Sarah Pleaugh, Associate Director of Regulatory Affairs, MCRA LLC11.13.23
Medical device manufacturers must document the process of deciding whether a change to an existing U.S. Food and Drug Administration (FDA) 510(k)-cleared product exceeds the regulatory threshold of 21 CFR 807.81(a)(3) for submission and clearance of a new 510(k). FDA’s 2017 guidance, “Deciding When to Submit a 510(k) for a Change to an Existing Device,” provides direction for manufacturers when determining whether the change was made with intent to significantly affect device safety or effectiveness using a risk-based assessment, evaluating any unintended consequences, and cumulative effect. The role of verification and validation activities in evaluating a change, as well as the appropriate comparative device, are also discussed as guiding principles. Lastly, the FDA guidance and quality system regulations require manufacturers to document device changes and their decision-making process. Many manufacturers call these internal documentation “Letters to File (LTFs).”
The 2017 FDA guidance supersedes the 1997 version [510(k) Memorandum K97-1]. Both editions provide a decision-making framework with flowcharts for evaluating labeling, technology, or performance, and material changes; manufacturers are expected to use risk-based assessments to determine if the change raises new issues of safety or effectiveness.
A common mistake involves using the wrong comparator device. The guidance requires the changed device to be compared to the product previously found to be substantially equivalent in the most recently cleared 510(k) (i.e., the “original device”). Manufacturers should not compare the changed device to any other predicate when evaluating a change. For instance, in an original 510(k), a worst-case spinal construct tested per ASTM F1717 static compression testing had a 150 N yield load and was determined to be substantially equivalent to a predicate with a 130 N yield load. After clearance, the company added a secondary processing step to the component manufacturing process. After repeating identical testing, the changed device had a 130 N yield load. In this case, the comparison must be made to the original device’s 150 N yield load.
Additionally, many manufacturers find that changes were improperly documented between the 1997 and 2017 guidance versions. Such a gap makes it difficult to evaluate the cumulative effect of change over time, especially for legacy devices. For instance, a device cleared in 2002 might have undergone five changes that were reviewed and documented in accordance with the 1997 guidance version. But a sixth change in 2018 must be evaluated individually as well as for its cumulative effect on the product using the new guidance version. Given the more detailed 2017 document, the manufacturer may now determine that any one of the previous changes or sum total of changes was significant and should have necessitated a new 510(k) premarket review. With changing company leadership and/or regulatory personnel, this type of change evaluation and decision-making can challenge a quality system and lead to varying guidance interpretations.
So, what can be done when a previous change was improperly documented via LTF? Perhaps a company is evaluating the subsequent change and now must consider the change’s cumulative effect. Or maybe the FDA requests a list of all changes to the device since its last 510(k) clearance [asking perhaps during an audit or a new 510(k) submission for an unrelated line extension]. Regulatory professionals like to call these LTFs a “skeleton in the closet” because over time, evaluating change and documenting LTFs can become a slippery slope.
Let’s explore potential scenarios and the proper questions to ask when navigating a complex LTF scenario.
Companies also must carefully consider the point within the development process in which a change is made. For example, manufacturers planning to submit a new 510(k) for an upcoming line extension might be better off waiting to make an interim change until the FDA reviews the new 510(k) and original device modification. If, however, there is no new 510(k) planned in the device’s near future, the manufacturer might want to submit a “catch-up” 510(k) so FDA can review the product’s modifications and clear the changed device.
Another potential scenario can occur when a manufacturer uses its own significantly changed device as a predicate in a future 510(k). In this situation, the new 510(k) submission must include a section disclosing any changes to the predicate device that were internally documented. This section should include a summary of each change, any verification or validation testing conducted, and the decision-making rationale for documenting an LTF at the time of the change. This situation is common amongst legacy products, when changes evaluated to the 1997 guidance version would require a new 510(k) (according to current FDA guidelines); however, historical changes may be evaluated against the guidance that was current when the change was made.
An important note: For any comparisons to support substantial equivalence, the new (changed) device must be compared to the original cleared version of the product. If needed, manufacturers may need to produce the original device for acceptance criteria when testing the new device. Not surprisingly, this can be challenging if the original device specifications or manufacturing process have become obsolete. Moreover, if the new device has strayed far enough away from its fundamental technology, the manufacturer may need to leverage reference devices for any modified features or performance in order to adequately determine substantial equivalence for the new device.
The real-world “when-to-submit” decision-making process can be highly complex. In situations where LTF skeletons are hiding in the closet, honesty is always the best policy. Device manufacturers should be transparent with FDA and take appropriate actions to ensure patient safety. All change evaluations should be conducted with consultation from experienced regulatory professionals to help navigate the gray areas of FDA guidance and avoid the slippery slope with FDA.
Sarah Pleaugh is associate director for Regulatory Affairs at MCRA, focusing primarily on U.S. regulatory submissions for orthopedic and spinal devices. A graduate of the Michigan Technological University, Sarah has worked in medical device regulatory affairs in the medtech industry since 2007 and for MCRA since 2021. Sarah provides MCRA clients with FDA regulatory strategies and submission support, such as pre-submissions for non-clinical and clinical data development, 510(k)s, Breakthrough Device Designations, and Premarket Approvals.
