In this blog, I've referred several times to Scite.AI, a subscription service that brings specialized AI and writing skills to PubMed.
One feature is "Scite Assistant" which drafts initial articles on a requested topic. Here's the request:
Provide a summary of major historical policy articles that review the FDA's authority and history in efforts to regulate Laboratory Developed Tests.
Here's the output back to me, generated by Scite in a few seconds.
Its initial response didn't include 2023-2024 citations, so I asked again and got that. I print the original essay below, and then, the 2023-2024 update. I show one comprehensive bibliography at bottom. (Scite.AI cited a paper where I'm a coauthor; Huang). Note that SCITE knows it should spell out terms before using abbreviations.
OUTPUT PART ONE
Provide a summary of major historical policy articles that review the FDA's authority and history in efforts to regulate Laboratory Developed Tests.
Historically, LDTs have been developed and utilized within individual laboratories without the stringent oversight that applies to commercially manufactured in vitro diagnostics (IVDs). This regulatory landscape began to shift notably in the early 2010s when the FDA expressed intentions to assert its authority over LDTs, which had previously been largely unregulated under the Clinical Laboratory Improvement Amendments (CLIA) of 1988 (Vance, 2011; Sharfstein, 2015; Genzen et al., 2017).
In 2014, the FDA released draft guidance proposing a framework for the regulation of LDTs, which sparked considerable debate among stakeholders, including laboratory professionals and public health advocates. The guidance aimed to ensure that LDTs meet the same standards of safety and effectiveness as other medical devices, particularly in light of concerns regarding the accuracy and reliability of these tests (Ratner, 2014; Caliendo et al., 2016). The Infectious Diseases Society of America and other professional organizations voiced apprehensions that stringent regulations could limit access to essential diagnostic tests, particularly in the context of infectious diseases (Caliendo et al., 2016; Sidawy, 2015).
The FDA's approach has been characterized by a recognition of the unique role that LDTs play in clinical practice, particularly in areas where commercial tests are unavailable or inadequate. For instance, the FDA has acknowledged that LDTs are often tailored to meet specific patient needs and can provide critical diagnostic information, especially in rapidly evolving fields such as pharmacogenomics and infectious disease testing (Adashi & Cohen, 2022; Gill et al., 2021; Hillebrenner et al., 2015). However, the lack of uniform oversight has raised concerns about variations in test quality and the potential for misleading results, which can have serious implications for patient care (Genzen, 2019; Huang et al., 2021).
Recent developments, particularly during the COVID-19 pandemic, have further highlighted the need for a regulatory framework that can adapt to emerging public health needs. The FDA's Emergency Use Authorization (EUA) process allowed for the rapid deployment of LDTs for SARS-CoV-2 testing, demonstrating the agency's capacity to exercise oversight in urgent situations (Marble et al., 2021; Schreier et al., 2019). This experience has prompted discussions about the future of LDT regulation, including potential legislative reforms such as the Verifying Accurate Leading-edge In Vitro Clinical Test Development (VALID) Act, which seeks to create a more cohesive regulatory environment for both LDTs and traditional IVDs (Hillebrenner et al., 2015; Peaper et al., 2021; Rychert et al., 2022).
In summary, the historical trajectory of FDA regulation of LDTs reflects a growing recognition of the need for oversight that balances innovation with patient safety. As the landscape continues to evolve, ongoing dialogue among stakeholders will be crucial in shaping a regulatory framework that supports the development of high-quality diagnostic tests while ensuring their reliability and accessibility in clinical practice.
###
2023 2024
Do you have access to any articles about the FDA LDT regulations proposed in 2023 and finalized in 2024?
OUTPUT PART TWO
The regulatory landscape surrounding Laboratory Developed
Tests (LDTs) has undergone significant changes with the FDA's proposed rule
released in October 2023, which aims to end the enforcement discretion that has
historically allowed LDTs to operate outside the stringent regulatory framework
applied to commercial in vitro diagnostics (IVDs). This proposed rule has been
met with a mix of support and criticism from various stakeholders, reflecting
the complexities of ensuring patient safety while fostering innovation in
laboratory testing (Miller, 2024; Smith, 2024; Offit et al., 2023).
