Guest Column | March 12, 2024

Notable Public Comments On The FDA's Proposed Regulation For Laboratory Developed Tests

By Erika L. Roberts, ELR Lab Services LLC

Group Discussions-GettyImages-1216169131

The proposed FDA regulation for laboratory developed tests (LDTs), as outlined in FDA-2023-N-2177-0001, marks a significant step toward the FDA trying to standardize oversight for these diagnostic tools. The document articulates a framework to bring LDTs under a more comprehensive regulatory umbrella, even though regulatory bodies like CLIA currently oversee laboratory testing. Aiming to address concerns surrounding the reliability and clinical validity of these tests, and emphasizing the need for premarket review, the FDA proposes a nuanced approach that considers the unique characteristics of certain LDTs, particularly those employed in urgent, lifesaving situations. The proposal navigates the delicate balance between safeguarding patient care and preventing potential risks associated with inadequately validated tests.

As the FDA seeks public input, stakeholders grapple with the implications of increased regulatory scrutiny, debating its impact on patient access, innovation, and the overall landscape of diagnostic testing in the United States. Public comments on this have reached over 6,700, and this topic is being hotly debated in the laboratory community from all levels and complexities of laboratory testing. Here are a few highlights of comments that illustrate the main themes of the comments: both for and against the new regulation, along with pleas for longer public comment time. This snapshot of public sentiments about this proposed regulation should alert many laboratories to the need to keep up to date on changing regulations that could impact routine testing of patient samples and how they are regulated.

Comment number FDA-2023-N-2177-0125:

I strongly endorse FDA regulation of LDTs as proposed in FDA-2023-N-2177-0001. As a retired CLIA high-complexity remote laboratory director, I've personally witnessed over 15 CLIA-registered labs across the U.S. contracting with nucleic acid sequencing or PCR-based research companies for infectious disease 'diagnostic' assays. While larger academia centers have the budgetary means and minimize conflict of interest surrounding LDT approvals, larger facilities make up a minority of total labs that offer LDTs. Many LDTs are offered by labs that use LDTs as a profit-based business model rather than a patient care means.

LDTs developed by non-academia centers generally perform poorly and do not have any clinical studies supporting their use. Occasionally, proposed specimen types (e.g., urine, stool, saliva) don't align with evidence-based medicine or traditional research. I've often stepped into roles like Laboratory Director (LD) or Clinical Consultant (CC) for labs using assays approved by their former LDs. These former LDs are rarely formally trained in infectious disease and, despite having medical licenses, often lack recent field practice. Moreover, their direct payment is from the labs they approve tests for and create conflicts of interest, making them more inclined to approve inadequately validated assays. Failure to approve a test or consistent push-back threatens the longevity and tenure of the contracted LD and/or CC which perpetuates the 'rubber stamping' of LDT tests.

Here are examples from my career that illustrate the negative outcomes linked to improperly or inadequately approved LDTs:

1. Two providers believed they had a methicillin-resistant S. aureus strain due to its detection in a urine sample and the mecA gene. However, the LDT urine genomic sequencing panel didn't include non-S. aureus species. The patient was treated with vancomycin. Later, traditional culture techniques revealed S. epidermis contamination, and the S. aureus strain was methicillin-sensitive.

2. Genomic stool sequencing suggested C. difficile presence without detecting the toxin gene. The provider treated for C. difficile infection when it was just a transient colonizer not causing symptoms, altering patient treatment unnecessarily.

3. Labs approved saliva specimens for influenza testing, despite it not being a recommended specimen type. The LDT method reduced sensitivity and performance compared to FDA-approved tests, potentially causing false negatives in patients with true infections.

4. Sequencing diabetic superficial wound swabs to identify infectious agents resulted in reports detecting 4+ organisms without quantification or organism viability determination. The patient was treated with multiple antibiotics based solely on sequences.

I wholeheartedly support proposed legislation to standardize LDT quality, enhance patient care safety, and prevent research-based methods from being accepted as diagnostic tests with limited clinical performance studies and medical relevance.”

