The Food and Drug Administration has issued new rules aimed at bolstering the agency’s oversight and regulation of the diagnostic testing field.

Specifically, the FDA is taking aim at Laboratory-Developed Tests (LDTs), which are defined as in vitro medical tests designed, manufactured, and processed by a single clinical laboratory. Historically, LDTs were unique, highly targeted tests developed within large hospital systems for use solely within those systems. More recently, however, many LDTs have entered the market for wider commercial use.

Under prior rules established in the late 1970s, the FDA took a lenient “general enforcement discretion” approach to LDTs. That meant these tests were not subject to pre-market approval, nor to the more intensive scrutiny the agency applies to medical devices and test methods intended for more general use in diverse clinical settings.

This was back-stopped by the Clinical Laboratory Improvement Act (CLIA) of 1988. FDA assumed that if a clinical lab itself could meet rigorous CLIA certification standards, then the individual tests it produced did not require pre-market scrutiny and approval.

“Without greater oversight of the safety and effectiveness of LDTs, patients may be more likely to initiate unnecessary treatment, or delay or forego proper treatment based on inaccurate test results or tests promoted with false or misleading claims.”

Jeff Shuren, MD, JD, Director of the FDA’s Center for Devices and Radiological Health,

In essence, enforcement discretion meant the FDA only took action on LDTs when there was a strong reason to do so. That strategy made sense 40 years ago when there were fewer LDTs, and most were used within hospital silos, often for rare diseases, very specific indications, or distinct patient sub-groups.

New Situation, New Rules

In the ensuing decades, LDTs have proliferated vigorously. There are now thousands of such tests on the open market—though the FDA acknowledges that since there is no central registry for such tests, regulators do not know precisely how many LDTs are now in use, nor how many labs are making and commercializing them.

But one need only look at the surge in direct-to-consumer medical tests to recognize that this field has rapidly expanded.  People can now get their genomes analyzed for the price of a steak dinner, and microbiome test kits are available in retail pharmacies. The realm of diagnostic testing today is markedly different from what it was in the ‘70s.

Under the new rule, FDA will phase out its old general enforcement discretion system over a four-year period, while simultaneously phasing in the new requirements such as pre-market review and establishment of the central LDT registry.

For several years now, regulators have voiced concern that loose regulation of LDTs has left a lot of room for inaccurate, fraudulent, potentially misleading tests to reach people, and in some cases, adversely affect their medical decisions.

“LDTs are being used more widely than ever before – for use in newborn screening, to help predict a person’s risk of cancer, or aid in diagnosing heart disease and Alzheimer’s. The agency cannot stand by while Americans continue to rely on results of these tests without assurance that they work,” said FDA Commissioner Robert M. Califf, MD, in a press briefing following the announcement of the new rules on April 29.

Jeff Shuren, MD, JD, Director of the FDA’s Center for Devices and Radiological Health, added that, “The FDA is aware of numerous examples of potentially inaccurate, unsafe, ineffective or poor quality in vitro diagnostics (IVDs) offered as LDTs that caused or may have caused patient harm, including tests used to select cancer treatment, aid in the diagnosis of COVID-19, aid in the management of patients with rare diseases and identify a patient’s risk of cancer.”

The CDRH oversees medical devices, diagnostic tests, and radiation-emitting medical and non-medical appliances, and will be responsible for implementing the new LDT regulations.

“Without greater oversight of the safety and effectiveness of LDTs, patients may be more likely to initiate unnecessary treatment, or delay or forego proper treatment based on inaccurate test results or tests promoted with false or misleading claims,” Shuren stated.

Dx Tests Are “Devices”

The new rule formally and explicitly classifies LDTs, along with all types of IVDs, as devices under the federal Food, Drug & Cosmetic Act. Going forward, LDTs will be subject to the tighter requirements applied to all other IVDs, and to medical devices. In practical terms, this means:

• Pre-market review
• Requirements for adverse event reporting
• Product registration
• Device listing,
• Adherence to labeling requirements,
• Investigational use requirements,
• Quality system requirements

Dr. Shuren stressed the importance of establishing a central, publicly-accessible registry of all tests in clinical use.

