Response to Comments: MolDX: Biomarker Testing in Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Dysfunction-Associated Steatohepatitis

The following comment was submitted to Palmetto GBA, CGS, and WPS:

On behalf of the Association for Molecular Pathology (AMP), we thank you for the opportunity to comment on the draft Local Coverage Determination (dLCD) entitled MolDX: Biomarker Testing for Risk Stratification in Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Dysfunction-Associated Steatohepatitis.

AMP is an international medical and professional association representing approximately 3,100 physicians, doctoral scientists, and medical laboratory scientists (technologists) who perform or are involved with laboratory testing based on knowledge derived from molecular biology, genetics, and genomics. Membership includes professionals from academic medicine, hospital-based and private clinical laboratories, the government, and the in vitro diagnostics industry. AMP members are highly involved in the development, validation, and interpretation of molecular diagnostic tests, including biomarker tests for the diagnosis and management of liver fibrosis in the setting of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH).

AMP greatly appreciates that MolDX is proposing to generally cover biomarker testing for assessing the risk of liver fibrosis in the setting of MASLD or MASH, when certain conditions are met. We have identified several changes, outlined in the information below, that we believe will help streamline the policy and ensure that patients have timely access to this essential testing.

Coverage Indications, Limitations, and/or Medical Necessity

Removal of Ambiguous Language Regarding Test Compliance

AMP strongly urges MolDX to remove the following sentence from Criterion 9:

“New tests that become available with significantly improved performance may render older tests no longer compliant with this policy.”

This statement is subjective and lacks any measurable criteria for determining coverage. Without clear standards for what constitutes significantly improved performance for new tests as compared to long-established tests, it risks creating uncertainty for laboratories, clinicians, and patients. Given the rapid pace of innovation in biomarker testing, maintaining ambiguous language of this kind will undermine predictability in coverage decisions, discourage continued use of clinically validated tests, and ultimately disrupt patient access to medically necessary testing.

Instead, AMP recommends that any future coverage changes be based on explicit, evidence-based criteria developed through a transparent process.

Allow More Flexibility in Testing

AMP is concerned that Criterion 5, which restricts testing within 12 months following a liver biopsy, is too restrictive. Thus, AMP recommends that Criterion 5 reads as follows:

“Testing is not performed more than once within a 12-month period nor within 12 months following a liver biopsy testing biopsy with successful fatty liver disease scoring by a pathologist.”

An unsuccessful fatty liver disease scoring leads to diagnostic ambiguity and will compromise patient care if there is no repeat scoring within the 12-month period mentioned in the criterion 5. This revision balances appropriate safeguards on testing with clinical flexibility, ensuring patients receive necessary testing for accurate risk stratification in MASLD or MASH testing

Remove Redundant Criteria

AMP recommends removing Criteria 6 and 7, as their content is duplicative of the requirements already outlined in the technical assessment process. The focus of the coverage criteria should be on outlining coverage and medical necessity for testing, not repeating standards addressed within the technical assessment.

Additionally, if MolDX chooses to maintain Criterion 6, we strongly urge you to revise the following sentence:

“Clinical validity (CV) of any analytes or profiles must be established through a study published in the peer-reviewed literature for the intended use of the test in the intended population with demonstrated reproducibility across clinical study cohorts.”

The current language could be misinterpreted to mean that each laboratory must independently publish clinical studies for tests already supported by published evidence. We recommend clarifying that laboratories are not required to generate or publish their own CV data if such evidence already exists in the literature. If Criteria 6 and 7 remain in the LCD, we urge consistent language across all LCDs, ensuring that these criteria do not impose requirements more stringent than those found in existing technical assessment forms.

Thank you again for the opportunity to review and comment on this draft policy.

Thank you for your suggestions.

The intent of Criterion 5 is to preclude blood-based testing in patients with unequivocal findings on biopsy that would not reasonably be expected to change significantly in the interval before retesting. This has been reworded to “Testing is not performed more than once within a 12-month period nor within 12 months following a liver biopsy with definitive histologic interpretation by a pathologist.”

Criteria 6 through 9 have been edited and rearranged. The word “novel” has been added to indicate that CV may already be established by prior publications for the exact same test. The statement regarding potential non-compliance of older tests has been removed. MolDX expects that future laboratory implementation and clinical utilization will be driven by improved performance metrics such that obsolete tests are naturally removed from production. MolDX also maintains the prerogative to request additional Technical Assessment documentation for any service to ensure maintained compliance with policy.

