Three strategies to accelerate MASH trials in a competitive, rapidly shifting market

The global prevalence of metabolic-associated steatotic liver disease (MASLD) is reported to be 38% of all adults, with 3 to 5% experiencing severe, progressive disease known as metabolic-associated steatohepatitis (MASH)¹.  Although MASH is primarily a liver disease, its connection to metabolic abnormalities links it to several cardiovascular, metabolic, gastrointestinal, and endocrine comorbidities. MASH is increasing, reflecting the global rise in obesity, and is now among the leading causes of cirrhosis, hepatocellular carcinoma, and liver transplantation worldwide.² 

MASH is a complex disease where fat silently builds up in the liver, leading to inflammation and damage that often go unnoticed until it becomes advanced. Primary care physicians typically only address MASH when liver enzymes are persistently high, possibly missing asymptomatic patients with significant fibrosis. They often lack the time and resources to explain the disease process, manage referrals, or perform costly screening tests.

The MASH care pathway has shifted from observation to intervention

Two newly approved treatments, along with emerging non-invasive diagnostics (instead of liver biopsies), have prompted a shift from passive observation to active intervention in managing MASH. The FDA and EMA approved Rezdiffra (resmetirom), a thyroid hormone receptor-beta (THR-beta) agonist, in 2024 and 2025, respectively, and Wegovy (semaglutide), a glucagon-like peptide-1 (GLP-1) receptor agonist, in 2025 and 2026. Physicians can now focus on liver health, weight loss, or both for their patients. GLP-1 agonists, second- and third-generation dual/triple agonists, FGF21 analogs, and other new modalities are at the forefront of a rapid rise in MASH R&D and clinical trials.

However, operationalizing MASH clinical trials has become increasingly complex. The widespread testing of GLP-1s for diabetes and obesity has intensified competition for patients and changed the standard of care. Pivotal MASH trials routinely excluded patients on GLP-1s in the past; now, it is less feasible to do so. While GLP-1s are effective at managing the broad metabolic drivers of MASH, targeted therapies remain essential to directly address and reverse fibrosis progression.

At Parexel, we’ve found that three strategies are critical to conducting efficient MASH clinical trials in a crowded, competitive, and rapidly evolving therapeutic, regulatory, and commercial landscape.

1. Combat high screen failure rates with innovative approaches

Screen failure rates in MASH trials are reported in the 40% to 80% range and create significant bottlenecks to recruitment. Failures are often due to stringent criteria for fibrosis and metabolic markers. At Parexel, site selection for MASH trials follows a highly detailed, structured process to identify sites best positioned to deliver these complex studies. Our approach evaluates not only the availability of all required infrastructure and access to invasive and non‑invasive testing, as well as imaging technologies essential for patient identification and screening, but also confirmed staff expertise, availability, and operational capacity to support intensive screening, enrollment, and follow‑up activities. Recognizing that even experienced sites may face variability in equipment readiness, training needs, or throughput constraints, we implement proactive risk mitigation early through readiness checklists, targeted training, vendor and equipment qualification, pre‑activation process walkthroughs, and real‑time screening oversight—to minimize avoidable screen failures, rework, and delays.

We recently worked on a large international Phase 3 study for patients with moderate MASH.  The trial used MRI‑based proton density fat fraction (MRI‑PDFF) assessments and vibration‑controlled transient elastography (VCTE) to evaluate hepatic steatosis and stiffness. Although non‑invasive, these modalities required specialized equipment and trained personnel. To ensure operational readiness before site activation, we collaborated very early with qualified imaging vendors to support the implementation of MRI‑PDFF and FibroScan, and we established a streamlined process for direct image transfer to the central reader. Centralized eligibility review based on these assessments improved data consistency, reduced avoidable screen failures, and supported more efficient patient enrollment.

We have also explored innovative recruitment strategies that implement a "pre-screening" filter through free on-site screenings and professional counseling. We can identify patients with the correct fibrosis levels by deploying portable FibroScan devices at community-based "open-door" events to provide immediate, non-invasive liver stiffness measurements. Trained technicians and nurses screen "all comers" from high-risk groups—such as those with Type 2 Diabetes or obesity—filtering for the specific liver stiffness scores required by the trial’s inclusion criteria. By coupling these real-time results with on-site medical counseling, staff can instantly assess a patient's physiological suitability, explain the clinical significance of their fibrosis level, and transition eligible candidates into the formal screening funnel, effectively "pre-qualifying" the patient population before they ever reach the high-cost diagnostic phase of the trial.

This approach not only targets underserved and high-prevalence demographics (such as Hispanic and South Asian communities) to improve enrollment diversity but also utilizes a tiered site strategy—integrating primary research sites, local referral networks, and mobile units—to ensure that only candidates with a high probability of meeting inclusion criteria are advanced to the clinical trial.

