The Estimand Framework had Implications in Time to Patient-Reported Outcomes Deterioration Analyses in Cancer Clinical Trials.
Cottone F., Efficace F., Cella D., Aaronson NK., Giesinger JM., Bachet J-B., Louvet C., Charton E., Collins GS., Anota A.
OBJECTIVES: To apply the estimand framework in time to deterioration (TTD) analysis of patient-reported outcomes (PROs), and identify the appropriate statistical methods to deal with intercurrent event (IEs) such as death. STUDY DESIGN AND SETTING: Data from phase II randomized trial were used. We estimated TTD using EORTC QLQ-C30 questionnaire with death as the IE, by applying Kaplan-Meier (KM) estimator and Cox proportional hazards (PH) model. The Fine-Gray approach was explored, accounting for death as a competing risk. The estimands targeted by the aforementioned methods were defined. RESULTS: We analyzed data of 64 patients with available questionnaire at baseline. The most notable differences in TTD estimates were observed for deterioration in physical functioning: the hazard ratios were 0.44 [95%CI 0.22-0.90] and 0.62 [95%CI 0.36-1.07] by either ignoring death (31 events) or considering it as deterioration (58 events), respectively (Cox-PH model). When considering death as a competing event (Fine-Gray model), the sub-HR was 0.51 [95%CI 0.26-1.01]. CONCLUSION: Depending on the proportion and distribution of deaths occurring before deterioration between arms, the Fine-Gray competing risks model should be considered rather than KM estimator and Cox PH model to reflect the patient's experience of the disease and treatment burden.