Digital Twins as Synthetic Controls in Single-Arm Trials
Authors: Daniele Bertolini, Franklin Fuller, Aaron M. Smith, Jonathan R. Walsh, Run Zhuang
Abstract
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 We also outline practical considerations for deploying digital twins within the framework of recent FDA draft guidance on the use of artificial intelligence in drug development.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.
Single-arm trials accelerate study timelines by reducing the number of patients that must be recruited for a concurrent control group. However, these designs require an alternative comparator to estimate treatment effects. One approach is to construct a virtual control arm using a machine learning (ML) model trained on external control data to predict the counterfactual outcomes of the treatment arm. Our aim in this study was to leverage virtual controls by developing and evaluating ML-based counterfactual outcome models trained on IFX-treated patients to predict 1-year steroid-free clinical remission (SFCR ) and a composite of C-reactive protein remission plus steroid-free clinical remission (CRP-SFCR) for ADA-treated pediatric Crohn's disease patients, and to compare the resulting IFX-versus-ADA treatment effect estimates with those obtained using propensity score matching to external controls. Five ML models were used to train counterfactual models on the observed IFX cohort data. The resulting models were used to predict the counterfactual outcomes for the ADA arm patients. LGBM yields the best OR closest to the propensity score matched reference, and all 95% CI results align with the conclusion from the reference study that no statistical difference in the primary and secondary outcomes has been observed between the patients treated with ADA or IFX. Our study supports virtual controls as a viable and effective substitute for expensive, lengthy or unethical patient recruitment in an inflammatory bowel disease (IBD) trial. The developed gradient boosted prediction model can be used as a pretrained model to generate IFX counterfactual predictions in future studies, pending external validation and assessment of transportability.
LLM-based digital twins promise to reduce repeated human data collection by generating person- specific responses, yet existing evaluations provide little evidence about whether they can reduce human measurement while preserving valid inference. To address this, we introduce statistical substitutability, an inferential criterion that evaluates the extent to which twin predictions can reduce human measurement for a particular estimand while preserving valid inference. We develop a framework, grounded in mixed-subject and prediction-powered inference, that evaluates statistical substitutability along four dimensions: aggregate fidelity, paired respondent-level signal, finite-sample human-label recovery, and stability across populations. Across two empirical evaluations spanning behavioral experiments, multiple models, and alternative respondent representations, we find that digital twins can reproduce average human effects while providing little information about which individuals differ from those averages. Newer models and richer respondent information improve some dimensions of performance but do not reliably translate into human-data savings. Human calibration can reduce aggregate prediction error, yet limited labeled samples often fail to produce stable precision gains. Importantly, these findings demonstrate that behavioral fidelity is neither necessary nor sufficient for statistical substitutability. More broadly, they suggest that AI-generated evidence should be evaluated based on its ability to support valid scientific inference rather than its ability to reproduce human outcomes alone. Digital twins should therefore be judged for confirmatory use by whether they reduce uncertainty about human quantities, not merely by whether they reproduce human means, distributions, or effects.
Mobile-health interventions increasingly use online learning and decision making algorithms to personalize when to nudge users toward healthier behavior, but a poorly designed algorithm can burden and disengage participants. New algorithm design decisions should therefore be vetted against realistic simulated users before each real-life deployment. We propose a method to develop ``JITAI-Twins'': digital twins of a target subpopulation for comparing candidate online algorithms before a just-in-time adaptive intervention (JITAI) deployment. The method builds on a conditional time-series diffusion model that is temporally consistent (future actions do not affect the generated past), and it supports repeated updating from three sources of information, in three steps: pre-training on a large observational dataset, fine-tuning on small prior intervention deployments in related populations, and inference-time calibration to the next target population from domain-scientist expertise. We validate the twin at each pre-deployment stage of the long-running HeartSteps series (v2 through v4) of physical-activity suggestion intervention deployments, treating each successive deployment as an upcoming study. The proposed method reproduces the target subpopulation's temporal and between-participant structure better than simpler simulators. These results suggest that our twin can be used to simulate a target deployment before it runs, the prerequisite for testing and informing online algorithm design decisions.