Single-arm trials are an important study design for evaluating drug efficacy and safety without enrolling patients into a control arm. Although they do not provide the gold-standard evidence of randomized controlled trials, they are increasingly used in clinical development as they offer an efficient, ethical, and practical alternative. A wide variety of approaches can be used to construct control comparators and estimate treatment effects, from fixed comparators informed by clinical knowledge to data-based and model-based patient-level comparators, also known as synthetic controls. Powerful and flexible machine learning models can allow outcome-model-based synthetic controls to overcome key limitations of direct data-based approaches, yield more robust estimates of treatment effects, and provide a principled way to incorporate corrections or encode additional assumptions when external data are not directly comparable. In this work, we argue that outcome-model-based synthetic control arms are an important tool for single-arm trials. We focus on digital twins, personalized predictions of disease progression generated from machine learning models trained on historical datasets, which naturally leverage these flexible approaches. We review doubly robust estimators, present power and sample size formulas, and discuss trade-offs in selecting historical data for training and analysis. We also outline practical considerations for deploying digital twins within the framework of recent FDA draft guidance on the use of artificial intelligence in drug development. Finally, we reanalyze data from trials in amyotrophic lateral sclerosis and Huntington's disease to demonstrate the proposed methods.

The doubly robust (DR) estimator, which consists of two nuisance parameters, the conditional mean outcome and the logging policy (the probability of choosing an action), is crucial in causal inference. This paper proposes a DR estimator for dependent samples obtained from adaptive experiments. To obtain an asymptotically normal semiparametric estimator from dependent samples with non-Donsker nuisance estimators, we propose adaptive-fitting as a variant of sample-splitting. We also report an empirical paradox that our proposed DR estimator tends to show better performances compared to other estimators utilizing the true logging policy. While a similar phenomenon is known for estimators with i.i.d.

As the amount of data increases, the question arises as to how best to deal with the large datasets. While computational platforms such as Spark [28] and Ray [23] help process large datasets once a desired model is chosen, simply using smaller data can be a faster solution for exploratory data modeling, rapid prototyping, or other tasks where the accuracy obtainable from the full dataset is notneeded.

Suppose an online platform wants to compare a treatment and control policy, e.g.,