FDA’s proposed rule for the regulation of laboratory-developed tests

ABSTRACT

In October 2023, the Food and Drug Administration (FDA) released a proposed rule that ends enforcement discretion for laboratory-developed tests (LDTs). The FDA’s proposal outlines a five-stage implementation to begin regulating LDTs as they do for commercial in vitro diagnostics (IVDs), including modified FDA-approved/cleared tests. We outline here concerns from the clinical and public health microbiology laboratory perspective. It is our opinion that LDTs performed by individual Clinical Laboratory Improvement Amendments-certified diagnostic laboratories should not be regulated in the same way as commercial IVDs. This rule, if finalized, will negatively impact the diagnostic services currently offered by clinical and public health laboratories and, therefore, patients and the providers who care for them. Ending enforcement discretion will likely stifle diagnostic innovation and decrease access to diagnostic testing and health equity. Furthermore, the lack of infrastructure, including personnel and funding, at the FDA and diagnostic laboratories to support the required submissions for review is an obstacle. Like the FDA, diagnostic laboratories prioritize patient safety, accurate clinical diagnostics, and health equity. Since the scope of the LDT landscape is currently unknown, we are supportive of a registration process, along with non-burdensome adverse event reporting, to first understand the scope of clinical use of LDTs and any associated safety concerns. Any regulatory rule should be based on data that have been gathered systematically, not anecdotes or case reports. A rule must also balance the potential negative impact to patient care with realistic safety risks for infectious disease diagnostics.

COMMENTARY

Laboratory developed tests (LDTs) are regulated through two separate frameworks; the Medical Device Amendments, which granted the Food and Drug Administration (FDA) broad authority over diagnostic tests more than 45 years ago, and the Clinical Laboratory Improvement Amendments (CLIA) of 1988, which provides for the oversight of laboratory practices. These two laws are carried out by the FDA and the Centers for Medicare & Medicaid Services (CMS), respectively, and until the proposed rule was published on October 3, 2023, the FDA considered enforcement discretion sufficient for LDTs (1). However, the agency focused its attention on oversight of commercial test kits, which were manufactured, broadly marketed, and sold for use in many facilities. Meanwhile, under CLIA, laboratory standards are set and enforced for any facilities that test human specimens for health assessment or to diagnose, prevent, or treat disease. CLIA, which is enforced by CMS (in partnership with the Centers for Disease Control and Prevention [CDC]), establishes performance characteristics relating to analytical validity for the use of that test system in the laboratory’s environment. CLIA regulations establish quality standards for laboratory testing performed on human specimens for the purpose of diagnosis, prevention, or treatment of disease, or assessment of health. While CLIA ensures accuracy and reliability of testing, only the FDA assesses the clinical validity of a test.

In 2010, the FDA announced its intent, for the first time, to regulate all LDTs. This was due to a growing concern at the FDA that LDTs were becoming more complex and amid high-profile cases, including the ovarian cancer test OvaSure that led to unnecessary surgeries in women who received false positives for ovarian cancer blood biomarkers. By 2014, following technologic and scientific advancements related to genetic and biomarker testing across multiple disease areas, the agency made its intent to regulate LDTs official by notifying Congress and issuing draft guidance (2). The FDA’s overarching goal was to shift the baseline standard for these tests from one of safety and effectiveness to one that increasingly focuses on clinical and analytical validity. This was also the point when Congressional attention on the issue increased, spurring the House Energy and Commerce Committee to hold hearings on the topic. Members of Congress began considering legislative proposals to address the FDA’s concerns and reinforce its authority to regulate all in vitro diagnostics (IVDs), including LDTs.

The 2014 draft guidance outlined a regulatory framework of how the FDA would move beyond enforcement discretion to requiring pre-market review of these tests. The proposed framework was risk-based, and the guidance suggested that LDTs could be categorized into the following three classes: (1) tests that would be exempt from regulation (2); tests that would only require FDA registration and adverse event reporting; and (3) tests that require pre-market review and defined quality system (3). Those tests deemed “high risk” would be required to go through the full pre-market review process. Notably, while the FDA maintained that it had enforcement discretion authority, Congressional supporters, alongside other agency leaders, believed that the FDA’s position needed to be strengthened with legislation. The question of the FDA’s authority to regulate these tests and how such oversight would align with the current regulation of clinical laboratory operations under CLIA remain a point of debate.