As a retired high-complexity laboratory director, the individual strongly endorses the proposed FDA regulation of LDTs as outlined in FDA-2023-N-2177-0001. Having witnessed firsthand the practices in over 15 CLIA-registered labs across the U.S., this highlights the prevalent issue of labs contracting with nucleic acid sequencing or PCR-based research companies for infectious disease “diagnostic” assays. The director emphasizes the disproportionate reliance on larger academia centers, noting that larger facilities represent a minority of total labs offering LDTs.

With a focus on patient care over profit, this commenter notes that LDTs developed by non-academic centers often perform poorly in their experience, and there is a lack clinical studies supporting their use. The director provides real-life examples from their career, illustrating the adverse outcomes associated with improperly or inadequately approved LDTs. These examples include misdiagnoses, unnecessary treatments, and potential patient harm. The call for FDA regulation is grounded in the director's extensive experience and commitment to improving the integrity of laboratory practices nationwide.

Comment number FDA-2023-N-2177-1825:

“As a member of the laboratory medicine community, I am writing to urge the FDA to extend the comment period on its recent proposed rule on laboratory developed tests (LDTs). I am very concerned that several professional societies were informed that the FDA had decided to not extend the comment period an additional 60 days before the FDA had received comments from all members of the public.”

“LDTs are essential to the timely diagnosis and treatment of numerous diseases and conditions, especially when no FDA-approved tests exist. The FDA’s proposed rule would create a highly complex process for LDT oversight, with the agency estimating half of these tests would require premarket review. Under the proposal, laboratories with LDTs may be required to comply with premarket review, quality systems, labeling, medical device reporting, and other requirements. These requirements are unfamiliar to most laboratories, as regulatory oversight for LDTs has generally been provided under the Clinical Laboratory Improvement Amendments. To avoid unintended consequences, it is imperative that the public have sufficient time to assess the impact this rule could have on their operations. I urge that FDA extend the comment period by 60 days (to a total of 120 days).”

In advocating for the vital role of LDTs in the prompt diagnosis and treatment of various diseases, this commenter emphasizes the unique importance of LDTs, particularly when no FDA-approved tests are available. The focus shifts to the proposed FDA rule, which introduces a complex oversight process for LDTs. The agency estimates that approximately half of these tests would necessitate premarket review, bringing forth a range of requirements, including compliance with quality systems, labeling, medical device reporting, and more. The unintended consequence would be a greater cost burden on patients and the laboratories that provide testing, especially in rural areas and underserved communities. Extending the comment period is essential for proper public comment and discourse from all parties involved in this change.

By expressing concern over the unfamiliarity of most laboratories with these proposed regulations, the commenter notes that historically, regulatory oversight for LDTs has fallen under the purview of the Clinical Laboratory Improvement Amendments (CLIA). To mitigate potential unintended consequences, the speaker urges the extension of the comment period by 60 days, thereby allowing a total of 120 days for the public to thoroughly assess the potential impact of the proposed rule on their operations. There are hundreds, if not thousands, of these comments pleading with the FDA to extend the comment period.

Comment number FDA-2023-N-2177-1209:

“Regarding LDTs, the FDA has stated in the proposed rule that "HLA LDTs for transplantation used in histocompatibility laboratories that meet the regulatory requirements under CLIA to perform high complexity testing, when used in connection with organ, stem cell and tissue transplantation for certain purposes as described in this paragraph, are unique in that they are generally developed, and the testing is generally performed, in urgent, life-saving situations for the patient." While I believe this to be true, I believe that blood group typing, immunohematology, and compatibility testing procedures used in hospital blood banks and in blood collection centers should also be allowed to continue as today, regardless of whether a tube based method or an automated platform is selected.

Some blood banks and blood collection centers/immunohematology laboratories operate as networks and some of the language in the proposed rule limiting use to "a single laboratory" may have the unintended consequence of impacting compatibility testing for blood at large academic centers or national blood collection services.”

