By Aaron Krol 

August 1, 2014 | On Thursday afternoon, the FDA announced that it plans, for the first time, to regulate laboratory developed tests in the same way it does other diagnostics. Up until now, this particular type of test has been free of FDA oversight, although a different federal agency, the Centers for Medicare and Medicaid Services, has had a certain amount of jurisdiction in the area.

Laboratory developed tests now represent a fairly major industry all their own, as independent laboratories have offered a huge variety of diagnostic tests to hospitals and other healthcare providers. As such, there are significant financial interests at stake if the FDA begins requiring these labs to go through the standard approval process for diagnostic tests. However, this issue is by no means all about money. The American healthcare system relies heavily on these laboratories for many kinds of tests that simply aren’t available elsewhere. Laboratory developed tests are particularly important for patients with very rare disorders, who often cannot be diagnosed by any FDA-approved tests. This is just one of many reasons that the FDA has been very cautious in exerting its authority over laboratory developed tests.

There’s a lot to digest in this issue, but here we will try to answer some of the most pressing questions.

Those with some basic familiarity with this issue should skip to question three. 

What is a laboratory developed test? 

A laboratory developed test, or LDT, is a type of in vitro diagnostic, which means it uses a sample taken from a patient, like blood, saliva, or a tissue biopsy, to diagnose a medical condition. Most in vitro diagnostics are sold by large life science companies directly to healthcare facilities, which then perform the tests in their own labs. The FDA has regulated these commercial in vitro diagnostics since 1976, when Congress passed the Medical Device Amendments (MDA) making clear that these tests fall under the definition of a “medical device” subject to FDA authority.

Some tests, however, don’t pass between manufacturers and healthcare providers. Instead, a single lab invents a new test, validates the test on its own, and performs the test entirely in-house. Labs used to call these tests “homebrews,” although that term has now mostly been replaced with the more serious-sounding LDT.

Some labs offering LDTs are themselves attached to large hospital systems, although more and more are completely independent. LDTs can have a very wide reach — some labs offer their services all across the country and even internationally — but samples are always shipped to the same lab, and the tests are always performed by the same team of technicians, who also designed the test in the first place.

There are many kinds of LDTs, but any new regulations would have especially large consequences for genetic testing. Almost all genetic tests offered in the United States are LDTs. This is almost necessarily true, because only one really up-to-date gene sequencing instrument, the MiSeqDx manufactured by Illumina, is currently approved by the FDA for clinical use. That device only won its FDA clearance last November, and just a handful of tests have so far been approved for it.

The FDA has approved a much larger number of tests using older DNA analysis technologies, like polymerase chain reaction, and these are widely used in clinical diagnostics. But for really complex, exploratory, or high-volume genetic tests, you need a gene sequencing instrument. In practice, that means contracting out with a lab that offers LDTs.

Why were LDTs not previously subject to regulation? 

Technically, the FDA believes that LDTs have always been subject to regulation — or at least since 1976, when Congress passed the MDA. Until now, the agency has merely been exercising its “enforcement discretion,” in effect turning a blind eye to these tests, but reserving the right to regulate them if it ever feels they pose a risk to public health.

When that policy was first decided back in the 70’s, LDTs were in general very different than they are today. These tests were mostly designed within hospital systems, and only used locally. The hospital labs that created them tended to use equipment and materials that had FDA approval for other purposes, since that was what they had on hand. LDTs also tended to be a sort of last resort, for rare conditions that could not be diagnosed by any other means. All of this led the FDA to believe that they posed minimal risk to patients.

Over the past forty years, however, the unique regulatory position of LDTs has created an industry all its own. Labs found that they could provide cutting-edge diagnostics much more quickly if they just kept them in-house, and could even become profitable businesses in their own right. They could use all the latest instruments and materials that were reserved for research labs, like high-throughput gene sequencers, and they could swiftly expand into revolutionary new areas of medicine. Today, LDTs are often used for “personalized medicine,” looking at patients’ unique genetic codes to personally tailor treatments.

The original reasons to practice enforcement discretion around LDTs have largely faded away, but new factors have replaced them. The healthcare system as a whole is much more reliant on LDTs than it was forty years ago, and the FDA is rightly worried that removing these tests from the market would be a major blow to both patients and providers. Cancer care is a good example: more and more oncologists want to consider a tumor’s genetic signature in choosing the best course of therapy. While a few FDA-approved tests will flag one or two major genetic markers in a tumor, many labs offer LDTs that look at huge swathes of the tumor’s genome, a process that is much more likely to turn up an unexpected treatment suggestion.

It’s also important to note that LDTs are not completely unregulated. The labs that offer these tests need to be certified under the Clinical Laboratory Improvement Amendments (CLIA) of 1988. Under this legislation, the Centers for Medicare and Medicaid Services will inspect any lab that performs clinical tests on humans to make sure the personnel are well trained and the equipment is functional and accurate. CLIA certification has to be renewed every two years, so a negligent lab would quickly find its certification revoked.

