A week before Christmas, CDRH issued a revised draft of the Replacement Reagent policy. When finalized, the revised draft guidance will replace the 2003 final guidance. According to FDA, the revised guidance “is intended to update and provide clarity on” the existing policy. FDA has long commented that the 2003 guidance was overused and often misunderstood. As discussed below, the draft guidance that will replace the existing Replacement Reagent policy takes a more limited view of the replacement reagent policy. This means that fewer reagent instrument combinations will be able to enter the market via this approach. It is somewhat ironic then that the guidance states, in its introduction, that this revised policy “is important for public health as it promotes more timely availability of a wider array of clinical laboratory tests for patient benefit.” In fact, it appears likely to have the opposite effect.
At a high-level the policy is unchanged, 510(k)-cleared reagents can be used on certain additional instruments that were not included in the reagent 510(k) without the need for a new 510(k). Specifically, the additional instruments can include:
- 510(k)-cleared instruments that were not included in the reagents 510(k) clearance; and
- instruments in the same instrument family as the instruments on which the reagents were validated in their 510(k).
The guidance does not apply to certain assays, including Class III devices, point-of-care devices, and prescription home use devices, among others. The new policy notes that certain assay-specific guidances exclude application of the Replacement Reagent policy, for example, the clinical multiplex test system guidance. The revised draft guidance also excludes “modifications other than application of a cleared assay to a new instrument.” This exclusion is modified from the 2003 policy, which stated “changes in the intended use of a cleared product.” The exclusion in the proposed policy is significantly broader and could exclude minor modifications that would not otherwise require a 510(k) clearance (e.g., a minor change to the 510(k) cleared reagents that is unrelated to the application of the reagents to the new instrument platform). Thus, at the outset, the policy appears to be more limited in scope than the original guidance meaning that fewer assays will be eligible.
In addition, the revised draft guidance notes that the policy has been historically applied to traditional laboratory automated chemistry systems and immunoassays. The guidance indicates that manufacturers can contact FDA regarding the policy’s applicability to “evolving technology” (e.g., via the pre-sub process). It is unclear, however, how FDA defines an “evolving technology.” Is it any technology other than traditional laboratory automated chemistry systems and immunoassays? There are many well-known technologies in this category, for example, liquid chromatography and mass spectrometry. Or something truly new and not yet known? In short, the revised draft guidance may apply to a narrower subset of the universe of instruments than its erstwhile predecessor. This exclusion for “evolving technology” appears to even further limit the scope of the guidance.
While the broad objective of the draft policy is fundamentally the same as the 2003 version, the revised draft does include a new recommendation that the manufacturer seeking to apply the policy perform a risk assessment of the change. The risk assessment is intended to identify the risks associated with applying the 510(k)-cleared reagents to a new instrument. These risks and associated verification and validation results will be used to determine whether the proposed change fits within the Replacement Reagent policy or if a new 510(k) is required. This approach is consistent with the new, final guidance “Deciding When to Submit a 510(k) for a Change to an Existing Device,” but adds a layer not found in the current policy.
The revised draft policy also provides specific suggested tests to be performed as part of the verification and validation of the cleared assay on a new instrument. The guidance also notes, “if an updated, FDA-recognized standard or guidance has been published since the time of assay clearance, it is preferable that the manufacturer follow this; however, it is also acceptable to use the same standard or guidance that was followed to support the cleared 510(k).” This could be a dangerous suggestion – what if an assay does not pass the updated standard but does pass the original standard? Will the policy still apply? It is unclear and could become a problem for companies seeking to utilize this policy for their assays.
For the Instrument Family Policy to apply, an instrument must be in the same family as the cleared instrument, including sharing a common design history file. The revised draft guidance makes clear that instruments in the same family are essentially just iterations of the same original instrument. The guidance “encourages” communication between the reagent and instrument manufacturers, when they are not the same company. However, without a formal relationship, the reagent manufacturer may have trouble knowing if one instrument is in the same family as another. We anticipate that, particularly for assay-only manufacturers, that this will further limit the ability for companies to utilize this policy.
The new draft guidance replaces the flowcharts in the 2003 guidance with numerous examples. The guidance also provides additional recommendations as to how to present information in a CLIA categorization request when an assay and instrument combination enter the market through this policy. While the guidance does provide some additional useful information, the scopes appears to be so much more limited and the requirements more burdensome now that its utility will yet to be seen.