is not an assessment of all applicable requirements. 
To approve a PMA application or grant a De Novo request, FDA must find, among other things, that there 
is a reasonable assurance of safety and effectiveness for the device.  FDA determines whether there is a 
reasonable assurance of safety and effectiveness by weighing any benefit to health from the use of the 
device against any risk of injury or illness for such use, among other relevant factors. To grant a De Novo 
request, FDA must find that general controls or general and special controls provide a reasonable 
assurance of safety and effectiveness for the device. 
If you answer yes for any Q5-8, explain your rationale for how the benefits outweigh the risks.  You 
should also consider and recommend actions that would enhance the benefit-risk profile of the device, 
such as modifications to the proposed labeling, which may include additional appropriate warnings and 
precautions, instructions for use, or presentation of data, to help ensure the product labeling is transparent 
with respect to the benefits and risks.  
If you answer unable to conclude for Q5-8, please provide the information that you believe would be 
needed to support a determination that the benefits outweigh the risks for the Indications for Use under 
consideration in the summary text boxes and also proceed to Q9. 
Q5: Do the Benefits outweigh the Risks, considering the assessment of Benefit 
and Risk and the extent of uncertainty identified above? 
  
 Yes  the benefits outweigh the risks such that, for this device, additional 

consideration of relevant factors would not change that determination  
 Unable to conclude that benefits outweigh the risks  further discussion and 

consideration of relevant factors is appropriate  Continue to Q6  
 
Summary of the Assessment of Benefit-Risk 
For the Proposed Indications for Use: 
The device will confer a substantial benefit for a defined and predictable subgroup of patients and a 
minimal benefit for another defined and predictable subgroup. Even though the clinical trial was small, 
the quality of the data was good and the resulting confidence intervals are reasonably narrow. The 
uncertainty about results is based on the small sample size and the usual uncertainty resulting from 
drawing inferences from a sample in the study to the population in the market. The risks associated with 
the device are great.  Based solely on the benefits, risks and degree of uncertainty, it cannot be concluded 
that the benefits outweigh the risks. 
 
6.  Do the Benefits outweigh the Risks, when taking into account the following additional 
considerations? Select relevant considerations, and then answer the question in the box below. 
  51  Contains Nonbinding Recommendations 
 
 Understanding of patient willingness or unwillingness to accept a large extent of uncertainty in 

the benefits and/or risks 
 Available patient preference information (PPI) showing patient willingness or unwillingness to 

accept the risks in exchange for the benefits. In circumstances where it is not feasible to 
obtain PPI (e.g., some pediatric or impaired patient populations), care-partner perspectives 
may be considered. 
 Understanding of care-partner perspectives on the benefits and risks for a device intended to 

provide benefit to the care-partner (e.g., ease of care) 
 Understanding of healthcare professional perspectives on the benefits and risks for a device 

intended to provide benefit to the healthcare professional (e.g., reduction of radiation 
exposure) 
 Available qualitative or quantitative PPI on the relative desirability or acceptability to patients 

of outcomes or other attributes that differ among alternative health interventions 
 Understanding how the size of the patient population impacts feasibility of conducting large 

trials and affects public health need for both rare and common diseases or conditions 
 Understanding that the device represents novel technology for which the current device 

technology is different 
 Ability to manage or diagnose the condition and consideration of natural history of disease 

progression in the absence of the intervention or diagnostic information with the device 
under review 
 No legally marketed alternative medical product or medical intervention exists, or the device 

offers advantages over existing alternatives 
 The device fills an unmet medical need or niche for more effective treatment or diagnosis of 

life-threatening or irreversibly debilitating human disease/conditions 
 The device avoids serious harm associated with available therapies for the disease or condition 

 The adverse events associated with use of the device are reversible 

 Type of intervention required to address the harmful event (e.g., medication, surgery) 

 The study is a first of a kind (robustness of the analysis) 

 Tipping point and/or worst-case sensitivity analysis continuing to show clinical benefit 

 Understanding of mechanistic plausibility and/or class effect (e.g., familiarity with similar 

technology) 
 Other(s):  

 None 

 
Q6: Do the Benefits outweigh the Risks, when taking into account additional 
relevant considerations? 
 
 Yes  the benefits outweigh the risks such that, for this device, additional 

consideration of relevant factors would not change that determination 
 Unable to conclude that benefits outweigh the risks  further discussion and 

consideration of risk mitigation measures is appropriate  Continue to Q7 
 
Summary of the Assessment of Benefit-Risk, taking into account additional relevant considerations 
For the Proposed Indications for Use: 
The sponsor provided data showing that many patients who suffer from memory disorders are willing to 
try novel approaches that have significant risk, in order to preserve their memories and quality of life. The 
  52  Contains Nonbinding Recommendations 
 
fact that there are no alternative treatments for this condition is another important consideration. Even 
though the device-related risks are high, they are tolerable to some patients because of the probable 
benefits the device offers, and the progressive nature of the untreated condition.  However, given the 
small sample size and the high-risk nature of the device, including the fact that this is a permanent 
implant, the benefits do not outweigh the risks without additional labeling limitations and postmarket data 
collection. 
 
7.  Can the risks be mitigated, so that Benefits outweigh the Risks? Consider if the Benefits 
outweigh the Risks if risk mitigation strategies are incorporated to lower the probability of 
a harmful event occurring and improve the benefit-risk profile of the device.  Select relevant 
considerations, and then answer the question in the box below. 
 
 Additional descriptions of known and probable benefits and risks in physician and patient 

labeling including appropriate Contraindications, Warnings, and Precautions and 
description of the clinical events 
 Additional warnings noting limitations of safety information (e.g., The safety of the use of 

this device in [situation] has not been evaluated.) 
 Labeling the device Prescription Only 

Training: 
 Limitation to caregivers with certain qualifications or clinical training 

 Limit to users with a minimum set of qualifications and/or training 

 Physician/user training program 

Other: 
 Device tracking 

 Other(s): requiring the labeling to prominently address the 8% serious adverse event rate 

 None 

 
Q7: Can the risks be mitigated, so that Benefits outweigh the Risks? 
 
