The Food and Drug Administration has released a guidance document that offers insight into their decision-making when reviewing 510(k) premarket notification applications. Medical device sponsors submit a 510(k) to FDA in order for the agency to clear their device for marketing. During the review of a 510(k) submission, FDA must determine whether a new device is “substantially equivalent” to a predicate device, that is, a device that is already legally marketed. Until FDA issues an order declaring a device to be “substantially equivalent,” the submitter may not proceed to market the device.
FDA’s guidance, entitled Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics, outlines the factors FDA considers when the agency makes premarket notification submission decisions for new devices. The agency believes their outline will improve the predictability, consistency, and transparency of the device premarket notification process. We have covered 510(k) clearances over the years, including HHS-OIG studies of the process and new approval pathways for medical devices.
Comments on the guidance is due by October 14, according to the Federal Register notice. Stakeholders should submit electronic comments on the draft guidance to http://www.regulations.gov. Written comments sould be submitted to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
Background
Most devices reach the market in one of three ways under FDA regulation:
- (1) Premarket approval (PMA) application, which requires the submission of clinical data supporting a product’s safety and efficacy;
- (2) Premarket notification [510(k)], which relies upon already-approved predicate devices, to which the new device claims to be substantially equivalent
- (3) Certain devices are exempted by FDA because they meet established standards recognized by FDA, or because they are recognized as low-risk devices.
This guidance focuses on (2).
A 510(k) is a premarket submission made to FDA to demonstrate that the device to be marketed is at least as safe and effective, or “substantially equivalent,” to a legally marketed device that is not subject to premarket approval. Submitters must compare their device to one or more similar legally marketed devices and make and support their substantial equivalency claims.
Section 510(k) of the Food, Drug and Cosmetic Act requires medical device manufacturers to notify FDA if they intend to market a medical device at least 90 days in advance. This event is known as “Premarket Notification,” also known as PMN or 510(k). The purpose is for FDA to determine whether the device is considered equivalent to a device already classified into one of three categories. Therefore, new devices—not in commercial distribution before May 28, 1976—that have not been already classified can be properly identified.
The 510(k) premarket notification process involves regulators assessing the safety and efficacy of the device. The agency bases this on the devices’ substantial equivalence to products already on the market, also known as predicate devices. Much of the focus in the 510(k) process is on the ways the new device is not substantially equivalent to predicate devices.
Consequently, medical device manufacturers are required to submit a premarket notification if they intend to introduce a device into commercial distribution for the first time or reintroduce a device that will be significantly changed or modified to the extent that its safety or effectiveness could be affected. Such change or modification could relate to the design, material, chemical composition, energy source, manufacturing process, or intended use.
Focus of the Guidance
The guidance document does not focus on the first step of the 510(k) review process, during which FDA must find that the intended use of the device and its predicate are “the same,” but instead focuses on the step of the review process after FDA has determined that the new device and the predicate device have different technological characteristics and that the new device does not raise different questions of safety and effectiveness. At this point in the review process, FDA must determine whether the new device is “as safe and effective” as the predicate device.
The guidance describes the principal benefit and risk factors that FDA considers during this step in the 510(k) review process to assist in making a substantial equivalence determination. The agency also specifies that the guidance applies to both diagnostic and therapeutic devices.
Benefit and Risk Factors
Although the degree of difference in the benefits and risks of the new device that FDA may find acceptable in a substantial equivalence decision will be assessed on a case-by-case basis, examples of how differences in benefit and risk of the new device may be evaluated as compared to the predicate device include both decreased benefit/decreased risk and also increased risk/increased benefit.
Decreased Benefit/Decreased Risk: If there are different technological characteristics between the new device and the predicate device and FDA finds that there are decreased benefits with the new device as compared to the predicate device, FDA may still determine that the new device is substantially equivalent to the predicate device if, for example, there are also decreased risks as compared to the predicate. When looking at the smaller benefits in the new device, FDA may consider the amount by which the benefit has decreased when determining whether the device is substantially equivalent. Depending on the decrease in benefit of the new device as compared to the predicate device, FDA may determine that the new device is not substantially equivalent to the predicate device, even despite decreased risks of the new device.
Increased Risk/Increased Benefit: Furthermore, if the risks associated with the new device increase as compared to the predicate, FDA may still determine that the new device is substantially equivalent to the predicate device if, for example, FDA finds from a review of the new device’s performance data that there are also increased benefits with the new device. When evaluating increased risks posed by the new device, FDA may consider the degree of risk compared to the predicate device and whether additional measures may mitigate the risk.
FDA’s Assessment of Device Benefits
FDA assesses information provided to the agency by considering the type of benefits, the magnitude of the benefit, the probability of the patient experiencing one or more benefits, and the duration of effects. To illustrate how FDA may assess possible benefits of a diagnostic device, the agency could evaluate the benefit 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.
FDA’s Assessment of Device Risks
To assess the probable risks or harms of a device, FDA takes into account the severity, types, number, and rates of harmful events associated with the device. This includes device-related serious adverse events, non-serious adverse events, and procedure-related complications. Additionally, FDA also assesses the probability of a harmful event occurring, probability of the patient experiencing one or more potential harmful events, the duration of the harmful events, and the risk from false-positive or false-negative results for diagnostic devices.
FDA may 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.
Additional Factors in the Assessment of the Benefits and Risks of Devices
In the guidance, FDA listed additional factors used in the assessment of the benefits and risks of devices. The first is uncertainty. To make this determination, FDA may consider factors such as “less than optimal design” or “less than optimal conduct of bench testing, animal or clinical studies,” or “inadequate analysis of data,” which 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, FDA notes that 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.
FDA also considers the characterization of the particular disease or condition, patient tolerance for risk and perspective on benefit, the benefit for the healthcare professional or caregiver, and proper “risk mitigation” in its assessment.
Finally, FDA notes the importance of postmarket data as a factor for consideration. This data provides a greater understanding of a device’s risks and benefits, and the risks and benefits of similar devices. 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.