The 2014 FDA draft guidance, coupled with Congressional attention, sparked controversy in the medical and clinical laboratory communities and incensed those who believed the guidance encroached on the practice of medicine and treated laboratories as if they were device manufacturers. On the other side of the debate, concerns centered on patient safety and the fact that patients are indifferent to what methods are used or where the test is performed; they just want it to be accurate. Concerns were also expressed that having two regulatory paths (i.e., manufacturers going through pre-market approval, while LDTs do not) created an uneven playing field. By 2016, the FDA had held public meetings and received thousands of public comments on the draft guidance, but Obama’s Administration was in its final weeks in office, and a decision was made to delay the issuance of any final guidance. At the beginning of Trump’s Administration in 2017, a decision was made to halt work completely on final guidance and instead allow time for a robust community discussion and legislative approach.

The new legislative approach focused on creating a new definition and framework under IVDs called “in vitro clinical tests” (IVCTs) that would have included all assay software and diagnostic tests, including LDTs. There have been several iterations of legislation since 2014, but the proposal that received the most traction on Capitol Hill was the bipartisan Verifying Accurate and Leading-edge In Vitro Diagnostics (VALID) Act. This bill ultimately failed to pass at the end of 2022, which led the FDA to proceed with its own rulemaking.

FDA’s CASE FOR ENDING ENFORCEMENT DISCRETION

The proposed rule sets forth the FDA’s case for phasing out enforcement discretion for LDTs. Many reasons are cited, but the premise is that the agency no longer believes that enforcement discretion is sufficient to ensure clinical validity of LDTs and to protect patients from faulty tests that could have harmful consequences on patient health. The FDA believes that LDTs should be subject to the same pre-market approval process as commercially developed test kits, and the agency also suggests that it cannot protect patients when it does not know the “universe” of LDTs in use and there is no required adverse event reporting for them. While LDTs in medical disciplines like cancer and genetic and newborn screening have become increasingly complex and critical to medical decision-making that can have life or death consequences, infectious disease testing largely was out of the spotlight until the COVID-19 pandemic. The proposed rule’s justification cites quality issues related to emergency use authorizations requested for COVID-19 tests over the course of the public health emergency (4).

Beyond patient safety and clinical validity concerns, the FDA asserts that the enforcement discretion for LDTs stifles innovation by companies because it presents an alternative pathway and disincentive for these companies to develop newer diagnostics. The FDA suggests that ending enforcement discretion will stabilize the testing marketplace. The agency also states that increased oversight of LDTs will advance health equity, citing concerns that inaccurate results from LDTs may exacerbate inequities in underrepresented populations.

WHY LABORATORIES DEVELOP, VALIDATE, AND IMPLEMENT LDTs

Clinical and public health laboratories implement LDTs for a variety of practical reasons. In many instances, innovative approaches were needed to address challenging clinical scenarios, such as diagnosing fungal infections, detecting viral infections in transplant patients, or providing antimicrobial susceptibility data for new antimicrobials. In the absence of FDA-approved/cleared tests for these indications, laboratories responded to the needs of providers and patients by leveraging their expertise to develop, validate, and implement LDTs.

Considerable gaps remain in the FDA-approved/cleared diagnostic armamentarium available to providers and laboratories. For example, clinical guidelines and the CDC recommend molecular detection of Pneumocystis jirovecii in a variety of patient samples, but there are no FDA-approved/cleared single-target molecular assays to date for this pathogen (5, 6). There is only one commercially available FDA-approved platform for the detection of Mycobacterium tuberculosis, and it is limited to a single specimen type. In addition, the only available DNA probes for rapid identification of M. tuberculosis and other mycobacteria from positive cultures have been withdrawn from the market (7). There are also almost no reliable FDA-approved/cleared tests for many fungal infections including aspergillosis and coccidioidomycosis (8). There are insufficient or no FDA-approved/cleared antimicrobial susceptibility panels for yeast, non-tuberculous mycobacteria, or Nocardia, even though there is a significant clinical need (9, 10). Due to limitations with IVD antimicrobial susceptibility test systems, such as lack of antimicrobials included on a panel or performance limitations, laboratories may validate and implement non-FDA approved/cleared breakpoints and/or disk or gradient diffusion testing. Commercial matrix-assisted laser desporption ionization - time of flight mass spectrometry (MALDI-TOF MS) microbial identification databases do not encompass all clinically relevant organisms, so laboratories have used these systems off-label by validating additional organisms. In addition, laboratories have validated alternative extractions, media, and colony age to improve time to MALDI-TOF MS results. For organisms that are not identifiable by MALDI-TOF MS (or other commercial identification systems), many laboratories (including the FDA) use sequencing as a reference method; there are no FDA-approved/cleared sequencing identification tests available.

