Differential Treatment Effects of Subgroup Analyses in Phase 3 Oncology Trials From 2004 to 2020

Alexander D. Sherry, Andrew W. Hahn, Zachary R. Mccaw, Joseph Abi Jaoude, Ramez Kouzy, Timothy A. Lin, Bruce Minsky, C. David Fuller, Tomer Meirson, Pavlos Msaouel*, Ethan B. Ludmir*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Importance: Subgroup analyses are often performed in oncology to investigate differential treatment effects and may even constitute the basis for regulatory approvals. Current understanding of the features, results, and quality of subgroup analyses is limited. Objective: To evaluate forest plot interpretability and credibility of differential treatment effect claims among oncology trials. Design, Setting, and Participants: This cross-sectional study included randomized phase 3 clinical oncology trials published prior to 2021. Trials were screened from ClinicalTrials.gov. Main Outcomes and Measures: Missing visual elements in forest plots were defined as a missing point estimate or use of a linear x-axis scale for hazard and odds ratios. Multiplicity of testing control was recorded. Differential treatment effect claims were rated using the Instrument for Assessing the Credibility of Effect Modification Analyses. Linear and logistic regressions evaluated associations with outcomes. Results: Among 785 trials, 379 studies (48%) enrolling 331653 patients reported a subgroup analysis. The forest plots of 43% of trials (156 of 363) were missing visual elements impeding interpretability. While 4148 subgroup effects were evaluated, only 1 trial (0.3%) controlled for multiple testing. On average, trials that did not meet the primary end point conducted 2 more subgroup effect tests compared with trials meeting the primary end point (95% CI, 0.59-3.43 tests; P =.006). A total of 101 differential treatment effects were claimed across 15% of trials (55 of 379). Interaction testing was missing in 53% of trials (29 of 55) claiming differential treatment effects. Trials not meeting the primary end point were associated with greater odds of no interaction testing (odds ratio, 4.47; 95% CI, 1.42-15.55, P =.01). The credibility of differential treatment effect claims was rated as low or very low in 93% of cases (94 of 101). Conclusions and Relevance: In this cross-sectional study of phase 3 oncology trials, nearly half of trials presented a subgroup analysis in their primary publication. However, forest plots of these subgroup analyses largely lacked essential features for interpretation, and most differential treatment effect claims were not supported. Oncology subgroup analyses should be interpreted with caution, and improvements to the quality of subgroup analyses are needed.

Original languageEnglish
Pages (from-to)E243379
JournalJAMA network open
Issue number3
StatePublished - 28 Mar 2024
Externally publishedYes


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