Drawing on the experience and perspectives of Prof. Dr. Manuel Castro Cabezas, Scientific Officer at P95 Julius Clinical, and Prof. Dr. Diederick (Rick) E. Grobbee, Chief Scientific Officer at P95 Julius Clinical, this article explores how sponsors and CROs can address the operational challenges that continue to undermine MASH clinical trials.

MASH drug development has never been more promising. Yet despite advances in disease understanding, biomarkers, and therapeutic innovation, sponsors continue to face a difficult reality: demonstrating efficacy in MASH remains extraordinarily challenging.

Recent research suggests that MASH therapeutic trials experience screen failure rates of 70-80%, highlighting the significant operational burden associated with identifying eligible patients and generating reliable efficacy signals.

Yet not every trial setback is driven by biology alone. Many of the factors that undermine MASH studies emerge long before the primary endpoint is assessed. They originate in patient identification, screening strategy, site execution, and the complex interaction between lifestyle change and disease progression. As Prof. Dr. Castro Cabezas explains, “The success of a MASH trial depends on many factors. Not only the study design and the type of compound that has been chosen, but also patient selection.”

For sponsors, this presents an opportunity. While no CRO can influence the mechanism of an investigational therapy, the right partner can help address several of the operational risks that frequently threaten trial success.

MASH Is Not a Uniform Disease

One of the greatest challenges in MASH research is patient heterogeneity. Patients who meet similar eligibility criteria may have very different disease trajectories, metabolic profiles, and responses to intervention. Some are on a path toward progressive fibrosis. Others may achieve significant improvements through weight loss or lifestyle modification alone.

That variability creates risk. If patient populations are not carefully characterized during recruitment and screening, sponsors may struggle to demonstrate meaningful treatment effects, even when investigating a promising therapy.

This is why patient selection must be viewed as more than a recruitment exercise. It is a scientific and operational strategy designed to ensure that the right patients enter the study at the right time.

The Lifestyle Effect

Perhaps one of the most underappreciated challenges in MASH trials is the impact of lifestyle change. Unlike many therapeutic areas, MASH outcomes can be substantially influenced by dietary improvements, weight loss, increased physical activity, and greater healthcare engagement. Patients entering a clinical trial often become more attentive to their health simply by virtue of participation.

The result is a challenge that sponsors know well: placebo groups may improve. As Prof. Dr. Castro Cabezas observed during discussions on MASH trial design, “This is not a patient that you would have wanted to have in your clinical trial because you know that lifestyle intervention will almost start immediately when people participate in such trials.”

For CROs, this highlights the importance of helping sponsors understand enrollment populations, establish consistent patient-management approaches, and reduce unnecessary variability wherever possible.

Screening Strategy Matters

The traditional view of screening is straightforward: determine whether a patient meets the protocol’s eligibility criteria.

In MASH, however, screening is about far more than inclusion and exclusion criteria. The screening process plays a critical role in determining the overall quality of the study population and, ultimately, the likelihood of demonstrating a treatment effect. The choice of screening tools, referral pathways, site selection strategy, and patient qualification process can all influence trial efficiency and data quality.

Prof. Dr. Castro Cabezas has raised important questions about how commonly used screening pathways perform in certain high-risk populations, particularly patients with type 2 diabetes. While these tools remain valuable in clinical practice, sponsors must continually assess whether their recruitment and screening strategies are identifying patients who are truly representative of the intended study population.

This is where experienced CROs can add strategic value. Beyond supporting recruitment, CROs can help sponsors evaluate the performance of non-invasive screening approaches, implement more targeted patient-identification pathways, optimize site selection, and identify potential enrollment bottlenecks before they become costly timeline risks.

The stakes are significant. Every unnecessary screen failure consumes site resources, increases patient burden, extends recruitment timelines, and adds to overall study costs. In a competitive development environment, even modest delays can have meaningful financial implications. Effective patient qualification strategies are therefore not simply operational improvements; they are an essential component of trial risk management.

Standardization Protects Data Quality

MASH trials are operationally complex. Imaging assessments, FibroScan measurements, pathology reviews, laboratory testing, and clinical evaluations may occur across dozens or hundreds of sites spanning multiple countries. Even small differences in execution can influence study outcomes.

Consistent training, centralized oversight, quality control, and standardized procedures are essential for reducing variability and ensuring that site performance supports the scientific objectives of the trial.

While these activities often occur behind the scenes, they directly influence the reliability of study results.

Awareness Remains Part of the Challenge

Another theme emphasized by both Prof. Dr. Castro Cabezas and Prof. Dr. Grobbee is the continued need for greater disease awareness. Many patients remain undiagnosed despite having clear risk factors such as obesity, type 2 diabetes, hypertension, or metabolic syndrome. At the same time, screening practices vary considerably across healthcare systems.

Low disease awareness creates a downstream challenge for clinical development. Patients cannot be referred to research studies if they remain undiagnosed, and sites cannot recruit from populations they are unable to identify. For sponsors, awareness gaps ultimately translate into slower enrollment and increased recruitment costs.

As Prof. Dr. Grobbee has noted, improving the pathways that connect healthcare providers, patients, and research networks remains an important step toward identifying eligible patients earlier.

For CROs, this means viewing recruitment as part of a broader ecosystem rather than an isolated activity.

A CRO’s Role Is No Longer Just Execution

The most successful MASH trials are rarely defined by a single factor. They are the product of hundreds of decisions involving site selection, patient identification, screening, qualification, training, oversight, and study execution.

Sponsors still need innovative therapies. But innovative therapies alone are not enough. As Prof. Dr. Castro Cabezas summarized, “You need a great compound. Then you need to very closely select the right patients using a very strict protocol.”

That second challenge is where CROs can have their greatest impact.

By helping sponsors improve patient qualification, reduce screen failures, strengthen screening pathways, standardize study execution, and mitigate operational risk, CROs play an increasingly important role in determining whether promising therapies ultimately achieve their potential.

In MASH, every screen failure, enrollment delay, and source of variability introduces risk to a development program. The right CRO partner can help sponsors identify and mitigate those risks before they become costly setbacks. In an increasingly competitive landscape, that can make the difference between a promising therapy that reaches patients and one that never gets the chance.