Every MASH trial protocol sitting in a sponsor’s document management system right now carries the same assumption baked into its eligibility criteria: biopsy-confirmed diagnosis at baseline. The LITMUS prospective multicentre diagnostic accuracy study, published in The Lancet, just put a number on how much of that assumption was costing sponsors, patients, and the field. Single non-invasive markers, FIB-4 and APRI included, showed variable and limited diagnostic performance against histology for detecting at-risk MASH. Multimarker proteomic panels showed strong diagnostic performance. That gap between single markers and proteomic panels is the signal clinical operations leaders need to act on now.
Biopsy-gated enrollment is not a scientific preference. At this point, it is institutional inertia dressed up as rigor.
What the LITMUS Signal Actually Means
The LITMUS programme, the Liver Investigation: Testing Marker Utility in Steatohepatitis study, was built as a prospective, multicentre diagnostic accuracy study designed to validate non-invasive tests against histology in metabolic dysfunction-associated steatotic liver disease. The results confirm what hepatologists have suspected for years, but now with the evidentiary weight that regulators require: no single biomarker reaches the accuracy threshold necessary to replace biopsy outright, but a proteomic panel combination does. That distinction carries direct operational consequences for sponsors designing MASH trials today.
The old assumption was that non-invasive tests could serve as enrichment tools at most, useful for screening populations before the biopsy confirmed eligibility. The LITMUS data changes that framing. Proteomic panels, by aggregating multiple molecular signals simultaneously, resolve the specificity limitations that have historically disqualified single-marker approaches from primary diagnostic roles. Sponsors who continue designing protocols around biopsy-only baseline confirmation are not being rigorous. They are leaving a validated alternative on the table while their recruitment timelines lengthen and their screen failure rates compound.
The regulatory environment is moving, but not fast enough to match the science. On August 27, 2025, the FDA accepted a Letter of Intent to qualify Liver Stiffness Measurement by Vibration-Controlled Transient Elastography as a reasonably likely surrogate endpoint for trials in non-cirrhotic MASH with moderate-to-advanced fibrosis. That acceptance confirms the agency’s willingness to move beyond biopsy as the sole evidentiary anchor, but it covers one imaging modality, not the proteomic panel architecture the LITMUS data now supports. The gap between what FDA has formally accepted and what the LITMUS results demonstrate is where sponsors are operating blind.
Who Gets Disrupted First
The therapeutic areas most immediately affected are those running Phase II and Phase III trials in non-cirrhotic MASH with fibrosis staging as a primary or key secondary endpoint. These trials depend on histological fibrosis scores at baseline and follow-up, and biopsy procedures drive both screen failure rates and patient dropout. Protocols requiring two biopsies, one for eligibility and one for endpoint assessment, face compounded burden. LITMUS-validated proteomic panels inserted at the screening stage could reduce screen failures dramatically by identifying at-risk patients earlier and with less procedural attrition.
The EASL-EASD-EASO Clinical Practice Guidelines published in the Journal of Hepatology in 2024 already endorsed non-invasive tools for initial risk stratification in MASLD management, but stopped short of recommending them as primary eligibility determinants in interventional trials. The LITMUS proteomic panel data gives guideline bodies the prospective accuracy evidence they cited as the missing link. An EASL guideline update incorporating this data would provide sponsors with the scientific consensus document they need to justify protocol amendments to FDA reviewers who flag departures from biopsy-confirmed eligibility.
The cost dimension is not marginal. The RADIcAL-1 multinational randomized trial, published in 2025, found that multiparametric MRI for MASLD diagnosis carried an Incremental Cost-Effectiveness Ratio of approximately 4,929 euros per QALY gained, demonstrating that non-invasive imaging is cost-effective even when upfront procedural costs exceed those of standard care. Proteomic panels with the diagnostic specificity documented by LITMUS would likely perform at least as favorably given that blood-based proteomics carry lower procedural overhead than imaging. For sponsors running 400-patient Phase IIb trials with 30% screen failure rates attributable to biopsy ineligibility, the arithmetic on switching to proteomic-led enrollment is not subtle.
The Directive for Clinical Ops Leaders
If your MASH protocol currently requires biopsy-confirmed diagnosis as the sole eligibility gateway and you are in the design or amendment phase, the LITMUS proteomic panel data now constitutes prospective multicentre diagnostic accuracy evidence sufficient to justify a non-invasive testing strategy in a pre-IND or Type B meeting submission. The practical move is to request an expedited Type B meeting with FDA’s Division of Hepatology and Nutrition to propose a proteomic panel-led eligibility determination with biopsy confirmation reserved for a confirmatory subset rather than all enrollees. The FDA’s August 2025 acceptance of elastography as a surrogate endpoint signals the agency’s receptiveness to the underlying principle. Sponsors who bring the LITMUS data into those meetings with a clearly defined analytical validation plan will have a stronger negotiating position than those waiting for a formal guidance update that may not arrive before their enrollment windows close.
The next signal to watch arrives from two directions simultaneously. FDA’s formal response to the elastography surrogate endpoint qualification, expected to generate a full biomarker qualification review, will establish the evidentiary standard against which proteomic panel submissions get measured. Watch whether the agency’s review framework accommodates multi-analyte blood-based panels or defaults to imaging-centric metrics. In parallel, any EASL guideline revision incorporating the LITMUS prospective data will serve as the scientific consensus document that anchors the regulatory argument. The sponsor that files the first NDA supported by proteomic-panel-confirmed enrollment data rather than universal biopsy will force that conversation whether the guidance is ready or not.
References
- The Lancet, “Non-invasive tests in metabolic dysfunction-associated steatotic liver disease: the LITMUS prospective multicentre diagnostic accuracy study”
- FDA CDER, “FDA Accepts Proposal for Reasonably Likely Surrogate Endpoint in MASH” (August 27, 2025)
- Frontiers in Medicine, EASL-EASD-EASO Clinical Practice Guidelines on MASLD Management (2024)
- BioSpace, “New Multinational Study Shows MRI Is Cost-Effective in the Diagnosis and Management of Steatotic Liver Disease” (RADIcAL-1 study)
- CLP Magazine, “LITMUS Studies Validate Noninvasive MASLD/MASH Biomarker Tests”
Moe Alsumidaie, MBA, MSF, is founder and Chief Editor of Vanguard Publications, which publishes Clinical Trial Vanguard, Pharma Vanguard and BullScope, and Head of Research at CliniBiz. He has two decades in clinical trial operations and data science, with earlier roles at Genentech, Abbott Vascular and Stanford University Medical Center, and is a guest lecturer in clinical trial sciences at Rutgers University.
