FDA has released a new draft guidance for In Vitro Diagnostic Multivariate Index Assays (“IVDMIAs”). The first version, which was released on September 7, 2006, attracted many critical comments. The new draft seeks to address some (but not all) of those concerns.
Creating a new classification of devices called IVDMIAs, FDA is seeking to regulate a subset of laboratory developed tests. Even though they would not be sold outside of a single laboratory, IVDMIAs would be subject to the full device regulatory scheme, including the need for FDA clearance or approval.
One of the major criticisms of the first draft was that the definition of an IVDMIA was not clear. The proposed definition has been modified. An IVDMIA is now defined as a device that:
1) Combines the values of multiple variables using an interpretation function to yield a single, patient-specific result (e.g., a “classification,” “score,” “index,” etc.), that is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment or prevention of disease, and
2) Provides a result whose derivation is non-transparent and cannot be independently derived or verified by the end user.
The second prong of the definition is likely to attract the most attention, since it will not always be clear whether a result is “non-transparent” or how the phrase “cannot be independently derived or verified” will be applied. FDA has given some examples of tests that are IVDMIAs, and some that are not. These illustrations provide some greater clarity, but even so there will almost certainly be controversy over whether a particular test falls inside or outside the IVDMIA definition.
Another area of concern for commenters related to the scope of the IVDMIA “device.” Was the device the algorithm; the algorithm and software; the algorithm, software, and laboratory tests; or something else? FDA has definitively answered that question, although not in a way that will satisfy those who proposed a narrow definition. The new draft guidance states:
FDA believes that any safety and effectiveness determinations that are part of the premarket review process should include review of the performance of the entire system, including the accurate measurement of the input variables, directions for use, and expected analytical or clinical performance, rather than a review of only certain subcomponents of the test.
The impact of that broad definition may be partially softened (at least in the short term) by FDA’s acknowledgement that the Clinical Laboratory Improvement Amendments (“CLIA”) “requirements may partially fulfill corresponding” Quality System (“QS”) requirements. FDA states that it will issue guidance to help laboratories comply with QS requirements. Furthermore, FDA will “exercise enforcement discretion” (i.e., presumably not apply QS requirements until the final guidance has been issued). How FDA will ultimately minimize the overlapping requirements of CLIA and the QS regulations is not discussed in the document.
FDA also adopted the suggestion offered by many commenters that there be a transition period. The grace period will be 12 months from the date of the final guidance document “for currently marketed” IVDMIAs, and then six more months if a 510(k) or premarket approval application is submitted. These transition periods are certainly better than requiring immediate compliance, but they are significantly shorter than some commenters had proposed.
While FDA did adopt the concept of a transition period, it rejected the many comments that requested the agency to proceed through notice and comment rulemaking. FDA’s decision to use the guidance document process instead of rulemaking may result in a legal challenge over whether FDA violated the Administrative Procedure Act. Even more fundamentally, FDA continued to assert that IVDMIAs are devices that are subject to FDA regulation. This position, too, has been sharply questioned.
The comment period is a rather short 30 days. After the first draft guidance was issued, FDA extended the initial 90-day comment period by 90 days. It remains to be seen whether FDA will extend the comment period again in light of the significant impact that would follow adoption of an IVDMIA category.