Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classifications

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.
 
[1] 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”
 
 

Factor

Questions to Consider

Notes

Assessment of Benefits of Devices
 

Type of benefit(s)

  • What primary endpoints or surrogate endpoints were evaluated?
  • What key secondary endpoints or surrogate endpoints were evaluated?
  • What value do patients place on the benefit?
 

Magnitude of the benefit(s)

  • For each primary and secondary endpoint or surrogate endpoints evaluated:
    • What was the magnitude of each treatment effect?
  • What scale is used to measure the benefit?
    • How did the benefit rank on that scale?
 

Probability of the patient experiencing one or more benefit(s)

  • Was the study able to predict which patients will experience a benefit?
  • What is the probability that a patient for whom the device is intended will experience a benefit?
  • How did the benefits evaluated vary across sub-populations? (If the study was sufficiently powered for subpopulations, note specific subpopulations, nature of difference and any known reasons for these differences.)
  • Was there a variation in public health benefit for different populations?
  • Even if the benefit is in a small portion of the population, do those patients who would experience the benefit value it?
 

Duration of effect(s)

  • Could the duration, if relevant, of each treatment effect, including primary and secondary endpoints be determined?  If so, what was it?
  • Is the duration of the benefit achieved of value to patients?
Assessment of Risks of Devices
Severity, types, number and rates of harmful events (events and consequences):
  • Device-related serious adverse events

 

  • What are the device-related serious adverse events for this product?
  • Device-related non-serious adverse events

 

  • What are the device-related non-serious adverse events for this product?
  • Procedure-related complications

 

  • What other procedure-related complications may a patient be subject to?
Probability of a harmful event
  • What percent of the intended patient population would expect to experience a harmful event?
  • What is the incidence of each harmful event in the study population?
  • How much uncertainty is in that estimate?
  • How does the incidence of harmful events vary by subpopulation (if applicable)?
  • Are patients willing to accept the probable risk of the harmful event, given the probable benefits of the device?
Duration of harmful events
  • How long does the harmful event last?
  • Is the harmful event reversible?
  • What type of intervention is required to address the harmful event?
Risk from false-positive or false-negative results for diagnostics
  • What are the consequences of a false positive?
  • What are the consequences of a false negative?
  • Is this the only means of diagnosing the problem, or is it part of an overall diagnostic plan?
Additional Factors in Assessing Probable Benefits and Risks of Devices
Uncertainty:
  • Quality of the study design
  • How robust were the data?
  • Quality of the conduct of the study
  • How was the trial designed, conducted and analyzed?
  • Are there missing data?
  • Robustness of the analysis of the study results
  • Are the study results repeatable?
  • Is this study a first of a kind?
  • Are there other studies that achieved similar results?
  • Generalizability of results
  • Can the results of the study be applied to the population generally, or are they more intended for discrete, specific groups?
Patient-centric assessments and patient-reported outcomes (PROs)
  • Do the device benefits and risks include effects on the health-related quality of life or other patient-reported outcomes
Characterization of the
Disease
  • How does the disease affect the patients that have it?
  • Is the condition treatable?
  • How does the condition progress?
Patient perspectives:
 

  • Benefit and risk considerations of patient preference information
  • What benefit(s) from this device is (are) of most importance to patients?
  • What risk(s) from this device is (are) of most importance to patients?
  • Is there available qualitative or quantitative patient preference information (PPI) on the relative desirability or acceptability to patients of outcomes or other attributes that differ among alternative health interventions?
  • Does available PPI show patients are willing to accept the probable risk(s) of this device in exchange for the probable benefit(s)?
  • Does available PPI show patient perspectives on maximum acceptable risk and minimum acceptable benefit, for meaningful changes in each risk?
  • Does PPI demonstrate that most or all of the patient population with the disease or condition consider benefit-risk tradeoffs acceptable in light of disease severity, chronicity, or lack of alternative treatments?
  • PPI relevance and comprehension
  • Are the risks identifiable and definable?
  • Do patients understand the type of risk(s) and the likelihood of the risk(s)?
  • Do patients understand the type of benefit(s) and the likelihood of the benefit(s)?
  • PPI generalizability and heterogeneity
  • Does available PPI show that preferences vary according to the stage of disease severity, chronicity, or other definable patient characteristic? If so, how?
  • Does available PPI include preferences of patients across the spectrum of the intended use population? If no, specify the PPI study population
Availability of alternative treatments or diagnostics
  • What other therapies are available for this condition?
  • How effective are the alternative treatments?
    • How does their effectiveness vary by subpopulation?
  • How well-tolerated are the alternative therapies?
    • How does their tolerance vary by subpopulation?
  • What risks are presented by any available alternative treatments?
Risk mitigation and indication limiting
  • Could you identify ways to mitigate the risks (including limiting the indication for use to a subset of the population in which benefit outweighs risk considerations) such as using product labeling, establishing education programs, providing add-on therapy, etc?
  • What is the type of risk mitigation proposed?
Postmarket data
  • Are there other devices with similar indications on the market? Are the probabilities for effectiveness and rates of harmful events from those devices similar to what is expected for the device under review?
  • Is postmarket data available that changes the risk/benefit evaluation from what was available when the previous devices were evaluated?
  • Is there reason to consider evaluation of any of the following elements further in the postmarket setting due to the risk/benefit evaluation as described above?
    • Longer-term device performance
    • Effectiveness of training programs or provider preferences in use of device
    • Sub-groups (e.g., pediatrics, women)
    • Rare adverse events
  • Is there reason to expect a significant difference between “real world” performance of the device and the performance found in premarket experience with the device?
  • Is there data that otherwise would be provided to support approval that could be deferred to the postmarket setting?
Novel technology addressing unmet medical need
  • How well is the medical need this device addresses being met by currently available therapies?
Summary of the Benefit(s) Summary of the Risk(s) Summary of Other Factors
Conclusions
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.

If you have questions about this guidance or need assistance please contact us by email at info@boston-biomedical.com or fill out our contact form.

Alyssa Woodcock
awoodcock@boston-biomedical.com

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