American Association for Cancer Research
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Supplementary Data from Design and Evaluation of an External Control Arm Using Prior Clinical Trials and Real-World Data

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posted on 2023-03-31, 21:29 authored by Steffen Ventz, Albert Lai, Timothy F. Cloughesy, Patrick Y. Wen, Lorenzo Trippa, Brian M. Alexander

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ARTICLE ABSTRACT

We discuss designs and interpretable metrics of bias and statistical efficiency of “externally controlled” trials (ECT) and compare ECT performance to randomized and single-arm designs. We specify an ECT design that leverages information from real-world data (RWD) and prior clinical trials to reduce bias associated with interstudy variations of the enrolled populations. We then used a collection of clinical studies in glioblastoma (GBM) and RWD from patients treated with the current standard of care to evaluate ECTs. Validation is based on a “leave one out” scheme, with iterative selection of a single-arm from one of the studies, for which we estimate treatment effects using the remaining studies as external control. This produces interpretable and robust estimates on ECT bias and type I errors. We developed a model-free approach to evaluate ECTs based on collections of clinical trials and RWD. For GBM, we verified that inflated false positive error rates of standard single-arm trials can be considerably reduced (up to 30%) by using external control data. The use of ECT designs in GBM, with adjustments for the clinical profiles of the enrolled patients, should be preferred to single-arm studies with fixed efficacy thresholds extracted from published results on the current standard of care.

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