 Yes  the benefits outweigh the risks such that, for this device, additional 

consideration of relevant factors would not change that determination  
 Unable to conclude that benefits outweigh the risks  further discussion and 

consideration of postmarket actions is appropriate  Continue to Q8 
 
Summary of the Assessment of Benefit-Risk, considering risk mitigation strategies 
For the Proposed Indications for Use: 
While the risks associated with the device are great, they can be partially mitigated by prominently 
explaining the 8% serious adverse event rate in the labeling, limiting device to use to physicians with 
appropriate expertise and by training the physicians who implant/explant (if necessary) the device.  
However, without postmarket data collection, the probable benefits do not outweigh the probable risks. 
           
8.  Do the Benefits outweigh the Risks considering the use of postmarket actions?  Select 
appropriate postmarket action(s), and then answer the question in the box below. 
  
 Collection of additional and/or confirmatory non-clinical performance data in the postmarket 

  53  Contains Nonbinding Recommendations 
 
space 
 Collection of additional and/or confirmatory clinical data in the postmarket space (e.g., post-

approval study, postmarket surveillance) 
If either non-clinical or clinical performance data collections in the postmarket space are 
checked, consider: 
 The feasibility of postmarket data collection and likelihood that postmarket data 

collection will be completed within a reasonable timeframe  Whether it would be 

appropriate for labeling to include description of postmarket data collection and its 
purpose 
 Other(s):  

 None 

 
Q8: Do the Benefits outweigh the Risks considering the use of postmarket actions? 
  
 Yes  The benefits outweigh the risks 

 Unable to conclude that benefits outweigh the risks  Continue to Q9 

 
Summary of the Assessment of Benefit-Risk, considering postmarket actions 
For the Proposed Indications for Use: 
After full consideration of the probable benefits and risks provided by the device, the likelihood of, and 
timeframe for, progression of disease and the predictability of future impairment without intervention, 
FDA is likely to approve the device as long as the labeling and training requirements described above are 
addressed and post-approval study is conducted to evaluate longer term performance, including 
maintenance of effectiveness, long term adverse events, and device duration. 
 
 
 
Q9: Is there any evidence of clinical benefit for a modified Indications for Use? 
  
 Yes  Return to Q1 and proceed with modified Indications for Use 

 No   Do not approve/grant 

 
 
 
 
  54  Contains Nonbinding Recommendations 
 
Benefit-Risk Assessment Summary
 
 
Based on the totality of the data  Proposed Indications for Use  
Device Name: Hypothetical Example 2  The device is indicated as a memory replacement device for 
PMA/De Novo Number:  patients with Alzheimers disease, dementia, and other memory 
 Interim    Final  disorders 
 
Considering benefit in terms of 
  Type    Patient perspective (or care-
  Magnitude  partner and/or healthcare 
Assessment of Benefit 
  Probability  professional perspectives, if 
  Duration of effects  applicable) 
  Other 
 YES  Q2  
1. Is there any evidence of clinical  
 NO  Do not approve/grant for proposed Indications for Use; 
benefit?  
proceed to Q9 
2. What is the extent of uncertainty for   High   Med  Low 
  
the benefits?   Continue to Q3 
Considering risk in terms of   
  Severity, types, number    Risks from false-positive or 
and rates of harmful  false-negative results  
events    Patient perspective (or care-
Assessment of Risk 
  Probability of a harmful  partner and/or healthcare 
event  professional perspectives, if 
  Duration of harmful  applicable) 
events    Other 
3. Are known/probable risks more than   YES  Q4  

minimal?   NO  Q4 

4. What is the extent of uncertainty for   High   Med  Low 
  
the Risks?   Continue to Q5 
Assessment of Benefit-Risk 
 YES  Worksheet complete  
5. Do the Benefits outweigh the Risks?  
 Unable to conclude that benefits outweigh the risks  Q6 

6. Do the Benefits outweigh the Risks, 
 YES  Worksheet complete  
taking into account additional  
 Unable to conclude that benefits outweigh the risks  Q7 
considerations?  
7. Can the risks be mitigated, so that   YES  Worksheet complete  

Benefits outweigh the Risks?   Unable to conclude that benefits outweigh the risks  Q8 

8. Do the Benefits outweigh the Risks 
 YES  Worksheet complete 
considering the use of postmarket  
 Unable to conclude that benefits outweigh the risks  Q9 
actions?  
 YES  Return to Q1 and proceed with modified Indications for 
9. Is there any evidence of clinical benefit  
Use 
for a modified Indications for Use? 
 NO  Do not approve/grant 

  55  Contains Nonbinding Recommendations 
 
Worksheet for Hypothetical Example 3 
 
Instructions for FDA staff: You should make your recommendation regarding the benefit-risk assessment 
based on the totality of the evidence. The benefit-risk assessment is part of the decision whether to 
approve the application, but it does not include an assessment of all applicable requirements for approval. 
An indication from these tools that the benefits outweigh the risks does not mean that the application 
satisfies other applicable requirements for a PMA application or a De Novo request. 
 
The following questions are intended as a sequential method to help weigh various factors as part of the 
benefit-risk assessment. As such, the questions are intended to help identify and explain which factors and 
considerations are critical in making a benefit-risk assessment for a particular device. However, the 
questions are not intended to suggest that considerations other than those listed in the completed 
worksheet are irrelevant. This checklist should be used when non-clinical and/or clinical evidence has 
been submitted in the form of valid scientific evidence. 
 
Consider questions 1-8 for the proposed Indications for Use, until you reach a recommendation either that 
the benefits outweigh the risks or to move to question 9, which prompts you to consider a modified 
Indications for Use.  When considering an acceptable, modified Indications for Use, interact with the 
sponsor to reach agreement on a modified Indications for Use. However, as reflected under question 1, if 
the evidence does not support a finding of benefit under the proposed Indications for Use (or narrowed 
Indications for Use), or evidence does not support a finding of benefit for the proposed Indications for 
Use and agreement on a modified Indications for Use is not achievable or applicable, the application 
would not be approvable or grantable. 
 
Assessment of Benefit 
 
1.  Is there any evidence of clinical benefit?   
Is a clinical benefit demonstrated for the device for this indication (e.g., from any one or more 
of the primary and/or secondary datasets or from associated real-world evidence)? Benefit 
may be considered in terms of how a patient feels, functions, survives, or an acceptable 
surrogate outcome.  This information may be collected using validated tools such as quality 
of life questionnaires.  Benefit may also be considered in terms of convenience in managing 
or diagnosing a disease or condition.  Benefit should be considered based on the assessment 
of the data, whether or not the results are statistically significant.  Select any of the following 
that demonstrate benefit, and then answer the question in the box below. 
      
