Defining "High Risk"
Another major issue that will fundamentally affect the impact of the policy relates to its reach. While many speakers agreed FDA should play a role in regulating high-risk LDTs, there is not an agreement as to which tests fall into that category. Classifying the criteria will not be easy but it will be vital, since it will determine which LDTs will need to comply with FDA requirements.
To FDA, high risk means the risk to the patient of an incorrect result. FDA does not consider the risk/benefit ratio. Nor is performance likely to be a factor—a test will still be high risk even if the assay has excellent sensitivity and specificity. However, in conversations with laboratory personnel, they rarely say their test is high risk—they point to someone else’s test instead as an example of a test that ought to be regulated.
Clear criteria are also important for another reason—uncertainty imposes its own costs on innovation and investment. The lack of clarity as to which regulatory scheme applies to a particular test can itself chill innovation.
FDA has a fairly well-developed system now for classifying IVD kits. However, companies still cannot always predict whether they will need a 510(k) or premarket approval application, and FDA cannot always tell manufacturers up front how they will be classified. Developing a clear, straightforward approach to stratifying tests as high risk (or whatever the threshold is) will be indispensable.
Another important issue is ensuring that low-volume tests are not impeded. Many tests will not be offered if device regulation applies, because the costs will be too great for the limited market. The Humanitarian Use Device program—the device analogue to orphan drugs—has a low ceiling: 4,000 patients tested per year.
There was broad agreement at the meeting that maintaining patient access to low-volume LDTs is important. Regulating LDTs for small populations will have unintended negative consequences. In many cases, companies would not offer IVDs because sales would be too low in comparison with the regulatory costs. The details of how the regulatory scheme would protect are unsettled.
A related concern is that once a product is cleared or approved, any significant modifications may trigger the need for a new FDA clearance or approval. LDTs are often modified. This may result from new technology, enhanced clinical understanding of the disease, new biomarkers, improved bioinformatics, or evolving diseases.
IVD kit companies sometimes defer making improvements because of the costs and time needed to go through the regulatory process. Applying the same model to LDTs could level the playing field but also delay or prevent beneficial improvements in the test.