FDA

LDTs, FDA-Approved Companion Diagnostics Perform Similarly; Off-Label Use of Companion Diagnostic Kits Common

One of the arguments for U.S. Food and Drug Administration oversight over laboratory-developed tests (LDTs) involves the need for greater assurances regarding the quality and consistency of these tests. A brief report published December 14 in JAMA Oncology may allay some of these concerns.

A study of close to 7,000 College of American Pathologists proficiency testing samples found that LDTs and FDA-approved companion diagnostics (FDACDs) had similarly high accuracy for detecting variants in three oncology-related genes—BRAF, EGFR, and KRAS. However, the researchers found that more than 60 percent of laboratories report modifying the intended use of FDA-CDs, essentially making them LDTs.

The researchers compared analytical validity and associated preanalytic practices for 6,897 proficiency testing responses. Combined, both LDTs and FDA-CDs exceeded 97 percent accuracy across all the samples.

  • For BRAF mutations, LDTs outperformed FDA-CDs with a 96.6 percent acceptable rate while FDA-CDs results were significantly lower at 93.0 percent. The researchers attributed this difference primarily to analysis of the BRAF p.V600K mutation (88.0 percent for LDTs versus 66.1 percent acceptable rate for FDA-CDs).
  • For EGFR, LDTs performed slightly, but significantly, less well than the FDA-CDs (97.6 percent acceptability for LDT versus 99.1 percent for FDA-CDs). This discrepancy was driven by detection of the EGFR p.L861Q mutation (91 percent for LDTs versus 100 percent for FDA-CDs).
  • For KRAS, there was no significant difference between acceptability rates for LDTs and the FDA-CDs overall or by individual variants.

The researchers importantly found that more than 60 percent of participants using FDA-CDs report modifying the approved preanalytic methods to broaden clinical use. This off-label practice essentially turns the FDA-CDs into LDTs. Reported off-label practices include unapproved specimen types and tumor types, as well as accepting specimens with lower tumor content than are required for the approved assay and not quantifying DNA before performing the assay.

"The preanalytic questions highlight the fact that many FDA-CD laboratories conduct practices that are not in accord with their FDA-approved methods."

—Annette Kim, M.D., Ph.D.

"The preanalytic questions highlight the fact that many FDA-CD laboratories conduct practices that are not in accord with their FDA-approved methods," write the authors led by Annette Kim, M.D., Ph.D., from Brigham and Women’s Hospital in Boston, Mass. "Although this flexibility is advantageous for patient care, it is important to recognize that the use of specimens other than formalin-fixed paraffin-embedded samples of the specified tumor type for the FDA-CDs is off-label, resulting in reclassification of the assay as an LDT."

Several authors report financial ties to the diagnostics industry.

Takeaway: While it may be reassuring that LDTs and FDA-CDs perform with similar access for detection of oncology-related genetic mutations, it may concern regulators the extent to which FDA-approved in vitro diagnostic kits are being used off-label.

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