 
 A favorable change in at least 1 clinical assessment that is equal to or greater than seen 

in the control group 
 A favorable change in at least 1 clinical assessment that meets a predetermined 

performance goal 
 A favorable change in at least 1 clinical assessment that meets or surpasses a 

minimally important clinical difference 
 A favorable change in at least 1 clinical assessment that is equal to or greater than 

changes seen with other available modalities for the disease or condition 
 A favorable change in at least 1 clinical assessment that would be meaningful to 

patients considering the severity, chronicity, etc., of the condition, taking into 
consideration patient-reported outcomes and health-related quality of life 
Other: 
56 
  Contains Nonbinding Recommendations 
 
 A favorable change in non-clinical data or modeling that is deemed to be predictive of 

clinical outcomes 
 A favorable clinical performance characteristic (e.g., sensitivity/PPA,31 

specificity/NPA32, etc.) for screening, diagnosis, prognosis, monitoring or 
treatment selection  
 Acceptable performance characteristics for analytical validation of the device 
 Other(s): 

 None 

      
Q1: Is there any evidence of clinical benefit? 
     
 YES  Continue to Question 2 

 NO  Move to Question 9 

   
                                                           
31 PPA: Positive Percent Agreement 
32 NPA: Negative Percent Agreement 
57 
  Contains Nonbinding Recommendations 
 
 
2.  What is the extent of uncertainty for the benefits? 
Recognizing that some extent of uncertainty always exists, select the sources of uncertainty, 
if applicable, in the data that affect your assessment of the clinical benefit. Consider sources 
of uncertainty related to clinical and/or analytical performance characteristics (e.g., 
sensitivity, specificity, accuracy, precision, reproducibility). Select any of the following that 
demonstrate sources of uncertainty for the benefits, and then answer the question in the box 
below. 
 Inconsistent or conflicting results between studies 

 Wide confidence intervals surrounding the point estimate(s) and/or odds ratio(s)) 

 A significantly underpowered study with statistical insignificance in outcome 

measure(s)  
 High subject or specimen loss-to-follow-up at critical assessment point(s) 

 Large amount of missing data at critical assessment time(s) +/- imputation 

 Significant number of major protocol deviations 

 Impact of confounding interventions or physiological factors 

 Inconsistent user experience or user experience not representative of likely real-world 

user 
 Unclear correlation between non-clinical data, pre-selected enriched data, or computer 

modeling and clinical performance  
 Surrogate endpoint has not yet been demonstrated to correlate with a clinical outcome 

 Real World Evidence (RWE) is not relevant or reliable for the purposes of the 

proposed analysis 
 Inspectional findings 

 Study design or results lead to lack of generalizability for the intended use population 

or specific clinical subpopulations. 
 Physiological or clinically meaningful range of the diagnostic output is unknown, or 

generalizability of proposed clinical cut-off is unknown 
 Imperfect comparator method used to calculate performance characteristics 

 Other(s): Clinical impact of breast cancers missed among patients with BI-RADS 4 

mammography results may not be equivalent to the clinical impact of breast 
cancers among patients who have BI-RADS 3 results 
 None 

 
Q2: What is the degree of uncertainty for the benefits? 
   
 Low  Continue to Question 3 

 Med  Continue to Question 3 

 High  Continue to Question 3 

 
 
Summary of the Assessment of Benefit 
For the Proposed Indications for Use: 
The main benefit from use of the device is avoiding morbidity associated with an immediate biopsy for 
58 
  Contains Nonbinding Recommendations 
 
the 57% of the 400 subjects in the clinical trial whose test results indicate a low probability of having 
breast cancer. This is demonstrated based on sensitivity and specificity values of 97% and 75%, 
respectively, and PPV and NPVs of 56.4% and 98.7%, respectively. 
 
Assessment of Risk
 
3.  Are known/probable risks more than minimal?  
Select any of the following elements that demonstrate sources of known/probable risks that are 
more than minimal, then answer the question in the box below. 
 
 Adverse events (AEs) or outcomes related to the device itself 

 AEs or outcomes related to the use of the device or procedure to use the device 

 AEs or outcomes related to anesthesia or sedation to use the device 

 AEs or outcomes due to subsequent tests/treatments needed (e.g., radiation from CT scans) 

 AEs or outcomes, not seen in the study/data, but probable based on class effect or events 

known to occur with similar technologies 
 False positive/false negative/failed to provide a result for diagnostics 

 Treatment or diagnostic intended to be used as a standalone rather than an adjunctive use 

 Other(s):  

 None 

 
Q3: Are known/probable risks more than minimal? 
  
  YES  Continue to Question 4 

  NO  Continue to Question 4 

 
 
4.  What is the extent of uncertainty for the risks?  
Recognizing that some extent of uncertainty always exists, select the sources of uncertainty, if 
applicable, in the data regarding the adverse events/outcomes or risks. Select any of the following 
that demonstrate sources of uncertainty for the risks, and then answer the question in the box 
below. 
 
 Insufficient patient numbers to detect serious events or false positives/false negatives  

 Insufficient duration of follow-up to detect delayed/late events 

 Lack of data on repeated exposure to the device/use 

 Inconsistent or conflicting results between studies 

 Proper evaluations not performed as part of the study protocol to adequately detect certain AEs 

 Poor or inconsistent adverse event definitions and documentation 

 Events likely confounded by, and attributed to, other comorbidities or treatment modalities 

 High subject loss-to-follow-up at critical assessment point(s) 

 Large amount of missing data at critical assessment time(s) +/- imputation 

 Significant number of major protocol deviations 

59 
  Contains Nonbinding Recommendations 
 
 Inconsistent user experience or user experience not representative of likely real-world user 

 Concerns related to performance characteristics (e.g., sensitivity/PPA, specificity/NPA)  

 Imperfect comparator method used to calculate performance characteristics 

 Other(s): Prolonged natural history of breast cancer increases uncertainty with respect to the 

ultimate results of clinical follow-up 
 None 

 
Q4: What is the extent of uncertainty for the risks? 
  
 Low  Continue to Question 5 

 Med  Continue to Question 5 

 High  Continue to Question 5 

 
Summary of the Assessment of Risk 
If you answered No to Question 3 but High to Question 4, please explain here. 
 
