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Understanding randomized controlled trial generalizability through an embedded molecular diagnostics trial
Patrick Lewicki1, Arnav Srivastava1, Ralph Jiang2
1Department of Urology, University of Michigan, Ann Arbor, MI, United States.
JNCI Cancer Spectrum
|April 24, 2026
Summary
Randomized controlled trials (RCTs) may have generalizability issues due to differing patient management, not just participant selection. Real-world data shows shorter treatment times compared to RCTs, suggesting management variations impact outcomes.
Area of Science:
- Urology
- Oncology
- Clinical Trials
Background:
- Randomized controlled trials (RCTs) are crucial for establishing treatment efficacy, but their generalizability to real-world settings is often questioned.
- Differences in patient management between clinical trial contexts and routine practice may contribute to observed outcome disparities.
- The impact of a genomic classifier (GC) on treatment decisions for high-risk prostate cancer post-radical prostatectomy (RP) was evaluated in the G-MINOR RCT.
Purpose of the Study:
- To investigate whether differences in patient management contribute to generalizability issues in randomized controlled trials (RCTs).
- To compare the management and treatment patterns of high-risk prostate cancer patients undergoing radical prostatectomy (RP) within an RCT versus a real-world setting.
Main Methods:
- The study compared patients within the G-MINOR RCT (N=338) to propensity score-matched cohorts from the Michigan Urological Surgery Improvement Collaborative (MUSIC) (N=1014 contemporary, N=338 pre-trial).
- Rates and time to secondary treatment (adjuvant or salvage therapy) after RP were analyzed.
- Key clinicopathologic factors were controlled for in the analysis.
Main Results:
- Patients in the real-world MUSIC cohorts received secondary treatment more frequently and sooner after RP compared to G-MINOR RCT participants.
- Estimated 2-year treatment-free survival was significantly lower in the real-world cohort (74%) compared to the RCT cohort (84%).
- Significant differences in management were observed even after stratifying patients by genomic risk.
Conclusions:
- Patient management strategies differ significantly between RCTs and real-world settings, even when controlling for clinical and genomic factors.
- These management variations, beyond participant selection, pose challenges to the generalizability of RCT findings.
- Discrepancies in patient outcomes observed between RCTs and real-world data may be partly explained by these differing management approaches.