The following comment was submitted to Palmetto GBA, CGS, Noridian, and WPS:

On behalf of Roche Diagnostics, thank you for the opportunity to comment on the above proposed LCD related to biomarker testing for risk stratification in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction-Associated Steatohepatitis (MASH).¹ Roche Diagnostics develops and produces medical tests and digital tools that provide information to help healthcare professionals find the right treatment for patients and deliver the best patient care to improve, prolong, and save lives. Our approach is to support patients and providers with diagnostics solutions, decision support and disease management.

Specific to this diagnostic area, in May 2025, Roche announced the launch of its Elecsys^® PRO-C3 test, a new diagnostic solution designed to assess the severity of liver fibrosis in patients showing signs of metabolic dysfunction–associated steatotic liver disease (MASLD).² The assay, which is CE-marked, is intended to be used as part of the ADAPT algorithm (patient age, diabetes status, PRO-C3, platelet count) to assess the severity of hepatic fibrosis in patients showing evidence or signs of metabolic dysfunction-associated steatotic liver disease (MASLD). The ADAPT result must be interpreted in conjunction with other methods and in accordance with standard clinical management guidelines.³

We support MolDX’s efforts to expand coverage for innovative biomarker-based approaches in MASLD and MASH, and to recognize the important role of noninvasive diagnostics in improving patient risk stratification and access to treatment including emerging therapies. More specifically, we commend MolDX for listening to feedback from stakeholders and recognizing this testing which is an important step toward improving care pathways for patients at risk of advanced liver fibrosis due to MASLD and MASH.

Coverage Criteria

Under the draft LCD, biomarker testing for risk stratification in MASLD and MASH is considered reasonable and necessary when all nine criteria detailed in the policy are met. While we support most criteria proposed, we request the revision of the two criteria as outlined below.

Criteria 2. A primary risk assessment based on non-molecular/ proteomic laboratory testing, as outlined by consensus guidelines, does not indicate low risk [e.g., fibrosis-4 index (FIB-4) ≥ 1.3].

We support a sequential approach to MASLD and MASH evaluation and risk assessment, with a primary rule-out assessment followed by secondary risk assessment as indicated. However, we do not support limiting the primary risk assessment to non-molecular/proteomic laboratory testing such as FIB-4. Guidelines from the American Gastroenterological Association (AGA) Clinical Practice Update on the Role of Noninvasive Biomarkers in the Evaluation and Management of Nonalcoholic Fatty Liver Disease⁴ advise that noninvasive tests “should be interpreted with context and consideration of pertinent clinical data (eg, physical examination, biochemical, radiographic, and endoscopic) to optimize positive predictive value in the identification of patients with advanced fibrosis” (Best Practice Advice 5).

Similarly, the American Association for the Study of Liver Diseases (AASLD) Practice Guidance on the Clinical Assessment and Management of Nonalcoholic Fatty Liver Disease⁵ recommends secondary assessment when elevated liver chemistries or other clinical risk features are present, recognizing that FIB-4 accuracy is limited in certain populations. Together, these guidelines support that clinical findings — such as persistently abnormal liver enzymes, high metabolic risk, or ultrasound-detected steatosis — may appropriately prompt progression to secondary noninvasive testing when clinical suspicion for advanced fibrosis remains high despite a low-risk FIB-4 result.

Criteria 9. Molecular and proteomic tests utilizing a similar methodology or evaluating similar analytes as a test for which existing coverage has been established must demonstrate equivalent or superior test performance (i.e., sensitivity and/or specificity) when used for the same indication in the same intended use population. New tests that become available with significantly improved performance may render older tests no longer compliant with this policy.

We support the requirement that new tests must demonstrate equivalent or superior test performance (as demonstrated by the test’s sensitivity and/or specificity) to tests with established coverage where the new test has a comparable indication for use in the same patient population. That requirement establishes a minimum bar for coverage which benefits Medicare beneficiaries by ensuring a consistency in the level of performance across the different tests. However, we do not support the position that when newer tests establish a higher level of performance, then the older tests may become non-covered.

