The control arm of a randomized clinical trial plays a fundamental role in estimating the efficacy and safety of an investigational therapy. Concurrently randomized control arms allow for an understanding of the temporally relevant factors associated with the natural history of the disease, particularly with respect to current standards of clinical care. This contemporaneous control permits an estimation of treatment effect that is attributable to the experimental arm of interest, and randomization minimizes concern for bias by removing systematic imbalances between arms in measured and unmeasured prognostic factors. When a concurrently randomized arm is not feasible in an oncology trial due to practical or ethical concerns, single-arm trials may be appropriate. In single-arm trials, tumor response rates are an appropriate endpoint to assess treatment effect, as an individual patient's own baseline tumor measurement serves as an internal control with the assumption that most tumor types will not shrink without intervention or treatment.

 However, if tumor response cannot be reasonably measured due to disease characteristics (such as in certain neuro-oncologic tumors) or there is interest in estimating a comparative treatment effect within the population of interest, approaches have been explored to supplement single-arm data with data external to the clinical trial, also referred to as an external control arm...