25 Aug Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classifications
On August 24, 2016, the FDA issued a final version of the Guidance “Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classifications.” The draft of the guidance was released on August 15, 2011.
The purpose of the guidance is to explain the principal factors that the FDA considers when making benefit-risk determinations during the premarket review process for certain medical devices. The FDA hopes this will bring predictability, consistency, and transparency to the premarket review process for PMAs and De Novo classification requests. The guidance applies to both diagnostic and therapeutic devices
The factors identified in the guidance should also be considering during the pre-IDE and IDE phases of device development as well. Additionally, both clinical and non-clinical data can play a role in FDA’s benefit-risk determinations, and the factors discussed in this guidance are informed by both types of data.
Factors FDA Considers in Making Benefit-Risk Determinations
- Assessment of the Benefits of Devices: the extent of the probable benefit(s) is determined based on the following factors individually and in the aggregate:
- The type of benefit(s) –Impact on clinical management, patient health, and patient satisfaction in the target population
- The magnitude of the benefit(s) – The change in participants’ condition or clinical management as measured on that scale, or as determined by an improvement or worsening of the endpoint
- The probability of the patient experiencing one or more benefit(s) – The FDA considers magnitude and probability together when weighing benefits against risks. I.e. a large benefit experienced by a small proportion of participants may raise different considerations than does a small benefit experienced by a large proportion of participants
- The duration of effect(s) – How long the benefit can be expected to last for the patient
- Assessment of the Risks of Devices: The extent of the probable risk(s)/harm(s) is determined based on the following factors individually and in the aggregate:
- Severity, types, number and rates of harmful events associated with the use of the device:
- Device-related serious adverse events – those events that may have been or were attributed to the use of the device and produce an injury or illness that is life-threatening, results in permanent impairment or damage to the body, or requires medical or surgical intervention to prevent permanent harm to the body.
- Device-related non-serious adverse events – those events that may have been or were attributed to the use of the device and that do not meet the criteria for classification as a device-related serious adverse event.
- Procedure-related complications – harms to the patient that would not be included under serious or non-serious adverse events, and that do not directly result from use of the device.
- Probability of a harmful event – The proportion of the intended population that would be expected to experience a harmful event and whether an event occurs once or repeatedly into the measurement of probability.
- Duration of harmful events – how long the adverse consequences last. FDA considers the severity of the harm along with its duration.
- Risk from false-positive or false-negative results for diagnostics – If a diagnostic device gives a false-positive result, the patient might, for example, receive an unnecessary treatment and incur all the risks that accompany that treatment, or might be incorrectly diagnosed with a serious disease. The risks associated with false-positives and false-negatives can be multifold, but are considered by FDA in light of probable risks.
- The number of different types of harmful events that may result from using the device and the severity of their aggregate effect
- Additional Factors in the Assessment of the Probable Benefits and Risks of Devices
- Uncertainty – The degree of certainty of the benefits and risks of a device. Factors such as poor design or poor conduct of clinical trials, or inadequate analysis of data, can render the outcomes of the study unreliable.
- Patient-centric assessments and patient-reported outcomes (PROs) – These types of metrics allow the physician to better quantify the impact of the device on the patient’s well-being and help the patient make a more informed decision.
- Characterization of the disease – the treated or diagnosed condition, its clinical manifestation, how it affects the patients who have it, how and whether a diagnosed condition is treated, and the condition’s natural history and progression
- Patient perspectives – if the risks are identifiable and definable, risk tolerance will vary among patients, and this will affect individual patient decisions as to whether the risks are acceptable in exchange for a probable benefit
- Severity of disease or condition – patients suffering from very severe diseases (i.e., those that are life-threatening) may tolerate more risk for devices used in treatment.
- Disease chronicity
- Availability of alternative treatment/diagnostic options – For a device with a known benefit and a probability of high risk that treats a condition for which no alternative treatments are available, FDA would consider the risk to the patient of having no treatment if a device were not approved
- Risk mitigation – the use of mitigations, when appropriate, can minimize the probability of a harmful event occurring and improve the benefit-risk profile
- Postmarket data – Provides insight into the use of devices in a real world setting
- Novel technology addressing unmet medical need – Whether a device represents or incorporates breakthrough technologies and addresses an unmet medical need.
Intersection of this Guidance with ISO 14971
As part of the premarket review process, the FDA considers a manufacturer’s risk management decisions as they pertain to the requirements to market a device in the United States. The medical device manufacturer’s risk management decisions that are directly and/or indirectly evaluated include:
- Risk estimation
- Risk evaluation
- Risk acceptability
- Risk control measures
- Overall residual risk.
Good documentation of risk management decisions by manufacturers helps to streamline the premarket review process for both FDA and manufacturers.
Worksheet for Benefit-Risk Determinations
The worksheet provided below, is taken from the guidance and has been recommended as the one that reviewers will use in making benefit-risk determinations as part of the premarket review process.
 The FDA refers here to the Guidance titled “Patient Preference Information – Voluntary Submission, Review in PMAs, HDE Applications, and De Novo Requests, and Inclusion in Decision Summaries and Device Labeling”
Questions to Consider
|Assessment of Benefits of Devices|
Type of benefit(s)
Magnitude of the benefit(s)
Probability of the patient experiencing one or more benefit(s)
Duration of effect(s)
|Assessment of Risks of Devices|
|Severity, types, number and rates of harmful events (events and consequences):|
|Probability of a harmful event|
|Duration of harmful events|
|Risk from false-positive or false-negative results for diagnostics|
|Additional Factors in Assessing Probable Benefits and Risks of Devices|
|Patient-centric assessments and patient-reported outcomes (PROs)|
|Characterization of the |
|Availability of alternative treatments or diagnostics|
|Risk mitigation and indication limiting|
|Novel technology addressing unmet medical need|
|Summary of the Benefit(s)||Summary of the Risk(s)||Summary of Other Factors|
Do the probable benefits outweigh the probable risks?
Boston Biomedical Associates has extensive experience assisting companies in meeting FDA’s expectations for benefit/risk determinations and providing submission support. We can help your company to understand what the FDA expects when they receive a PMA or De Novo Request as well as provide assistance in executing the preparation and submission process.