If MolDX seeks to remove coverage for any test based on the aforementioned criteria, it should not be able to remove coverage summarily. Rather, MolDX should only do so after the impacted test developer (1) receives sufficient notice of the contractor’s intent to remove coverage and the specific basis (e.g., published evidence) for this change, and (2) gives the test developer reasonable time to respond to the rationale for non-coverage (e.g., submitting additional data or undergoing a new technical assessment by the MAC). This request is consistent with the requirements specific to local coverage determinations as outlined in Chapter 13 in the Medicare Program Integrity Manual.⁶

Diagnosis Codes

We appreciate the effort that goes into developing comprehensive CPT and diagnosis code lists for inclusion in the accompanying Billing & Coding Article.⁷ Metabolic dysfunction–associated steatotic liver disease (MASLD) is a type of chronic liver disease characterized by hepatic steatosis (>5% liver fat) in individuals with one or more cardiometabolic risk factors—such as obesity, hyperglycemia or type 2 diabetes mellitus (T2D), hypertension, or dyslipidemia. Because these metabolic comorbidities are intrinsic to the disease definition and often the clinical context in which patients are evaluated, it is important that diagnosis codes reflecting these risk factors be represented in the Billing & Coding list.

We have identified several ICD-10-CM diagnosis codes that appear to be omitted from the draft but are clinically relevant to the service and, in our view, should be included to support accurate and complete claim adjudication.

The following examples are provided as representative of diagnostic scenarios commonly associated with MASLD and not as an exhaustive list. We respectfully request that the contractor review and consider their inclusion in the final version:

R94.5 Abnormal results of liver function studies

E11.* Type 2 diabetes mellitus (with or without complications)

E78.2 Mixed hyperlipidemia

E78.5 Hyperlipidemia, unspecified

Including these and other related codes would help ensure appropriate claims processing for patients with metabolic risk factors and laboratory findings that prompt evaluation for MASLD.

We appreciate the opportunity to submit comments to this draft LCD. With the modifications and additions noted above, we support the finalization of this policy.

References were provided for review.

Thank you for your careful review.

The Evaluation of liver fibrosis section in the Summary of Evidence recognizes that FIB-4 has limitations. Although the original draft LCD listed quantitative FIB-4 result as an example, not necessarily a requirement, language has been added to Criterion 2 to include clinical evaluation as a component of the primary assessment. Please see Response 1 regarding Criterion 9.

The assistance in identifying applicable ICD-10 codes is appreciated. The proposed codes have been added to the Billing and Coding Article.

The following comment was submitted to Palmetto GBA, CGS, Noridian, and WPS:

We, Labcorp, are writing provide comments on the draft Local Coverage Determination MolDX: Biomarker Testing for Risk Stratification in Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Dysfunction-Associated Steatohepatitis (“dLCD”) and the draft Billing and Coding Article (Billing and Coding: MolDX: Biomarker Testing for Risk Stratification in Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Dysfunction-Associated Steatohepatitis).

We support both documents and believe that Medicare beneficiaries will be well served by these reasonable and necessary services.

We make one recommendation to MolDX:

We recommend striking the last sentence of Criteria 9 as shown:

9. Molecular and proteomic tests utilizing a similar methodology or evaluating similar analytes as a test for which existing coverage has been established must demonstrate equivalent or superior test performance (i.e., sensitivity and/or specificity) when used for the same indication in the same intended use population. New tests that become available with significantly improved performance may render older tests no longer compliant with this policy

We believe that this sentence is unnecessary. MAC’s have the opportunity and obligation to change LCDs (and coverage for existing tests) through the processes defined in the Program Integrity Manual (“PIM” Chapter 13) which includes notice and comment.

Thank you for your support.

Please see Response 1 regarding Criterion 9.

The following comment was submitted to Palmetto GBA:

MetaSight Diagnostics is writing to offer public comment on MolDX’s Proposed LCD (“MolDX: Biomarker Testing for Risk Stratification in Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Dysfunction-Associated Steatohepatitis”). As the developer of the MASH-Fib™ Liquid Biopsy test for diagnosis and monitoring of metabolic dysfunction-associated steatohepatitis (MASH)-fibrosis, MetaSight strongly supports the Proposed LCD and urges its expeditious finalization.

We respectfully request the following revisions to the Proposed LCD:

1. Revision of the coverage requirement of FIB-4 of at least 1.3 in high-risk patients (Criterion #2).
2. Clarification of evidence expectations for demonstrating clinical utility and performance.

We appreciate MolDX’s review of our recommendations, and encourage you to reach out should you have any questions.