For the Proposed Indications for Use: 
The main risk from use of the device is in failing to biopsy some BI-RADS 4 patients who have biopsy-
detectable breast cancer, thus delaying their diagnosis and treatment. Concerning this risk, the sponsor 
asserts that a clinically acceptable negative predictive value for cancer among non-biopsied BI-RADS 4 
subjects is 98% or higher. This cut-off was based on the clinical acceptability of a 2% prevalence for 
cancer in BI-RADS 3 patients who are usually counseled not to have an immediate biopsy (waiting a few 
months, instead, for further evaluation, such as follow-up diagnostic imaging in 6 months). There is no 
assurance that the clinical impact of breast cancers missed among patients with BI-RADS 4 
mammography results is equivalent to the clinical impact of breast cancers among patients who have BI-
RADS 3 results. Hence, there is high uncertainty about the extent of the probable risk(s)/harm(s).  
   
60 
  Contains Nonbinding Recommendations 
 
Assessment of Benefit-Risk
 
Instructions for FDA staff: Provide a recommendation based on the totality of the evidence. As noted 
above, the benefit-risk assessment is part of the decision regarding whether to approve a PMA application 
or grant a De Novo request but is not an assessment of all applicable requirements. 
To approve a PMA application or grant a De Novo request, FDA must find, among other things, that there 
is a reasonable assurance of safety and effectiveness for the device.  FDA determines whether there is a 
reasonable assurance of safety and effectiveness by weighing any benefit to health from the use of the 
device against any risk of injury or illness for such use, among other relevant factors. To grant a De Novo 
request, FDA must find that general controls or general and special controls provide a reasonable 
assurance of safety and effectiveness for the device. 
If you answer yes for any Q5-8, explain your rationale for how the benefits outweigh the risks.  You 
should also consider and recommend actions that would enhance the benefit-risk profile of the device, 
such as modifications to the proposed labeling, which may include additional appropriate warnings and 
precautions, instructions for use, or presentation of data, to help ensure the product labeling is transparent 
with respect to the benefits and risks.  
If you answer unable to conclude for Q5-8, please provide the information that you believe would be 
needed to support a determination that the benefits outweigh the risks for the Indications for Use under 
consideration in the summary text boxes and also proceed to Q9. 
Q5: Do the Benefits outweigh the Risks, considering the assessment of Benefit 
and Risk and the extent of uncertainty identified above? 
  
 Yes  the benefits outweigh the risks such that, for this device, additional 

consideration of relevant factors would not change that determination  
 Unable to conclude that benefits outweigh the risks  further discussion and 

consideration of relevant factors is appropriate  Continue to Q6  
 
Summary of the Assessment of Benefit-Risk 
For the Proposed Indications for Use: 
Based solely on the benefits and risks as demonstrated by the performance data and its associated 
uncertainties, the benefits associated with avoiding a biopsy-related morbidity do not outweigh the risks 
associated with missing a biopsy detectable cancer. Based on the available information, FDA cannot 
establish that there is a reasonable assurance of safety and effectiveness for the proposed benefit to health 
and additional information is needed to establish that the overall benefits outweigh the risks. 
 
6.  Do the Benefits outweigh the Risks, when taking into account the following additional 
considerations? Select relevant considerations, and then answer the question in the box below. 
 Understanding of patient willingness or unwillingness to accept a large extent of uncertainty in 

the benefits and/or risks 
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 Available patient preference information (PPI) showing patient willingness or unwillingness to 

accept the risks in exchange for the benefits. In circumstances where it is not feasible to 
obtain PPI (e.g., some pediatric or impaired patient population), care-partner perspectives 
may be considered. 
 Understanding of care-partner perspectives on the benefits and risks for a device intended to 

provide benefit to the care-partner (e.g., ease of care) 
 Understanding of healthcare professional perspectives on the benefits and risks for a device 

intended to provide benefit to the healthcare professional (e.g., reduction of radiation 
exposure) 
 Available qualitative or quantitative PPI on the relative desirability or acceptability to patients 

of outcomes or other attributes that differ among alternative health interventions 
 Understanding how the size of the patient population impacts feasibility of conducting large 

trials and affects public health need for both rare and common diseases or conditions 
 Understanding that the device represents novel technology for which the current device 

technology is different 
 Ability to manage or diagnose the condition and consideration of natural history of disease 

progression in the absence of the intervention or diagnostic information with the device 
under review 
 No legally marketed alternative medical product or medical intervention exists, or the device 

offers advantages over existing alternatives 
 The device fills an unmet medical need or niche for more effective treatment or diagnosis of 

life-threatening or irreversibly debilitating human disease/conditions 
 The device avoids serious harm associated with available therapies for the disease or condition 

 The adverse events associated with use of the device are reversible 

 Type of intervention required to address the harmful event (e.g., medication, surgery) 

 The study is a first of a kind (robustness of the analysis) 

 Tipping point and/or worst-case sensitivity analysis continuing to show clinical benefit 

 Understanding of mechanistic plausibility and/or class effect (e.g., familiarity with similar 

technology) 
 Other(s):  

 None 

 
Q6: Do the Benefits outweigh the Risks, when taking into account additional 
relevant considerations? 
 
 Yes  the benefits outweigh the risks such that, for this device, additional 

consideration of relevant factors would not change that determination 
 Unable to conclude that benefits outweigh the risks  further discussion and 

consideration of risk mitigation measures is appropriate  Continue to Q7 
 
Summary of the Assessment of Benefit-Risk, taking into account additional relevant considerations 
For the Proposed Indications for Use: 
Detailed patient preference information (PPI) showing patient willingness to accept the probable risks in 
exchange for the proposed benefits was not obtained for this in vitro diagnostic. Care-partner and/or 
healthcare professional perspectives were also not obtained. However, patients tolerance for delayed 
diagnosis and treatment of breast cancer typically is low. This needs to be weighed against the value that 
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patients place on avoiding biopsy-related morbidity. Delayed diagnosis of breast cancer may result in a 
more advanced stage of cancer requiring serious medical intervention, such as aggressive chemotherapy, 
surgery or radiation, and may be associated with increased mortality. There are no legally marketed 
alternative in vitro diagnostics, it is not apparent that the device offers advantages over existing 
alternatives. It is unknown if patients with missed breast cancer diagnoses and BI-RADS 4 
mammography results will have similar clinical outcomes to patients with BI-RADS 3 mammography 
results. Therefore, the additional relevant considerations do not clearly demonstrate that the benefits 
outweigh the risks for the proposed assay. 
 
