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Factors to Consider When Making 

Benefit-Risk Determinations for Medical 

Device Investigational Device 

Exemptions (IDEs): Final Guidance

Karen Ulisney, M.S.,CRNP

Policy Analyst

Clinical Trials Program 

Office of Device Evaluation

Center for Devices and Radiological Health

February 23, 2017 CDRH Webinar
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Agenda

• Highlights and Scope of Final Guidance

• Differences Between Draft and Final Guidance 

• Overview of selected Benefit-Risk (B-R) Guidance Sections

Regulatory Standards and Subject Protections For IDE’s 

B-R Framework Applied To Stages of Device Development

Assessing Benefits and Risks For IDE Applications – Risk 

Characterization and Risk Management

Appendix A – Recommended General Framework for B-R 

Assessment 

• Questions 
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Highlights of Final Guidance

• Contributes to FDA’s on-going efforts to improve patient access 

to new devices by strengthening and streamlining clinical trials.

• Clarifies the principal factors that FDA considers when assessing 

the benefits and risks of medical devices in IDE submissions to 

improve transparency, predictability and consistency of this 

process.

• Does not propose to revise the sponsor requirements for 

providing a Benefit-Risk analysis as part of an IDE application or 

the way FDA reviews IDE submissions. 
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Scope

Diagnostic 

Therapeutic 

IDE’s

(21 CFR 812) 

IDEs for New 

Devices

Amendments 

Supplements 

To IDEs

IDEs For New 

Indications 
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Differences Between Draft and Final Guidance

• Minor changes included clarification on terminology and modify 

language to align with our regulations. 

• Minor modifications to the text and the examples to clarify how 

study design considerations, the stage of device development 

and incorporation of patient preference principles and tools can 

impact the B-R assessment.
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Regulatory Standards for IDEs

Regulations that apply to the review of IDE applications in the 

context of B-R and grounds for disapproval:

 21 CFR 812.30(b)(4) “There is reason to believe that the risks to the 

subjects are not outweighed by the anticipated benefits to the 

subjects and the importance of the knowledge to be gained, or 

informed consent is inadequate, or the investigation is scientifically 

unsound, or there is reason to believe that the device as used is 

ineffective” 

 21 CFR 812.30(b)(5) “It is otherwise unreasonable to begin or to 

continue the investigation owing to the way in which the device is 

used or the inadequacy of (i) the report of prior investigations or the 

investigational plan; (ii) the methods, facilities, and controls used for 

the manufacturing, processing, packaging, storage, and where 

appropriate, installation of the device; or (iii) monitoring and review 

of the investigation”
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Regulatory Standards for IDEs

A Key principle of subjects protections in Clinical Investigations is 

the Informed Consent Process

Sponsors are required to address B-R in the clinical study Informed 

Consent Document– 

 21 CFR 50.25 Basic elements of informed consent. In seeking 

informed consent, the following information shall be provided 

to each subject:...

(2) A description of any reasonably foreseeable risks or discomforts 

to the subject. 

(3) A description of any benefits to the subject or to others which 

may reasonably be expected from the research. 
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B-R Framework Applied To Device 

Development Regulatory Pathway

EFS Traditional

Feasibility

Pivotal Post Market

Uncertainty 

Stages of Device Development
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How Does the B-R Assessment For IDEs 

Differ From B-R assessment For Marketing 

Applications? 

• Clinical investigations by definition are research studies with 

greater uncertainty regarding :

 Relative benefits and risks of a given device

 Device technology

 Treatment with the Device

• Less evidence available for IDE applications compared to 

marketing submissions.

• Benefits of the research study are considered directly to the 

subject and to others (e.g., indirect – knowledge to be gained 

from research or contribute to developing treatments)
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Assessing Benefits and Risks in the IDE 

Realm 

BENEFITS RISKS

Type 

Magnitude

Probability

Duration

Type /Severity 

Likelihood

Duration

Management

Risk Controls/ 

Mitigation
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Assessing Risks for IDE Applications

21 CFR 812.25

The investigational plan shall include...

(c) Risk analysis. 

• a description and analysis of all increased risks to which 

subjects will be exposed by the investigation; 

• the manner in which these risks will be minimized; 

• a justification for the investigation; 

• and a description of the patient population, including the 

number, age, sex, and condition.
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Risk Management 

The B-R Guidance incorporates the principles from ANSI/AMMI/ISO 

14971: Application of risk management to medical devices

• ISO 14971 describes a process through which the medical device 

manufacturer can...estimate and evaluate risks, control these 

risks, and monitor the effectiveness of those controls through 

the product’s lifecycle. 
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Assessing Risks for IDE Applications

Assessing Risk of the Investigation:

• Harms – Specifying how a hazard could lead to clinical sequelae 

including length of time experienced and residual affect (if any) 

or other harmful event

• Likelihood – Focusing on severity of a risk along with likelihood 

is important for a complete estimation of that risk.