I. Background on the MASH-Fib diagnostic test

The MASH-Fib test is a protein-signature blood-test for diagnosing significant and advanced metabolic dysfunction-associated steatohepatitis (MASH)-fibrosis (see EASL 2023 and AASLD 2024). The test involves measuring the concentration of three novel serum protein biomarkers associated with liver fibrosis and inflammation and combining them into a fibrosis score. It is aimed for patients with high risk of MASH – either based on FIB4>1.3 or clinical risk factor (T2D or multiple features of metabolic syndrome). Clinical utility involves facilitating patient referral to hepatology care and treatment initiation at the earliest stage eligible for approved therapies such as resmetirom and semaglutide. The MASH-Fib test is expected to launch in a United States CLIA lab as an LDT early 2026.

The MASH-Fib test has been validated in six cohorts totaling approximately 2,000 samples, the vast majority with biopsy data as the gold standard comparator, from different geographical locations and diverse clinical settings, including secondary and tertiary hepatology care centers, a therapeutics clinical trial, and a prospective population-scale real-world screening study. The test has demonstrated high diagnostic performance for significant fibrosis (see preliminary results in Garcia et al., AASLD 2023), with an AUC of 0.84 and sensitivity of 62% at 90% specificity; reflecting a PPV of 61-80% with an assumed prevalence of 20-40% (in hepatology care or other clinical settings managing patients at increased metabolic risk for MASH). For advanced fibrosis, the method achieves an AUC of 0.89 and sensitivity 73% at 90% specificity: reflecting a PPV of 45-65% with an assumed prevalence of 10-20%. In head-to-head comparison, MASH- Fib demonstrated statistically significant higher diagnostic performance in significant fibrosis (sensitivity at 90% specificity) than both ELF (p<0.002; n=194) and FibroScan (p<0.0007; n=194). MetaSight plans to reach out to MolDX with these data when they are published.

II. Support Finalization of DL40187 with Technical Modifications

MetaSight appreciates MolDX’s diligent work in developing this Proposed LCD. We strongly support finalization of the policy to establish transparent and rigorous coverage criteria for risk stratification tests for MASH. We agree that the recent FDA approval of Resmetirom and Semaglutide as the first pharmacotherapy for the treatment of adults with MASH with moderate to advanced stages of liver fibrosis (stages F2-F3) make the development of MolDX coverage standards for these tests timely. As MolDX notes, the “clinical utility of accurate stratification for risk of fibrosis has been broadly accepted by the hepatology community, and non-invasive assessment of disease through the use of blood-based testing is increasingly incorporated into best practices.”

MetaSight respectfully requests the following technical modifications and clarifications relative to the Proposed LCD:

A. Revision of Coverage Criteria to Remove FIB-4 “Gatekeeping”

As proposed, Coverage Criterion #2 would require that a “primary risk assessment based on non- molecular/proteomic laboratory testing, as outlined by consensus guidelines, does not indicate low risk [e.g., fibrosis-4 index (FIB-4) ≥ 1.3].” FIB-4 has been useful for ruling out advanced fibrosis (based on the 1.3 cutoff), while its low cost makes it applicable for wide population screening; requiring secondary testing modalities to confirm liver fibrosis, as recommended by AASLD. However, FIB-4 has poor sensitivity in detecting significant fibrosis, and will miss the detection of a substantial fraction of patients with significant fibrosis who are recommended for treatment. For example, Singh et al found that in T2D patients, FIB-4 (with a cutoff of 1.3) misses the detection of ~33% of the patients with significant fibrosis, as determined by vibration- controlled transient elastography (Jasleen Singh 1, 2024). The low sensitivity of FIB-4 is further evident in recent Phase 3 studies for resmiteron and semaglutide, where 50% (Stephen A Harrison 1, 2024) and 34.5% (Arun J. Sanyal, 2025) of the patients had FIB-4 < 1.3, respectively.

Addressing the poor sensitivity of FIB-4, some clinical societies recommend patients with high- risk of liver fibrosis and a FIB-4 < 1.3 to still perform additional assessment of liver fibrosis via either imaging or blood based tests. For example, an AGA Clinical Practice Update (Cusi et al., Clin Gastroenterol Hepatol 2021) recommends that clinicians should consider further assessing patients with FIB-4 < 1.3 but with T2D or ≥ 2 metabolic risk factors, using imaging (FibroScan/VCTE) or blood-based NITs (such as ELF).

