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March 4, 2022

SARS-CoV-2 Laboratory-Developed Tests: Integrity Restored

Author Affiliations
  • 1Department of Medical Science, Brown University, Providence, Rhode Island
  • 2Harvard Law School, Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics, Cambridge, Massachusetts
JAMA. 2022;327(13):1229-1230. doi:10.1001/jama.2022.3382

On November 15, 2021, the US Department of Health and Human Services (HHS) rescinded a Trump-era policy that had directed the US Food and Drug Administration (FDA) to discontinue the premarket reviews of laboratory-developed tests (LDTs), including those for SARS-CoV-2.1 In a statement detailing the reversal, HHS Secretary Xavier Becerra noted that the policy “limited FDA’s ability to address certain problematic COVID-19 tests.”1 Secretary Becerra also noted that restoring the integrity of the regulatory process required that the FDA reinstate its “longstanding approach” to the oversight of the LDTs.1 Given the ever-growing demand for LDTs for detecting SARS-CoV-2, the restoration of integrity to the FDA review process could not be more timely. In this Viewpoint, we review the regulatory oversight of the LDTs, discuss its recent policy permutations, and explore potential future considerations.

Regulatory Oversight

LDTs constitute a subset of in vitro diagnostic devices (IVDs) that the FDA regulates. As a rule, LDTs make use of “general purpose reagents” (eg, pH buffer) and “analyte-specific reagents” (eg, antibodies or primers and probes) that are “intended for clinical use” and “designed, manufactured, and used within a single laboratory.”2 A “single laboratory” denotes a “facility with a single CLIA certificate” issued by the Centers for Medicare & Medicaid Services (CMS). Enabled by the Clinical Laboratory Improvement Amendments (CLIA) of 1988, CMS is entrusted with the “accreditation, inspection and certification process for laboratories.” Only those laboratories certified to conduct high-complexity testing can develop, validate, and use LDTs per CLIA.

The FDA has the discretionary role to ascertain the safety and effectiveness of LDTs as well as the quality of their design and manufacture. Diagnostic tests that do not meet the definition of an LDT but are being marketed or used as one may be deemed incompliant with the Federal Food, Drug, and Cosmetic Act and as such may be subject to FDA intercession. CMS, in turn, is entrusted with determining whether the test meets the specification that the laboratory has set. The FDA, for its part, reviews if the test validations are appropriate and if the performance quality of the test is sufficient to be safe and effective.

The regulation of LDTs by the FDA has been evolving for some time.2 This reality is due, in part, to the increase in the number and complexity of LDTs. LDTs do not generally require FDA clearance or approval before use due to “enforcement discretion.” It follows that most LDTs have neither undergone premarket review nor received FDA clearance or approval. A major exception to this regulatory policy was the oversight of LDTs or their components that were destined for direct-to-consumer commercial marketing or for home specimen collection. Special attention was also being paid to those LDTs that were deemed to be of the higher-risk variety in terms of potential risk and harm to patients.

Recent Policy Developments

On February 29, 2020, in the face of a plethora of high–complexity SARS-CoV-2 LDTs, the FDA proceeded to reaffirm the requirement that all laboratories secure Emergency Use Authorization (EUA) for any and all LDTs prior to their deployment to expedite access to validated LDTs during an emergency. The rationale for this added level of FDA oversight was reinforced on April 24, 2020, by the Oversight Subcommittee on Economic and Consumer Policy of the House of Representatives according to which “numerous companies appear to be marketing fraudulent [SARS-CoV-2] tests.”3

On August 19, 2020, the HHS announced that, effective immediately, the FDA will not “require premarket review for these tests absent a notice-and-comment rulemaking process.”4 The categories of premarket reviews affected by the new policy included application approvals, 510(k) clearance submissions, and EUA requests. It followed that going forward, LDTs (including SARS-CoV-2 LDTs) could be marketed without a premarket review by the FDA. The HHS announcement, applicable to all LDTs, went on to state that the new regulatory policy could not be modified absent the conduct of “a notice-and-comment rulemaking” process by the FDA. Although lacking in a stated rationale, the policy reversal was positioned by HHS as one meant to reduce regulatory barriers that hinder the development of novel diagnostics and reduce patient access to clinical tests. This line of reasoning, however, ran counter to the conclusions of an earlier survey of the Association of Molecular Pathology members, according to which the path of SARS-CoV-2 LDTs to the market was determined to be largely unencumbered.

The decision to curtail rather than enhance the authority of the FDA drew wide-ranging expressions of concern as to the future safety of SARS-CoV-2 LDTs. Representative Frank Pallone (D, New Jersey), chair of the House Committee on Energy and Commerce, requested an immediate briefing from then HHS Secretary Alex M. Azar II. A similar request was made by Senator Patty Murray (D, Washington), ranking member of the Senate Health, Education, Labor, and Pensions Committee. The curtailment of the authority of the FDA was also opposed by former FDA Commissioner Scott Gottlieb, MD, who foresaw a “plethora of [direct-to-consumer] COVID tests…outside FDA oversight.”5 Similar concerns were articulated by senior FDA officers who noted that “in analyzing 125 EUA requests from laboratories, we identified 82 with design or validation problems, and several have been denied authorization.”6