The 2017 FDA guidance supersedes the 1997 version [510(k) Memorandum K97-1]. Both editions provide a decision-making framework with flowcharts for evaluating labeling, technology, or performance, and material changes; manufacturers are expected to use risk-based assessments to determine if the change raises new issues of safety or effectiveness.
Guidance Ambiguity and Its Repercussions
There are various medical devices and types of changes required to maintain a product and its manufacturing. Although the FDA provides a framework for evaluating such changes, the guidance is intentionally vague, thus allowing manufacturers to decide for themselves whether the change is significant. This ambiguity, however, often causes manufacturers to make incorrect decisions about documenting a change versus submitting a new 510(k) premarket notification.A common mistake involves using the wrong comparator device. The guidance requires the changed device to be compared to the product previously found to be substantially equivalent in the most recently cleared 510(k) (i.e., the “original device”). Manufacturers should not compare the changed device to any other predicate when evaluating a change. For instance, in an original 510(k), a worst-case spinal construct tested per ASTM F1717 static compression testing had a 150 N yield load and was determined to be substantially equivalent to a predicate with a 130 N yield load. After clearance, the company added a secondary processing step to the component manufacturing process. After repeating identical testing, the changed device had a 130 N yield load. In this case, the comparison must be made to the original device’s 150 N yield load.
Additionally, many manufacturers find that changes were improperly documented between the 1997 and 2017 guidance versions. Such a gap makes it difficult to evaluate the cumulative effect of change over time, especially for legacy devices. For instance, a device cleared in 2002 might have undergone five changes that were reviewed and documented in accordance with the 1997 guidance version. But a sixth change in 2018 must be evaluated individually as well as for its cumulative effect on the product using the new guidance version. Given the more detailed 2017 document, the manufacturer may now determine that any one of the previous changes or sum total of changes was significant and should have necessitated a new 510(k) premarket review. With changing company leadership and/or regulatory personnel, this type of change evaluation and decision-making can challenge a quality system and lead to varying guidance interpretations.
So, what can be done when a previous change was improperly documented via LTF? Perhaps a company is evaluating the subsequent change and now must consider the change’s cumulative effect. Or maybe the FDA requests a list of all changes to the device since its last 510(k) clearance [asking perhaps during an audit or a new 510(k) submission for an unrelated line extension]. Regulatory professionals like to call these LTFs a “skeleton in the closet” because over time, evaluating change and documenting LTFs can become a slippery slope.
Let’s explore potential scenarios and the proper questions to ask when navigating a complex LTF scenario.
Conquering the LTF ‘Slippery Slope’
The first consideration is whether the changed device presents any new patient safety risks. If it does, companies should decide if they should suspend new device shipments while further testing, risk assessment, or an FDA review is conducted. There have been documented cases of manufacturers suffering unintended consequences with their products because a change’s cumulative effect modified device safety. Such cases might trigger a recall. The manufacturer may consider changing the device to its original specifications to protect patient safety until the modification can be fully evaluated and submitted to the FDA for review.Companies also must carefully consider the point within the development process in which a change is made. For example, manufacturers planning to submit a new 510(k) for an upcoming line extension might be better off waiting to make an interim change until the FDA reviews the new 510(k) and original device modification. If, however, there is no new 510(k) planned in the device’s near future, the manufacturer might want to submit a “catch-up” 510(k) so FDA can review the product’s modifications and clear the changed device.
Another potential scenario can occur when a manufacturer uses its own significantly changed device as a predicate in a future 510(k). In this situation, the new 510(k) submission must include a section disclosing any changes to the predicate device that were internally documented. This section should include a summary of each change, any verification or validation testing conducted, and the decision-making rationale for documenting an LTF at the time of the change. This situation is common amongst legacy products, when changes evaluated to the 1997 guidance version would require a new 510(k) (according to current FDA guidelines); however, historical changes may be evaluated against the guidance that was current when the change was made.
An important note: For any comparisons to support substantial equivalence, the new (changed) device must be compared to the original cleared version of the product. If needed, manufacturers may need to produce the original device for acceptance criteria when testing the new device. Not surprisingly, this can be challenging if the original device specifications or manufacturing process have become obsolete. Moreover, if the new device has strayed far enough away from its fundamental technology, the manufacturer may need to leverage reference devices for any modified features or performance in order to adequately determine substantial equivalence for the new device.
The real-world “when-to-submit” decision-making process can be highly complex. In situations where LTF skeletons are hiding in the closet, honesty is always the best policy. Device manufacturers should be transparent with FDA and take appropriate actions to ensure patient safety. All change evaluations should be conducted with consultation from experienced regulatory professionals to help navigate the gray areas of FDA guidance and avoid the slippery slope with FDA.
Sarah Pleaugh is associate director for Regulatory Affairs at MCRA, focusing primarily on U.S. regulatory submissions for orthopedic and spinal devices. A graduate of the Michigan Technological University, Sarah has worked in medical device regulatory affairs in the medtech industry since 2007 and for MCRA since 2021. Sarah provides MCRA clients with FDA regulatory strategies and submission support, such as pre-submissions for non-clinical and clinical data development, 510(k)s, Breakthrough Device Designations, and Premarket Approvals.