We recommend changing Coverage Criterion #2 to enable coverage of testing of high-risk patient groups (e.g. T2D) even in case of FIB4 < 1.3. The MASH-Fib test enables primary risk assessment exactly in such high risk groups. For example, our data shows high performance in detecting significant fibrosis in T2D patients with FIB4 < 1.3, with an AUC of ~0.8. As currently proposed, the requirement that FIB-4 be at least 1.3 risks beneficiary access delays for well- validated testing. If this coverage criterion is finalized, and MolDX subsequently determines that MASH-Fib should be covered for T2D patients with FIB4 < 1.3 based on the clinical evidence, it would need to repeat the entire LCD process via a reconsideration. Modifications to Coverage Criterion #2 to allow for coverage of a test with FIB4 < 1.3 does not obligate MolDX to cover any particular test; rather, the appropriate FIB-4 for an individual test can be adjudicated in the TA process.

B. Clarification of Evidence Expectations to Demonstrate Clinical Utility and Performance

As proposed, Criterion #9 requires that “[m]olecular and proteomic tests utilizing a similar methodology or evaluating similar analytes as a test for which existing coverage has been established must demonstrate equivalent or superior test performance (i.e., sensitivity and/or specificity) when used for the same indication in the same intended use population.” We respectfully request that MolDX clarify how this criterion will apply in practice. MetaSight believes that it is important for laboratories to have transparency as to the minimum performance thresholds that will support coverage as they plan and conduct their studies. We urge MolDX to ensure that this information is available to laboratories and up to date as new tests are approved.

We likewise request MolDX to confirm the evidence expectations for clinical utility under this LCD. It is our understanding that a new test may be covered based on established evidence from assays already recognized in clinical guidelines and reviewed in the LCD (e.g., ELF), provided that the new test independently demonstrates clinical validity at a comparable or superior level for the same indication. We wish to confirm that this is the case and that new clinical utility studies (real world outcomes or otherwise) would not be required unless coverage is sought for an indication not supported by existing clinical utility evidence.

III. Conclusion and Meeting Request

MetaSight strongly supports finalization and appreciates MolDX’s hard work to develop a coverage policy in this important area of diagnostic testing. While we generally believe that the Proposed LCD’s analysis and coverage criteria are appropriate, we respectfully request the above modifications and clarifications in order to ensure that the LCD has the flexibility to accommodate the validated intended uses of new and innovative risk stratification tests for MASH, like our MASH-Fib Liquid Biopsy test. This will avoid unnecessary reconsiderations and beneficiary access delays while allowing reasonableness and necessity to be rigorously adjudicated in the TA process.

MetaSight requests the opportunity to meet with MolDX after the comment period and review our test and evidence to date.

Thank you for your consideration of these comments.

References were provided for review.

Thank you for your support.

Please see Responses 2 and 1 regarding Criteria 2 and 9, respectively.

In general, the establishment of a coverage policy recognizes the CU of a type of testing, and any further requirements are already incorporated into coverage criteria.

The following comment was submitted to Palmetto GBA:

Thank you for the opportunity to review and comment on the MolDX proposed coverage policy for MolDX: MolDX: Biomarker Testing for Risk Stratification in Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Dysfunction-Associated Steatohepatitis. As the world’s largest organization of board-certified pathologists and leading provider of laboratory accreditation and proficiency testing programs, the College of American Pathologists (CAP) serves patients, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide.

The CAP appreciates MolDX’s willingness to cover biomarker testing for assessing the risk of liver fibrosis in the setting of metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH). Our members have reviewed the proposal and given the level of evidence at this time the CAP finds the coverage criteria outlined in the proposed policy to be reasonable.

Thank you for your support.

The following comment was submitted to Palmetto GBA and WPS:

I am writing on behalf of the American Clinical Laboratory Association (ACLA) to provide comments on the draft Local Coverage Determination MolDX: Biomarker Testing for Risk Stratification in Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Dysfunction-Associated Steatohepatitis¹ (“dLCD”). ACLA is the national trade association representing leading laboratories that deliver essential diagnostic health information to patients and providers by advocating for policies that expand access to the highest quality clinical laboratory services, improve patient outcomes, and advance the next generation of personalized care. Many ACLA member laboratories submit claims to Medicare Administrative Contractors (MACs) that follow MolDX policies and have an interest in the program’s coverage determinations and operations.

