Courtney A. Stevens, Esq. |Senior Attorney, Medmarc Loss Control
FDA’s newest guidance for medical device manufacturers, Deciding When to Submit a 510(k) for a Change to an Existing Device, issued August 8, addresses a question manufacturers commonly face,—when a 510(k) is necessary for a change to an already cleared device. Manufacturers’ failures to submit 510(k)s are frequently cited in warning letters as rendering a device adulterated. As such, it’s an issue medical device companies can’t be too careful in scrutinizing. Thankfully, this guidance does provide such much-needed clarity on exactly when a 510(k) is necessary, and when processing the change in accordance with Quality System (QS) requirements (e.g., documentation of changes and approvals in the master record, verification and revalidation, etc.) is sufficient.
The confusion over whether a 510(k) is necessary is largely due to the subjective, relative language in the regulations, requiring device-makers to submit a 510(k) when a change “could significantly affect the safety or effectiveness of the device.” (21 CFR 807.81 (a)(3)). The Agency tried to clarify its interpretation of that language in its first guidance document on this issue, published in 1997, but clearly, as evidenced by the frequency with which the manufacturers’ determination of “significant” changes differed from the Agency’s, greater clarity was needed still. (Once finalized, this draft guidance will supersede the 1997 Guidance on the subject.)
This guidance document improves upon its predecessor by providing a number of exacting flow chart-decision trees to guide manufacturers through the determination of a 510(k)s’ necessity with regard to different types of changes.
It begins by setting out the guidance principles to be first considered in determining the propriety of a 510(k), which I briefly summarize here:
- Modifications made with intent to significantly affect safety or effectiveness of a device. This is the same language as is found in the regulations, and its meaning is fleshed out in the remainder of the document.
- Could “significantly affect” evaluation and the role of testing. In order to determine significance of the effect, manufacturers must conduct risk-based assessments.
- Unintended consequences of changes. One component deemed to make up a “significant effect” is if the change would result in unintended consequences or effects. The draft guidance provides sterilization as an example which may affect device materials, thereby affecting performance of the device.
- Use of risk management. Here, the draft refers to ISO 147981: Medical devices – Application of risk management to medical devices, and instructs manufacturers to utilize an assessment combining the probability of occurrence of harm and the severity of that harm in determining “significant effect.”
- Evaluating simultaneous changes. Even though changes may occur simultaneously, each change should be assessed individually and in combination.
- Appropriate comparative device and cumulative effect of changes. In making the determination of a 510(k)’s propriety, manufacturers need to consider (1) how different a change makes the device from its initial or most recent iteration as described in their most recently cleared 510(k); and (2) the cumulative effect of all changes since the last 510(k) cleared for this device. That is, though previous changes did not require a 510(k) when made in isolation, does the cumulative effect of this change with those previously made nor warrant a 510(k), even if it, by itself, would not?
- Documentation required. Even if a manufacturer determines a 510(k) is appropriate for a particular change, this does not alleviate them from compliance with all existing QS requirements, including all documentation, verification, and validation duties.
- 510(k) submission for modified devices. When a 510(k) is submitted for a device with multiple modifications since its last cleared 510(k), the 510(k) should describe not only the most recent change that warranted the 510(k), but also all previous modifications even though they did not merit the submission of 510(k)s in and of themselves.
- Substantial equivalence determination. Manufacturers need understand that submission of a 510(k) for a change pursuant to everything outlined in the regulation and this guidance document does not assure that a substantial equivalence determination will be provided.
With these considerations in mind, manufacturers may proceed to the different parts of the guidance instructing them on decision-making for different kinds of changes—labeling, control mechanisms, operating principles, etc. In each of these, manufactures will find the aforementioned decision trees to guide them through submission criteria.
An example of the flow charts included in this draft guidance:
In addition to charts guiding decision making, the guidance also provides examples of documenting changes and written regulatory change assessments.
This should go a long way in facilitating manufacturers’ understanding of when 510(k)s for changes are necessary, and reduce the number of warning letters for companies’ failure to submit them, accordingly.