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Conference Number: PWXW9487331
Consideration of Uncertainty in Making Benefit-Risk 

Determinations in Medical Device Premarket Approvals, 

De Novo Classifications and Humanitarian Device 

Exemptions - Final Guidance

Pablo Morales

Chief Medical Officer

Division of Circulatory Support, Structural and Vascular Devices

Office of Cardiovascular Devices

Office of Product Evaluation and Quality

Charles Viviano, MD, PhD

Deputy Office Director/Medical Officer

Office of Gastrorenal, ObGyn, General Hospital and Urology Devices

Office of Product Evaluation and Quality 

Center for Devices and Radiological Health

October 16, 2019
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o Objectives and Background

o CDRH’s Benefit-Risk Guidances

o Uncertainty and Benefit-Risk

o Scope of the Guidance 

o Factors When Considering Uncertainty in Benefit-Risk Determinations

o Application: Breakthrough Devices Subject to PMA

o Mitigations for Greater Uncertainty

o Application: Devices for Small Patient Populations Subject to PMA

o Examples

o Resources and Questions

Agenda
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Objectives

o Understand how uncertainty fits within the FDA’s 

Benefit-Risk Framework

o Understand the factors the FDA considers in assessing 

the appropriate extent of uncertainty about a device’s 

benefits and risks

o Understand how these factors are applied 

o Breakthrough Devices

o Devices for Small Populations
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Background

o The “Uncertainty Guidance” supplements existing 

Benefit-Risk Guidance Documents and Policies

o Provides further clarity on factors to consider related 

to uncertainty in benefit-risk determinations

o Outlines a rigorous, methodical approach for the 

consideration of uncertainty

www.fda.gov
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Background

o Focuses on the balance between acceptable 

uncertainty in the premarket setting and postmarket 

setting

o The appropriate extent of uncertainty used in benefitrisk determinations to support premarket decisions is 

flexible and depends on multiple varying factors

o Provides a framework for determining what data 

collection is appropriate at the right time (for example, 

premarket vs. postmarket)

www.fda.gov
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CDRH’s Benefit-Risk Guidances

• Factors to Consider When Making Benefit-Risk 

Determinations in Medical Device Premarket Approval 

and De Novo Classifications

• Benefit-Risk Factors to Consider When Determining 

Substantial Equivalence in Premarket Notifications 

(510(k)) with Different Technological Characteristics

• Factors to Consider When Making Benefit-Risk 

Determinations for Medical Device Investigational 

Device Exemptions

• Factors to Consider Regarding Benefit-Risk in Medical 

Device Product Availability, Compliance, and 

Enforcement Decisions
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Uncertainty and Benefit-Risk

o The FDA considers the totality of evidence regarding 

the extent of probable benefits and extent of 

probable risks of a device, including the extent of 

uncertainty in the benefit-risk information 

o The FDA also considers the appropriateness of risk 

mitigations and the collection of postmarket data to 

address uncertainty in benefit-risk information
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o There can be uncertainty around the type, 

magnitude, duration, frequency, and other 

aspects of a device’s benefits and risks to 

patients

Uncertainty and Benefit-Risk (Cont’d) 
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“This guidance recognizes that to meet FDA’s mission to 

promote the public health in light of inherent 

uncertainties involved in the provision of medical care, it 

is important to acknowledge and appropriately address 

uncertainty in benefit-risk determinations supporting 

certain FDA premarket decisions, based on the factors 

outlined below and the specific context.”

Uncertainty and Benefit-Risk (Cont’d) 
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Scope of the Guidance 

o Applies to the FDA’s consideration of 

uncertainty in benefit-risk determinations for 

Premarket Approval Applications (PMA), De 

Novo requests, and Humanitarian Device 

Exemption (HDE) applications

o Examples include PMAs for Breakthrough Devices 

and PMAs for devices intended for small patient 

populations
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Factors When Considering Uncertainty in 

Benefit-Risk Determinations

o The appropriate extent of uncertainty in benefit-risk 

determinations to support premarket decisions is 

flexible and depends on multiple varying factors.

o The balance between the appropriate extent of 

uncertainty in the premarket setting, relative to a 

product’s probable benefits and risks – and, in turn, 

how much reliance the FDA can place on postmarket 

follow-up studies – is determined by these factors. 
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Factors When Considering Uncertainty 

in Benefit-Risk Determinations (Cont’d) 

o The extent of the probable benefits of the device, 

taking into account the type, magnitude, probability, 

duration, and frequency of those benefits, including if 

the probable benefits are greater than those of 

approved or cleared alternative treatments or 

diagnostics or the standard of care
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Factors When Considering Uncertainty in 

Benefit-Risk Determinations (Cont’d) 

o The extent of the probable risks of the device, taking 

into account the severity, type, number, rates, 

probability, and duration of those risks, including if the 

probable risks are less than those of approved or 

cleared alternative treatments or diagnostics or the 

standard of care
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Factors When Considering Uncertainty in 

