LDTs are regulated — albeit somewhat indirectly — by the Clinical Laboratory Improvement Amendments (CLIA) of 1998. CLIA requires clinical laboratories to be certified by the Centers for Medicare and Medicaid Services (CMS) before they can receive samples from humans for testing.4 Scientists at clinical laboratories develop LDTs when there is a clinical need to do so (ie, when the need is not met by an existing FDA-approved commercial assay) and when they perform the tests only within their own laboratory.

Because LDTs are considered high-complexity tests, clinical laboratories must meet personnel, quality, and proficiency requirements for high-complexity testing, and the locations are subject to surprise inspections by accreditation organizations approved by CMS.5

“Most labs that I’ve ever been associated with — and I’ve only been in academic labs throughout my career — take this extremely seriously,” said Dr Lindeman. “It’s just not worth it for us to develop [a test] that is not done right, because the penalties for doing it incorrectly are severe.”

The penalties that a laboratory can incur depend on the degree of the lab’s noncompliance, but could involve daily fines of thousands of dollars or revocation of a CLIA certification, which would suspend the laboratory’s receipt of Medicare payments for services.6


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Intentional violations may even subject personnel to criminal penalties. In 2004, for instance, 5 labs were convicted under federal or state laws relating to fraud and abuse, false billing, or kickbacks, and one owner was sent to prison for 60 months and asked to pay more than $2.5 million in restitution.6

LDTs are essential for helping diagnose cancer and even guiding treatment for cancer patients — and can be adapted much more quickly than FDA-approved tests. For example, if a new study shows that a particular biomarker is important for treatment, an LDT can be modified quickly to detect that biomarker, whereas an existing FDA-approved assay must go through a formal revision process.

“The ability to respond quickly requires LDTs,” Dr Lindeman said.

Some existing evidence even suggests that LDTs can offer a level of accuracy comparable to FDA-approved assays. A 2018 study evaluated the analytical performance of LDTs and FDA-approved assays for BRAF, EGFR, and KRAS testing and found that both had “excellent” performance.7

The study also revealed that most laboratories evaluated actually started with an FDA-approved assay and then modified it, automatically reclassifying the assay as an LDT.7 Anytime a commercial test is performed in any way that deviates from the approved indication, it becomes an LDT.

“When the FDA approves a test, it is approved to be done in a very specific manner on a very specific set of samples for a very specific indication, but not every patient that could benefit from that test necessarily meets all those criteria,” explained Dr Lindeman.

Although the regulatory oversight of LDTs remains essentially unchanged for now, legislation has been proposed to reform oversight. Earlier this year, in March 2020, the Verifying Accurate, Leading-edge IVCT Development (VALID) Act was introduced into Congress.8 The VALID Act would establish a risk-based framework, allowing the FDA to regulate tests it deemed to be “high-risk” by requiring premarket review.

Dr Myles noted that the criteria for what would make a test “high-risk” have not yet been clearly defined — but that the VALID Act would help better outline that risk characterization.

References

  1. US Department of Health and Human Services. Rescission of guidances and other informal issuances concerning premarket review of laboratory developed tests. Last reviewed September 1, 2020. Accessed October 7,2020.
  2. Genzen JR, Mohlman JS, Lynch JL, Squires MW, Weiss RL. Laboratory-developed tests: A legislative and regulatory review. Clin Chem. 2017;63(10):1575-1584. doi:10.1373/clinchem.2017.275164
  3. American Society of Clinical Oncology (ASCO). Removing FDA oversight of laboratory developed test approvals threatens safety of cancer care [press release]. Published September 4, 2020. Accessed October 7, 2020.
  4. US Food and Drug Administration. Clinical Laboratory Improvement Amendments (CLIA). Current as of February 25, 2020. Accessed October 7, 2020.
  5. Centers for Medicare and Medicaid Services. LDT and CLIA FAQs. Published October 22, 2013. Accessed October 7, 2020.
  6. American College of Physicians. CLIA & your laboratory: A guide for physicians and their staff. Published November 2014. Accessed October 7, 2020.
  7. Kim AS, Bartley AN, Bridge JA, et al. Comparison of laboratory-developed tests and FDA-approved assays for BRAF, EGFR, and KRAS testing. JAMA Oncol. 2018;4(6):838-841. doi:10.1001/jamaoncol.2017.4021
  8. S. 3404 — 116th Congress: VALID Act of 2020. www.GovTrack.us. 2020. Introduced March 5, 2020. Accessed October 7, 2020.