In Laboratory Developed Tests: Greater Role Leads to Increased Federal Oversight – PART 1, I discussed both the historical perspective of regulation of LDTs, the current landscape and the relationship between direct to consumer testing and LDTs. Now I’d like to discuss the existing controversy regarding how FDA regulations can be applied to LDTs.

The decision about whether, and how, to regulate LDTs remains far from unanimous. Below are some of the pro and con statements of professional associations and ad hoc groups:

American Society for Clinical Pathology (ASCP)

The American Society for Clinical Pathology published a Policy Statement regarding regulation of laboratory developed tests:

“Accrediting bodies should continue to monitor the performance and quality of LDTs, but that role should be post-clearance, to avoid any conflicts of interest”.   It advocated for the establishment of an independent, third party reviewer to verify quality and accuracy of claims prior to review by FDA,  and the federal CLIA-regulating agencies that would enhance the transparency of the process. The criteria established by the FDA should be risk-based, and while high risk LDTs should fall under the purview of the FDA, lower risk LDTs, those not deemed to be “in vitro diagnostic multivariate assays” should continue to be regulated by CLIA.  Implementation should be in a step-wise fashion, and could first require compliance for high-risk tests, and later implement requirements for moderate and low-risk tests. Finally, evaluation of LDTs, as with any other diagnostic laboratory test, should include the test’s analytic and clinical validity[i].

American Association for Clinical Chemistry (AACC)[ii]

“Some members of Congress have been floating a proposal to increase regulatory oversight of LDTs, suggesting that Congress create a new agency within FDA to oversee all lab tests, including LDTs.

Some aspects of this proposal make sense—such as getting labs to demonstrate the accuracy of LDTs, and exempting critical tests, such as those for public health emergencies and newborn screening, from increased regulatory scrutiny, AACC wrote in a letter to Congress.

However, the association is concerned that dual scrutiny from both CMS and FDA would impede patient access to testing, since many hospitals and rural testing facilities do not have the resources to comply with FDA’s requirements and would be forced to stop performing laboratory developed tests,” AACC’s letter stated.

Instead, Congress should work within CMS’s regulatory framework to tighten scrutiny of LDTs. Rather than have FDA assume the task of assessing the clinical validity of LDTs, handing that responsibility to CMS would “be a relatively minor adjustment considering many CMS-accredited laboratories are already required by private accrediting bodies to demonstrate clinical validity,” the letter said.

American Clinical Laboratory Association (ACLA)[iii]

The American ­Clinical Laboratory Association has repeatedly argued that LDTs already face stringent oversight under a federal law that requires monitoring of the reliability of the tests.

“FDA regulation of LDTs would be contrary to the public health. Numerous critical tests are only available as LDTs, including many “gold standard” DNA sequencing assays, newborn screening tests, and tests for rare diseases. If FDA were to require clearance or approval for LDTs, laboratories may be unable to continue offering them. Some testing currently performed at laboratories as LDTs will never generate the financial returns to justify the costs of obtaining FDA clearance or approval. Patients served by these tests would be left with no testing options. Similarly, critical testing would be unavailable in the “lag time” between development of new tests and FDA authorizing them, and subsequent improvements on existing tests would slow significantly under the rigid, inflexible, and duplicative FDA regulatory scheme.”[iv]

Previously, the agency (FDA) has taken a hands-off approach to the studies, because they were simple, confined to local labs, and often used to diagnose rare conditions, Dr. Peter Lurie, Associate Commissioner for Public Health Strategy and Analysis, said in an FDA Voice blog on November 16 (2015) “LDTs have increased in complexity and availability and are now frequently used to diagnose common, serious medical conditions, including cancer and heart disease, with potentially greater impact on patients. And yet, LDTs are still under a general policy of enforcement discretion,” Lurie wrote. “That means they have rarely undergone FDA review to determine whether they are accurate, reliable, and provide clinically meaningful results. It also means that FDA’s own adverse event reporting databases rarely capture problems associated with a faulty LDT.” In addition to a lack of adverse event reporting, the FDA report found that there is no premarket review of LDTs, manufacturers often make unsupported claims about their effectiveness, there is inadequate product labeling, a lack of transparency, and that other laboratories that have to go through official vetting processes are at an unfair disadvantage to LDTs. The agency’s report also noted that LDTs could be a threat to the scientific integrity of clinical trials when researchers rely on their results.


Nearly two dozen university lab directors from around the country expressed opposition in a recent letter to the Office of Management and Budget (OMB), arguing that LDTs are not technically medical devices and that allowing the FDA to regulate them would slow the development of critical testing and ultimately do a disservice to patients. The OMB must approve regulations proposed by federal agencies.

“The ability of laboratories to develop custom diagnostic tests has been critical to the growth of personalized medicine and keeping pace with the changing face of disease to best serve patients and clinicians,” they wrote. “FDA regulation of laboratory developed tests would stifle the medical innovation occurring in academic medical centers today, and interfere with our ability to care for patients”.[v]


When a laboratory develops a test system such as an LDT in-house without receiving FDA clearance or approval, CLIA prohibits the release of any test results prior to the laboratory establishing certain performance characteristics relating to analytical validity for the use of that test system in the laboratory’s own environment.  This analytical validation is limited, however, to the specific conditions, staff, equipment and patient population of the particular laboratory, so the findings of these laboratory-specific analytical validation are not meaningful outside of the laboratory that did the analysis. Furthermore, the laboratory’s analytical validation of LDTs is reviewed during its routine biennial survey – after the laboratory has already started testing.