Overall, ACLA views the dLCD favorably and is supportive of the dLCD. While we appreciate the policy, we recommend one change to provide stability and predictability for laboratories furnishing tests under this policy. For coverage criteria 9, ACLA recommends the following redline edits:

“Molecular and proteomic tests utilizing a similar methodology or evaluating similar analytes as a test for which existing coverage has been established must demonstrate equivalent or superior test performance (i.e., sensitivity and/or specificity) when used for the same indication in the same intended use population.”

If tests become “no longer compliant,” the MAC has an existing process, which involves posting a non- coverage policy notice and soliciting comments from stakeholders, that it should follow. Our suggested edit will ensure that any changes to coverage of older tests will be consistent with the normal timeframe for coverage changes through the LCD development and review process.

Thank you again for the opportunity to provide feedback on the dLCD.

Reference provided for review.

Thank you for your support.

Please see Response 1 regarding Criterion 9.

The following comment was submitted to Palmetto GBA, CGS, Noridian, and WPS:

Siemens Healthineers is pleased to provide comments on the draft Local Coverage Determination (LCD) for Biomarker Testing for Risk Stratification in Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Dysfunction-Associated Steatohepatitis. We appreciate the opportunity to contribute to the review process and commend CMS for its efforts to ensure appropriate and effective use of the Enhanced Liver Fibrosis (ELF™) test in metabolic care.

At Siemens Healthineers, our purpose is to enable healthcare providers to deliver greater value in medical delivery towards expanding precision medicine, transforming care delivery, and improving patient experience, all enabled by digitalizing healthcare. An estimated five million patients globally everyday benefit from our innovative technologies and services in the areas of diagnostic and therapeutic imaging, radiation oncology, laboratory diagnostics and molecular medicine, as well as digital health and enterprise services. We are a leading medical technology company with over 120 years of experience and 18,500 patents globally. With over 73,000 dedicated colleagues in over 70 countries, we continue to innovate and shape the future of healthcare.

We would like to thank CMS for addressing this critical topic and developing policies that support and enable medically necessary care for Medicare beneficiaries. The inclusion of the ELF™ test in this LCD represents a significant step forward in the diagnosis and management of liver fibrosis in the setting of MASLD and MASH. We support the policy as a whole and believe it will greatly benefit patients and healthcare providers alike and support the finalization of the policy.

However, we have one recommendation to further improve the policy and ensure comprehensive patient care.

We recommend that the draft LCD be revised to:

Remove the limitation language “Liver stiffness measurement (LSM) by imaging [e.g., vibration controlled transient elastography (VCTE), magnetic resonance elastography (MRE)] is indeterminate or not performed”

We respectfully request “LSM by imaging is indeterminate or not performed” to be removed from the limitations. Even if an image is successfully obtained, results may vary which can impact patient access to appropriate care and ultimately long-term patient outcomes. Additionally, secondary testing using the ELF™ test may be necessary to validate varying imaging results.

VCTE requires specialized equipment and a highly trained operator, limiting access to only those patients who live near a trained operator (likely at a large hospital or radiology practice). VCTE access is also limited to hepatology and gastroenterology clinics, which see a fraction of the patients suspected of having MASH. It uses ultrasonic technology (with probe selection based principally on the patient’s body mass index (BMI)) to assess a portion of the liver for elasticity, as fibrotic damage produces progressively damaged and “stiff” tissue. When VCTE is accessible and successful, it is a clinically useful and well-validated technology. However, VCTE may have a notable failure or unreliable results rate (~3-20% or higher) and is reportedly impacted by multiple factors including operator experience, probe selection, inflammation, central adiposity, failure to fast, venous pressure, cholestasis, amyloid deposition, and coefficients of variation (CV) in the data acquisition readings that can exceed 30%.^1-9 Inconsistency in results using the same patient have been reported. One study found that back-to-back examinations with FibroScan resulted in a “significant” rate of disagreement for LSM of 18%.⁴ While a well-validated and recommended test, failure to obtain a reliable assessment with VCTE can challenge clinical utility and render unmet need in the targeted testing population.

The ELF™ test is a fully automated immunoassay available at many local, regional, and national testing sites (most notably Quest and LabCorp, which have 4,200 outpatient laboratory draw sites combined).^10,11 The ELF™ test is accessible to any primary care physician or specialist who treats patients suspected of having MASH. In contrast to elastography, the ELF™ test is a biochemical measure of “active fibrosis”, assessing fibrotic activity (extracellular matrix deposition) that can progressively damage the tissue that results in “liver stiffness”. The ELF™ test has fewer reported limitations compared to VCTE. The ELF™ test requires only a routine phlebotomy sample (serum), offering broader access to testing with minimal delays in turn-around time compared to some imaging sites that may book out days or weeks in advance, even when sites are accessible. Additionally, the ELF™ test does not require a patient to fast, is not impacted by a patient’s BMI, and is not subject to interoperability issues.

