On April 9, 2013, FDA published a Federal Register notice announcing a new draft guidance on molecular diagnostic instruments with “combined functions” — i.e., combining functions subject to FDA approval or clearance as well as functions not subject to FDA approval or clearance (such as research use only (RUO)). The draft guidance has significant implications for manufacturers of molecular diagnostic instruments and software, especially with respect to provisions that call for FDA review of the impact of functions not otherwise subject to approval/clearance.
Molecular diagnostic instruments are generally approved or cleared by FDA in conjunction with specific assays used with them because FDA cannot evaluate their performance without reference to the assays they run. For example, molecular diagnostic instruments such as thermocyclers can be used to run polymerase chain reactions having a variety of applications, and separate FDA approvals/clearances may be required for each such application.
These same molecular diagnostic instruments may also have uses that do not require FDA approval or clearance, such as basic scientific research (RUO functionality) or uses involving laboratory-developed tests (LDTs). FDA’s draft guidance sets out a framework for how the agency intends to apply its premarket and postmarket requirements to a molecular diagnostic instrument marketed for combined functions.
Approval or Clearances of New Molecular Diagnostic Instruments
The draft guidance discusses the approval or clearance process for molecular diagnostic instruments having both uses that require FDA approval or clearance and uses that do not. The draft guidance applies to molecular diagnostic instruments (hardware) as well as software intended to operate the instruments and standalone software.
The draft guidance states that FDA will consider the following factors in reviewing 510(k) notifications and premarket approval applications (PMAs) for molecular diagnostic instruments with combined functions: (1) whether the sponsor demonstrates that unregulated functions do not interfere with approved/cleared functions; (2) whether the sponsor provides a risk/hazard analysis addressing unregulated functions in coexistence with approved/cleared functions; (3) whether the sponsor develops separate labeling for approved/cleared functions and unregulated functions; and (4) whether the sponsor’s promotional activity would improperly imply that FDA has approved or cleared functions for which approval/clearance is not required.
It is not clear whether FDA is expecting manufacturers to ask their customers about the unapproved/uncleared uses to which they will put the device. But it seems to be so, since the manufacturers would need to provide risk mitigation information and non-interference data. As to the first factor on interference with regulated functions, according to FDA, one way sponsors of new molecular diagnostic instruments may comply with the first factor is to develop software to separate the operation of approved/cleared functions from the operation of unapproved functions (i.e., by requiring the user to switch between functions by going to a selection or “start-up” screen).
Although these recommendations should be addressed in any new premarket submissions, manufacturers need not submit supplements or new 510(k) submissions for existing approved/cleared instruments having combined functions. Nevertheless, manufacturers of existing approved/cleared instruments should adhere to additional guidance addressing labeling, promotion, software/hardware modifications, and MDR reporting, as discussed below.
MDR Reporting, Software/Hardware Changes, and Promotion and Labeling
The draft guidance also has important implications for manufacturers of already approved/cleared molecular diagnostic instruments with combined functions. Most importantly, the draft guidance states that manufacturers and user facilities should comply with medical device reporting (MDR) requirements for adverse events associated with unregulated functions. This means that, even if a malfunction or injury is associated with functions that were not required to be cleared/approved, FDA expects manufacturers to report the adverse event under 21 C.F.R. Part 803.
In another important step, the draft guidance states that PMA supplements or new 510(k) submissions may be required when changes are made to the unregulated functions of the device, based on the agency’s view that changes to unregulated functions may impact the safety or effectiveness of the approved/cleared functions of the device.
The draft guidance also provides examples of acceptable labeling and promotional practices for such devices, generally emphasizing that claims regarding approved/cleared functions should not be intermingled with claims regarding functions that are not approved/cleared.
Finally, the draft guidance states that third parties developing assays for use with user-configurable molecular diagnostic instruments should provide complete instructions to allow the end user to perform the approved/cleared assay on a specific instrument, including instructions to avoid interference from unregulated functions. In addition, the third-party developer should not refer in labeling to a part of the instrument’s user manual that is not part of an approved/cleared portion of the instrument’s labeling.
FDA has encouraged stakeholders to submit comments by July 8, 2013, so that comments can be considered before FDA begins work on a final guidance.