FDA regulation of LDTs — an update

Sept. 2, 2015

Almost three years ago I had an article published in MLO about laboratory-developed test (LDT) regulation and what seemed to be coming from the U.S. Food and Drug Administration (FDA).1 Since then, there have been more than a few developments on this topic. Let’s revisit.

First some relevant background: LDTs have been in existence as long as labs have, and in the past their validation and performance have been regulated by the Clinical Laboratory Improvement Amendments of 1988 (CLIA) (42 CFR 493.1253(b)(2)) in all accredited laboratories. Initially, LDTs were developed primarily for local, and often specific-needs, populations. The lab developed a test intended to be used on its own patient population, and everything occurred under regulations of the agencies with laboratory oversight.

In the last several years, however, the FDA has claimed that it has always had oversight of LDTs, on the grounds that LDTs are in vitro diagnostic (IVD) “devices” which fall under its purview. This change in the regulatory climate has been spurred, to a large degree, by the boom in commercial laboratories and molecular diagnostic testing. Not only are hospital and reference labs continuing to provide LDTs to their own populations, but large commercial ventures are developing tests as LDTs, essentially circumventing FDA regulation and quality oversight of the IVD industry and, from the FDA’s perspective, putting the public health at risk. The FDA took note of the changing nature of LDTs and stepped up its regulatory activities. When I last wrote on this topic in these pages in October 2012, the FDA had released a draft guidance document about its intent to regulate all LDTs.

So what has happened since then? Quite a lot, actually. Despite considerable pushback from laboratory and biotech groups on the original draft document, including pushback on whether regulation of these LDTs actually falls within the FDA purview, in October 2014 the FDA released two new LDT regulatory draft guidance documents for a 120-day comment period.  These documents, “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)”2 and “FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs),”3 provide the FDA’s regulatory oversight framework and timeline, as well as the process to be required for clinical labs to inform the FDA of their current LDTs and institute various reporting requirements. 

In the framework document, the FDA makes a distinction between traditional and nontraditional LDTs. The first category includes low-risk LDTs developed by a single lab and used within a single hospital or patient population. For traditional LDTs, the FDA essentially proposes that the lab notify the FDA of its performance of such tests and implement adverse event reporting for the tests. Most hospital lab testing should fall into this category.

The second category includes LDTs that are not confined to a single healthcare system; are highly complex, with multi-signal devices and non-transparent algorithms; are used to direct critical treatment decisions; are made with components not marketed legally for clinical use; and/or are used widely to screen for common diseases rather than rare diseases. These tests will be classified as either moderate- or high-risk tests and will have significantly more regulation. This suggests that the organizations that will face the most FDA regulation are reference labs, hospital outreach systems, and biotechnology companies selling proprietary tests.

Thus the effect of this regulation and the burden on hospital labs will be determined by whether the FDA defines their tests as “traditional” LDTs or not. Note: the fact that a test is developed and implemented in a hospital lab does not necessarily make it “traditional.” In addition, development of any new LDTs would be required to follow the entire premarket process for determining level of risk prior to assay development. 

During the 120-day comment period on the new draft guideline, many groups have weighed in.4 The American Clinical Laboratory Association (ACLA) stated its concerns in a “Washington Report” published in MLO in November 2014.5 The American Association of Clinical Chemistry (AACC) published a position statement related to LDT regulation the same month.6 The Association for Molecular Pathology (AMP) had already published a statement in January 2014,7 recommending both that the FDA carefully consider its regulatory proposals and the damage they could do to the medical profession and that the FDA work with established laboratory regulatory agencies when they move forward.

In addition, a coalition of groups, including the AACC, ACLA, the American Medical Association (AMA), American Hospital Association (AHA), American College of Medical Genetics and Genomics (ACMG), and 45 others recommended to the FDA that it withdraw its guideline and move forward toward regulating LDTs by using notice and comment rulemaking process rather than simply finalizing the Guidance document.8 Using the rulemaking process would make the FDA responsible for an economic impact assessment of its regulatory proposal and require the agency to publicly respond to comments.

