ASM Responds to RFI on Regulations of Clinical Tests

April 3, 2024

The Honorable Bill Cassidy 
Ranking Member U.S. Senate Committee on Health, Education, Labor and Pensions
428 Dirksen Senate Office Building 
Washington, D.C. 20510  

Dear Ranking Member Cassidy:  

On behalf of the American Society for Microbiology (ASM), thank you for the opportunity to provide feedback on the appropriate regulatory frameworks for laboratory services and diagnostic products. ASM is one of the oldest and largest single life science societies with 36,000 members in the U.S. and around the world, whose mission is to promote and advance the microbial sciences. ASM members perform testing for the diagnosis of infectious diseases (ID) in clinical and public health laboratories in a range of urban and rural settings, including academic and university based medical centers, large healthcare systems, private and public community hospitals, independent laboratories and public health departments.    

ASM has serious concerns about the impact on ID testing of the recent Food and Drug Administration (FDA) proposed rule on Medical Devices; Laboratory Developed Tests. According to a fall 2023 survey of ASM members, 90% of clinical and public health laboratories use laboratory developed tests (LDTs) for the diagnosis and monitoring of myriad infectious diseases. The proposed changes would have far-reaching implications for these laboratories, affecting public health, patients and the clinicians that serve them.  

To offer the most comprehensive ID testing, development of novel tests, as well as test modifications of FDA-approved assays, are often necessary to account for gaps in available FDA-approved laboratory test kits. Under the proposed regulatory process, test modifications are considered “remanufactured,” and could require additional review that would require time and human and financial resources that do not exist in many laboratories. In the 2023 survey, ASM found that 73% of surveyed laboratories currently use modified FDA-approved assays to better serve their patient population. Modifications range from using a chemically equivalent transport media that is not the exact company or product number as indicated in package inserts, to using a non-approved, but clinically relevant, sample type. While the modifications are often minor, the impact on patient care of not being able to quickly adapt tests could be catastrophic.  

ASM shares Congress’ and the FDA’s goal of protecting public health by ensuring the safety and accuracy of LDTs. Many laboratories operate on thin financial margins and face severe staffing shortages. Staffing vacancies as high as 25% have been reported with the average vacancy at around 8.5%; rural areas are particularly impacted. The consequences of the proposed rule, which would require additional staffing and financial resources for compliance, will reduce patient access to high-quality and timely ID testing, negatively impact health equity and stifle innovation of the development of new essential diagnostics. The medical device pathway is ill-suited for LDTs focused on ID because it does not provide the necessary flexibility and accompanying risk-based framework to meet the real-world needs of ID testing and patient care. Below are responses to specific questions posed in the request for information.  

Question 7: Does FDA’s current risk classification framework properly measure risk versus regulatory controls for diagnostics products?  

No; the current FDA medical device pathways do not account for a risk classification that would be suitable for all diagnostic products. Clinicians rely on commercial tests and LDTs, typically used in combination with comprehensive clinical assessments, to diagnose many infectious diseases and support the management of complex patients. ID test results are not viewed in a vacuum and, instead, are used as pieces of a puzzle (e.g., traditional bacterial culture, antigen testing and molecular testing may be ordered together). This allows information to be compared and conclusions to be drawn based on the whole picture, which lowers the inherent risk associated with ID testing and supports a framework that could allow for continued enforcement discretion.   
ASM recommends any FDA diagnostic approval process include a well-defined risk classification structure. For example, a “low risk” category for ID LDTs will allow clinical microbiology laboratories to continue using most ID LDTs to serve the most vulnerable communities and serve as sentinel laboratories to local and state public health entities during public health emergencies. After collecting data on the usage of LDTs, as well as more robust adverse event reporting, the FDA, in conjunction with stakeholders and the public, will be better able to determine a more effective approach to regulation of these tests than the one outlined in the proposed rule. 

Question 8: In considering reforms to FDA’s risk classification framework for diagnostics, what types of IVDs should be exempt from premarket review?  

ASM recommends that any regulations should consider exceptions for antimicrobial susceptibility testing. Susceptibility test panels for bacteria, fungi, Nocardia and mycobacteria are mostly LDTs, as the few FDA-cleared panels have substantial limitations, and there is lack of FDA clearance for less common pathogens. There are no FDA breakpoints for susceptibility tests for many of the pathogens listed as CDC urgent, and serious antibiotic resistance threats (including Candida auris, drug resistant N. gonorrhoeae, carbapenem-resistant Acinetobacter baumannii and more). Without a breakpoint, a laboratory would unlikely be able to get FDA clearance for a test that applies non-FDA interpretive breakpoints (CLSI or EUCAST), which creates a “catch-22” situation, given the agency’s role in breakpoint approval. Laboratories will have to default to the breakpoints for which the assays received FDA approval, which are also out of sync with many of the CLSI updated breakpoints.

