FDA Proposal for LDTs Risks Serious Consequences

When the FDA recently proposed to regulate lab-developed tests in the same way it regulates commercial in vitro diagnostics, it may have overlooked some unintended consequences. Phasing out the FDA’s general enforcement discretion, which the FDA traditionally has applied to lab-developed tests, would cause lab-developed tests (LDTs) to undergo the same level of scrutiny as commercial in vitro diagnostics, making the costs of developing such tests untenable for many labs, some lab leaders say. As a result, innovation and patient care will likely suffer, they add.

The proposal, which is open for public comment until December 4, explicitly notes that in vitro diagnostic products are devices under the Federal Food, Drug, and Cosmetic Act. The FDA proposes to level the playing field for most tests during a four-year period that will end no earlier than April 1, 2028.¹

LTD/IVF purposes differ

The FDA says this change is meant “to protect the public health.”¹ However, according to Melissa Budelier, PhD, director of clinical chemistry and toxicology at TriCore Reference Laboratories in New Mexico, “It would affect our patients’ ability to access many of the tests they need.”

Lab-developed tests are designed to fill gaps not addressed by commercial tests and to meet specific, local needs. Mass spectrometry tests designed for organ transplant patients are one example. Commercial tests, in contrast, typically are designed to diagnose major conditions found in large populations. Therefore, Budelier says, “The idea of FDA regulation for LDTs is concerning, because LDTs and commercial tests serve two different purposes.”

High costs and delays expected

The FDA estimates that, if implemented, national costs of the proposed changes will range from a low of $2.39 billion, to a high of $19.45 billion per year for each of the next 20 years. Estimated benefits (without including any averted costs, like lawsuits) for that time frame range from $1.81 billion to more than $86 billion per year.¹

For many labs, the costs of compliance are unaffordable, Jonathan R. Genzen, MD, PhD, chief medical officer at ARUP Laboratories in Utah, points out. “The current, standard fees for submitting a 510(k) application (the regulation governing medical devices) are $21,760 per submission, and pre-market approval fees are $483,560 per submission. While some laboratories may qualify for small business discounts, many clinical laboratories are under the corporate umbrella of a larger hospital or health system that likely exceeds the small business fee threshold.”

In addition to submissions costs, labs also would bear the costs of medical device reporting, extending and maintaining supply chain quality control systems, and adding personnel to handle the paperwork. “This will be extremely burdensome financially,” Genzen says.

Additionally, the requirement to conduct clinical trials for many LDTs will add years to tests’ development time, thus delaying their clinical applications. Many diagnostics, however, are needed immediately for patients and to meet emerging needs. Tests to detect xylazine (a veterinary tranquilizer increasingly linked to human drug abuse and overdoses), fentanyl, or other often-abused drugs are examples. Yet, adding a new panel to an existing test or optimizing an assay would require FDA review and approval.

“If we had to go back to the FDA, we couldn’t do that,” Budelier says. “Saying lab-developed tests are no different than in vitro diagnostics puts laboratories in a position in which many won’t be able to offer these tests to their patients.”

FDA concerns

The FDA says the differences between lab-developed tests and commercial tests in terms of complexity and target population are dwindling. Discretionary enforcement, therefore, could allow flawed diagnostics to be put into service, where they affect medical decisions. Therefore, the FDA reasons, all diagnostic tests should be subjected to the same level of scrutiny before they can be used with patients.¹

Lab leaders, however, say safety concerns with most LDTs are already addressed. “The majority of lab-developed tests are for things like newborn screening, drug confirmations, and detecting cancer mutations,” Budelier says. “They are performed in clinical laboratories under the oversight of a lab director who is trained in ensuring the test is well-validated.”

Nonetheless, based upon premarket submission reviews, the FDA cites multiple examples of inadequate or inappropriate validation studies; instruments and other components that were inadequately controlled for clinical use; and labs that offered their tests even though they don’t perform as intended. FDA review, it suggests, would curb these problems.¹

CLIA’s role

Lab-developed tests are regulated, though, lab leaders point out. The Clinical Laboratory Improvement Amendments (CLIA), administered by the Centers for Medicare & Medicaid Services, the FDA, and the Centers for Disease Control and Prevention, provides certification and oversight for labs testing human specimens to improve health. Furthermore, guidelines from the College of American Pathologists (CAP) “meet and exceed the CLIA guidelines,” Budelier says.

Rather than bringing lab-developed tests under FDA regulations, she suggests using the existing regulatory framework, and making CLIA certification more stringent to equal or exceed the robustness of CAP or the New York State Department of Health Clinical Laboratory Evaluation Program. The FDA mentioned a similar possibility in its proposed rule, citing the New York program and the Veterans Health Administration as models.

Academic medical centers

As part of the FDA’s request for comment on these proposed guidelines, it asks the lab community to consider whether academic medical centers should be treated differently from other labs and, if so, how.

As Genzen acknowledges, academic medical centers are unique. Because they combine basic, clinical, and translational research, “academic medical centers are often at the forefront of diagnostic innovation. Development of lab-developed tests at these facilities often predates the existence of any FDA-cleared or approved alternatives.”

He adds that these laboratories tend to work closely with clinicians treating patients, have deep expertise, and offer a more extensive range of tests than most other labs. Allowing enforcement discretion for these medical centers, therefore, may make sense.

Innovation under siege

Lab-developed tests tend to provide diagnostics for needs that typically have too little volume to attract commercial assay developers. Requiring labs to undergo the same regulatory process as commercially-developed in vitro diagnostics, Genzen says, “would significantly hinder diagnostic innovation and, ultimately, patient care, as there would be a negative financial incentive to implement tests that, by definition, have low volumes, such as testing for rare disorders,” or testing for emerging pathogens that may never become threats to public health.

The FDA proposal suggests that tests could be developed through some existing programs, like the Humanitarian Use Devices/Humanitarian Device Exemption program (often used for rare diseases) and Breakthrough Devices program. That approval pathway, it suggests, could reduce labs’ regulatory burden and speed development.

“Testing should be conducted as close to the patient as possible, and the proposed rules will make that more difficult,” Genzen says. If the FDA proposal regarding LDTs is adopted, he predicts the variety of available tests will decrease because of the increased burden on labs. Consequently, physicians’ abilities to diagnose their patients quickly and accurately will decrease.

In its proposed rule, the FDA encouraged lab leaders and other stakeholders to share their thoughts and concerns about the rule, to minimize the risk of such “unintended consequences.”¹ Apart from voicing its concerns, the lab industry can only wait to see how the FDA proceeds with the LDTs issue after the agency reviews these comments.

References:

1. 1. https://www.federalregister.gov/documents/2023/10/03/2023-21662/medical-devices-laboratory-developed-tests