Federal medical device regulators issued new draft guidance this week hoping to clarify the agency’s process for determining the benefits and risks of 510(k) devices.
The new guidance wouldn’t change any of the FDA’s existing policies for evaluating 510(k) submissions, but the agency hopes the document will help device makers better understand the agency’s thinking.
Companies hoping to obtain 510(k) clearance must 1st demonstrate that their device has the same intended use as a technology already on the market. Secondly, companies must either show that their devices are technologically the same as a predicate, or else provide documentation showing that the device is as safe and effective as the predicate. The draft, titled "Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] With Different Technological Characteristics," focuses on the 2nd half of the 510(k) or premarket notification application.
During that 2nd phase, the FDA weighs the benefits and risks of a new device in order to establish substantial equivalence. The agency detailed its general outline for assessing new devices, but noted that decisions are still made on a case-by-case basis, and guidance documents are neither all-inclusive or universally applicable to every application.
The principal factors that the FDA considers for 510(k) documents, as detailed by the FDA, are as follows (or see the full draft guidance here):
A. Assessment of the Benefits of Devices
Extent of the probable benefit(s): FDA assesses information provided in a 510(k) submission concerning the extent of the probable benefit(s) by taking into account the following factors individually and in the aggregate as compared to the predicate device:
- Type of benefit(s) – examples include, but are not limited to, the device’s impact on clinical management, patient health, and patient satisfaction in the target population, such as the effect on patient management and quality of life, probability of survival, improvement of patient function, prevention of loss of function, and relief from symptoms. These endpoints denoting clinical benefit are usually measured directly, but in some cases may be demonstrated by use of validated surrogate endpoints. For diagnostic devices, a benefit may be assessed in reference to the nature of the public health impact of a particular device due to its ability to identify a specific disease, provide diagnosis at different stages of a disease, predict future disease onset, and/or identify patients more likely to respond to a given therapy and therefore enable treatment of the disease or reduce/prevent its spread.
- Magnitude of the benefit(s) – we often assess benefit along a scale or according to specific endpoints or criteria (e.g., types of benefits), or by evaluating whether a pre-identified health threshold was achieved. The change in clinical study subjects’ condition or clinical management as measured on that scale, or as shown by an improvement or worsening of the endpoint, is what allows us to assess the magnitude of the benefit in subjects. Absent explicit outcome data, the magnitude of benefit for diagnostic devices is defined in large part by the accuracy and reproducibility of test results and by the expected effect of clinically applying those results. Variation in the magnitude of the benefit across a population may also be considered.
- Probability of the patient experiencing one or more benefit(s) – based on the data provided, it is sometimes possible to predict which patients may experience a benefit, whereas other times this cannot be accurately predicted. The data may show that a benefit may be experienced only by a small portion of patients in the target population, or, on the other hand, that a benefit may occur frequently in patients throughout the target population. Demonstration of a large benefit experienced by a small proportion of subjects may raise considerations that differ from those in instances where a small benefit is experienced by a large proportion of subjects.
- Duration of effect(s) (i.e., how long the benefit can be expected to last for the patient) – some treatments are curative, whereas, some may need to be repeated frequently over the patient’s lifetime. To the extent that it is known, the duration of a treatment’s effect may directly influence how its benefit is defined. Treatments that must be repeated over time may introduce greater risk, or the benefit experienced may diminish each time the treatment is repeated.
B. Assessment of the Risks of Devices
Extent of the probable risk(s)/harm(s): FDA assesses the extent of the probable risk(s)/harm(s) by taking into account 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 that cause or contribute to a death or 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 indirectly result from use of the device. Examples include anesthetic-related complications associated with the implantation of a device or risks associated with the collection of human biological materials.
- Probability of a harmful event – the proportion of the intended population that would be expected to experience a harmful event. FDA would factor whether an event occurs once or repeatedly into the measurement of probability.
- Probability of the patient experiencing one or more harmful event(s) – based on the data provided, it is sometimes possible to predict which patients may experience a harmful event, whereas other times this cannot be accurately predicted. The data may show that a harmful event may be experienced only by a small portion of patients in the target population, or, on the other hand, that a harmful event may occur frequently in patients throughout the target population.
- Duration of harmful events (i.e., how long the adverse consequences last) – some devices can cause temporary, minor harm; some devices can cause repeated but reversible harm; and other devices can cause permanent, debilitating injury. FDA would consider 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. If a diagnostic device gives a false-negative result, the patient might not receive an effective treatment (thereby missing out on the benefits that treatment would confer), or might not be diagnosed with the correct disease or condition. These risks and other risks arising from false test results are considered in terms of their likelihood and severity.
We also consider the number of different types of harmful events that can potentially result from using the device and the severity of their aggregate effect. When multiple harmful events occur at once, they have a greater aggregate effect. For example, there may be a harmful event that is considered minor when it occurs on its own, but, when it occurs along with other harmful events, the aggregate effect on the patient can be substantial.
C. Additional Factors in the Assessment of the Benefits and Risks of Devices
Uncertainty – when determining if a new device is as safe and effective as a predicate device, we consider the degree of certainty of the benefits and risks of a device. Factors such as – less than optimal design or less than optimal conduct of bench testing, animal or clinical studies, or inadequate analysis of data — can render the outcomes of the test or study unreliable and may not provide the degree of information necessary to fully understand the effects of the new technology. Additionally, for certain device types, it is sometimes difficult to distinguish between a real effect and a placebo effect in the absence of a design that is capable of blinding investigators and subjects. Furthermore, repeatability of the study results, validation of the analytical approach, and results of other similar studies can all influence the level of certainty.