This modification will enhance patient access to vital diagnostic tools, leading to better clinical outcomes and appropriate use of healthcare resources. As an automated immunoassay, the ELF™ test can readily be scaled for volume testing, unlike imaging with a finite capacity for testing at available locations. For those lacking ready access to VCTE or related elastography, ELF™ testing offers an accessible and perhaps more expedient alternative.

Thank you for considering this request and thank you again for your diligent work on this important policy. We support the finalization of this policy and look forward to the continued advancement of metabolic care through comprehensive and inclusive coverage policies.

References provided for review

Thank you for your support and comment.

The disadvantages of VCTE are acknowledged in the Evaluation of liver fibrosis section of the Summary of Evidence (references 28-32). The original wording of Criterion 3 addresses the accessibility issue by allowing for blood-based testing if VCTE is not performed. However, the syntax has been updated to clarify the intent to preclude blood-based testing in patients who have a recent definitive VCTE result.

The following comment was submitted to Palmetto GBA, CGS, Noridian, and WPS:

On behalf of the Advanced Medical Technology Association (AdvaMed), we appreciate the opportunity to provide comments on the draft Local Coverage Determination (LCD) for Biomarker Testing for Risk Stratification in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction-Associated Steatohepatitis (MASH).

Functioning as an association within AdvaMed, AdvaMedDx is the only multi-faceted, policy organization that deals exclusively with issues facing in vitro diagnostic companies in the United States and abroad. AdvaMedDx member companies produce advanced, in vitro diagnostic tests that facilitate evidence-based medicine, improve quality of patient care, enable early detection of disease and reduce overall health care costs. Our membership includes manufacturers engaged in the development of innovative diagnostic technologies supporting the advancement of public health, helping to deliver cutting-edge care to patients worldwide.

We commend CMS and its contractors for bringing forward this important policy which considers molecular or proteomic biomarker testing for the assessment of risk of liver fibrosis in the setting of MASLD or MASH reasonable and necessary. The recognition of this testing in this LCD is an important step toward improving care pathways for patients at risk of advanced liver fibrosis due to MASLD and MASH. Additionally, we support the inclusion of the Enhanced Liver Fibrosis (ELF™) test (ELF™ test) as part of this LCD and believe that finalization of this coverage policy will ensure Medicare beneficiaries have access to an important diagnostic tool that can significantly impact patient outcomes.

At the same time, we encourage CMS to revise one aspect of the draft LCD in order to better align coverage with real-world clinical practice and to avoid unnecessary barriers to patient access. Specifically, we recommend removal of the limitation language stating:

“Liver stiffness measurement (LSM) by imaging [e.g., vibration controlled transient elastography (VCTE), magnetic resonance elastography (MRE)] is indeterminate or not performed.”

We respectfully request this condition be removed. While elastography technologies such as VCTE can provide valuable clinical information, they face well-documented limitations—including accessibility challenges, operator-dependence, probe selection, and technical failure rates.^{1,2,3,4,5,6,7,8,9} Published data highlight variability in results, sometimes within the same patient, and significant disagreement rates have been reported in repeat measurements. These limitations can result in gaps in care or delays in diagnosis, particularly for patients who lack access to specialty sites equipped with the technology. By contrast, biomarker-based tests for risk stratification offer a broadly accessible, scalable, and efficient option for evaluating patients with suspected MASLD or MASH.

Removing this limitation language will help ensure that patients across geographic and clinical settings can access appropriate biomarker testing, without unnecessary restrictions tied to the availability or reliability of elastography. Doing so will strengthen the LCD’s goal of improving clinical outcomes and ensuring appropriate resource use within the Medicare program.

AdvaMed greatly appreciates your attention to this issue and your ongoing work to ensure Medicare beneficiaries can benefit from the most effective and reliable diagnostic technologies. We strongly support finalization of this policy with the recommended revision and look forward to continued collaboration to advance patient-centered policies for liver disease and beyond.

References were provided for review.

Thank you for your comment.

Please see Response 7 regarding Criterion 3.

The following comment was submitted to Noridian:

We thank you for publishing this draft medical policy proposing limited coverage for testing in patients with clinical suspicion or diagnosis of MASLD or MASH.

