º£½ÇÉçÇøapp

Timely and accurate diagnosis of infectious diseases are foundational to effective treatment plans and improved outcomes for patients. Although Food and Drug Administration (FDA)-approved assays exist for the detection of common and well-known pathogens, such as influenza, SARS-CoV-2, Salmonella and Neisseria gonorrhoeae, the availability of tests for important, but less-common or emerging infections is even more limited. Even when FDA-approved assays are available, they may not be approved for specific needs, for example, those involving specific specimen types (e.g., lung tissue for tuberculosis molecular testing) or for certain age groups (e.g., not approved for pediatric patients).

The absence of readily available and accessible FDA-approved assays disproportionately affects underserved racial and ethnic groups, financially under-resourced communities, rural populations and pediatric and immunocompromised patients. This is where Lab Developed Tests (LDTs) can help bridge the gap and address such disparities.

What Are LDTs?

as in vitro diagnostic tests that are developed, manufactured and used within a single laboratory. They —the ability to be developed and adapted to meet specific population needs, even in the absence of widespread use or profit. To ensure LDTs meet stringent standards, each laboratory must validate that the LDT results are accurate, and that the assay meets the requirements of designated accrediting bodies, such as the . While these tests currently do not require formal FDA review, LDTs have become a reliable and important tool of testing for less common and emerging infections, providing access to millions of patients whose conditions might otherwise go undetected. LDTs allow smaller, local labs to continue providing care for their patients.

Furthermore, LDTs are widely used across all laboratory settings, ranging from small community hospitals to large reference centers. In fact, º£½ÇÉçÇøappconducted an LDT utilization survey in 2023, which showed that over 90% of surveyed º£½ÇÉçÇøappmember clinical microbiology laboratories performed LDTs as of October 2023.

This LDT utilization survey also highlighted the reasons that medical laboratory professionals use LDTs in their laboratories:

• 70% cited no FDA approved assay for a particular pathogen.
• 74% cited no FDA approved assay for the specimen.
• 42% cited no FDA approved assay for the patient population.
• 49% cited limitations of FDA approved assay (transport media requirements, etc.).
• 41% cited the test was not available on currently used platforms.

The Value of LDTs

Importantly, there are countless numbers of LDTs for infectious disease testing in existence. The examples that follow are intended to provide a frame of reference for just how impactful these tests can be when it comes to diagnosis of pathogens of all types. From emerging to actively circulating, rarely to more commonly encountered, fungal to viral—this list scratches only the surface.

COVID-19

LDTs are often the first line of defense against emerging and reemerging infections that put underserved and vulnerable populations at risk. At the beginning of the COVID-19 pandemic, there was a delay in commercially available COVID-19 tests, due to novelty of the virus. Completely new assays had to be created in order to facilitate diagnosis and attempt to slow transmission of COVID-19. Labs quickly turned to developing and submitting LDTs for FDA Emergency Use Authorization (EUA). Notably, EUA is a pathway that allowed LDTs that had not yet received FDA approval to be used to diagnose or prevent serious or life-threatening disease during the COVID-19 pandemic (a declared public health emergency), when no other alternatives were available. Thus, in-house production of diagnostic tests became critical for timely testing and accurate diagnosis during the COVID-19 pandemic.

These COVID-19 LDTs also played a critical role in promoting health equities as COVID-19 , with Hispanic and Latino individuals making up the highest proportion of hospitalized patients. Socioeconomic status, clinical care quality, race and ethnicity were factors associated with a that warranted subsequent intensive care unit (ICU) admission. Having access to accurate, timely COVID-19 tests, which were at the beginning of the pandemic, was paramount to ensure that the highest-risk demographics would have access to diagnostics and subsequent care.

Monkeypox

In 2022, there was an unprecedented global outbreak of mpox (formally called monkeypox), a viral infection caused by the monkeypox virus (MPXV). Unlike previous U.S. cases, the current MPXV strain was mainly spread through sexual contact, posing a new challenge for transmission prevention. Furthermore, because mpox presents with symptoms that are similar to varicella zoster virus (VZV), herpes simplex virus (HSV) and other common viruses, a diagnostic assay is essential to accurately diagnose and prevent transmission of disease. However, as MPXV was not previously common in the U.S., there were no FDA-approved assays available for its detection when the 2022 outbreak occurred. Thus, LDTs were the only option for diagnosis and were critical for preventing transmission. The LGBTQIA+ community was disproportionately impacted by this outbreak, and as laboratories created LDTs for MPXV, affected individuals were able to receive better access to care.

