Faculty, Staff and Student Publications
Language
English
Publication Date
2-15-2026
Journal
Cancer
DOI
10.1002/cncr.70306
PMID
41653086
PMCID
PMC12882696
PubMedCentral® Posted Date
2-7-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Background: 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. The objective of this study was to estimate the prevalence of control arm overperformance in phase 3 oncology RCTs.
Methods: The authors conducted a meta-epidemiological study of two-arm, superiority-design, phase 3 oncology RCTs. They reviewed articles/publications and protocols for power calculations, justification, and outcomes. Control arm performance was measured as the ratio of observed control arm outcomes relative to pretrial estimates, and overperformance was defined as a 10% improvement.
Results: In total, 385 RCTs met inclusion criteria. The primary end point was overall survival (OS) in 134 RCTs (35%). Of 311 RCTs (81%) that provided a pretrial estimate for control arm performance, 138 RCTs (44%) cited a justification for the estimate. Greater than expected control arm performance was associated with lower odds of meeting the primary end point (adjusted odds ratio, 0.989; 95% confidence interval, 0.981-0.998; p = 0.015). Of 244 RCTs that were evaluable for control arm performance, 104 (43%) exhibited overperformance. RCTs that used OS as a primary end point were more likely to exhibit control arm overperformance compared with RCTs that used other primary end points (56% vs. 33%; adjusted odds ratio, 2.43; 95% confidence interval, 1.42-4.15; p = .001).
Conclusions: Control arm overperformance is common in phase 3 oncology RCTs and is associated with trial outcomes, suggesting an effect on study power. Because overperformance appears to be especially prevalent when OS is the primary end point, the effects of postprogression therapies on OS may be underappreciated. Alternative strategies for designing trials should be considered for reliable estimation of treatment effects.
Keywords
control arm estimate, methodology, overall survival, phase 3 trials, postprogression therapy, primary end point, trial design
Published Open-Access
yes
Recommended Citation
Nalin, Ansel P; Msaouel, Pavlos; Grippin, Adam J; et al., "Control Arm Overperformance in Phase 3 Oncology Clinical Trials" (2026). Faculty, Staff and Student Publications. 6313.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6313
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Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons