A green and black spiral pattern

A recent shift in the Department of Health and Human Services’ (HHS) approach to regulation of laboratory developed tests (LDTs) has left the waters surrounding these tests murkier than ever and has many in the laboratory community concerned about duplicative oversight.

Department of Health and Human Services (HHS) Secretary Xavier Becerra said in November that the agency was withdrawing a policy established under the Trump Administration that limited the Food and Drug Administration’s (FDA) review of LDTs. The Trump Administration’s move was designed to speed up access to newly developed tests for SARS-CoV-2. Prior to the Trump Administration policy, FDA had used “enforcement discretion” in its regulatory approach to LDTs. Essentially, this meant that FDA employed a hands-off approach to LDTs unless there was a specific need to regulate them.

Jeff Shuren, MD, director of FDA’s Center for Devices and Radiological Health, said in a statement in November that the latest actions were aimed at increasing access to “accurate and reliable” SARS-CoV-2 tests. But what exactly does this action mean for other LDTs? Will FDA start cracking down on tests developed by labs for use in-house? Probably not, according to experts, who note that FDA has not pursued oversight of LDTs unless there are known problems with them or in the case of a public health emergency.

 “FDA has generally not enforced premarket review and other applicable FDA requirements for most LDTs, except in certain situations such as declared public health emergencies or when a test or tests pose a significant public health concern,” said an FDA spokesperson in an email.

But even if FDA maintains a laissez-faire approach to most LDTs, dueling bills in Congress have the potential to shake up the field.

Long-Time Debate

The recent action by HHS does nothing to deal with the long-time debate over whether FDA should have oversight authority over LDTs. Many in the lab community, including AACC, emphasize that these tests are already regulated under CLIA. All LDTs are classified as high-complexity tests, and labs performing them must comply with rigorous quality control, proficiency testing, and personnel requirements—and must demonstrate the test’s analytical validity. Although CLIA does not require clinical laboratories to establish clinical validity, the major private sector accrediting organizations, such as the College of American Pathologists and the Joint Commission, do require that labs document clinical validation.

Manufacturers of diagnostic test kits, however, have long argued that LDTs should be required to go through the same review process as the IVD industry.

Figuring out how to protect the need for testing for rare disorders while also ensuring the safety of patients subject to tests that have not gone through an extensive outside review process is difficult and has fueled debate for years.

Patricia Jones, PhD, clinical director of the Chemistry and Metabolic Disease Lab at Children’s Medical Center in Dallas, and chair of AACC’s Policy & External Affairs Core Committee, acknowledges that FDA oversight of COVID-19 testing is a difficult balancing act, especially with the number of “pop-up” laboratories established to offer SARS-CoV-2 tests. But she believes that the vast majority of LDTs—tests that are developed in-house and run only in that particular laboratory—are already sufficiently regulated under CLIA and should not be regulated by FDA.

“We don’t need double regulation,” Jones said. “We need better definitions. The tests I develop in my laboratory, I use for my patients. I don’t sell them for others to perform, and I don’t market them.” Jones added that most LDTs are developed because there is not already an FDA-approved test available, and in her lab, they are mostly used to diagnose rare conditions, such as genetic abnormalities in newborns.

“We’re talking about [phenylketonuria] or maple syrup urine disease—these are not simple tests, they require 20-step extractions,” she said. “If we had to file with FDA and go through premarket review for all of these tests, we probably would stop doing them altogether.”

Dennis Dietzen, PhD, professor of pathology and immunology at Washington University in St. Louis, agrees. “LDTs fill a void where there is no FDA-approved test,” he said. “We need to be able to build these things with a healthy amount of regulation, but not a burdensome amount of regulation. We don’t make any money running LDTs. If labs had to go through premarket review for all their LDTs, it would make the assays more expensive to run, and I think a lot of laboratories would just throw in the towel.”

Both Jones and Dietzen believe that LDTs developed by large reference laboratories that sell these tests for profit should be treated differently than LDTs that are used only in a single laboratory. “That’s a different ball game,” noted Dietzen. “When you start to market them broadly, the tests look less like traditional LDTs, and the regulatory bar might need to be a bit different.”

Risk-Based Oversight

Over the years, many have argued that FDA oversight of LDTs should be based on risk. Most recently, an October 2021 report by the PEW Research Center, "The Role of Lab Developed Tests in the In Vitro Diagnostics Market," made the case for such an approach. The report maintained that while the LDT regulatory process offers labs significant flexibility and enables a more rapid response to public health needs when no FDA-cleared or -approved test exists, the relative lack of oversight for LDTs puts the health of patients at risk.

The current diagnostic testing regulatory system—in which tests are regulated according to where they are developed and used, rather than the risk they pose if they are inaccurate—creates double standards and potential loopholes that undermine public health objectives, the report said. The authors argued that while labs that develop LDTs are subject to Centers for Medicare and Medicaid Services regulation under CLIA, they are not required to demonstrate clinical validity or report cases of patient harm from their products, requirements that FDA applies to manufacturers that develop, distribute, or sell IVDs for use in multiple facilities.

“Although regulatory harmonization has been discussed for decades, the current dual system—and the public health vulnerabilities that it perpetuates—remains in force,” the report said. “The COVID-19 pandemic only underscores the need to establish a unified regulatory framework that ensures the safe and effective use of all tests.”

