Re: CMS-3485-NC; Request for Information; Clinical Laboratory Improvement Amendments of 1988 (CLIA) Regulations

Dear Administrator Oz and Director Schwartz:

On behalf of the ASM Clinical and Public Health Microbiology community, thank you for the opportunity to provide input on potential updates to the Clinical Laboratory Improvement Amendments of 1988 (CLIA) regulations. ASM, with more than 38,000 members in the United States and around the world, is one of the oldest and largest life science societies, and our mission is to promote and advance the microbial sciences. ASM members perform testing for the diagnosis of infectious diseases in clinical, commercial and public health laboratories in a range of urban and rural settings, including academic medical centers, large health care systems, community hospitals, independent laboratories and public health departments.

ASM supports CMS and CDC’s effort to modernize CLIA to reflect advances in laboratory testing and current laboratory practice. Clinical microbiology has changed substantially since the CLIA regulations were first implemented, including through advances in molecular diagnostics, next-generation sequencing (NGS), automation, artificial intelligence and other technologies. At the same time, clinical and public health laboratories continue to play essential roles in detecting emerging pathogens, supporting antimicrobial stewardship and responding to public health emergencies. Updates to CLIA should strengthen quality and patient safety while preserving the flexibility laboratories need to respond to evolving technologies, pathogens and patient needs.

Our comments focus on providing background and resources for areas of relevance to clinical and public health microbiology, with emphasis on topics impacting our broad membership. We have encouraged our member labs to submit individual comments to share specific incidences and impacts.

B.3. Suboptimal Specimens

Question 1: What are the circumstances under which the laboratory tests suboptimal specimens?

Clinical microbiology laboratories establish specimen acceptance and rejection criteria to ensure the quality and reliability of test results. Preanalytic quality, including appropriate specimen collection, handling and transport, is an essential component of diagnostic stewardship and accurate patient testing. However, there are circumstances in which testing a specimen that does not fully meet established criteria may be more appropriate for patient care than rejecting it.

This is particularly important when a specimen is difficult or impossible to recollect. Examples may include cerebrospinal fluid (CSF), surgically-obtained biopsy material, specimens collected before initiation of antimicrobial therapy that would inhibit recovery of pathogens and specimens from pediatric or neonatal patients where sample volume is necessarily limited. Other circumstances may include lower-than-recommended specimen volumes, delays in transport beyond optimal stability, use of a nonpreferred collection or transport device or other deviations from the validated assay.

Existing ASM-published quality-management guidance specifically recognizes that compromised but irreplaceable specimens require a defined process for determining whether testing can proceed, documenting why the specimen cannot be recollected and communicating the potential limitation in the final report.

A rigid requirement to reject every specimen falling outside established acceptability criteria could result in loss of clinically important information or require patients to undergo invasive, difficult or potentially impossible repeat collection.

Question 2: How often does your laboratory test suboptimal specimens annually?

ASM represents laboratories that differ substantially in patient population, testing volume, specimen types and clinical setting and therefore cannot provide a meaningful society-wide estimate of how frequently suboptimal specimens are tested.

There is no standard definition of “suboptimal,” therefore determining frequency is a challenge.  For example, a specimen with a minor transport delay presents a substantially different quality concern from a mislabeled specimen, while low-volume specimens may be an unavoidable reality for some patient populations (e.g., neonatal patients). A 2025 multicenter study of blood culture practices, for example, found that 51 of 52 participating hospitals processed blood culture bottles regardless of whether the volume met recommended targets. 

Question 3: How does the laboratory document and report results from suboptimal specimens?

ASM-published guidance recommends documenting the reason an irreplaceable compromised specimen was accepted and denoting its compromised status in the final report. More recent ASM Laboratory Practices Subcommittee work similarly emphasizes the laboratory’s role in communicating test limitations and using reporting comments or direct provider communication when preanalytic or analytic limitations could affect interpretation.

