Contains Nonbinding Recommendations 
 
Factors to Consider Regarding Benefit-
Risk in Medical Device Product 
Availability, Compliance, and 
Enforcement Decisions 
______________________________________________________________________________ 
Guidance for Industry and  
Food and Drug Administration Staff 
 
 
Document issued on December 27, 2016. 
The draft of this document was issued on June 16, 2016 
 
For questions about this document regarding CDRH-regulated devices, contact the Office of 
Compliance at 301-796-5900.  
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Devices and Radiological Health 
1 
  Contains Nonbinding Recommendations 
 
Preface 
Public Comment  
You may submit electronic comments and suggestions at any time for Agency consideration to 
http://www.regulations.gov . Submit written comments to the Division of Dockets Management, 
Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 20852. 
Identify all comments with the docket number FDA-2016-D-1495.  Comments may not be acted 
upon by the Agency until the document is next revised or updated. 
Additional Copies 
Additional copies are available from the Internet. You may also send an e-mail request to CDRH-
Guidance@fda.hhs.gov to receive a copy of the guidance. Please use the document number 
1500065 to identify the guidance you are requesting. 
2 
  Contains Nonbinding Recommendations 
 
Table of Contents 
I.  Introduction ...............................................................................................................................................4
II.  Scope.........................................................................................................................................................5
III.  Patient Focused Benefit-Risk Assessments for Medical Device Product Availability, Compliance, and 
Enforcement Decisions ............................................................................................................................. 7
IV.  Description of Factors to Consider Regarding Benefit-Risk for Medical Device Product Availability, 
Compliance, and Enforcement Decisions .................................................................................................8
A.  Factors for the Assessment of Medical Device Benefits.......................................................................8
B.  Factors for the Assessment of Medical Device Risks .......................................................................... 10
C.  Additional Benefit-Risk Factors to Consider When Making Product Availability, Compliance, and 
Enforcement Decisions ........................................................................................................................ 12
V.  How FDA Considers Benefit-Risk in Patient Focused Medical Device Product Availability, 
Compliance, and Enforcement Decisions ............................................................................................... 13
VI.  Examples Demonstrating Benefit-Risk Assessments for Medical Devices ............................................ 15
A.  Examples Related to Product Availability Decisions ........................................................................... 15
B.  Examples Related to Compliance and Enforcement Decisions ........................................................... 21
Appendix A - Intersection of this Guidance with ISO 14971: Medical devices  Application of risk 
management to medical devices ............................................................................................................. 24
Appendix B - Worksheets for Benefit Assessments ....................................................................................... 25
Appendix C - Worksheets for Risk Assessments ........................................................................................... 28
Appendix D - Worksheet for assessing potential decisions based on the Benefit-Risk Assessment Outcome
 ................................................................................................................................................................ 31
3 
  Contains Nonbinding Recommendations 
 
Factors to Consider Regarding Benefit-
Risk in Medical Device Product 
Availability, Compliance, and 
Enforcement Decisions 
 
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 clarity for FDA staff and industry regarding 
the benefit and risk factors FDA may consider in prioritizing resources for compliance and 
enforcement efforts to maximize medical device quality1 and patient safety. This guidance is not 
intended to limit FDA action; rather, it describes the general framework for medical device 
decision making in the product availability, compliance, and enforcement arenas. Product 
availability and other medical device compliance and enforcement decisions are generally fact-
specific. However, FDA believes that explaining how we consider the factors listed in this 
guidance document will improve the consistency and transparency of these kinds of decisions. A 
common understanding of how FDA considers benefit and risk may better align industrys and 
FDAs focus on actions that maximize benefit to patients, improve medical device quality, and 
reduce risk to patients.  
This guidance is intended to provide a framework for FDA and stakeholders that sets forth 
overarching benefit-risk principles. FDA may consider the types of benefit-risk factors described in 
                                                           
1 As used in this guidance, quality has the same meaning as in 21 CFR part 820.  Quality means the totality of 
features and characteristics that bear on the ability of a device to satisfy fitness-for-use, including safety and 
performance. 21 CFR 820.3(s). 
4 
  Contains Nonbinding Recommendations 
 
this guidanceincluding reliable patient input2 from a representative sampleon a case-by-case 
basis when determining the appropriate actions to take and to help ensure that informed and 
science-based decisions are made to the greatest extent practicable. Factors may be weighted 
differently for different decisions and as the timeframe allows. FDA intends to use pilots and other 
evaluation techniques to help determine how to apply the benefit-risk framework described in this 
guidance. Because of the variability in the facts of, and data available for, each decision, specific 
factors which will inform FDAs thinking may vary.  
In addition, this guidance is intended to harmonize FDAs approach to weighing benefits and risks 
for medical device product availability, compliance, and enforcement decisions with FDAs 
benefit-risk framework for assessing medical device marketing and investigational device 
exemption (IDE) applications. The benefit-risk factors in this guidance also support assessment of 
medical devices with real world evidence. While the benefit-risk factors in this guidance are not 
identical to the other frameworks, this guidance builds upon FDAs premarket review benefit-risk 
policy in an effort to improve consistency in our patient centered approach and decision making 
across the total product life cycle. This guidance is intended to complement, not supplant, FDAs 
Guidance for Industry and Food and Drug Administration Staff - Factors to Consider When 
Making Benefit-Risk Determinations in Medical Device Premarket Approvals and De Novo 
Classifications3. 
For the current edition of the FDA-recognized standard(s) referenced in this document, see the 
FDA Recognized Consensus Standards Database Web site at 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm.
FDAs guidance documents, including this one, do not establish legally enforceable 
responsibilities. Instead, guidance documents describe the Agencys current thinking on a topic and 
should be viewed only as recommendations, unless specific regulatory or statutory requirements 
are cited. The use of the word should in Agency guidance documents means that something is 
suggested or recommended, but not required. 
II.  Scope 
The framework described in this guidance may be applicable to both industry and FDA decisions. 
The benefit-risk factors may be considered when device manufacturers evaluate appropriate 
responses to nonconforming product or regulatory compliance issues, such as determining 
                                                           
2 For purposes of this guidance, patient input has the same meaning as set forth in FDAs Guidance for Industry, 
Food and Drug Administration Staff, and Other Stakeholders Patient Preference Information  Voluntary Submission, 
Review in Premarket Approval Applications, Humanitarian Device Exemption Applications, and De Novo Requests, 
and Inclusion in Decision Summaries and Device Labeling,  August 24, 2016 (Patient Preference Information 
Guidance), http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ 
UCM446680.pdf.  While the Patient Preference Information Guidance focuses on FDAs consideration of patient 
preference information during the review of Premarket Approval (PMA) applications, HDE applications and de novo 
requests, FDA and manufacturers may use patient preference information, and other types of patient input throughout 
the total product lifecycle. Therefore, some recommendations in the Patient Preference Information Guidance may be 
helpful for manufacturers considering collection or use of patient input at other points in the product life cycle.  
3 The text version of the url for this guidance document is 
http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm517504.pdf.
5 
  Contains Nonbinding Recommendations 
 
whether to limit the availability of a medical device (e.g., a voluntary recall or market 
withdrawal). FDA may consider the benefit-risk factors during, for example, evaluation of device 
shortage situations, selection of the appropriate regulatory engagement mechanism following an 
inspection during which regulatory non-compliance was observed, evaluation of recalls, and 
consideration of petitions for variance from those sections of the Quality System (QS) regulation 
(21 CFR part 820) for which there were inspectional observations during a PMA pre-approval 
inspection. Premarket submission review decisions, such as premarket notification (510(k)) 
substantial equivalence determinations, de novo classification, and PMA, Humanitarian Device 
Exemption (HDE) or IDE application approval decisions, are beyond the scope of this guidance.  
Because of the potentially direct effect on patients, medical device compliance and enforcement 
decisions that affect product availability should generally include consideration of specific factors. 
The factors described in this document can apply to many situations where the Agency or 
manufacturer has information that leads to quality, compliance, or other concerns regarding a 
medical device and considers taking action that could have a direct effect on the devices 
availability. These situations may include information about new risks or about known risks 
occurring at greater than expected frequency or severity. To support a common understanding of 
other kinds of compliance and enforcement decision making, the factors in this guidance may also 
be considered when the Agency or manufacturer considers taking action that is unlikely to directly 
affect product availability but seeks to minimize risks to patients associated with manufacturer 
quality and regulatory compliance issues (e.g., issues in design, manufacturing, or reporting related 
to the device), while also considering the benefits patients may receive from the device. The 
intersection of this guidance with ISO 14971: Medical devices  Application of risk management to 
medical devices is discussed in Appendix A. 
This guidance applies to both diagnostic and therapeutic medical devices subject to, and exempt 
from, premarket review. The scope of this guidance excludes medical devices regulated by FDAs 
Center for Biologics Evaluation and Research (CBER); combination products, as defined in 21 
CFR 3.2(e), for which CDRH is not the lead Center; and electronic products that are not devices as 
defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), as regulated 
by CDRH under the Electronic Product Radiation Control (EPRC) provisions in the FD&C Act
and implementing regulations (21 CFR Subchapter JRadiological Health). This guidance also 
does not apply to products (e.g., drugs, biologics, dietary supplements, foods, tobacco products, or 
cosmetics) regulated by other FDA Centers.  
Guidance documents, including this guidance, are not binding, and the concepts and factors 
described herein generally explain how benefit-risk assessments can be made. This guidance does 
not preclude FDA from taking regulatory or other action in response to a violation of applicable 
law or regulation.  
6 
  Contains Nonbinding Recommendations 
 