7.  Can the risks be mitigated, so that Benefits outweigh the Risks? Consider if the Benefits 
outweigh the Risks if risk mitigation strategies are incorporated to lower the probability of 
a harmful event occurring and improve the benefit-risk profile of the device.  Select relevant 
considerations, and then answer the question in the box below. 
 
 Additional descriptions of known and probable benefits and risks in physician and patient 

labeling including appropriate Contraindications, Warnings, and Precautions and 
description of the clinical events 
 Additional warnings noting limitations of safety information (e.g., The safety of the use of 

this device in [situation] has not been evaluated.) 
 Labeling the device Prescription Only 

Training: 
 Limitation to caregivers with certain qualifications or clinical training 

 Limit to users with a minimum set of qualifications and/or training 

 Physician/user training program 

Other: 
 Device tracking 

 Other(s):  

 None 

 
Q7: Can the risks be mitigated, so that Benefits outweigh the Risks? 
 
 Yes  the benefits outweigh the risks such that, for this device, additional 

consideration of relevant factors would not change that determination  
 Unable to conclude that benefits outweigh the risks  further discussion and 

consideration of postmarket actions is appropriate  Continue to Q8 
 
Summary of the Assessment of Benefit-Risk, considering risk mitigation strategies 
For the Proposed Indications for Use: 
Additional risk mitigation strategies are not sufficient for the proposed assay, due to the underlying 
uncertainty regarding clinical outcomes in patients with a missed breast cancer diagnosis and a BI-RADS 
4 mammography result. Additional descriptions of the benefits and risks cannot be added to the device 
labeling due to limited knowledge of the clinical outcomes associated with a missed cancer diagnosis. 
Similarly, there is insufficient information to establish an effective physician/user training program to 
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mitigate the risks.  
           
8.  Do the Benefits outweigh the Risks considering the use of postmarket actions?  Select 
appropriate postmarket action(s), and then answer the question in the box below. 
  
 Collection of additional and/or confirmatory non-clinical performance data in the postmarket 

space 
 Collection of additional and/or confirmatory clinical data in the postmarket space (e.g., post-

approval study, postmarket surveillance) 
If either non-clinical or clinical performance data collections in the postmarket space are 
checked, consider: 
 The feasibility of postmarket data collection and likelihood that postmarket data 

collection will be completed within a reasonable timeframe  
 Whether it would be appropriate for labeling to include description of postmarket data 

collection and its purpose 
 Other(s):  

 None 

 
Q8: Do the Benefits outweigh the Risks considering the use of postmarket actions? 
  
 Yes  The benefits outweigh the risks 

 Unable to conclude that benefits outweigh the risks  Continue to Q9 

 
Summary of the Assessment of Benefit-Risk, considering postmarket actions 
For the Proposed Indications for Use: 
We are unable to conclude that benefits outweigh risks based on the available data, and due to the high 
degree of uncertainty and the clinical impact of a missed cancer diagnosis, postmarket actions are not 
sufficient to address these issues.  
 
 
Q9: Is there any evidence of clinical benefit for a modified Indications for Use? 
  
 Yes  Return to Q1 and proceed with modified Indications for Use 

 No   Do not approve/grant 
 
At this time, FDA is unable to approve the PMA because we are unable to conclude that the benefits 
outweigh the risks. Given that the benefits are uncertain and the risk for a small number of patients could 
be substantial, FDA cannot conclude that there is reasonable assurance of safety and effectiveness to 
support approval of the premarket application at this time, however an advisory panel may be considered 
to further evaluate the benefit-risk profile of the assay for the proposed or a modified Indications for Use. 
 
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Benefit-Risk Assessment Summary 
 
Proposed Indications for Use  
Based on the totality of the data  The in vitro diagnostic test measures 10 peptide analytes and 
Device Name: Hypothetical Example 3  yields a single qualitative result. The test is intended for females 
PMA/De Novo Number:   40 years or older following mammography of a breast lesion with 
 Interim    Final  a BI-RADS of 4 result to aid physicians in the decision to 
 
recommend a breast biopsy. 
Considering benefit in terms of 
  Type    Patient perspective (or care-
  Magnitude  partner and/or healthcare 
Assessment of Benefit 
  Probability  professional perspectives, if 
  Duration of effects  applicable) 
  Other 
 YES  Q2  
1. Is there any evidence of clinical  
 NO  Do not approve/grant for proposed Indications for Use; 
benefit?  
proceed to Q9 
2. What is the extent of uncertainty for   High   Med  Low 
  
the benefits?   Continue to Q3 
Considering risk in terms of   
  Severity, types, number    Risks from false-positive or 
and rates of harmful  false-negative results  
events    Patient perspective (or care-
Assessment of Risk 
  Probability of a harmful  partner and/or healthcare 
event  professional perspectives, if 
  Duration of harmful  applicable) 
events 
3. Are known/probable risks more than   YES  Q4  

minimal?   NO  Q4 

4. What is the extent of uncertainty for   High   Med  Low 
  
the Risks?   Continue to Q5 
Assessment of Benefit-Risk 
 YES  Worksheet complete  
5. Do the Benefits outweigh the Risks?  
 Unable to conclude that benefits outweigh the risks  Q6 

6. Do the Benefits outweigh the Risks, 
 YES  Worksheet complete  
taking into account additional  
 Unable to conclude that benefits outweigh the risks  Q7 
considerations?  
7. Can the risks be mitigated, so that   YES  Worksheet complete  

Benefits outweigh the Risks?   Unable to conclude that benefits outweigh the risks  Q8 

8. Do the Benefits outweigh the Risks 
 YES  Worksheet complete 
considering the use of postmarket  
 Unable to conclude that benefits outweigh the risks  Q9 
actions?  
 YES  Return to Q1 and proceed with modified Indications for 
9. Is there any evidence of clinical benefit  
Use 
for a modified Indications for Use? 
 NO  Do not approve/grant 

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Worksheet for Hypothetical Example 4 
 
Instructions for FDA staff: You should make your recommendation regarding the benefit-risk assessment 
based on the totality of the evidence. The benefit-risk assessment is part of the decision whether to 
approve the application, but it does not include an assessment of all applicable requirements for approval. 
An indication from these tools that the benefits outweigh the risks does not mean that the application 
satisfies other applicable requirements for a PMA application or a De Novo request. 
 
