Laboratory Developed Tests (LDTs) have been clinically available for decades and are defined by the US Food and Drug Administration (FDA) as an “IVD [in vitro diagnostic] that is intended for clinical use and designed, manufactured and used within a single laboratory.” These tests are ordered routinely by clinicians and are critical for patient care. Although LDTs have not been regulated by the FDA previously, there has been a recent shift in policy that is changing the governing landscape of laboratory medicine. Some embrace the FDA position, while others vehemently oppose the FDA stepping into this space. This topic is complex, as laboratory medicine has evolved considerably over the last several decades. There is a balance between proper regulation and promoting an atmosphere of innovation. Above all, patient safety is paramount to clinical labs and regulators alike.
The FDA was given regulatory oversight of medical devices under the Medical Device Amendments of 1976 to the Federal Food, Drug and Cosmetic Act. This established different classes of medical devices based on patient safety and potential risk. Historically, the FDA’s policy regarding LDT regulation has been to “exercise enforcement discretion,” which effectively states that although the FDA has the jurisdiction to regulate LDTs, it was choosing NOT to do so. Interestingly, the FDA has acknowledged that LDTs have improved standard medical care and enforcing regulation may negatively impact public health.
FDA-cleared tests are commercially developed tests that typically measure well-established analytes; examples may include a comprehensive metabolic panel or a complete blood count. However, there are some FDA-approved tests that are very complex, including molecular genetic tests for breast and/or ovarian cancer risk, among others. LDTs were created to fill the gap where there is not an available FDA-cleared test. Additionally, there are multiple LDTs that are considered the “gold standard” in laboratory medicine, making them critical to patient care. The process of obtaining FDA approval for a clinical test can be lengthy and expensive. Furthermore, LDTs have a degree of adaptability (due to changing clinical needs or technological discovery) whereas the FDA process is rigid and once a test is approved by the FDA, the procedure of performing the test must not be changed. LDTs are studied, validated, and used clinically under the guidance of laboratory directors who have a doctoral degree and board certification.
Although LDTs have not historically been regulated by the FDA, there is still oversight of the laboratories that make such tests clinically available. The Centers for Medicare and Medicaid Services (CMS) regulates clinical labs under the Clinical Laboratory Improvements Amendments of 1988 (CLIA). There are rigorous standards to obtaining and maintaining CLIA certification including the studies that must be performed in order for a LDT to be offered clinically. Representatives from CLIA inspect and audit accredited labs periodically to determine analytical validity of the commercialized LDTs. However, CMS has restricted capabilities to investigate the clinical utility of laboratory tests that are available to clinicians.
There are two recent stories in laboratory medicine, which some may argue, demonstrate the need for additional regulation. Theranos was a company that sought to revolutionize laboratory medicine by performing multiple blood tests with just a few microliters of blood via a small finger prick, instead of the typical milliliters of blood obtained through venipuncture. The company had a $10 billion valuation at its peak. However, an investigation determined the tests that Theranos was attempting to commercialize were based on fraudulent science and unscrupulous business practices. The former CEO is now in prison and the company is defunct. Another story in the New York Times reviewed how some non-invasive prenatal screens are marketed to clinicians and patients, along with the accuracy of screening for microdeletion syndromes that are considered rare. In response to the original story reported by the New York Times, the FDA released statements regarding their concerns about the current regulatory landscape of LDTs. Remarkably, Theranos was CLIA-certified (which was later revoked) and the labs that perform non-invasive prenatal screening are also certified by CLIA.
However, some may contend that these examples are extreme cases, and do not represent the overwhelming majority of institutions offering LDTs. CLIA already regulates labs for analytical validity. Professional medical societies also have guidelines and resources for laboratory medicine, including the American Association for Diagnostics & Laboratory Medicine, American Society for Clinical Pathology, American College of Medical Genetics and Genomics, and others. The College of American Pathologists also offers a Laboratory Accreditation Program, like CLIA. Furthermore, some clinicians and laboratory professionals fear there would be a massive bottleneck for the FDA to review and (hopefully) approve the thousands of LDT applications over the next several years.
After the FDA announced their intention to regulate LDTs, there was the typical 60-day period for feedback and comments from stakeholders starting October 3rd, 2023. There were multiple requests to extend the time for comments, which was denied by the FDA. Additionally, there will be no allowance for grandfathering in tests that are already commercially available. The FDA proposes to roll out the regulation of LDTs in five stages:
- End the general enforcement discretion approach for requiring adverse event reporting of medical devices and correction/removal requirements one year after FDA publishes the final phase-out policy.
- End the general enforcement discretion approach with respect to registration, labeling, etc., two years after FDA publishes the final phase-out policy.
- End the general enforcement discretion approach with respect to quality system requirements three years after FDA publishes the final phase-out policy.
- End the general enforcement discretion approach with respect to premarket review requirements for high-risk IVDs [i.e., LDTs] 3.5 years after FDA publishes the final phase-out policy, but not before Oct. 1, 2027.
- End the general enforcement discretion approach with respect to premarket review requirements for moderate risk and low risk IVDs four years after FDA publishes the final phase-out policy, but not before April 1, 2028.
The evolving landscape of LDT regulation by the FDA demonstrates the complexity of this issue and the need for a balanced approach. While there is consensus on the importance of ensuring the accuracy of LDTs and patient safety, finding the right regulatory framework is challenging and multifaceted. Laboratory medical technology will continue to evolve, especially in genetics, molecular biology, and personalized medicine. Regulation and innovation must be balanced and should not be mutually exclusive. Hopefully, there will be collaboration between laboratories and regulators that will prioritize patient safety while allowing for innovation in a structured regulatory framework.
*Note: this is a current and emerging topic. There may be additional information that was not available at the time the article was written and published.
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American Clinical Laboratory Association:
ACLA Opposes Unilateral FDA Action to Regulate Laboratory Developed Tests Under Medical Device Authority
Association for the Advancement of Blood & Biotherapies:
FDA Issues Proposed Rule Regulating Laboratory-Developed Tests
FDA targets more oversight of lab-made tests
Centers for Medicare and Medicaid Services (CMS):
Clinical Laboratory Improvement Amendments (CLIA)
Certification Boards for Laboratory Directors of High Complexity Testing
Federal Register – The Daily Journal of the United States Government:
Medical Devices; Laboratory Developed Tests
Genetic Engineering & Biotechnology News:
Theranos and Its CEO Slapped with CMS Sanctions
National Public Radio:
Elizabeth Holmes has started her 11-year prison sentence. Here’s what to Know.
Patient advocacy groups urge FDA to regulate lab-developed tests if VALID Act doesn’t pass
U.S. Food & Drug Administration (FDA):
FDA Proposes Rule Aimed at Helping to Ensure Safety and Effectiveness of Laboratory Developed Tests
A History of Medical Device Regulation & Oversight in the United States
List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools)
Laboratory Developed Tests