Of concern to the FDA, however, are the many regulations that LDTs do not have to meet: namely, labs do not have to demonstrate that an LDT measures the outcome it claims to, do not have to report any adverse events or deaths that might be linked to an LDT, do not have to use devices the FDA believes are clinically accurate, and can release new tests in between CLIA certification visits, meaning LDTs can be marketed without any kind of prior assessment.

So what did the FDA announce this week? 

The most important announcement was that the FDA plans to stop exercising enforcement discretion for certain types of LDTs. It expects almost all labs performing LDTs to provide the agency with basic information about the tests they offer, although not all of those labs will have to take further steps to secure FDA approval. The agency also sketched a rough timeline for when different labs can expect to see different regulations kick in.

All these plans are outlined in a detailed “Framework for Oversight of Laboratory Developed Tests” that the agency released on Thursday. However, the FDA has not officially “issued” this document, an important distinction. That’s because Congress has required the FDA to give 60 days’ notice before issuing any draft guidance for the regulation of LDTs.

Some fierce political wrangling is now expected in the run-up to the official publication of the draft guidance.

Wait, why would this be a political issue? 

LDTs are a business, and businesses have lobbyists. So do hospitals, which use LDTs regularly. Back in 2012, as part of a series of legislative deals needed to renew the FDA’s right to collect user fees from the pharmaceutical industry, the House of Representatives added the 60-day provision regarding LDT regulations. Broadly speaking, Republicans have favored the status quo around LDTs, and Democrats have backed some level of FDA oversight, but the issue does not (yet) break down strictly on partisan lines.

Members of the FDA have publicly chafed at the 60-day provision, which they see as unnecessary because any draft guidance would offer plenty of time for laboratories to adapt to new regulations. Last year, the American Association for Clinical Chemistry reported that Alberto Guitierrez, director of the FDA’s Office of In Vitro Diagnostics and Radiological Health, had specifically mentioned the amendment during an address calling for greater oversight of LDTs. “It seems to me that the only reason Congress wants to know 60 days before is because they have lobbyists who want to prevent the guidance from coming out,” Guitierrez reportedly told the association.

Meanwhile, a group of five Democratic senators, representing the party’s most liberal wing, wrote to the Office of Management and Budget one month ago to request that a draft guidance on LDTs be released. That appears to be the immediate spur that led the FDA to announce its planned new policy, although the agency has been signaling an interest in regulating LDTs since at least 2006.

So after 60 days, will LDTs have to come off the market? 

Definitely not. Even the gentlest changes the FDA has proposed would not kick in until six months after the draft guidance is officially issued. Those first changes would require labs to let the agency know what LDTs they are offering. They would also require most labs to report adverse events, like patient death or injury, that they have any cause to believe might be linked to an LDT.

The FDA does, however, ultimately want to apply “premarket clearance” to LDTs, which is the major hurdle that other in vitro diagnostics have to pass before being sold. The biggest obstacle to premarket clearance is proving clinical validity: that is, whether a test really does what it says for the patient. For instance, if a lab says that its LDT tests a tumor’s sensitivity to the cancer drug Herceptin, it would have to demonstrate that Herceptin really does work better on the tumors the test identifies.

That may sound like a no-brainer, but it generally cannot be proven without going through clinical trials, which are expensive and lengthy processes. That’s why CLIA labs have often relied on other forms of evidence in designing LDTs. In our example, Herceptin works by targeting HER2 proteins, which are sometimes overexpressed in cancer. It stands to reason, then, that a tumor with mutations to the HER2 gene might be vulnerable to Herceptin. An LDT that looked at HER2 mutations might have a strong case for suggesting Herceptin use — but without measuring the results in actual patients, it wouldn’t have clinical validity.

The FDA’s draft guidance actually makes some allowance for this. “Where an LDT’s analytes/markers that are measured/assessed have had their clinical validity already established in the literature,” it states, “FDA believes it may not be necessary for sponsors to conduct extensive new studies to demonstrate clinical validity.” In other words, if some other device has already pegged HER2 mutations to a better Herceptin response, a lab offering a new LDT for the same indication could piggyback on those results. It would only have to prove to the FDA that any differences in its testing method don’t affect patient outcomes.

The FDA wants to start subjecting LDTs to premarket clearance 12 months after its draft guidance is issued. Even then, however, it plans to roll out regulations slowly, starting with the LDTs it sees as presenting the greatest risk to patients, and working its way down over a period of at least eight years.

Didn’t you say some conditions can only be diagnosed with LDTs? 

Yes, and the FDA is aware of that. For certain LDTs, which the agency feels would be highly disruptive to take off the market even temporarily, it plans to continue its policy of enforcement discretion for some or all regulations.

The FDA has announced that no changes will be made for LDTs used for organ, stem cell, or tissue transplants. These procedures require a very careful and complex matching of donor to recipient, and rely heavily on sequencing the complicated HLA system of the human genome. This testing is so particularized to each patient that it would be almost impossible to win FDA approval for any specific test. LDTs used in law enforcement will also get a complete pass.