III.  Patient4 Focused Benefit-Risk Assessments for Medical 
Device Product Availability, Compliance, and 
Enforcement Decisions 
FDA has authority to limit the availability of violative medical devices and to pursue other 
compliance and enforcement actions related to violative medical devices. FDA recognizes that, to 
achieve the Agencys goal of protecting and promoting the public health, decisions regarding these 
actions should be made while focusing on the impact for patients. Considering the benefit-risk 
profile of the device may prevent regulatory actions with unintended adverse impact for patients 
(e.g., shortage of medically necessary devices).  
In certain situations involving risks of patient harm, FDA and industry, individually or 
collaboratively, can help maximize benefit and reduce risk to patients by assessing the situation, 
considering patients perspectives, evaluating any regulatory non-compliance or device 
nonconformity in light of the benefit-risk profile of the device,5 factoring in alternatives, where 
available, considering the benefit-risk balance for patients of each decision option, and determining 
the most appropriate next steps.  
When FDA is working with a manufacturer to address a failure to comply with applicable statutes 
or regulations, observed unanticipated harm to patients or users, or identified device 
nonconformities, FDA strives to be clear with that manufacturer about the benefits and risks the 
Agency is considering. As with certain premarket review decisions, when making medical device 
product availability, compliance, and enforcement decisions informed by benefit-risk, FDA may 
consider relevant, reliable information relating to patient perspectives on what constitutes 
meaningful benefit, what constitutes risk, and what options patients are willing to accept, if such 
information is available at the time of decision, as well as what alternatives are available. Before 
arriving at a decision, FDA may also consider the manufacturers approach to minimize harm or to 
mitigate the increased risks that result from regulatory non-compliance or device nonconformity, 
the manufacturers compliance history, and the scope of the issue.  
By providing greater clarity about the factors we consider, we intend to improve consistency and 
transparency and to better align industrys and FDAs focus on actions that maximize benefit to 
patients, improve medical device quality, and reduce risk to patients. In Appendices B, C, and D, 
benefit-risk assessment worksheets have been provided to support consideration of the factors by 
FDA staff and industry.  
                                                           
4 Although this guidance focuses on patients, when relevant, the benefit-risk factors also take into account benefits or 
risks for non-patient users of medical devices, such as healthcare professionals and caregivers.  
 
5 As used in this guidance, nonconformity has the same meaning as in 21 CFR part 820.  Nonconformity means the 
nonfulfillment of a specified requirement. 21 CFR 820.3(q).  In the preamble to the final rule for the QS regulation, 
FDA emphasizes that a nonconformity may not always rise to the level of a product defect or failure, but a product 
defect or failure will typically constitute a nonconformity. (61 FR 52610.) 
7 
  Contains Nonbinding Recommendations 
 
Note that as with premarket benefit-risk determinations made when evaluating marketing and IDE 
applications, benefit-risk assessments made in product availability, compliance, and enforcement 
contexts may change over time. For example, as the practice of medicine evolves, clinical 
experience increases, or additional treatment options become available to patients, a benefit-risk 
conclusion may change. 
IV.  Description of Factors to Consider Regarding Benefit-
Risk for Medical Device Product Availability, 
Compliance, and Enforcement Decisions 
In assessing benefit-risk factors for purposes of medical device product availability, compliance, 
and enforcement decisions, FDA considers relevant and reliable evidence and data available to the 
Agency at the time of a decisionincluding reliable patient input from a representative sample 
on a case-by-case basis, to help ensure that informed and science-based decisions are made to the 
greatest extent practicable. FDA may use available evidence or request data to assess these factors, 
as appropriate. The benefit-risk assessments covered in this guidance document may compare the 
benefits and risks identified based on currently available information to those benefits and risks 
that were identified during premarket review benefit-risk assessments (or early risk assessments 
documented as part of a manufacturers risk management process) in order to understand whether 
there has been a change in the benefit-risk analysis over time. We generally consider our device 
benefit-risk assessment along with evidence and data related to benefit-risk factors outlined in the 
guidance to reach our judgment about how to proceed in each situation.  
A.  Factors for the Assessment of Medical Device Benefits  
When prioritizing compliance and enforcement efforts to maximize medical device quality and 
patient safety, FDA may assess the extent of benefit of a device by considering factors such as 
those listed below. The following factors, when relevant, should be considered in the aggregate. 
The factors may be considered early in the medical device product life cycle and reassessed as the 
device is used more widely.  
Benefit, as described by the potential benefit factors, may change over time. The text below 
describes each factor for the purposes of this guidance and provides examples of how each factor 
may be considered.  
Type of benefit(s) includes, but is not limited to, the medical devices impact on patient health and 
clinical management. Examples include the effect of the device on patient treatment plans and 
quality of life; impact on survival and on ability to perform activities of daily living; and how 
much the medical device can aid in improving patient function, preventing loss of function, or 
providing relief from the symptoms of the disease or condition that the medical device is intended 
to treat.  
As a medical device is used, clinicians may find unanticipated ways to use the medical device and 
additional types of benefit. For example, a surgical tool may be cleared for use in hernia repair 
surgery. Real world evidence may show that surgeons have found additional uses for the surgical 
tool that may lead to clearance of new uses, thus increasing the types of benefit. 
8 
  Contains Nonbinding Recommendations 
 
Magnitude of benefit(s) is the degree to which patients experience the treatment benefit or the 
effectiveness of the medical device. The change in patients conditions or the change in necessary 
clinical management may allow FDA to determine the magnitude of the benefit. Magnitude of 
benefit may be assessed against standards of care and expected performance and may change over 
time. 
Likelihood of patients experiencing one or more benefits is the likelihood that the medical 
device will effectively treat or diagnose the patients disease or condition. A medical device may 
not provide effective treatment or diagnosis for all patients. One method of determining the 
likelihood of benefit, for a particular patient population, is to determine the number of patients 
treated effectively and divide this by the total number of patients treated. We encourage 
manufacturers wishing to provide data and calculations for use in evaluating this factor to contact 
FDA regarding what information may be relevant and appropriate to the issue being assessed. 
In assessing benefit, FDA may consider whether there are subpopulations included in the 
indication for use that are more likely to retain expected benefits than the overall population. If 
the subgroups can be identified, the likelihood of those patients experiencing benefit from the 
device may increase. The benefit for a subpopulation may also be greater than for the population 
as a whole, and this greater benefit should be considered in the overall benefit-risk assessment. 
Duration of effects is how long the benefit can be expected to last for the patient. Curative 
treatments may be seen as providing higher benefit because of a longer duration of effect. 
Knowledge of the duration of treatment effect may change as the medical device is used. For 
example, a medical device may have been approved with clinical endpoint data demonstrating 
effectiveness for 6 months. As the medical device is used, patients may experience significantly 
longer treatment effects than those described in the device labeling.  
Patient perspective on benefit is the value that patients place on use of the medical device. 
Faced with a severe or chronic disease, a patient may highly value the benefit provided by a 
medical device in light of the specific condition that patient has. For example, patients dying of 
congestive heart failure may highly value a medical device that extends their lives for a few 
months. Patients with less severe or chronic diseases may or may not place the same value on a 
device with a short-term benefit. 
Benefit factors for healthcare professionals or caregivers include the benefit that healthcare 
professionals or caregivers experience by improving the way they care for patients, whether this 
directly improves patient outcomes or improves clinical practice. Benefit factors for healthcare 
professionals or caregivers may include, for example, a reduction in the procedural time, 
improvements in overall training and utility for practitioners or caregivers with varying skill levels.  
FDA recognizes that certain devices, such as surgical tools that allow different techniques or 
devices that positively affect ongoing patient management, may improve the benefit profile. 
Medical necessity should be considered if a medical device provides benefits or addresses needs 
unmet by other medical devices or therapies. Benefit considerations should include an 
9 
  Contains Nonbinding Recommendations 
 
assessment of whether another medical device or therapy could be used in substitution, and the 
availability of that other medical device or therapy. 
B.  Factors for the Assessment of Medical Device Risks 
 
