1. Home
  2. Insights
  3. Blog
  4. Are non-invasive tests bridging the biopsy gap for MASH patients?

Are non-invasive tests bridging the biopsy gap for MASH patients?

Biopsies are the gold standard for MASH clinical trials. But what about in clinical practice? 

A typical MASH patient pathway is often far less biopsy-driven than the clinical trial pathway. Many patients are risk-stratified and monitored through blood-based tests, FibroScan or other imaging, and specialist assessment. Some patients may know their fibrosis risk category while others may still be moving between primary care, endocrinology and hepatology before a formal diagnosis is established. As the disease progresses, they may be referred for a clinical trial. It’s a chance to access a newer therapy, contribute to research, and potentially benefit from closer clinical oversight. 

And the first requirement is a liver biopsy. 

For a patient who has never needed one, who has managed without one, this is a major ask. It is the moment the research pathway and the care pathway diverge—and for a significant number of patients, it is the moment they walk away. This is the biopsy gap, the growing divide between how MASH is diagnosed and managed in clinical practice and how it is studied in clinical trials. 

This expanding gap is also a development bottleneck that introduces operational complexity, limited scalability and additional hurdles for trial participants. Understanding it is essential not just to improving trial efficiency, but to ensuring that the patients who bear the greatest burden of this disease are the ones research is actually designed to serve.

One disease, two worlds

Only a small percentage of MASH patients in the United States have ever had a liver biopsy. One large academic health-system study found biopsy documentation in just 3.3% of patients with a NASH/MASH diagnosis (478 of 14,403 patients) while a broader U.S. EMR analysis reported biopsy rates of only 1–5% among patients at risk of NASH (n = 167,560).1
 
In routine practice, patients are commonly risk-stratified and monitored using non-invasive tests, including blood-based scores such as FIB-4, liver stiffness measurement by VCTE/FibroScan, ELF testing, and composite algorithms. These tools are familiar, accessible and increasingly trusted across clinical practice. Clinicians use them to initiate treatment, monitor progression and adjust care.

In clinical trials, however, biopsy remains the standard requirement for enrolment in pivotal MASH studies. This reflects the long-standing reliance on histology in liver disease drug development, where biopsy has been used to confirm steatohepatitis, establish fibrosis stage and assess treatment effect against accepted regulatory endpoints. Even as approved therapies are now prescribed without biopsy confirmation, trials for the next generation of treatments still ask patients to undergo an invasive procedure their own doctor has not required. This can be jarring for patients, forcing them to weigh the burden of participation against the potential outcomes. For many with MASH and its host of concomitant diseases, the risk-benefit doesn’t balance.

According to ICON clinical experts’ firsthand experience, 40-50% of patients decline to enter MASH trials specifically because of the biopsy requirement. The mismatch between what patients experience in care and what they are asked to accept in research is a major barrier to participation. 

The personal cost of the MASH biopsy gap

The screen failure rates in biopsy-gated MASH trials are among the highest in clinical development. Rates of 70-80% are common and inter-reader variability means that some participants are retrospectively made ineligible during the central re-read.

Biopsies are invasive procedures, a large needle is inserted into the liver, causing mild-to-severe pain in 84% of people who must then be observed for complications or adverse reactions.2 Though the complication rate is low, it is still a risk the participant must willingly shoulder. To take the risk and undergo a biopsy, and then be disqualified, is a hard reality for so many MASH patients.

Patients who screen out after biopsy do not simply disappear from the equation. They carry an experience of clinical research that may make them less willing to participate in the future. At a time when the MASH trial landscape is expanding rapidly, that erosion of patient trust has long-term consequences for the entire field.

Selection bias at the biopsy gate

Among the millions living with MASH globally, only a small fraction is ever screened for trials, and of those, 70-80% will not qualify based partly on the requirement for histologically confirmed steatohepatitis with a defined activity threshold, commonly described in protocols using NAS or comparable MASH histologic activity criteria, and fibrosis stage F2 or greater.3 But between the broad MASH population and the patients who ultimately enrol, there is a subtler problem of selection bias.

Those who make it through biopsy-gated enrolment are not necessarily a representative sample. Biopsy-gated trial populations may be enriched for patients with more advanced or specialist-managed disease, greater motivation to access treatment, or closer proximity to centres capable of running biopsy-based programs. Some have joined trials specifically to access treatment they cannot otherwise obtain. Others may be more geographically advantaged, simply located nearer to specialist centres capable of running biopsy programs.

