Meta-epidemiological study of control arm overperformance in phase 3 oncology clinical trials

In randomized clinical trials (RCTs), anticipating control arm outcomes is important for power calculations and enrollment goals. Unexpected overperformance of the control arm can underpower RCTs. A meta-epidemiological study of two-arm, superiority-design, phase 3 oncology RCTs estimated the prevalence of control arm overperformance. In total, 385 RCTs met inclusion criteria. The primary endpoint was overall survival (OS) in 134 RCTs (35%). Of 311 RCTs (81%) that provided at pretrial estimate for control arm performance, 138 (44%) cited a justification for the estimate. Greater than expected control arm performance was associated with lower odds of meeting the primary endpoint (aOR 0.989; p=0.015). Of 244 RCTs that were evaluable for control arm performance, 104 (43%) exhibited control arm overperformance. RCTs that used OS as a primary endpoint were more likely to exhibit control arm overperformance compared with RCTs that used other primary endpoints (56% versus 33%; aOR 2.43; p=0.001). The authors conclude that control arm overperformance is common in phase 3 oncology RCTs and is associated with trial outcomes, suggesting an effect on study power.