When prioritizing compliance and enforcement efforts to maximize medical device quality and 
patient safety, FDA may assess the risk that a medical device will cause direct or indirect patient 
harm by considering factors such as those listed below. The following factors, when relevant, 
should be considered in aggregate. Each factor may be considered early in the medical device 
product life cycle and reassessed as the device is used more widely. Changes in risk should be 
noted in the manufacturers risk management documentation. Changes in risk may occur due to, 
among other things, observed unanticipated harm to patients exposed to the device or to device 
users, changes in the medical device use environment, identified medical device nonconformities, 
and issues related to the design or manufacturing of the device.  
It should be noted that all devices have some level of anticipated risk, even without device 
nonconformities or regulatory non-compliance, and hazards can occur both when a device 
functions normally and if it malfunctions. Medical device nonconformities may increase risk or 
introduce new risks. Failure to comply with applicable statutes or regulations also may be a 
negative indicator of a manufacturers ability to consistently manufacture high quality medical 
devices, even if a device made by such a manufacturer still performs as expected. Postmarket data 
may also show that risk is higher than anticipated, even in the absence of a medical device 
nonconformity or regulatory non-compliance. Therefore, the risk factors listed below take into 
account considerations related to nonconforming devices, failure to comply with applicable statutes 
or regulations, and harm potentially unrelated to compliance with legal requirements or device 
nonconformities.  
Risk, as described by the potential risk factors, may change over time. The text below describes 
each risk factor for purposes of this guidance and provides examples of how the risk factor may be 
considered.  
Severity of harm is categorized into three levels, each of which includes a duration 
component. The three levels are medical device-related deaths or serious injuries, medical 
device-related non-serious adverse events, and medical device-related events without reported 
harm. 
Medical device-related deaths and serious injuries6 include those events (including 
procedure related complications) that may have been or were attributed to the use of the 
medical device and that cause or contribute to a death or 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. 
                                                           
6 As used in this guidance, serious injury has the same meaning as in 21 CFR part 803. Serious injury means an 
injury or illness that: (1) Is life-threatening, (2) Results in permanent impairment of a body function or permanent 
damage to a body structure, or (3) Necessitates medical or surgical intervention to preclude permanent impairment of a 
body function or permanent damage to a body structure. Permanent means irreversible impairment or damage to a 
body structure or function, excluding trivial impairment or damage.  See 21 CFR 803.3(w) 
10 
  Contains Nonbinding Recommendations 
 
Medical device-related non-serious adverse events include those events (including 
procedure related complications) that may have been or were attributed to the use of the 
medical device and that cause or contribute to minor, temporary or medically reversible 
injuries that do not meet the criteria for classification as a medical device-related serious 
injury. 
Medical device-related events without reported harm include medical device 
nonconformities which have no related harm, medical device malfunctions7 which have no 
related harm, procedure related complications with no related harm, and instances where a 
nonconformity or regulatory noncompliance was observed at the medical device 
manufacturing facility and no defective devices were released to the market. A medical 
device nonconformity or malfunction can include the failure of a medical device to meet 
its performance specifications even though the device still performs adequately to meet the 
needs of a given patient.  
Likelihood of risk considers risk factors related to the potential number of patients at risk of 
experiencing harm: the likelihood that a medical device will have problems, the likelihood of a 
patient experiencing harm, and the total number of patients exposed. We encourage manufacturers 
wishing to provide data and calculations for use in evaluating this factor to contact FDA regarding 
what information may be relevant and appropriate to the issue being assessed.    
Distribution of nonconforming devices includes whether nonconforming product has been 
distributed and if so, how many nonconforming devices are on the market. 
Duration of exposure to population is the length of time between initial patient exposure to 
the device with the identified risk of harm and the point at which the risk of harm is 
successfully addressed.  
False-positive or false-negative results are important risk factors for diagnostics. If a diagnostic 
medical device gives a false-positive result, the patient might, for example, be incorrectly 
diagnosed with a serious disease and receive an unnecessary treatment, incurring all the risks that 
accompany that treatment. If a diagnostic medical device gives a false-negative result, the patient 
might not be diagnosed with the correct disease or condition and might not receive an effective 
treatment (thereby missing out on the benefits that treatment would confer). The risks associated 
with false positives and false negatives can be multifold, but are considered by FDA in light of 
probable risks.  
Patient tolerance of risk is the level of concern that patients have regarding harm or potential 
harm caused by the device. Patient tolerance of risk may take into account both the patients 
willingness and unwillingness to use a nonconforming medical device, to use a device 
                                                           
7 As used in this guidance, malfunction has the same meaning as in 21 CFR part 803.  Malfunction means the 
failure of a device to meet its performance specifications or otherwise perform as intended. Performance specifications 
include all claims made in the labeling for the device.  The intended performance of a device refers to the intended use 
for which the device is labeled or marketed, as defined in [21 CFR 801.4]. 21 CFR 803.3(k).   
11 
  Contains Nonbinding Recommendations 
 
manufactured by a non-compliant manufacturer, or to tolerate harm (both probable and actual). 
Risk tolerance varies among patients, and affects individual patients decisions as to whether risks 
associated with the medical devices technology are acceptable in exchange for the benefit. Risk 
tolerance may also vary with risk severity (e.g., there may be special subpopulations in which risk 
severity is higher). Patients may not understand device-related risks for all types of devices. For 
prescription devices, a patients assessment of risk would be appropriately informed by 
information from his or her clinician. 
Risk factors for healthcare professionals or caregivers may be considered when the risk may 
have an adverse impact on the clinician or caregiver. 
C.  Additional Benefit-Risk Factors to Consider When Making 
Product Availability, Compliance, and Enforcement Decisions  
In addition to the benefit-risk factors described above, FDA may consider additional important 
benefit-risk factors related to product availability, compliance, and enforcement decisions, such as 
those listed below.  
Uncertainty is an important factor, since at any point in the total product life cycle, there is never 
100% certainty regarding the safety, effectiveness, or quality of a device. However, the degree of 
certainty of the benefits and risks of a device is a factor FDA considers when making benefit-risk 
assessments. Issues that may inform the degree of uncertainty include, but are not limited to, the 
type of clinical information available (e.g., clinical trial data, real world evidence derived from 
registries or commercial experience), the degree to which the available information is 
representative (sample size, generalizability of the sample to the population exposed to the device), 
and the statistical inferences and limitations that can be drawn from the information. 
Mitigations are actions taken by the manufacturer, by FDA, or by other stakeholders to recover 
benefit or to limit harm. Mitigations could address, among other considerations, as applicable: 
clinical practice; use errors; unmet medical needs; the use environment; user population; user 
skill level; clinical understanding in assessing risk; current expectations in clinical use; any 
changes in medical practice, e.g., standard of care, that could increase risk; and use in 
emergency/crisis situations. Risk acceptability is assessed after any appropriate mitigation. 
Detectability refers to whether nonconformity could be identified, either by the manufacturer 
or by the user. A nonconformity which can be identified prior to use of the device may harm 
fewer patients than a nonconformity which is not identified prior to use. A detected 
nonconforming device may still cause patient harm (e.g., a mislabeled implant may cause a 
delay in surgery).  
Failure mode is the specific method or type of failure. The failure mode may be used to identify 
the cause of the nonconformance, including whether the nonconformance is related to 
manufacturing, design, use conditions, or environment. For example, an intermittent electrical 
connection due to faulty soldering (manufacturing failure) may indicate a different cause of the 
nonconformance than an error in wiring design that affects all devices (design failure). 
12 
  Contains Nonbinding Recommendations 
 
