Rare disease clinical trials face a confluence of challenges: limited patient populations, heterogeneity in disease progression, and often a lack of established outcome measures. Yet the stakes involved are exceptionally high. For the over 300 million people living with a rare disease worldwide, most of whom lack access to effective therapies, each trial represents a vital opportunity – not just to generate evidence, but to shape treatments that meaningfully improve the patients’ lives.

Traditional clinical trial designs, typically focusing on a single primary endpoint, are often ill-suited for this complex task. They frequently simplify the multidimensional reality of how patients, caregivers, and clinicians define meaningful treatment benefit into a single dimension. For instance, a therapy may slow disease progression but negatively impact quality of life; it may show modest improvement in the main endpoint yet substantially improve fine motor functions or reduce intolerable side effects. In rare diseases, where patient numbers are limited and the burden of participation is high, trials must do more than test hypotheses – they must produce data that reflects what matters most to those affected.

The Net Treatment Benefit (NTB) emerges as a patient-centric, statistically rigorous approach that allows for the prioritisation and integration of multiple outcomes into a single, interpretable measure of treatment effects.2 When coupled with early engagement from patients, investigators, and key experts to define outcome hierarchies, NTB offers a practical path to trials that are both more efficient and more aligned with real-world needs.