A Win for Clinicians?

“Currently there is no national monitoring or reporting of problems with LDTs, or a database of all the LDTs being used in the US, meaning no one truly knows exactly how many of these tests are out there or who makes which one, let alone which tests have a concerning number of issues such as inaccurate results. As a result of the FDA’s action, for the first time, patients and providers will have a more comprehensive database of available IVDs, including LDTs, and important information about those tests to better inform their decision-making.”

FDA officials contend that tighter test regulations will be a big win for clinicians and their patients. “Increased compliance with device requirements…will put patients and health care providers in a better position to have confidence in IVDs regardless of where they are manufactured,” said Kristina Wieghmink, a communications officer with the CDRH.

But in seeking to strengthen oversight of LDTs, FDA officials face a difficult challenge: how to address the perceived need to protect the public without stifling innovation, elevating the costs of test production, or rendering useful tests inaccessible.

A Balancing Act

The Covid-19 pandemic showed clearly that an effective response to a major public health threat depends in part on moving new tests from the research sector rapidly out to the public. Over the course of 2020, polymerase chain reaction (PCR) testing went from virology labs to family medicine cabinets very quickly. Continued innovation in lab testing is an important public health priority.

Pre-market registration and review of new and existing tests could potentially add significant upfront costs—a prospect that has some industry-watchers worried.

Of concern for holistic, naturopathic, and functional medicine practitioners is the question of whether tests like stool analysis, nutrigenomic tests, serum nutrient measurements, and single-nucleotide polymorphism (SNP) tests will be affected by the new regulation. It is a safe bet that they will.

Under the new rule, FDA will phase out its old general enforcement discretion system over a four-year period, while simultaneously phasing in the new requirements such as pre-market review and establishment of the central LDT registry.

The regulations will ultimately apply to all LDTs already on the market, as well as those now in development. But during the initial phase-in, those tests that were on the market prior to May 1, 2024 will still be under the old general enforcement standards, to give labs and manufacturers time to comply.

FDA says the stepped phase-in is intended to avert the possibility that patients—especially those with rare diseases—would be “deprived of critically needed LDTs,” and that it will give labs time “to identify any problems with their LDT and may help inform appropriate use and interpretation of such LDTs.”

The means by which FDA will enforce the new regulations, and the full scope of the new rules remains to be seen.

Ms. Wieghmink, in the FDA’s communications office, says the agency already has much of what it needs to get started, without major new budget appropriations or elaborate new procedures.

“The FDA already has a process and database for establishment registration and device listing, and there is no need to establish a new “registry” for LDTs,” she told Holistic Primary Care. Guidelines for labeling requirements on IVDs already exist. “Given the existing statutory and regulatory framework, there is no need to establish a new system for LDT review and regulation.”

What About Fx Med Tests?

Of concern for holistic, naturopathic, and functional medicine practitioners is the question of whether tests like stool analysis, nutrigenomic tests, serum nutrient measurements, and single-nucleotide polymorphism (SNP) tests will be affected by the new regulation.

These tests are not truly “diagnostic” in the strict sense of the word, since most are not used to rule in or rule out a specific disease. Rather, they provide information about health status, metabolic imbalances, or predilections for disease states. Many such tests are LDTs in that they were developed by the labs that market them, and have not undergone FDA review prior to entering the market.  

FDA is quick to assure clinicians that the regulations apply to the tests themselves and the labs that manufacture them, not to clinicians who use the tests.

Though the agency would not comment specifically about whether or not the new rules will be applied to these types of tests, it is safe to assume that they will be.

James McKinney, an FDA press officer told Holistic Primary Care that the agency defines In Vitro Diagnostics as “tests done on samples such as blood or tissue that have been taken from the human body” and used to, “detect diseases or other conditions, and can be used to monitor a person’s overall health to help cure, treat, or prevent diseases.”

The new requirements apply to tests “used to measure or detect substances or analytes, such as proteins, glucose, cholesterol or DNA, to provide information about a patient’s health, including to identify, monitor or determine treatment for diseases and conditions.” That covers a very broad spectrum of clinical tests, and would likely include the various types of tests used by functional medicine practitioners.

