On Wednesday, 27 July 2011, the Food and Drug Administration's (FDA or "the Agency") Center for Devices and Radiological Health (CDRH) issued a draft guidance addressing the types of device modifications that require the submission of a new premarket notification (510(k)).1 The draft guidance, titled Draft Guidance for Industry and FDA Staff – 510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device (Draft Guidance), provides a framework for manufacturers to use when determining whether a change to a 510(k)-cleared device necessitates a new 510(k) submission, as well as examples of device modifications that illustrate the guiding principles. If finalized, this Draft Guidance would supersede the earlier guidance document, Deciding When to Submit a 510(k) for a Change to an Existing Device, issued 10 January 1997 (1997 Guidance).

Background

The Draft Guidance comes on the heels of the FDA's review of the 510(k) process. In August 2010, CDRH released a preliminary report of an internal agency working group evaluating ways to improve the premarket notification 510(k) program. In January 2011, the FDA released its summary and overview of comments to the August 2010 report, and unveiled a plan containing 25 actions that it intends to implement in 2011. One of the key initiatives of the action plan included updating the 1997 Guidance to address issues associated with software and other evolving technologies and to provide additional clarity about device changes that do not require a new 510(k).

Comparison to the 1997 Guidance

The basic framework of the Draft Guidance is very similar to the 1997 Guidance, and does not appear to significantly alter the type of analysis that the FDA expects manufacturers to conduct in response to a device change. Both guidance documents seek to clarify the FDA regulation, 21 C.F.R. § 807.71(a)(3), which requires that a manufacturer submit a new 510(k) when a change or modification "could significantly affect" either the safety or effectiveness of a device. Like the 1997 Guidance, the Draft Guidance outlines the general principles for manufacturers to follow in determining whether a change to a cleared device is considered "significant" and thus requires submission of a new 510(k). Both the 1997 Guidance and the Draft Guidance identify categories of potential device changes, including labeling changes, technology, engineering, and performance changes, and materials changes. However, there are several changes that are worth noting and may have an impact on future 510(k) device modification analyses.

