A previously published IVDT article (Commentary, April 2006) discussed how the new molecular marker business would consist of complex testing for­mats requiring multiplexed assays and advancements in software. Since then, FDA has provided a new draft guidance document for a category of IVDs called in vitro diagnostic multivariate index assays (IVDMIAs) (www.fda.gov/cdrh/oivd/ guidance/1610.html). IVDMIAs are typically multiplexed tests that use a computer software package to analyze the test results to make a final diagnosis or diagnostic recommendations. FDA's Office of In Vitro Diagnostic Device Evaluation and Safety has been instructing IVD manufacturers that complete test systems that require the assay and the algorithm in order to obtain meaningful test results will fall under this new category.

With this new guidance, FDA appears to be exerting its regulatory power, and it is expected that IVDMIAs will now be regulated as either Class II devices (requiring 510(k) clearance) or Class III devices (requiring the submission of a rigorous premarket approval, or PMA, application). In the past, most IVDMIAs were manufactured and performed in commercial testing laboratories and fell into a category called home-brew tests.

Even though FDA does not regulate home-brew tests, laboratories offering home-brew testing must comply with the regulations under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). However, with the new guidance, all manufacturers of IVDMIAs may be required to comply with the FDA quality system regulation and report adverse events.

On the same day that FDA issued the IVDMIA guidance, the agency also published a new draft guidance for analyte specific reagents (ASRs). This ASR guidance may affect the IVD industry even more than the IVDMIA guidance since those multiplexed tests that have been on the market for some time would now require FDA approval through the 510(k) or PMA process. The new ASR guidance specifically targets molecular diagnostic ASRs containing more than one primer, which is shocking since all real-time polymerase chain reaction (PCR) ASRs contain at least a mixture of both forward and reverse primers. According to the guidance, this would add up to two separate ASRs that could not be combined.

But what are more likely to undergo greater FDA regulation are multiplexed tests. The new ASR guidance puts IVD companies on notice that multiple-analyte tests (i.e., more than one target being analyzed) do not fall under the ASR category. Terms used in the new guidance to define ASRs include single moiety and single endpoint. There are a number of multianalyte ASRs on the market today that test for pathogens (flu A and flu B) and genetic markers (multimutation cystic fibrosis tests). Under the new guidance, many of these tests will no longer be considered ASRs and may require FDA approval.

Paying Attention

So why is all of this governmental posturing so important for the molecular marker industry? The IVD industry was beginning to see a resurgence brought on by the Human Genome Project and further accelerated recently by pharmaceutical companies taking an interest in targeted medicine. However, the industry could face financial and regulatory concerns that threaten to reverse this forward surge. To cope with possible increased costs, development interruptions, and various other concerns, IVD manufacturers and testing laboratories will need to pay careful attention to how FDA implements and enforces the IVDMIA and ASR guidance documents, once they are finalized and go into effect. Taking the lead, both the American Clinical Laboratory Association and the College of American Pathologists weighed in at the February public hearing, stating that CLIA has already provided sufficient safeguards for IVDMIAs. In addition, a newly formed group comprising mostly diagnostic companies called the Coalition for 21st Century Medicine (www.twentyfirstcenturymedicine.org) has been focusing on the IVDMIA guidance. On the same day of the public hearing, the coalition sent out a press release stating that “FDA should go through formal rule making procedures and carefully consider the alternatives.”

In July, FDA issued the second draft of the IVDMIA guidance. The new draft adopted the concept of a transition period and modified the IVDMIA definition. However, the agency continued to claim that the devices are subject to FDA regulation and that it will use the guidance document process instead of rule making. Stay tuned as the IVD industry and FDA will surely continue the discussion.