Scope of the device issue should be evaluated to assess whether the risks identified are potentially 
inherent to similar devices of this type (i.e., whether the risk is specific to a single device, a single 
manufacturer, or is industry wide). 
Patient impact is the impact on the health and quality of life of patients if a particular compliance 
or enforcement action is, or is not, taken or if the device relevant to the nonconformity or 
regulatory non-compliance is not available. FDA and, where appropriate, industry should consider 
whether patients are better off if the device is or is not available.  
Preference for availability relates to both the patient and the caregiver. FDA and industry, where 
appropriate, should understand whether patients and caregivers would prefer to have access to the 
device relevant to the nonconformity or regulatory non-compliance and whether patients and 
caregivers adequately understand related benefits and risks. 
Nature of violations/Nonconforming product may include whether the violation was systemic or 
non-systemic in nature as well as the extent of any product nonconformity.  
Firm compliance history may include the manufacturers regulatory history and initiative in 
identifying and correcting issues, the repetitiveness of such issues, and the manufacturers 
communication with FDA. When considering the firms compliance history, FDA may determine 
that it is appropriate to provide prior notice to the manufacturer as to what is required, what 
violations appear to exist, and, in the case of violations of regulatory significance, that failure to 
comply may result in the initiation of enforcement action.8 
V.  How FDA Considers Benefit-Risk in Patient Focused 
Medical Device Product Availability, Compliance, and 
Enforcement Decisions  
An FDA benefit-risk assessment for medical device product availability, compliance, and 
enforcement decisions may be prompted by eventssuch as a recall, variance petition, new safety 
information or analysis, or medical device nonconformitythat may lead FDA to take regulatory 
action.  For example, consistent with the benefit risk framework described in this guidance, FDA 
intends to evaluate benefit and the degree to which product remains unused in the market during 
health risk assessments (HRAs) that help FDA and manufacturers determine if any actions, such as 
recall or notifying the public regarding a risk, are necessary.  
FDA initiates a benefit-risk assessment by evaluating available benefit information on the 
applicable medical device and assessing the benefit information by considering the relevant benefit 
factors described in Section IV and in Appendix B  Worksheets for Benefit Assessments. Some 
potential sources of benefit information include literature, prior premarket submissions for the 
subject device (including information regarding similar competitor devices, if available), clinical 
                                                           
8 For additional FDA information regarding prior notice, see Regulatory Procedures Manual Chapter 10  Other 
Procedures, Section 2  Prior Notice, updated 6/19/2015,   
http://www.fda.gov/ICECI/ComplianceManuals/RegulatoryProceduresManual/ucm179537.htm.   
13 
  Contains Nonbinding Recommendations 
 
studies, registries, patient input, experienced clinicians, and risk management documentation 
voluntarily supplied by the manufacturer. FDA encourages manufacturers that wish to provide 
such documentation to do so through the designated FDA point of contact for the issue being 
assessed, such as by contacting a district recall coordinator in the context of a potential recall 
situation.  
FDA would next assess the available risk information on the medical device by considering the 
relevant risk factors described in Section IV and Appendix C  Worksheets for Risk Assessments. 
Some potential sources of risk information include medical device reports (MDRs), inspection 
reports, literature, prior premarket submissions for the subject device (including information 
regarding similar competitor devices, if available), clinical studies, registries, patient input, 
experienced clinicians and risk management documentation voluntarily supplied by the 
manufacturer.  
FDA would complete the benefit-risk assessment by considering any factors from Appendix D that 
are relevant for assessing decision options.  
When appropriate, FDA would use the outcome of a benefit-risk assessment to inform decisions 
related to product availability. The types of product availability decisions where this may be useful 
include: 
  What actions, if any, may FDA take when continued access to a nonconforming device or a 
device manufactured by a firm with regulatory compliance issues might be needed during a 
shortage situation? 
  When is it in the best interest of the public health to grant a variance from certain QS 
regulation requirements for QS issues identified during a PMA pre-approval inspection? 
  When might FDA exercise enforcement discretion and not take immediate action against a 
company for marketing a device with a significant change or modification prior to 
obtaining clearance, as required by 21 CFR 807.81(a)(3)? 
Before making a decision that is likely to affect product availability, FDA may also consider the 
impact on the patient if the device is available or not available, whether the issue affects a single 
manufacturer or the whole industry, and patient or caregiver preference for availability. Specific 
benefit-risk assessments should be viewed in the larger context that includes consideration of the 
additional factors described in Section IV.C, but generally, if the benefit-risk assessment indicates 
high benefit to patients with little risk, FDA may be more likely to decide that it is appropriate for 
patients to have access to a nonconforming device while the long-term corrective action is taken if 
appropriate alternative treatments are not available. Alternatively, if the benefit-risk assessment 
indicates low benefit to patients with high risk, FDA would be more likely to take action to limit 
product availability.  
In addition to compliance and enforcement decisions that potentially have a direct effect on 
product availability, when appropriate FDA may use the outcome of a benefit-risk assessment to 
inform other decisions related to compliance and enforcement. Examples of the other types of 
compliance and enforcement decisions where this may be useful include: 
14 
  Contains Nonbinding Recommendations 
 
  Is a manufacturers proposed correction strategy adequate given the benefit-risk 
assessments and mitigation activities? 
  Upon observing a violation, when might FDA initiate advisory, administrative or judicial 
action, and when would it be appropriate to take a more informal approach?  
When making compliance and enforcement decisions that are unlikely to directly affect product 
availability, FDA may also consider whether regulatory non-compliance increases risk of harm to 
patients, whether taking (or not taking) a contemplated compliance or enforcement action would 
impact patients, the manufacturers regulatory history, and steps taken by the manufacturer to 
address the situation. Specific benefit-risk analyses will again need to be viewed in context, but 
generally, if FDAs benefit-risk assessment indicates high benefit to patients with little risk, FDA 
may decide to work with the manufacturer to address the underlying issue without initiating a 
formal compliance or enforcement action. If FDAs benefit-risk assessment indicates low benefit 
to patients with high risk, FDA would likely take formal compliance or enforcement action to 
address the problem. 
VI.  Examples Demonstrating Benefit-Risk Assessments for 
Medical Devices  
The examples below are hypothetical or simplified real-world situations, and are offered only for 
illustrative purposes; i.e., no example is a complete treatment of the benefit-risk issues associated 
with any actual FDA decision. The decisions described in these examples are not predictive of 
future FDA decisions; rather, they are hypothetical outcomes and are intended only to demonstrate 
how FDA considers the factors described in this guidance, including how we assess benefits and 
risks during product availability, compliance, and enforcement decisions. Similar scenarios may 
result in different outcomes depending on the circumstances.  
A.  Examples Related to Product Availability Decisions 
Example 1: Recall and potential shortage of a high benefit implantable coated 
device with low additional risk9  
Background: An implantable coated device was developed which reduced thrombosis by more than 
80%. There were three field complaints for a malfunction in the devices first few months of wide 
scale commercial use. This malfunction represented an anticipated failure mode that appeared to be 
occurring more frequently than expected. During these events associated with the malfunction, 
blood loss occurred, but no serious injuries occurred. The manufacturer submitted MDRs for these 
events.  
Removal of the product from the field would have resulted in the cancellation of hundreds of 
surgeries.  However, the company determined that it had product in the field with a nonconformity 
requiring a correction or removal, which must be reported to FDA under 21 CFR 806.10.  The 
                                                           
