Clinical Researcher—April 2026 (Volume 40, Issue 2)
PRESCRIPTIONS FOR BUSINESS
Rudradev Sengupta, MS, PhD
For many early-career clinical researchers, trial design can feel rigid. A primary endpoint is selected, the study is powered around it, and success is determined by that single measure. But patients do not experience treatment effects through one outcome. They experience a combination of efficacy, side effects, symptoms, and quality of life. Reducing this to a single outcome can risk missing the bigger picture. A more patient-centered approach, when integrated into trial design, might help to better capture this complexity, particularly from Phase II onward when key development decisions are made.
Moving beyond single outcome starts with how trials are designed. A single measure of efficacy is typically considered the most important outcome and determines success or failure. Other outcomes are collected but often have limited influence on conclusions. This can create a disconnect between what the study aims to show and what patients really experience.
One treatment may improve efficacy but come with meaningful toxicity, while another may offer similar efficacy with better tolerability or quality of life. These differences matter to patients but are not always reflected in traditional analyses.
A patient-centric trial begins during the design of the trial. Instead of asking what the single best outcome is, a more relevant question is: What combination of outcomes reflects how patients judge benefit? This leads to multidimensional endpoints, where several outcomes are considered together.
Designing these endpoints requires prioritization. There is usually one measure of efficacy in a traditional primary endpoint that is considered the most important outcome, but what follows depends on the population. Some patients may prioritize other efficacy outcomes whereas others may value minimizing severe side effects or a better quality of life.
Patients, clinicians, investigators, and patient advocates can all contribute to defining which outcomes matter the most and in what order. This prioritization becomes central to how treatment benefit is evaluated.
Understanding Net Treatment Benefit
The Net Treatment Benefit (NTB) framework provides a practical way to analyze these multidimensional endpoints. It compares all possible pairs of patients taken from the treatment and the control group across a prioritized list of outcomes. Each comparison starts with the most important outcome. If one patient does better, the comparison stops. If not, it moves to the next outcome. This continues until a patient pair is classified or all outcomes are considered.
This process is repeated across all possible patient pairs. For example, with 10 patients in each group, 100 pairwise comparisons are performed. The result is a single metric that reflects how often patients on the new treatment do better overall, considering all prioritized outcomes. The key idea is simple: NTB allows for capturing trade-offs between benefits and risks in a way that mirrors real clinical decision-making.
This links directly to the concept of “totality of the evidence.” Trials collect large amounts of clinically meaningful data, but much of it is underused when only one endpoint drives the analysis.
The NTB approach integrates multiple outcomes into a single assessment of treatment benefit. For patients, this better reflects real experience. For sponsors, it improves the ability to detect meaningful effects, which is particularly important in Phase II, where decisions are critical for future development. For researchers, it provides a clearer and more complete understanding of treatment impact.
From Phase II onward, this approach supports better decision-making. Early trials often involve small sample sizes and difficult choices around dose selection or progression to Phase III. Evaluating multiple prioritized outcomes provides a more balanced view of benefit and risk, reducing the chance of advancing ineffective treatments or stopping promising ones too early.
By Phase III, this framework creates continuity. The same prioritized outcomes can be carried forward—either as the primary endpoint or as a key secondary endpoint—ensuring consistency from early development through to confirmatory trials.
Far-Reaching Impacts of NTB
The impacts of NTB extend beyond clinical development. Regulators are increasingly focused on benefit-risk assessment and patient-relevant outcomes. A multidimensional approach supported by NTB offers a structured way to present this information.
Health technology assessment bodies and payers also require evidence of value beyond efficacy. This includes quality of life, safety, and broader impact on healthcare systems. By summarizing multiple outcomes into a single measure, NTB aligns well with these expectations and strengthens the overall evidence package.
Examples from cardiovascular research show that this approach is already established. In transthyretin amyloid cardiomyopathy, treatment benefit has been assessed by prioritizing survival followed by hospitalization, reflecting outcomes that matter the most to patients and clinicians. This type of analysis has already been used to support regulatory decision-making and demonstrate the value of integrating multiple endpoints into a single framework.{1,2}
A similar approach is valuable in more complex populations. In elderly patients with rectal cancer, treatment decisions often involve balancing efficacy with tolerability and quality of life. A single endpoint does not capture these trade-offs. Evaluating outcomes such as survival, disease progression, and severe toxicity together provides a more realistic assessment of treatment benefit. This has been applied in trials designed for older rectal cancer patients, where maintaining quality of life could be considered by the patients as important as extending survival.{3}
Conclusion
For those starting in clinical research, the takeaway is straightforward. Trial design is not just about selecting a statistically acceptable endpoint; it is about generating evidence that reflects how treatments are experienced and valued in real life.
Multidimensional endpoints and NTB offer a practical way to do this. They allow patient preferences to be incorporated, make better use of collected data, and create a consistent strategy from Phase II through approval and market access. This approach does not complicate trials unnecessarily; it makes them more relevant, more informative, and better aligned with the needs of patients and the broader healthcare system.
References
- Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, … Rapezzi C. 2018. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. New England Journal of Medicine 379(11):1007–16.
- Gillmore JD, Judge DP, Cappelli F, Fontana M, Garcia-Pavia P, Gibbs S, … Fox JC. 2024. Efficacy and safety of acoramidis in transthyretin amyloid cardiomyopathy. New England Journal of Medicine390(2):132–42.
- Saúde-Conde R, Vandamme T, De Backer M, Martinive P, Covas A, Deleporte A, … Sclafani F. 2024. Efficacy and safety of short-course radiotherapy versus total neoadjuvant therapy in older rectal cancer patients: a randomised pragmatic trial (SHAPERS). ESMO gastrointestinal oncology 4:100067.
Rudradev Sengupta, MS, PhD, Senior Trial Design Lead at One2Treat in Belgium, is an accomplished biostatistician with more than a decade of experience in the pharmaceutical industry. He specializes in translating complex biostatistical data into actionable healthcare insights, with expertise in statistical modeling, advanced analytics, and computing. At One2Treat, he leverages his expertise to design patient-centric clinical trials, ensuring that innovative treatments are developed with the utmost precision and relevance. He is also committed to academic excellence, teaching, and mentoring the next generation of biostatisticians at UHasselt.