Characterization of the disease/condition – the treated or diagnosed disease/condition, its clinical manifestation, how it affects the patients who have it, how and whether a diagnosed disease/condition is treated, and the condition’s natural history and progression (i.e., does it get progressively better or worse over time for the patient and at what expected rate) are all important factors that FDA considers when evaluating the benefits and risks of the new device.
Patient tolerance for risk and perspective on benefit – risk tolerance varies among patients, and affects individual patient’s decisions as to whether higher risks in the new device’s technology as compared to the predicate device are acceptable in exchange for a higher probable benefit. When evaluating benefits and risks, FDA recognizes that a patient-centric assessment of risk may identify patients who are reasonably willing to accept a higher level of risk to achieve a higher probable benefit or an additional type of benefit (e.g., an improvement in quality of life stemming from greater comfort or ease of use). At the same time, other patients may be more risk-averse. Patient-centric assessments should take into account both the patients’ willingness and unwillingness to use a device or tolerate risk when evaluating the relative safety and efficacy of the new device. FDA may also consider evidence relating to patients’ perspective on what constitutes a meaningful benefit, as some set of patients may value a benefit more than others. Assessing patient tolerance for risk and perspective on benefit may be an informative and helpful factor in evaluating the overall benefit-risk profile of a device and whether a device is as safe and effective as a predicate. For example, inconvenience or discomfort may reduce patient compliance with instructions for use, which could result in lower effectiveness. FDA recommends that any submitter who is considering developing or presenting valid measurement methods and/or data concerning patient risk tolerance or perspective on benefit in its 510(k) submission have early interaction with the appropriate FDA review division.
Benefit for the healthcare professional or caregiver – FDA recognizes that certain devices, such as surgical tools that allow different techniques or devices that positively affect ongoing patient management, may benefit healthcare professionals or caregivers by improving the way they care for the patients and consequently improving patient outcomes. Examples could include surgical instruments with improved ergonomic design for ease of use or patient monitoring devices with wireless capabilities. For these devices, submitters may consider developing or presenting valid measurement methods and/or data concerning perspective on benefit for healthcare professionals or caregivers. FDA recommends that any submitter who is considering developing or presenting valid measurement methods and/or data concerning perspective on benefit for healthcare professionals or caregivers in the submitter’s 510(k) submission have early interaction with the appropriate FDA review division.
Risk mitigation – the use of mitigations, when appropriate, can minimize the probability of a harmful event occurring and improve the benefit-risk profile. Even if a new device has an increased risk, if the risk is appropriately mitigated, FDA may determine that the new device has a comparable benefit-risk profile to the predicate device and therefore determine that the new device is as safe and effective as the predicate device. The most common form of risk mitigation is to include appropriate information within labeling (e.g., warnings, precautions, contraindications). Some risks can be mitigated through other forms of risk communication, including training and professional and patient labeling. For in vitro diagnostic devices, risks may be mitigated by the use of complementary or supplementary diagnostic tests and/or controls.
Postmarket data – the use of devices in a postmarket setting provides a greater understanding of their risks and benefits, and the risks and benefits of similar devices. When reviewing a new device and assessing different technological characteristics in accordance with this guidance, FDA may consider any postmarket data (e.g., literature, recalls, registry data, medical device reports) collected on marketed devices of the same type. This assessment may clarify the magnitude and effect of mitigations, and may provide additional information regarding the benefits and risks when evaluating benefits and risks of the new device in accordance with a substantial equivalence determination. In some cases, postmarket information can be used to confirm that certain risks have been mitigated or to identify which patients are most likely to suffer adverse events. In addition, FDA has the authority to require postmarket surveillance for certain class II devices, and may order postmarket surveillance for a new device that is expected to have significant use in pediatric populations as a condition to a substantial equivalence determination. Postmarket surveillance for a new device that is expected to have a significant pediatric use can serve to complement premarket data.
Furthermore, section 513(i)(1)(C) of the FD&C Act (21 U.S.C. § 360c(i)(1)(C)) requires FDA to consider the use of postmarket controls in the review of 510(k) submissions, stating "[t]o facilitate reviews of reports submitted to the Secretary under section 510(k), the Secretary shall consider the extent to which reliance on postmarket controls may expedite the classification of devices …." As discussed in FDA’s guidance, "The Least Burdensome Provisions of the FDA Modernization Act of 1997: Concept and Principles," issued October 4, 2002, reliance on postmarket controls (e.g., Quality System regulations, postmarket surveillance, and the Medical Device Reporting requirements) should be considered as a mechanism to reduce the extent of the premarket data for 510(k) submissions, while still ensuring the safety and effectiveness of the device. In some cases, FDA may accept a greater degree of premarket uncertainty regarding a device’s benefit-risk profile through a greater reliance on postmarket controls, such as postmarket surveillance where applicable, in order to reduce the premarket burden for a 510(k) submission, if FDA’s overall assessment is sufficiently balanced by other factors to support substantial equivalence and taking into account FDA’s limitations with respect to requiring postmarket studies for 510(k)s.
Innovative technology – When a new device has technological improvements that are important for public health, we may accept greater uncertainty in an assessment of benefits and risks as compared to the predicate device than for most established technologies in order to facilitate patient access to these innovative technologies if FDA’s overall assessment is sufficiently balanced by other factors to support a determination that the new device is SE to the predicate device. Innovative changes are evaluated on a case-by-case basis in terms of the degree of the advantage.