9 When additional risk is mentioned in this guidance, it refers to the additional risk presented by a nonconformity or 
noncompliance.   
15 
  Contains Nonbinding Recommendations 
 
company proposed to send to customers a communication that included a supplement to the 
original labeling and alerted users to the potential increased risk.  The company further proposed to 
continue monitoring the events in the field to better understand how best to address the issue in the 
long term. 
Benefits: The patient population for this device includes those patients at elevated risk of 
thrombosis. There was no indication that the malfunction affected the devices reduction of 
thrombosis.  As noted above, this device reduces thrombosis by more than 80%. The likelihood of 
the benefit was high. A reduction in thrombosis has significant impact on patient outcomes. The 
magnitude of the benefit was high. There were no other comparable treatment options.  
Risks: For the different patient subpopulations that may be treated with the device, FDA 
considered the risks of additional blood loss and increased associated surgery time should a device 
with this nonconformity be used. Three malfunctions with no serious adverse events had been 
reported. The severity of the additional risk appeared to be low. The manufacturer shared 
information indicating that 3000 devices had been implanted. The likelihood of the risk appears 
low.  
Patient tolerance for risk and perspective on benefit: Patients appreciate the benefit of limiting 
thrombosis. Thrombosis is a concern for many patients using these types of devices. A 
representative sample of patients was informed about the increased incidence of temporary and 
medically reversible adverse events and indicated that they generally still would prefer to use the 
beneficial device.  
Uncertainty: FDA considered the uncertainty of the adverse event rate. It was unclear if the adverse 
event rate would increase. There were 300 patients in a clinical trial, and there had been 3000 
devices implanted in the first few months of wide scale commercial use. As experience with the 
device increases, if the number of adverse events and the number of implantations are accurately 
tracked, the uncertainty regarding the adverse event rate would decrease. 
Mitigation: During the HRA, FDA reviewed the manufacturers risk management information, 
including how this malfunction can be addressed during surgery to minimize the impact on the 
patient. FDA also reviewed the proposed communication to users explaining the issue and the 
proposed supplement to the labeling. 
Patient impact: FDA considered the impact on patients if the device was not available in the 
marketplace, which included delayed surgeries or treatment with a less beneficial device. 
Decision: FDA found the benefits to be high and the additional risks to be low in this situation. The 
manufacturer shared highly detailed information with FDA, which allowed FDA to better 
understand the malfunction rate and mitigation methods. After evaluating benefit and risk, the 
manufacturer developed a recall strategy, which included a correction through the communication 
that included a supplement to the labeling but did not recommend removal of the product. After 
16 
  Contains Nonbinding Recommendations 
 
conducting a Health Hazard Evaluation, FDA classified this recall as a Class II10 recall and agreed 
that the proposed correction was in the best interest of public health. FDA and the manufacturer 
continued actively monitoring the situation to determine the most appropriate long-term solution. 
Example 2: Evaluation of a variance petition related to a high benefit drug 
delivery system for which risks posed by QS issues were sufficiently mitigated 
Background: A drug delivery system was developed that included a safety feature not available 
with other medical devices. This system is programmable to automatically suspend drug delivery 
when it detects that a predefined threshold has been reached. FDA noted inspectional observations 
for deviations from the QS regulation during a PMA pre-approval inspection of the drug delivery 
system manufacturers facility. The manufacturer petitioned for a variance under section 520(f)(2) 
of the FD&C Act (21 U.S.C. 360j(f)(2)) and 21 CFR 820.1(e) from those sections of the QS 
regulation for which there were inspectional observations.  
Benefits: The medical device had a safety feature to stop drug delivery not available on medical 
devices already on the market. The unique safety feature stopped drug delivery when the medical 
device detected that continued delivery of the drug was no longer indicated and could be harmful. 
The magnitude and likelihood of benefit is high. 
Risks: Several observations of non-compliance with the QS regulation were identified during the 
pre-approval inspection. Specifically, the manufacturer did not have a well-functioning CAPA 
(corrective and preventive action) system, and several processes lacked documented procedures. 
The CAPA system observations did not have a direct impact on patient safety. For the currently 
marketed devices manufactured at the facility, there was no indication that nonconforming devices 
had been released. FDA determined that the severity and likelihood of risk related to the 
observations of non-compliance were low in this case if corrected within a certain time period, 
although this does not mean that non-compliance with CAPA regulations is generally low risk. 
Patient tolerance for risk and perspective on benefit: Data collected during clinical trials show that 
patients and caregivers highly valued the devices unique safety feature, as it greatly decreased 
overdose related fears. Patients were informed that there was a small increase in risk that they may 
be exposed to a nonconforming device and believed that the benefits of using the drug delivery 
system outweighed the risks.  
Mitigation: As part of the variance, the manufacturer agreed to resolve all of the QS violations by a 
set date, and to proactively contact all of the users of the medical device every 90 days to collect 
information about the medical device and any malfunctions that might have occurred. The 
manufacturer also agreed to investigate all complaints and provide quarterly reports detailing the 
results of its surveillance program related to the device to FDA.  
                                                           
10 Recall classification means the numerical designation, i.e., I, II, or III, assigned by the Food and Drug 
Administration to a particular product recall to indicate the relative degree of health hazard presented by the product 
being recalled. 21 CFR 7.3(m). 
17 
  Contains Nonbinding Recommendations 
 
Decision: FDA found the benefits to be high and the risks to be sufficiently mitigated in this 
situation. FDA agreed that the proposed variance plan provided methods and controls that satisfied 
FDAs concerns in the areas where the QS violations were identified and that were sufficient to 
assure that the device will be safe and effective. Given the need in the patient community for a 
medical device with the unique safety feature, FDA determined that granting the variance was in 
the best interest of the public health. 
Example 3: Continued access to nonconforming biological indicator with high 
benefit and mitigated additional risk  
Background: A biological indicator used in monitoring hospital steam sterilization was not 
performing as expected in the field. During its internal investigation of this postmarket quality 
nonconformity, the manufacturer determined that the source of the problem was with the 
manufacturing line and identified which lots were and were not impacted. The manufacturer 
initiated a voluntary recall, which it reported to FDA under 21 CFR 806.10.  FDA classified this 
recall as Class II. 
The manufacturer had no history of regulatory noncompliance. It opened a CAPA item to address 
the root cause of the problem and notified FDA that the long-term correction would result in a 
decrease in the volume of biological indicators available to hospitals. The decrease in volume was 
projected to last for 18 months. Within a few months, FDA received notification from multiple 
sources that surgeries were being delayed due to the lack of biological indicators. The 
manufacturer provided information regarding the level of certainty for successful completion of a 
sterilization cycle when using the nonconforming biological indicators in accordance with 
proposed modified labeling. After consulting with FDA, the manufacturer determined that the 
proposed labeling change was one that would require submission of a new 510(k) under 21 CFR 
807.81(a)(3).  
Benefits: The manufacturer provided information on the benefit of using the nonconforming 
biological indicators according to the modified labeling. While the benefit had decreased from the 
anticipated benefit considered for conforming biological indicators during premarket review, the 
benefit for this use of the nonconforming biological indicators remained high and included an 
assurance of sterility and a reduction in surgical delays.  
Risks: FDA considered the risks associated with use of nonconforming biological indicators. FDA 
received no reports of infection or injury related to the biological indicator or the hospital steam 
sterilizers for the time that the nonconforming biological indicator was in the field. FDA also 
recognized that a properly maintained and operated sterilizer is expected to result in effective 
sterilization cycles; the biological indicators provide confirmation. Based on the data and 
information available to FDA, the likelihood of risk of harm to patients was assessed to be low if 
the nonconforming biological indicators were used in accordance with the proposed modified 
labeling.  
Mitigation: In this situation the benefit-risk profile of the nonconforming biological indicators was 
not sufficiently positive to justify the continued use of the nonconforming device, without some 
18 
  Contains Nonbinding Recommendations 
 
additional mitigation step. The manufacturers proposal to modify labeling for the nonconforming 
devices adequately mitigated potential harm to patients.  
Patient tolerance for risk and perspective on benefit: Patient input on risks associated with the 
nonconforming biological indicators was not readily available.  
Patient impact: FDA considered the impact on patient health and quality of life if the 
nonconforming biological indicators were not available, which included delayed surgeries or 
prioritization of critical surgeries over other surgeries as a result of rationing biological indicators. 
Contact with hospitals indicated that they were seeking FDAs assistance on how best to manage 
the shortage of biological indicators needed to monitor steam sterilization cycles while still 
protecting their patients from the potential use of non-sterile devices. The hospitals expressed 
concern about a shortage. FDA considered this as well as other evidence and concurred with the 
concern. 
Decision: FDA found the benefits to be high and that the proposed modification to the labeling 
would sufficiently mitigate risk under these circumstances. In this situation, where alternatives 
were not readily available, FDA worked with the manufacturer to identify data that supported use 
of the nonconforming biological indicators with the proposed modified labeling. FDA concluded 
that it would not take action against the manufacturer for marketing the nonconforming biological 
indicators with that labeling modification while the manufacturer worked to implement its long-
term correction and while the decreased volume of conforming biological indicators continued. 
FDA determined that this course of action would provide the most beneficial option for patients 
compared to other options. Consequently, the company was able to provide the marketplace with a 
sufficient volume of biological indicators while correcting the underlying problem. 
Example 4: Malfunction of a pregnancy test with low benefit and moderate 
additional risk 
Background:  A device indicated for over-the-counter (OTC) use for the detection of human 
chorionic gonadotropin (hCG) in urine to aid in early detection of pregnancy was determined to 
have a higher rate of false positive results than expected based on performance data submitted in 
the 510(k) for the device. A malfunction was identified after healthcare providers noticed an 
increase in patients reporting positive test results when using this particular device, who were not 
then confirmed pregnant by serum beta hCG testing. The manufacturer determined that only 
specific lots were affected. Lay users would be unlikely to detect the malfunction. 
There are many similar pregnancy testing devices on the market, and FDA has no information 
suggesting that those similar devices are not performing as expected. The firm contacted FDA to 
discuss whether devices from the affected lots should continue to be available to patients. The firm 
also provided its risk management documentation assessing the benefit-risk balance for this 
situation. 
Benefits:  The device helps the patient determine whether she is pregnant. However, there are also 
many alternative devices on the market that are readily available to patients.  Because of the 
potential lack of accuracy, the benefit of the devices in the affected lots is reduced.  
19 
  Contains Nonbinding Recommendations 
 