Measles

Measles is a highly contagious infection caused by an airborne virus that remains in the air for hours. Pregnant people, immunocompromised populations and those under 1 year of age, who cannot be vaccinated, are at the highest risk for , including encephalitis, pneumonia and even death. While measles is a vaccine preventable disease, due to declining vaccination rates, there have been an increased number of measles outbreaks within the U.S and worldwide. Yet, there are no FDA-approved molecular measles tests available, and specimens for testing, causing delays in results, subsequent contact tracing and isolation. LDTs are, therefore, essential for curbing major outbreaks and protecting the most vulnerable patient populations.

As of January 2024, there is an in Philadelphia that is linked to transmission within a hospital and has since spread to daycare settings, exposing those hospitalized for other conditions, as well as those too young to be vaccinated. This outbreak highlights the necessity for rapid testing, diagnosis and isolation to prevent those most at risk from being exposed.

Hantavirus and Coccidiomycosis

Arizona and New Mexico experience endemic infectious diseases like (a family of viruses that are primarily spread by rodents and cause illness in humans) and (fungal infection also known as Valley fever). Both can be fatal and require rapid diagnosis. Indigenous American populations living in regions where these diseases are endemic have been at a higher risk for exposure and subsequent infection. There are no FDA-approved molecular or antigen assays available for hantavirus or coccidiomycosis. This is, in part, because these infections occur infrequently in the general population. Without LDTs for these infections, Indigenous American populations who reside in endemic areas are at greater risk for infection.

Fungal Infections

LDTs are critical for diagnosis of countless other infectious diseases, including those caused by a variety of other fungi. Fungal infections require rapid diagnosis, treatment or isolation, but there is a major gap in diagnostic availability. Aspergillus, Coccidioides, Blastomyces, Histoplasma, Mucor, Pneumocystis jirovecii and Candida auris are examples of such fungi, all of which have a low, slow or zero recovery rate in fungal culture, meaning that the fungi does not grow well in culture. This hinders laboratory diagnosis and leads to misdiagnosis and underdiagnosis of these fungal diseases. Immunocompromised patients are at a significantly increased risk for these fungal infections, as well as other infections (both viral—HHV-6 and West Nile Virus—and fungal) where there is no FDA-approved molecular assay available.

Advocating for LDT Regulations

In October 2023, the FDA proposed a aimed at regulating LDTs. Importantly, infectious diseases test results are not viewed in a vacuum (i.e., they are viewed in conjunction with other clinical data, including imaging, clinical presentation, risk factors, chemistry labs and other microbiology lab results) and are typically considered low risk tests.

Yet, with the proposed rule, disparities in infectious disease testing will be exacerbated as many clinical microbiology laboratories will be required to stop using LDTs. The survey conducted by º£½ÇÉçÇøappin fall 2023 (which included 88 laboratories spanning academic medical, public health, reference laboratories, community hospitals and other settings) revealed that 90% of surveyed laboratories performed infectious disease LDTs, highlighting the prevalent use of these assays. If the proposed rule is finalized as it is currently written, roughly 82% of laboratories would consider discontinuing their LDT offerings, which could significantly impact clinical care. ASM, alongside other vested stakeholders, remains steadfast in advocating for revisions to the proposed rule concerning LDTs. As part of this effort, º£½ÇÉçÇøapppromptly submitted a comprehensive letter to the FDA, highlighting concerns associated with the proposed rule.

The FDA is expected to finalize its rule on the regulation of LDTs this spring, leaving the future of LDTs uncertain. Championing the rationale and importance of LDTs, enhanced testing methodologies and fairer practices is imperative as these discussions and deliberations persist. Submission for approval of FDA-approved assays is expensive and time-consuming, with requirements that overburden clinical and public health laboratories, making the FDA approval route infeasible for noncommercial manufacturers. This further limits access to testing and worsens existing health disparities and inequities. LDTs are a key approach to breaking down barriers to access and enhancing equity in clinical practices and health care. The absence of such advocacy and communal support may perpetuate disparities, particularly limited health care access during disease outbreaks.

Recognizing the critical role of LDTs, promoting improved testing and striving for equitable practices is paramount to ensuring health care access and fostering laboratory equity for all individuals.

Are you interested in learning more about lab equity? What is it? Why is it important? How can you take active steps to promote equity in your laboratory today? Contact the º£½ÇÉçÇøappLab Equity Working Group today!