Depending on the nature of the problem and test performed, this may include a comment explaining that a negative or otherwise affected result should be interpreted cautiously because of limited specimen volume, delayed transport or another preanalytic limitation.

Question 4: How does the laboratory communicate with ordering providers regarding suboptimal specimens?

Communication should be appropriate to the clinical significance of the specimen issue and its potential effect on the result. In some circumstances, a comment appended to the laboratory report may adequately communicate the limitation. In others, particularly where the laboratory must decide whether to test or reject an irreplaceable specimen, direct communication with the ordering provider may be necessary.

To ensure that providers are aware of the limitations of using suboptimal specimens and to track the number of such requests, laboratories should maintain procedures for documenting these communications and for escalating cases to the laboratory director or other qualified laboratory personnel when medical judgment is required. This allows the laboratory and treating clinician to weigh the risks associated with testing a compromised specimen against those associated with recollection, delayed testing or loss of the opportunity to test altogether.

Question 5: What quality assurance measures does the laboratory apply to the testing of suboptimal specimens?

As documented in the Clinical Microbiology Procedures Handbook, quality assurance begins with clear specimen collection, transport, acceptance and rejection criteria. Laboratories should make specimen requirements readily available to clinicians and other personnel involved in collection and should monitor recurring specimen-quality problems as part of their quality-management and diagnostic-stewardship activities.

When a laboratory makes an exception for a suboptimal specimen, the reason for the exception and relevant limitations should be documented. Laboratories should also evaluate trends in suboptimal specimen submission and provide education and feedback to clinical areas or personnel when recurring issues are identified.

Where a particular nonoptimal specimen type or condition is routinely encountered—for example, limited specimen volumes in certain pediatric populations—the laboratory may determine whether additional validation or other quality measures are appropriate.

Question 6: What challenges does the laboratory face in managing suboptimal specimens while ensuring test result quality?

A central challenge is that laboratories are responsible for ensuring quality across the total testing process, even though many preanalytic activities occur outside the laboratory. Recent ASM Laboratory Practices Subcommittee guidance emphasizes that appropriate specimen collection and handling are central to diagnostic quality and often require multidisciplinary institutional involvement.

Clinical laboratories may establish specimen requirements, provide education and monitor specimen quality but have limited direct authority over patient-facing clinical teams. This can make persistent collection-quality problems difficult to prevent, particularly in environments experiencing workforce turnover and competing clinical priorities. This issue is particularly relevant to blood culture contamination, discussed further in section D.4, where laboratories frequently monitor quality outcomes even though specimen collection is performed outside the laboratory.

Laboratories also cannot validate every possible combination of suboptimal specimen type, volume, transport condition or other deviation. Medical judgment is therefore necessary to determine whether the potential clinical value of testing outweighs the potential limitations associated with the specimen. CLIA supports laboratory director discretion in these cases and recognizes that specimen quality is a shared responsibility across the healthcare system, aligning with our membership needs.

B.4. Establishment and Verification of Performance Specifications

Question 1: For tests that are not FDA-cleared or approved, including modifications of FDA-cleared or approved tests, what challenges does the laboratory encounter when establishing adequate performance specifications and appropriate acceptance criteria? Specify the relevant test or procedure associated with such challenges.

Clinical and public health microbiology laboratories rely on laboratory-developed tests (LDTs) and modifications to FDA-cleared or approved assays to address gaps in available infectious disease diagnostics. In a 2023 ASM survey of 88 clinical and public health microbiology laboratories, 90% of respondents reported using LDTs and 73% reported using modified FDA-cleared or approved assays. Laboratories reported relying on LDTs because no FDA-approved assay was available for the pathogen, specimen type or patient population or because of limitations associated with available FDA-approved assays.

Modifications to FDA-cleared or approved tests are frequently necessary to provide accepted standards of care. Examples include clinically appropriate specimen types not included in manufacturers’ instructions for use, alternative transport media and implementation of updated antimicrobial susceptibility testing breakpoints on existing test systems. 