Hindering, and potentially losing, susceptibility testing in laboratories close to the patient is harmful to patient care. Without this capability, antimicrobial stewardship will be compromised, greatly increasing the risk that patients will not receive appropriate treatment. Beyond the harm this causes the patient, it contributes to antimicrobial resistance and affects public health.   

Question 10: Do the proposed reforms to FDA’s device framework warrant the establishment of a new regulatory pathway specific to diagnostics? If yes, what are the principles that should guide such a new framework, as it would be applied to diagnostics currently subject to FDA premarket review?  

As mentioned, ASM has serious concerns with the impact on ID testing from the proposed reforms to the FDA’s framework, and we would like to work with Congress and the Administration to find the right approach. ASM recognizes that there is a lack of information on the current LDTs on the market. ASM supports registration and listing requirements and severe adverse event reporting for LDTs as a first step toward collecting necessary data and developing a regulatory path for LDTs that is consistent with the realities of how these tests are used in infectious disease care. The proposed rule moves forward with regulations without a complete picture of ID LDTs and how they are used in patient care and clinical practice, instead relying on anecdotes about errors related to LDTs, primarily focused on non-ID LDTs. 

We agree that more complete data regarding the actual incidence of inaccurate results/patient harm with LDTs should be compiled and made publicly available. Accredited clinical and public health laboratories have quality reporting metrics in place as part of the laboratory and hospital-based quality systems, making LDT severe adverse event reporting feasible. We urge FDA to ensure registration, listing and reporting requirements are streamlined and do not strain the limited human and financial resources of clinical microbiology and public health laboratories, which do not have dedicated regulatory staff and do not have the funding to hire new staff for these tasks.    

Any new regulatory mechanism must also take into account the cost of the process, especially for smaller laboratories that lack resources to pay FDA user fees. Many laboratories where ASM members work are not-for-profit and therefore cannot be classified as “small businesses,” and few meet the proposed criteria of less than $150,000 in annual revenue to allow an exemption as proposed in the rule. Instituting a user-fee program for LDT review as part of the device pathway ignores the enormous difference between commercial device manufacturers and clinical and public health laboratories that develop LDTs for patient care. The latter often operate on a thin financial margin within health care facilities without access to the financial and personnel resources available to commercial test developers. It is unreasonable to include these laboratories in the same business category as commercial entities because clinical and public health laboratories are not manufacturers. Many ID LDTs are often developed to address a clinical need at the local level and are not packaged and distributed like commercial IVDs. Applying the funding mechanism associated with the medical device pathway to clinical microbiology and public health laboratories will lead to these entities reducing or ceasing LDT use altogether, the result will be reduced patient access to timely, accurate and reliable tests.   

In many instances, including the 2022 mpox outbreak, LDTs are the first available tests for an emerging infectious disease and are central to outbreak responses. ASM is concerned that the proposed rule will hinder innovation in ID test development—a consideration that must be acknowledged when developing a new regulatory framework. LDTs have been at the forefront of clinical innovation in the detection and management of infectious diseases, often leading to their incorporation into guidelines and CDC recommendations. According to the ASM survey, 42% of laboratories reported performing more than 10 LDTs. The investment in personnel, time and resources required to obtain FDA approval for existing LDTs will halt the development of novel diagnostics, hindering the innovation and diagnostic progress necessary to keep up with emerging and evolving pathogens. 

In an era of rising incidence of vaccine preventable diseases and climate change driving spread of pathogens beyond their traditional endemic areas, clinical microbiology laboratories serve as sentinel laboratories for the public health network and will likely be the first point of contact for emerging diseases. The FDA LDT proposal will limit these laboratories' ability to respond to local needs promptly. In addition, the challenges the medical device approval pathway will present to clinical laboratories running LDTs will lead to loss of expertise in performance of these tests over time. This will degrade our ability to identify and respond to future pandemics and novel pathogens.   

Thank you again for the opportunity to provide comments on the appropriate regulatory framework for LDTs. We look forward to working with your office to ensure that we have the correct framework that accounts for the needs of ID testing, protecting patient access to appropriate testing to get the correct diagnosis and reducing the risk of transmission. Please feel free to reach out to Amalia Corby, ASM Interim Director of Federal Affairs at acorby@asmusa.org with any questions.  

Sincerely, 

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Allen D. Segal
Chief Strategy and Public Affairs Officer

Author: ASM Advocacy

ASM Advocacy
ASM Advocacy is making it easy and providing opportunities for members to advocate for evidence-based scientific policy.