Creating a synthetic control arm from previous clinical trials: Application to establishing early end points as indicators of overall survival in acute myeloid leukemia (AML).

Abstract

7021 Background: Clinical trials of experimental drugs require controls. Concurrently randomized controls are the gold standard for judging drug effect. Historical controls are not ideal but are much more efficient and economical. Historical controls derived from a single clinical trial have the biases of that trial. Using many trials with comparable end points and eligibility minimizes such bias. Medidata’s archive contains >3000 trials with clinical data rights for deidentified aggregated analyses. We used this resource to develop a synthetic control arm (SCA) for a particular phase I/II single-arm trial in AML. We demonstrate the utility of this approach by addressing a different but equally important issue: establishing early end points as predictors of long term clinical outcomes. Methods: We built an SCA from 7 relapsed/refractory AML trials completed in last 5 yrs. They had similar eligibility criteria as a particular phase I/II trial for an investigational agent. We selected subjects for the SCA who had baseline covariates matching the subjects in the tri.al. Data cleaning and standardization ensured consistency of data fields. The primary outcomes were CR (complete remission) and CRi (CR without hematologic recovery) at 56 days, and overall survival (OS) subsequent to 56 days. Non-CR/non-CRi deaths before 56 days were set to OS=0. We used a landmark analysis to correlate CR and CRi with OS, calculating the hazard ratio (HR) of OS of CR and CRi vs its comparison group. Results: The SCA included 340 subjects (median age 63 yrs, 55% male, 77% White Non-Hispanic, 28% ECOG 0). Results are in this table. Conclusions: The Medidata trial archive is a resource for creating SCAs. The example SCA we created identified well-defined subjects for whom a CR or CRi is associated with longer OS. Investigations of SCAs for other drugs could aid in addressing the types of subjects and drug categories for which CR or CR/CRi predict longer OS. Such information can help build more efficient and more informative adaptive clinical trials. [Table: see text]