The use of LDTs has been incorporated as a critical component of clinical guidelines and recommendations, including testing for hepatitis B or hepatitis C antiviral resistance; quantification of HHV-6, adenovirus, or BKV in transplant patients; testing oral and rectal swabs or pediatric patients for sexually transmitted infections; and antimicrobial susceptibility testing of non-tuberculous mycobacteria (6, 9, 11 – 16). For many years, HIV viral load testing was only FDA-approved for the monitoring of response to therapy, even though CDC guidance recommended the use of molecular assays for diagnosis (17). Viral load assays for the detection of cytomegalovirus were initially only approved for specific subsets of transplant patients, but not for others. Some of these assays have since received FDA approval/clearance, but their early adoption and use as LDTs drove the development of guidelines that improved patient care. Furthermore, the use of LDTs, including off-label IVDs, created the incentive and market demand for diagnostic manufacturers to consider investing the considerable resources required to obtain FDA approval/clearance and bring a test to the market (e.g., oral and rectal swabs for chlamydia and gonorrhea).

In some cases, FDA-approved/cleared tests are only available from a single diagnostic manufacturer (e.g., BKV and EBV quantitative viral load testing). While it is commendable that there are now IVD options available for these pathogens, it may still be challenging for labs to immediately transition to the IVD assay. Often, this involves significant capital investment, and the use of the platform may be challenging to justify for just one or more low-volume assays. It may also be counterproductive to expect labs to immediately grant a de facto monopoly to the first diagnostic manufacturer to receive FDA approval/clearance. Contrary to the FDA’s assertion, the use of LDTs for most clinical and public health microbiology laboratories is not a cost saving measure but requires a significant investment of scarce time and resources to develop and maintain. Laboratories are forced to resort to the development of LDTs to address the critical diagnostic gaps listed previously. LDTs are subject to greater regulatory scrutiny under the current CLIA-based laboratory accreditation process than FDA-approved/cleared assays used by the same laboratory. A significant amount of labor is involved not just in the initial validation of these assays but also in the quality control and oversight. For these reasons, labs generally transition to FDA-approved/cleared options when feasible.

Some LDTs are available only at national or regional reference laboratories, and the FDA’s proposed rule will likely only increase the trend toward utilization of reference labs for testing, which might otherwise have been performed locally. Overreliance on reference lab testing often falls short of serving the needs of both the patient and the healthcare institution. For example, diagnostic needs may be locally specific and not available at a reference laboratory, such as specialized pediatric testing or molecular detection of antimicrobial resistance in areas with high STI prevalence. The delays involved in utilizing reference laboratory testing are at odds with the need for timely results to ensure better patient outcomes (18). Relying solely on reference laboratories also makes it nearly impossible to have a meaningful interface between the care providers and the laboratory performing the assay. This relationship is critical to fine-tuning the appropriate interpretation and utilization of all laboratory assays, including LDTs. Furthermore, the ability to develop LDTs allows labs to serve the unique needs of the local population (including niche underserved groups), which has been a key component in the battle against infectious diseases. The ability of labs that are directly integrated with local patient care to develop LDTs in concert with the providers caring for these patients is not just a matter of providing the best possible clinical care but has been the cornerstone of improving diagnostic algorithms that have become integral to the standard of care.

OVERVIEW OF PROPOSED RULE 2023

The proposed rule issued by the FDA’s Center for Devices and Radiological Health on October 3, 2023 proposes to amend regulations to make explicit that all IVDs are devices under the Federal Food, Drug, and Cosmetic Act, including when the “manufacturer” of an IVD is a laboratory. The rule also asserts that test systems manufactured by laboratories are devices. Second, the rule proposes to phase out enforcement discretion for LDTs under the device authority so that after 4 years, most LDTs will be subject to pre-market review requirements.