This commenter highlights the FDA's acknowledgment of the unique nature of human leukocyte antigen (HLA) LDTs used in transplantation in histocompatibility laboratories. These tests, when meeting CLIA regulatory requirements for high complexity testing, play a critical role in urgent, lifesaving situations related to organ, stem cell, and tissue transplantation. However, the commenter expresses that certain procedures integral to blood banking, such as blood group typing, immunohematology, and compatibility testing, should be exempt from significant changes. Regardless of whether traditional tube-based methods or automated platforms are utilized, the speaker contends that these vital procedures, conducted in hospital blood banks and blood collection centers, should continue without additional restrictions.

Another significant concern raised by the commenter is the potential unintended consequences of the language in the proposed rule that limits the use of these procedures to "a single laboratory." This restriction could impact compatibility testing for blood, especially in scenarios where blood banks, blood collection centers, or immunohematology laboratories operate as networks, as seen in large academic centers or national blood collection services. This commenter advocates for careful consideration to avoid unintended impacts on critical processes within these broader healthcare networks.

Comment number FDA-2023-N-2177-1212:

“I am a physician in St. Louis, Missouri, and ask that you please oppose the LDT legislation. The proposed regulatory framework for LDTs would negatively impact patient care as new regulatory burdens would cause care delays and jeopardize patients’ access to medically necessary tests. In my hospital, these regulations would impact our transfusion and perioperative services. The tests performed by my laboratories did not contribute to the safety concerns driving the proposed regulation of LDTs since the tests are performed in urgent, lifesaving situations and are always performed for and to support patients being treated in a health care setting. In addition, we ensure the quality and validity of our tests through the existing regulatory framework and safeguards, including: (1) federal and state licensure of the facility; (2) CLIA certification; (3) compliance with extensive FDA regulatory requirements; (4) state requirements; and (5) CAP accreditation.”

This physician is expressing concern for the potential negative impact on patient care and emphasizes that the proposed regulatory framework could lead to care delays and jeopardize patients' access to medically necessary tests. The commenter specifically highlights the implications for transfusion and perioperative services within their hospital, stressing that the tests conducted in their laboratories are essential in urgent, lifesaving situations. These tests are integral to supporting patients undergoing treatment in a healthcare setting. Moreover, the commenter underscores that the tests performed in their facility do not contribute to the safety concerns that are driving the proposed regulation of LDTs. They argue that existing regulatory frameworks and safeguards already ensure the quality and validity of their tests. These include federal and state licensure, CLIA certification, compliance with extensive FDA regulatory requirements, adherence to state regulations, and accreditation by the College of American Pathologists (CAP). The physician advocates for a nuanced approach that considers the existing comprehensive regulatory measures in place and the critical role these tests play in urgent healthcare scenarios.

Comment number FDA-2023-N-2177-5023:

“I am writing in support of the FDA’s proposed rule titled Medical Devices; Laboratory Developed Tests.

As a patient and consumer, I want assurance that the medical tests my doctors and I rely upon to make important medical decisions are accurate. This can only be achieved through oversight by the FDA.

The FDA regulation of LDTs will ensure that doctors, patients, and consumers are getting results that are reliable and clinically meaningful. This proposed rule is designed to ensure that critical clinical decisions rest on a secure evidence base. I appreciate your work to protect public health.”

The comment section had hundreds of these comments in support of the FDA's proposed rule. The comments express the importance of FDA oversight in ensuring the reliability and clinical meaningfulness of medical test results upon which doctors and patients rely for making critical medical decisions. The individual underscores the belief that FDA regulation of LDTs is crucial for providing confidence to doctors, patients, and consumers. The proposed rule is seen by this commenter to establish a secure evidence base, ensuring that critical clinical decisions are based on accurate and trustworthy information. The support for FDA regulation is rooted in the commitment to ensuring the quality and dependability of medical tests in the interest of patient well-being.

Comment number FDA-2023-N-2177-1857:

“Premarket review of LDTs is needed. Input from Federal agencies especially on the clinical benefits and harms should be considered. For example, numerous tests on the market package PCRs for vaginal organisms, many of which are colonizers and not pathogens. Patients end [up] being treated with antibiotics just because a test is positive, when testing and treatment were not needed. (M gen, Ureaplasma spp). Also, some LDTS claim to detect resistance when there is not clinical correlation and the panic, consultations, resources, and retreatments are not necessary (GC resistance markers; Chlamydia resistance markers). We need to protect patients better.”