Benefit-Risk Determinations (Cont’d) 

o The extent of uncertainty regarding the benefit-risk 

profile of approved or cleared alternative treatments 

or diagnostics or the standard of care (for example., 

the strength of the evidence supporting the alternative 

treatment or diagnostic)
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Factors When Considering Uncertainty 

in Benefit-Risk Determinations (Cont’d) 

o Patients’ perspective on appropriate uncertainty about 

the probable benefits and risks of the device, if 

available

o See the FDA’s Guidance Patient Preference Information 

- Voluntary Submission, Review in Premarket Approval 

Applications, Humanitarian Device Exemption 

Applications, and De Novo Requests, and Inclusion in 

Decision Summaries and Device Labeling
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Factors When Considering Uncertainty in 

Benefit-Risk Determinations (Cont’d) 

o The extent of the public health need (for example, 

seriousness of the illness; benefit-risk profile of other 

available therapeutics or diagnostics, if any, including 

the current standard of care; the portion of the target 

population for whom there would be a positive 

benefit-risk profile)
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Factors When Considering Uncertainty in 

Benefit-Risk Determinations (Cont’d) 

o The feasibility of generating extensive clinical evidence 

premarket based on appropriate considerations (for 

example, taking into account the prevalence of the 

disease or condition)
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Factors When Considering Uncertainty in 

Benefit-Risk Determinations (Cont’d) 

o The ability to reduce or resolve remaining uncertainty 

of a device’s benefit-risk profile postmarket (for 

example, consideration of the FDA’s authority to 

require postmarket data collection and the likelihood 

that the necessary postmarket data collection will be 

completed within reasonable timeframes)
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Factors When Considering Uncertainty in 

Benefit-Risk Determinations (Cont’d) 

o The likely effectiveness of mitigations, such as labeling, 

and other tools to help provide a reasonable assurance 

of safety and effectiveness of the device, as applicable
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Factors When Considering Uncertainty in 

Benefit-Risk Determinations (Cont’d) 

o The type of decision being made (for example, there is 

generally likely to be more uncertainty surrounding a 

device’s benefit-risk profile based on the evidence 

submitted in an HDE application, as compared to a 

PMA, because the standards for approval are different) 
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Factors When Considering Uncertainty in 

Benefit-Risk Determinations (Cont’d)

o The probable benefits of earlier patient access to the 

device

o The FDA’s consideration of these factors should be 

consistent with the FDA’s statutory and regulatory 

authorities and requirements 
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Application: Breakthrough Devices Subject to PMA

o Breakthrough Devices, by their nature, generally have 

the potential to address unmet needs in serious 

conditions, and patients generally may be more willing 

to accept greater uncertainty in benefits and risks with 

respect to such products

o To meet the statutory standards for approval, including 

that the device’s probable benefits outweigh its probable 

risks, the FDA may accept greater uncertainty regarding 

the device’s probable benefits and risks, when 

appropriate, because of the greater probable public 

health benefits of earlier patient access
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Application: Breakthrough Devices Subject to PMA 

(Cont’d) 

o If greater uncertainty is deemed appropriate, certain 

postmarket controls might be necessary:

• Timely postmarket data collection

• Transparency

• Accountability
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Mitigations for Greater Uncertainty

o Timely Postmarket Data Collection

• Require a postmarket study as a condition of approval 

within a specific, appropriate timeframe

• Ensure the FDA expectations are explicit in 522 orders and 

PMA/HDE conditions of approval

o Transparency

• Labeling to describe when postmarket data collection is 

required to address greater uncertainty

• Include this info in the Summary of Safety and 

Effectiveness (SSED), Summary of Safety and Probable 

Benefit (SSPB), or De Novo Transparency Summary
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Mitigations for Greater Uncertainty (Cont’d) 

o Accountability

• Hold an advisory committee meeting: If we have 

questions about whether postmarket data continues to 

support a reasonable assurance of safety and 

effectiveness

• Taking into account committee recommendation and 

postmarket data, consider issuing a withdrawal order or 

certain restrictions on sale/distribution or narrow 

indications for use
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Application: Devices for Small Patient 

Populations Subject to PMA

o Because of the rarity of the disease or condition, it 

is generally infeasible or highly resource or time 

intensive to generate extensive clinical evidence 

premarket, and

o There is an unmet medical need that is addressed 

by the device, such as there are no available 

therapeutics or diagnostics for that patient 

population
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Application: Devices for Small Patient Populations 

Subject to PMA (Cont’d)

o When not eligible for Breakthrough or HDE status

o While there is not a specific number of patients that 

would be considered a “small patient population,” 

this approach could be used for patients with a rare 

disease or condition or for patients within a 

clinically meaningful subset of a broader population
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Example 1: Breakthrough Devices - PMA 

