FDA Issues Safety Warning Regarding Non-Invasive Prenatal Testing Raising Questions About the Future of FDA Regulation of LDTs

May 25, 2022By Allyson B. Mullen & Jeffrey N. Gibbs & Gail H. Javitt

On April 19, FDA issued a safety communication regarding genetic non-invasive prenatal screening, commonly referred to as non-invasive prenatal tests or NIPT (here).  NIPT are intended to screen for genetic abnormalities in a fetus.  The tests are not intended to diagnose any genetic conditions – that must be done through subsequent invasive testing.  The safety communication acknowledges that the tests “may provide useful information to assess the risk that a fetus has (or does not have) a genetic abnormality.”  Indeed, the communication identifies several medical societies (the American College of Obstetricians and Gynecologists (ACOG), the Society for Maternal-Fetal Medicine (SMFM), and the American College of Medical Genetics and Genomics (ACMG)) that recommend use of these types of tests as part of standard prenatal care.

The communication, however, warns patients and healthcare providers of the potential of NIPT to produce erroneous results, particularly false positive results (“these tests can give false results, such as reporting a genetic abnormality when the fetus does not actually have one”).  While scientific literature reports high negative predictive value of NIPT, the positive predictive value varies across conditions.  According to FDA, the positive predictive value of Down Syndrome is about 90% while the positive predictive value (PPV) of microdeletion is significantly lower, “ranging from about 2% to 30%, depending on the condition.”  It is not uncommon for some in vitro diagnostic tests to suffer from poor positive predictive value, in part due to the rarity of the disease.  Even a highly accurate test can have a low positive predictive value if the condition is very uncommon.  However, even with a low PPV, a test can provide clinically useful information to providers and patients.

The safety communication states that FDA is aware of reports of pregnant women making medical decisions based on the results of NIPT without confirmatory testing by the physician.  This is – of course – not the intended use of these tests.  The value of a test cannot be fairly judged by focusing on physicians who choose to make medical decisions that are inconsistent with the intended use.

Furthermore, although FDA’s safety communication refers broadly to published literature and media reports supporting its assertions, it provides no specific evidence for these claims.  Unfortunately, this is not the first time FDA has issued a safety alert regarding LDTs without citing evidence of the alleged harm; in 2018, FDA issued a safety communication regarding pharmacogenomic tests, alleging that these tests put patients at risk.  FDA ultimately walked back its threats of enforcement action against labs offering these tests, admitting that pharmacogenomic information could be clinically useful to physicians and patients.

Nor is this the first time that FDA has raised concerns with NIPT.  In fact, NIPT were one of 20 “bad tests” that Dr. Shuren identified in the Agency’s November 2015 “Public Health Evidence for FDA Oversight of Laboratory Developed Tests” (here).  Our readers will recall that this report was issued shortly after FDA’s release of its draft guidance documents seeking to regulate laboratory developed tests.  The report was intended to make the case that FDA’s oversight of LDTs was necessary because there were rampant unvalidated and inaccurate tests on the market.  Many critics were singularly unimpressed with this list (see our prior post here).

Notably, this safety communication follows a January article published by The New York Times which highlights similar concerns regarding the performance of NIPT (article here).  It is not clear why FDA waited three months after the NY Times published the study to issue its own alert.  Perhaps not so coincidentally, FDA issued the communication just as Congress began consideration of the VALID Act (see our prior post on the VALID Act here).

FDA appears to be making another run at gaining express regulatory oversight of LDTs.  Earlier this week, the Senate HELP Committee released a discussion draft of the Food and Drug Administration Safety and Landmark Advancements Act of 2022 (or FDASLA) (available here).  FDASLA incorporates a modified version of the VALID Act.  The VALID Act would give FDA authority to regulate laboratory developed tests and fundamentally change the regulatory paradigm for all in vitro diagnostic tests.  (As of this writing, the Senate version of the user fee legislation contains the VALID Act; the House version does not.)

This recent development along with the lack of new evidence cited in the safety communication leaves us wondering about FDA’s true motivation for releasing it now.  To be sure, the communication can be expected to raise patient anxiety and leave physicians uncertain about whether to order these tests.  If safety were the real driver, it seems to us there would be more recent and detailed information, in the safety communication, to give providers and patients about the true risks of these tests.  The failure to provide specific evidence to support the Agency’s claims is irresponsible; if there are data to support the risks of these tests this information should be disclosed to providers and patients so that they make informed decisions.  In the absence of such evidence, the safety communication raises alarm without context, conveying the impression that the product is unduly risky, and sowing doubt about the accuracy and reliability of LDTs more generally.

Categories: Medical Devices