The FDA is pushing its LDT regulatory oversight forward; however, it is listening to all concerned parties. In May, the FDA announced an interagency taskforce is being assembled to look at LDT oversight, comprised at this point of the FDA and the Centers for Medicare and Medicaid Services (CMS). Other stakeholders will, it is hoped, be involved along the way.

No one doubts that oversight of LDTs is necessary in theory and needed in practice: LDTs have changed. (Whether they are legitimately to be considered as “devices” is another thing, however.) Clinical laboratory professionals hope that the task force will address two key questions: Is the FDA the best agency to provide that oversight? And, is the route the FDA is now taking the best way to provide it? Those are two of many questions currently being posed.

However those questions are addressed and eventually answered, LDT regulation will not be a quick process. The October 2014 Draft Guidance document and the FDA have laid out a nine-year time-frame for implementing full LDT regulation. In addition, the official, non-draft Guidance document will need to be published first. After that document has been published in final form, it appears that the FDA will focus on those LDTs it classifies as “high-risk” for the first several years. The general timeline the agency has put forward is as follows:

  • Immediate premarket review begins for all new, high-risk LDTs.
  • FDA notification of performance and adverse event reporting begins for all LDTs within the first six months.
  • Premarket review for certain high risk LDTs currently performed, including companion diagnostics, begins by the end of the first year.
  • The FDA will publish a priority list for all remaining high-risk LDTs by the end of the second year.
  • Premarket review for the first high-risk group will be completed by the end of year three.
  • In year four, the FDA will publish the list of moderate-risk LDTs.
  • Premarket review of all high-risk LDTs will be completed by the end of year five.
  • Premarket review of moderate-risk tests may take five to nine years to complete.

Laboratory and medical professionals and associations must continue to be vigilant and to make their voices heard with the FDA and all agencies which seek to regulate their operation. At this critical juncture, it’s imperative that clinical lab leaders be as much a part of the process of LDT regulation as possible. Everyone is striving for increased assurance of patient safety and improved patient care. To accomplish those goals, the profession and its regulators must find the best way to ensure that labs utilize LDTs to provide accurate and clinically useful information for maintaining health and for the most effective diagnosis and treatment of disease.


Jones PM. Laboratory developed tests: What may be coming. MLO. 2012.44(10):24-26. https://www.mlo-online.com/articles/201210/laboratory-developed-tests-what-may-be-coming.php. Accessed July 19, 2015.

Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs). Issued October 3, 2014. Accessed July 19, 2015. http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm416685.pdf. Accessed July 19. 2015.

FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs). Issued October 3, 2014. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM416684.pdf. Accessed July 19, 2015.

O’Reilly KB. FDA’s LDT proposal means “whole new ballgame” for labs. CAP Today online. October 2014. http://www.captodayonline.com/fdas-ldt-proposal-means-whole-new-ballgame-labs/?print=pdf. Accessed July 19, 2015.

Mertz A. Duplicative and unnecessary regulation of LDTs will hamper diagnostic innovation. MLO. 2014;46(11):44. https://www.mlo-online.com/articles/201411/duplicative-and-unnecessary-regulation-of-ldts-will-hamper-diagnostic-innovation.php. Accessed July 19, 2015.

AACC Position Statement: Oversight of Laboratory Developed Tests, November 2014. https://www.aacc.org/~/media/files/position-statements/laboratorydevelopedtestspositionstatement2014.pdf?roi=echo4-28748002775-52819957-01002a2f3973cd0600105462b033d3f6&. Accessed July 19, 2015.

Ferreira-Gonzalez A, Emmadi R, Day SP et al. Revisiting oversight and regulation of molecular-based laboratory-developed tests: a position statement of the Association for Molecular Pathology. J Mol Diagn. 2014;16[1]:3–6.

Coalition letter. November 2014. https://www.aacc.org/~/media/files/legislative-issues/2014/ama_ldt_letter.pdf?la=en. Accessed July 19, 2015.