Including comparative observational evidence in trial-level surrogate endpoint evaluation: assessing relapse-free survival as a surrogate endpoint for overall survival in patients with acute myeloid leukemia post-transplant.

OBJECTIVES: Overall survival (OS) is the gold standard outcome for the assessment of treatment benefits in oncology trials. However, OS requires lengthy patient follow-up and can be confounded by competing risks. This study aims to assess the validity of relapse-free survival (RFS) as a trial-level surrogate end point for OS in acute myeloid leukemia (AML) and develop novel methods to combine data from randomized controlled trials (RCTs) and comparative observational evidence (COE) studies.

STUDY DESIGN AND SETTING: A systematic review was conducted to identify RCTs and COE studies reporting treatment effects on both RFS and OS in adult patients with AML receiving posthematopoietic stem-cell transplant (HSCT) maintenance therapy. Bayesian meta-analytic models were used to evaluate the RFS-OS surrogate relationship, and statistical methods were developed to enable information sharing, in both adaptive and user-specified manners, between RCTs and COE studies.

RESULTS: Six RCTs and 14 COE studies were identified. Analysis of RCT data resulted in a weaker surrogate relationship, with parameters obtained with considerable uncertainty. Borrowing strength from COE studies, in both an adaptive and a user-controlled fashion, resulted in a stronger RFS-OS surrogate relationship with more precise parameters, and adaptive information-sharing models did not suggest any prior-data conflict between the RCTs and COE studies.

CONCLUSION: We present evidence for a potential RFS-OS surrogate relationship in patients with AML post-HSCT. Our novel methodology for borrowing information from COE studies reduced uncertainty in this surrogate relationship, alleviating the issue of a limited RCT evidence base.