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The Importance of Early Participation of Liver Patients in Clinical Trial Design

Liver diseases—such as non-alcoholic steatohepatitis (NASH), hepatitis, cirrhosis, and hepatocellular carcinoma (HCC)—pose significant challenges to drug development, with clinical trials often struggling to translate scientific promise into patient benefit. The complexity of liver pathology, patient variability, and trial design hurdles, exemplified by the MAESTRO-NASH trial for Rezdiffra (resmetirom), highlight a critical need: early participation of liver patients in trial design. Engaging patients from the outset, as of March 2025, is increasingly recognized as vital to crafting trials that are feasible, patient-centered, and aligned with real-world needs, ultimately improving outcomes for millions affected by liver disease.

Understanding Liver Disease Trial Challenges

Liver diseases are biologically intricate, involving steatosis, inflammation, fibrosis, and malignancy, often progressing silently over years. The MAESTRO-NASH trial, which led to Rezdiffra’s 2024 FDA approval for NASH with F2-F3 fibrosis, tackled this by targeting dual histological endpoints—NASH resolution and fibrosis improvement—via biopsies at baseline and week 52. Yet, this complexity strained trial design, requiring large cohorts and long timelines. Patient heterogeneity—genetic factors (e.g., PNPLA3), comorbidities (e.g., diabetes), and lifestyle—further complicated recruitment, as seen in the trial’s slow enrollment of biopsy-confirmed cases. Diagnostic reliance on invasive biopsies, despite supplementary non-invasive tests (NITs) like MRI-PDFF and FibroScan, added burden, while endpoint debates (surrogates vs. hard outcomes) and high placebo responses (14.2% fibrosis improvement) muddied efficacy signals. These challenges, common across liver trials, underscore why patient input is essential from the start.

Enhancing Trial Relevance Through Patient Perspectives

Early patient participation ensures trials address outcomes that matter most to those affected. Liver disease patients, particularly in NASH or early cirrhosis, often prioritize quality of life—fatigue, abdominal discomfort, or metabolic health—over histological markers like fibrosis stage, which dominated MAESTRO-NASH’s endpoints. Involving patients during design could shift focus to patient-reported outcomes (PROs), such as symptom relief or functional capacity, alongside biopsies or NITs. For instance, resmetirom’s fat reduction (70% of 100 mg patients via MRI-PDFF) might resonate more if patients helped define “meaningful improvement” beyond pathologist scores, aligning trials with lived experiences and increasing participant buy-in.

Improving Recruitment and Retention

Recruitment woes plague liver trials due to slow disease progression and strict criteria, as MAESTRO-NASH’s biopsy requirement illustrated. Patients can identify barriers—fear of invasive procedures, travel burdens, or distrust of research—and suggest solutions. Early input might have prompted greater emphasis on NITs (e.g., ELF test, FibroScan) during screening, reducing biopsy reliance and broadening eligibility. Patients could also advocate for decentralized trial elements—home monitoring or telehealth—easing participation, especially for rural or underserved groups with high hepatitis or ALD prevalence. Retention improves when patients co-design protocols, ensuring visit schedules or follow-ups (e.g., MAESTRO-NASH’s 52-week biopsy) are tolerable, reducing dropout rates that inflate costs and timelines.

Refining Diagnostic Approaches

Diagnostics are a bottleneck in liver trials, with biopsies’ invasiveness clashing with NITs’ evolving reliability. MAESTRO-NASH used both—biopsies for primary endpoints (e.g., 29.9% NASH resolution in 100 mg arm) and NITs like MRI-PDFF as secondary measures—reflecting a transitional phase. Patients involved early could weigh in on this balance, voicing preferences for less invasive methods. For example, discomfort with repeat biopsies might have accelerated NIT validation, aligning with the FDA’s post-approval shift to NIT-based Rezdiffra use. Patient feedback could also refine NIT selection—favoring accessible tools like FibroScan over costly MRE—ensuring trials mirror clinical practice and reduce site variability, a logistical challenge in multicenter studies.

Optimizing Endpoint Selection

Endpoint choice—surrogate (e.g., fibrosis improvement) versus hard outcomes (e.g., survival)—is contentious, as MAESTRO-NASH’s accelerated approval with ongoing confirmatory trials shows. Patients can bridge this gap by defining meaningful endpoints. While regulators favored histological proof (25.9% fibrosis improvement in 100 mg arm), patients might prioritize preventing decompensation or reducing HCC risk, outcomes requiring longer trials but resonating with their fears. Early dialogue could blend PROs with biomarkers—e.g., fatigue scores alongside ELF reductions—creating composite endpoints that satisfy both science and patient needs, potentially lowering placebo effects (14.2% in MAESTRO-NASH) by focusing on tangible benefits.

Addressing Ethical and Practical Control Arm Issues

Placebo arms, as in MAESTRO-NASH, raise ethical questions when diseases progress, yet active comparators increase complexity. Patients can guide this ethically fraught area. In NASH, where no prior therapy existed, placebo was feasible, but patients might have pushed for crossover designs—switching to resmetirom after 52 weeks—reducing untreated time. Their input could also mitigate lifestyle-driven placebo responses by co-designing standardized diet/exercise counseling, ensuring fair efficacy comparisons. For hepatitis or HCC trials with existing treatments, patients could advocate for pragmatic designs, testing new drugs against standards in ways that feel equitable and relevant.

Meeting Regulatory and Real-World Needs

Regulatory demands—e.g., MAESTRO-NASH’s biopsy-driven approval and post-market studies—often diverge from patient realities. Early participation aligns trials with both. Patients might have foreseen the FDA’s eventual NIT reliance for Rezdiffra, pushing for earlier NIT-focused endpoints, streamlining approval. They can also highlight safety concerns—e.g., resmetirom’s mild side effects (diarrhea)—ensuring monitoring reflects their tolerance, not just regulators’. This bridges trials to practice, as seen in NASH’s shift from biopsy-centric research to NIT-based care, a transition patients could accelerate.

Reducing Logistical and Economic Burdens

Liver trials like MAESTRO-NASH face logistical strains—multicenter coordination, biopsy costs, and NIT equipment variability. Patients can propose cost-effective tweaks, like home-based NITs (e.g., portable ultrasound) or fewer in-person visits, lowering expenses that deter small biotechs (e.g., 89bio, Akero) from late-stage trials. Their insights into daily burdens—travel, time off work—could optimize site selection or virtual engagement, stretching budgets and democratizing access, especially in resource-poor regions with high liver disease rates.

Fostering Trust and Collaboration

Beyond logistics, early patient involvement builds trust, crucial in liver disease communities wary of research due to historical inequities or invasive procedures. Co-designing MAESTRO-NASH might have eased biopsy fears through education or consent processes shaped by patients, boosting participation. This collaboration—via patient advisory boards or focus groups—ensures trials like those for FGF21 analogs (pegozafermin, efruxifermin) reflect diverse voices, enhancing credibility and uptake post-approval.

Conclusion

The Rezdiffra experience in MAESTRO-NASH underscores liver trial challenges—complexity, recruitment, diagnostics, endpoints—that early patient participation can address. As of March 2025, involving liver patients from the design phase ensures trials are relevant, feasible, and ethical, aligning scientific rigor with human needs. By refining recruitment, diagnostics, and endpoints, patients help bridge research to practice, as seen in NASH’s NIT evolution. With liver disease’s rising toll, their early voice is not just valuable—it’s indispensable to unlocking effective treatments.