FDA Will Regulate Diagnostic Tests. Yes, Those for Alzheimer’s, Too.

For decades, the U.S. Food and Drug Administration has taken a light touch to regulating diagnostic tests that use body fluids or tissues. Such assays, very much including cerebrospinal fluid and blood tests for Alzheimer’s disease, were able to be marketed without providing proof of accuracy in the intended population. Now, the FDA is bringing down the hammer. In a May 6 ruling, the agency said future laboratory-developed tests (LDTs) will need to meet the same standards as medical devices, including passing quality benchmarks and reporting adverse events. The ruling will take effect July 5, but the new standard will be phased in over four years to give laboratories time to comply. Existing assays will be largely exempt, but it is expected they will comply to maintain a competitive edge.

  • FDA ruling requires in vitro diagnostics to meet the same standards as medical devices.
  • New tests will have to prove accuracy for detecting underlying disease.
  • The policy will phase in over four years; existing tests are exempt.

The ruling has sparked political controversy, and analysts expect industry to file lawsuits challenging the policy. However, scientists and clinicians contacted by Alzforum were uniformly enthusiastic about the change. “Increased oversight of LDTs is long overdue but very welcome,” Thomas Beach at Banner Sun Health Research Institute in Sun City, Arizona, wrote to Alzforum. Suzanne Schindler at the University of Washington, St. Louis, was of a similar mind. “This seems like a much-needed change that will help patients, providers, and the field have greater confidence in the results of Alzheimer’s disease blood tests,” she wrote. Researchers expect the FDA ruling to have positive effects beyond the U.S. as well. “It will surely be a guideline to other countries,” Colin Masters at the University of Melbourne, Australia, wrote to Alzforum (comments below).

Bringing Order to a Chaotic Field
Until now, in vitro diagnostics in the U.S. have existed in a nebulous regulatory space. Unlike imaging tests, which have always been regulated as medical devices, assays using body fluids or tissues received “enforcement discretion” from the FDA, meaning the agency mostly let them be. Instead, the Clinical Laboratory Improvement Amendments (CLIA) program administered by the Centers for Medicare and Medicaid Services certified tests for use. Importantly, however, CLIA only assesses a test’s reproducibility, not its accuracy for detecting disease. In theory, this means an inaccurate test can be sold, so long as it is reproducibly and consistently inaccurate. Over time, this has resulted in shoddy tests flooding the market, with no way for physicians to know which ones were best.

For example, Beach noted that the accuracies of α-synuclein skin assays for Parkinson’s disease vary from 24 to 98 percent. For Alzheimer's blood tests, only some have published accuracies as high as 90 percent. “Other tests are little better than flipping a coin, and no validation data has been published … [this] has led to confusion and skepticism about use of Alzheimer’s disease blood tests in clinical care,” Schindler wrote.

In a press release, the FDA noted that low-quality cancer and COVID-19 tests have harmed patients. Because LDTs are becoming more widely used to make important healthcare decisions, the agency believes a more rigorous standard is now required.

How will it work? Tests that come on the market after July 5 will be subject to the new ruling. By 2028, laboratories will have to ensure their tests meet minimum accuracy standards, determine how well they work in different populations, and report adverse events. As with medical devices, quality testing would be done by third parties, such as contract research organizations.

So as not to disrupt patient care, existing assays will be grandfathered in. However, any protocol changes or updates to those assays will be subject to the new standard, hence the FDA expects that over time, most tests will conform. A few LDTs will remain exempt, including tests developed to deal with public health emergencies such as pandemics, and those that meet a special need for which no FDA-approved assays are available.

The American Clinical Laboratory Association expressed disappointment in the ruling. The trade association, which represents laboratories that make tests, predicted it would hike the costs of testing, and suppress innovation. Senator Bill Cassidy (R-LA) said the FDA is overstepping its authority by issuing this rule, and called on Congress to act. Analysts believe legal challenges are likely (Endpoints article).

How Do Alzheimer’s Tests Stack Up?
If the ruling stands, how will it affect tests for Alzheimer’s disease? The answer will likely vary by company. For example, Fujirebio received FDA approval for its automated Aβ42/40 CSF assay, and Roche for its automated Aβ42/p-tau181 and Aβ42/t-tau CSF tests (May 2022 news; Dec 2022 news; Jun 2023 news). Because these tests have already been validated against amyloid PET, the companies may need to do little to bring them into full compliance with the new standard. Roche and Fujirebio representatives did not respond to a request for comment.

Joel Braunstein at C2N Diagnostics believes the effect on his company will be limited. “We do not believe the FDA’s recent final rule will change much of our strategy and approach to commercializing in vitro diagnostic tests,” he wrote to Alzforum. He pointed out that C2N has been working under a similar FDA quality standard since 2021, and routinely validates both the analytical and clinical performance of its tests (Nov 2020 news).

How about other companies? Quest Diagnostics at one point marketed an AD blood test directly to consumers, sparking backlash from the field (Aug 2023 news). The company has paused consumer marketing and currently focuses on delivering that test to primary care physicians, according to Quest communications director Wendy Bost. “Our menu isn’t changing at this time. We are reviewing the [FDA] rule to understand its requirements, and it will take some time to assess what effect, if any, it may have on our menu,” Bost wrote to Alzforum.

More AD tests are entering the market. For example, the laboratory services provider Labcorp, based in Burlington, North Carolina, recently announced that it's now offering a blood test for inflammatory marker GFAP based on Roche’s electrochemiluminescence system. The company did not respond to a request for comment.

Alzheimer’s researchers believe the ruling has global implications. “This regulation aligns well with the in vitro diagnostic regulation of the European Union, which also requires evidence on analytical and clinical validity and a quality and monitoring system for tests used for clinical decision making,” noted Charlotte Teunissen at Amsterdam University Medical Center.

Philip Scheltens at EQT Life Sciences Dementia Fund said reliable tests should report sensitivity, specificity, cutoff thresholds, and positive and negative predictive values in diverse populations. “One can only say that for the AD blood-based biomarkers, that is not yet the case, so this FDA ruling should be an incentive for those who develop these tests to get their act together,” he wrote to Alzforum (comments below).—Madolyn Bowman Rogers

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References

News Citations

  1. FDA Approves Fujirebio’s CSF Test for AD—Quest Diagnostic Offers Plasma Test
  2. Blood Amyloid Test May Help Diagnose Alzheimer’s, but Questions Remain
  3. FDA Clears Roche’s CSF Aβ42/tTau Assay
  4. Plasma Aβ Test Wins Approval—Are p-Tau Tests Far Behind?
  5. Direct-to-Consumer Alzheimer’s Blood Test Opens Pandora’s Box

External Citations

  1. May 6 ruling
  2. press release
  3. Endpoints article
  4. announced

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