The Future of Laboratory-Developed Tests

On October 3, 2023, the U.S. Food and Drug Administration (FDA) released its most recent proposal¹ regarding laboratory-developed tests (LDTs)—aiming to make it explicit that these tests are considered in vitro diagnostic devices and therefore subject to regulation and enforcement. The proposal also outlines a four-year plan to phase out the agency’s general enforcement discretion approach to LDTs and require them to meet the same regulatory requirements as other in vitro diagnostic devices.

Understandably, this proposal has raised concerns both within the laboratory community and among members of the public—but the FDA states that the rule “is aimed at helping to ensure safety and effectiveness of Laboratory Developed Tests.”² The agency highlights the risk false positive and negative results can carry for patients, the advances in LDT technology since the Medical Device Amendments of 1976, the frequent lack of transparency (especially with respect to algorithms and automation), and the increased impact modern LDTs have on diagnosis and management.

The public comment period for the proposed rule ended on December 4, 2023—and, with nearly 7,000 comments received,³ strong opinions were delivered on all sides.

Comments in favor

An anonymous commenter said, “LDTs developed by non-academia centers generally perform poorly and do not have any clinical studies supporting their use. Occasionally, proposed specimen types (e.g., urine, stool, saliva) don’t align with evidence-based medicine or traditional research.”⁴ The commenter, who stated that they are “a retired CLIA high-complexity remote laboratory director,” offered several examples from their career: a urine genomic sequencing panel unable to detect Staphylococcus species other than S. aureus, a stool sequencing test that falsely diagnosed Clostridioides difficile infection, influenza testing via saliva (not a recommended sample type), and wound swab sequencing that failed to quantify or confirm the viability of potential pathogens. On a commercial note, they added, “Many LDTs are offered by labs that use LDTs as a profit-based business model rather than a patient care means . . . Their direct payment is from the labs they approve tests for and create conflicts of interest, making them more inclined to approve inadequately validated assays.”

Claude Pritchard, a member of the public, agreed with a cautious approach and shared a number of observations regarding the scope of the proposed regulation, such as that it should include tests used in a law enforcement setting (“The FDA approval of such tests would likely enhance the fairness of the judicial system by increasing the accuracy and validity of such tests”) and those developed by laboratories of all sizes (“There is no difference in potential patient harm from faulty tests based on size of the lab”). Overall, he stated, “Approval of emergency use tests should be more tightly regulated, but the FDA should better weigh the risks against the benefits in granting approval.”⁵

A number of organizations also commented on the proposed rule. In an open letter, members of the Patient, Consumer, and Public Health Coalition stated, “We strongly support FDA’s conclusion that it has the authority to regulate all in vitro diagnostic tests, including laboratory-developed tests, under the Federal Food, Drug, and Cosmetic Act . . . We urge the FDA to phase out enforcement discretion as quickly as possible, with priority to the LDTs with the greatest implications for patients’ health and wellbeing.”⁶ The U.S. Public Interest Research Group shared this desire for haste, describing the proposed rule as “essential to patient safety” and calling for a shorter implementation timeframe. “We applaud the rule and urge the FDA to finalize the rule swiftly so the process to improve diagnostic accuracy of laboratory developed tests will begin,” the group wrote.⁷

Comments against

Reactions to the proposed rule were far from united, though, with many respondents questioning the need for extended regulation.

An anonymous commenter referred to the proposal as “regulatory overreach and unnecessary”⁸ given existing oversight via the Clinical Laboratory Improvement Amendments of 1988 (CLIA) regulations. “LDTs used in a laboratory are typically not large-scale manufactured medical devices and CLIA provides a regulatory mechanism to ensure accurate and reliable test results. When a laboratory develops a test system such as an LDT in-house . . . CLIA prohibits the release of any test results prior to the laboratory establishing certain performance characteristics relating to analytical validity for the use of that test system in the laboratory’s own environment, see 42 CFR 493.1253(b)(2).”⁹ The commenter also pointed out that few laboratories have the time, resources, and expertise to ensure that every LDT complies with extensive regulatory requirements. “Removing competition will not benefit our communities. The proposed rule will dramatically reduce the availability of tests and is unlikely to result in more accurate or reliable tests. This will result in needless delays and less innovation when new diagnostics are needed.”