The gradual phase out of enforcement discretion would take place in five stages through 4 years post issuance of a final rule, but not before April 1, 2028 (Fig. 1). The process begins with a phase out after 1 year of general enforcement discretion for medical device reporting (MDR) requirements and correction and removal reporting requirements, followed by registration and additional requirements by the end of the second year, followed by an end to enforcement discretion for high-risk tests (not before October 27, 2027), and finally, the end of enforcement discretion for low-risk tests after 4 years.

Fig 1.

Summary of the FDA’s five stages of ending enforcement discretion for LDTs. MDR: medical device reporting and QS: quality system

The proposed rule, by following the medical device authority provided to the FDA, takes a far more inflexible approach than that proposed in the most recent iteration of the VALID Act. For example, there are no “grandfathering” provisions for LDTs already in the market; there is no maintenance of general enforcement discretion for low-risk tests, and the implementation period is less than half of which was outlined in the legislation (4 years versus 9 years.) The VALID Act also included more exemptions to pre-market review than the proposed rule, including antimicrobial susceptibility testing and humanitarian use.

CONCERNS FROM THE CLINICAL AND PUBLIC HEALTH LABORATORY PERSPECTIVES

Misrepresentation that LDTs are unsafe

We are concerned that the FDA has painted a picture that LDTs are unsafe and are harmful to the health of the public. The proposed rule provides several anecdotal examples of unsafe LDTs. Except for the COVID-19 EUA reference, these examples are not infectious disease tests. Most people do not appreciate that LDTs are already regulated through CMS/CLIA and that labs already have quality systems in place. In fact, the scope of the potential issue is unknown. No one knows the total number of LDTs being used by clinical laboratories, and no one knows the number of severe adverse events specifically associated with LDTs. Likewise, we have not quantified the benefits to the health of the public that LDTs have provided. For example, LDTs provide additional infectious disease diagnoses and may prevent additional unnecessary sampling, testing, and treatment. What is the risk–benefit ratio as it relates to the potential burden of overregulation? How do the error rates of LDTs compare to those of IVD tests? To assume based on anecdotal evidence, not systematically collected data, that unsafe LDTs are an extensive problem and have error rates higher than those of IVD tests is not supported scientifically.

Unclear definition of an LDT

A major premise of the proposed rule is that LDTs are medical devices and should be regulated as such. LDTs developed, validated, and implemented by individual laboratories CLIA-certified to perform high-complexity testing are not manufactured, packaged, and sold for use; testing is performed only at the originating laboratory. LDTs have been better described as laboratory-developed procedures (19). Many clinical laboratories, clinicians, and professional and medical societies have argued that LDTs are not medical devices as intended by the 1976 Amendment to the FD&C Act. Given that Congress has debated legislation that would give the FDA the authority to regulate LDTs (i.e., VALID), it is reasonable to assume that the FDA does not currently have the authority to regulate them as medical devices.

The proposed rule does not clearly define what will be considered an LDT requiring FDA submission and review. There is mention of LDTs that are not “1976-like,” but it is not obvious what constitutes out-of-scope LDTs beyond tests that include manual, non-automated processes, which is subject to interpretation. We agree that there have been significant diagnostic advances since 1976, but how will laboratories determine what is truly an LDT? Does this include validating and testing additional specimen types or transport media for an FDA-approved/cleared IVD? Does this include testing patients not specifically claimed in the instructions for use (i.e., pediatrics, immunocompromised but not post-transplant)? Are microscopic or culture-based methods non-exempt if there is an automation component? Are phenotypic antimicrobial susceptibility tests or resistance detection methods in scope? If the definition of an LDT extends to these examples, diagnostic microbiology will be grossly impacted, such that there will be significant patient care consequences.

