FDA Issues Report Saying Many Laboratory-Developed Tests Are Dangerous

The U.S. Food and Drug Administration (FDA) has taken its gloves off when it comes to the matter of handling laboratory-developed tests (LDTs).

The issue has been a fractious one in the laboratory sector. There are thousands of LDTs on the market, and many laboratory operators see a move by the FDA to regulate them as a threat to the way they have done business for decades. They fear lengthy delays to obtain approvals for LDTs if the FDA begins regulating them.

Most laboratory lobbying bodies have said that the Clinical Laboratory Improvement Amendments (CLIA), which were developed in the 1980s, serve as a perfectly fine set of regulations for LDTs. However, the FDA has been insistent that the ever-growing complexity of LDTs means that they require closer regulation.

In addition to its attempt to regulate LDTs, the FDA has also announced its intent to regulate assays that rely on next-generation sequencing, which has also created consternation within the lab sector. It also issued a 43-page guidance document last year outlining how it would regulate LDTs. Many would be subject to an approval process similar to that of point-of-care tests or medical devices, dependent primarily on how each test scores in a risk-assessment process that would determine their ability to impact care and potentially harm patients.

The issue of the FDA's presence in laboratory testing prompted the American Clinical Laboratory Association (ACLA) last year to retain the services of Laurence H. Tribe and Paul Clement, two of the most prominent appellate attorneys in the nation, strongly suggesting it would litigate the matter of the FDA's authority in the federal courts. Such a move is the equivalent of bare-knuckle sparring in lobbying circles. That may be among the reasons why the FDA issued a far-ranging report suggesting that many LDTs had the potential to endanger patients by prompting them to seek unnecessary care.

The report took some lab executives by surprise. "It was shocking," said Susan Hertzberg, chief executive officer of Boston Heart Diagnostics, which markets several LDTs related to cardiac health. The FDA cited a cardiac test related to the KIF6 gene, although Boston Heart does not offer that on its menu. Altogether, the report cited 20 different LDTs as potentially dangerous. Some have never been brought to market or were withdrawn, but they include several tests currently being used on an ongoing basis.

"In some cases, due to false-positive tests, patients were told they have conditions they do not really have, causing unnecessary distress and resulting in unneeded treatment," read the report's executive summary. "In other cases, the LDTs were prone to false-negative results, in which patients' life-threatening diseases went undetected. As a result, patients failed to receive effective treatments."

Among the tests cited was OncotypeDX, developed by California- based laboratory Genomic Health to help determine whether certain drug regimens would be helpful to patients diagnosed with breast cancer, based on the presence and intensity of HER2 proteins.

"The underlying issue is that there is no demonstrated direct correlation between number of RNA copies of the gene, the basis for Oncotype DX (test) and the number of protein copies on the cell surface. As a consequence, it is not possible to infer that high or low amounts of RNA correspond to high or low amounts of HER2 protein," the FDA said in its report.

Genomic Health spokesperson Victoria Steiner criticized the FDA report, saying it mischaracterized the test's reliance on detecting HER2. "To address the misinformed and inaccurate characterization of Oncotype DX in this report, we will continue to work with the FDA to ensure they understand both the critical role that the Oncotype DX test plays in breast cancer treatment planning, and importantly, the wealth of evidence that has supported its use to help guide chemotherapy treatment decisions in more than 500,000 breast cancer patients to date," she said in an email.

The ACLA was also highly critical of the report saying in a statement that much of the data in the report "is not based on peer-reviewed literature (and) refer(s) to outdated data or tests no longer being offered ... the report also fails to make any comparison of degree or frequency between the alleged errors amongst LDTs relative to problems seen in the post-market of FDA approved or cleared products."

Added ACLA President Alan Mertz, "clinical laboratories and LDTs are currently highly regulated and when a small number of case studies are used to characterize an entire dedicated and compassionate industry, it detracts from the true task at hand—and that is to effectively strengthen the current regulatory framework for LDTs in a way that continues to advance diagnostic innovation," said Alan Mertz, President of ACLA. "The FDA's own proposed guidance to regulate LDTs would be highly disruptive to laboratory services and compromise patient care."

Takeaway: The FDA's new report on the potential dangers of laboratory-developed tests is likely to sharpen the battle over the agency's attempt to regulate such assays.