A Tale of Two Assays, Part 1

Vol. 25 • Issue 6 • Page 18


“It was the best of times, it was the worst of times, it was the age of wisdom, it was the age of foolishness, it was the epoch of belief, it was the epoch of incredulity, it was the season of Light, it was the season of Darkness, it was the spring of hope, it was the winter of despair, we had everything before us, we had nothing before us. Some of its noisiest authorities insisted on its being received, for good or for evil.”

– Charles Dickens, “A Tale of Two Cities”

The extremes of opinions between laboratories and the FDA over proposed regulation of laboratory developed tests (LDTs) seem as monumental as the play of superlatives in Charles Dickens’ opening lines.

Medical science is, indeed, in the best of times as a collective knowledge base gallops forward with nearly incredulous speed, mining new data, new biomarkers and new diagnostic possibilities. It articulates the light of hope for patients. But could we be facing the worst of times, if medical innovation and subsequent progress of LDTs are tied to the FDA regulatory process? Will that authority “insist on being received?”

Karen Kaul, MD, PhD, chair, Pathology and Laboratory Medicine, NorthShore University HealthSystem, Evanston, Ill., clearly hopes not. She offers a compelling argument from a non-apologetic laboratory perspective.

“There is a spectrum of activities that take place in medicine, but it is unclear where certain lines are drawn along that spectrum,” she began. “For example, a surgeon does surgery-a medical procedure-and the FDA would not try to regulate that. It is clearly the practice of medicine, a ‘procedure.’ But a kit, or medical instrument, such as a pulse oximeter, is a ‘device’ and comes under regulatory scrutiny by the FDA.”

Sadly, smack dab in the middle of all this are many lab procedures. “If we purchase a kit that is going onto an instrument that will measure a patient’s sodium, for example, that kit-considered a device-must be regulated by the FDA,” Kaul explained. “However, in pathology labs, we examine tissue through the microscope. We look at the histology, we might add immunostains or biomarkers to characterize specific cells, or use a molecular test, and ultimately, we render a diagnosis. So is all of this a procedure, a kit or a device? This is the gray zone in which the lab world is living.”

The pressing question at hand today is: Are LDTs “procedures,” which are performed according to requirements set by Clinical Laboratory Improvement Amendments (CLIA), or “devices,” which could fall to FDA regulatory limbo? It depends on who you ask.

Why Now?

In November 2015, the FDA issued a report1 summarizing evidence to support regulation of LDTs. In it, the FDA cited increasing complexity and higher risks associated with LDTs, and offered examples of “inaccurate tests placing patients at otherwise avoidable risk.” It examined events involving 20 LDTs performed under minimum requirements of CLIA, leading to potential or actual harm to patients. (Of note, the Association of Molecular Pathology provided detailed commentary,2 outlining how many of these examples actually involved incorrectly ordered tests or misinterpreted results, rather than the assay itself.)

A bullet-point list of FDA concerns regarding LDTs included:

  • Lack of evidence supporting the clinical validity of tests
  • Deficient adverse event reporting
  • No premarket review of pewrformance data
  • Unsupported manufacturer claims
  • Inadequate product labeling
  • Lack of transparency
  • Uneven playing field (i.e., placing companies going through the FDA process at a disadvantage)
  • Threats to the scientific integrity of clinical trials
  • Non comprehensive listing of all LDTs currently being used.

Kaul agreed that there has been a proliferation of tests being marketed by various companies to hospitals, physicians and even the public under the auspices of LDT. “I suppose you could say they are operating in a ‘loophole,'” opined Kaul. “For example, one such test assesses risk for disease or disease progression with a proprietary panel of genetic alterations, which, according to the company’s algorithms, might indicate increased risk. That concerns the FDA, and in some instances with good reason.”

Hospital labs, however, are not making kits or selling services nationwide, but have optimized their procedures to work within their own system. Kaul believes that one reason companies are working around the FDA is because its gold-standard process for reviewing new test kits takes an arduously long time-typically many years-requiring prospective clinical trials at a cost of many millions of dollars.


  1. FDA, Office of Public Health Strategy and Analysis. The Public Health Evidence for FDA Oversight of Laboratory Developed Tests: 20 Case Studies. http://tinyurl.com/oxmrnur
  2. Association for Molecular Pathology. Facts FDA Ignored: An analysis of the FDA report, “The Public Health Evidence for FDA Oversight of Laboratory Developed Tests: 20 Case Studies.” http://tinyurl.com/j9fdw8l

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