Health utility adjusted survival: A composite endpoint for clinical trial designs

Many randomized trials have used overall survival as the primary endpoint for establishing non-inferiority of one treatment compared to another. However, if a treatment is non-inferior to another treatment in terms of overall survival, clinicians may be interested in further exploring which treatment results in better health utility scores for patients. Examining health utility in a secondary analysis is feasible, however, since health utility is not the primary endpoint, it is usually not considered in the sample size calculation, hence the power to detect a difference of health utility is not guaranteed. Furthermore, often the premise of non-inferiority trials is to test the assumption that an intervention provides superior quality of life or toxicity profile without compromising survival when compared to the existing standard. Based on this consideration, it may be beneficial to consider both survival and utility when designing a trial. There have been methods that can combine survival and quality of life into a single measure, but they either have strong restrictions or lack theoretical frameworks. In this manuscript, we propose a method called health utility adjusted survival, which can combine survival outcome and longitudinal utility measures for treatment comparison. We propose an innovative statistical framework as well as procedures to conduct power analysis and sample size calculation. By comprehensive simulation studies involving summary statistics from the PET-NECK trial, we demonstrate that our new approach can achieve superior power performance using relatively small sample sizes, and our composite endpoint can be considered as an alternative to overall survival in future clinical trial design and analysis where both survival and health utility are of interest.