An Application of the Patient Rule-Induction Method to Detect Clinically Meaningful Subgroups from Failed Phase III Clinical Trials

BACKGROUND: Phase III superiority clinical trials have negative results (new treatment is not statistically better than standard of care) due to a number of factors, including patient and disease heterogeneity. However, even a treatment regime that fails to show population-level clinical improvement will have a subgroup of patients that attain a measurable clinical benefit. OBJECTIVE: The goal of this paper is to modify the Patient Rule-Induction Method to identify statistically significant subgroups, defined by clinical and/or demographic factors, of the clinical trial population where the experimental treatment performs better than the standard of care and better than observed in the entire clinical trial sample. RESULTS: We illustrate this method using part A of the SUCCESS clinical trial, which showed no overall difference between treatment arms: HR (95% CI) = 0.97 (0.78, 1.20). Using PRIM, we identified one subgroup defined by the mutational profile in BRCA1 which resulted in a significant benefit for adding Gemcitabine to the standard treatment: HR (95% CI) = 0.59 (0.40, 0.87). CONCLUSION: This result demonstrates that useful information can be extracted from existing databases that could provide insight into why a phase III trial failed and assist in the design of future clinical trials involving the experimental treatment.