Risks:  Women with false positive results may seek unnecessary prenatal care.  In addition, some 
OTC urine pregnancy tests are used in the health care provider setting (e.g., CLIA waived doctors 
offices, outpatient centers) to rule out pregnancy so that patients can begin treatment with certain 
drugs, or have certain procedures. False positive results could delay these treatments, some of 
which may be medically necessary. 
Patient tolerance for risk and perspective on benefit:  Patients appreciate the benefit of an OTC test 
to help them determine whether they are pregnant. FDA does not have data related to patient 
tolerance of risk for these devices. 
Mitigation:  The firm did not identify a mitigation to address the additional risk related to the 
malfunction other than removing the affected lots from the market.  
Patient impact:  FDA considered the impact on patients if the device was not available in the 
marketplace and determined that other similar devices could provide similar benefit without the 
additional risk related to the malfunction.  
Decision:  FDA found the benefits to patients for the device with the malfunction to be low.  For 
tests used in the health care provider setting, FDA found the risk to be moderate based on potential 
delay of medically necessary treatments for some patients.  After conducting independent HRAs, 
FDA and the manufacturer both concluded that there was no need to support continued availability 
for the affected lots. The firm notified retailers and distributors to remove the affected lots. The 
manufacturer appropriately reported this action to FDA per 21 CFR 806.10. FDA classified this 
recall as a Class II recall and agreed that the proposed communication to the retailers and 
distributors to discard the affected lots was in the best interest of public health. FDA and the 
manufacturer continued to actively monitor the situation to determine if additional action was 
needed. 
Example 5: Recall of a radiation therapy device with high benefit and increased 
risk for some patients  
Background: Real world evidence and other data suggest that a radiation therapy device is less 
accurate than was estimated in premarket testing.  In addition, real world evidence and other data 
have indicated that the probability of damaging healthy tissue with the device may be higher than 
other treatment options for some patients.  The higher risk patients appear to be in an identifiable 
subgroup of the original population covered by the indications for use.  The manufacturer assesses 
the issue and determines that the lower accuracy is inherent to the technology and not a result of 
issues with the particular device design or manufacturing process.    
Benefit: Both premarket data and real world evidence indicate that the device is 80% more 
effective at treating certain types of aggressive cancers than other technologies on the market, and 
the magnitude of benefit for patients with those types of aggressive cancers is high. While other 
treatment options for patients with these types of cancers are available on the market, none is as 
effective as the radiation therapy device at issue. 
Risks: The manufacturer performs a risk assessment and determines the level of risk is higher than 
anticipated for some patients due to the increased probability of damaging healthy tissue. Because 
20 
  Contains Nonbinding Recommendations 
 
the higher risk patients appear to be in an identifiable subgroup of the original population covered 
by the indications for use, the risk for patients outside of that subgroup does not appear to have 
increased. 
Mitigation: The manufacturer proposes updating its labeling with respect to accuracy of the device 
and to include a warning regarding the increased risk of healthy tissue damage for the identifiable 
subgroup.  In addition, the manufacturer proposes issuing a customer notification letter that 
includes the updated labeling for devices in the field and explains that the risk may be greater than 
originally defined for an identifiable subgroup of the original population covered by the indications 
for use.   
Patient impact: As noted above, the device is 80% more effective at treating certain types of 
aggressive cancers than other technologies on the market, thereby providing patients an option they 
did not otherwise have. Removing the device from the market would eliminate the device as a 
treatment option for patients, including those who do not appear to be at higher risk of healthy 
tissue damage based on the available data. If the device remains available, patients in the higher 
risk subgroup could be exposed to a higher risk of damage to otherwise healthy tissues if they 
receive treatment with the device.   
Decision: FDA found the benefits of the device to be high in this situation, given its more effective 
treatment of aggressive cancers compared to other available technology. Although the risk of 
damage to healthy tissue appears to be higher than expected in a subgroup of patients, the 
additional warning that the manufacturer proposes to add to the labeling will help identify patients 
who may be affected by this risk.  After reviewing the available data and the information provided 
by the manufacturer, FDA determines that the warning is important to the safe use of the device.  
FDA concurs with the manufacturers proposed recall action, which includes a correction to make 
labeling changes that the firm reports to FDA under 21 CFR 806.10.  Many patients who could 
benefit from use of the device fall outside the higher risk subgroup, and the correction would not 
prevent access to the device for those patients.   
 
B.  Examples Related to Compliance and Enforcement 
Decisions 
Example 1: Evaluating whether to send a Warning Letter or take an alternative 
approach for a low benefit, low additional risk aesthetic device 
Background: During an inspection of an aesthetic device manufacturers facility, FDA 
investigators observed, among other things, that the firm did not maintain adequate complaint files. 
Noted deficiencies in the complaint system included a backlog of complaints related to the device 
that the manufacturer had not evaluated to determine if an MDR or investigation was necessary 
and pending complaint investigations that were not resolved in a timely manner according to 
proper complaint handling processes. The manufacturer did not submit a response to the Form 
FDA 483 (FDA 483), List of Inspectional Observations issued at the close of the inspection. 
21 
  Contains Nonbinding Recommendations 
 
Benefits: Reported clinical studies demonstrated that some patients treated saw long-term aesthetic 
improvement. The magnitude and likelihood of benefit for the device was assessed to be moderate. 
However, the device was not medically necessary, and there was no evidence that it provided a 
unique treatment effect or benefit compared to similar devices on the market.  
Risks: Available information indicated that the likelihood and severity of risk for similar devices 
was low. During the inspection, however, the FDA investigators review of a sample of the 
complaints received for the device at issue indicated that some patients had experienced adverse 
events of varying severity. Based on the information in those complaints, it was unclear if those 
adverse events may have been caused by use of the device. Without additional information, FDA 
could not determine the likelihood of risk for the device. 
Patient tolerance for risk and perspective on benefit: There was information indicating that patients 
preferred similar devices on the market. 
Uncertainty: The significant deficiencies in the manufacturers complaint system created 
uncertainty about the risks for this device: the manufacturer could not provide complete 
information regarding the number of complaints involving adverse events and the failure to timely 
and adequately evaluate complaints may have allowed malfunctions, defects, or other 
nonconformities to go undetected. 
Patient impact: FDA determined that there would be no substantial negative impact for patients if it 
issued a Warning Letter. Patients or healthcare professionals reluctant to choose a device for which 
a Warning Letter has been issued would have alternative products available, and there was not a 
strong patient preference for the device.  
Firm compliance history: Some of FDAs observations related to the manufacturers complaint 
handling system were repeat observations that had been noted during the previous inspection.  
Decision: After considering the relevant benefit factors in aggregate, FDA found the benefit to 
patients to be low and the potential additional risk to be low; however, FDA did not have a high 
degree of certainty in the level of risk for the device. After thorough evaluation, FDA decided to 
issue a Warning Letter to the firm and to investigate further whether the device may have caused 
adverse events. Although the device provided a benefit, that benefit was available to patients 
through alternatives, and there was significant uncertainty regarding the likelihood of risk for the 
device. In addition, the failure to correct previously noted deficiencies in its complaint system and 
the failure to respond to the FDA 483 indicated that other forms of communications with the firm 
might be ineffective for achieving compliance and minimizing risk to patients. If, after gathering 
further information regarding adverse events, FDA determined that the device presented a higher 
risk to patients, the Agency would consider taking additional action, including action to limit 
availability of the device. 
Example 2: Evaluation of potential actions following an inspection with 
observed QS deficiencies regarding a high benefit spinal fixation system  
Background: FDAs inspection of a manufacturing facility for a spinal fixation system intended for 
posterior, non-cervical pedicle fixation resulted in the issuance of an FDA 483, which noted, 
22 
  Contains Nonbinding Recommendations 
 