In contrast, the FDA’s review of analytical validity is done prior to the marketing of the test system, and therefore, prior to the use of the test system on patient specimens in the clinical diagnosis/treatment context. Moreover, the FDA’s premarket clearance and approval processes assess the analytical validity of a test system in greater depth and scope. The FDA’s processes also assess clinical validity, which is the accuracy with which the test identifies, measures, or predicts the presence or absence of a clinical condition or predisposition in a patient, as part of the review that is focused on the safety and effectiveness of the test system.

Furthermore, unlike the FDA regulatory scheme, CMS’ CLIA program does not address the clinical validity of any test.

Thus, the two agencies’ regulatory schemes are different in focus, scope and purpose, but they are intended to be complementary.

 Food and Drug Administration (FDA)

The FDA 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. The FDA is concerned that people could initiate unnecessary treatment or delay or forego treatment altogether for a health condition, which could result in illness or death. The FDA is aware of faulty LDTs that could have led to: patients being over- or undertreated for heart disease; cancer patients being exposed to inappropriate therapies or not getting effective therapies; incorrect diagnosis of autism; unnecessary antibiotic treatments; and exposure to unnecessary, harmful treatments for certain diseases such as Lyme disease.

To help health care providers and patients better rely on the thousands of laboratory tests that are used every day to diagnose disease or other conditions or guide treatment and to encourage the advance of personalized medicine, on July 31, 2014 the FDA notified Congress of the Agency’s intent to issue a draft oversight framework for LDTs based on risk to patients rather than whether they were made by a conventional manufacturer or a single laboratory. This draft oversight framework includes pre-market review for higher-risk LDTs, like those used to guide treatment decisions, including the many companion diagnostics that have entered the market as LDTs. In addition, under the draft framework, the FDA would continue to exercise enforcement discretion for low-risk LDTs and LDTs for rare diseases, among others. The framework would be phased in over many years.”[vii]


Laboratory developed tests or LDTs are increasingly being integrated into standard practice for diagnosing and managing disease, predicting the risk of developing disease, and informing decisions about lifestyle and behavior. These tests are enabling improved prevention, treatment, and disease management for an array of common chronic conditions such as cancer, heart disease, and diabetes, as well as rare genetic disorders. They have become indispensable tools in the practice of medicine.

Since 1988, the laboratories performing LDTs have been highly regulated by a comprehensive federal statutory framework under the Clinical Laboratory Improvement Amendments (CLIA), which requires continuous monitoring to ensure validity and reliability of LDTs. For the last few years, however, the Food and Drug Administration (FDA) has expressed its intent to regulate LDTs as medical devices.

While concerns about the effect of more oversight and regulation by the FDA on the development of new LDTs have been expressed by numerous laboratory professionals and organizations, all indications point to implementation of the new FDA guidance.

The FDA will focus its initial efforts on reviewing LDTs that have the same intended use as an FDA-approved or -cleared companion diagnostic or class III medical device, as well as LDTs that determine the safety or efficacy of blood or blood products. The FDA intends to continue to exercise enforcement discretion with respect to quality system regulation requirements until a manufacturer of a given LDT submits a Pre-market Approval or the FDA issues a 510(k) clearance order for the LDT.

Implementing the FDA’s proposed guidelines on regulating moderate- and high-risk LDTs is likely to have a profound impact on the market for personalized medicine. Around 11,000 tests developed by 2000 different laboratories are predicted to fall under FDA’s proposed framework  Thus, it is becoming increasingly evident that providers of moderate-risk and high-risk LDTs that were once largely shielded from FDA oversight will now have to seek FDA approval or clearance[viii].

[i] American Society for Clinical Pathology: Policy Statement.  Regulation of laboratory Developed Tests (LDTs). (Policy Number 10-02).
[ii] AACC CLN Staff. Capitol Hill Scrimmage on LDT Oversight.  December 2015.
[iii] American Clinical Laboratory Association (ACLA) Issues: Laboratory developed Tests.
[iv] I Jackson. Laboratory Developed Tests May harm patients Without FDA Oversite, Agency Warns. November 25, 2015.
[v] D Brady.  The Washington Post. FDA to Begin Regulating laboratory Test Devices.  July 31, 2014.
[vi] CMS  CLIA.  CLIA Overview… What is CMS’ authority regarding Laboratory Developed Tests (LDTs) and how does it differ from FDA’s authority?
[vii] Food and Drug Administration (FDA)  Medical Devices.  Laboratory Developed Tests. November 17, 2015.
[viii] J Fernandez, J Ewing, L Collins, J Lin, L Wu. Advance For laboratory Administrators. Laboratory Developed Tests: An Emerging area of FDA Regulation. December 28, 2015.

Send this to a friend