atient-centricity has become a focal point in the evolution of clinical trials, emphasizing outcomes meaningful to patients. The challenge lies in balancing rigorous scientific evaluation with incorporating patient experiences and preferences.

Current approaches to evaluating treatment efficacy often fail to capture the complexity of patient needs, particularly in conditions with diverse symptomatic or functional impacts. Conventional statistical analyses typically assess outcomes in isolation, neglecting their interactions and the multidimensional nature of treatment effects. This narrow focus can overlook clinically relevant improvements in symptoms, function, or tolerability, leading to an incomplete understanding of a treatment’s true benefits and risks.

Balancing the demands of scientific rigor with the reality of how patients experience illness is now a central challenge in trial design—one that requires solutions capable of integrating clinical relevance with lived experience. Today, market authorizations for new treatments are based on demonstrating superiority on a single clinical outcome. This paradigm can disregard the constellation of diverse effects a treatment may produce and the multidimensional needs and preferences of patients. As a result, it often fails to capture the complexity of patient experiences and overlooks important interactions and broader implications of treatment effects that matter greatly to those living with illness.

As clinical research moves toward greater patient-centricity, trials must evolve to reflect outcomes genuinely meaningful to those they seek to help.

The Net Treatment Benefit (NTB), a robust statistical measure derived from the Generalized Pairwise Comparisons (GPC) methodology, addresses this challenge. NTB integrates multiple prioritized outcomes into a single, interpretable metric, comprehensively reflecting treatment impacts. By aligning trial designs more closely with patient preferences and clinical realities, NTB enhances clinical relevance, optimizes trial efficiency, and ensures that trials truly reflect patient needs and priorities. Adopting such innovative methodologies will drive the next generation of clinical trials toward greater alignment with patient realities and preferences.

Towards Patient-Centric Clinical Trials

In recent years, regulatory agencies have been increasingly encouraging such approaches. The US Food and Drug Administration (FDA) has underscored the importance of incorporating patient perspectives into the drug development process, notably through its Patient-Focused Drug Development (PFDD) guidance series. The European Medicines Agency (EMA) has similarly called for the integration of patient perspectives in benefit-risk assessments and clinical trial designs. These documents encourage sponsors to systematically capture and integrate patient input when defining clinical outcomes, recognizing that patients may prioritize aspects of treatment beyond traditional clinical endpoints.

However, moving from intention to implementation remains a major challenge. Despite clear guidance, most trials continue to fall back on conventional endpoints, in part because there is no standard method to translate patient preferences into structured, regulatory-grade evidence. Sponsors are often left asking:

• Which outcomes should we prioritize?
• How do we quantify their relevance?
• And how can we analyze them together in a way that remains statistically sound and acceptable to regulators?

Introducing the Net Treatment Benefit

The Net Treatment Benefit (NTB) offers a scientifically grounded and patient-centered way to evaluate treatment effects. Developed over more than a decade of academic research and rooted in the Generalized Pairwise Comparisons (GPC) framework, NTB provides a robust and validated alternative to single-endpoint analyses. It allows multiple outcomes—of any type, including efficacy, safety, and patient-reported measures—to be integrated into a single, interpretable hierarchical composite endpoint.

Rather than analyzing outcomes marginally, NTB considers them jointly, respecting both their clinical importance and the order in which they matter. This makes it particularly well suited for trials that aim to reflect patient preferences and experiences. It is both statistically rigorous and adaptable to the complexity of modern clinical research.

Applications in Cardiovascular and Rare Disease and Regulatory Considerations

The practicality and real-world relevance of the Net Treatment Benefit have been demonstrated across several therapeutic areas, most notably in oncology, cardiovascular disease, and rare disorders, three settings where conventional approaches often fall short.

In the cardiovascular domain, NTB played a pivotal role in the approval of two treatments for transthyretin amyloid cardiomyopathy, a progressive and life-threatening condition. In both of these phase 3 trials, the NTB methodology was used as the prespecified primary analysis, prioritizing survival over hospitalization. This allowed the trials to more effectively capture the composite clinical benefit of treatment—not just prolonging life, but reducing the frequency of hospital stays, which are highly relevant to patients and healthcare systems alike. Importantly, numerous trial designs incorporating this methodology are now widely accepted by regulators, establishing NTB as a standard approach that meets evidentiary requirements for market authorization while providing a more patient-relevant assessment of treatment effects. Reflecting this growing acceptance, a search of the NIH-affiliated website ClinicalTrials.gov in May 2025 identified 24 phase 3 industry-sponsored trials in cardiometabolic diseases and obesity that employed the methodology for their primary endpoint.

Similarly, in the rare disease space, NTB has offered important insights where traditional methods have fallen short. For example, in Pompe disease—a progressive neuromuscular disorder—the phase 3 COMET trial originally failed to meet its primary endpoint using a conventional, single-outcome analysis focused on forced vital capacity. However, a subsequent GPC-based analysis, which integrated additional functional outcomes such as the six-minute walk test, revealed a statistically significant advantage for the experimental therapy. This reanalysis captured a broader picture of benefit, better aligned with patient experiences and expectations. In rare diseases, where trials are often constrained by small sample sizes and symptom heterogeneity, NTB provides a valuable way to maximize information gained from each participant while highlighting clinically meaningful effects.

Together, these examples illustrate how NTB can strengthen the case for therapeutic benefit by offering a more complete, patient-centered assessment—one that is not only methodologically sound but also compatible with regulatory expectations.

From Principles to Practice

As clinical research embraces patient-centricity, trial methodologies must evolve to meet the moment. Relying on univariate primary endpoints is no longer sufficient in a landscape where patients demand, and regulators support, a fuller picture of the benefits and risks of treatment. The NTB can offer a statistically robust, flexible, patient-aligned solution—one capable of integrating what matters most to patients into a single, interpretable assessment.

With case studies in different therapeutic areas, including cardiovascular and rare diseases, and demonstrated acceptability by regulators, NTB moves beyond theory into practical impact. It not only strengthens the scientific integrity of trials but also ensures that the evidence generated is truly reflective of patient priorities.

Realizing the full potential of NTB requires active collaboration across stakeholders to determine which clinical outcomes should be prioritized and incorporated into the primary endpoint. Patients, investigators, and clinicians should be engaged as early as possible to capture the preferences of this diverse group of stakeholders. Embracing this shift toward patient-centered outcome prioritization can offer sponsors a strategic advantage, while regulators and HTA bodies can play a key role by clarifying how such composite endpoints will be evaluated, supporting broader adoption in clinical development. Finally, sponsors must embrace this shift—not just as a compliance obligation but as a strategic advantage. Trials designed with NTB can be faster, leaner, and more aligned with payer expectations, increasing the likelihood of both regulatory success and patient impact.

As the expectations of patients, regulators, and health systems evolve, so must our tools. Methodologies like NTB represent a necessary step forward—transforming patient-centricity from a guiding principle into a measurable standard in clinical trial design.