Establishing performance specifications for these tests can be particularly challenging when the pathogen, specimen type or patient population is uncommon. Laboratories may have difficulty obtaining sufficient positive clinical specimens for validation—for example, cerebrospinal fluid positive for Mycobacterium tuberculosis or pediatric specimens positive for Chlamydia trachomatis or Neisseria gonorrhoeae. Similar challenges arise for low-volume infectious disease tests for which there may be little commercial incentive for manufacturers to pursue FDA clearance (e.g., Mycobacterium tuberculosis testing on tissue specimens). 

Antimicrobial susceptibility testing presents a particularly important example. Current clinical standards may change faster than FDA-cleared test systems and manufacturers’ labeling, causing a delay between updated CLSI breakpoints and FDA approval. Laboratories may therefore need to validate updated susceptibility breakpoints on existing systems to provide clinicians with current information to identify and treat antimicrobial-resistant infections.

Questions 2.a and 2.b: What testing methods and/or specific applications have unique performance characteristics that need to be established and are not already addressed in CLIA regulations or guidance? What are those performance characteristics?

NGS and other advanced molecular diagnostics increasingly support clinical and public health applications including pathogen identification, genomic characterization, surveillance and detection or prediction of antimicrobial resistance. A 2026 CDC/APHL NGS Quality Initiative report highlights the particular complexity of these workflows and the need for quality systems capable of addressing NGS.

Quality assessment for NGS extends beyond the analytical performance of the sequencing instrument. Relevant considerations include complex wet-laboratory workflows; quality-control checkpoints; reagent and equipment management; data integrity; specialized bioinformatics; validation and ongoing verification of bioinformatic pipelines; reference database governance and curation; personnel training; and change control for frequently updated software, sequencing chemistries and platforms.  

The CDC/APHL initiative also notes that NGS-based assays can require more complex and time-consuming validation and verification than conventional assays, and that frequent hardware and software updates may require additional verification or revalidation. These characteristics make flexibility particularly important in any future CLIA framework.

ASM recommends that CMS use an application- and risk-appropriate approach to NGS validation and quality management rather than apply conventional test requirements without accounting for the complexity and dynamic nature of sequencing workflows. CMS should build upon current CDC/APHL quality-management work and engage clinical and public health microbiologists as requirements and guidance evolve.

The RFI also asks whether clinical validity should be considered an additional performance characteristic. Tests used for patient care should be supported by appropriate scientific evidence. However, the nature of evidence necessary to establish clinical validity will vary significantly based on the test, patient population and intended use.

Recent work published in the Journal of Clinical Microbiology specifically addressing infectious disease LDTs notes that laboratories often must address rare infections, uncommon specimen types and unmet diagnostic needs for which formal clinical-trial data may not exist. The authors describe an approach that maintains analytical rigor while allowing clinical validity to be supported by evidence from medical literature and clinical judgment.

For many infectious disease LDTs and modified assays, appropriate support for clinical validity may, therefore, include peer-reviewed literature, professional guidelines, comparison with established methods and other accumulated clinical evidence. Requiring every individual laboratory to independently generate clinical-trial-level data could make specialized or low-volume testing impractical and reduce access to needed diagnostics.

If CMS considers incorporating clinical validity into CLIA, the agency should clearly define the requirement, recognize multiple scientifically appropriate sources of evidence and avoid requiring individual laboratories to independently conduct clinical trials when existing evidence adequately establishes clinical validity.

Question 3: How does the laboratory currently design, develop and prepare reagents for tests developed in-house?

The development and preparation of reagents for LDTs vary according to the methodology, laboratory expertise, available resources and clinical need. Some laboratories design individual assay components, such as primers, probes or antibodies, and manufacture or custom-order those components. Other laboratories evaluate and validate components developed by third parties with expertise in a particular pathogen or methodology. Laboratories may also use a combination of these approaches.