Impact on diagnostic innovation

The proposed rule will likely not spur innovation as is stated by the FDA. In reality, it will stifle innovation by both commercial manufacturers and independent CLIA-certified laboratories without additional considerations to incentivize filling diagnostic gaps. As discussed previously, clinical laboratories have validated and implemented LDTs because there was a diagnostic gap associated with a clinical need. Many, but not all, of these tests are relatively low volume, either due to the specialized circumstances in which a patient may need the diagnostic test (i.e., severely immunocompromised, serology-positive) or due to the overall prevalence of disease in their patient population. Although the number of commercially available IVD products for infectious diseases has increased in the last couple of decades, there is still a threshold that a commercial manufacturer must consider when investing in the studies and FDA application needed to bring a new IVD to the market. Simply put, the investment must be worth the anticipated profit. Specialized, low-volume tests that may require unique specimen types or be associated with a low prevalence infectious disease would be very expensive to commercially develop as IVDs. There is currently no incentive for companies to fill existing diagnostic gaps that are currently filled by LDTs in many laboratories. Even if there are select tests that commercial manufacturers bring to the market (which we agree is good), there will still be a significant delay and impact to patient care if LDTs become unavailable. Not only will commercial innovation likely not increase, but the innovation offered by independent CLIA-certified clinical laboratories will be stifled. Many clinical laboratories will discontinue current LDTs and will no longer develop LDTs when new clinical needs arise due to the regulatory and financial burden. The ability of innovative clinical and public health laboratories to offer LDTs and publish the associated clinical utility is more likely to spur commercial innovation than overregulation of such tests.

Health equity impact

In contrast to the claims in the proposed rule, we believe that health equity will be negatively impacted if the rule is finalized. Local clinical laboratories certified to perform high-complexity testing, including LDTs, provide access to testing close to the site of patient care. A potential complication of the rule will be the diversion of testing to centralized reference laboratories. Even this assumption is predicated on the ability of reference laboratories to submit and receive FDA approval/clearance for LDTs. If national testing is funneled to one or a few reference laboratories, the time to result will grossly increase. This is understandable as reference laboratories also have resource constraints, including the current shortage of medical laboratory scientists. Substantially increased testing turnaround times were observed when laboratories were dependent on a few national laboratories in the beginning of the COVID-19 and mpox outbreaks. Increased time to results negatively impacts patient care; patients in rural areas will have a greater impact due to logistical challenges and delays in getting samples to reference laboratories (18, 20).

A further concern that would negatively impact health equity is whether the burden to continue offering LDTs at local hospitals (including major academic medical centers that may serve as a multi-hospital health system) will reduce the value proposition of local or regional laboratory testing. Any expectations on the part of the FDA that hospital administrations will take on the significant cost and staffing burdens required to comply with the FDA’s proposal should be tempered with the reality on the ground. The financial pressures of declining reimbursement and other challenges are driving hospitals to monetize their clinical labs through their sale to national reference laboratory chains with the subsequent less than optimal impact on the quality of clinical care (18, 21). If finalized, the rule may accelerate the trend of consolidation and acquisition of local laboratories by national, commercial laboratories. It is our opinion that losing access to local and regional testing, which may be accelerated by the discontinuation of LDTs, will further reduce access to testing and therefore health equity.

In addition, we have seen an increasing number of emerging infectious diseases and associated outbreaks in recent decades. These outbreaks are not predictable, and many of them occur locally or regionally and may not initially (or ever) rise to the level of a public health emergency (i.e., multidrug-resistant organisms, Candida auris, rapidly growing Mycobacterium, dengue, and arboviral encephalitides). The proposed rule restricts our ability to rapidly develop and implement LDTs to address local emerging infectious diseases of clinical consequence, which will disproportionately impact traditionally underserved areas (see “Clinical laboratories and the public health network” below).

Lack of infrastructure (FDA and laboratory)

The Pew Trust estimates that ~12,000 clinical laboratories perform LDTs (22). It is unknown how many LDTs are performed per lab, or the volume of tests, but it reasonable to project that there are well over 100,000 LDTs that would be subject to the proposed rule. Even with the staggered approach proposed for submission and review, a low estimate of the submission volume per year would be many thousands of LDTs. Based on our experience during the COVID-19 EUA submission process, the FDA does not currently have the bandwidth or infrastructure to support such high numbers of submissions. User fees (discussed as follows) will not solve all of these problems. The proposed third-party review system would need to be very robust to support this number of initial submissions. The inability to review submissions in a reasonable time frame will delay the much needed access to testing for patient care. The potential for a massive influx of submissions will also have the unintended negative consequence of lengthening the review process for commercial diagnostic manufacturers.