Existing accreditation requirements were a common rebuttal to the proposed rule. “Lab tests are not medical devices and do not qualify as the same risk category,” said commenter K. Ski. “Labs certified by CAP/CLIA/NYS follow rigorous development and validation along with annual and even monthly verification. Instead of requiring labs to follow medical devices regulations which will waste excessive amounts of money/effort, the better path would be to require all lab testing to be certified by CAP/CLIA/NYS, which has the depth of knowledge and experience to best verify the safety/accuracy of lab testing.”¹⁰

The big picture

Overall, views on the FDA’s proposed LDT regulation are divided. Although experts and the public agree that medical testing should be safe, accurate, and reliable, they are less aligned on the best way to achieve these goals. Common threads included the need to maintain patients’ access to testing, concerns regarding potential effect on competition and innovation, queries around definitions and timeframes, and the benefit-cost ratio of adding a complex FDA approval process to labs already regulated by CLIA and other guidance. Numerous additional issues remain under debate, including whether and to what extent existing LDTs will be grandfathered, whether certain alternative programs would continue to fall under the FDA’s general enforcement discretion, and how—from a practical perspective—the new rule would be implemented, if approved.

There’s no set timeline for a decision on the rule; however, the proposed rule is included in the federal government’s Fall 2023 Unified Agenda of Regulatory and Deregulatory Actions with a final action date of April 2024.¹¹

References:

1. 1. U.S. Food and Drug Administration. Medical Devices; Laboratory Developed Tests. Federal Register. October 3, 2023. https://www.govinfo.gov/content/pkg/FR-2023-10-03/pdf/2023-21662.pdf.

1. 1. U.S. Food and Drug Administration. FDA’s Proposed Rule Regarding Laboratory Developed Tests. October 31, 2023. https://www.fda.gov/media/173457/download.

1. 1. U.S. Food and Drug Administration. Proposed Rule: Medical Devices; Laboratory Developed Tests. October 2, 2023. https://www.regulations.gov/document/FDA-2023-N-2177-0001.

1. 1. Anonymous. Comment from Anonymous. October 4, 2023. https://www.regulations.gov/comment/FDA-2023-N-2177-0125.

1. 1. Pritchard C. Comment from Claude Pritchard. October 4, 2023. https://www.regulations.gov/comment/FDA-2023-N-2177-0126.

1. 1. National Center for Health Research. Patient, Consumer, and Public Health Coalition Comments on the FDA Proposed Rule Regarding Laboratory Developed Tests. December 4, 2023. https://www.center4research.org/coalition-lab-developed-tests-guidance.

1. 1. Kelmar P. Re: Docket No. FDA-2023-N-2177 Medical Devices; Laboratory Developed Tests. December 1, 2023. https://publicinterestnetwork.org/wp-content/uploads/2023/12/U.S.-PIRG-Comments-to-FDA-rule-on-Laboratory-Developed-Tests-Dec-1-2023.pdf.

1. 1. Anonymous. Comment from Anonymous. October 11, 2023. https://www.regulations.gov/comment/FDA-2023-N-2177-0137.

1. 1. Centers for Medicare & Medicaid Services. § 493.1253 Standard: Establishment and verification of performance specifications. December 7, 2023. https://www.govinfo.gov/content/pkg/CFR-2022-title42-vol5/pdf/CFR-2022-title42-vol5-sec493-1253.pdf.

1. 1. Ski K. Comment from K ski. October 9, 2023. https://www.regulations.gov/comment/FDA-2023-N-2177-0136.

1. 1. Office of Information and Regulatory Affairs. Fall 2023 Unified Agenda of Regulatory and Deregulatory Actions. December 7, 2023. https://www.reginfo.gov/public/do/eAgendaViewRule?pubId=202310&RIN=0910-AI85.