Will the FDA regulate Sequenom (and other cfDNA labs)?

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Sequenom launched its MaterniT21 cell free DNA screen on the marketplace in October 2011. Four years later, screens like Sequenom’s remain largely unregulated. The FDA is moving to change that.

Currently, cfDNA laboratories are only regulated by the Centers for Medicare & Medicaid Services under its Clinical Laboratory Improvement Amendments (CLIA) for laboratory developed tests (LDTs). However, as reported by Turna Ray at GenomeWeb, :

… for 40 years, the [FDA] has regulated diagnostic kits (performed at multiple labs), leaving oversight of LDTs (performed at a single lab) to CMS under CLIA, because these tests were relatively simple and performed locally for small numbers of people. This is no longer the case …

As evidenced of how LDTs have changed in scope, and why the FDA argues it should regulate them, the FDA issued a report that:

examined events involving 20 LDTs that illustrate, in the absence of compliance with FDA requirements, that these products may have caused or have caused actual harm to patients

Here are excerpts from the FDA report that concern cfDNA screens:

FDA Heading

FDA cfDNA table3

FDA cfDNA table1

FDA cfDNA table2

(click to enlarge and for a clearer picture).

The narrative in the FDA report following the table is quoted below in full:

At least four companies in the U.S. have recently begun offering these tests, using a technique called cell-free DNA testing (cfDNA). Marketing materials cite very high accuracy rates. One company claims that its test has a “very low false-positive rate,” while another company claims a specificity of 99.9% for trisomy 18 (1 out of every 1000 results expected to be a false-positive) and 99.95% for trisomy 13 (5 out of every 10,000 results expected to be a false-positive).

However, trisomy 18 and 13 are so rare (1 in 5,000 for trisomy 18 and 1 in 10,000 for trisomy 13) that even these high specificities should yield more false-positive than true-positive results, requiring followup testing for confirmation. A clinical case series describes 8 women who received false-positive NIPT results for trisomy 18 and 13, including one patient who terminated her pregnancy after screening positive for trisomy 13, but was found to have a normal pregnancy on post-abortion testing. Further testing showed the fetus had normal chromosomes. A 2014 investigative report described three families who considered abortions based on what further testing showed to be false-positive results.

A study of one test calculated a PPV of 83% for 4 tested genetic conditions, and found that 22 (6%) of women who received positive results obtained abortions without a follow-up invasive diagnostic test. Citing concern that these tests could be used in the general, low-risk population with resulting low PPVs, the American College of Obstetricians and Gynecologists issued a statement in December 2012 that NIPT should not be offered to such women.

Although the main concern is over the test’s PPV for the rarer trisomies, in 2012, a patient reported a false-negative result to FDA after she received normal NIPT results and unexpectedly delivered an infant with trisomy 21. Additional cases were documented in an investigative report in the Boston Globe in 2014.

(emphasis added) (citations omitted).

The House Energy & Commerce Committee held a hearing following the FDA’s report. By coincidence, I was attending the Association of University Centers for Disabilities (AUCD) annual conference in Washington DC and was able to attend the hearing (photographic evidence at the top of this post).

As summarized by the first paragraph of the GenomeWeb report:

The US Food and Drug Administration and the Centers for Medicare & Medicaid Services presented a unified front before Congress today, making the case that the FDA needs to play a leading role in evaluating the safety and efficacy of laboratory-developed tests (LDTs) and that CMS doesn’t have the expertise or resources to take up the task as some in the lab and pathology community have suggested.

But, the FDA knows there are critics of its oversight. Indeed, the American Clinical Laboratory Association (ACLA) is bringing a legal challenge to FDA’s authority to regulate LDTs. Anticipating this resistance, the FDA concluded its report with this tickdown of the need for its regulation:

Despite arguments 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. Specifically, CLIA does not:

• Ensure the safety and effectiveness of LDTs prior to marketing.
• Assess the quality of the design and manufacture of devices.
• Ensure test labeling provides adequate directions for use.
• Require truth in marketing materials and other labeling.
• Require adverse event reporting.
• Permit removal of unsafe devices from the market.
• Require informed consent for patients participating in clinical studies of LDTs.
• Establish procedures for the conduct of such studies.

The FDA’s listing of CLIAs deficiencies explains a lot of the comments this blog has received from expectant mothers given false positives and inaccurate information from cfDNA laboratories. But the question remains:

Will the FDA (finally) regulate cfDNA laboratories?


  1. Let’s hope they do! It’s about time.

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