The widening gap between the majority of the MASH population and the clinical trial populations—those willing and able to accept an invasive procedure as a cover charge for trial entry—may effectively skew the evidence base. In turn, the tested therapy may not produce the same outcomes for those to whom it is prescribed in the real world. Patients, it is important to note, that do not have to undergo a biopsy to be prescribed said therapy. 

NITs as the bridge between MASH care and research

Non-invasive tests (NITs) are proliferating on both sides of the gap, in clinical practice and in clinical trials, and are becoming part of the infrastructure for how modern MASH trials are designed and delivered. They offer a way for the trial experience to meet participants closer to where clinical care already finds them.

Importantly, NITs enable earlier identification of likely eligible patients, reduce unnecessary biopsies and support repeatable longitudinal measurement. With them, the field is generating the evidence needed to support long-term regulatory evolution, while recognising that full replacement of biopsy for pivotal efficacy assessment remains an evolving area that requires robust validation, clear context-of-use definitions and linkage to clinically meaningful outcomes.

In practical trial design, NITs are being deployed in two complementary ways: 

  1. As pre-screening instruments including blood-based markers and imaging tools identify likely-eligible patients before biopsy are considered, reducing the number of patients who undergo an invasive procedure unnecessarily. 
  2. As longitudinal monitoring tools collecting data in parallel with biopsy data to build the evidence base for future regulatory acceptance of NIT-based endpoints. In some settings, targeted biopsy confirmation may still be required, but smarter sequencing can reduce patient burden while preserving scientific and regulatory integrity. 

Together, these approaches create a pathway toward trials that function more like the clinical practice patients already navigate.

Trials incorporating NIT-led pre-screening consistently show lower screen failure rates and lower dropout. ICON's clinical teams work directly with sponsors to design and execute NIT-integrated screening strategies across global, multi-site trials. That includes site qualification for FibroScan and MRI-based assessments, harmonisation of data collection protocols across regions with uneven access to imaging infrastructure, and alignment of biomarker panels with regulatory expectations at each phase of development.

Integrating NITs and data management platforms into a protocol thoughtfully can support operational scalability, standardised imaging acquisition, central quality control, harmonised biomarker collection, reduced unnecessary biopsies and a better participant journey.

Closing the gap for patient-centred studies

Although regulation is unlikely to change in the near-term, the direction toward NITs is clear. As evidence supporting NITs grows, regulators are increasingly open to their role not only in screening but in endpoint development. And they are already making moves: in August 2025, the FDA accepted Echosens' Letter of Intent to qualify liver stiffness measurement by vibration-controlled transient elastography (VCTE) as a reasonably likely surrogate endpoint for MASH trials in adults with non-cirrhotic moderate-to-advanced fibrosis.4 In the FDA's own words, moving away from biopsy requirements could help with trial recruitment, enable representative patient populations, and accelerate drug development.

NITs are gaining momentum, but momentum alone will not close the gap. Continued effort to design protocol around NITs, improving tool selection and sequencing, and building operational infrastructure that can scale a NIT-led environment will keep the wheels turning.

Individuals with MASH have every reason to weigh the burden of participation against its uncertain benefit. Making more accessible trials with the right non-invasive tools generating the right evidence can close the distance for better MASH therapies for patients in the real world. 


Connect with us to learn more about designing and supporting patient-centred MASH studies.

Contact us

References

  1. lagan-Ying YC, Xu J, Lim JK, Do A. Low real-world eligibility rates for nonalcoholic steatohepatitis patients for phase 3 clinical trial criteria application in a large academic health system. Eur J Gastroenterol Hepatol. 2021;33(3):424-429. doi:10.1097/MEG.0000000000001758.
  2. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD. Liver biopsy. Hepatology. 2009;49(3):1017-1044. doi:10.1002/hep.22742
  3. Fichez J, Mouillot T, Vonghia L, Costentin C, Moreau C, Roux M, et al. Non-invasive tests for fibrotic MASH for reducing screen failure in therapeutic trials. JHEP Rep. 2025;7(4):101351. doi:10.1016/j.jhepr.2025.101351
  4. US Food and Drug Administration. FDA accepts proposal for reasonably likely surrogate endpoint for ‘MASH’ all-cause mortality or liver-related events. Published August 27, 2025. Accessed May 22, 2026. https://www.fda.gov/drugs/drug-safety-and-availability/fda-accepts-proposal-reasonably-likely-surrogate-endpoint-mash-all-cause-mortality-or-liver-related
In this section

Connect with us