However, in late 2020, the reinstatement of the regulatory authority of the FDA over LDTs was just a matter of time. A formal congressional request to this effect was submitted in May 2021 to Secretary Becerra by Representatives Pallone, Anna Eshoo (D, California), and Diana DeGette (D, Colorado). Acting on behalf of the Energy and Commerce Committee, the congressional leaders requested that steps be taken “to ensure the quality of these tests by reversing the…misguided policy on LDTs and restoring FDA’s premarket review authority.”7 Similar concerns were raised by the American Clinical Laboratory Association and the Pew Charitable Trust. The latter made special note of the recent class I recall8 of SARS-CoV-2 LDTs (marketed by Lepu Medical Technology) due likely to “a high risk of false results.” Other examples of recalled SARS-CoV-2 LDTs include, but are not limited to those manufactured by Ellume, Abbott Molecular Inc, Empowered Diagnostics, Innova Medical Group, and Acon Laboratories, to name a few. On November 15, 2021, Secretary Becerra had officially restored the authority of the FDA to regulate all LDTs including those focused on the diagnosis of SARS-CoV-2.1

Future Considerations

Going forward, the locus of authority for the regulation of the LDTs may well be determined by Congress. The bipartisan and bicameral Verifying Accurate Leading-edge IVCT Development Act of 2021,9 a bill introduced by Representatives DeGette and Larry Bucshon (R, Indiana) as well as by Senators Michael Bennet (D, Colorado) and Richard Burr (R, North Carolina), seeks to establish a new FDA authority for the regulation of in vitro clinical tests (IVCTs) including LDTs. In contrast, the Verified Innovative Testing in American Laboratories Act of 2021,10 a bill introduced by Senator Rand Paul (R, Kentucky), would place the regulatory responsibility for LDTs with CMS (under its CLIA authority) rather than with the FDA. Whether the aforementioned bills will be brought for a vote during the current session of the 117th US Congress remains uncertain. Until such time, however, uncertainties as to the long-term locus of regulation of LDTs are destined to persist. The above notwithstanding, the recent reinstatement of FDA oversight over SARS-CoV-2 LDTs helps ensure that higher-quality products proceed to the market and that they do so in a timely fashion.

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Article Information

Corresponding Author: Eli Y. Adashi, MD, MS, Department of Medical Science, Brown University, 222 Richmond St, Providence, RI 02903 (eli_adashi@brown.edu).

Published Online: March 4, 2022. doi:10.1001/jama.2022.3382

Conflict of Interest Disclosures: Dr Cohen reported serving on the bioethics advisory board of Illumina Serves, as a bioethics consultant for Otsuka and for DawnLight, and the bioethics council of Bayer. No other disclosures were reported.

Statement by HHS Secretary Xavier Becerra on withdrawal of HHS policy on laboratory-developed tests. November 15, 2021. Accessed December 16, 2021. https://www.hhs.gov/about/news/2021/11/15/statement-hhs-secretary-xavier-becerra-withdrawal-hhs-policy-laboratory-developed-tests.html
Genzen  JR.  Regulation of laboratory-developed tests.   Am J Clin Pathol. 2019;152(2):122-131. doi:10.1093/ajcp/aqz096PubMedGoogle ScholarCrossref
Preliminary findings of the subcommittee’s coronavirus antibody testing investigation. House of Representatives Committee on Oversight and Reform. To: Democratic Members of the Subcommittee on Economic and Consumer Policy. Subcommittee staff memorandum. April 24, 2020. Accessed December 16, 2021. https://oversight.house.gov/sites/democrats.oversight.house.gov/files/ECP%20Staff%20Report%20on%20Preliminary%20Findings%20of%20the%20Subcommittee%E2%80%99s%20Coronavirus%20Antibody%20Testing%20Investigation.pdf
Congressional Research Service. HHS announcement on FDA premarket review of laboratory-developed tests (LDTs). December 3, 2020. Accessed December 16, 2021. https://crsreports.congress.gov/product/pdf/IN/IN11548
@scottgottliebmd. We'll see a plethora of DTC Covid tests enter the market, where tests ship directly to consumers and are processed in a central lab operating outside FDA oversight. CMS oversees lab operations, but there’s no process for ensuring clinical accuracy prior to coming to market 10/x. August 22, 2020. Accessed December 16, 2021. https://twitter.com/scottgottliebmd/status/1297157024594223104
Shuren  J, Stenzel  T.  Covid-19 molecular diagnostic testing—lessons learned.   N Engl J Med. 2020;383(17):e97. doi:10.1056/NEJMp2023830PubMedGoogle Scholar
E&C health leaders urge secretary Becerra to restore FDA’s Authority over COVID-19 LDTs. News release. House Committee on Energy and Commerce. May 11, 2021. Accessed February 25, 2022. https://energycommerce.house.gov/newsroom/press-releases/ec-health-leaders-urge-secretary-becerra-to-restore-fda-s-authority-over
US Food and Drug Administration. Stop using Lepu Medical Technology SARS-CoV-2 antigen and leccurate antibody tests: FDA safety communication. May 28, 2021. Accessed December 16, 2021. https://www.fda.gov/medical-devices/safety-communications/stop-using-lepu-medical-technology-sars-cov-2-antigen-and-leccurate-antibody-tests-fda-safety
Verifying Accurate Leading-edge IVCT Development Act of 2021. HR 4128, 117th Cong, 1st Sess (2021). Accessed December 16, 2021. https://www.congress.gov/bill/117th-congress/house-bill/4128/text?
Verified Innovative Testing in American Laboratories Act of 2021. S 1666, 117th Cong, 1st Sess (2021-2022). Accessed December 16, 2021. https://www.congress.gov/bill/117th-congress/senate-bill/1666?s=1&r=28
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