among other things, two complaint records that lacked evaluations to determine if an MDR was 
required to be filed, a CAPA record with no documentation of an investigation, and deficiencies in 
a process validation. This was FDAs first inspection of the facility, and some deficiencies were 
more significant than others, although none of the deficiencies were significant enough to warrant 
a Warning Letter. FDA conducted a benefit-risk analysis as part of its evaluation of whether to 
issue an Untitled Letter or to engage with the firm in a less formal manner, such as in a regulatory 
meeting. 
Benefits: This firms particular spinal fixation system had unique features that made it less invasive 
and therefore associated with a shorter surgical time than other devices of its type. Clinical studies 
included in the premarket submission for the device demonstrated patient benefits, including 
quicker recovery and reduced postsurgical pain. The magnitude and likelihood of the benefit for 
this device were assessed to be high. 
Risks: The two complaints that lacked an evaluation for whether an MDR must be submitted did 
not involve a death or serious injury, and searches of FDAs Manufacturer and User Facility 
Device Experience (MAUDE) database revealed no MDRs reporting that the device may have 
caused or contributed to a death or serious injury. The likelihood of risk to patients was assessed to 
be low. FDA reviewed the firms data during and after the inspection and determined that the data 
were within the expected specifications for the device. There was no indication that nonconforming 
product had been released.  
Patient tolerance for risk and perspective on benefit: FDA considered patient input. Patients 
expressed a strong preference for this spinal fixation system because of the reduction in pain and 
recovery time.  
Mitigation: The firms responses to the FDA 483 issued at the end of the inspection indicated the 
firms identification and early implementation of voluntary corrective actions that appeared to be 
significant steps to achieve compliance.  
Nature of violations/Nonconforming product: In addition, the inspection did not reveal evidence of 
widespread QS deficiencies or nonconformities that were attributed to other QS failures. 
Firm compliance history: This manufacturer had no history of regulatory non-compliance. 
Decision: FDA found the benefit to patients to be high and the potential additional risk from the 
QS deficiencies to be low. Since, among other things, the firms data were within the expected 
specifications for the device, FDA determined that there was low risk to patients associated with 
the inspectional observations. After careful consideration of all available information, including 
real world evidence, FDA pursued a regulatory meeting with the firm instead of issuing an Untitled 
Letter to address the manufacturers inspectional deficiencies. FDA decided that, in this lower risk 
situation, a regulatory meeting would be the most efficient means of achieving compliance, as it 
would engage the manufacturer in a dialogue on its proposed corrections/corrective actions and 
help mitigate potential additional risk from the QS deficiencies. If the manufacturer fails to 
progress toward voluntary compliance in a timely manner, then FDA may consider conducting a 
follow-up inspection, issuing a Warning or Untitled Letter, or other consequences. 
23 
  Contains Nonbinding Recommendations 
 
Appendix A - Intersection of this Guidance with ISO 14971: 
Medical devices  Application of risk management to medical 
devices 
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 life cycle. 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 life 
cycle. 
ISO 14971 is an FDA-recognized standard, and assuring conformity with this standard may help 
device manufacturers meet the requirements specified in the design controls section (21 CFR 
820.30) and other sections of 21 CFR Part 820. Both ISO 14971 and 21 CFR Part 820 take a total 
life cycle approach to management of risks associated with medical devices, and expect that 
manufacturers will incorporate postmarket data into their device risk management process, 
including new and changes to existing risks identified after the device is on the market. There may 
be benefits to manufacturers in incorporating ISO 14971 into their quality management system. 
The concepts within ISO 14971 and output from a firm's quality management system that 
incorporates ISO 14971 may be used as inputs to benefit-risk assessments described in this 
guidance document. 
This guidance document provides a benefit-risk framework for FDA and stakeholders regarding 
use of benefit-risk information in medical device product availability, compliance, and 
enforcement decisions. This guidance documents focus is supporting these types of decisions, and 
the risk management language used in this guidance document is not completely harmonized with 
ISO 14971.  Good documentation of risk management decisions by manufacturers using an ISO 
14971 based risk management process may help to streamline medical device product availability, 
compliance, and enforcement decisions for both FDA and manufacturers, produce outcomes for 
patients that deliver the most benefit for the least amount of risk, and provide a reasonable 
assurance of safety and effectiveness. 
24 
  Contains Nonbinding Recommendations 
 
Appendix B - Worksheets for Benefit Assessments 
The following worksheet identifies factors that may be considered in the assessment of benefit for product 
availability, compliance and enforcement decisions across the total product life cycle. This worksheet is 
intended to support consideration of the factors by FDA staff and industry; its use is optional. 
Anticipated benefit  Initial assessment during design  Current assessment 
and testing 
Type of benefit(s)   What is the medical devices  Using real world data or other 
anticipated impact on clinical  available data, what is the medical 
management and patient health?  devices impact on clinical 
What benefits were initially  management and patient health? 
anticipated?   Does the marketed product achieve 
Was a clinical trial conducted?  the anticipated benefits? 
What benefits were expected based on  Have additional benefits been 
similar devices?  observed? 
Magnitude of benefit(s)   For each benefit assessed:   For each benefit assessed:  
What was the medical devices  What is the medical devices impact 
originally anticipated impact on  on patient health and clinical 
patient health and clinical  management? 
management?  Is the effect of the device on patient 
What was the originally anticipated  management and quality of life, 
effect of the device on patient  likelihood of survival, improving 
management and quality of life,  patient function, preventing loss of 
likelihood of survival, improving  function, or providing relief from the 
patient function, preventing loss of  symptoms of the disease or 
function, or providing relief from the  condition as anticipated? 
symptoms of the disease or condition?  Did the magnitude of each treatment 
What was the anticipated magnitude  effect increase or decrease?  
of each treatment effect?   For each benefit assessed, do real 
What scale is used to directly measure  world data demonstrate the same 
the anticipated benefit?   rate of successful diagnosis or 
How did the anticipated benefit rank  treatment? 
on that scale?  Has the benefit rank on that scale 
Is the device life supporting or life  increased or decreased over time? 
sustaining?  Has real world practice led to new 
benefits? 
25 
  Contains Nonbinding Recommendations 
 
Anticipated benefit Initial assessment during design  Current assessment
and testing
Likelihood of patients  What proportion of patients was  Using real world data or other 
experiencing one or  expected to benefit from the device?  available data, what proportion of 
more benefits   Did the original labeling indicate  patients have been observed to 
which patients will experience a  benefit from the device? 
benefit?   Has the likelihood of a patient 
How did the benefits assessed vary  within a subpopulation experiencing 
across subpopulations?   benefit changed? 
Was there a variation in public health  Has there been a change in variation 
benefit for different populations?  of benefits across sub-populations?  
Has use of the medical device 
exposed a variation in public health 
benefit for different populations? 
Duration of effects   Does the device cure a disease or  Is the duration of effect consistent 
provide a temporary treatment?   with the anticipated duration of 
Could the duration, if relevant, of  effect? 
each treatment effect, be determined?   Were there assumptions that proved 
If so, what was it?  to be inaccurate?  
Patient perspective on  What is the severity of the disease  What is the severity of the disease 
benefit  state?  state? 
Is this a chronic disease?  Is this a chronic disease? 
If chronic, can the illness be managed  If chronic, can the illness be 
with other treatments or therapies?  managed with other treatments or 
How long do patients live with the  therapies? 
disease?  How long do patients live with the 
Even if the benefit is in a small  disease? 
portion of the population, do those  Even if the benefit is in a small 
patients who would experience the  portion of the population, do those 
benefit value it?  patients who would experience the 
Is the duration of the benefit achieved  benefit value it? 
of value to patients?  Is the duration of the benefit 
How much do patients value this  achieved of value to patients? 
treatment?   How much do patients value this 
Does the treatment improve overall  treatment?  
quality of life?   Does the treatment improve overall 
Are the benefits of the medical device  quality of life?  
well understood?  Are the benefits of the medical 
Is communication regarding change in  device well understood? 
benefit realistic?  Is communication regarding change 
in benefit realistic? 
Benefit factors for  Were there anticipated benefits to  Does real world experience change 
healthcare professionals  healthcare professionals or  the understanding of benefits to 
or caregivers  caregivers?  healthcare professionals or 
caregivers? 
26 
  Contains Nonbinding Recommendations 
 