Given this diversity, ASM recommends that CMS focus regulatory expectations on demonstrated assay performance, appropriate quality control and documentation rather than establish a single prescriptive process for the design or development of reagents used in LDTs.

Question 4: What types of modifications does the laboratory commonly make to FDA-cleared or approved test systems?

Common modifications to infectious disease test systems include alternative specimen types, transport media, extraction methods and updated antimicrobial susceptibility breakpoints, among other changes necessary to provide clinically appropriate testing.

Many such modifications address limitations in a manufacturer’s cleared instructions for use rather than fundamentally changing the analytical principle or intended clinical purpose of the assay. ASM recommends that CMS continue to recognize the important role appropriately validated modifications play in infectious disease diagnostics and avoid requirements that unnecessarily discourage laboratories from adapting tests to meet established clinical needs.

C.1. Emergency Preparedness

Question 1: What are best practices for laboratory emergency preparedness?

Clinical, public health and reference laboratories are essential components of the nation’s preparedness and response infrastructure. Clinical laboratories, also known as sentinel laboratories, frequently serve as a first point of diagnostic contact when an emerging infectious disease reaches a community, coordinating closely with the public health laboratories. CDC’s Laboratory Response Network (LRN) similarly relies on sentinel laboratories to provide routine diagnostic services and to recognize, rule out and refer potential biological threats. 

Laboratory emergency preparedness should be scalable to the laboratory and the threats it is likely to encounter. Important elements may include continuity-of-operations planning; laboratory-specific risk assessments and biosafety procedures; supply-chain contingency planning; workforce continuity and surge capacity; procedures for implementing or expanding testing; specimen referral and transportation; communication with public health partners; and periodic training or exercises.

Question 2: What challenges does the laboratory face in maintaining operations during emergencies such as natural and human-caused disasters, facility emergencies and emerging infectious diseases?

The challenges laboratories experience vary with the nature and scope of an emergency but may include workforce shortages, supply-chain disruptions, sudden increases in testing demand, infrastructure failures, biosafety concerns and maintaining routine diagnostic services while simultaneously responding to the emergency. The COVID-19 pandemic demonstrated the importance of these capabilities. A national survey involving ASM and other laboratory organizations documented critical shortages of testing supplies and qualified personnel during the pandemic, with effects extending beyond SARS-CoV-2 testing to other essential laboratory services. 

Emerging infectious disease events present an additional challenge because laboratories may need to rapidly develop or implement new testing capabilities. During the early COVID-19 response, ASM raised concerns that then-current federal EUA policy prevented clinical laboratories from deploying LDTs outside the CDC and public health laboratory framework, limiting the ability of qualified laboratories to expand testing capacity. ASM later recommended that federal emergency testing policies establish sufficiently early and clear pathways for qualified clinical and public health laboratories to develop and deploy testing during emerging infectious disease events. 

These experiences demonstrate that laboratory preparedness is not limited to internal continuity planning. Effective response also requires clear federal regulatory pathways and communication and coordination among federal agencies, public health laboratories and clinical laboratories.

Question 3: What elements does the laboratory include in its current emergency preparedness plans and protocols?

Depending on the laboratory and the emergency, preparedness plans may address:

• Continuity of essential laboratory services and identification of testing that may be delayed or referred during an emergency.
• Workforce continuity, cross-training and surge capacity.
• Supply-chain resilience and contingency plans for critical reagents, consumables and collection supplies.
• Laboratory information system, communications and other downtime procedures.
• Laboratory-specific biosafety procedures and risk assessments for emerging or high-consequence pathogens.
• Specimen referral, transportation and coordination with public health laboratories.
• Procedures for rapidly implementing or expanding testing for an emerging pathogen.
• Periodic review, exercises and staff training.

CMS should recognize that a large hospital or reference laboratory, a public health laboratory and a small physician-office laboratory have substantially different capabilities, responsibilities and risks. Any CLIA preparedness requirement should therefore be scalable and risk-based rather than prescriptive.

Question 4: What lessons has the laboratory learned from recent emergency situations?

