How To Interpret Subgroup Analyses from Prospective Randomized Clinical Trials: What Clinicians Need To Know

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Inflated type I errors

Most RCTs are designed to test the overall treatment effect and not for detection of effects in subgroups. With each additional subgroup comparison, the likelihood of a false-positive result increases. For example, testing five independent subgroups yields a 23% chance of observing at least one p value <0.05 by chance alone, which rises to 40% with ten independent subgroups (Fig. 1A). Moreover, the probability of seeing a reversal of a treatment effect in at least one subgroup is surprisingly

Levels of evidence and the role of meta-analysis

The credibility of a subgroup claim depends on the study design and context. Prespecified analyses with adequate power, significant interaction tests, and a biological rationale carry more weight than post hoc findings (Fig. 2A). In the CHAARTED trial, a prespecified subgroup analysis showed that men with high-disease volume metastatic hormone-sensitive prostate cancer (mHSPC) had longer OS with androgen deprivation therapy (ADT) + docetaxel than with ADT alone (hazard ratio 0.60, 95%

Traditional versus data-driven subgroup definitions

Subgroup definitions have traditionally relied on clinical judgment and biological rationale, such as classification of patients by tumor stage, biomarker expression, or prior treatments. These categories are grounded in existing knowledge and are easier to interpret and communicate. However, they may overlook more complex predictors of treatment heterogeneity.By contrast, data-driven methods such as recursive partitioning, clustering, and machine-learning algorithms can uncover unrecognized

Conclusions

Subgroup analyses must be approached with caution. Unless such analyses are prespecified at the design stage, any findings should be considered exploratory and confirmed in future trials (Fig. 2B). Poorly designed subgroup analyses risk misleading interpretation and may erode trust among clinicians, regulators, and the public. Credible subgroup claims require safeguards such as prespecification, adequate power, formal interaction testing, and meta-analysis. Statistical reporting should