Commentary Contributed by Tom Mann, One2Treat 

April 25, 2025 | Pharmaceutical companies and regulators are increasingly aligning around the need to better incorporate patient preferences into clinical trial design. This shift stems from a broader movement to measure whether treatments are efficacious on terms that are also valuable from the patient’s perspective. 

Recent regulatory initiatives are accelerating this transformation. The FDA’s Project Optimus, for example, is challenging the paradigm of testing oncology drugs at the maximum tolerated dose. Instead, it encourages companies to optimize doses based on both efficacy and tolerability, a clear signal that regulators are placing more emphasis on patient quality of life.  

These changes reflect a fundamental truth: patients have diverse needs and may consider different factors than usual when defining what makes a treatment better. They care about how well it works, how tolerable it is, and how it impacts their daily lives. Designing trials to capture these priorities will not only improve the real-world relevance of trial results but could also accelerate regulatory approvals and market adoption. 

What is the Net Treatment Benefit? 

The Net Treatment Benefit (NTB) offers a powerful way to align clinical trial analysis with patient priorities. It is an estimator of treatment effects derived from the Generalized Pairwise Comparisons (GPC) statistical methodology, which has been supported through numerous peer-reviewed publications over the past 20 years. 

At its core, NTB works by forming pairs between each patient in the treatment group and every patient in the control group. Each pair is then compared across multiple prioritized outcomes, ranked hierarchically according to their clinical importance. For example, a trial could prioritize overall survival first, followed by quality of life, and finally side effects. 

The NTB is simply the net difference between the probability that a patient in the treatment group has a better outcome than a patient in the control group, and the probability of the opposite occurring. This allows NTB to integrate multiple outcomes into a single metric, reflecting both efficacy and safety in one comprehensive measure. 

Unlike traditional clinical trial design that typically selects one primary outcome, the NTB can be used to create a multi-dimensional primary endpoint that offers a more holistic view of treatment effects—an endpoint that aligns with how patients and clinicians experience treatments in the real world. 

Demonstrate the Full Value of a Treatment Leveraging the Totality of the Evidence 

Traditional clinical trials generate enormous amounts of data across multiple endpoints—yet most of that data can remain unused when the analysis focuses on a single primary outcome. This underutilization is especially frustrating given that many of these secondary outcomes are highly relevant to patients. 

By leveraging information from all clinically meaningful outcomes, the NTB can improve the statistical power of clinical trials. This means that trials can potentially achieve the same level of confidence with fewer patients—a significant advantage in making trials more efficient and cost-effective. 

In the rare disease domain, a post-hoc analysis of the randomized, double-blind, phase 3 COMET trial, prioritizing the primary (forced vital capacity) and secondary outcome (6MWT), provided evidence of efficacy of avalglucosidase alfa therapy (n = 51) over alglucosidase alfa (n = 49) in Pompe disease, while the original analysis failed to significantly show superiority of treatment on the primary endpoint.  

The methodology is widely used in other therapeutic areas and has been successfully included in regulatory submissions. Notably, it was used as the primary analysis in the phase 3 ATTR-ACT trial, where the analysis prioritized time to death over time to hospitalization. Results demonstrated the efficacy of tafamidis (n = 264) over placebo (n = 177) and led to the drug approval for patients with transthyretin amyloid cardiomyopathy. 

Putting Patients in the Driver’s Seat 

One of the most exciting aspects of the NTB is its potential to incorporate patient preferences directly into trial design. 

Different stakeholders in clinical research often have different priorities. Clinicians may prioritize survival outcomes, while patients might place equal weight on quality of life or side effect management. NTB makes it possible to tailor endpoint hierarchies to reflect what matters most to patients—either by engaging patient advocacy groups or even by giving individual patients a direct voice in shaping trial endpoints. 

Beyond scientific rigor, NTB also offers strategic advantages for market access and reimbursement. Payers are increasingly demanding comprehensive benefit-risk assessments that demonstrate not just efficacy but real-world value. 

By generating a single, multidimensional estimate of treatment benefit, NTB can help sponsors align their evidence packages with payer expectations. This approach makes trial data more compelling, particularly when NTB hierarchies are designed in collaboration with patients, clinicians, and payers from the outset. 

Early planning will be crucial to unlock these benefits. Sponsors who engage all stakeholders upfront and embed NTB into their clinical development strategies will be better positioned for regulatory approvals, faster market access, and wider adoption by clinicians. 

Conclusion 

The Net Treatment Benefit (NTB) represents a paradigm shift in clinical trial design—one that could redefine how treatment effects are estimated, particularly in patient-focused clinical research. By integrating multiple outcomes into a single, comprehensive measure, NTB aligns trial analysis with the way patients and clinicians experience treatments in the real world. 

As regulatory agencies push for more holistic assessments of treatment effects, NTB has the potential to make trials smaller, faster, and more relevant to patients. However, the true transformation will come from sponsors who embed patient insights into trial design from the earliest phases, reshaping endpoints to reflect what truly matters to the people who stand to benefit from new treatments. 

By combining innovative statistical methods with patient-focused thinking, NTB-based trial designs will not only improve how treatments are evaluated. They will help ensure that the therapies of tomorrow deliver real, tangible benefits to patients. 

Tom Mann is the Clinical Solutions Engagement Lead at One2Treat. He brings over 15 years of experience in tech start-ups and scale-ups, where he played a pivotal role in driving customer engagement, marketing initiatives, and strategic partnerships. At One2Treat, Tom's expertise and fresh perspective are invaluable as we continue to develop solutions that integrate key patient-relevant outcomes into a single holistic treatment assessment. With a strong background in SaaS companies, Tom has a deep understanding of customer needs. His ability to translate those needs into actionable solutions will be essential in expanding One2Treat’s reach and impact within the clinical research landscape. At the same time, he ensures that our approach remains both innovative and patient-focused. He can be reached out at tom.mann@one2treat.com.