Hospital laboratories lack the necessary infrastructure to support the FDA submission process, including finances and people. In the proposed rule, the FDA estimates billions of dollars in costs, only some of which is accounted for by user fees. Diagnostic laboratories are already experiencing financial challenges in part due to the Protecting Access to Medicare Act (PAMA) that was passed in 2014 and reduced payments for common laboratory tests by as much as 59% (23). Laboratories are under increasing pressure to sustain current workloads due to severe staffing shortages that have been exacerbated post-COVID-19 (24). Staff vacancy rates averaged 8.5% overall but were as high as 25% in some locations and were particularly problematic in rural areas (25). These challenges are expected to grow as an aging workforce retires and the pipeline of medical laboratory scientists shrinks (24). Most clinical and public health laboratories are unfamiliar with the logistics, pathways, and even terminology associated with FDA approval/clearance of LDTs. Additional staffing, with expertise in regulatory affairs, will be needed by institutions seeking FDA approval/clearance for their LDTs. Without the resources and regulatory expertise to prepare an FDA submission of an LDT under the IVD path, laboratories will be left with no option but to discontinue testing. This will result in either all testing being sent to a reference lab that may have the resources to submit their test or will widen the diagnostic gap.

The FDA assumption that hospital administration is able to provide the resources necessary to comply with the proposed regulation is incorrect. Risk-averse hospital administrations will be hesitant to commit the resources needed to navigate the uncertainties of the new regulatory landscape especially if missteps may result in FDA inspection or sanctions. Depending on the demands associated with LDT submission, it is possible that even reference laboratories will decide they cannot support submission for low-volume, esoteric assays. This will create a national crisis in infectious disease diagnostics.

User fees

For medical devices regulated by the FDA under the Medical Device Amendments of 1976, user fees are collected from companies to supplement Congressional appropriations and ensure the FDA has the resources needed to meet the targets for device approval. The Medical Device User Fee Act (MDUFA) was initially passed in 2002 and is reauthorized every 5 years as companies renegotiate the rates. The FDA has implied that user fees will be applicable to LDTs under the proposed rule, and the implementation of the rule coincides with the next cycle of the MDUFA. While the FDA has suggested that the small business exception under the program could be applied to not-for-profit laboratories and reduce or waive fees altogether, we have grave concerns about the establishment and implementation of a user-fee program for LDTs. Clinical microbiology and public health laboratories already operate on a thin margin within healthcare facilities and are not profit centers. It is unreasonable to include the academic, independent, and hospital-based laboratories in the same business category as commercial entities, even with a small business exception in place. These fees will be yet another reason laboratories will cease developing infectious disease-specific testLDTs.

Clinical validity

The FDA has made a delineation between CMS/CLIA and FDA test validation requirements; clinical validity is required by the FDA but not explicitly required as a component of test validation by CMS/CLIA. For many LDTs, clinical laboratories rely on published literature showing clinical validity. While this may not have been true 10 years ago, there is now a significant amount of published literature on the clinical validity for most LDTs being used today in infectious disease testing. The clinical trial needed for a laboratory to independently establish clinical validity for a new LDT is beyond the scope of clinical and public health laboratories. The FDA will need to provide clear guidance for obtaining proof of clinical validity in the context of LDTs that are used at a single facility and not marketed.

Risk-based strategy

Unlike the 2014 FDA guidance and the proposed VALID legislation, the current proposed rule eliminates a risk-based strategy. Although the current class I, II, and III system is risk-based, it is not clear how de novo LDTs will be classified. In our opinion, the medical device class system is not applicable to infectious disease LDTs. Unlike oncology and pharmacogenomic tests, most infectious disease tests are low risk, particularly when performed in laboratories with extensive experience with LDTs and associated quality systems. This assertion is based on the fact that when diagnosing infectious diseases, there is usually not one single test that makes a definitive diagnosis and informs a patient’s treatment plan. With infectious diseases, tests of multiple testing modalities are ordered—culture, antigen or nucleic acid detection, and serology. Each test result (whether IVD or LDT) is then used in the context of other results, along with the patient presentation, risk factors, and exposures. The physician then uses all the clinical and laboratory information in the practice of medicine to diagnose and treat the patient, if warranted. Infectious disease diagnostic tests, including LDTs, are just one tool that must be interpreted in the clinical context.

