Design and Evaluation of an External Control Arm Using Prior Clinical Trials and Real-World Data

Clin Cancer Res. 2019 Aug 15;25(16):4993-5001. doi: 10.1158/1078-0432.CCR-19-0820. Epub 2019 Jun 7.


Purpose: 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.

Experimental design: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Clinical Trials as Topic*
  • Humans
  • Models, Theoretical
  • Prognosis
  • Proportional Hazards Models
  • Randomized Controlled Trials as Topic
  • Research Design*
  • Treatment Outcome