  • Elimination of flowcharts - In the 1997 Guidance, the FDA provided several flowcharts to serve as the basis for a manufacturer's device modification analysis in determining whether a new 510(k) was warranted. In contrast, in the Draft Guidance, the FDA only provides examples to illustrate the types of changes to a cleared device that may or may not require submission of a new 510(k). It is important to note that these examples do not provide all instances of changes that may require the submission of a new 510(k) submission; rather, they are provided to generally demonstrate the FDA's position on a particular type of device modification. In addition, it is important to note that the elimination of the flowcharts also appears to reflect a narrowing of the types of technological changes that may be implemented via a memorandum to file. Previously, the guidance indicated that for certain types of technology changes, no new 510(k) was required if three criteria were satisfied: (1) no change in indications; (2) no need for clinical testing; and (3) no new issues arising from verification/validation testing. The new guidance eliminates these three criteria, providing instead illustrative examples of what types of technological changes may be regarded as significant and, therefore, require a new 510(k). For example, in the case of a change in performance specifications, under the old guidance if the manufacturer answered in the negative for each of the questions mentioned above, theoretically no new 510(k) would be required. However, in the Draft Guidance, if such a change "significantly alters" the performance specifications, then a new 510(k) is likely required. Manufacturers should carefully review the examples provided by the FDA in order to gain clarity regarding the types of changes that may or may not require a 510(k).
  • Modified device comparisons - Like the 1997 Guidance, the Draft Guidance requires manufacturers to compare the modified device to the most recently cleared version of the device and to determine whether the modification could significantly affect the safety or effectiveness of the device. In the Draft Guidance, however, the FDA clarifies that the modified device should not be compared to multiple devices; nor should the manufacturer compare the modified device to a version of the device that has not yet received clearance by the FDA. Although this is consistent with the Agency's past position on the correct approach, the Draft Guidance explains this in more detail. The Agency also advises a manufacturer to avoid comparisons to any other devices produced by the manufacturer or another manufacturer, even if the other device could serve as a predicate to the modified device. Thus, to the extent that a manufacturer has used a memorandum to file process to make non-significant changes to a device, each new individual change to the device must be compared to the version of the device that was last cleared by the FDA, not to the most recent iteration of the device, and should take into account the effect of all prior changes.
  • Labeling changes - In the Draft Guidance, the FDA clarifies that the term "labeling" as used in the guidance refers not just to the instructions for use, but consistent with the FDA's current interpretation of the term, refers to "all written, printed, or graphic matter on or accompanying a medical device." As a result, manufacturers should be aware that changes to the promotional materials for a device may require a new 510(k) submission if they meet the criteria laid out in the FDA's Draft Guidance. While this general requirement is not new, in a change from the 1997 Guidance, the FDA specifically distinguishes a modification in the indications for use that removes certain indications or limits use within the currently cleared indication, depending on the reason for the change. If the labeling change is "due strictly for marketing reasons" (e.g., the marketplace has changed and eliminated the need for one of the indications), then that change does not require a new 510(k). If, however, a manufacturer limits the indications due to other reasons, such as other changes made to the device or due to complaints or corrective actions, the FDA could consider the removal of the indications for use as a "major change" that requires a new 510(k).
  • How a device is used in practice - For the first time, the FDA addresses changes that affect how the device is likely to be used in practice. The Agency notes that these kinds of changes may require changes in the labeling, such as new directions for use. However, a change made regarding off-label uses of a device, such as a limitation to address the potential that an off-label use could cause harm, is identified by the FDA as requiring a new 510(k). Furthermore, if the device is modified to alter or expand the use of the device, or address use of the device in a new, expanded, or more specific patient population, a new 510(k) may be warranted. This section of the updated guidance reflects principles similar to some of those articulated in the FDA's 1998 Guidance for Industry: General/Specific Intended Use.
  • Home use - The Draft Guidance notes that changes intended to allow a device to be used by a lay person outside of a clinical setting are likely to require a new 510(k). Previously, the 1997 Guidance had provided this as an example of a change that would not typically trigger the need for a new 510(k) so long as the device remain prescription use only.
  • Changes in ergonomics or patient/user interface - In the Draft Guidance, the FDA introduces ergonomics or patient/user interface changes, and explains that changes that are made only to increase comfort and could not affect safety or effectiveness do not require a new 510(k). The FDA further explains that manufacturers must consider the change's effect on the safety or effectiveness of the device since simple changes could have unintended consequences. The FDA uses as an example a surgical handpiece handle that was modified to make the device less bulky by relocating the motor closer to the proximal end of the device. Because changing the proximity of the motor had the potential to cause burns in the patient or affect device performance, the FDA recommends that a new 510(k) be submitted for this change.
  • Change in dimensional specifications - Also unaddressed in the 1997 Guidance are changes to the dimensional specifications of a device, which the Draft Guidance now indicates may require a new 510(k). In particular, the FDA singles out a change to a device dimension that is related to the performance of a device outside of the cleared dimensional tolerance range. To the extent a manufacturer changes the dimensional specifications of a device, the FDA recommends that the manufacturer discuss this change with the appropriate review board.
  • Software changes - Given the incorporation of increasingly complex software in devices since the issuance of the 1997 Guidance, the Draft Guidance provides expanded discussion about the types of software changes that will require a new 510(k). Generally, manufacturers must consider whether the software change could expand the capability of the device or affect device performance, in which case a new 510(k) would be required. Thus, it is possible that software updates may require a new 510(k), depending on the particular changes made to the software. Moreover, the FDA notes that changes that could affect a clinical algorithm (an algorithm that controls how software analyzes, interprets, or uses patient data), would also warrant a new 510(k). Changes that affect how the device receives, transmits, or displays electrical signals or data would also require a new 510(k). Furthermore, device changes that take control of the device away from the user or are used to assist or take away decision-making from a user are viewed as potentially introducing new risks and therefore necessitating submission of a new 510(k). In summary, manufacturers should carefully analyze any software changes to determine whether they fit within the category of changes identified by the FDA as requiring a new 510(k). The increased focus on software changes is consistent with the recent increase in the FDA focus on related products, including medical device data systems.2
  • Nanotechnology – The Draft Guidance also introduces nanotechnology to the device modifications guidance. With respect to devices that contain nanomaterials or involve nanotechnology, the FDA recommends that manufacturers consult with the Agency for any nanotechnology changes to determine whether and how the proposed change may affect the safety and effectiveness of the device.
  • Manufacturing process changes – Another new category of changes introduced in the Draft Guidance relates to manufacturing process changes. At the time of the 1997 Guidance, the FDA's Quality System Regulation had not yet been issued. According to the Draft Guidance, the FDA will view manufacturing process changes as important and likely to require a new 510(k) if the manufacturing process information was reviewed in the original 510(k) submission. However, where the manufacturing process was not part of the original 510(k) review, a new 510(k) may not be required. In addition, changes to device specifications may also require a new 510(k) as they can significantly affect device performance and thus safety and effectiveness.
  • Clinical data - The Draft Guidance elevates a statement regarding the effect of clinical data on the need for a new 510(k). The 1997 Guidance contained a note, in the section addressing technology, engineering, and performance changes, clarifying that if a manufacturer determined that a change required clinical data to assess safety or efficacy, then a new 510(k) should be submitted. The Draft Guidance moves the discussion of the need for clinical data to a separate section and notes that a manufacturer's determination that clinical data is needed because bench testing or simulations are not sufficient to assess the safety or effectiveness of a modified device is a "sure sign" that the change could significantly affect safety or effectiveness and that a new 510(k) is required. 

Conclusion

The Draft Guidance updates the FDA's policy regarding which types of changes to a legally marketed device require the submission of a new 510(k). Generally, the Draft Guidance has the same basic principles as the original 1997 Guidance; however, the updated Draft Guidance no longer relies on a flowchart to assist manufacturers in making the determination that a device change requires a new 510(k). Instead, the FDA provides several examples as illustrations of the types of changes that may require a new submission. The FDA also expands upon the types of changes addressed in the guidance, including manufacturing process changes and further discussion about software changes. Although the Draft Guidance does not dramatically alter a manufacturer's approach to determining whether a specific device change requires a new 510(k), certain of the changes may impact the conclusions reached in the future regarding whether a new 510(k) is needed. Given the direction of the Draft Guidance, manufacturers can expect to submit an increasing number of new 510(k)s for modifications made to their devices, and may no longer rely on a memorandum to file to document many of these changes. In addition, given the recommendations made in the recent Institute of Medicine report on the 510(k) process,3 it is possible that the FDA will ultimately strengthen some of the guidance language when the final version is issued.

The FDA is seeking comments on the Draft Guidance. Comments must be submitted by 25 October 2011.