In advocating for premarket review of LDTs, this comment emphasizes the necessity of incorporating input from federal agencies, particularly in assessing the clinical benefits and harms associated with these tests. The comment cites concerns regarding certain tests on the market, specifically those packaging polymerase chain reactions (PCRs) for vaginal organisms. Many of these organisms, while detected by the tests, are identified as colonizers rather than pathogens, leading to unnecessary antibiotic treatments for patients.

Highlighting examples such as M gen and Ureaplasma, the commenter points out instances where patients receive treatment based on positive test results, even when testing and treatment may not be warranted. Additionally, the comment raises concerns about LDTs claiming to detect resistance without clinical correlation, leading to unnecessary panic, consultations, resource utilization, and retreatments, as seen with resistance markers for gonorrhea (GC) and chlamydia.

Public Entity Comments

The County of San Luis Obispo Public Health Laboratory submitted a comment on the proposed rule. As a high-complexity CLIA laboratory, it expressed concerns about potential negative impacts on the public health of the proposed rule. The letter outlines several key points, including the importance of LDTs in responding to low-incidence, high-priority threats, the financial and operational challenges for non-commercial laboratories, and the potential disparities in healthcare services. The letter suggests designating centers of excellence for LDT development and validation, preserving flexibility while ensuring safety. The author requests the FDA to continue exercising enforcement discretion on existing LDTs meeting specific conditions, emphasizing the critical role of these tests in effective outbreak response and serving underserved populations.

The Consumer Healthcare Products Association (CHPA) provided comment. Representing the consumer healthcare products industry for over 142 years, CHPA advocates for leading manufacturers and marketers of over-the-counter medical products. Expressing concerns about the proposed rule, CHPA highlights the FDA's intention to regulate LDTs as in vitro diagnostic products (IVDs) and requests confirmation that the rule does not impact general wellness products. CHPA emphasizes its commitment to ensuring all Americans have access to safe, effective, and affordable therapies for common ailments, urging careful consideration of the regulation’s implications on consumer healthcare.

Cincinnati Children’s Hospital Medical Center, in its own comment, acknowledges the importance of regulating LDTs for public health. While stating that it supports the FDA's mission, the hospital urges revisions to address the unique healthcare needs of children, emphasizing that they are not merely small adults. Children's hospitals play a crucial role in pediatric healthcare, requiring specialized medications, diagnostics, therapeutics, and equipment. The hospital advocates for maintaining the current enforcement discretion for hospitals and health system LDTs, especially those related to infancy or childhood, altered for pediatric off-label use, associated with rare and orphan diseases, exclusive to pediatric laboratories, or performed in hospitals for immediate patient care. The goal is to ensure continued access to lifesaving diagnostics and timely care for all children, including those with rare and difficult-to-diagnose disorders.


The proposed FDA regulation for LDTs represents a step toward standardizing oversight for these diagnostic tools under their purview. While the document proposed rule provides a comprehensive framework to regulate LDTs under the FDA, concerns within the laboratory community have arisen about potential impacts on patient care, innovation, reimbursement, CLIA vs. FDA regulations, and the broader landscape of diagnostic testing. With over 6,700 public comments, the discussion is polarized, with individuals and entities both supporting and opposing the proposed rule; however, there is more of an observable trend toward strongly opposing the new regulation. As stakeholders grapple with these complexities, the fate of LDT regulation remains a pivotal point in the ongoing dialogue on patient care, innovation, and the future of diagnostic testing, and an extension of the comment period should be considered by the FDA.

About The Author:

Erika L. Roberts, MFS, is principal consultant and owner of ELR Lab Services LLC. Having more than 15 years of experience working in many different areas of the pharmaceutical/biotech manufacturing quality environments, she has particular expertise in sterility testing, microbial identification training, HPLC analysis, cGMP training, analytical chemistry, and pharmaceutical regulations. Roberts obtained a master’s in forensic science in 2006 with an emphasis in document examination.