In a recent letter to the Office of Management and Budget (OMB), the directors of 23 major clinical labs urged OMB to reject FDA’s draft guidance on LDT regulation. In this letter, one of the reasons given for rejecting FDA regulation of LDTs is that it would stifle innovation.

This post will look in a bit more detail at this issue of biomarker innovation, while ignoring completely the issue of safety. The need for safer testing is the primary argument for FDA oversight of LDTs, and while surely an important one to explore, is a topic for another post (and one which I am not currently in a position to write, lacking quantitative data on adverse events from improperly validated LDTs and IVDs).

Since the draft guidance has yet to be released by OMB, despite a recent request by five U.S. senators (and my recent FOIA request!), we are unable to assess the specific impacts that FDA regulation would have on LDTs and innovation. We can, however, make conclusions about the general potential for adverse impacts by looking at two of the defining characteristics of FDA review processes over the last decade.

1. FDA Moves Most Slowly with Biomarker-Based Tests

Of all the medical devices that FDA reviews, it takes the longest with biomarker-based IVDs, and has increased its average review period by 300% since 2003. In 2003 it took an average of 78 days for FDA to clear a biomarker-based IVD by 510(k), and in 2013 it took an average of 233 days. Of the 102 biomarker-based tests cleared by FDA in 2013, over 10% were under review for over a year.

Variability in review periods has also increased dramatically, with the standard deviation growing from 60 days to 146 days over the decade.

As we have previously reported, review periods have in fact decreased over the last two years, a positive trend surely, but a recent and relatively modest one as well. Review periods still remain very long compared to historic averages.

In their letter to OMB, the lab directors also point out that manufacturers of tests that have already been cleared or approved by FDA can be reluctant to add new claims or improvements to their tests, due to the costly burden of further FDA review.

2. Novel Biomarkers Rarely Come to Market in Tests Reviewed by FDA

At least partially as a consequence of these increasingly long review periods, an average of only 3 novel biomarker targets per year have made their way into FDA-cleared and approved tests over the last decade. While the exact figures for novel targets being released in LDTs over the same period are unavailable due to the lack of a central LDT registry, it is clear to anyone who watches the industry closely that the number is vastly higher.

In highlighting this point in their letter to OMB, the lab directors specifically called out the impact that novel biomarkers have had on improving cancer care, with some cancer biomarkers being available in an LDT “almost a decade” before an approved or cleared test was released.

The directors also pointed out that many LDTs serve patient populations that are too small to justify the investment in a cleared or approved IVD under current regulatory requirements, and so restricting their use could harm at-risk and under-served patient populations. This point should not be taken lightly in terms of its impact on modern healthcare.

Speaking from my own prior experience as CEO of MitoSciences (now part of Abcam) we helped a physician/researcher at Children’s Hospital of Philadelphia to validate our lateral flow immunoassay for frataxin as a diagnostic LDT for Friedreich’s Ataxia, the most common form of inherited ataxia.

This was before sequencing was in regular clinical use, and the the test was able to contribute to shortening the diagnostic odyssey that so many families suffered with inherited diseases. There is no way that it could have been a marketable cleared or approved IVD, but it helped to solve a key need for a period.


Seeking FDA clearance or approval can cause the death of promising diagnostics companies, or hold back market penetration in competitive spaces. Whether 510(k) or PMA, FDA review is a costly and time-consuming process that would place considerable burdens on the LDT market if applied directly in either of its forms.

LDT developers also face their own market challenges in reimbursement and adoption, which often require validation through clinical studies as for cleared and approved IVDs. These studies can be burdensome enough to shutter companies, so the pressure for validation is already extent in the market as a necessary check on innovation.

LDT developers are the fastest growing segment of the biomarker-based test market, and capital markets are rewarding them. The impact of LDT regulation on biomarker innovation could be significant, and has hopefully been considered carefully by FDA in drafting its proposed regulatory framework.