Two pieces of legislation are pending in Congress to tackle the thorny issue of LDT regulation. The Verified Innovative Testing in American Laboratories (VITAL) Act would place LDTs solely under the oversight of CLIA regulations and would exclude FDA from any oversight over LDTs, even during a public health emergency. AACC endorsed the bill in 2020.

The Verifying Accurate Leading-Edge IVCT Development (VALID) Act would explicitly grant FDA the authority to regulate LDTs through a risk-based format that categorizes LDTs as high-risk or low-risk, with high-risk tests facing approval requirements that are comparable to existing medical device regulations. The legislative proposal would unify the separate paradigms of traditional IVDs and LDTs into a common regulatory framework for in vitro clinical tests (IVCTs).

Notably, the measure would employ “technology certification” for LDTs that are not high risk. The developer of the test would submit FDA information on a representative test, along with an assessment of the developer’s methods and procedures for test development, validation, and maintenance. If FDA granted approval, the test developer would be able to modify the test or develop related versions of the test within the scope of that approval.

Jochen Lennerz, MD, PhD, medical director of the Massachusetts General Center for Integrated Diagnostics, believes that the concept of technology certification could bridge the gap between FDA review of all LDTs and no FDA review of any LDTs. In a September 2021 study that examined how FDA regulated SARS-CoV-2 LDTs and what this might mean for the broader universe of LDTs, Lennerz suggested that technology certification, which was used to validate SARS-CoV-2 tests, could serve as a blueprint for regulation of LDTs (Journal of Molecular Diagnostics 2021; doi: 10.1016/j.jmoldx.2021.07.011).

However, both Jones and Dietzen maintain that technology certification is not the answer. “For one thing, it’s still far from clear how it would actually work,” Jones said. “More importantly, though, it’s still duplicate regulation, and it appears to be almost as onerous as the usual premarket approval process.”

Many in the laboratory community, including AACC, warn that a new regulatory framework could disrupt innovation and limit patient access if clinical laboratories face new requirements, such as FDA registration, quality requirements, investigational studies, premarket review and approval, adverse event reporting, and product corrections and removals.

AACC supports modernizing CLIA to ensure that it continues to meet the changing needs of the healthcare community and recommends that revisions to the regulations deal with the laboratory inspection process, quality control recommendations, proficiency testing requirements, and the definition of what constitutes an LDT.

“Much of the discussion pertaining to laboratory developed tests focuses on how the tests should be regulated rather than what constitutes an LDT,” AACC said in a December 2021 position statement, “Modernization of CLIA: Laboratory Developed Tests.”

“It is clear that a new test developed and used in one laboratory without FDA clearance or approval is an LDT. However, there is considerable uncertainty around when a modification to an approved or cleared test warrants the label of LDT.” AACC recommends a definition of LDTs that is based on the clinical claims of the laboratory and that would restrict the application of the term for modified tests to those with new clinical claims.

Lennerz agrees that it is important to note the distinction between tests based on novel biomarkers versus tests based on biomarkers that have already been established. “In this case, there should be two separate regulatory pathways,” he said, adding that there should also be two separate pathways for true novel LDTs that are used solely in a single lab and novel tests that are distributed outside the lab.

The VALID Act continues to be refined to address some of these concerns, Lennerz said, and he believes that the VITAL Act is unlikely to move forward. He believes those who oppose VALID have provided few concrete suggestions on just how CLIA would be reformed. To truly improve diagnostics regulation, Lennerz believes stakeholders either need to provide a detailed proposal on how to modernize CLIA or work to optimize the proposals in the VALID Act.

Those who oppose the VALID Act still maintain that FDA oversight of LDTs would be duplicative and that the regulatory framework proposed under VALID is misguided. In addition, AACC’s position statement lays out seven proposals for how clinical validity, third-party review, updated proficiency testing, and other measures can strengthen existing regulation under CLIA (See Sidebar page 12).

“In an ideal world, FDA reform would be independent of reform of LDTs,” Dietzen noted. “We believe that oversight of diagnostics does need some reform, but the VALID Act is not the right way to do it. Our preference would be to redo some of this regulation in terms of CLIA modernization.”

Kimberly Scott is a freelance writer who lives in Lewes, Delaware. +Email: [email protected]

AACC’s Position on Modernization of CLIA and Laboratory Developed Tests

In a position statement issued in December 2021, AACC argues that CLIA, under the Centers for Medicare and Medicaid Services (CMS), should remain the primary mechanism for overseeing clinical laboratories and laboratory-developed tests (LDTs). AACC also issues recommendations for modernizing CLIA to ensure it meets the healthcare community’s needs. Core recommendations of the document include:

  • CLIA should be updated to require laboratories to demonstrate that LDTs are clinically valid for use in medical decisions.

  • AACC encourages CMS to credential third-party organizations to review a laboratory’s clinical validation data for LDTs.

  • Additional guidance from CMS to laboratories performing LDTs is recommended to help ensure that the results consistently meet clinical needs and expectations.

  • AACC urges CMS and its deemed accrediting organizations to ensure that CLIA inspection teams include individuals with specialized method expertise to evaluate LDTs.

  • CMS should update CLIA proficiency testing (PT)requirements to allow for the addition or deletion of required analytes subject to PT and to reevaluate the number of challenges and scoring criteria.

  • AACC urges policymakers to define LDTs as "new" or significantly modified tests for which the modification alters the clinical claims.