Imagine nearly ending a pregnancy because a lab test was wrong. In January 2022, a story in the New York Times recounted one pregnant woman's experience with an inaccurate genetic non-invasive prenatal screening (NIPS) test. These blood tests analyze small pieces of fetal DNA that cross the placenta into the mother's circulation to assess the risk for genetic abnormalities in the fetus. Though NIPS tests for more common conditions like Down syndrome are very useful clinically, tests for serious but rare conditions like Prader-Willi syndrome -- a condition associated with distinctive facial features, poor muscle tone, weight gain, and behavioral disturbances -- are prone to false-positives. Because Prader-Willi is so rare, it is actually more likely that a positive test is false than true.
And that is exactly what happened in this case. After her test came back positive for fetal Prader-Willi syndrome, the woman contemplated terminating her pregnancy. Luckily, she underwent a follow-up invasive procedure and learned that the initial result was indeed a false-positive. She went through with the pregnancy and delivered a baby with no indication of Prader-Willi syndrome. But it was a close call and the psychological toll was immense.
NIPS tests are a type of medical device called laboratory-developed tests (LDTs). Unlike conventionally manufactured medical devices, LDTs are developed and used in one laboratory and providers send their tests to that facility. At first, LDTs were largely confined to isolated academic laboratories, but with time the number and complexity of such tests has burgeoned as companies are increasingly offering them for more common conditions.
The FDA has the uncontested authority to review all medical devices -- including LDTs -- for safety and efficacy under the Federal Food, Drug, and Cosmetic Act. However, the agency has chosen not to use its authority to regulate LDTs to date. As a result, the FDA does not know how many of these tests are on the market, let alone whether they are safe or effective.
Defenders of the status quo love to point out that regulation of LDTs currently falls under the CMS Clinical Laboratory Improvement Amendments, thus rendering FDA regulation unnecessary in their view. But CMS regulates labs themselves rather than the safety and effectiveness of tests. CMS also only requires labs to have documentation of their tests' "analytical validity" but does not require "clinical validity" data. This means that, for example, CMS would only assess whether a pancreatic cancer test accurately detects cancer proteins, not whether the detection of the proteins is a reliable way to diagnose pancreatic cancer. Or CMS regulation would determine whether a test detects Prader-Willi in fetal DNA, not establish the likelihood that the fetus actually has the condition -- as FDA regulation would. Consequently, regulation under FDA would be much more comprehensive, include communication to doctors and patients, and would allow the agency to track the tests on the market. In sum, it would close critical gaps that allow the marketing of inaccurate LDTs.
The issues arising from the lack of LDT regulation can be seen as similar to the challenges in the early fumbled approach to COVID. Early COVID-19 diagnostic tests were in effect regulated like LDTs in that FDA, anxious to get new tests into the market, allowed them to be marketed without review until the agency had a chance to review their applications for emergency use authorization. Once the agency was able to review the applications, it found validation or design issues in over 65% of a sample of 125 tests submitted for authorization. False-positive COVID-19 tests may have led to unnecessary quarantining and false-negative tests may have led to additional spread of the virus.
By establishing a risk-based framework for FDA regulation of all in vitro clinical tests, regardless of where they are produced and used, the Verifying Accurate Leading-edge IVCT Development Act of 2021 (VALID) sets forth a potential solution to the problem of inaccurate LDTs. The bill creates a tiered system whereby tests that carry risks of serious harm if inaccurate undergo full premarket review, those that pose less-serious risks of harm submit less-detailed documentation of their analytical and clinical validity, and those that are likely to result in minimal harm are exempt from review. The bill also authorizes FDA to require test developers to conduct surveillance of higher-risk tests once they are on the market and mandates adverse event reporting by developers. These processes are standard for drugs. While not a perfect solution, VALID would help ensure the highest-risk tests are properly vetted by the FDA for their safety and effectiveness.
In May 2022, VALID was incorporated into the Senate version of the user fee reauthorization bill, a piece of legislation that must pass every 5 years because it funds a large portion of FDA activities. Unfortunately, Congress instead passed a stripped-down continuing resolution that left out all LDT provisions.
Now that the midterms are behind us, Congress gets a second bite at the apple when the continuing resolution expires on December 16. FDA's current commissioner, Robert Califf, MD, and device chief, Jeffrey Shuren, MD, JD -- and even former Trump-era FDA commissioner Scott Gottlieb, MD -- have supported Congressional action on LDTs. The window of opportunity for LDT reform appears to be closing; let's pass consumer-protective legislation before it slams securely shut.
Stephanie Rogus, PhD, RDN, is a research scientist and campaign manager for scientific integrity at the Center for Science in the Public Interest. Peter G. Lurie, MD, MPH, is president of the Center for Science in the Public Interest, and a former associate commissioner of the FDA.