Adaptive-TMLE for the average treatment effect based on randomized controlled trial augmented with real-world data

Abstract We consider the problem of estimating the average treatment effect (ATE) when both randomized control trial (RCT) data and external real-world data (RWD) are available. We decompose the ATE estimand as the difference between a pooled-ATE estimand that integrates RCT and RWD and a bias estimand that captures the conditional effect of RCT enrollment on the outcome. We introduce an adaptive targeted maximum likelihood estimation (A-TMLE) framework to estimate them. We prove that the A-TMLE estimator is n $\sqrt{n}$ -consistent and asymptotically normal. Moreover, in finite sample, it achieves the super-efficiency one would obtain had one known the oracle model for the conditional effect of the RCT enrollment on the outcome. Consequently, the smaller and more parsimonious the working model of the bias induced by the RWD is, the greater our estimator’s efficiency, while our estimator will always be at least as efficient as an efficient estimator that uses the RCT data only. A-TMLE outperforms existing methods in simulations by having smaller mean-squared-error and 95 % confidence intervals. We apply A-TMLE to augment the DEVOTE trial with external data from the Optum Clinformatics Data Mart, demonstrating its potential to establish treatment superiority in noninferiority trials. A-TMLE could utilize external RWD to help improve the power of randomized trials without biasing the estimates of intervention effects. This approach could allow for smaller, faster trials, decreasing the time until patients can receive effective treatments.