Many Questions About FDA Regulation of LDTs

Federal agency intends to look at patient risk as a primary factor in how it will regulate LDTs

CEO SUMMARY: Ask most pathologists and laboratory administrators about the FDA’s intent to regulate laboratory-developed tests (LDTs), and they will likely answer that it is to control web-based direct-to-consumer lab testing companies and the rapidly- growing number of proprietary tests. Although that is true, any move to regulate LDTs also has the potential to cover a huge number of long-established and clinically-accepted homebrew tests that are performed daily in almost every lab in the country.

FEW PATHOLOGISTS AND LABORATORY PROFESSIONALS recognize the wide-reaching impact that FDA regulation of laboratory-developed tests (LDTs) could have on the entire laboratory testing industry.

That’s probably because, when the FDA does comment on why it needs to regulate LDTs, it most commonly identifies the rapidly expanding number of molecular and genetic tests that companies introduce into clinical practice using the LDT exemption. The FDA also expresses concern about the lack of regulation in the direct-to-consumer lab testing market, which is awash in LDTs that have little or no clinical research data in support of their accuracy and efficacy.

It is for these reasons that many pathologists and laboratory professionals have not paid closer attention to the FDA’s plans to regulate laboratory-developed tests, also known as “homebrew” tests. However, any effort by the FDA to regulate LDTs is likely to require every academic center lab, clinical lab, and pathology group in the nation to comply. That is because nearly every lab in the United States currently offers some number of laboratory-developed tests.

On pages 3-5 of this issue, THE DARK REPORT explained why FDA regulation of LDTs would have profound consequences for virtually every laboratory in the United States doing high-complexity testing. Regulation of LDTs has the potential to turn into a serious threat to the clinical integrity and financial stability of the nation’s laboratories. That fact has not yet been fully recognized and acknowledged by the majority of lab administrators and pathologists in this country.

FDA Soliciting Comment

In recent months, the FDA has accelerated its efforts to design a regulatory scheme involving LDTs. The FDA is actively gathering public comment about its stated goal of regulating LDTs. Several lab industry associations and organizations are in discussions with FDA officials.

At the American Clinical Laboratory Association (ACLA), President Alan Mertz has taken part in meetings with FDA officials and other health policymakers on the subject of FDA regulation of LDTs. “This is truly a sleeper issue for much of the laboratory testing community,” said Mertz, “The FDA has threatened to regulate LDTs for a long time. However, since this spring, FDA officials have begun spending more time on this issue and wide-ranging new regulations could soon emerge.

Regulating All LDTs

“Amidst all the recent publicity about the FDA’s intentions, what escapes the notice of many laboratory professionals is that the FDA is looking at regulating all LDTs!” he emphasized. “This goes beyond the LDTs run by the largest laboratories and the various genetic tests offered by specialty lab companies. The FDA would regulate the laboratory-developed tests run daily by hospitals, physician group practices, small genetic testing laboratories, reference laboratories, regional laboratories, and national laboratories.

“It doesn’t matter whether it’s a small laboratory or a big laboratory; whether its an independent lab company or a community hospital lab that offers an LDT—the FDA is looking at the risk to the patient,” said Mertz. “It was clear in those public meetings that the FDA doesn’t intend to regulate based on the type of lab test. Rather, it intends to regulate based on how high the risk is to the patient.”

“Although the popular perception is that the FDA is targeting primarily genetic tests, that is not the full story,” explained Mertz. “LDT’s cover a wide range of lab tests performed daily in hospital-based labs and other sites. We’re talking about flow cytometry, FISH testing, and infectious disease testing, as well as all the tests for cancer—even cultures and microbiology.

“A high number of these assays are LDTs,” he continued. “Many of them are adapted lab-by-lab, hospital-by-hospital, and academic center-by-academic center. Each laboratory makes adjustments to their LDTs to deal with specific populations, local needs, or diseases that have changed or mutated. HIV genotyping is a good example of the latter.