Clinical laboratories and the public health network

The Association of Public Health Laboratories defines a sentinel clinical laboratory as any laboratory capable of analyzing or referring samples that may contain microbial agents. In the absence of a comprehensive public health network, sentinel laboratories serve as the first point of contact with a pathogen of public health importance, including potential biothreat agents and pathogens with emerging antimicrobial resistance (AMR). A confluence of factors including vaccine refusals and interrupted vaccination schedules due to the COVID-19 pandemic have contributed to a global surge of vaccine-preventable diseases. In addition, climate change is driving the spread of diseases beyond their traditional geographic confines. There are no FDA-approved/cleared assays for the detection of acute infection due to emerging and re-emerging pathogens such as measles, mumps, and tickborne diseases. In addition, there are no FDA-approved/cleared AST devices or breakpoints for many of the pathogens of concern in CDC’s Antimicrobial Resistance Threats report (26). AMR is a rapidly evolving global threat. Losing the ability to detect emerging AMR and offer AST results for new antimicrobials not only impacts our ability to detect and monitor AMR but it also impedes our ability to support antimicrobial stewardship, which may lead to further development of AMR. Another recent example is multidrug-resistant Candida auris, which is transmitted in healthcare settings and can cause severe invasive infections. The CDC strongly recommends the use of PCR for screening, but there are currently no FDA-approved/cleared PCR-based assays for the detection of C. auris, and labs have no option but to rely on LDTs (27). Laboratories that are unwilling or unable to navigate the FDA LDT process will lose the ability to rapidly identify M. tuberculosis from positive cultures; the damage this will cause to our ability to limit the spread of this disease both within and outside healthcare institutions is yet to be determined.

Under the FDA’s proposal, labs will be strongly discouraged from developing LDTs for pathogens of public health importance. The expertise required to develop LDTs was critical in our COVID-19 pandemic response. When public health and national reference labs were overwhelmed by the volume of testing and patients faced huge delays in receiving test results, clinical labs were able to leverage their knowledge of LDTs to bring lifesaving results to patients in a timely manner (20). By their own admission, the FDA acknowledges that it is possible that “many laboratories (may) exit the market or discontinue offering certain IVDs rather than incur the costs of compliance with FDA requirements” (28). This will have a double effect—not only the likely loss of currently used LDTs for detection of public health importance but also the long-term loss of LDT development expertise in sentinel clinical and public health laboratories. The same expertise that served the nation during the COVID-19 pandemic will be lost under the burden of the new regulatory system. The net effect will be the degradation of the public health network over time and will compromise our ability to respond not just to the next pandemic but to pathogens of old that return during the era of vaccine skepticism and climate change.

ALTERNATIVE APPROACH

Clinical and public health laboratories invest considerable time and resources into maintaining the high quality of LDTs. As mentioned previously, this includes complying with existing CLIA requirements, regular proficiency testing, and both external and internal oversight with appropriately trained board-certified individuals. Any new regulatory burden should build on and supplement these processes without dangerously undermining a critical component of healthcare in this country. Considering the potentially serious detrimental impact of the proposed rule on the clinical and public health laboratory landscape, a more reasoned and data-driven approach needs to be considered. It can be argued that certain entities have taken advantage of gaps in the current regulatory process for LDTs, but these examples are not reflective of the greater clinical and public health laboratory landscape. Keeping in mind that by the FDA’s own admission, its new approach could result in reduction of access to timely testing for patients, there needs to be an initiative to collect the data needed to create a regulatory system that meets the needs of patients while truly improving the quality of care. A starting point could be requiring laboratories to register all LDTs that are utilized for patient care. This registration might include information on general methodology, organism(s), specimen types, and test volumes, among other defined parameters. In addition, labs should develop a mechanism for reporting serious adverse events as defined by the FDA (29). While striving to capture all the relevant information, the process should not place an unreasonable burden on laboratories. The information collected could serve to guide the development of a more appropriate regulatory regimen for LDTs.

SUMMARY

In the proposed rule, the FDA makes it clear that its overarching goal is to foster innovation and improve equity and access to testing while safeguarding the interests of patients. These are also the goals of clinical and public health laboratories. A regulatory regimen that was primarily developed for diagnostic manufacturers with significant financial and logistical resources at their disposal seems an unlikely route to achieve this goal. Rather, we believe a regulatory pathway that both ensures the highest risk tests are safe and effective and provides flexibility aligned with the realities of infectious disease testing will best serve patients and minimize harm to the laboratories that serve them.