The following questions are intended as a sequential method to help weigh various factors as part of the 
benefit-risk assessment. As such, the questions are intended to help identify and explain which factors and 
considerations are critical in making a benefit-risk assessment for a particular device. However, the 
questions are not intended to suggest that considerations other than those listed in the completed 
worksheet are irrelevant. This checklist should be used when non-clinical and/or clinical evidence has 
been submitted in the form of valid scientific evidence. 
 
Consider questions 1-8 for the proposed Indications for Use, until you reach a recommendation either that 
the benefits outweigh the risks or to move to question 9, which prompts you to consider a modified 
Indications for Use.  When considering an acceptable, modified Indications for Use, interact with the 
sponsor to reach agreement on a modified Indications for Use. However, as reflected under question 1, if 
the evidence does not support a finding of benefit under the proposed Indications for Use (or narrowed 
Indications for Use), or evidence does not support a finding of benefit for the proposed Indications for 
Use and agreement on a modified Indications for Use is not achievable or applicable, the application 
would not be approvable or grantable. 
 
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Assessment of Benefit 
 
1.  Is there any evidence of clinical benefit?   
Is a clinical benefit demonstrated for the device for this indication (e.g., from any one or more 
of the primary and/or secondary datasets or from associated real-world evidence)? Benefit 
may be considered in terms of how a patient feels, functions, survives, or an acceptable 
surrogate outcome.  This information may be collected using validated tools such as quality 
of life questionnaires.  Benefit may also be considered in terms of convenience in managing 
or diagnosing a disease or condition.  Benefit should be considered based on the assessment 
of the data, whether or not the results are statistically significant.  Select any of the following 
that demonstrate benefit, and then answer the question in the box below. 
      
 A favorable change in at least 1 clinical assessment that is equal to or greater than seen 

in the control group 
 A favorable change in at least 1 clinical assessment that meets a predetermined 

performance goal 
 A favorable change in at least 1 clinical assessment that meets or surpasses a 

minimally important clinical difference 
 A favorable change in at least 1 clinical assessment that is equal to or greater than 

changes seen with other available modalities for the disease or condition 
 A favorable change in at least 1 clinical assessment that would be meaningful to 

patients considering the severity, chronicity, etc., of the condition, taking into 
consideration patient-reported outcomes and health-related quality of life 
Other: 
 A favorable change in non-clinical data or modeling that is deemed to be predictive of 

clinical outcomes 
 A favorable clinical performance characteristic (e.g., sensitivity/PPA,33 

specificity/NPA34, etc.) for screening, diagnosis, prognosis, monitoring or 
treatment selection  
 Acceptable performance characteristics for analytical validation of the device 

 Other(s): 

 None 

      
Q1: Is there any evidence of clinical benefit? 
     
 YES  Continue to Question 2 

 NO  Move to Question 9 

   
                                                           
33 PPA: Positive Percent Agreement 
34 NPA: Negative Percent Agreement 
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2.  What is the extent of uncertainty for the benefits? 
Recognizing that some extent of uncertainty always exists, select the sources of uncertainty, 
if applicable, in the data that affect your assessment of the clinical benefit. Consider sources 
of uncertainty related to clinical and/or analytical performance characteristics (e.g., 
sensitivity, specificity, accuracy, precision, reproducibility, as applicable). Select any of the 
following that demonstrate sources of uncertainty for the benefits, and then answer the 
question in the box below. 
 Inconsistent or conflicting results between studies 

 Wide confidence intervals surrounding the point estimate(s) and/or odds ratio(s)) 

 A significantly underpowered study with statistical insignificance in outcome 

measure(s)  
 High subject or specimen loss-to-follow-up at critical assessment point(s) 

 Large amount of missing data at critical assessment time(s) +/- imputation 

 Significant number of major protocol deviations 

 Impact of confounding interventions or physiological factors 

 Inconsistent user experience or user experience not representative of likely real-world 

user 
 Unclear correlation between non-clinical data, pre-selected enriched data, or computer 

modeling and clinical performance  
 Surrogate endpoint has not yet been demonstrated to correlate with a clinical outcome 

 Real World Evidence (RWE) is not relevant or reliable for the purposes of the 

proposed analysis 
 Inspectional findings 

 Study design or results lead to lack of generalizability for the intended use population 

or specific clinical subpopulations. 
 Physiological or clinically meaningful range of the diagnostic output is unknown, or 

generalizability of proposed clinical cut-off is unknown 
 Imperfect comparator method used to calculate performance characteristics 

 Other(s): limited duration of follow-up 

 None 

 
Q2: What is the degree of uncertainty for the benefits? 
   
 Low  Continue to Question 3 

 Med  Continue to Question 3 

 High  Continue to Question 3 

 
 
Summary of the Assessment of Benefit 
For the Proposed Indications for Use: 
Through one year of follow-up, no subject experienced device movement; therefore, there is a very high 
probability (almost 100%) of reduction of primary device migration.  This is a significant improvement 
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over primary device performance when implanted alone and gives a very high predictive probability that 
a patient receiving the device will not experience device movement. 
 
While the data only demonstrates benefit for up to one year, the benefit is expected to last for as long as 
the device remains implanted. 
 
Assessment of Risk
 
3.  Are known/probable risks more than minimal?  
Select any of the following elements that demonstrate sources of known/probable risks that are 
more than minimal, then answer the question in the box below. 
 
 Adverse events (AEs) or outcomes related to the device itself 

 AEs or outcomes related to the use of the device or procedure to use the device 

 AEs or outcomes related to anesthesia or sedation to use the device 

 AEs or outcomes due to subsequent tests/treatments needed (e.g., radiation from CT scans) 

 AEs or outcomes, not seen in the study/data, but probable based on class effect or events 

known to occur with similar technologies 
 False positive/false negative/failed to provide a result for diagnostics 

 Treatment or diagnostic intended to be used as a standalone rather than an adjunctive use 

 Other(s):  

 None 

 
Q3: Are known/probable risks more than minimal? 
  
  YES  Continue to Question 4 

  NO  Continue to Question 4 

 
 
4.  What is the extent of uncertainty for the risks?  
Recognizing that some extent of uncertainty always exists, select the sources of uncertainty, if 
applicable, in the data regarding the adverse events/outcomes or risks. Select any of the following 
that demonstrate sources of uncertainty for the risks, and then answer the question in the box 
below. 
 
