TY - JOUR
T1 - Design and evaluation of an external control arm using prior clinical trials and real-world data
AU - Ventz, Steffen
AU - Lai, Albert
AU - Cloughesy, Timothy F.
AU - Wen, Patrick Y.
AU - Trippa, Lorenzo
AU - Alexander, Brian M.
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/8/15
Y1 - 2019/8/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-19-0820
DO - 10.1158/1078-0432.CCR-19-0820
M3 - Article
C2 - 31175098
AN - SCOPUS:85070687524
SN - 1078-0432
VL - 25
SP - 4993
EP - 5001
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -