Chris Anderson

The debate on laboratory developed tests boils down to whether clinical labs should come under the agency’s control.

If the tenor of the overflow crowd at November’s Association for Molecular Pathology (AMP) Annual Conference to hear FDA’s Alberto Gutierrez, Ph.D., is any indication, the agency’s move to tightly regulate laboratory developed tests (LDTs) faces an uphill battle to win over those who run the thousands of molecular pathology labs across the country. Dr. Gutierrez, director, office of in vitro diagnostics and radiological Health at FDA, noted the agency was legally provided with regulatory oversight of tests developed in labs in 1976. But based on the types of “homebrew” tests used at the time, the agency decided to exercise regulatory discretion regarding LDTs.

But things have shifted dramatically over the past 40 years as companion diagnostics have multiplied in number and molecular pathology labs now routinely search for specific genetic mutations and other markers to both identify specific subtypes of cancer and to suggest precision therapies. Along with these advances, clinical labs have developed a broad range of LDTs, many of them created to provide the same information and results as predictive and companion diagnostics from companies that have invested the time and money to gain FDA approval.

“What has happened is there has been a dual path to get (diagnostics) on the market,” Gutierrez said. “One path is manufacturers come to the FDA, [the test] gets reviewed, and the agency determines if the test is safe and effective or not. Or the other path, a lab or diagnostic company develops its own test and moves it to market (without gaining FDA approval) via the loophole that has been created.” The result, he added, is an abundance of tests that are being developed by some laboratories and diagnostic companies that look more like traditional manufacturers using and marketing these LDTs without FDA approval.

“The FDA is saying LDTs are very common and are being used to diagnose some of the most complex and advanced diseases and make decisions on treatment choices,” noted Peter M. Krein, Ph.D., director of medical affairs with Qiagen. “Therefore, they have concerns around the adequacy of the evidence of the tests; things like controls and the claims these laboratories are making for their clinical customers.

“It is clear that the ability of certain institutions to establish their own CLIA labs and then market LDTs for a broader impact rather than in a hospital setting has changed the way medicine is practiced in the United States.”

Who Should Regulate Clinical Labs?

While there is significant uncertainty in the industry until the final LDT regulations are published, expected sometime in 2015, a significant portion of the debate about LDTs focuses on whether or not clinical laboratories should come under the purview of FDA.

“Right now we have a CLIA-centric view. We believe CLIA is the place for regulation of clinical laboratories,” noted Roger Klein, chair of the professional relations committee for AMP. “At this point we want to work with FDA and CLIA through CMS to really help solve any problems that stakeholders are concerned about.”

Yet not all in the industry are convinced that keeping the status quo for LDTs or even modernizing the CLIA statute, as AMP has suggested, will do enough to safeguard diagnostic tests that are used to directly influence what type of care or therapies patients receive. It is these LDTs, which FDA considers to be high-risk Class 3 medical devices, which will be subject to immediate scrutiny under the proposed FDA regulations.

“I don’t think (updating CLIA) will work for the high-risk devices,” said Steven Binder, Senior Director, technology development in the clinical diagnostics group at Bio-Rad Laboratories. “Everyone knows, whether they will say it or not, that the CLIA inspectors do not come to look at the evidence to support a high-risk test.”

As Dr. Gutierrez noted, FDA has been taking an increased interest in the activities at molecular laboratories for more than 20 years, as evidenced by regulations released in 1998 to put more stringent controls on the use of test kits labeled either as research use only (RUOs) or investigation use only (IUOs). At about the same time in the 1990s, it also moved to shore up what it saw as holes in its oversight of analyte-specific reagents (ASRs). FDA issued revised guidance for RUOs and IUOs in late 2013, and updated its ASR guidance in 2007, but there still remains plenty of room for interpretation and neither specifically addresses the issue of LDT use.

Potential Burden on Labs

Another point of contention among AMP members is the idea that LDTs are medical devices. “What FDA is proposing to do is designate clinical laboratories that provide service using laboratory developed tests, or laboratory developed procedures as we like to call them, as medical device manufacturers. We don’t see that regulatory framework or regulatory scheme as being at all appropriate to the regulation of clinical laboratories,” said Klein, who is also medical director of molecular oncology at the Cleveland Clinic.

While some might consider this a semantic argument, there is no escaping the reality that virtually all labs use LDTs and smaller labs could be squeezed financially if LDTs need to gain regulatory approval. “If these labs decide it will be too much of a burden, or if they can’t afford them because, quite frankly the process is quite expensive from a manpower, time and financial perspective, depending on the outcome of the final guidance, there could be decisions within some hospitals to stop offering the tests,” said Qiagen’s Krein.

FDA has come under criticism that it chose to issue draft guidance for the new regulations to purposely avoid any kind of financial impact studies that would be triggered had it chosen a formal rule making route, which would have triggered a study of the financial impacts as a required part of the process.

But Binder points out that FDA is not one to take into account the potential economic impact either broadly across the industry or on individual labs should the proposed regulatory framework move forward. “The FDA is driven by safety and risk not by financial considerations,” he said. “You can’t go to the FDA and say ‘I charge $300 for this companion diagnostic and my lab will close if I can’t run my test.’ Their question is how many patients will die because no one validated the test properly. They don’t care at all about whether a test is vital to a lab’s future.”

Are LDTs Unsafe?

Most in the industry agree the main target of the proposed regulations are LDTs used as companion diagnostics to ensure the accuracy of any tests that directly inform patient care. According to the FDA, the proposed regulatory framework for LDTs is necessary because the agency “has identified problems with several high-risk LDTs including: claims that are not adequately supported with evidence; lack of appropriate controls yielding erroneous results; and falsification of data.”

What is not clear is how widespread these problems are within molecular labs. AMP’s Klein is doubtful there is a significant problem with LDTs as the FDA contends. “I am unaware of evidence of systemic problems with testing and the lack of complaints and the lack of lawsuits suggest there probably aren’t serious patient harms taking place in any systemic way,” Klein pointed out.

Binder agrees generally with Klein’s point, noting that while there have clearly been some bad LDTs those likely number in the dozens of tests, not hundreds. However, because there is no system in place to test the LDTs “how do you know if an LDT is bad anyway?” he asked. “There is no inter-laboratory testing; there are no publications that you can judge whether they are well designed or not; and people can change their software willy-nilly without telling anyone.”

Qiagen's Krein can see both sides of the debate because his company both supplies reagents to molecular labs across the country—a business segment that may be affected should labs discontinue using their LDTs—and also markets FDA approved diagnostics that could stand to see greater sales if the framework is adopted. While he and Qiagen are staying on neutral ground he does understand FDA’s desire to push forward.

“It is wonderful that you have an analytic marker that you can test with some precision. However, we have seen routinely that if you can have one patient cohort with a biomarker that looks fantastic for predictive or prognostic value but in another population it doesn’t hold up,” Krein noted. “And this is what the FDA’s concern is. If you have an analytical marker that looks good in one peer-reviewed population or a particular setting, those markers, without the clinical validation, may not be as effective as some of the claims that are being made for it.” 

Chris Anderson is the former Chief Editor of Drug Discovery News, which he helped launch in 2005. ([email protected])

This article was originally published in the January 2015 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this digital publication, go to

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