Recent emergencies have underscored the importance of planning for disruptions that extend beyond the immediate cause of the emergency. During COVID-19, shortages affected supplies used for pandemic testing as well as other diagnostic testing, while workforce constraints reduced laboratories’ ability to rapidly increase capacity.

Laboratories also must consider how testing for a high-consequence pathogen may affect routine laboratory operations, including biosafety procedures, decontamination, instrument use and access to instrument service.

C.2. Biosafety and Biosecurity

Question 1: What challenges does the laboratory face in biosafety and biosecurity?

Clinical microbiology laboratories routinely encounter organisms before their identity or potential risk is known. The 2026 sixth edition of CDC and NIH’s Biosafety in Microbiological and Biomedical Laboratories (BMBL) includes an appendix addressing clinical laboratory biosafety and emphasizes protocol-driven risk assessment as a core principle of laboratory biosafety practice. 

This risk-based approach is particularly important for clinical microbiology because laboratories routinely work with unknown specimens and because technology and organism-identification methods continue to evolve.

ASM, in coordination with the Association of Public Health Laboratories (APHL) and CDC, maintains Laboratory Response Network Sentinel Level Clinical Laboratory Guidelines designed to provide practical methods for recognizing, ruling out or referring suspected biological-threat agents. The guidelines are undergoing active updates as taxonomy, testing technologies and laboratory practice change. 

One challenge identified by ASM members is that routine clinical microbiology has evolved considerably from the workflows on which some traditional rule-out procedures were based. Technologies, such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), have replaced or reduced reliance on some traditional biochemical identification methods.

Members also identified challenges associated with proficiency assessment for biological-threat rule-out procedures. Existing exercises may assess important elements, such as packaging, reporting and communication, but may not fully reproduce the uncertainty involved when an unexpected organism is encountered during routine clinical testing. 

Question 2 and Question 3: What elements or best practices does the laboratory include in its current biosafety and biosecurity plans and protocols? How does the laboratory train personnel on biosafety and biosecurity plans and protocols?

ASM recommends biosafety and biosecurity programs be grounded in laboratory-specific risk assessment and appropriate risk mitigation. The 2026 BMBL recommends a protocol-driven approach in which risks and appropriate mitigations are evaluated based on the procedures performed, hazards involved and laboratory setting. Its clinical laboratory appendix specifically addresses biological risk management in clinical laboratories.

Depending on the laboratory, appropriate elements may include documented biological risk assessments; engineering and administrative controls; personal protective equipment; procedures for specimen and isolate handling, transport and referral; decontamination and waste management; exposure and incident response; access and security measures appropriate to the materials being handled; and procedures for timely communication and referral to public health authorities.

For potential biological-threat organisms, sentinel clinical laboratories should maintain procedures consistent with current ASM/APHL Sentinel Level Clinical Laboratory Guidelines and coordinate with their local or state LRN reference laboratory.

CMS should build upon these established and evolving frameworks rather than create a duplicative biosafety and biosecurity system under CLIA. Requirements should remain risk- and performance-based so laboratory directors and biosafety professionals can adapt practices as organisms, procedures and technologies change.

D.4. Microbiology—Blood Culture Contamination

Question 1: What best practices has the laboratory implemented to reduce and monitor blood culture contamination?

Blood culture contamination is an important patient-safety, diagnostic-stewardship and antimicrobial-stewardship issue. Contaminated blood cultures can result in unnecessary antimicrobial use, additional diagnostic testing, increased costs and delayed or incorrect diagnoses.

ASM supports routine monitoring of blood culture contamination as part of laboratory quality management. An ASM Laboratory Practices Subcommittee report recommends monitoring contamination rates, preparing reports and providing feedback to appropriate stakeholders throughout the healthcare system.

ASM’s evidence-based laboratory medicine practice guideline identifies several interventions associated with reductions in contamination, including appropriate skin antisepsis, blood-diversion approaches, standardized sterile collection practices, specially trained phlebotomy teams and education and training programs. No single intervention is appropriate for every institution, and successful contamination reduction requires implementation, training and institutional engagement.