The proposed rule outlines a phased implementation plan that would require LDTs to undergo the same regulatory scrutiny as commercially available tests. This shift is intended to address concerns regarding the quality and reliability of LDTs, which have been developed and validated under the Clinical Laboratory Improvement Amendments (CLIA) but without the comprehensive oversight that the FDA applies to IVDs (Miller, 2024; Bogdanoski, 2024). Critics of the FDA's approach have expressed concerns about the potential impact on patient access to essential diagnostic tests, particularly in specialized areas where LDTs have historically filled gaps left by commercial offerings (Saitman, 2023; Smith, 2024).
In addition to the proposed rule, the ongoing discussions surrounding the Verifying Accurate Leading-edge IVCT Development (VALID) Act further complicate the regulatory environment for LDTs. This legislation aims to create a more cohesive regulatory framework that would encompass both LDTs and traditional IVDs, addressing some of the fragmentation in oversight that has characterized the field (Saitman, 2023; Offit et al., 2023). The VALID Act has been viewed as a potential solution to harmonize regulations and ensure that all diagnostic tests meet high standards of safety and efficacy (Offit et al., 2023).
The implications of these regulatory changes are profound, particularly in light of the COVID-19 pandemic, which highlighted both the critical role of LDTs in public health and the challenges associated with their regulation. The FDA's experience during the pandemic, where it granted Emergency Use Authorizations (EUAs) for numerous LDTs, has informed its current regulatory stance and the proposed rule (Miller, 2024; Bogdanoski, 2024). Stakeholders are now grappling with the balance between ensuring rigorous testing standards and maintaining access to innovative diagnostic solutions that are essential for patient care (Miller, 2024; Saitman, 2023).
In conclusion, the FDA's proposed rule and the discussions surrounding the VALID Act represent a pivotal moment in the regulation of LDTs. As the FDA seeks to assert greater oversight, the ongoing dialogue among clinicians, laboratory professionals, and regulatory bodies will be crucial in shaping a regulatory framework that supports both patient safety and the advancement of diagnostic testing.
Cumulative References (Both Original and 2023 Update)References:
Adashi, E. and Cohen, I. (2022). Sars-cov-2
laboratory-developed tests. Jama, 327(13), 1229.
https://doi.org/10.1001/jama.2022.3382
Bogdanoski, G. (2024). Translating the regulatory landscape
of medical devices to create fit‐for‐purpose artificial intelligence
(ai) cytometry solutions. Cytometry Part B Clinical Cytometry, 106(4), 294-307.
https://doi.org/10.1002/cyto.b.22167
Caliendo, A., Couturier, M., Ginocchio, C., Hanson, K.,
Miller, M., Walker, K., … & Frank, G. (2016). Maintaining life-saving
testing for patients with infectious diseases: infectious diseases society of
america, american society for microbiology, and pan american society for
clinical virology recommendations on the regulation of laboratory-developed
tests. Clinical Infectious Diseases, 63(2), 151-154.
https://doi.org/10.1093/cid/ciw260
Genzen, J. (2019). Regulation of laboratory-developed tests.
American Journal of Clinical Pathology, 152(2), 122-131.
https://doi.org/10.1093/ajcp/aqz096
Genzen, J., Mohlman, J., Lynch, J., Squires, M., &
Weiss, R. (2017). Laboratory-developed tests: a legislative and regulatory
review. Clinical Chemistry, 63(10), 1575-1584.
