Home 5 Clinical Diagnostic Insider 5 FDA’s LDT Proposal Raises Questions About Clinical Validity

FDA’s LDT Proposal Raises Questions About Clinical Validity

by | Nov 22, 2023 | Clinical Diagnostic Insider, FDA-dtet

Debate is underway on whether current CLIA review of LDTs properly assesses a test’s likelihood to detect diseases.

As the public comment deadline approaches for a proposed federal rule to further regulate laboratory-developed tests (LDTs), lab scientists find themselves in a debate with the larger medical community about determining the clinical validity of such tests.

The proposal by the U.S. Food and Drug Administration (FDA) aims to bring LDT oversight under premarket review, similar to other in vitro diagnostic (IVD) devices. The agency cited patient safety concerns as a prime motivation to move LDT authority to the FDA from the Clinical Laboratory Improvement Amendments of 1988 (CLIA).

“The FDA is reacting to a real issue, but it is a relatively small issue in the global perspective of laboratory medicine and its practice in the United States,” says Steven Kroft, MD, chair of pathology at the Medical College of Wisconsin and medical director at Wisconsin Diagnostic Laboratories. “I don’t think anyone disagrees that there are opportunities for better oversight of certain types of tests, such as high-risk tests. The problem is, right now the FDA is proposing a blunt-force solution that threatens to incapacitate the lab industry.”

Can labs extrapolate clinical validity?

The FDA noted that CLIA does not assess a test’s clinical validity—in other words, whether the test accurately identifies a disease or other clinical condition in a patient. The New England Journal of Medicine threw its weight into the discussion with a November 4 piece that supported the FDA’s move.1

The article’s authors argued that because LDTs are currently handled under CLIA, review focuses on analytic validity (e.g., accurately identifying a biomarker or other characteristic) rather than clinical validity.

“Furthermore, results from LDTs are sometimes used to guide treatment selection, even in the absence of prospective, comparative data demonstrating utility,” the article stated. “In oncology, a large proportion of genomic information obtained by consumers from third-party companies is never confirmed in clinical settings, is based on tests with inconsistent measures of performance (e.g., sensitivity and specificity; positive and negative predictive value), and doesn’t result in substantial changes in clinical management.

These limitations can lead to misdiagnosis, increased unnecessary testing, and patient stress—or, conversely, insufficient follow-up—if adequate counseling isn’t provided,” the authors continued.1

Steven Kroft, MD

However, Kroft contends that clinical validity is often assessed by labs using LDTs, even if it is indirectly. “Take a step back and look at a test measuring an analyte,” he says. “The analyte that the test measures almost always has clinical validity. In other words, knowing whether someone has the Philadelphia chromosome clearly distinguishes chronic myeloid leukemia from other processes.”

Clinical validity can at times be directly determined by a lab, and in other cases, it is extrapolated from existing research and industry knowledge.

“To the FDA’s point, labs often don’t take it to that next level of specificity around clinical validity,” he adds. “But in most cases, it doesn’t really matter, because we already know from the entire body of literature that if we measure the analyte accurately, we’re predicting what we need to predict.”

FDA pushes ahead with December 4 deadline for LDT comments

In a curt post, the U.S. Food and Drug Administration (FDA) noted that it will not extend the public comment period for its proposed rulemaking about laboratory-developed tests past December 4.

While acknowledging that the agency has received requests from the lab industry for more time to comment on the proposal, the FDA said, “After considering the requests and other factors, including the extensive background of public comment on this topic and the public health benefits of proceeding expeditiously, the FDA has determined to proceed with the standard 60-day comment period.”4

The agency provided no further explanation.

An online campaign by the American Society for Clinical Pathology is underway to push the FDA to reconsider its decision.5

FDA draws parallels between IVDs and LDTs

On December 4, the public comment window will close for the proposed LDT rule. As of November 22, the FDA has received more than 4,700 comments about the proposal. The FDA indicated it will not extend the comment period (see sidebar).

Key to the proposal’s wording is the idea that LDTs are akin to IVDs. “FDA is proposing to amend its regulations to make explicit that IVDs are devices under the [Food, Drug, and Cosmetic] Act, including when the manufacturer of the IVD is a laboratory,” the agency wrote in its proposed rule, published on October 3.2

The proposal also explicitly calls for an end to what the FDA calls “discretionary enforcement” of LDT oversight, a phrase that generally refers to LDT review being conducted under CLIA.

“FDA is also proposing a policy under which FDA intends to phase out its general enforcement discretion approach for LDTs so that IVDs manufactured by a laboratory would generally fall under the same enforcement approach as other IVDs,” the agency wrote.2

This four-year phaseout, if completed as outlined in the proposed rule, could end by 2028, after which point any new LDT requirements would be fully in effect. As previously reported by G2 Intelligence, the proposal carries a hefty price tag in terms of estimated premarket review costs: anywhere from $2.4 billion to $19 billion per year for each of the next 20 years. The FDA estimates patient-related benefits for that same period range from $1.8 billion to more than $86 billion per year.3


  1. https://www.nejm.org/doi/full/10.1056/NEJMp2307585
  2. https://www.federalregister.gov/documents/2023/10/03/2023-21662/medical-devices-laboratory-developed-tests
  3. https://www.g2intelligence.com/fda-proposal-for-ldts-risks-serious-consequences/
  4. https://www.fda.gov/medical-devices/in-vitro-diagnostics/laboratory-developed-tests
  5. https://www.ascp.org/content/news-archive/news-detail/2023/11/02/fda-rejects-requests-to-extend-ldt-proposed-rule-comment-period#

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