Anticipated benefit Initial assessment during design  Current assessment
and testing
Medical necessity  Is the device essential to the survival  Is the device essential to the survival 
of patients?  of patients? 
Are alternative treatments available?  Are alternative treatments available? 
What other therapies are available for  What other therapies are available 
this condition?   for this condition?  
For appropriate treatment, is it  How effective are the alternative 
critical that the device be used  treatments?  
without interruption?  How well-tolerated are the 
How effective are the alternative  alternative therapies?  
treatments?   How have treatment options 
How well-tolerated are the alternative  changed since medical device 
therapies?   development? 
27 
  Contains Nonbinding Recommendations 
 
 
Appendix C - Worksheets for Risk Assessments 
The following worksheet identifies factors that may be considered in the assessment of risk for 
product availability, compliance and enforcement decisions across the total product life cycle. This 
worksheet is intended to support consideration of the factors by FDA staff and industry; its use is 
optional. 
Initial assessment  Current assessment 
Risk categories 
during design and 
testing 
Factors Related to Severity of Harm 
Medical device-related deaths and  What serious adverse  Do real world data or other 
serious injuries   events related to this  available data show that medical 
medical device were  device-related deaths or serious 
known when FDA  injuries have occurred at expected 
authorized the device  severity? 
for marketing?  Are there unanticipated deaths or 
Were there any  serious injuries? 
variations in serious  Were there any changes or 
adverse events among  variations of serious adverse 
subpopulations?  events among subpopulations? 
Medical device-related non- What non-serious  Have temporary injuries related to 
serious adverse events  adverse events related  the medical device occurred at 
to this medical device  expected severity? 
were known at medical  Have medical device-related 
device clearance or  injuries which could be medically 
approval?  reversed occurred at expected 
Were there any  severity and frequency? 
variations in temporary  Are there any unanticipated 
injury and medically  temporary injuries or medically 
reversible injuries  reversible injuries? 
among  Were there any changes in 
subpopulations?  variations in serious adverse 
How long does the  events among subpopulations? 
harmful event last?   Is the duration of harmful events 
Is the harmful event  longer than anticipated?  
reversible?   Is the harmful event still 
What type of  reversible?  
intervention is needed  Has the type of intervention 
to address the harmful  needed to address the harmful 
event?  event changed? 
28 
  Contains Nonbinding Recommendations 
 
 
Medical device-related events  What medical device  Are there reports of medical 
without reported harm  malfunctions were  device malfunctions? 
anticipated when FDA  Are device malfunctions occurring 
authorized the device  at anticipated frequencies? 
for marketing?  Is the medical device 
Were there any  malfunctioning in a manner that 
variations in medical  was not anticipated? 
device events reported  Were there any changes in 
without harm among  variations in medical device 
subpopulations?  events reported without harm 
among subpopulations? 
Additional Risk Factors 
Likelihood of Risk  How frequently did the  How frequently does this specific 
manufacturer  failure mode or defect occur? 
anticipate this specific  Has the rate of medical device 
failure mode or defect  failures increased? 
would occur?  Has the mean time between 
failures decreased? 
How many medical devices are 
expected to have a problem? 
What proportion of patients 
treated with or diagnosed by the 
nonconforming medical device is 
harmed? 
How many patients were exposed 
to nonconforming devices? 
How many patients were exposed 
to a device manufactured by a 
noncompliant manufacturer? 
Distribution of Nonconforming  Has nonconforming product been 
Devices  distributed? 
What is the number of units on the 
market and market share? 
Duration of the exposure to the  How much time elapsed between 
population  initial exposure to a risk of harm 
and the point at which the risk of 
harm is successfully addressed? 
How long were affected 
populations exposed to the 
nonconforming device? 
  
29 
  Contains Nonbinding Recommendations 
 
 
Risk from false-positive or false- What are the  Have the consequences of 
negative results for diagnostics   consequences of a  diagnostic errors changed? 
false positive?   Have the practices related to 
What are the  diagnosing the problem changed? 
consequences of a  Does this increase or decrease the 
false negative?   risk? 
Is this the only means 
of diagnosing the 
problem, or is it part of 
an overall diagnostic 
plan? 
Patient tolerance of risk  What level of concern  What level of concern do patients 
do patients have  have regarding the risks? 
regarding the risks?  Even if the risk is in a small 
Even if the risk is in a  portion of the population, do those 
small portion of the  patients who would experience the 
population, do those  risk understand it? 
patients who would  Are patients willing to take the 
experience the risk  risk of this treatment to achieve 
understand it?  the benefit?  
Are patients willing to  How well are patients able to 
take the risk of this  understand the risks of the 
treatment to achieve  treatment?  
the benefit?  
How well are patients 
able to understand the 
risks of the treatment?  
Risk Factors for healthcare  Are there risks to the  Are there any changes in 
professionals or caregivers  healthcare professional  frequency or severity of risks for 
or caregiver?  healthcare professionals and/or 
How significant are  caregivers? 
these risks?  Do any changes in the frequency 
or severity of risk for the 
healthcare provider or caregiver 
impact the risks to the patient? 
30 
  Contains Nonbinding Recommendations 
 
 
Appendix D - Worksheet for assessing potential decisions 
based on the Benefit-Risk Assessment Outcome 
The following worksheet identifies additional factors that may be considered for product 
availability, compliance and enforcement decisions at all phases of the total product life cycle. This 
worksheet is intended to support consideration of the factors by FDA staff and industry; its use is
optional.  
Factors  Assessment Questions 
Uncertainty  What information does FDA have to assess benefit and risk? 
What is the quality of the information FDA is using (for 
example, MDRs, literature, registry or clinical trial data, limited 
case studies, inspectional data etc.)? Is the quality of information 
a reliable source for making an objective and unbiased benefit or 
risk decision? 
What is the uncertainty related to current understanding of 
benefits and risks? 
Mitigations   Could you identify ways to mitigate the risks such as using 
product labeling, establishing education programs, etc.?  
What is the type of mitigation proposed?  
Is the intervention related to design, labeling, or training? 
Has the manufacturer corrected the cause of the nonconformity? 
Detectability  Can the user easily recognize the hazard to avoid the harm? 
Can the problem with the medical device be corrected before use 
by the user? 
Failure Mode   Has the manufacture identified the underlying cause? 
Has the firm submitted testing to the FDA? 
Has FDA conducted testing? What were the results? 
Scope of the device issue  Are the risks identified potentially inherent to similar medical 
devices of this type (i.e., industry wide)? 
Patient impact  What are the risks to patients if the device is not available? 
Are patients better off if the device is available? 
What is the potential impact on patients related to the 
inspectional observation or regulatory non-compliance? 
Does the observation or violation directly relate to product 
quality? 
Does the observed regulatory non-compliance raise concerns 
regarding the firms ability to produce safe and effective medical 
devices? 
Preference for availability  Would patients and caregivers prefer to have access to the 
device? 
Are the benefits and risks adequately understood? 
31 
  Contains Nonbinding Recommendations 
 
 
Nature of  Was the violation systemic or non-systemic in nature? 
violations/Nonconforming  To what extent are the products nonconforming? 
product 
Firm compliance history   Has the same or a similar inspectional observation or regulatory 
violation been observed at the manufacturer in the past 2 years? 
In the past 5 years? In the past 10 years? 
Does the firm have a history of regulatory compliance and high 
quality device production? 
Has the firm demonstrated chronic and systematic regulatory 
non-compliance over time? 
Is the regulatory non-compliance significant enough that FDA 
would take regulatory action? 
Was the harm anticipated in the firm risk management 
documentation? 
Was the harm reported to FDA by the firm quickly? 
Would providing notice to the firm assist in informing the firm of 
its legal responsibilities? 
32