 Insufficient patient numbers to detect serious events or false positives/false negatives  

 Insufficient duration of follow-up to detect delayed/late events 

 Lack of data on repeated exposure to the device/use 

 Inconsistent or conflicting results between studies 

 Proper evaluations not performed as part of the study protocol to adequately detect certain AEs 

 Poor or inconsistent adverse event definitions and documentation 

 Events likely confounded by, and attributed to, other comorbidities or treatment modalities 

 High subject loss-to-follow-up at critical assessment point(s) 

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 Large amount of missing data at critical assessment time(s) +/- imputation 

 Significant number of major protocol deviations 

 Inconsistent user experience or user experience not representative of likely real-world user 

 Concerns related to performance characteristics (e.g., sensitivity/PPA, specificity/NPA)  

 Imperfect comparator method used to calculate performance characteristics 

 Other(s):  

 None 

 
Q4: What is the extent of uncertainty for the risks? 
  
 Low  Continue to Question 5 

 Med  Continue to Question 5 

 High  Continue to Question 5 

 
Summary of the Assessment of Risk 
If you answered No to Question 3 but High to Question 4, please explain here. 
 
For the Proposed Indications for Use: 
Through one year of follow-up, there were no device-related serious adverse events (no fractures of any 
primary device) and only a handful of malfunctions of the support system, none of which lead to serious 
adverse events. Despite the insufficient duration of follow-up to detect delayed events, the risks of failure 
of the support system are not high because even if the support system fails, it is unlikely to lead to an 
overall failure of the primary device.  Two subjects experienced complications related to the device 
malfunctioning (device movement).  Even though all implanted devices that require a surgical procedure 
carry with them their own set of risks (e.g., 1% chance of death from surgery), this device is implanted 
along with the primary device and consequently does not require an additional surgery to implant. Or, if it 
is placed to enhance the performance of a malfunctioning primary device, it is put in during a surgery that 
would have otherwise been performed to fix the malfunctioning primary device. Therefore, the data 
suggest that adding the support device during surgery does not appear to substantially increase the risk to 
the patient. 
 
   
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Assessment of Benefit-Risk
 
Instructions for FDA staff: Provide a recommendation based on the totality of the evidence. As noted 
above, the benefit-risk assessment is part of the decision regarding whether to approve a PMA application 
or grant a De Novo request but is not an assessment of all applicable requirements. 
To approve a PMA application or grant a De Novo request, FDA must find, among other things, that there 
is a reasonable assurance of safety and effectiveness for the device.  FDA determines whether there is a 
reasonable assurance of safety and effectiveness by weighing any benefit to health from the use of the 
device against any risk of injury or illness for such use, among other relevant factors. To grant a De Novo 
request, FDA must find that general controls or general and special controls provide a reasonable 
assurance of safety and effectiveness for the device. 
If you answer yes for any Q5-8, explain your rationale for how the benefits outweigh the risks.  You 
should also consider and recommend actions that would enhance the benefit-risk profile of the device, 
such as modifications to the proposed labeling, which may include additional appropriate warnings and 
precautions, instructions for use, or presentation of data, to help ensure the product labeling is transparent 
with respect to the benefits and risks.  
If you answer unable to conclude for Q5-8, please provide the information that you believe would be 
needed to support a determination that the benefits outweigh the risks for the Indications for Use under 
consideration in the summary text boxes and also proceed to Q9. 
Q5: Do the Benefits outweigh the Risks, considering the assessment of Benefit 
and Risk and the extent of uncertainty identified above? 
  
 Yes  the benefits outweigh the risks such that, for this device, additional 
consideration of relevant factors would not change that determination  
 Unable to conclude that benefits outweigh the risks  further discussion and 

consideration of relevant factors is appropriate  Continue to Q6  
 
Summary of the Assessment of Benefit-Risk 
For the Proposed Indications for Use: 
The clinical trial was well-designed and conducted, and the results are robust.  The clinical trial results 
provide assurance of at least one year of clinical effectiveness of the device, with a high probability of 
reduction of primary device migration. Furthermore, it is important to consider that the device merely 
supports and supplements the effectiveness of another device and its failure would not significantly affect 
the performance of the primary device. The device does not pose risks that would rise to the level of a 
Class III device. Any safety concerns regarding device failure can be readily addressed through special 
controls related to appropriate testing and labeling. 
 
6.  Do the Benefits outweigh the Risks, when taking into account the following additional 
considerations? Select relevant considerations, and then answer the question in the box below. 
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 Understanding of patient willingness or unwillingness to accept a large extent of uncertainty in 

the benefits and/or risks 
 Available patient preference information (PPI) showing patient willingness or unwillingness to 

accept the risks in exchange for the benefits. In circumstances where it is not feasible to 
obtain PPI (e.g., some pediatric or impaired patient population), care-partner perspectives 
may be considered. 
 Understanding of care-partner perspectives on the benefits and risks for a device intended to 

provide benefit to the care-partner (e.g., ease of care) 
 Understanding of healthcare professional perspectives on the benefits and risks for a device 

intended to provide benefit to the healthcare professional (e.g., reduction of radiation 
exposure) 
 Available qualitative or quantitative PPI on the relative desirability or acceptability to patients 

of outcomes or other attributes that differ among alternative health interventions 
 Understanding how the size of the patient population impacts feasibility of conducting large 

trials and affects public health need for both rare and common diseases or conditions 
 Understanding that the device represents novel technology for which the current device 

technology is different 
 Ability to manage or diagnose the condition and consideration of natural history of disease 

progression in the absence of the intervention or diagnostic information with the device 
under review 
 No legally marketed alternative medical product or medical intervention exists, or the device 

offers advantages over existing alternatives 
 The device fills an unmet medical need or niche for more effective treatment or diagnosis of 

life-threatening or irreversibly debilitating human disease/conditions 
 The device avoids serious harm associated with available therapies for the disease or condition 

 The adverse events associated with use of the device are reversible 

 Type of intervention required to address the harmful event (e.g., medication, surgery) 

 The study is a first of a kind (robustness of the analysis) 

 Tipping point and/or worst-case sensitivity analysis continuing to show clinical benefit 

 Understanding of mechanistic plausibility and/or class effect (e.g., familiarity with similar 

technology) 
 Other(s):  

 None 

 
Q6: Do the Benefits outweigh the Risks, when taking into account additional 
relevant considerations? 
 
