Choice of index date for an externally controlled arm in oncology trials for late line therapies

Music City Center 

External control arms (ECAs) are increasingly used in clinical trials for rare diseases or when ethical concerns prevent the use of a placebo. A significant challenge in including an ECA in oncology trials for pre-treated patients is to determine the proper time zero (index date) such that they are comparable with the clinical trial patients. Because the number of prior lines of therapy and patient characteristics heavily influence the assessment of clinical benefits, a naïve comparison between external controls and the treated cohort in the current trial may lead to biased estimates of the causal treatment effect. We propose an Emax frailty model to simulate the correlated recurrent event times for multiple lines of therapy. We conduct extensive simulation studies to assess the impact on the bias of treatment effect, Type 1 error, and power of the Wald test from Cox models. Various methods of selecting time zero for a starting treatment line are considered, including random selection, all lines with and without variance adjustment, and matching treatment lines using propensity scores. We also assess the impact of adjusting for both measured and unmeasured confounders.

External control

Index date

Emax model



frailty

Propensity score 

Biopharmaceutical Section