Based on these guidelines, ASM recommends that CMS focus on an effective quality-management process rather than prescribe a particular collection device, technology or commercial product. Blood-diversion devices may be one effective tool but should be considered alongside other evidence-based interventions and should not substitute for proper collection technique, training and competency.

Recent multicenter data provide additional evidence that blood culture contamination surveillance would benefit from greater standardization. A 2025 study involving 52 U.S. acute-care hospitals found substantial variation in how institutions defined contamination, which thresholds they used and which additional blood culture quality measures they tracked. The calculated contamination rate also varied depending on the definition used.

ASM therefore recommends that CMS work with clinical microbiologists and other stakeholders to establish a more consistent approach to defining, calculating, monitoring and reporting blood culture contamination. Standardized surveillance would allow laboratories and health systems to meaningfully compare performance and identify opportunities for improvement.

At the same time, CMS should exercise caution in using a single numerical contamination rate as an inflexible CLIA pass/fail standard. A contamination rate below 3% has historically been used as an acceptable benchmark, while lower rates may be achievable in some settings. However, contamination rates can be affected by the definition used, patient population, collection location, collection method and other institutional factors.

A modern CLIA framework should therefore promote consistent surveillance methodology and evidence-based quality benchmarks while emphasizing investigation, corrective action and continuous improvement rather than automatic noncompliance based solely on a single numerical result.

Question 2: What challenges does the laboratory face in maintaining low blood culture contamination rates?

One of the most significant challenges is that contamination generally occurs during specimen collection, while the microbiology laboratory often does not directly supervise or have authority over all personnel responsible for collecting specimens. Depending on the institution, blood cultures may be collected by dedicated phlebotomy teams, nurses, patient care technicians, emergency department personnel or other members of the clinical care team.

Collection technique and trained personnel are central to reducing contamination. ASM’s evidence-based guideline found benefits associated with standardized sterile collection practices, dedicated or specially trained phlebotomists and education and training programs. The ASM Laboratory Practices Subcommittee also recommends monitoring contamination data and providing actionable feedback to departments and personnel involved in collection.

Recent multicenter evidence further supports treating blood culture quality as an institutional rather than solely laboratory responsibility. The 2025 multicenter study found that sharing contamination data outside the laboratory and limiting central-catheter blood cultures were associated with lower contamination rates.

Laboratories may nevertheless be responsible for monitoring contamination rates, identifying problems and providing education without having direct authority to enforce collection practices across the healthcare system. Workforce shortages and turnover, limited availability of dedicated phlebotomy teams, high patient volumes, difficult venous access and competing clinical priorities can further contribute to inconsistent collection practices.

This creates an important accountability issue for any future CLIA requirement. CMS should not place sole responsibility for blood culture contamination rates on the microbiology laboratory when many of the practices influencing contamination occur outside the laboratory’s direct control. Improving performance requires shared institutional responsibility among laboratory leadership, nursing, phlebotomy, emergency medicine, infection prevention, antimicrobial stewardship and hospital administration.

CMS should consider approaches that give laboratories the data and institutional support necessary to identify and address collection problems. Where feasible, healthcare systems should be able to evaluate contamination by patient-care location, collection method and collector or collector type so the data can support targeted education, competency assessment and corrective action.

Thank you for the opportunity to comment on potential updates to the CLIA regulations. ASM supports modernization that strengthens the quality and reliability of laboratory testing while recognizing the rapid evolution of clinical microbiology and the diversity of laboratories subject to CLIA. ASM and its members stand ready to work with CMS and CDC as the agencies consider future regulatory or subregulatory changes.

If we can be of further assistance, please contact ASM Government Relations Manager JR Kane at jkane@asm.org.

Sincerely,

Erin Graf, Ph.D., D(ABMM)
Chair, ASM Clinical and Public Health Microbiology