• Residual risk and completeness of risk control – Many identified 

risks are reduced to an acceptable level through effective risk 

controls. 
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Assessment of Risk to Study Subjects

• Focus on risks supported by objective scientific evidence and are 

reasonably foreseeable

• Include a description and analysis of incremental risks subjects 

will be exposed to in the study and how the risks will be 

minimized

• Describe the relationship between Hazards (potential source of 

harm) and ultimate Harm (injury or damage)
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Assessment of Risk – Characterization

The extent of risk(s)/harm(s) in an IDE study takes into account the 

following factors, individually and in aggregate:

1. Type of Risk(s) (including severity) – Basic safety, device-related 

serious and non-serious adverse events, procedure-related 

complications due to the investigation, risk associated with the 

study itself (not resulting directly from use of the device), and Risk 

from false-positive or false-negative results for diagnostics.
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Assessment of Risk – Characterization

2. Probability or Likelihood of Risk(s) – Use of relevant historical 

data, prediction using analytical or simulation techniques, use of 

data from prior investigations, reliability estimates, production 

data and post production information, and use of expert judgment. 

• During earlier device development stages, this may be less 

certain. Probability levels within an estimated range may be 

acceptable.

• Includes the likelihood of the hazard resulting in a harmful 

event. FDA considers whether an event occurs once or 

repeatedly in assessing the probability of risks.
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Assessment of Risk – Characterization 

3. Duration of Risk(s) - Exposure to subjects temporary, minor 

harm; cause repeated but reversible harm; cause permanent, 

debilitating injury. 

• Duration or how long the adverse consequence lasts should be 

considered along with severity of risk.
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Assessment of Risk – Management 

4. Risk Management – Provides a summary and assessment of 

efforts to mitigate the identified safety concerns, or ensure device 

use is directed to participants for whom the risk is considered 

acceptable so not to outweigh the potential for benefit.

• Risk control measures (including risk mitigation): 

reduce the likelihood and severity of harm to study subjects

improve the B-R profile of the proposed study

intended to reduce the risk to an acceptable level
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Assessment of Risk – Management

• Sponsors should:

Conduct an initial determination of which risk controls are 

appropriate 

B-R assessment should focus on residual risk and reduction 

to acceptable levels relative to the anticipated benefits to 

subjects 

Provide a clear justification for the investigation considering 

risks for the intended study participants and plan for 

minimizing those risks.

 
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Assessment of Risk – Management

• Forms of risk controls that may be applied to IDE studies are 

outlined in detail in the guidance under A.4. Risk Management.

Examples:

 Safety by Design 

– Device features and/or modifications to improve safety

 Protective Measures 

– Study Design

– Study Oversight

– Adverse Event Reporting 
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Assessment of Risk – Management

5. Residual Risk Evaluation – After risk control measures are 

applied, the following measures may be considered when 

evaluating residual risk:

• Risk communication and disclosure of residual risk during the 

informed consent process (e.g., how subjects can/should act to 

further control or mitigate risk)

• When reliable information is available, consider subject 

perspective and tolerance for assuming risk relative to anticipated 

benefit

• Initially limit study subjects most likely to experience benefits or 

subject subset where B-R profile is more favorable (e.g., 

treatment-refractory patients)
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Assessment of Other Risks Considerations

In addition to the previously discussed Risk Characterizations and 

Management FDA may consider other risks as well:

• Risks related to interpretation of the study data 

 Risk of drawing a false conclusion based on clinical data obtained

 Risk of data which are inconclusive or difficult to interpret

• Risks to others to consider for example:

 Risk of radiation exposure of health care practitioner

 Treated subjects become drowsy while operating a vehicle
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Assessing Benefits and Risks in the IDE 

Realm 

BENEFITS RISKS

Type 

Magnitude

Probability

Duration

Type /Severity 

Likelihood

Duration

Management

Risk Controls/ 

Mitigation
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Assessment of Anticipated Benefits to Study 

Subjects

Direct Benefits: Benefits that may be realized by subjects 

participating in the research include:

• Type of benefit(s) – Examples include; closer surveillance of 

clinical management and QoL. For diagnostics; identify a specific 

disease for early intervention, or identify patients more likely to 

respond to therapy.