https://doi.org/10.1373/clinchem.2017.275164
Gill, P., Yu, F., Porter-Gill, P., Boyanton, B., Allen, J.,
Veerapandiyan, A., … & Schaefer, G. (2021). Implementing pharmacogenomics
testing: single center experience at arkansas children’s hospital. Journal of
Personalized Medicine, 11(5), 394. https://doi.org/10.3390/jpm11050394
Hillebrenner, E., Litwack, E., Bradley, P., Donigan, K.,
Lowe, T., Serrano, K., … & Gutiérrez, A. (2015). Fda oversight of
laboratory‐developed tests will facilitate adoption of
pharmacogenetic testing into routine clinical care. The Journal of Clinical
Pharmacology, 55(7), 728-730. https://doi.org/10.1002/jcph.521
Huang, R., Lasiter, L., Bard, A., Quinn, B., Young, C.,
Salgado, R., … & Lennerz, J. (2021). National maintenance cost for
precision diagnostics under the verifying accurate leading-edge in vitro
clinical test development (valid) act of 2020. Jco Oncology Practice, 17(11),
e1763-e1773. https://doi.org/10.1200/op.20.00862
Marble, H., Bard, A., Mizrachi, M., & Lennerz, J.
(2021). Temporary regulatory deviations and the coronavirus disease 2019
(covid-19) pcr labeling update study indicate what laboratory-developed test
regulation by the us food and drug administration (fda) could look like.
Journal of Molecular Diagnostics, 23(10), 1207-1217.
https://doi.org/10.1016/j.jmoldx.2021.07.011
Miller, M. (2024). Fda’s proposed rule for the regulation of
laboratory-developed tests. Journal of Clinical Microbiology, 62(2).
https://doi.org/10.1128/jcm.01488-23
Offit, K., Sharkey, C., Green, D., Wu, X., Trottier, M.,
Hamilton, J., … & Stadler, Z. (2023). Regulation of laboratory-developed
tests in preventive oncology: emerging needs and opportunities. Journal of
Clinical Oncology, 41(1), 11-21. https://doi.org/10.1200/jco.22.00995
Peaper, D., Rhoads, D., Sullivan, K., Couturier, M.,
Humphries, R., Martin, I., … & Wojewoda, C. (2021). Considerations from the College of american pathologists for implementation of an assay for sars-cov-2
testing after a change in regulatory status. Journal of Clinical Microbiology,
59(10). https://doi.org/10.1128/jcm.01167-21
Ratner, M. (2014). Fda pushes for control over
laboratory-developed tests. Nature Biotechnology, 32(9), 855-855.
https://doi.org/10.1038/nbt0914-855a
Rychert, J., Schmidt, R., & Genzen, J. (2022).
Laboratory-developed test orders in an academic health system..
https://doi.org/10.1101/2022.12.12.22283358
Saitman, A. (2023). How the VALID act could affect patient
access to laboratory developed testing for therapeutic drug monitoring. Journal
of Mass Spectrometry and Advances in the Clinical Lab, 28, 56-59.
https://doi.org/10.1016/j.jmsacl.2023.02.004
Schreier, J., Feeney, R., & Keeling, P. (2019).
Diagnostics reform and harmonization of clinical laboratory testing. Journal of
Molecular Diagnostics, 21(5), 737-745.
https://doi.org/10.1016/j.jmoldx.2019.04.002
Sharfstein, J. (2015). FDA regulation of
laboratory-developed diagnostic tests. Jama, 313(7), 667.
https://doi.org/10.1001/jama.2014.18135
Sidawy, M. (2015). US food and drug administration
regulatory oversight of laboratory‐developed tests: commentary on the
draft guidance. Cancer Cytopathology, 123(10), 573-575.
https://doi.org/10.1002/cncy.21566
Smith, L. (2024). The us FDA's proposed rule on
laboratory-developed tests: impacts on clinical laboratory testing. Practical
Laboratory Medicine, 40, e00407. https://doi.org/10.1016/j.plabm.2024.e00407
Vance, G. (2011). College of american pathologists proposal for the oversight of laboratory-developed tests. Archives of Pathology & Laboratory Medicine, 135(11), 1432-1435. https://doi.org/10.5858/arpa.2011-0304-sa