2. Retain patients with flexible trial designs and strong science

For sponsors conducting MASH trials, enrollment competition is intensified by the fact that early-stage disease is frequently asymptomatic and therefore underdiagnosed. As a result, many patients with obesity, type 2 diabetes, and related cardiometabolic risk—who may also have unrecognized MASH remain eligible for larger, less restrictive obesity and cardiovascular trials, which can divert potential participants from dedicated MASH studies that require intensive screening and specialized assessments. With two FDA-approved therapies now available for MASH with moderate-to-advanced fibrosis, and a rapidly expanding trial landscape in MASH and adjacent indications, sponsors must adopt more targeted identification, referral, and pre-screening strategies to access the right patients and minimize avoidable screen failures.

First, sponsors must reduce the burdens of participating in trials. Frequent site visits, inflexible schedules, and excessive secondary endpoints conflict with patients’ lives. 

Recently, we worked on a complex MASH study that included multiple dose groups and cohorts with mandatory treatment gaps. The protocol’s assessment schedule included 18 site visits, multiple overnight stays, frequent lab draws, fasting periods, and lengthy appointments. Patients were allowed a one-day window for visit dates. To combat these challenges, we developed a “Window Allowance Tool” to give patients more flexibility and ensured travel reimbursement and patient (and caregiver) stipends to ease the burden.

Mobile phlebotomy and decentralized home health visits can reduce travel requirements, especially for patients living farther from the research centers. For example, we recently analyzed a sponsor’s Phase 2 MASH protocol and identified four relatively low-intensity site visits. To make them more convenient for patients, we proposed providing telehealth visits or phone calls as options. 

In our experience, patient engagement is strengthened when participants and their caregivers are supported in understanding the underlying science of the disease, as well as the potential benefits and considerations associated with available treatment options. Providing clear, balanced information empowers patients to make informed decisions and can positively influence long-term study participation. 

Sponsors play an important role in this process by offering educational materials written in clear, non‑technical language that explain the investigational drug’s mechanism of action, potential risks and benefits, and the natural progression of MASH.  At Parexel, we create study branding to ensure each MASH trial has a unique and recognizable profile that distinguishes it from competing trials. We create patient‑ and caregiver‑focused materials, including study brochures and patient letters, acknowledging the important role caregivers often play in supporting patient engagement and ongoing participation in clinical research.
In longer Phase 3 trials that include a placebo arm, proactive strategies to support patient retention are particularly important, as some participants may question their treatment assignment over time. Trial-specific educational materials can help reinforce understanding that individual experiences vary and that treatment responses and side effects are not uniform across participants. In parallel, patient‑centered support measures, such as access to counseling, reimbursement for travel expenses, fair‑market‑value stipends aligned with visit burden, and optional wellness resources, can help reduce participation burden and support sustained engagement throughout the study. 

Site engagement and support are also crucial to retaining patients. At Parexel, we are continually expanding our network of sites eligible to enroll in MASH studies. The Parexel Site Alliance – Emerging Site Program is a development pathway within Parexel’s broader Site Alliance Program designed to identify, mentor, and operationally support newer or community‑based research sites that have strong patient access and investigator motivation but limited prior clinical trial experience. By expanding our site infrastructure for MASH trials, we avoid the major centers that are saturated with competing trials and reach new patient populations.

3. Anticipate the regulatory evolution of MASH endpoints

Liver biopsy remains the gold-standard endpoint for pivotal MASH trials. However, MASH clinical research is increasingly adopting AI‑assisted pathology to address variability in histologic assessment, alongside a gradual shift toward non‑invasive assessments to reduce patient burden. In August of 2025, the FDA accepted a Letter of Intent for the qualification of a biomarker (“Liver Stiffness Measurement by Vibration-Controlled Transient Elastography”) as a surrogate endpoint for MASH all-cause mortality or liver-related events. A few months later, in December, the agency qualified the first AI drug development tool to help pathologists assess MASH disease activity in clinical trials. The EMA had earlier qualified the tool in March of 2025. 

Sponsors and regulators must ultimately resolve the current endpoint dilemma of biopsies versus NITs. The mandatory liver biopsy remains the most significant deterrent for patients and one of the causes of high screen-failure rates. The ongoing push is for the regulators to accept NITs as primary surrogates to bypass the subjectivity of biopsy-based tests. One possible solution to limit patient burden is to organize a sequential screening strategy in which patients first undergo FIB-4 blood testing, then VCTE or MRI-PDFF, and only then proceed to biopsy.

Sponsors must develop MASH assets while being aware of how regulatory standards and tools may evolve over the next five to ten years. For example, the safety bar for poly-metabolic patients includes addressing regulatory concerns regarding how new products interact with the current "standard trio" of GLP-1s, SGLT2 inhibitors, and statins. At Parexel, we advise sponsors to think broadly and strategically about their development programs and how recent FDA changes could affect their plans.

MASH sponsors face rising logistical friction from biopsy-heavy protocols and a primary care awareness gap that often leaves high-risk patients undiagnosed. Success in 2026 and beyond requires a move away from overly complex protocols and a return to patient-centric trust-building, meticulous site selection and training, and an adaptive regulatory strategy.
 

Resources

1. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Mechanisms, Clinical Implications, and Therapeutic Advances, Endocrinology, Diabetes & Metabolism (November 19, 2025).
2. Non-invasive tests for fibrotic MASH for reducing screen failure in therapeutic trials, JHEP Reports (February 4, 2025).
    

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