“Another factor is that published literature and the science changes continuously,” he added. “It is why these laboratory tests are continually improved and updated—often in a site-specific manner to meet the needs of the local patient population. Some of these updated tests are LDTs. Some are test kits that need to be modified to keep up with the disease.

“There is another aspect to LDTs,” observed Mertz. “Many laboratory-developed tests are for rare diseases that affect a very small population. It would be prohibitively expensive to run each type of such lab tests through the FDA review process.

“Amidst all the recent publicity about the FDA’s intentions, what escapes the notice of many laboratory professionals is that the FDA is looking at regulating all LDTs!” emphasized Mertz.

“This is important testing which is typically performed on a small scale,” he noted. “The lab may perform tens of tests or several hundreds of tests—even as it adjusts that testing for very small populations. How could such a lab go through the 510(k) FDA process that costs potentially millions of dollars, and could take months or years to adjust the lab test for 12 patients? This illustrates why the FDA faces a challenge in regulating LDTs.”

The FDA’s Approach

Mertz says that, based on public and private meetings about LDT regulation, it appears FDA officials do not fully understand the role that these types of laboratory-developed tests play in personalized medicine.

“On the plus side, however, indications are that the FDA does at least recognize the burden that requiring pre-market approval would impose on laboratory tests that must be modified: 1) on an individual basis; or, 2) for very small groups; or, 3) for rare diseases,” he commented. “The FDA is also saying that it does not intend to disrupt the majority of tests that are well established, clinically validated, and in use.

“The intention of the ACLA and our representative healthcare organizations is to help the FDA to concentrate its regulatory focus on a small subset of laboratory tests that it truly considers to entail patient risk and that would warrant independent government validation, such as tests that are the sole determinant of whether a patient receives a particular treatment,” Mertz said.

Traditionally, FDA involvement in laboratory medicine has been restricted to the in vitro diagnostic (IVD) and commercial vendor sector of the industry. These com- panies understand the FDA’s pre-market approval process. Laboratory analyzers and lab test kits cleared by the FDA through this process can then be sold to laboratories throughout the United States.

Impact Of FDA Regulation

Were the FDA to regulate the full range of laboratory-developed tests currently in use, there would be significant changes to laboratory medicine as it is practiced today. “What the laboratory medicine profession needs to understand is that FDA regulation of all LDTs currently in use today would—for the first time—directly affect the daily activities of pathologists and working clinicians as they go about their normal medical practice,” stated Mertz.

“Over recent decades, working pathologists and laboratory scientists in inde- pendent laboratories and community hospital-based laboratories have had little interaction with the FDA’s various authorities and processes,” he explained. “Were the FDA to regulate the broad range of laboratory-developed tests, it would require working laboratory scientists to interact with the FDA. That would create a serious problem and has the potential to disrupt long-established clinical testing practices in ways that could set back patient care.

“We did bring this problem to the attention of the FDA,” stated Mertz. “It is a fact that the working side of the laboratory medicine community doesn’t interface or interact with the FDA in the same manner as the IVD or commercial side.

Interaction With The FDA

“Unlike the staff of the large IVD manufacturers, most pathologists and clinical chemists don’t likely speak the FDA language. To a large extent, the FDA doesn’t (and they admit this) completely understand the world of clinical lab testing and laboratory medicine.

“This is why a number of laboratory industry associations and groups are having conversations with the FDA about its goal of regulating LDTs,” said Mertz. “We believe this input is essential before the FDA publishes proposed rules, or new requirements involving LDTs are made into law.”

However, Mertz wants to encourage wider discourse between the laboratory testing profession and the FDA. “The entire lab community needs to be engaged in this dialogue with the FDA,” stressed Mertz. “LDTs are not limited to just test- ing labs or big national labs that do research. LDTs are not just performed in academic medical centers.

Comments From Labs

“The FDA’s regulatory scheme for LDTs will affect all of us,” continued Mertz. “This is why we all need to get involved during the next open comment period. If this reg- ulation isn’t done correctly, it could be very disruptive. That’s why we’re so intent on working with the FDA to get it right. That’s also why informed comment by laboratory professionals from any and all labs and pathology groups is needed during the coming months.”


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