 Yes  the benefits outweigh the risks such that, for this device, additional 

consideration of relevant factors would not change that determination 
 Unable to conclude that benefits outweigh the risks  further discussion and 

consideration of risk mitigation measures is appropriate  Continue to Q7 
 
Summary of the Assessment of Benefit-Risk, taking into account additional relevant considerations 
For the Proposed Indications for Use: 
Summarize the clinical benefit(s) that have been demonstrated for the proposed Indications for Use and 
your assessment of how Benefit(s) compare to Risks.  Include a description of how available alternative 
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modalities, including their benefits and risks, affect your assessment.  Include a description of how 
uncertainty regarding Benefit(s) and Risks affects your assessment.  Include a description of how patient 
perspectives affected your assessment. 
 
7.  Can the risks be mitigated, so that Benefits outweigh the Risks? Consider if the Benefits 
outweigh the Risks if risk mitigation strategies are incorporated to lower the probability of 
a harmful event occurring and improve the benefit-risk profile of the device.  Select relevant 
considerations, and then answer the question in the box below. 
 
 Additional descriptions of known and probable benefits and risks in physician and patient 

labeling including appropriate Contraindications, Warnings, and Precautions and 
description of the clinical events 
 Additional warnings noting limitations of safety information (e.g., The safety of the use of 

this device in [situation] has not been evaluated.) 
 Labeling the device Prescription Only 

Training: 
 Limitation to caregivers with certain qualifications or clinical training 

 Limit to users with a minimum set of qualifications and/or training 

 Physician/user training program 

Other: 
 Device tracking 

 Other(s):  

 None 

 
Q7: Can the risks be mitigated, so that Benefits outweigh the Risks? 
 
 Yes  the benefits outweigh the risks such that, for this device, additional 

consideration of relevant factors would not change that determination  
 Unable to conclude that benefits outweigh the risks  further discussion and 

consideration of postmarket actions is appropriate  Continue to Q8 
 
Summary of the Assessment of Benefit-Risk, considering risk mitigation strategies 
For the Proposed Indications for Use: 
Summarize the clinical benefit(s) that have been demonstrated for the proposed Indications for Use and 
your assessment of how Benefit(s) compare to Risks.  Include a description of how available alternative 
modalities, including their benefits and risks, affect your assessment.  Include a description of how 
uncertainty regarding Benefit(s) and Risks affects your assessment.  Include a description of how patient 
perspectives affected your assessment. 
           
8.  Do the Benefits outweigh the Risks considering the use of postmarket actions?  Select 
appropriate postmarket action(s), and then answer the question in the box below. 
  
 Collection of additional and/or confirmatory non-clinical performance data in the postmarket 

space 
 Collection of additional and/or confirmatory clinical data in the postmarket space (e.g., post-

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approval study, postmarket surveillance) 
If either non-clinical or clinical performance data collections in the postmarket space are 
checked, consider: 
 The feasibility of postmarket data collection and likelihood that postmarket data 

collection will be completed within a reasonable timeframe  Whether it would be 

appropriate for labeling to include description of postmarket data collection and its 
purpose 
 Other(s):  

 None 

 
Q8: Do the Benefits outweigh the Risks considering the use of postmarket actions? 
  
 Yes  The benefits outweigh the risks 

 Unable to conclude that benefits outweigh the risks  Continue to Q9 

 
Summary of the Assessment of Benefit-Risk, considering postmarket actions 
For the Proposed Indications for Use: 
Summarize the benefit(s) that have been demonstrated for the proposed Indications for Use and your 
assessment of how Benefit(s) compare to Risks.  Include a description of how available alternative 
modalities, including their benefits and risks, affect your assessment.  Include a description of how 
uncertainty regarding benefit(s) and risks affects your assessment.  Include a description of how patient 
perspectives affected your assessment.  
 
 
Q9: Is there any evidence of clinical benefit for a modified Indications for Use? 
  
 Yes  Return to Q1 and proceed with modified Indications for Use 

 No   Do not approve/grant 

 
 
   
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Benefit-Risk Assessment Summary
 
 
Based on the totality of the data  Proposed Indications for Use  
Device Name: Hypothetical Example 4  The device is indicated as an adjunct to provide enhanced stability 
PMA/De Novo Number:   for other implanted devices, which could otherwise affix themselves 
 Interim    Final  without support. 
 
Considering benefit in terms of 
  Type    Patient perspective (or care-
  Magnitude  partner and/or healthcare 
Assessment of Benefit 
  Probability  professional perspectives, if 
  Duration of effects  applicable) 
  Other 
 YES  Q2  
1. Is there any evidence of clinical  
 NO  Do not approve/grant for proposed Indications for Use; 
benefit?  
proceed to Q9 
2. What is the extent of uncertainty for   High   Med  Low 
  
the benefits?   Continue to Q3 
Considering risk in terms of   
  Severity, types, number    Risks from false-positive or false-
and rates of harmful  negative results  
events    Patient perspective (or care-
Assessment of Risk 
  Probability of a harmful  partner and/or healthcare 
event  professional perspectives, if 
  Duration of harmful  applicable) 
events 
3. Are known/probable risks more than   YES  Q4  

minimal?   NO  Q4 

4. What is the extent of uncertainty for   High   Med  Low 
  
the Risks?   Continue to Q5 
Assessment of Benefit-Risk 
 YES  Worksheet complete  
5. Do the Benefits outweigh the Risks?  
 Unable to conclude that benefits outweigh the risks  Q6 

6. Do the Benefits outweigh the Risks, 
 YES  Worksheet complete  
taking into account additional  
 Unable to conclude that benefits outweigh the risks  Q7 
considerations?  
7. Can the risks be mitigated, so that   YES  Worksheet complete  

Benefits outweigh the Risks?   Unable to conclude that benefits outweigh the risks  Q8 

8. Do the Benefits outweigh the Risks 
 YES  Worksheet complete 
considering the use of postmarket  
 Unable to conclude that benefits outweigh the risks  Q9 
actions?  
 YES  Return to Q1 and proceed with modified Indications for 
9. Is there any evidence of clinical benefit  
Use 
for a modified Indications for Use? 
 NO  Do not approve/grant 

 
75