• Magnitude of benefit(s) – anticipated change in subjects 

condition or clinical management, questionnaire analysis 

provides insight into subjects’ preference
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Assessment of Anticipated Benefits to Study 

Subjects

Direct Benefits (cont.): 

• Probability of subject experiencing one or more benefit(s) – 

Based on evidence from prior investigations and early stages of 

device development it may not be possible to assess the 

probability of subjects experiencing one or more benefits.

• Duration of effect(s) – How long can the benefit be expected to 

last? Some treatments are curative and others are repeated 

over time. To the extent the effect is known, the duration of 

effect may influence how the benefit is defined over time.
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Assessment of Benefits to Others

A benefit to others of an investigational study is the “importance 

of knowledge to be gained” (21 CFR 812.30(b)(4))

• A societal benefit or increases the understanding of a disease 

condition, potential treatment or diagnostic applications

• Benefit unique to research (e.g., doesn’t apply to marketing 

applications) 

• Subjects may not receive direct benefit but willingness to 

participate due to indirect benefits of increasing generalizable 

about the disorder or condition being studied. 
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Putting It All Together - Framework 

For B-R Assessment

Type 

Magnitude 

Probability

Duration

Type 

Severity 

Likelihood

Duration

Management

DISEASE /

CONDITION

AVAILABLE 

ALTERNATIVES 

BENEFITS

RISKS/HARM

RISK 

CONTROLS

Risk 

Mitigation 

UNCERTAINTY 

EVIDENCE + 

KNOWLEDGE 

CONTEXT 

Includes benefit to 

others & importance 

of knowledge to be 

gained

Domains – clinical, 

non-clinical, patient

PATIENT 

PERSPECTIVE 
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Assessing Benefit and Risks for IDE 

Applications – Device Description

Regulations require that the Investigational Plan includes:

Description of this device (a description of each important 

component, ingredient, property, and principle of operation of the 

device and any anticipated changes in the device during 

investigation - 21 CFR 812.25(d) 

• Appendix C in the guidance lists the device attributes that 

FDA recommends to include in the IDE application; Device 

Description Section

• Deficiencies related to an incomplete or inadequate device 

description are the single most common type of nonprotocol related deficiency and results in failure to attain 

full IDE approval
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Assessing Benefit and Risks For IDE 

Applications – B-R Framework

Appendix A – Guidance 

1. Context of Proposed Investigation

 Summary of the disease/condition, context of 

currently available treatment or diagnostic options, 

brief description of trial objective/design.

2. Assessment of Risks 

 Summary of key risk elements identified in Section 5 of 

the guidance including risk characterization, risk control 

measures (i.e.; risk mitigation) and residual risk. 
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Assessing Benefit and Risks For IDE 

Applications – B-R Framework

3. Assessment of Benefits

 Summary of key benefits identified in Section 5 of the 

guidance including direct benefits to study subjects and 

benefits to others (importance of knowledge to be 

gained or contribute to developing a treatment) 

4. Consideration of Patient Preference Information

 Summary of patient preference information if 

available. If none, state that none available.
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Assessing Benefit and Risks For IDE 

Applications – B-R Framework

5. Assessment of Uncertainty

 Summarize key sources of uncertainty in the available 

evidence and proposed investigation identified in 

Section 5 of the guidance. 

 Provide a rationale for why the level of uncertainty is 

acceptable for the proposed investigation.

6. Conclusions

 Summarize how the consideration of the factors 

discussed in this summary justify the decision to 

proceed with the clinical investigation.
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References

Guidance Document Links 

• Factors to Consider When Making Benefit-Risk Determinations for 

Medical Device Investigational Device Exemptions - 2017

• Factors to Consider When Making Benefit-Risk Determinations in 

Medical Device Premarket Approval and De Novo Classifications - 

2016

• FDA Decisions for Investigational Device Exemption Clinical 

 Investigations - 2014 

• Investigational Device Exemptions (IDEs) for Early Feasibility 

Medical Device Clinical Studies, Including Certain First in Human 

(FIH) Studies - 2013 

• 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 - 2016
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Panel Discussants

• Karen Ulisney, M.S., CRNP, Policy Analyst, Clinical Trials Program, 

Office of Device Evaluation

• Owen Faris, Ph.D.; Director, Clinical Trials Program, Office of 

Device Evaluation

• Soma Kalb, Ph.D.; Director, IDE Program, Office of Device 

Evaluation

• Special Thank you to Katie O’Callaghan (CDRH, Assistant 

Director for Strategic Programs) for her expertise and 

contribution to this guidance development 
Questions?

Division of Industry and Consumer Education: 

DICE@fda.hhs.gov

Slide Presentation, Transcript and Webinar Recording 

will be available at:

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

Under Heading: How to Study and Market your Device

Clinical Studies/IDE