For another set of LDTs, the FDA wants to be notified of what tests are being performed, and to receive adverse event reports, but will not require premarket approval. These include any LDT to diagnose a condition so rare that fewer than 4,000 people a year could be tested for it. The FDA also makes allowance for LDTs for “unmet needs,” meaning that there is no equivalent FDA-approved test. These tests would be allowed to go forward without premarket approval, as long as they stay within a single hospital system and are not offered to outside users.

Finally, the FDA still fully approves of what it calls “traditional” LDTs — that is, the ones that take place entirely in one hospital system, do not use any non-FDA-approved devices or materials, and do not use software to deliver the results. These will also be exempted from premarket approval.

What are the tests the FDA is most worried about? 

For tests that aren’t covered by one of the above exemptions, the FDA has planned three phases of regulation. These correspond to the three classes of medical devices the agency uses when approving any new test. If the FDA decides an LDT falls under Class III, the highest-risk category, it will come up for the premarket approval process between one and five years after the draft guidance is issued. LDTs in Class II will have their own four-year approval phase after that, and the FDA may allow third parties to review these tests to relieve the bottleneck of going through a single agency. LDTs in Class I will be generally exempt.

The greatest uncertainty for CLIA labs now — assuming the regulations go through at all — is which class their tests will fall under. In general, any test for a completely new use falls under Class III by default, which would be a problem for both labs and the FDA’s resources for enforcement. The draft guidance states that “when warranted, FDA plans to down classify such LDTs into the appropriate lower risk class,” but details remain up in the air.

Fortunately, labs have advance notice of which tests the FDA plans to tackle first. The top priority tests, which would be the first batch of Class III devices to undergo the premarket approval process, will be tests that act like companion diagnostics, major screening tests for healthy patients, and blood tests for a certain set of high-risk patients.

Companion diagnostics are tests that are paired with a specific treatment; our HER2 test for Herceptin treatment is an example. The FDA, however, is concerned about tests that act like companion diagnostics, but were not actually developed alongside the treatments they address. The agency believes these present a significant risk of choosing an inappropriate treatment for a patient.

The screening tests the FDA is worried about are any tests that diagnose a very serious condition, like cancer or severe heart disease, but which are used in the absence of other tests that could confirm the diagnosis. The concern is that the chance of a misdiagnosis with these tests may be unacceptably high.

Finally, the FDA has prioritized any blood test for infectious disease used on very vulnerable patients, like those with HIV or those who are recovering from an organ transplant.

If your LDT does not fall into one of those categories, you likely won’t know what to expect for at least another year. The FDA does state that it will “prioritize all other LDTs based on risk using a public process, including expert advisory panels as appropriate,” so it is likely that both CLIA labs and the providers they serve will have some level of input on these decisions. The process of laying down general guidelines on Class I, II, and III devices is scheduled to take up to two years.

How are labs taking this news? 

When reached for comment, a number of CLIA labs declined to take a position on the draft guidance. (I would have done the same; it was only published yesterday.)

However, a group of academic lab directors did write to the Office of Management and Budget in July, in response to the action by the five Democratic senators two weeks prior. The authors of this letter are in many ways model representatives for the LDT industry: they work for nonprofit centers, and are intimately involved in patient care.

The letter is strongly opposed to any FDA regulation of LDTs, asserting that CLIA certification already provides “extensive validation and continuous monitoring to ensure the performance, quality and reliability of diagnostic services.” The authors are especially vigilant to the possibility that some tests may become completely and permanently unavailable if LDTs become subject to premarket approval. “Some testing currently performed at laboratories as LDTs will never generate the financial returns to justify the costs of obtaining FDA clearance or approval,” they write. “Patients served by these tests would be left with no testing options.”

The weakest argument of the letter, but one we can expect to see repeated many times in the coming weeks, is that LDTs are not “medical devices” and therefore cannot fall under the FDA’s jurisdiction. While it’s true that the plain reading of the phrase “medical device” does not seem to naturally fit tests performed with a series of reagents on multiple instruments, the FDA’s authority over in vitro diagnostics has been enshrined in law for almost forty years.

It is important to remember that this letter was posted before the draft guidance document was made public. It is possible that the exemptions proposed by the FDA will quell at least some of the concerns that lab directors have over the regulation of their tests. The authors of this letter are also not representative of all LDT providers, although they do include leaders of several prominent labs, including those at Brigham and Women’s Hospital, the Icahn School of Medicine at Mount Sinai, and the Mayo Clinic.

A big contingent not represented in this letter is commercial CLIA labs. Some of these, like Foundation Medicine and Myriad Genetics, have quickly become staples of the healthcare industry, and may sell tens of thousands of tests a year. Their reactions are eagerly awaited.

Clinical Informatics News will continue to cover this issue as it develops.