But the agency is quick to assure clinicians that the regulations apply to the tests themselves and the labs that manufacture them, not to clinicians who use the tests.

The Legacy of Theranos

Underscoring the rationale for strengthening regulation of LDTs, Dr. Califf noted that the risks associated with current LDTs are far greater than they were when FDA adopted its enforcement discretion approach, based on the Medical Device Amendments of 1976.

Some industry observers contend that one of the main motivators was the Theranos debacle of 2015.

Founded by Elizabeth Holmes, a whiz-kid Stanford University biotech entrepreneur, Theranos was a diagnostic testing innovator that claimed its “lab on a chip” technology could provide more than 200 diagnostic and health-risk tests—everything from detection of Herpes simplex to assessing proper warfarin dosages—from a fingerstick blood spot.

The Theranos debacle was, indeed, a black eye for the FDA. In its wake, the agency began clamoring for greater oversight of the clinical testing space, particularly the LDT sector.

The company became a magnet for Silicon Valley investors. At its peak it was valued at roughly $10 billion, and garnered massive partnership deals with Safeway, the Cleveland Clinic, and several large health insurers. Several very prominent political figures including former Senator Bill Frist, and two former Secretaries of State—Henry Kissinger and George Schultz—served on Theranos’ board of directors.

The downfall began in February 2015, when John Ioannidis, MD, a physician-researcher also affiliated with Stanford, alerted the Journal of the American Medical Association that there was no evidence in peer-reviewed journals to substantiate Theranos’ claims. This prompted an investigative report by John Carreyrou in the Wall Street Journal, alleging widespread fraud.

Fast-forward several years, and an investigation by the Securities Exchange Commission (SEC) resulted in a total shutdown of the company. Holmes, and co-founder Sunny Balwani were convicted of multiple counts of fraud. Both are now serving long prison sentences.

Most of Theranos’ tests were LDTs.

Some advocates for greater regulation hold that tighter LDT regulation would have prevented the company’s questionable tests to remain on the market for so long.

Joe El-Khoury, PhD, Director of the Clinical Chemistry Laboratory at Yale, believes the Theranos saga was, indeed, a black eye for the FDA. In its wake, the agency began clamoring for greater oversight of the clinical testing space, particularly the LDT sector.

Yet he doubts whether the sort of regulatory framework implied by the FDA’s new rules would have averted the spectacular Theranos disaster.

In an article published by Yale last February, El-Khoury is quoted saying, “The FDA claims that if it regulated LDTs, Theranos wouldn’t have happened—but that’s not true. The agency approved one of its blood tests [for herpes simplex 1], and it’s even still listed under the approved category,” he explains. “What brought down Theranos was [revocation of] CLIA (certification) and investigative journalism.”

Bill Beakey, co-founder and director of Professional Co-op Laboratory Services—which provides medical professionals with access to a wide range of clinical tests at very good prices—called the Theranos situation “a total failure of oversight.”

Beakey believes it is high time for greater scrutiny of the testing field, especially given the proliferation of companies that are “commingling under one roof diagnostic tests with supplement recommendations that allege to remedy the (test) findings.”

He told Holistic Primary Care that the reality of the testing world is that many tests enter the market that later prove ineffective. “Money is spent and lost, with patients not getting the information needed to help them.” For example, a number of Lyme disease tests—each touted to be the answer to the Lyme conundrum—have come and gone.

That said, Beakey has reservations about the FDA’s actual ability to clean up the space. “FDA’s track record for protecting the public is a dubious one. My concern is that they will selectively go after tests that impact profits of favored corporations, regardless of their usefulness.”

Uncontrolled Resale

Beyond the question of test quality and accuracy, Beakey says he’s very concerned about the uncontrolled resale of medical tests direct to consumers, and outside the clinical sphere. Internet-based vendors have developed systems that allow “just about anyone to sell blood tests to just about anyone else.” This sort of business is booming.