DEVICE: Breakthrough Device intended to treat a currently 

treatment-resistant condition 

PERFORMANCE GOAL = 70% in a proposed premarket single arm study

Assess for “conventional,” modest, and high extent of uncertainty 

in the clinical trial reflected by the one-sided significance level 

manifest by difference in sample size with implementation of 

appropriate postmarket controls
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Example 1: Breakthrough Devices – PMA (Cont’d) 

SCENARIO 1 – CONVENTIONAL UNCERTAINTY

Based upon Factors above and other relevant information, the FDA is not 

willing to accept additional uncertainty in premarket study design

o 1-sided significance = 2.5%

o Observed Performance Goal (PG) = 74%

o Expect sample size = 535 subjects to be 97.5% confident the PG is 

above 70%
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Example 1: Breakthrough Devices - PMA (Cont’d) 

SCENARIO 2 – MODEST UNCERTAINTY

Based upon Factors above and other relevant information, the FDA is 

willing to accept additional modest uncertainty in premarket study 

design with resulting modest pre- to postmarket shift

o 1-sided significance = 5%

o Observed Performance Goal = 74%

o Expect sample size = 385 subjects to be 95% confident the PG is above 

70%

o “Modest” postmarket study as Condition of Approval, noted on 

website
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Example 1: Breakthrough Devices - PMA (Cont’d) 

SCENARIO 3 – HIGH UNCERTAINTY

Based upon Factors above and other relevant information, the FDA is willing to 

accept additional high uncertainty in premarket study design with significant 

pre- to postmarket shift

o 1-sided significance = 20%

o Observed Performance Goal = 74%

o Expect sample size = 125 subjects to be 80% confident the PG is above 70%

o Robust postmarket study with reliable source (for example., registry) to 

assure data collection

o Condition of Approval that postmarket study noted in labeling, Summary of 

Safety and Effectiveness (SSED), and on website, as appropriate
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Example 2: Devices for Small Patient Populations – PMA 

DEVICE: Intended to treat a disease with incidence of 10,000 new 

cases annually

o Not a Breakthrough Device, because the disease is not life-threatening 

or irreversibly debilitating

o Indicated disease is serious

o No available therapies

o Acceptable Performance Goal = 60%
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Example 2: Devices for Small Patient Populations - PMA 

(Cont’d)

SCENARIO 1 – CONVENTIONAL UNCERTAINTY

Based upon Factors above and other relevant information, the FDA is not 

willing to accept additional uncertainty in premarket study design

o 1-sided significance = 2.5%

o Observed Performance Goal = 66%

o Expect sample size = 274 subjects to be 97.5% confident the 

Performance Goal is above 60%
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Example 2: Devices for Small Patient Populations- PMA (Cont’d) 

SCENARIO 2 – MODEST UNCERTAINTY

Based upon Factors above and other relevant information (patient recruitment 

would be challenging and a conventional premarket study appears infeasible), 

the FDA is willing to accept additional modest uncertainty in premarket study 

design with resulting modest pre- to postmarket shift

o 1-sided significance = 10%

o Observed Performance Goal = 66%

o Expect sample size = 128 subjects to be 90% confident the Performance Goal 

is above 60%

o “Modest” postmarket study as Condition of Approval, noted on website
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Example 2: Devices for Small Patient Populations- PMA 

(Cont’d) 

SCENARIO 3 – HIGH UNCERTAINTY

Based upon Factors above, relevant information above, and there is a reliable 

source of postmarket data (for example., registry), the FDA is willing to accept 

additional high uncertainty in premarket study design with significant pre- to 

postmarket shift

o 1-sided significance = 20%

o Observed Performance Goal = 66%

o Expect sample size = 65 subjects to be 80% confident the Performance Goal 

is above 60%

o Robust postmarket study with reliable source (for example., registry) to 

assure data collection

o Condition of Approval that postmarket study noted in labeling, Summary of 

Safety and Effectiveness (SSED), and on website, as appropriate
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o Factors to Consider When Making Benefit-Risk Determinations in 

Medical Device Premarket Approval and De Novo Classifications, issued 

August 30, 2019 

o Benefit-Risk Factors to Consider When Determining Substantial 

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

Technological Characteristics, issued on September 25, 2018

o Factors to Consider When Making Benefit-Risk Determinations for 

Medical Device Investigational Device Exemptions, issued on January 13, 

2017

o Factors to Consider Regarding Benefit-Risk in Medical Device Product 

Availability, Compliance, and Enforcement Decisions, issued on 

December 27, 2016

Resources
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Questions?

Division of Industry and Consumer Education: 

DICE@fda.hhs.gov

Slide Presentation, Transcript and Webinar 

Recording will be available at:

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Under Heading: How to Study and Market Your 

Device; Sub-Heading: Cross-Cutting Premarket 

Policy 

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