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The Food and Drug Administration’s (FDA’s) proposal to gain more oversight of laboratory-developed tests (LDTs) is winning support among its fellow regulators and members of Congress. Yet, AACC cautions that such a move would create more burdensome regulations and hinder patient care by discouraging testing facilities from developing and performing LDTs. 

Ensuring the quality and accuracy of LDTs falls under the purview of the Centers for Medicare and Medicaid Services (CMS). In AACC’s view, Congress should take what already exists and enhance CMS’s role in ensuring the quality and accuracy of these tests rather than create a dual regulatory process for LDTs. 

Though disputed, FDA claims it has enforcement authority over premarket evaluation and other requirements for LDTs but that it typically exercises enforcement discretion. “As such, the Agency generally does not review such tests for clinical validity prior to such tests being marketed,” nor does CMS, Jeffrey Shuren, MD, director of FDA’s Center for Devices and Radiological Health, told the House Energy & Commerce Committee at a Nov. 17 hearing. 

CMS Deputy Administrator Patrick Conway, MD, told the House panel that FDA was better suited than CMS to assess the clinical validity of LDTs, adding that CMS lacked the resources and expertise to perform this task.  

FDA has made its case for increased oversight in draft guidance that outlines a new regulatory framework for LDTs. It also issued a report, which highlighted 20 case studies in which LDTs either had the potential to harm or actually caused harm to patients. 

Labs offering LDTs are subject to requirements of the Federal Food, Drug, and Cosmetic Act and the Clinical Laboratory Improvement Amendments (CLIA). “Despite the contention from some that ‘CLIA is enough,’ all of the tests described as problematic in this report were offered from laboratories following the minimum requirements of CLIA,” according to the FDA’s report.

A number of examples involved LDTs used to predict or detect ovarian cancer. FDA indicated that the accuracy claims of these tests were overinflated, which could result in false positive results and unnecessary surgeries for women. 

One such case involved the OvaSure test, which “grew out of the lifelong ambition of a clinical/medical scientist who lost a patient to ovarian cancer early in his career,” according to Catherine A. Hammett-Stabler, PhD, DABCC, FACB, who did some analysis on the FDA report. “The scientist thought that if he linked together several biomarkers, he might improve sensitivity and specificity.” 

The test did well in a small clinical trial and was commercialized by a major reference lab for use in high risk-patients. “Unfortunately, it turned out that the scientist used the prevalence of ovarian cancer in the study population for the PPV [positive predictive value] calculation when he should have used the prevalence in the general population,” Hammett-Stabler, director of Core Laboratories at McLendon Clinical Laboratories at UNC Medical Center in Chapel Hill, North Carolina, told CLN Stat. Had he done this, the PPV would have been 6.5% instead of the near-perfect result he obtained in his trial. 

In other cases, an LDT prone to yielding too many false negatives meant that a serious illness went undetected and untreated. Other tests, such as noninvasive prenatal testing used to detect fetal chromosomal abnormalities, have the potential to yield too many false-negative and false-positive results, according to FDA. 

Some have questioned the findings of FDA’s investigation. One of the report’s case studies, which described inaccurate result reporting based on a pertussis LDT at Dartmouth University Hospital in 2006, “completely misrepresents” the situation, according to Gregory J. Tsongalis, PhD, HCLD, CC, director of the Laboratory for Clinical Genomics and Advanced Technology at Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire. 

“There was no issue with the LDT being used, but the FDA and others failed to recognize the decision made by a clinical task force to treat patients with symptoms rather than wait for confirmatory testing,” Tsongalis told CLN Stat. 

Some members of Congress have been floating a proposal to increase regulatory oversight of LDTs, suggesting that Congress create a new agency within FDA to oversee all lab tests, including LDTs.

Some aspects of this proposal make sense—such as getting labs to demonstrate the accuracy of LDTs, and exempting critical tests, such as those for public health emergencies and newborn screening, from increased regulatory scrutiny, AACC wrote in a letter to Congress. 

However, the association is concerned that dual scrutiny from both CMS and FDA would “impede patient access to testing, since many hospitals and rural testing facilities do not have the resources to comply with FDA’s requirements and would be forced to stop performing laboratory developed tests,” AACC’s letter stated. 

Instead, Congress should work within CMS’s regulatory framework to tighten scrutiny of LDTs. Rather than have FDA assume the task of assessing the clinical validity of LDTs, handing that responsibility to CMS would “be a relatively minor adjustment considering many CMS-accredited laboratories are already required by private accrediting bodies to demonstrate clinical validity,” the letter said. 

Putting all of this into context, Hammett-Stabler offers that FDA’s proposal won’t solve all of the issues related to LDT use. “There seems to be a thought that more FDA oversight will make test results perfect—there is no such thing. We have issues each week with things—instruments and reagents—that the FDA approved. Their stamp of approval doesn’t mean a test will work perfectly 100% of the time nor does it mean that the test has good clinical validity!” she said.

Labs perform strong validation studies of FDA-approved tests and LDTs and implement strong quality management practices that help detect some issues, Hammett-Stabler continued. “But in the end, our best quality control is the physician who calls us saying: this result doesn’t make sense.”