Labs will “develop a relationship with, or employ, a doctor who “signs” requisitions and then, in one way or another, sell them to an unlicensed “affiliate” for resale to the public. Some platforms allow these resellers to add a commission if the patient is paying the company directly. The only real relationship between the doctor, affiliate, and patient involves the transfer of money.”

This phenomenon will likely be even more difficult for the FDA and other regulatory agencies to control.

Potential Cost Burdens

The FDA has acknowledged that prior to issuing its final LDT rules in April, it received

 “a large volume of comments” on the notice of proposed rule-making earlier this year. Some of those comments vigorously opposed the FDA’s move.

The American Hospital Association has been a strong opponent, claiming that the new rules will impose burdensome costs and bureaucratic hassles on hospital-based labs that develop or have developed useful tests.

“While we support the need for additional oversight of the development and use of some LDTs and in-vitro diagnostics (IVDs) offered as LDTs, the FDA’s proposal to apply its device regulations to hospital and health system LDTs is misguided,” the AHA stated in a letter to FDA Commissioner Califf last December.

“These tests are not devices — they are diagnostic tools developed and used for essential patient care. Regulating LDTs under the FDA’s device regulatory framework could cause patients to lose access to many critical tests and stifle innovative advances in hospital and health system laboratory medicine.”

The AHA, which has nearly 5,000 member hospitals, contends that the process for FDA review and approval of a single medical device takes up to 8 months, and costs anywhere from $20,000 to over $441,000. Some large hospital system labs offer upward of 1,600 individual LDTs. If the labs have to submit each of these tests for pre-market approval as “devices,” the costs would be staggering.

AHA has urged Congress to insist that hospitals and hospital systems either be exempted from the new LDT rules, or that the rules be adapted to ensure hospitals can continue to provide LDTs without incurring unsustainable costs.

Not surprisingly, the American Clinical Laboratory Association has also objected to the reclassification of LDTs as devices. Like AHA, this lab trade group contends that the new rules will raise costs to the point that many tests will no longer be economically viable. Ultimately, patients will be the big losers.

Yale’s clinical lab scientists raise questions about whether FDA can, in fact, meet its stated goal of eliminating problematic tests.

Marie-Louise Landry, MD, professor of laboratory medicine says, “We’ve actually seen more problems with the FDA-cleared commercial tests than we have with our laboratory-developed tests.” In an article posted by Yale, she pointed out that “If there is a problem identified with an LDT, we have the ability to correct it promptly, whereas it can take years for a manufacturer to take corrective action and to obtain FDA approval.”

Cautionary Tales

The situation with LDTs and the FDA’s new plan for regulating them is, in some ways, analogous to the situation with dietary supplements.

As with LDTs, the FDA and many policymakers view the supplement industry as a poorly regulated sector plagued by questionably effective, potentially fraudulent products boasting bold claims, and sold freely without pre-market approval.

Implementation of the FDA’s new plan for oversight of LDTs could potentially provide important object lessons for the dietary supplement industry and for practitioners who use and recommend supplements.

Similar to LDTs, there’s no central federal registry that includes all supplements currently on the market, their manufacturers, their constituent ingredients, their labeling information, and their claims. This is something the FDA intends to rectify. But calls for “Mandatory Product Listings (MPLs)” have met with mixed and contentious responses from some industry trade groups and thought leaders.

Though the industry is regulated under the Dietary Supplements Health & Education Act (DSHEA) of 1994, enforcement is at the discretion of the FDA and FTC, and has been spotty at best. Though there has not (yet) been a fraud case of Theranos proportions in the supplement space, examples of poorly made products and false or misleading claims are not hard to find.

Many outside the industry, and even a lot of insiders, believe some sort of regulatory revision is needed. DSHEA is 30 years old, and was established at a time when the supplement field was far smaller and far less ubiquitous than it is now.

Efforts to re-regulate supplements will inevitably run into the same conundrum as the drive to regulate LDTs: how to ensure quality and safety without adding unsustainable costs that squelch innovation and constrain public access to potentially beneficial products?

Implementation of the FDA’s new plan for oversight of LDTs could potentially provide important object lessons for the supplement industry and for practitioners who use and recommend these products. Time will tell!

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