The policy in general is a very positive step forward to improve management of patients with liver disease. Guardant has a few comments to assist with clarifying the coverage proposed by this policy.

1. The first is related to the verbiage in coverage criteria and how it interplays with criterion #2. The first criterion states that: “The patient is an adult with clinical suspicion or diagnosis of MASLD or MASH”.

The second requirement goes on to state that the patient has completed a primary risk assessment per guidelines and that assessment “does not indicate low risk”. It would appear that patients who have already undergone guideline recommended risk assessment and do not have a low risk finding, would no longer be classified as only having “clinical suspicion” of disease. We would appreciate clarity on the definition of “clinical suspicion” and the requirements for meeting this definition in order to be covered by this policy.

2. Coverage criterion 5 states that: “Testing is not performed more than once within a 12-month period nor within 12 months following a liver biopsy.” We believe that the first part of the criterion (performing the test only once within 12 months) is reasonable and aligned with current recommendations for identifying patients with liver disease who can benefit from resmetirom.

However, as MolDx rightfully acknowledges, liver biopsies in this setting suffer from sampling errors and pathologist interobserver variability, both of which can contribute to false negative results. Because of these limitations, while it is reasonable not to test patients with a conclusive positive liver biopsy, denying access to the test for patients with liver biopsies that can represent a false negative result, or those with inconclusive biopsies, could delay the identification and appropriate management of high-risk patients.

Therefore, we recommend rewriting this criterion to read: “Testing is not performed more than once within a 12-month period nor within 12 months following a definitive liver biopsy result.” This change enables a patient with high clinical suspicion of advanced fibrosis, but a negative biopsy to have access to testing.

A definitive liver biopsy in this case would be one that clearly shows histopathological evidence of liver fibrosis. Combining this criterion with the 12-month testing period allows patients the best opportunity to be surveilled for this disease.

3. Coverage criterion 6 discusses peer-reviewed literature requirements for Clinical Validity. We agree that this is an important requirement for coverage. What appears unclear is whether this requirement is asking for multiple publications that demonstrate validity across at least 2(?) clinical cohorts. It is unclear why multiple cohorts are required for this use case which has not been the historic standard for MolDx coverage. It is also unclear how multiple, potentially small cohorts that correlate are superior to a single well-designed trial that is appropriately designed with enough power to conclude that the test has clinical validity. We would request review of this requirement to determine if a single study may be sufficient, which would be consistent with the precedent for other LCDs. If it is determined that a single study is not sufficient, what specifically about this use case requires expanded reproducibility across multiple cohorts in order to establish clinical validity?
4. In coverage criterion 9 the final sentence states: “New tests that become available with significantly improved performance may render older tests no longer compliant with this policy.” While we understand that MolDx reserves the right to take into context new technologies and may rescind coverage when appropriate, we would urge thoughtfulness in the timing of removing coverage for services. For instance, if there was a well-established technology on the market for several years, a completion of a technical assessment for the new technology should not rescind coverage for the old technology. There are several reasons that may lead to access to care gaps for patients. The new technology may not be able to immediately commercialize. The new technology may not have the capacity to accommodate the testing volume that is addressed by the current technology, etc.

We would request at a minimum that MolDx privately inform the laboratory/company offering the older test that their technology may be under review for coverage removal and be provided an adequate amount of time to address the perceived deficiencies. We would also request that there is a minimum lead time from notification to removal of coverage for services, if the deficiency is simply a performance difference and not a safety issue. It would seem that a one year time frame would be sufficient, which is similar to the response enabled by establishing a formal non-coverage through the LCD process.

Once again, we applaud this policy and believe that it will significantly help patients with liver disease. We encourage finalizing this policy with the proposed changes and clarifications we proposed above.

Thank you for your feedback.

Criterion 1 has been reworded to clarify that the patient must display appropriate signs and/or symptoms of disease. Testing should not be performed as broad population screening nor in patients with other types of chronic liver disease.

Please see Response 1 regarding Criteria 5 and 9.

Criterion 6 is not intended to imply that multiple publications are required, as the same study may contain multiple cohorts. The language has been revised to clarify an expectation of equivalence across subpopulations.

The following comment was submitted to Noridian:

Quest Diagnostics supports the proposed LCD “MolDX: Biomarker Testing for Risk Stratification in Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Dysfunction-Associated Steatohepatitis.”

Thank you for your support.